Improved mortality prediction for pediatric acute liver failure using dynamic prediction strategy.

OBJECTIVES: To develop and validate a prediction tool for pediatric acute liver failure (PALF) mortality risks that captures the rapid and heterogeneous clinical course for accurate and updated prediction. METHODS: Data included 1144 participants with PALF enrolled during three phases of the PALF registry study over 15 years. Using joint modeling, we built a dynamic prediction tool for mortality by combining longitudinal trajectories of multiple laboratory and clinical variables. The predictive performance for 7-day and 21-day mortality was assessed using the area under curve (AUC) through cross-validation and split-by-time validation. RESULTS: We constructed a prognostic joint model that combines the temporal trajectories of international normalized ratio, total bilirubin, hepatic encephalopathy, platelet count, and serum creatinine. Dynamic prediction using updated information improved predictive performance over static prediction using the information at enrollment (Day 0) only. In cross-validation, AUC increased from 0.784 to 0.887 when measurements obtained between Days 1 and 2 were incorporated. AUC remained similar when we used the earlier subset of the sample for training and the later subset for testing. CONCLUSIONS: Serial measurements of five variables in the first few days of PALF capture the dynamic clinical course of the disease and improve risk prediction for mortality. Continuous disease monitoring and updating risk prognosis are beneficial for timely and judicious medical decisions.

Agreement of zero-heat-flux thermometry with the oesophageal and tympanic core temperature measurement in patient receiving major surgery.

To identify and prevent perioperative hypothermia, most surgical patients require a non-invasive, accurate, convenient, and continuous core temperature method, especially for patients undergoing major surgery. This study validated the precision and accuracy of a cutaneous zero-heat-flux thermometer and its performance in detecting intraoperative hypothermia. Adults undergoing major non-cardiac surgeries with general anaesthesia were enrolled in the study. Core temperatures were measured with a zero-heat-flux thermometer, infrared tympanic membrane thermometer, and oesophagal monitoring at 15-minute intervals. Taking the average value of temperature measured in the tympanic membrane and oesophagus as a reference, we assessed the agreement using the Bland-Altman analysis and linear regression methods. Sensitivity, specificity, and predictive values of detecting hypothermia were estimated. 103 patients and one thousand sixty-eight sets of paired temperatures were analyzed. The mean difference between zero-heat-flux and the referenced measurements was -0.03 ± 0.25 °C, with 95% limits of agreement (-0.52 °C, 0.47 °C) was narrow, with 94.5% of the differences within 0.5 °C. Lin's concordance correlation coefficient was 0.90 (95%CI 0.89-0.92). The zero-heat-flux thermometry detected hypothermia with a sensitivity of 82% and a specificity of 90%. The zero-heat-flux thermometer is in good agreement with the reference core temperature based on tympanic and oesophagal temperature monitoring in patients undergoing major surgeries, and appears high performance in detecting hypothermia.

The short-term impact of comprehensive caries treatment on the supragingival microbiome of severe early childhood caries.

BACKGROUND: Children affected by severe early childhood caries (S-ECC) usually need comprehensive caries treatment due to the extensive of caries. How the oral microbiome changes after caries therapy within the short-term warrant further study. AIM: This study aimed to investigate the short-term impact of comprehensive caries treatment on the supragingival plaque microbiome of S-ECC children. DESIGN: Thirty-three children aged 2-4 years with severe caries (dt > 7) were recruited. Comprehensive caries treatment was performed under general anesthesia in one session and included restoration, pulp treatment, extraction, and fluoride application. Supragingival plaque was sampled pre- and 1-month posttreatment. The genomic DNA of the supragingival plaque was extracted, and bacterial 16S ribosomal RNA gene sequencing was performed. RESULTS: Our data showed that the microbial community evenness significantly decreased posttreatment. Furthermore, comprehensive caries treatment led to more diverse microbial structures among the subjects. The interbacterial interactions reflected by the microbial community's co-occurrence network tended to be less complex posttreatment. Caries treatment increased the relative abundance of Corynebacterium matruchotii, Corynebacterium durum, Actinomyces naeslundii, and Saccharibacteria HMT-347, as well as Aggregatibacter HMT-458 and Haemophilus influenzae. Meanwhile, the relative abundance of Streptococcus mutans, three species from Leptotrichia, Neisseria bacilliformis, and Provotella pallens significantly decreased posttreatment. CONCLUSION: Our results suggested that comprehensive caries treatment may contribute to the reconstruction of a healthier supragingival microbiome.

Dissection of pyroptosis-related prognostic signature and CASP6-mediated regulation in pancreatic adenocarcinoma: new sights to clinical decision-making.

Recent studies have indicated that pyroptosis may participate in the regulation of tumorigenesis and immune microenvironment. However, the role of pyroptosis-related genes (PRGs) in pancreatic adenocarcinoma (PAAD) remains unclear. Through multiple bioinformatics analysis, we constructed a prognostic gene model and competing endogenous RNA network. The correlation between PRGs and prognosis, immune infiltration, immune checkpoints, and tumor mutational burden was analyzed by Kaplan-Meier curve, univariate Cox, multivariate regression, and Spearman's analysis in PAAD patients. The qRT-PCR, Western blotting, CCK-8, Wound healing, and Transwell assay were applied to examine the role of CASP6 in PANC-1 cell. Thirty-one PRGs were upregulated in PAAD. Functional enrichment analysis revealed that the PRGs were mainly involved in pyroptosis, NOD-like receptor signaling pathway, and response to bacteria. We established a novel 4-gene signature related to PRGs for evaluating the prognosis of PAAD patients. Patients with PAAD in the low-risk group had a better prognosis than those in the high-risk group. The nomogram suggested that the 1-, 3-, and 5-years survival probability exhibited robust predictive performance. Significant correlation was observed between prognostic PRGs and immune infiltration, immune checkpoints, and tumor mutational burden. We first identified the potential competing endogenous RNA regulatory axis in PAAD: lncRNA PVT1/hsa-miR-16-5p/CASP6/CASP8. Moreover, knockdown of CASP6 dramatically inhibited the proliferation, migration, and invasion ability of PANC-1 cell in vitro. In conclusion, CASP6 could be a potential biomarker, promoting the occurrence and progression in PAAD. The lncRNA PVT1/hsa-miR-16-5p/CASP6/CASP8 regulatory axis plays an vital role in regulating the anti-tumor immune responses for PAAD.

Development of a Multivariate Prognostic Model for Lenvatinib Treatment in Hepatocellular Carcinoma.

BACKGROUND: Lenvatinib is a first-line agent for advanced hepatocellular carcinoma (HCC), but individual responses to treatment are highly heterogeneous. The aim of this study was to investigate the clinical parameters that influence the efficacy of Lenvatinib and to develop a prognostic model. METHODS: We retrospectively enrolled 333 Lenvatinib-treated patients with HCC with a median age of 57 years. Two hundred nd sixty-three of these patients had BCLC (2022) stage C. The median overall survival (mOS) time within the cohort was 12.1 months, and the median progression-free survival (mPFS) time was 4.7 months. Univariate Cox regression, best subset regression, and Lasso regression were used to screen primary variables for possible contribution to OS, multivariate Cox analysis was used to fit selected models, and the final model was selected using the maximum area under the curve (AUC) and minimum AIC. Receiver operating curves (ROC), calibration curves, and decision curve analysis were plotted to assess model performance, and 5-fold cross-validation was performed for internal validation. X-tile software was used to select the best cutoff points and to divide the study cohort into 3 different risk groups. RESULTS: Seven variables were included in the final model: BCLC stage, prior transarterial chemoembolization and immunotherapy history, tumor number, prognostic nutritional index, log (alpha-fetoprotein), and log (platelet-to-lymphocyte ratio). We named this final model the "multivariate prognostic model for Lenvatinib" (MPML), and a nomogram was constructed to predict the probability of survival at 6, 9, and 12 months. The MPML had good discrimination, calibration, and applicability. Cross-validation showed mean AUC values of 0.7779, 0.7738, and 0.7871 at 6, 9, and 12 months, respectively. According to nomogram points, mOS time was 21.57, 8.70, and 5.37 months in the low, medium, and high-risk groups, respectively (P < .001), and these differences were also observed in the PFS survival curve (P < .001). CONCLUSIONS: The MPML stratified patients according to baseline clinical characteristics had a strong performance in predicting Lenvatinib efficacy and has the potential for use as an auxiliary clinical tool for individualized decision-making.

Predictors of Revascularization in Lower-Extremity Peripheral Artery Disease: Insights From the PORTRAIT Study.

BACKGROUND: Peripheral artery disease (PAD) guidelines recommend revascularization only for patients with lifestyle-limiting claudication that is refractory to goal-directed medical therapy (class IIA, level of evidence A). However, real-world invasive treatment patterns and predictors of revascularization in patients with symptomatic lower-extremity PAD are still largely unknown. AIM: We aimed to examine rates, patient-level predictors, and site variability of early revascularization in patients with new or worsening PAD symptoms. METHODS: Among patients with new-onset or recent exacerbation of PAD in the 10-center Patient-centered Outcomes Related to TReatment practices in peripheral Arterial disease: Investigating Trajectories (PORTRAIT) study enrolled between June 2011 and September 2015, we classified early revascularization (endovascular or surgical) as procedures being performed within 3 months of presentation. Hierarchical logistic regression was used to identify patient characteristics associated with early revascularization. Variability across sites was estimated using the median odds ratio (OR). RESULTS: Among 797 participants, early revascularization procedures were performed in 224 (28.1%). Rutherford class 3 (vs Rutherford class 1; OR=1.86, 95% confidence interval [CI] 1.04-3.33) and having lesions in both iliofemoral and below-the-knee arterial segments (vs below the knee only; OR=1.75, 95% CI: 1.15-2.67) were associated with a higher odds of revascularization. Longer PAD duration >12 months (vs 1-6 months; OR=0.50, 95% CI: 0.32-0.77), higher ankle-brachial index scores (per 0.1 unit increase; OR=0.86, 95% CI: 0.78-0.96), and higher Peripheral Artery Questionnaire Summary scores (per 10 unit increase; OR=0.89, 95% CI: 0.80-0.99) were associated with a lower odds of revascularization. The raw rates for revascularization in different sites ranged from 6.25% to 66.28%, and the median OR was 1.88, 95% CI: 1.38-3.57. CONCLUSIONS: About 1 in 3 patients with symptomatic PAD received early revascularization. A more extensive disease and symptom burden were the main predictors of receiving early revascularization in PAD. There was significant site variability in revascularization patterns, and further studies will better understand the source of this variability and optimal selection criteria for early revascularization. CLINICAL IMPACT: Real world patterns and predictors of early revascularization in peripheral artery disease are not well understood. In this retrospective analysis of the POTRAIT study, about 1 out of 3 patients with PAD symptoms received early revascularization, with significant site variability. A more extensive disease and symptom burden were the main predictors of receiving early revascularization in PAD.

Competitive Chemical Reaction Kinetic Model of Nucleosome Assembly Using the Histone Variant H2A.Z and H2A In Vitro.

Nucleosomes not only serve as the basic building blocks for eukaryotic chromatin but also regulate many biological processes, such as DNA replication, repair, and recombination. To modulate gene expression in vivo, the histone variant H2A.Z can be dynamically incorporated into the nucleosome. However, the assembly dynamics of H2A.Z-containing nucleosomes remain elusive. Here, we demonstrate that our previous chemical kinetic model for nucleosome assembly can be extended to H2A.Z-containing nucleosome assembly processes. The efficiency of H2A.Z-containing nucleosome assembly, like that of canonical nucleosome assembly, was also positively correlated with the total histone octamer concentration, reaction rate constant, and reaction time. We expanded the kinetic model to represent the competitive dynamics of H2A and H2A.Z in nucleosome assembly, thus providing a novel method through which to assess the competitive ability of histones to assemble nucleosomes. Based on this model, we confirmed that histone H2A has a higher competitive ability to assemble nucleosomes in vitro than histone H2A.Z. Our competitive kinetic model and experimental results also confirmed that in vitro H2A.Z-containing nucleosome assembly is governed by chemical kinetic principles.

Genome-wide characterization of the MBF1 gene family and its expression pattern in different tissues and stresses in Zanthoxylum armatum.

BACKGROUND: Multiprotein bridging factor 1 (MBF1) is a crucial transcriptional coactivator in animals, plants, and some microorganisms, that plays a necessary role in growth development and stress tolerance. Zanthoxylum armatum is an important perennial plant for the condiments and pharmaceutical industries, whereas the potential information in the genes related to stress resistance remains poorly understood in Z. armatum.  RESULTS: Herein, six representative species were selected for use in a genome-wide investigation of the MBF1 family, including Arabidopsis thaliana, Oryza sativa, Populus trichocarpa, Citrus sinensis, Ginkgo biloba, and Z. armatum. The results showed that the MBF1 genes could be divided into two groups: Group I contained the MBF1a and MBF1b subfamilies, and group II was independent of the MBF1c subfamily.. Most species have at least two different MBF1 genes, and MBF1c is usually an essential member. The three ZaMBF1 genes were respectively located on ZaChr26, ZaChr32, and ZaChr4 of Zanthoxylum chromosomes. The collinearity were occurred between three ZaMBF1 genes, and ZaMBF1c showed the collinearity between Z. armatum and both P. trichocarpa and C. sinensis. Moreover, many cis-elements associated with abiotic stress and phytohormone pathways were detected in the promoter regions of MBF1 of six representative species. The ERF binding sites were the most abundant targets in the sequences of the ZaMBF1 family, and some transcription factor sites related to floral differentiation were also identified in ZaMBF1c, such as MADS, LFY, Dof, and AP2. ZaMBF1a was observed to be very highly expressed in 25 different samples except in the seeds, and ZaMBF1c may be associated with the male and female floral initiation processes. In addition, expression in all the ZaMBF1 genes could be significantly induced by water-logging, cold stress, ethephon, methyl jasmonate, and salicylic acid treatments, especially in ZaMBF1c. CONCLUSION: The present study carried out a comprehensive bioinformatic investigation related to the MBF1 family in six representative species, and the responsiveness of ZaMBF1 genes to various abiotic stresses and phytohormone inductions was also revealed. This work not only lays a solid foundation to uncover the biological roles of the ZaMBF1 family in Z. armatum, but also provides some broad references for conducting the MBF1 research in other plants.

hucMSC-Derived Exosomes Alleviate the Deterioration of Colitis via the miR-146a/SUMO1 Axis.

Human umbilical cord mesenchymal stem cell-derived exosome (hucMSC-Ex) plays an important role in tissue repair and immunomodulation, leading to the mitigation of inflammatory bowel disease. However, the preventive function of hucMSC-Ex in the onset and progression of colitis-associated colon cancer (CAC) is poorly understood. In the current study, dextran sodium sulfate/azoxymethane-induced colitis mouse model was established, and the mice disease activity index, body weight, colon length, tumor counts, survival curve, tissue H&E/immunohistochemistry, and cytokines expression were analyzed to evaluate the effects of hucMSC-Ex on CAC. In addition, miR-146a mimics were transfected into colonic epithelial cells (fetal human cells) to evaluate their role in the hucMSC-Ex-mediated regulation of SUMO1. The results showed that hucMSC-Ex inhibits the expression of SUMO1 to reduce the process of CAC progression. Further analysis indicated that miR-146a targets and inhibits SUMO1 expression and its binding to ß-catenin. In conclusion, our findings showed that hucMSC-Ex is effective in alleviating the deterioration of colitis via the miR-146a-mediated inhibition of SUMO1, which is crucial in this disease process.

The accuracy of using guided endodontics in access cavity preparation and the temperature changes of root surface: An in vitro study.

BACKGROUND: Guided endodontics is a successful technique that has been gradually applied to endodontic therapy in recent years without being affected by the operator's experience. However, the guided bur produces excessive heat during continuous rotation and friction with root canal walls, it is not clear whether the degree of temperature increase may lead to the periodontal ligament and alveolar bone damage. METHODS: A total of 58 teeth were used, of which 40 teeth were not grouped, all used to evaluate the accuracy. 40 single-rooted premolars were scanned using CBCT and an intra-oral scanner, and 3D-printed guided plates were made with the pre-designed access. A custom-made guided bur was used to prepare the access cavities. The postoperative CBCT data and pre-designed pathways were matched to evaluate the deviation between the planned and virtual paths. The other 18 teeth were randomly divided into three groups (ET20 and ProTaper F3 as the control group, guided endodontics as the test group), with 6 teeth in each group. The temperature changes on the root surfaces were inspected with a thermocouple thermometer. RESULTS: The average deviation on the tip and the base of the bur was 0.30 mm and 0.28 mm (mesial/distal), and 0.28 mm and 0.25 mm (buccal/lingual). The average angle deviation was 3.62°. The mean root surface temperature rise of the guided endodontics group was the lowest (5.07 °C) (P < 0.05). CONCLUSIONS: The access cavity preparation performed with guided endodontics has feasible accuracy and low-temperature rise on the root surfaces. Due to the limitations of the study, whether it has high reliability and safety in clinical applications needs to be further studied in vivo.

[Preparation and characterization of near-infrared responsive sinomenine hydrochloride reservoir microneedles].

The present study designed and prepared near-infrared responsive sinomenine hydrochloride(SIN) reservoir microneedles and evaluated the feasibility of this type of microneedles in increasing the drug loading and transdermal absorption by characterizing their mechanical properties and in vitro release characteristics.SIN was selected as the model drug, and methoxy poly(ethylene glycol) poly(caprolactone)(mPEG-PCL) copolymers and indocyanine green(ICG) were employed as amphiphilic block copolymers and light inductor to prepare near-infrared responsive nanoparticles.Based on the preparation principle of bubble microneedles, near-infrared responsive SIN reservoir microneedles were designed and prepared.The features of the near-infrared responsive SIN reservoir microneedles were characterized by measuring the morphology, length, mechanical properties, and skin penetration of microneedles.Meanwhile, the drug release performance of reservoir microneedles was evaluated by in vitro release assay.The results showed that the prepared SIN microneedles were conical, with an exposed tip height of about 650 µm.Each needle could load about 0.5 mg of drugs per square centi-meter, and this type of microneedle showed good mechanical properties and performance in skin penetration.The results of the in vitro release assay showed that the 24 h cumulative release per unit area and release rate of the microneedle were 825.61 µg·cm~(-2) and 74.3%, respectively, which indicated that its release kinetics was in line with the first-order kinetic model.This study preliminarily proved that the reservoir microneedle could effectively increase the drug loading with good mechanical properties and release perfor-mance.

Efficacy and Safety of a Naphthoquine-Azithromycin Coformulation for Malaria Prophylaxis in Southeast Asia: A Phase 3, Double-blind, Randomized, Placebo-controlled Trial.

BACKGROUND: A prophylactic antimalarial drug that is both effective for protection and improves compliance is in high demand. METHODS: We conducted a randomized, placebo-controlled, double-blinded phase 3 trial to evaluate the 1:1 fixed-dose combination of naphthoquine-azithromycin (NQAZ) for safety and protection against Plasmodium infections in villages along the China-Myanmar border. A total of 631 residents, 5-65 years of age, were randomized into the drug group (n = 319) and the placebo group (n = 312) to receive NZAQ and placebo, respectively, as a single-dose monthly treatment. Follow-ups were conducted weekly to monitor for adverse events and malaria infections. RESULTS: Of the 531 subjects completing the trial, there were 46 and 3 blood smear-positive Plasmodium infections in the placebo and treatment groups, respectively. For the intent-to-treat analysis, the single-dose monthly NQAZ treatment had 93.62% protective efficacy (95% confidence interval [CI]: 91.72%-95.52%). For the per-protocol analysis, NQAZ treatment provided a 93.04% protective efficacy (95% CI: 90.98%-95.1%). Three smear-positive cases in the NQAZ group were all due to acute falciparum malaria. In comparison, NQAZ treatment provided 100% protection against the relapsing malaria Plasmodium vivax and Plasmodium ovale. The treatment group had 5.6% of participants experiencing transient elevation of liver aminotransferases compared with 2.2% in the placebo group (P > .05). CONCLUSIONS: Monthly prophylaxis with NQAZ tablets was well tolerated and highly effective for preventing Plasmodium infections. It may prove useful for eliminating P. vivax in areas with a high prevalence of glucose-6-phosphate dehydrogenase deficiency in the population. CLINICAL TRIALS REGISTRATION: ChiCTR1800020140.

Increased mucin-degrading bacteria by high protein diet leads to thinner mucus layer and aggravates experimental colitis.

BACKGROUND AND AIM: Westernized high-fat diet increases the risk for inflammatory bowel diseases (IBDs), yet with insufficient understanding of the role of high-protein diet. We aimed to identify the effect of high-protein diets from different dietary proteins (casein, whey protein, soy protein) on experimental colitis and its impact on microbiota, structure and function of colonic mucus layer. METHODS: Female BALB/c mice were fed by standard diet, high-casein diet (HCD), high whey protein diet or high soy protein diet for 4 weeks. The susceptibility of dextran sulfate sodium (DSS)-induced colitis in mice and thickness of colonic mucus layer were compared after different dietary interventions, associated with the identification of the reversal effect of broad-spectrum antibiotic intervention (0.5 g/L of vancomycin and 1 g/L of neomycin sulfate, metronidazole and ampicillin in drinking water). Further analysis was performed on the synthesis of mucin, microbiota and sialidase involved in degradation of mucus layer. RESULTS: High-protein diets aggravated acute DSS-induced colitis independent of protein composition, while broad-spectrum antibiotics reversed this effect. HCD significantly altered the composition of bacteria in the colonic mucus layer, especially Bacteroides thetaiotaomicron and total mucin-degrading bacteria; besides, it increased sialidase concentration and reduced the thickness of mucus layer. However, it exhibited no significant effect on the synthesis of Muc2. Broad-spectrum antibiotics decreased the abundance of mucin-degrading bacteria and sialidase concentration while increased the thickness of mucus layer. CONCLUSION: High-protein diet shifts microbial composition and thickness of colonic mucus layer, leading to the aggravation of acute DSS-induced colitis.

3D Mesh Releasing Method: A Retrospective Analysis of Fractional CO2 Treatment on Contracture Scars.

BACKGROUND AND OBJECTIVES: There has been reports on fractional CO2 laser successfully improving contracture scars that impair the function of a joint. It seems that certain contracture problems could be solved by laser instead of surgery. However, the clinical application could be difficult when the efficacy of the method remains unknown. The purpose of this study is to report the releasing capacity of the fractional CO2 laser on contracture scars based on a defined treatment method. STUDY DESIGN/MATERIALS AND METHODS: We conducted a retrospective study in patients with limited function in joints caused by contracture scars. Fractional CO2 laser and our "3D mesh releasing" protocol were applied. The primary outcome was the improvement measured in range of motion (ROM) of the relevant joint before all intervention and 6 months after the last treatment. RESULT: From November 2016 to January 2018, 11 joints of 10 cases were treated by the fractional CO2 laser. Patients went through 2.27 (standard deviation [SD] 1.42, 1-5) sessions. The average progress of ROM before and 6 months after all treatments was 19.13° (SD 10.25, P < 0.02). In six cases, we recorded that there was an 8.53° (SD 5.81, P < 0.02) of increase in ROM immediately after the laser session, and the average improvement reached up to 13.58° (SD 8.15, P < 0.02) after 2-3 months during the next follow-up. CONCLUSION: The fractional CO2 laser could achieve functional improvement in contracture scars and it maintained its effect for at least 6 months. The "3D Mesh Releasing" protocol would help to standardize the treatment procedure. This modality has minimal-invasiveness and potentially could become a supplement to the current treatment choices for mild contracture scars. Lasers Surg. Med. © 2020 Wiley Periodicals LLC.

sRAGE downregulates the VEGF expression in OHSS ovarian granulosa cells.

OBJECTIVE: Ovarian hyperstimulation syndrome (OHSS) is mainly caused by human chorionic gonadotropin (hCG) through vasoactive mediators such as vascular endothelial growth factor (VEGF) and various inflammatory factors. Our previous study showed that soluble receptor for advanced glycation end products (sRAGE) played a protective role in PCOS by inhibiting VEGF, so wanted to explore the role of sRAGE in OHSS. METHODS: Two sets of experiments were performed in this study. In part one, sRAGE protein levels in follicular fluid (FF) samples from 60 patients with OHSS and 60 non-OHSS patients were measured by ELISA. In part two, ovarian granulosa cells were isolated from an additional 25 patients with OHSS and cultured. Then, ovarian granulosa cells were treated with different concentrations of sRAGE. Granulosa cells cultured without sRAGE stimulation were used as the control group. The levels of VEGF, amphiregulin (AREG), betacellulin (BTC), and epiregulin (EREG) mRNA were examined by quantitative RT-PCR. The protein levels of VEGF, AREG, BTC, and EREG were measured by ELISA. RESULTS: Compared with non-OHSS patients, patients with OHSS exhibited lower sRAGE levels in both serum and FF (p < .05). Treatment with sRAGE decreased the production of VEGF, and the effects were dependent on the concentration of sRAGE (p < .05). Simultaneously, the expression of the EGF-like growth factors AREG, BTC and EREG was decreased, and their expression was dependent on the concentration of sRAGE (p < .05). CONCLUSIONS: sRAGE downregulate VEGF expression in OHSS ovarian granulosa cells, in which EGF-like growth factor pathway may be involved, and sRAGE may play a potential protective role in OHSS.

[Enhancing effect and mechanism of muscone on transdermal penetration of traditional Chinese medicine ingredients with different log P value].

This study aimed to investigate the enhancing effect of muscone on the transdermal penetration of traditional Chinese medicine ingredients and explore its possible mechanism of action. The Franz diffusion cells were employed to investigate the effect of muscone on the transdermal permeation of a series of model drugs with a wide range of log P values. The solubilities at saturation and the stratum corneum(SC)/vehicle partition coefficients of model drugs were measured to evaluate the effect of muscone on drug thermodynamic activities and partition of drugs into SC. Attenuated total reflectance-Fourier transform infrared spectroscopy(ATR-FTIR) was employed to explore the effect of muscone on the molecular structure of SC. The results showed that muscone significantly promoted the transdermal penetration of hydrophilic and lipophilic drugs, and the enhancement ratio(ER) increased with the decrease in the log P. Muscone could interact with the SC lipids to increase the disorder and fluidity of lipid bilayer packing, which improved skin permeability and promoted transdermal absorption of drugs. This study provides a scientific basis for the application of muscone in traditional Chinese medicine topical preparations.

De novo transcriptome assembly for the five major organs of Zanthoxylum armatum and the identification of genes involved in terpenoid compound and fatty acid metabolism.

BACKGROUND: Zanthoxylum armatum (Z. armatum) is a highly economically important tree that presents a special numbing taste. However, the underlying regulatory mechanism of the numbing taste remains poorly understood. Thus, the elucidation of the key genes associated with numbing taste biosynthesis pathways is critical for providing genetic information on Z. armatumand the breeding of high-quality germplasms of this species. RESULTS: Here, de novo transcriptome assembly was performed for the five major organs of Z. armatum, including the roots, stems, leaf buds, mature leaves and fruits. A total of 111,318 unigenes were generated with an average length of 1014 bp. Additionally, a large number of SSRs were obtained to improve our understanding of the phylogeny and genetics of Z. armatum. The organ-specific unigenes of the five major samples were screened and annotated via GO and KEGG enrichment analysis. A total of 53 and 34 unigenes that were exclusively upregulated in fruit samples were identified as candidate unigenes for terpenoid biosynthesis or fatty acid biosynthesis, elongation and degradation pathways, respectively. Moreover, 40 days after fertilization (Fr4 stage) could be an important period for the accumulation of terpenoid compounds during the fruit development and maturation of Z. armatum. The Fr4 stage could be a key point at which the first few steps of the fatty acid biosynthesis process are promoted, and the catalysis of subsequent reactions could be significantly induced at 62 days after fertilization (Fr6 stage). CONCLUSIONS: The present study realized de novo transcriptome assembly for the five major organs of Z. armatum. To the best of our knowledge, this study provides the first comprehensive analysis revealing the genes underlying the special numbing taste of Z. armatum. The assembled transcriptome profiles expand the available genetic information on this species and will contribute to gene functional studies, which will aid in the engineering of high-quality cultivars of Z. armatum.

Evaluation of the Combination of Azithromycin and Naphthoquine in Animal Malaria Models.

Combination therapy using drugs with different mechanisms of action is the current state of the art in antimalarial treatment. However, except for artemisinin-based combination therapies, only a few other combinations are now available. Increasing concern regarding the emergence and spread of artemisinin resistance in Plasmodium falciparum has led to a need for the development of new antimalarials. Moreover, the efficacy of current available chemoprophylaxis is compromised by drug resistance and noncompliance due to intolerable adverse effects or complicated dosing regimens. Therefore, new antimalarials that are more effective, safer, and more convenient are also urgently needed for malaria chemoprophylaxis. In this study, we assessed the combination of azithromycin and naphthoquine in animal malaria models. A dose-dependent interaction was observed in Peters' 4-day suppressive test on P. berghei K173-infected mice. Moreover, at inhibition levels of ≥90%, synergistic effects were found for combinations at various ratios. At an optimal dose ratio of 1:1, the combination of azithromycin and naphthoquine acted synergistically even by 4 weeks after the first dose and provided a more effective and sustained prophylaxis than did naphthoquine alone in blood-stage P. berghei K173 and P. cynomolgibastianelli L challenge models. The ability of the combination to delay and slow down resistance development in P. berghei K173 was also shown. These results showed clear evidence for the benefit of the combination therapy with azithromycin and naphthoquine in animal malaria models, providing some insight for further development of this therapy for malaria treatment and prophylaxis.

Level of disease and association with health status in patients presenting with claudication from the PORTRAIT registry.

OBJECTIVE: Peripheral artery disease (PAD) has been shown to affect health status and quality of life; however, the disability associated by specific anatomic level of disease is unknown. We evaluated patients presenting with claudication by anatomic level and used the Peripheral Artery Questionnaire (PAQ), a PAD-specific validated tool, to quantify patients' symptoms, function, treatment satisfaction, and quality of life. METHODS: The Patient-centered Outcomes Related to Treatment Practices in peripheral Arterial disease: Investigating Trajectories (PORTRAIT) registry is a multicenter, international, prospective study of patients with PAD. Anatomic level of PAD was stratified as follows: aortoiliac only, femoral-popliteal only, infrapopliteal only, and multilevel disease. Health status information was collected at baseline and at 3, 6, and 12 months using the PAQ. Student t-test, χ2 test, and linear mixed effects models were examined. RESULTS: Anatomic data were present in 623 (48.9%) of 1275 patients: 127 aortoiliac (20.4%), 221 femoral-popliteal (35.5%), 39 infrapopliteal (6.3%), and 236 multilevel disease (37.9%). Groups were similar by sex and race. Baseline PAQ summary scores differed between lesions, with multilevel disease having the lowest (poorest) estimated PAQ summary score (P = .014). Patients with aortoiliac disease were significantly younger, were more likely to be smokers, and presented with higher ankle-brachial index (all P < .05). Almost one-fourth of patients underwent an intervention by 3 months, 83% of which were endovascular. Repeated-measures analyses demonstrated a significant association between anatomic lesion and PAQ scores over time (P = .016), even after adjustment for age, sex, work status, ankle-brachial index, smoking, history of diabetes and chronic kidney disease, and country. Multilevel disease had the lowest adjusted average PAQ summary score over time (63.1; 95% confidence interval [CI], 60.8-65.5) and was significantly lower than aortoiliac (68.1; 95% CI, 64.8-71.4; P = .02) and femoral-popliteal (68.2; 95% CI, 65.8-70.6; P = .002) but not infrapopliteal (66.2; 95% CI, 60.5-72.0; P = .32). CONCLUSIONS: Overall, patients with claudication had similar health status on presentation by level of disease, yet patients with isolated aortoiliac disease fared significantly better over time with regard to quality of life and PAQ scores. Subset analysis demonstrated that patients undergoing interventions for aortoiliac disease and multilevel disease, which were primarily endovascular procedures, appeared to improve health status more over time compared with femoral-popliteal and infrapopliteal interventions. No significant benefits were found with intervention for femoral-popliteal disease or infrapopliteal disease compared with medical management. Treatment of aortoiliac and multilevel disease for claudication should be considered by clinicians as it may represent the greatest potential benefit for improving overall health status in patients with PAD. Further studies evaluating intervention compared with medical management alone are needed to further evaluate this finding.

Financial barriers in accessing medical care for peripheral artery disease are associated with delay of presentation and adverse health status outcomes in the United States.

Patient-reported difficulties in affording health care and their association with health status outcomes in peripheral artery disease (PAD) have never been studied. We sought to determine whether financial barriers affected PAD symptoms at presentation, treatment patterns, and patient-reported health status in the year following presentation. A total of 797 United States (US) patients with PAD were identified from the Patient-centered Outcomes Related to TReatment Practices in Peripheral Arterial Disease: Investigating Trajectories (PORTRAIT) study, a prospective, multicenter registry of patients presenting to vascular specialty clinics with PAD. Financial barriers were defined as a composite of no insurance and underinsurance. Disease-specific health status was measured by Peripheral Artery Questionnaire (PAQ) and general health-related quality of life was measured by EuroQol 5 (EQ5D) dimensions at presentation and at 3, 6, and 12 months of follow-up. Among 797 US patients, 21% (n = 165) of patients reported financial barriers. Patients with financial barriers presented at an earlier age (64 ± 9.5 vs 70 ± 9.4 years), with longer duration of symptoms (59% vs 49%) (all p ⩽ 0.05), were more depressed and had higher levels of perceived stress and anxiety. After multivariable adjustment, health status was worse at presentation in patients with financial barriers (PAQ: -7.0 [-10.7, -3.4]; p < 0.001 and EQ5D: -9.2 [-12.74, -5.8]; p < 0.001) as well as through 12 months of follow-up (PAQ: -8.4 [-13.0, -3.8]; p < 0.001 and EQ5D: -9.7 [-13.2, -6.2]; p < 0.001). In conclusion, financial barriers are associated with later presentation as well as poorer health status at presentation and at 12 months. ClinicalTrials.gov Identifier: NCT01419080.