Maternal fasting serum C-peptide concentrations in the first and second trimesters and subsequent risk of gestational diabetes mellitus: A nested case-control study among Chinese women.

OBJECTIVE: To examine the association of serum connecting peptide (C-peptide) concentrations with gestational diabetes mellitus (GDM) risk among Chinese women. METHODS: A nested case-control study was conducted on 436 reproductive-aged women, involving 218 GDM cases and 218 controls matched at 1:1 by maternal age, in Beijing, China between January 2016 and December 2017. Fasting serum C-peptide were successively determined at 10-14 and 15-20 weeks of gestation. Restricted cubic spline and logistic regression analyses were utilized, and receiver operating characteristic (ROC) curves were generated to evaluate the predictive capacity of C-peptide for GDM. RESULTS: Fasting serum C-peptide concentrations exhibited a significant decrease from the initial to the subsequent trimester in females with normal glucose tolerance (NGT). For each 1 log ng/mL increase of fasting serum C-peptide during the first and second trimesters, GDM risk increased by 2.38-fold [odds ratio (OR): 2.38, 95% confidence intervals (95%CI): 1.33-4.40] and 3.07-fold (OR: 3.07, 95%CI: 1.49-6.62), respectively. The areas under the ROC curves for the first- and second-trimester C-peptide were 80.4% and 82.4%. CONCLUSION: Our findings revealed a positive correlation between fasting serum C-peptide during the first and second trimesters and the risk of GDM or its subtypes, underscoring the potential of C-peptide as a predictor for GDM development.

Responses of microbial interactions and functional genes to sulfamethoxazole in anammox consortia.

Sulfamethoxazole (SMX) has been widely detected in various environments and its potential environmental risks have caused great concerns. However, the impact mechanism of SMX on microbial interactions among anammox consortia remain unknown. A long-term exposure experiments (140 d) was carried out to systematically examine the influence of SMX (0-1000 µg/L) on the anammox system, especially microbial network dynamics and variations of key metabolic genes. Results showed that anammox system could adapt to SMX below 500 µg/L and maintain a high nitrogen removal efficiency (NRE) of 85.35 ± 2.42%, while 1000 µg/L SMX significantly decreased the abundance of functional microbes and deteriorated denitrification performance with NRE dropped to 36.92 ± 15.01%. Co-occurrence network analysis indicated that 1000 µg/L SMX decreased the interactions between Proteobacteria and Chloroflexi and limited AnAOB from playing an important role as central nodes in the subnetwork of Planctomycetes. Metagenomics analysis found that genes associated with nitrogen removal (i.e., hdh, hzs, nirS, and hao) showed lower expression level after addition of SMX, while SMX-related ARGs (sul1 and sul2) increased by 1.22 and 2.68 times. This study provided us a relatively comprehensive perspective in response of microbial interactions and metabolic activity to various SMX concentrations.

Maternal exposure to traffic-related ambient particles and risk of gestational diabetes mellitus with isolated fasting hyperglycaemia: A retrospective cohort study in Beijing, China.

BACKGROUND: Ambient particles have been associated with gestational diabetes mellitus (GDM), however, no study has evaluated the effects of traffic-related ambient particles on the risks of GDM subgroups classified by oral glucose tolerance test (OGTT) values. METHODS: A retrospective analysis was conducted among 24,001 pregnant women who underwent regular prenatal care and received OGTT at Haidian Maternal and Child Health Hospital in Beijing, China, 2014-2017. A total of 3,168 (13.2%) pregnant women were diagnosed with GDM, including 1,206 with isolated fasting hyperglycaemia (GDM-IFH). At a fixed-location monitoring station, routinely monitored ambient particles included fine particulate matter (PM2.5), black carbon (BC) and particles in size ranges of 5-560 nm (PNC5-560). Contributions of PNC5-560 sources were apportioned by positive matrix factorization model. Logistic regression model was applied to estimate odds ratio (OR) of ambient particles on GDM risk. RESULTS: Among the 24,001 pregnancy women recruited in this study, 3,168 (13.2%) were diagnosed with GDM, including 1,206 with isolated fasting hyperglycaemia (GDM-IFH) and 1,295 with isolated post-load hyperglycaemia (GDM-IPH). We observed increased GDM-IFH risk with per interquartile range increase in first-trimester exposures to PM2.5 (OR = 1.94; 95% Confidence Intervals: 1.23-3.07), BC (OR = 2.14; 1.73-2.66) and PNC5-560 (OR = 2.46; 1.90-3.19). PNC5-560 originated from diesel and gasoline vehicle emissions were found in associations with increases in GDM-IFH risk, but not in GDM-IPH risk. CONCLUSION: Our findings suggest that exposure to traffic-related ambient particles may increase GDM risk by exerting adverse effects on fasting glucose levels during pregnancy, and support continuing efforts to reduce traffic emissions for protecting vulnerable population who are at greater risk of glucose metabolism disorder.

Maternal exposures to fine and ultrafine particles and the risk of preterm birth from a retrospective study in Beijing, China.

Maternal exposure to fine particulate matter (PM2.5) has been associated with increased risk of preterm birth (PTB), but evidence on particles in smaller sizes and PTB risk remains limited. In this retrospective analysis, we included birth records of 24,001 singleton live births from Haidian Maternal and Child Health Hospital in Beijing, China, 2014-2017. Concurrently, number concentrations of size-fractioned particles in size ranges of 5-560 nm (PNC5-560) and mass concentrations of PM2.5, black carbon (BC) and gaseous pollutants were measured from a fixed-location monitoring station in central Haidian District. Logistic regression models were used to estimate the odds ratio (OR) of air pollutants on PTB risk after controlling for temperature, relative humidity, and individual covariates (e.g., maternal age, ethnicity, gravidity, parity, gestational weight gain, fetal gender, the year and season of conception). Positive matrix factorization models were then used to apportion the sources of PNC5-560. Among the 1062 (4.4%) PTBs, increased PTB risk was observed during the third trimester of pregnancy per 10 µg/m3 increase in PM2.5 [OR = 1.92; 95% Confidence Interval (95% CI): 1.76, 2.09], per 1000 particles/cm3 increase in PNC25-100 (OR = 1.09; 95% CI: 1.03, 1.15) and PNC100-560 (OR = 1.22; 95% CI: 1.05, 1.42). Among the identified sources of PNC5-560, emissions from gasoline and diesel vehicles were significantly associated with increased PTB risk, with ORs of 1.14 (95% CI: 1.01, 1.29) and 1.11 (95% CI: 1.04, 1.18), respectively. Exposures to other traffic-related air pollutants, such as BC and nitrogen dioxide (NO2) were also significantly associated with increased PTB risk. Our findings highlight the importance of traffic emission reduction in urban areas.

NLRP3 and mTOR Reciprocally Regulate Macrophage Phagolysosome Formation and Acidification Against Vibrio vulnificus Infection.

The marine bacterium Vibrio vulnificus causes potentially fatal bloodstream infections, typically in patients with chronic liver diseases. The inflammatory response and anti-bacterial function of phagocytes are crucial for limiting bacterial infection in the human hosts. How V. vulnificus affects macrophages after phagocytosis is unclear. In this report, we found that the bactericidal activity of macrophages to internalize V. vulnificus was dependent on mammalian target of rapamycin (mTOR) and NOD-like receptor (NLR) family pyrin domain containing 3 (NLRP3) interaction. Additionally, the NLRP3 expression was dependent on mTORC1 activation. Inhibited mTORC1 or absence of NLRP3 in macrophages impaired V. vulnificus-induced phagosome acidification and phagolysosome formation, leading to a reduction of intracellular bacterial clearance. mTORC1 signaling overactivation could increase NLRP3 expression and restore insufficient phagosome acidification. Together, these findings indicate that the intracellular bactericidal activity of macrophages responding to V. vulnificus infection is tightly controlled by the crosstalk of NLRP3 and mTOR and provide critical insight into the host bactericidal activity basis of clearance of V. vulnificus through lyso/phagosome.

Alterations in the Ocular Surface Microbiome in Traumatic Corneal Ulcer Patients.

Purpose: Corneal ulcers are a common eye inflammatory disease that can cause visual impairment or even blindness if not treated promptly. Ocular trauma is a major risk factor for corneal ulcers, and corneal trauma in agricultural work can rapidly progress to corneal ulcers. This study aims to evaluate the changes in the ocular surface (OS) microbiome of patients with traumatic corneal ulcer (TCU). Methods: Among 20 healthy control (HC) subjects and 22 patients with TCU, 42 eyes were examined to investigate the OS microbial flora using metagenomic shotgun sequencing. Results: At the taxonomic composition level, our findings showed that dysbiosis (alterations in richness and community structure) occurs in the OS microbiome of patients with TCU. Notably, Pseudomonas was present at a greater than 30% relative abundance in all individuals in the TCU group. At the species level, the abundance of Pseudomonas fluorescens and Pseudomonas aeruginosa was significantly elevated in the TCU group compared to the HC group. At the functional level, we identified significant differences in the HC and TCU groups. We observed that inflammation-related pathways involved in bacterial chemotaxis, flagellar assembly, and biofilm formation were significantly more abundant in the TCU group. Besides, the pathways related to biosynthesis, degradation, and metabolism were also increased significantly in the TCU group. Conclusions: These findings indicate an altered OS microbiome in the affected eyes of patients with TCU. Further research is needed to determine whether these alterations contribute to the pathogenesis of TCU or impact disease progression.

Influence of type and proportion of lyoprotectants on lyophilized ginsenoside Rg3 liposomes.

OBJECTIVES: To improve stability and shelf life, lyophilized formulations of 20(R)-Ginsenoside Rg3 liposomes (G-Rg3-Ls) were prepared. METHODS: Glucose, trehalose, sucrose, maltose, lactose, mannitol, inositol, hydroxypropyl-ß-cyclodextrin and polyethylene glycol were used as single lyoprotectant and then compared in terms of their ability to protect lyophilized G-Rg3-Ls. Further, a glucose-mannitol complex was used to determine the optimal lyophilized preparation. The analysis of lyophilized liposomes or lyoprotectant was further investigated by scanning electron microscopy, thermogravimetry-differential thermal analysis, X-ray diffractometry and Fourier transform infrared spectroscopy. Cytotoxicity assay was used to assess the cyto-inhibition of freshly prepared and lyophilized liposomes. KEY FINDINGS: When the ratio of glucose-mannitol to phospholipids was 4 : 2 : 1 (w/w) the lyophilized G-Rg3-Ls exhibited good appearance, high DRR (86.52% ± 5.02%), small change in particle size (45.83 ± 0.50%) and short rehydration reconstruction time (8.3 ± 1.5 s). All indices were considerably better than those of each single protective agent. Results indicated that when the two lyoprotectants were combined, the stabilizing effect of glucose and shaping effect of mannitol were well maintained. The cyto-inhibition of freshly prepared and lyophilized G-Rg3 liposomes showed that lyophilization did not affect the bioactivity of G-Rg3. CONCLUSIONS: The application of glucose-mannitol composite lyoprotectants can obtain a good G-Rg3 lyophilized preparation.

["PEG dilemma" for liposomes and its solving approaches].

Polyethylene glycol (PEG) is extensively used to increasing the in vivo and in vitro stability of liposomes. However, PEGylated liposomes also produce some negative effects with further research, such as low cellular uptake, poor "endosomal escape" of pH sensitive liposome (PSL) and accelerated blood clearance (ABC) phenomenon, and this situation is referred as the "PEG dilemma". "PEG dilemma" posed severe challenges for the targeted delivery of PEGylated liposomes-loaded anticancer drugs, effective intracellular release of PEGylated PSL-encapsulated gene and protein drugs, and repeated administration of PEGylated liposomes. Therefore, it is urgent to solve the "PEG dilemma". This review focused on the definition, classification of "PEG dilemma", and discussed several possible approaches to overcome "PEG dilemma".

Ginsenoside Rg3 bile salt-phosphatidylcholine-based mixed micelles: design, characterization, and evaluation.

20(R)-Ginsenoside Rg3 (G-Rg3) has good inhibition of tumor angiogenesis and anti-tumor effect. However, its poor aqueous solubility and liposolubility are not ideal for clinical applications. In this study, a G-Rg3 bile salt-phosphatidylcholine-based mixed micelle system (BS-PC-MMS) was prepared. The optimization of G-Rg3 BS-PC-MMS was carried out using response surface methodology based on a central composite design. The encapsulation efficiency (EE) and light transmission (LT) of the optimized formulation were 90.69±2.54% and 99.10±3.12%, respectively. The average particle size of micelles was 20 nm. To increase the stability of G-Rg3 BS-PC-MMS, the lyophilized formulation of micelles was prepared. The G-Rg3 BS-PC-MMS did not produce hemolysis of erythrocytes within a certain concentration range and exhibited a good inhibition of tumor cells. The chick embryo chorioallantoic membrane assay results showed that the G-Rg3 BS-PC-MMS significantly inhibited angiogenesis. The G-Rg3 BS-PC-MMS is thus shown to be a safe, stable, and promising drug delivery system.

Design and evaluation of pH-sensitive liposomes constructed by poly(2-ethyl-2-oxazoline)-cholesterol hemisuccinate for doxorubicin delivery.

In this study, a novel material, poly(2-ethyl-2-oxazoline)-cholesterol hemisuccinate (PEtOz-CHEMS), was synthesized to construct pH-sensitive liposomes. The structure of PEtOz-CHEMS was confirmed by thin-layer chromatography, Fourier transform infrared spectroscopy, and (1)H NMR. Anticancer fluorescent drug doxorubicin (DOX) was encapsulated into the liposomes. Compared with conventional liposomes (CL), CHEMS modified liposomes (CH-L) and PEGylated liposomes (PEG-L), the PEtOzylated liposomes (PEtOz-L) showed an acidic pH-induced increase in particle size. At pH 6.4, the heme release of PEtOz-L group was close to that of the positive control group, whereas that of CL, CH-L and PEG-L was close to that of the negative control group. In vitro drug release studies demonstrated that DOX was released from PEtOz-L in a pH-dependent manner, and the release of DOX from conventional DOX liposomes (CL-DOX), DOX loaded CH-L (CH-DOX-L) and PEGylated DOX liposomes (PEG-DOX-L) had no pronounced differences under each pH medium. In vitro cellular uptake assays showed that PEtOz-DOX-L indicated a significant fluorescence intensity at pH 6.4 compared with at pH 7.4. CL-DOX, CH-DOX-L and PEG-DOX-L did not achieve any obvious diversity at different pH conditions. Confocal laser scanning microscopy images showed that PEtOz-DOX-L can fuse with the endosomal membrane under acidic conditions of endosome, release DOX into the cytoplasm, then gather into the nucleus. Therefore, PEtOz can help liposomes achieve "endosomal escape". The in vitro cytotoxicity experiment results on A375 cells showed that PEtOz-DOX-L resulted in lower cell viability than CL-DOX, CH-DOX-L and PEG-DOX-L under low pH conditions. These results confirm that the pH-responsive PEtOz was a promising material for intracellular targeted delivery system and might be used for overcoming the "PEG dilemma".

[Preparation and evaluation of doxorubicin hydrochloride liposomes modified by poly(2-ethyl-2-oxazoline)-cholesteryl methyl carbonate].

In this study, the buffering capacity of amphiphilic pH-sensitivity copolymer poly(2-ethyl-2-oxazoline)-cholesteryl methyl carbonate (PEOZ-CHMC) was evaluated. The ammonium sulfate gradient method was used to prepare doxorubicin hydrochloride (DOX x HCl)-loaded liposomes (DOX-L), and then the post-insertion method was used to prepare PEOZ-CHMC and polyethylene glycol-distearoyl phosphatidyl ethanolamine (PEG-DSPE) modified DOX x HCl-loaded liposomes (PEOZ-DOX-L and PEG-DOX-L). The physico-chemical properties, in vitro drugs release behavior, cellular toxicity and intracellular delivery of liposomes were evaluated, separately. The results showed that PEOZ-CHMC has a satisfactory buffering capacity. The sephadex G-50 column centrifugation method and dynamic light scattering were used to determine the encapsulation efficiency (EE) and particle size of liposomes. The EE and particle size of DOX-L were (97.3 ± 1.4) % and 120 nm, respectively, and the addition of PEOZ-CHMC or PEG-DSPE had no influence on EE and particle size. The zeta potentials of three kinds of liposomes were negative. The release behavior of various DOX liposomes in vitro was investigated by dialysis method. In phosphate buffer solution (PBS) at pH 7.4, DOX x HCl was released from PEOZ-DOX-L in a sustained manner. While in PBS at pH 5.0, the release rate of DOX x HCl from PEOZ-DOX-L increased significantly, which suggested DOX x HCl was released from PEOZ-DOX-L in a pH-dependent manner. The intracellular delivery of liposomes was investigated by confocal laser scanning microscopy (CLSM). The CLSM images indicated that PEOZ-DOX-L showed efficient intracellular trafficking including endosomal escape and release DOX x HCl into nucleus, as well as the DOX-L and PEG-DOX-L had no this effect. The cytotoxicity of liposomes against MCF-7 cells was detected by using MTT assay. The results showed that antiproliferative effects of PEOZ-DOX-L enhanced with pH value decreased, whereas DOX-L and PEG-DOX-L did not have any significant difference in inhibitions at different pH conditions. Therefore, the problems of the inhibition of cellular uptake of liposomes and the failed endosomal escape of pH-sensitive liposomes by PEG chain can be overcome by the pH-sensitive liposomes constructed by PEOZ-CHMC.

Influence of phospholipid types and animal models on the accelerated blood clearance phenomenon of PEGylated liposomes upon repeated injection.

When polyethylene glycol (PEG)ylated liposomes were repeatedly injected into the same animal, the second dose of liposomes would rapidly clear from the bloodstream and enhance accumulation in the liver and spleen, and this phenomenon is called "accelerated blood clearance (ABC)". There are many factors known to influence ABC phenomenon, in this study, we mainly focused on the effects of different phospholipids (PL) types and animal models. The effects of PL types on ABC phenomenon were examined by repeating injection of PEGylated liposomes prepared by five different types of PL (hydrogenated soy phosphatidylcholine, egg sphingomyelin, soybean phosphatidycholin, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine and egg phosphatidycholin) in rats. Dramatically, repeated injection of different types of PL could induce ABC phenomenon altogether. Both t1/2 and AUC of experimental group (EG) were lower significantly than those of control group (CG). Our results also showed that the liver accumulation of second dose increased significantly (p < 0.01) in all EG as compared that of CG. Interestingly, ABC phenomenon of liposomes prepared by unsaturated PL was more obvious than that of saturated PL. All the first dose could induce the antibody (anti-PEG IgM) level increasing significantly (p < 0.01). For different animal models, we found that after repeated injection of PEGylated liposomes, rats, mice, rabbits and guinea pigs could produce ABC phenomenon. Various PL types and animal models could all produce the ABC phenomenon. However, their extent of accelerated clearance differed. ABC phenomenon is possibly a ubiquitous immune phenomenon in life.

Direct and indirect bonding of wire retainers to bovine enamel using three resin systems: shear bond strength comparisons / 대한치과교정학회지

OBJECTIVE: We compared the shear bond strength (SBS) of lingual retainers bonded to bovine enamel with three different resins using direct and indirect methods. METHODS: Both ends of pre-fabricated twisted ligature wires were bonded to bovine enamel surfaces using Light-Core, Tetric N-Flow, or Transbond XT. Phosphoric acid-etched enamel surfaces were primed with One-Step prior to bonding with Light-Core or Tetric N-Flow. Transbond XT primer was used prior to bonding with Transbond XT. After 24 hours in water at 37degrees C, we performed SBS tests on the samples. We also assigned adhesive remnant index (ARI) scores after debonding and predicted the clinical performance of materials and bonding techniques from Weibull analyses. RESULTS: Direct bonding produced significantly higher SBS values than indirect bonding for all materials. The SBS for Light-Core was significantly higher than that for Tetric N-Flow, and there was no significant difference between the direct bonding SBS of Transbond XT and that of Light-Core. Weibull analysis indicated Light-Core performed better than other indirectly bonded resins. CONCLUSIONS: When the SBS of a wire retainer is of primary concern, direct bonding methods are superior to indirect bonding methods. Light-Core may perform better than Transbond XT or Tetric N-Flow when bonded indirectly.