Complement inhibition alleviates donor brain death-induced liver injury and posttransplant cascade injury by regulating phosphoinositide 3-kinase signaling.

Brain death (BD) donors are the primary source of donor organs for liver transplantation. However, the effects of BD on donor livers and outcomes after liver transplantation remain unclear. Here, we explored the role of complement and the therapeutic effect of complement inhibition in BD-induced liver injury and posttransplantation injury in a mouse BD and liver transplantation model. For complement inhibition, we used complement receptor 2 (CR2)-Crry, a murine inhibitor of C3 activation that specifically targets sites of complement activation. In the mouse model, BD resulted in complement activation and liver injury in donor livers and a cascade liver injury posttransplantation, mediated in part through the C3a-C3aR (C3a receptor) signaling pathway, which was ameliorated by treatment with CR2-Crry. Treatment of BD donors with CR2-Crry improved graft survival, which was further improved when recipients received an additional dose of CR2-Crry posttransplantation. Mechanistically, we determined that complement inhibition alleviated BD-induced donor liver injury and posttransplant cascade injury by regulating phosphoinositide 3-kinase (PI3K) signaling pathways. Together, BD induced donor liver injury and cascade injury post-transplantation, which was mediated by complement activation products acting on PI3K signaling pathways. Our study provides an experimental basis for developing strategies to improve the survival of BD donor grafts in liver transplantation.

Population pharmacokinetics of mycophenolate mofetil in pediatric patients early after liver transplantation.

Objective: To investigate the factors influencing the pharmacokinetics of mycophenolate mofetil (MMF) in pediatric patients after liver transplantation, and to establish a population pharmacokinetics model, which can provide a reference for clinical dosage adjustment. Methods: A prospective study in a single center was performed on pediatric patients who were administrated with mycophenolate mofetil dispersible tablets (MMFdt) for at least 4 days after liver transplantation continuously. Blood samples were collected in ethylene diamine tetraacetic acid anticoagulant tubes before dosing and 0.5, 1, 2, 4, 8, and 12 h after the morning intake of MMFdt. The concentrations of mycophenolic acid (MPA) in plasma were assayed with a validated reverse-phase high-performance liquid chromatography method. UGT1A8 518C > G, UGT1A9 -275T > A, UGT1A9 -2152C > T, UGT2B7 211G > T, SLC O 1B1 521T > C polymorphism were determined by Sanger sequencing. Nonlinear mixed effects modeling was used to establish the population pharmacokinetics (PPK) model. The predictability and stability of the model were internally evaluated by the goodness of fit plots, visual prediction check, normalized prediction errors, and bootstraps. Results: A two-compartment model with first-order absorption and first-order elimination was established with 115 MPA concentrations from 20 pediatric patients. The final model were: CL/F (L/h) = 14.8×(WT/7.5)0.75×(DOSE/11.16)0.452×е0.06, Ka (h-1) = 2.02×(WT/7.5)-0.25, Vc/F (L) = 6.01×(WT/7.5), Vp/F (L) = 269 (fixed), Q/F (L/h) = 15.4×(WT/7.5)0.75×е1.39. Where CL/F was the apparent clearance rate, Ka was the absorption rate constant, Vc/F was the apparent distribution volume of the central compartment, Vp/F was the apparent distribution volume of the peripheral compartment, Q/F was the atrioventricular clearance rate, WT was the body weight of the subject, and DOSE was the MMFdt administered dose. The model indicated there was large inter-individual variability in CL/F and Q/F after multiple dosing of MMFdt. Internal evaluation results showed that the final model had good stability and prediction performance. Conclusion: A stable and predictive population pharmacokinetic model of MMFdt in pediatric patients after the early stage of liver transplantation was established. The pediatric patient's weight and the dose of MMFdt can be a reference to adjust the MMFdt dose.

Psychosocial Assessment of Donors in Pediatric Living Donor Liver Transplantation: A Systematic Review.

BACKGROUND: Pediatric living donor liver transplantation (LDLT) is the only way to save children with end-stage liver disease. The donor for liver transplantation (LT) may have a complicated psychosocial condition. PURPOSE: This review aims to identify the domains of the donor psychosocial questions that should be addressed and summarize the aspects and tools future psychosocial assessments should include. METHODS: We searched the PubMed, Medline, Cochrane Library, Embase, Web of Science, and Google Scholar databases for the terms pediatric, liver transplantation, donor, and psychosocial. We used the Joanna Briggs Institute Critical Appraisal Tool to appraise reporting quality. Two researchers independently selected the papers and performed data extraction and quality appraisal. RESULTS: The articles included in this review contain 26 quantitative studies and 2 qualitative studies. The study quality was moderate to high. Donors have ambivalence, anxiety, the need for family and social support, the need for adequate information, distress, and low self-esteem during the preoperative period. In the postoperative period they have poor psychological condition, panic disorder, conversion disorder and substance use/abuse disorder, abnormal family functioning, better psychosocial outcome, or among others. The assessment methods consisted of the questionnaire survey and semi-structured interview. Among the 28 studies, 17 different psychosocial domains were mentioned. The most frequently referred to was family and social support. CONCLUSION: The contents of the psychosocial assessment must include anxiety or depression, family and social support, ambivalence, information, and positive psychosocial characteristics. Assessment methods should use the questionnaire survey and semi-structured interview. According to this review, future research can develop a specific psychosocial assessment tool for pediatric LT donors.

The current status and outcomes of pediatric liver transplantation in western China: A multi-center retrospective study.

This retrospective study was conducted to examine the development and current status of pediatric liver transplantation (LT) in western China. Clinical, demographic, morbidity, and mortality data were collected to analyze. It included 260 consecutive pediatric LTs performed at three centers in western China between January 2000 and May 2019. Kaplan-Meier graft survival rates at 1, 3, 5, and 10 years were 82.1%, 77.2%, 76.6%, and 76.6%, respectively; corresponding patient survival rates were 84.7%, 80.7%, 80.0%, and 80.0%, respectively. More patients underwent living donor liver transplantation (LDLT; n = 188 (73.4%)) than deceased-donor liver transplantation (DDLT; n = 68 (26.6%)). Survival was better after LDLT (91.5%, 86.6%, and 80.6% at 1, 3, and 5 years, respectively) than after DDLT (80.9%, 72.4%, and 63.9%, respectively; P < .05). Biliary atresia was the leading LT indication (n = 141 (55.1%)), followed by metabolic disease (n = 36 (14.1%)), which was associated with the best recipient survival (88.5% at 5 years). The transplant era and graft-to-recipient body weight ratio (GRWR) also significantly predicted overall survival. Survival rates at 5 years were worst in 2000-2005 (54.5%) and best for GRWRs of 0.8%-4% (80.4%). The development of pediatric LT in western China began slowly, but the quantity and quality of pediatric LT has progressed in recent years. This procedure is now a promising and reliable treatment for children with end-stage liver disease in western China.

Complement C3 activation regulates the production of tRNA-derived fragments Gly-tRFs and promotes alcohol-induced liver injury and steatosis.

Complement is known to play a role in alcoholic fatty liver disease (AFLD), but the underlying mechanisms are poorly understood, thereby constraining the development of a rational approach for therapeutic intervention in the complement system. C3 deficiency has been shown to impart protective effects against ethanol-induced hepatic steatosis and inflammation. Here we demonstrate a protection effect in wild-type mice by treatment with CR2-Crry, a specific inhibitor of C3 activation. The expression of glycine transfer (t) RNA-derived fragments (Gly-tRFs) is upregulated in ethanol-fed mice and inhibition of Gly-tRFs in vivo decreases chronic ethanol feeding-induced hepatosteatosis without affecting inflammation. The expression of Gly-tRF was downregulated in C3-deficient or CR2-Crry-treated mice, but not in C5-deficient mice; Gly-tRF expression was restored by the C3 activation products C3a or Asp (C3a-des-Arg) via the regulation of CYP2E1. Transcriptome profiling of hepatic tissues showed that Gly-tRF inhibitors upregulate the expression of sirtuin1 (Sirt1) and subsequently affect downstream lipogenesis and ß-oxidation pathways. Mechanistically, Gly-tRF interacts with AGO3 to downregulate Sirt1 expression via sequence complementarity in the 3' UTR. Notably, the expression levels of C3d, CYP2E1 and Gly-tRF are upregulated, whereas Sirt1 is decreased in AFLD patients compared to healthy controls. Collectively, our findings suggest that C3 activation products contribute to hepatosteatosis by regulating the expression of Gly-tRF. Complement inhibition at the C3 activation step and treatment with Gly-tRF inhibitors may be potential and precise therapeutic approaches for AFLD.

Effects of modified penoplasty for concealed penis in children.

PURPOSE: To evaluate the effect of modified penoplasty in the management of concealed penis. METHODS: We retrospectively reviewed 96 consecutive patients with concealed penis, which had been surgically corrected between July 2013 and July 2015. All patients underwent modified Shiraki phalloplasty. All patients were scheduled for regular follow-up at 1, 3, and 6 months after the surgery. Data on the patients' age, operative time, postoperative complications, and parents' satisfaction grade were collected and analyzed. RESULTS: The mean follow-up period was 17.4 months (range 7-31 months). The mean operative time was 63.2 ± 8.7 min. The mean perpendicular penile length was 1.89 ± 0.77 cm preoperatively and 4.42 ± 0.87 cm postoperatively, with an improved mean length of 2.5 ± 0.68 cm in the flaccid state postoperatively (p < 0.05). The patients' satisfaction grades after the surgery were improved significantly (p < 0.05). Fifty-two patients had penile lymphedema postoperatively; however, it disappeared spontaneously within 3 months. Additionally, postoperative wound infection occurred in two patients. There were no complications such as flap necrosis, penile shaft contracture, voiding difficulty, and erection difficulties. CONCLUSION: The modified Shiraki phalloplasty for concealed penis can achieve maximum utilization of prepuce to assure coverage of the exposed penile shaft. It has fewer complications, achieving marked asthetics, and functional improvement. It is a relatively ideal means for treating concealed penis.

Relationship between apolipoprotein E gene polymorphism with triglyceride level in patients with renal diseases.

Apolipoprotein E (apoE), one of the major plasma lipoproteins, plays a major role in the transport and metabolism of lipids by acting as a ligand. apoE gene contains three potential alleles: ϵ2, ϵ3 and ϵ4, forming six genotypes: E2E2, E2E3, E2E4, E3E3, E3E3 and E4E4. Association between apoE gene polymorphism and triglyceride (TG) is still controversial. There was not any meta-analysis to explore the association of apoE gene polymorphism with triglyceride level, and this meta-analysis was performed to evaluate the association between apoE gene polymorphism and triglyceride in patients with renal diseases. A predefined literature search and selection of eligible relevant studies were performed to collect data from electronic databases. Twenty-four articles were identified for the analysis of association between apoE gene polymorphism and triglyceride level. Subjects with E2E3 or E3E4 had a higher TG than those with E3E3. Subjects with ϵ4 had a higher TG than those with ϵ3. Subjects with ϵ2 had a slightly higher TG than those with ϵ3, although there was no statistical difference. Interestingly, subjects with ϵ4 had a much higher TG than those with ϵ2. In conclusion, E2E3, E3E4 or ϵ4 was associated with higher level of TG. However, more studies should be performed in the future.

Lack of association of glutathione S-transferase M3 gene polymorphism with the susceptibility of lung cancer.

OBJECTIVE: The conclusions of published reports on the relationship between the glutathione S-transferase M3 (GSTM3) A/B gene polymorphism and the risk of lung cancer are still debated. This meta-analysis was performed to evaluate the association between GSTM3 and the risk of lung cancer. METHODS: Association investigations were identified from PubMed, Embase, and Cochrane Library, and eligible studies were included and synthesized using a meta-analysis method. RESULTS: Eight reports were included into this meta-analysis for the association of GSTM3 A/B gene polymorphism and lung cancer susceptibility, covering 1,854 patients with lung cancer and 1,926 controls. No association between the GSTM3 A/B gene polymorphism and lung cancer was found in this meta-analysis (B allele: OR = 1.25, 95% CI: 0.89-1.76, P = 0.20; BB genotype: OR = 1.53, 95% CI: 0.71-3.32, P = 0.28; AA genotype: OR = 0.85, 95% CI: 0.59-1.23, P = 0.39). CONCLUSIONS: The GSTM3 A/B gene polymorphism is not associated with lung cancer susceptibility. However, more studies on the relationship between GSTM3 A/B gene polymorphism and the risk of lung cancer should be performed in the future.

[Treatment and outcome of 14 children with hepatoblastoma].

OBJECTIVE: To assess the outcome of childhood hepatoblastoma after a combination therapy of resection and chemotherapy. METHODS: The clinical data of 14 children with hepatoblastoma was retrospectively reviewed. Their long-term survival was followed-up. RESULTS: Twelve cases received surgery and planned chemotherapy. The follow-up duration averaged 18 months (range 1.5-74 months). Nine survived free of events, 1 died, 1 survived with multiple lung metastases, and 1 with increased alpha-fetoprotein (AFP) content but without residual tumor. CONCLUSIONS: Surgery assisted with chemotherapy can improve the outcome of hepatoblastoma.