Machine perfusion combined with antibiotics prevents donor-derived infections caused by multidrug-resistant bacteria.

Donor infection affects organ utilization, especially the infections by multidrug-resistant bacteria, which may have disastrous outcomes. We established a rat model, inoculated with Escherichia coli or carbapenem-resistant Klebsiella pneumoniae (CRKP), to investigate whether hypothermic machine perfusion (HMP), normothermic machine perfusion (NMP), or static cold storage (SCS) combined with antibiotic (AB) could eliminate the bacteria. E. coli or CRKP-infected kidneys were treated with cefoperazone-sulbactam and tigecycline, respectively. The HMP+AB and NMP+AB treatments had significant therapeutic effects on E. coli or CRKP infection compared with the SCS+AB treatment. The bacterial load of CRKP-infected kidneys in the HMP+AB (22 050 ± 2884 CFU/g vs. 1900 ± 400 CFU/g, p = .007) and NMP+AB groups (25 433 ± 2059 CFU/g vs. 500 ± 458 CFU/g, p = .002) were significantly reduced, with no statistically significant difference between both groups. Subsequently, the CRKP-infected kidneys of the HMP+AB and SCS+AB groups were transplanted. The rats in the SCS+AB group were severe infected and euthanized on day 4 post-transplant. By contrast, the rats in the HMP+AB group were in good condition. In conclusion, HMP and NMP combined with AB seems to be efficient approaches to decrease bacterial load of infected kidneys. This might lead to higher utilization rates of donors with active infection.

Hypothermic oxygenated perfusion (HOPE) attenuates ischemia/reperfusion injury in the liver through inhibition of the TXNIP/NLRP3 inflammasome pathway in a rat model of donation after cardiac death.

Hypothermic oxygenated perfusion (HOPE) is a relatively new dynamic preservation procedure that has not been widely implemented in liver transplantation despite its advantages. Improved graft protection is one such advantage offered by HOPE and has been attributed to multiple mechanisms, one of which may be the modulation of the thioredoxin-interacting protein (TXNIP)/NOD-like receptor protein 3 (NLRP3) inflammasome pathway. The TXNIP/NLRP3 inflammasome pathway plays a critical role in sterile inflammation under oxidative stress as a result of ischemia/reperfusion injury (IRI). In the current study, we aimed to investigate the graft protection offered by HOPE and its impact on the TXNIP/NLRP3 inflammasome pathway. To simulate conditions of donation after cardiac death (DCD) liver transplantation, rat livers were exposed to 30 min of warm ischemia after cardiac arrest. Livers were then preserved under cold storage (CS) or with HOPE for 3 h. Livers were then subjected to 1 h of isolated reperfusion. Liver injuries were assessed on the isolated perfusion rat liver model system before and after reperfusion. Compared with the CS group, the HOPE group had a significant reduction in liver injury and improvement in liver function. Our findings also revealed that reperfusion injury induced liver damage and activated the TXNIP/NLRP3 inflammasome pathway in DCD rat livers. Pretreatment of DCD rat livers with HOPE inhibited the TXNIP/NLRP3 inflammasome pathway and attenuated liver IRI. Attenuation of oxidative stress as a result of HOPE led to the down-regulation of the TXNIP/NLRP3 inflammasome pathway and thus offered superior protection compared with the traditional CS method of organ preservation.-He, W., Ye, S., Zeng, C., Xue, S., Hu, X., Zhang, X., Gao, S., Xiong, Y., He, X., Vivalda, S., Li, L., Wang, Y., Ye, Q. Hypothermic oxygenated perfusion (HOPE) attenuates ischemia/reperfusion injury in the liver through inhibition of the TXNIP/NLRP3 inflammasome pathway in a rat model of donation after cardiac death.

Vitamin D levels and the risk of overactive bladder: a systematic review and meta-analysis.

CONTEXT: Overactive bladder is treated mainly with behavioral and drug therapy, and symptoms of urinary frequency and incontinence are challenging to eliminate. There is thus a continuous unmet need for new drugs with a substitution effect mechanism. OBJECTIVE: It not known whether vitamin D deficiency can lead to overactive bladder or urinary incontinence or whether vitamin D supplementation alleviates bladder symptoms. This comprehensive systematic review with meta-analysis was conducted to determine whether overactive bladder is associated with vitamin D deficiency. DATA SOURCES: The PubMed and Cochrane Library databases were searched systematically up to July 3, 2022. DATA EXTRACTION: Initially, 706 articles were identified in the literature search, of which 13 were included in the systematic review: 4 randomized controlled trials, 3 cohort studies, 3 cross-sectional studies, and 3 case-control studies. DATA ANALYSIS: An increased risk of overactive bladder and urinary incontinence was observed with vitamin D deficiency (odds ratio [OR] = 4.46; 95%CI, 1.03-19.33; P = 0.046 and OR = 1.30; 95%CI, 1.01-1.66; P = 0.036, respectively). Vitamin D levels were relatively low in patients with overactive bladder or urinary incontinence (SMD = -0.33; 95%CI, -0.61 to -0.06, P = 0.019). On the basis of existing data, the risk of urinary incontinence was reduced by 66% after vitamin D supplementation (OR = 0.34; 95%CI, 0.18-0.66; P = 0.001). Egger test was conducted to assess publication bias, and the results were tested for robustness using a sensitivity analysis. CONCLUSIONS: Vitamin D deficiency increases the risk of overactive bladder and urinary incontinence, and vitamin D supplementation reduces the risk of urinary incontinence. The development of new strategies to prevent or alleviate bladder symptoms is crucial. Vitamin D supplementation may be gaining recognition as an effective strategy for prevention or alleviation of bladder symptoms such as overactive bladder and incontinence. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42022351443.

Expression of Rab25 is down-regulated in the foreskin of children with hypospadias.

BACKGROUND: Hypospadias, a congenital malformation of the penis, is one of the newborns' most common developmental defects. The incidence of hypospadias is increasing yearly, and its pathogenesis is closely related to genetic susceptibility and environmental exposure to endocrine disruptors. Exploring the hypospadias' key molecular regulatory mechanism is crucial to reducing its incidence. OBJECTIVE: To examine the differential expression of Rab25 in hypospadias and normal penile tissue and to identify whether it is a candidate gene for exploring the mechanism of hypospadias. STUDY DESIGN: This study included 18 children aged 1-6 years undergoing hypospadias repair surgery at the Children's Hospital of Chongqing Medical University, and foreskin samples were collected. Children diagnosed with cryptorchidism, intersex status, or endocrine abnormalities were excluded from this study. Another 18 children aged 3-8 years with phimosis were included in the control group. The specimens were used for immunohistochemistry, western blotting, immunofluorescence, and polymerase chain reaction to assess the expression of Rab25. RESULTS: Rab25 protein expression was lower in the hypospadias group than in the control group [ (2.101 ± 0.1845), (0.7506 ± 0.1779), p = 0.0008 < 0.05). The hypospadias group showed decreased expression of Rab25 protein in the epithelial cell layer. Rab25 mRNA levels were downregulated in the foreskin of children with hypospadias compared with controls [(1.697 ± 0.2005), (0.7687 ± 0.2130), p = 0.0053 < 0.05)]. DISCUSSION: Rab25 mRNA and protein expressions in the hypospadias group were significantly downregulated compared with the control group. This was consistent with the results of single-cell sequencing of fetal mice reproductive nodules at 15.5 days of gestation (Zhang Z, Liu Z, Zhang Q, et al., unpublished observations). Our study represents the first report of abnormal Rab25 expression in the foreskin tissue of patients with hypospadias. More detailed research on the relationship between Rab25 and urethral development could be conducted to reveal the molecular mechanism of hypospadias. CONCLUSION: The expression of Rab25 in foreskin tissue was lower in the hypospadias group than in the control group. Rab25 is involved in the formation of the urethral seam and the occurrence of hypospadias. The potential mechanism by which Rab25 affects the canalization of the urethral plate needs to be further investigated.

Andrographis paniculata ameliorates estrogen deficiency-related osteoporosis by directing bone marrow mesenchymal stem cell fate.

Background: Although Andrographis paniculata (AP) exhibits various biological functions such as anticancer, anti-inflammatory, antimalarial, antimicrobial, antioxidant, cardioprotective and immunomodulatory, its role in estrogen deficiency-related osteoporosis remains unclear. Methods: Ovariectomy (OVX)-induced estrogen deficiency-related osteoporotic mouse models and sham mouse models were established using 8-week-old female C57BL/6J mice. Micro-computed tomography (µCT) scanning was performed to assess the skeletal phenotype. The differentiation potential of bone marrow mesenchymal stem cells (BMSCs) from the OVX and sham groups was assessed by osteogenic or adipogenic induction medium in vitro. To verify the effects of AP, alizarin red S (ARS) staining, alkaline phosphatase (ALP) staining and oil red O (ORO) staining, reverse transcription assay and quantitative real-time polymerase chain reaction were applied to detect the lineage differentiation ability of BMSCs. Results: µCT scanning showed that AP treatment attenuated the osteoporotic phenotype in OVX-induced estrogen deficiency-related osteoporotic mice. The results of ARS staining, ALP staining, ORO staining and quantitative real-time polymerase chain reaction indicated that BMSCs from OVX-induced osteoporotic mice displayed a significant reduction in osteogenic differentiation and an increase in adipogenic differentiation, which could be reversed by AP treatment. Conclusions: Our findings suggested that AP regulated the differentiation potential of BMSCs and ameliorated the development of estrogen deficiency-related osteoporosis, which might be an effective therapeutic method for estrogen deficiency-related osteoporosis.

Maternal smoking during pregnancy and the risk of congenital urogenital malformations: A systematic review and meta-analysis.

Background: Investigations regarding the association between maternal smoking and specific urogenital teratogenesis exist. However, an integrated systematic review and meta-analysis studying the relationship by encompassing the whole urogenital system is essential. Objective: Even though many studies about inborn urogenital malformations have been conducted, its etiologic factors and exact pathogenesis are still unclear. Our aim is to assess the risk of congenital urogenital malformations in offspring of smoking pregnant women. Results: The meta-analysis, covering 41 case-control and 11 cohort studies, suggested that maternal smoking was associated with an increased risk of urogenital teratogenesis (odds ratio [OR] = 1.13, 95% confidence interval [CI]: 1.04-1.23, p = 0.005), cryptorchidism (OR = 1.18, 95%CI: 1.12-1.24, p = 0.0001), hypospadias (OR = 1.16, 95%CI: 1.01-1.33, p = 0.039), and kidney malformations (OR = 1.30, 95%CI: 1.14-1.48, p = 0.0001). Moreover, paternal smoking during the mother's pregnancy was also significantly associated (OR = 1.26, 95%CI: 1.03-1.55, p = 0.028). The association between smoking > 10 cigarettes/day was evident but was not significant (OR = 1.24, 95%CI:0.81-1.88, p = 0.323). Conclusion: Our results showed that maternal smoking during pregnancy increased the risk of congenital urogenital malformations. In numerous epidemiological studies, maternal smoking during pregnancy has a significant role in fetal development. Therefore, quitting tobacco use may be an effective method for reducing the risk of congenital urogenital malformation in pregnant women.

Hypoxia-associated prognostic markers and competing endogenous RNA coexpression networks in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is the most common form of non-small cell lung cancer (NSCLC). Hypoxia has been found in 50-60% of locally advanced solid tumors and is associated with poor prognosis in various tumors, including NSCLC. This study focused on hypoxia-associated molecular hallmarks in LUAD. Fifteen hypoxia-related genes were selected to define the hypoxia status of LUAD by ConsensusClusterPlus based on data from The Cancer Genome Atlas (TCGA). Then, we investigated the immune status under different hypoxia statuses. Subsequently, we constructed prognostic models based on hypoxia-related differentially expressed genes (DEGs), identified hypoxia-related microRNAs, lncRNAs and mRNAs, and built a network based on the competing endogenous RNA (ceRNA) theory. Two clusters (Cluster 1 and Cluster 2) were identified with different hypoxia statuses. Cluster 1 was defined as the hypoxia subgroup, in which all 15 hypoxia-associated genes were upregulated. The infiltration of CD4+ T cells and Tfh cells was lower, while the infiltration of regulatory T (Treg) cells, the expression of PD-1/PD-L1 and TMB scores were higher in Cluster 1, indicating an immunosuppressive status. Based on the DEGs, a risk signature containing 7 genes was established. Furthermore, three differentially expressed microRNAs (hsa-miR-9, hsa-miR-31, hsa-miR-196b) associated with prognosis under different hypoxia clusters and their related mRNAs and lncRNAs were identified, and a ceRNA network was built. This study showed that hypoxia was associated with poor prognosis in LUAD and explored the potential mechanism from the perspective of the gene signature and ceRNA theory.

[Effect of interlocking intramedullary nail in treatment of open tibial and fibula fractures].

OBJECTIVE: To determine the effect of interlocking intramedullary nail in treatment of open tibial and fibula fractures and analyze the method to promote the bone union. METHODS: From December 2003 to June 2006, thirty-five patients with open tibial and fibula fracture were treated with emergency debridement, interlocked intramedullary fixation for tibia and fixed fibula at the same time. During operation, the bone marrow was collected and grafted into the fracture gaps. Among them, there were 27 males and 8 females, involving in 22 left legs and 13 right legs. Their ages ranged from 19 to 65 years, with an average of 34.7 years. The location of fracture was the middle of the tibia and fibula in 16 cases, the distal 1/3 of the tibia and fibula in 12 cases and the proximal 1/3 in 7 cases. According to the Gustilo classification of open injuries, there were 7 cases of type I, 19 cases of type II, 8 cases of type III a and 1 case of type III b. The mean range of knee motion was 48.3 degrees (45-70 degrees). The mean time from injury to operation was 4.3 hours (50 minutes to 7 hours). RESULTS: The mean operation time was 94 minutes (60-132 minutes) and the mean blood loss was 122 mL (100-350 mL). The wound healed by first intention in 32 patients. Incision was sutured in 2 cases of type III a fractures after operation 4 days, gastrocnemius flap graft was performed in 1 case of type III b fracture 1 week after operation. They all achieve good healing. No fractures split off, no iatrogenic nerve and vascular injury occurred, no osteofascial compartment syndromes or deep vein thrombus happened. Tension blisters appeared in 1 case of type II fracture after operation and subsided after 5 days. Patients were followed up for 14-43 months (mean 22 months). The X-ray films showed that fracture union was observe in 30 cases after 14 weeks of operation, in 3 cases after 18 weeks and in 1 case after 22 weeks of operation. The fractures union time was 15.2 weeks on average. About 2 cm nonunion in lateral tibial appeared in 1 case of type I fracture. No fracture occurred again. The mean range of knee motion was 127 degrees (121-135 degrees). The mean HSS score was 96.5 (87-100) at the end of the follow-up. The excellent and good rate was 100%. CONCLUSION: The curative effect of interlocking intramedullary nail is definite in treatment of open tibial and fibula fractures and it can enhance fracture union to plant bone marrow into the fracture gaps.