Correlation between essential and toxic elements in maternal blood during early pregnancy and atrial septal defects/ventricular septal defects/patent ductus arteriosus in offspring.

BACKGROUND: Congenital heart defects (CHDs) are the most common congenital malformation in the world. Recent studies have found that essential and toxic trace element levels may play a crucial role in the risk of neonatal malformation. However, the relationships between element levels in early pregnancy and CHD risk among humans remain unclear. This study investigates the association between maternal essential element (copper [Cu], zinc [Zn], calcium [Ca], manganese [Mg] and iron [Fe]) and toxic element (lead [Pb] and cadmium [Cd]) levels during early pregnancy and CHDs. METHODS: A hospital-based case-control study was conducted, including 181 cases and 218 controls. Eligible participants underwent antenatal examination during gestational weeks 11-14 and trace element levels were detected by the atomic absorption method. Multi-variable logistic regression was used to examine the associations between the level of maternal trace elements and CHD risks. RESULTS: Higher levels of Ca in early pregnancy were associated with lower risk of ASD/VSD risks. Moreover, higher Fe, Pb, and Cd levels in the first trimester were associated with higher risks of all CHD and the subtypes risks, and the tests for trend were significant (all p < .05). The restricted cubic spline analysis showed that there was a nonlinear inverted u-shaped dose-response relationship between levels of Zn, Pb, and Cd in the first trimester and risk of CHDs (non-linearity test p < .05). CONCLUSIONS: A moderate increase in Zn and Ca levels and a decrease in Pb and Cd levels during early pregnancy are needed to reduce the incidence of CHDs in the Chinese population.

The impacts of the national centralized drug procurement policy on the use of policy-related antibiotic agents: the case of Shaanxi province, China.

OBJECTIVES: The purpose of NCDP policy was to reduce the price of drugs. However, it is unclear that a reduction in the price of a single antibiotic will lead to an increase in other alternatives, which is crucial for antibiotic management. The aim of this study was to evaluate the impact of policy on the consumption of policy-related antibiotic. METHODS: Quasi-experimental interrupted time series methods were used to assess the effects of the policy. RESULTS: After the implementation of the policy, the consumption of the winning products increased rapidly, with a significant difference in growth (ß2 = 88.03). For nonwinning products, the level of purchase volume decreased (ß2=-22.83) in the intervention group, and after adding the comparison group, this number fell further in statistical significance (ß2=-114.53). Among all the nonwinning products, the level of purchase volume (ß2=-73.59) and expenditures (ß2=-346.71) of the generic drugs that passed the conformance evaluation decreased significantly after the policy in the difference model. The purchase volume of J01DC, J01DD and total antibiotics significantly increased in control group compared with the intervention. CONCLUSION: The implementation of the volume-based procurement policy promoted the use of winning products and decreased the usage of its alternative watch antibiotics.

Sirt6 inhibits vascular endothelial cell pyroptosis by regulation of the Lin28b/let-7 pathway in atherosclerosis.

Our previous study showed that Sirtuin 6 (Sirt6) plays an important role in the regulation of vascular endothelial cell inflammation. Recently, studies have reported that the RNA binding protein Lin28b directly regulates the let-7 microRNA (miRNA), which participates in the process of atherosclerosis (AS) by regulating inflammation. Pyroptosis is a form of programmed cell death that is accompanied by inflammation and is critical for AS. Thus, this study aimed to investigate the role of Sirt6 and Lin28b in vascular endothelial cell pyroptosis and the related mechanism. The present study showed that Lin28b expression was upregulated in the aortic intima and aorta of apolipoprotein E knockout (ApoE-/-) mice fed with a high-fat diet (HFD) for 8 or 12 weeks. Then, in vitro study found Lin28b was involved in tumor necrosis factor-α (TNF-α)-induced vascular endothelial cell pyroptosis, as indicated by the increased number of PI-positive cells and gasdermin D (GSDMD) cleavage, as well as the increased release of lactate dehydrogenase (LDH) and interleukin (IL)-1ß. Further studies demonstrated that TNF-α significantly decreased the expression of let-7, while Lin28b knockdown significantly increased the expression of let-7a, let-7d and let-7g. In addition, Sirt6 overexpression decreased Lin28b expression. Moreover, Sirt6 overexpression suppressed pyroptosis by decreasing the number of PI-positive cells and GSDMD cleavage, as well as by decreasing the release of LDH and IL-1ß in TNF-α-induced vascular endothelial cells. Further mechanistic studies revealed that Sirt6 directly interacted with and deacetylated Lin28b. Taken together, these findings indicate that Sirt6 inhibits vascular endothelial cell pyroptosis by negatively regulating the Lin28b/let-7 pathway in AS.

HDAC11 promotes both NLRP3/caspase-1/GSDMD and caspase-3/GSDME pathways causing pyroptosis via ERG in vascular endothelial cells.

Histone deacetylase 11 (HDAC11), a sole member of the class IV HDAC subfamily, participates in various cardiovascular diseases. Recent evidence showed that pyroptosis was a form of inflammatory programmed cell death and is critical for atherosclerosis (AS). However, little is known about the effect of HDAC11 on endothelial cell pyroptosis in AS. Thus, this study aims to investigate the role of HDAC11 in vascular endothelial cell pyroptosis and its molecular mechanism. Firstly, we found that HDAC11 expression was up-regulated and pyroptosis occurred in the aorta of ApoE-/- mice fed with a high-fat diet (HFD) for 8 or 12 weeks. Then, in vitro study found the treatment of human umbilical vein endothelial cells (HUVECs) with tumor necrosis factor-α (TNF-α) resulted in pyroptosis, as evidenced by activation of caspase-1 and caspase-3 activation, cleavage of downstream gasdermin D (GSDMD) and gasdermin E (GSDME/DFNA5), the release of pro-inflammatory cytokines interleukin (IL)-1ß, IL-6 and IL-18, as well as elevation of LDH activity and increase of propidium iodide (PI)-positive cells. Besides, TNF-α increased HDAC11 expression and induced pyroptosis via TNFR1 in HUVECs. HDAC11 knockdown mitigated pyroptosis by suppressing both NLRP3/caspase-1/GSDMD and caspase-3/GSDME pathways in TNF-α-induced HUVECs. Moreover, GSDME knockdown by siRNA significantly decreased pyroptosis and inflammatory response, while treatment with disulfiram or necrosulfonamide (NSA) further augmented the inhibitory effects of GSDME siRNA on pyroptosis and inflammatory response. Further studies found HDAC11 formed a complex with ERG and decreased the acetylation levels of ERG. More importantly, ERG knockdown augmented vascular endothelial cell pyroptosis in TNF-α-induced HUVECs. Taken together, our study suggests that HDAC11 might promote both NLRP3/caspase-1/GSDMD and caspase-3/GSDME pathways leading to pyroptosis via regulation of ERG acetylation in HUVECs. Modulation of HDAC11 may serve as a potential target for therapeutic strategies of AS.

Hydroxytyrosol Acetate Inhibits Vascular Endothelial Cell Pyroptosis via the HDAC11 Signaling Pathway in Atherosclerosis.

Hydroxytyrosol acetate (HT-AC), a natural polyphenolic compound in olive oil, exerts an anti-inflammatory effect in cardiovascular diseases (CVDs). Pyroptosis is a newly discovered form of programmed inflammatory cell death and is suggested to be involved in the atherosclerosis (AS) process. However, the effect of HT-AC on vascular endothelial cell pyroptosis remains unknown. Thus, we aimed to investigate the effect of HT-AC on vascular endothelial cell pyroptosis in AS and related signaling pathways. In vivo studies showed that HT-AC alleviated the formation of atherosclerotic lesions and inhibited pyroptosis in the aortic intima of ApoE-/- mice fed a high-fat diet (HFD) for 12 weeks. In vitro, we found that HT-AC treatment of human umbilical vein endothelial cells (HUVECs) alleviated tumor necrosis factor-alpha (TNF-α)-induced pyroptosis by decreasing the number of PI positive cells, decreasing the enhanced protein expressions of activated caspase-1 and gasdermin D (GSDMD), as well as by decreasing the release of pro-inflammatory interleukin (IL)-1ß and IL-6. Besides, HT-AC down-regulated HDAC11 expression in the aortic intima of HFD-fed ApoE-/- mice and TNF-α-stimulated HUVECs. To determine the underlying mechanism of action, molecular docking and drug affinity responsive target stability (DARTS) were utilized to identify whether HDAC11 protein is a target of HT-AC. The molecular docking result showed good compatibility between HT-AC and HDAC11. DARTS study's result showed that HDAC11 protein may be a target of HT-AC. Further study demonstrated that knockdown of HDAC11 augmented the inhibition of HT-AC on pyroptosis in TNF-α-stimulated HUVECs. These findings indicate that HT-AC might prevent vascular endothelial pyroptosis through down-regulation of HDAC11 related signaling pathway in AS.

Impact of the Expert Consensus on Carbapenem Consumption Trends and Patterns in Public Healthcare Institutes: An Interrupted Time Series Analysis, 2017-2020.

Background: Carbapenems are considered the last line of defence against bacterial infections, but their high consumption and the resulting antibacterial resistance are an increasing global concern. In this context, the Chinese health authority issued an expert consensus on the clinical applications of carbapenems. However, the long- and short-term effects of the expert consensus on carbapenem use are not clear. Methods: This study was conducted in Shaanxi, a northwest province of China. We collected all available carbapenem procurement data between January 2017 and December 2020 from the Provincial Drug Centralized Bidding Procurement System. A quasi-experimental interrupted time series analysis was used to evaluate the longitudinal effectiveness of expert consensus by measuring the change in the Defined Daily Dosesper 1,000 inhabitants per day (DID), the percentage of carbapenem expenditures to total antimicrobial expenditure, the total carbapenem expenditure, and the defined daily cost (DDDc). We used Stata SE version 15.0 for data analysis, and p < 0.05 was considered statistically significant. Results: After the distribution of the expert consensus, the level (p = 0.769) and trend (p = 0.184) of DID decreased, but the differences were not statistically significant. The percentage of carbapenem expenditures to total antimicrobial expenditure decreased abruptly (p < 0.001) after the intervention, but the long-term trend was still upward. There was no statistically significant relationship between the release of the expert consensus and carbapenem expenditure in the long term, but there was a decreasing trend (p = 0.032). However, the expert consensus had a positive impact on the economic burden of carbapenem usage in patients, as the level (p < 0.001), and trend (p = 0.003) of DDDc significantly decreased. Conclusion: The long-term effects of the distribution of the expert consensus on the use and expenditure of carbapenems in public health institutions in Shaanxi Province were not optimal. It is time to set up more administrative measures and scientific supervision to establish a specific index to limit the application of carbapenems.

The protective effect of hydroxytyrosol acetate against inflammation of vascular endothelial cells partly through the SIRT6-mediated PKM2 signaling pathway.

Hydroxytyrosol acetate (HT-AC), a polyphenolic compound in olive oil, exerts an anti-inflammatory effect on murine collagen-induced arthritis. However, the effect of HT-AC on inflammatory response in cardiovascular disease remains unclear. Thus, in this study, we aimed to investigate the effect of HT-AC on the inflammation response of vascular endothelial cells and the related molecular mechanism. Our results showed that HT-AC inhibited the inflammatory response in hypercholesterolemic mice and tumor necrosis factor (TNF)-stimulated HUVECs. Meanwhile, HT-AC also up-regulated SIRT6 expression in hypercholesterolemic mice and HUVECs. To further investigate whether SIRT6 is involved in the regulation of endothelial inflammatory response by HT-AC, endothelium-specific Sirt6 knockout (Sirt6endo-/-) mice were used. Our study found that Sirt6endo-/- abolished the inhibition of inflammatory response by HT-AC in the thoracic aorta of hypercholesterolemic mice. In vitro study also showed that knockdown of SIRT6 reduced the inhibition of inflammatory response by HT-AC, whereas overexpression of SIRT6 augmented the inhibition of inflammatory response by HT-AC in HUVECs. Further study demonstrated that HT-AC exerts its anti-inflammatory effect partly via the SIRT6-mediated PKM2 signaling pathway. In addition, HT-AC inhibited TNF-induced inflammatory response through the TNF receptor superfamily member 1A (TNFRSF1A) signaling pathway. These findings indicate that HT-AC regulates the vascular endothelial inflammatory response partly through the TNFRSF1A/SIRT6/PKM2-mediated signaling pathway.

Quantitative decision making for a groundwater monitoring and subsurface contamination early warning network.

With the increased development of oil and gas activities in northern Colorado, public concerns over the environmental impacts associated with well drilling and hydraulic fracturing have continued to rise. Issues such as leakages of "toxic" products from oil and gas operations to the subsurface environment (such as groundwater contamination) have led to community action and state regulations related to the establishment of groundwater quality monitoring sites in oil and gas activity areas, particularly those adjacent to urban development. Colorado Water Watch was a groundwater quality monitoring network comprised of seven monitoring wells in northern Colorado to monitor groundwater quality near oil and gas wells and give early warnings of contamination. Our study is aimed at developing a quantitative methodology to find ideal monitoring locations as well as evaluate them. We utilized hydraulic and geological data to select the most preferred sites to monitor groundwater quality, understand the temporal trends and identify unique anomaly signals in the oil and gas active area (Wattenberg field, northern Colorado). In addition to the site selection methodology, water quality data from Colorado Water Watch over 2 years is used to do evaluate the performance using entropy information and Principal Component Analysis. The analysis indicates that the earliest functional monitoring site (CHILL) is the most informative monitoring well, and the most recently installed monitoring sites (Gilcrest and LaSalle) are the least informative and least important stations due to their low data efficiency.

Identification of osteosarcoma-related specific proteins in serum samples using surface-enhanced laser desorption/ionization-time-of-flight mass spectrometry.

Osteosarcoma (OS) is the most common malignant bone tumor. To identify OS-related specific proteins for early diagnosis of OS, a novel approach, surface-enhanced laser desorption/ionization-time-of-flight mass spectrometry (SELDI-TOF-MS) to serum samples from 25 OS patients, 16 osteochondroma, and 26 age-matched normal human volunteers as controls, was performed. Two proteins showed a significantly different expression in OS serum samples from control groups. Proteomic profiles and external leave-one-out cross-validation analysis showed that the correct rate of allocation, the sensitivity, and the specificity of diagnosis were 100%. These two proteins were further identified by searching the EPO-KB database, and one of the proteins identified as Serine rich region profile is involved in various cellular signaling cascades and tumor genesis. The presence of these two proteins in OS patients but absence from premalignant and normal human controls implied that they can be potential biomarkers for early diagnosis of OS.

[Construction of standard allelic ladder of miniSTR loci by molecular cloning].

OBJECTIVE: To investigate the genetic polymorphism of five miniSTR loci (D9S2157, D9S1122, D10S1435, D12ATA63, D2S1776) in Hebei Han population and to construct standard allelic ladders. METHODS: Polymorphism of the five miniSTR loci in 120 unrelated individuals was analyzed by fluorescence PCR and ABI 310 Genetic Analyzer. Molecular cloning technique was employed to construct standard allelic ladder of the 5 loci. RESULTS: Of the five miniSTR loci, 8, 8, 7, 5 and 8 alleles were found, respectively. The polymorphism information component were 0.790, 0.720, 0.750, 0.630 and 0.850, respectively. CONCLUSION: The five loci have relatively abundant polymorphic information and their standard allelic ladders constructed by molecular cloning technique are useful in forensic science.

[Vascularized fibular combined with iliac grafting to repair bone defect after tumor extensive resection for giant cell tumor of bone around knee].

OBJECTIVE: To study the method and effect of the vascularized fibular combined with iliac grafting after the tumor extensive resection for giant cell tumor of the bone around the knee. METHODS: Twenty-five patients with giant cell tumor of the bone around the knee were reviewed, who had been admitted to our hospital from October 1996 to November 2002, including 17 patients undergoing the fibular and iliac transplantation with the vessels anastomosed after the extensive excision of the bone tumor. By the surgically-staged manner of Enneking, all the patients were grouped in the stage of I A; by the Campanacci's radioactive image staging, 11 patients were grouped in stage I, 5 in stage II , and 1 in stage III; by the Jaffe's pathological staging, 9 patients were grouped in stage I, 7 in stage II, and 1 in stage III. Of the patients, 9 were treated by the vascularized fibular combined with iliac grafting in the proximal tibia after the tumor extensive resection, and 8 were treated by the distal femur reconstruction by the operation. The following items were also analyzed: postoperative infection, growth of the bone graft, rate of local recurrence, tumor metastasis, and bone death. The function of the knee joint was evaluated. RESULTS: According the follow-up of the 17 patients for 26-87 months (mean, 54 months), all the bone graft healed well within 75-120 days (mean, 93 days) after operation. Two patients had a local recurrence and 3 had a mildly-narrowed joint. The flexion and extension function of the knee joint recovered, with a range of motion of the reconstructed distal femur of 80 degrees-105 degrees (mean, 96 degrees) while the proximal tibia had a range of motion of 90-120 degrees (mean, 110 degrees). The functional outcome was excellent in 11 patients, good in 3 patients, fair in 1 patient, and bad in 2 patients, with a total satisfactory rate of 82.4%. CONCLUSION: The vascularized fibular combined with iliac grafting after the tumor extensive resection to treat giant cell tumor of the bone around the knee has advantages of complete resection of the tumor and well-restored or reconstructed structure and function of the knee joint.