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BackgroundPrevious studies, in which the data were collected about half a century ago, suggested that elevated low density lipoprotein cholesterol (LDL-C) is not associated with increased risk of cardiovascular disease (CVD) in patients over 70 years old. However, what is the relationship between LDL-C and CVD risk in a contemporary population aged over 70 years has not been well examined in China.MethodsThe China Health and Retirement Longitudinal Study (CHARLS) is an ongoing nationally representative study. In this analysis, participants of CHARLS who did not taking statins and did not have heart disease and stroke at 2011 were include and were followed up to 2018. The outcome of this analysis was occurrence of CVD at follow up, which include heart disease and stroke. Cox regression was used to assess the harmful effect of LDL-C on CVD occurrence. We calculated e-values to quantify the effect of unmeasured confounding on our results.ResultsOf the 9,631 participants, 15.2% (N=1,463) were aged over 70 years and 52.5% (N=5,060) were female. During the 7 years follow-up, 1,437 participants had a first CVD attack. Risk of CVD occurrence increased 8% with each 10 mg/mL elevation in LDL-C in whole participants (adjusted HR, 1.08; 95% CI, 1.06-1.10) and age groups of ≥70 years, 60-69years and ConclusionsIn contemporary society of China, elevated the level of LDL-C also increased the risk of CVD in participants over 70 years old as in the relatively younger participants. These results should strengthen guideline recommendations for the use of lipid lowering therapies in those elderly.

AIMS This study aimed to explore the safety and efficacy of endoscopic retrograde cholangiopancreatography (ERCP) in patients over 90 years of age. METHODS The study included 176 patients aged over 85 years who received their ERCP from February 2002 to January 2021. In the case group (super-elderly group), 44 patients were 90 years old or above. In the control group (younger group), there were 132 patients aged 85-89 years. The control group was matched according to patient gender and the same indications of ERCP at a 1:3 ratio. Logistic regression models were employed to evaluate all complications. RESULTS The case group had higher acute physiology and chronic health evaluation scoring system (APACHE-II) scores and rate of hypoalbuminemia. APACHE-II scores (≥6 or 7) were significantly more common in the case group. The rates of technical success and complete success in the case group were 100% and 100% respectively, which were similar to the rates in the control group, namely a technical success rate of 98.5% and a complete success rate of 98.5%. The rate of complication in the case group was 9.1%, which was slightly lower than that of the control group (15.2%, P > 0.05). ERCP-related death occurred in one patient in the control group, who had malignant biliary obstruction and died from cholangitis. There was no significant difference in the incidence of complications such as pancreatitis, hemorrhage, and infection between the two groups. In the multivariate analysis, the independent risk factor was Charlson Comorbidity Index (CCI) for overall complication. CONCLUSIONS ERCP can be performed safely and successfully in patients aged ≥90 years. Geriatr Gerontol Int 2021; ••: ••-••.

Background Schistosomiasis japonica is a serious zoonotic parasitic disease. Preliminary studies have shown that the expression of microRNA-181a (miR-181a) in the liver, lung and spleen tissues of susceptible host BALB/c mice and resistant host reed vole (Microtus fortis) 10 days post-infection (dpi) with Schistosoma japonicum was significantly different from pre-infection levels. This difference suggests the possibility that miR-181a expression may be related to the regulation of the hosts’ early immune response against S. japonicum infection and thereby affect the development and survival of parasites in their final hosts. Methods BALB/c mice, M. fortis, Toll-like receptor 4 (TLR4)-deficient mice and wild-type mice (C57BL/6) were infected with S. japonicum, and differences in miR-181a expression between BALB/c mice and M. fortis over different time points post-infection (0, 3, 7, 10 and 14 dpi) were compared. MiR-181a mimic, miR-181a inhibitor and irrelevant miRNA, as well as lipopolysaccharide (LPS), a TLR4 receptor ligand, were used to transfect mouse RAW264.7 macrophages. The expression levels of the TLR4 pathway-related cytokines interleukin (IL)-1β, tumor necrosis factor α (TNF-α) and IL-6 were detected by quantitative PCR analysis. Results The expression of miR-181a was significantly upregulated in the serum and liver of mice infected with S. japonicum and downregulated in the serum and liver of M. fortis. T-helper cell (Th1)-type cytokines, such as TNF-α, IL-6 and IL-1β, and Th2-type cytokines, such as IL-10 and IL-4, were differentially expressed in M. fortis and BALB/c mice in the early stage of infection. The expression level of miR-181a in the serum was threefold higher in TLR4-deficient mice than in wild-type mice 10 dpi with S. japonicum. The expression of IL-1β, TNF-α and IL-6 decreased in RAW264.7 cells transfected with miR-181a mimic and increased in cells transfected with miR-181a inhibitor. miR-181a expression was downregulated and the expressions of TLR4 and three TLR4 pathway-related cytokines (IL-1β, IL-6, and TNF-α) were upregulated in RAW264.7 macrophages stimulated with the TLR4 receptor ligand LPS. Conclusion These results suggest the possibility of mutual regulation between miR-181a and the TLR4 signaling pathway during S. japonicum infection. miR-181a may regulate the expression of pro-inflammatory factors through the TLR4 receptor pathway and participate in the immunomodulatory effect of anti-S. japonicum infection. Graphical abstract

Introduction: Glomerular hyperfiltration (GHF) is an early kidney injury. We investigated whether GHF is associated with arterial stiffness expressed by increase of brachial–ankle pulse wave velocity (baPWV) and pulse pressure (PP), and whether the coexistence of GHF and abnormal metabolism increases the risk of arterial stiffness.Methods: In this prospective cohort study, 2,133 non-chronic kidney disease (CKD) participants aged ≥40 years were followed for a mean period of 3.3 years. The extent of arterial stiffness was expressed by measures of baPWV and PP. GHF was defined as eGFR exceeding the age- and sex-specific 90th percentile. Multivariate logistic regression models were used to assess the association between GHF/abnormal metabolism and increased baPWV/PP. The interaction indexes of GHF and abnormal metabolism on arterial stiffness were calculated based on the OR in a multivariate logistic regression model.Results: GHF alone was not associated with increased baPWV or PP in all participants in this study. However, when GHF coexisted with abnormal metabolism, the risk of increased PP increased 3.23-fold [OR = 3.23(1.47–7.13)] compared with participants with normal filtration and normal metabolism, in which the interaction accounted for 55.1% of the total effect and 79.8% of the effect from GHF and abnormal metabolism. After subtracting the independent effects of GHF and abnormal metabolism, their combined effect still resulted in a 1.78-fold increase in PP.Conclusion: GHF could interact with abnormal metabolism to significantly enhance arterial stiffness. Since abnormal metabolism commonly exists in the general population, even slight changes in renal function should be distinguished to prevent arterial stiffness risk.

BackgroundIt is uncertain whether measurement of circulating total atherogenic lipoprotein particle cholesterol mass (non-high-density lipoprotein cholesterol [non-HDL-C]) or particle concentration (apolipoprotein B [Apo B]) more accurately reflects risk of incident cardiovascular disease (CVD). We evaluated CVD risk among China population in whom these markers where discordant.MethodsIn total, 7,117 initially healthy participants from the China Health and Nutrition Survey were included. Logistic regressions among Apo B, non-HDL-C, and LDL-C, respectively, were used to examined CVD risk by categories of concordant and discordant values defined by residual differences. Mediation analysis was performed to explore the intermediary effect of Apo B between the obesity and the risk of CVD.ResultsAlthough all 3 biomarkers were correlated (r ≥ 0.81), discordance occurred in approximately 16% of China participants. Participants with discordant high Apo B were more likely to have higher proportion of traditional risk factors and dyslipidemia. During a follow-up of 6 years, 207 CVD cases were identified. High LDL-C, non-HDL-C and Apo B were associated with increased risk of CVD. Participants with discordant high Apo B relative to LDL-C or non-HDL-C had increased CVD risk compared with concordant levels, odds ratios were 1.38 (95% CI: 1.01 to 1.87), 1.40 (95% CI: 1.01 to 1.94), respectively. Furthermore, mediation analyses revealed 16.67% of association between obesity with CVD was mediated by Apo B.ConclusionsDiscordance analysis demonstrates that Apo B is a more accurate marker of CVD risk in China healthy participants than LDL-C and non-HDL-C. Direct measurement of lipoprotein particle concentration might help better inform clinical risk assessment and guide clinical decision making.

Background: Both baseline blood pressure (BP) and cumulative BP have been used to estimate cardiovascular event (CVE) risk of higher BP, but which one is more reliable for recommendation to routine clinical practice is unclear.Methods: In this prospective study, conducted in the Kailuan community of Tanshan City, China, a total of 95,702 participants free of CVEs at baseline (2006–2007) were included and followed up until 2017. Time-weighted cumulative BP that expresses the extent of cumulative BP exposure is defined as the sum of the mean of two consecutive systolic or diastolic BP times the interval between the two determinations, then normalized by the total follow-up duration. Incident CVEs during 2006–2017 were confirmed by review of medical records. We performed a competing risk regression analysis to assess CVE risk of the different durations of higher BP exposure. ROC analysis was performed to assess the predictive value of higher BP on CVE occurrence.Results: We found that when the risk of higher BP on CVE occurrence was estimated based on time-weighted cumulative BP, the hazard ratios (HRs) increased with the increase in duration of higher BP exposure in each of the four BP groups: Conclusions: Baseline BP remains a useful indicator for predicting future occurrence of CVEs. Nevertheless, time-weighted cumulative BP could more reliably estimate the CVE risk of higher BP exposure than baseline BP.

Endosomal trafficking is an essential cellular process that regulates a broad range of biological events. Proteins are internalized from the plasma membrane and then transported to the early endosomes. The internalized proteins could be transited to the lysosome for degradation or recycled back to the plasma membrane. A robust endocytic recycling pathway is required to balance the removal of membrane materials from endocytosis. Various proteins are reported to regulate the pathway, including ADP-ribosylation factor 6 (ARF6). Density gradient ultracentrifugation is a classical method for cell fractionation. After the centrifugation, organelles are sedimented at their isopycnic surface. The fractions are collected and used for other downstream applications. Described here is a protocol to obtain a recycling endosome-containing fraction from transfected mammalian cells using density gradient ultracentrifugation. The isolated fractions were subjected to standard Western blotting for analyzing their protein contents. By employing this method, we identified that the plasma membrane targeting of engulfment and cell motility 1 (ELMO1), a Ras-related C3 botulinum toxin substrate 1 (Rac1) guanine nucleotide exchange factor, is through ARF6-mediated endocytic recycling.

Wen-Kang Wei and Qin-Ling Chen are also at the Agro-biological Gene Research Center, Guangdong Academy of Agricultural Sciences Since the discovery of SARS-CoV-2 in Wuhan city, China, it has been reported in over 200 other countries and caused a global pandemic. Although some studies have suggested that bats and pangolins were potential hosts, the origin of SARS-CoV-2 remains unknown and the infection evidence of transmission from animals to people is not well established.1 On 28 February and 19 March …

The hippocampus is one of the two niches in mammalian brain with persistent neurogenesis into adulthood. The neurogenic capability of hippocampal neural stem cells (NSCs) declines with age but the molecular mechanisms of this process remain unknown. In this study, we found that fibroblast growth factors 13 (FGF13) is essential for the postnatal neurogenesis in mouse hippocampus and FGF13 deficiency impairs learning and memory. In particular, we found that the nuclear isoform of FGF13, FGF13A, is involved in the maintenance of NSCs and the suppression of neuron differentiation during postnatal hippocampal development. Furthermore, we found that FGF13A interacts with ARID1B, a unit of Brahma-associated factor chromatin remodeling complex, and suppresses the expression of neuron differentiation-associated genes through chromatin modification. Our results suggested that FGF13A is an important regulator for maintaining the self-renewal and neurogenic capacity of NSCs in postnatal hippocampus, revealing a novel epigenetic function of FGFs in neurogenesis.

Summary: The hippocampus is one of two niches in the mammalian brain with persistent neurogenesis into adulthood. The neurogenic capacity of hippocampal neural stem cells (NSCs) declines with age, but the molecular mechanisms of this process remain unknown. In this study, we find that fibroblast growth factor 13 (FGF13) is essential for the post-natal neurogenesis in mouse hippocampus, and FGF13 deficiency impairs learning and memory. In particular, we find that FGF13A, the nuclear isoform of FGF13, is involved in the maintenance of NSCs and the suppression of neuronal differentiation during post-natal hippocampal development. Furthermore, we find that FGF13A interacts with ARID1B, a unit of Brahma-associated factor chromatin remodeling complex, and suppresses the expression of neuron differentiation-associated genes through chromatin modification. Our results suggest that FGF13A is an important regulator for maintaining the self-renewal and neurogenic capacity of NSCs in post-natal hippocampus, revealing an epigenomic regulatory function of FGFs in neurogenesis.

Endoscopic resection (ER) is an effective and safe method for gastric submucosal tumors, mostly composed of gastrointestinal stromal tumors and leiomyomas. The role of ER in gastric schwannoma (GS) has rarely been described. Our aim was to evaluate the efficacy and safety of ER for GS. This is a retrospective study in consecutive patients who underwent ER for GS from March 2013 to October 2018 at our center. Clinicopathological, endoscopic, and follow-up data were collected and analyzed. A total of 16 consecutive patients (9 females, 56.3%) were included, with a mean age of 50.4 years (range 25–75 years). The mean tumor size was 22.9 ± 15.1 mm (range 10–55 mm). Thirteen tumors (81.3%) were located in the middle third of the stomach and 12 tumors (75%) grew with intraluminal pattern. Endoscopic submucosal excavation (ESE) was performed in 7 patients while endoscopic full-thickness resection (EFTR) was done in 9 patients. R0 resection was achieved in 14 patients (87.5%). The mean operative time was 91.6 ± 52.8 min (range 36–203 min) and the mean postoperative length of hospital stays was 8.3 ± 2.7 days (range 6–13 days). No adverse events were encountered except for fevers in 2 patients. No patients required surgical resection or intervention. During long-term follow-up of mean 21.8 months (range 6–62 months), no residue, recurrence, or metastasis was observed. ER is effective and safe for patients with GS with favorable long-term outcomes.

With the digestive endoscopic tunnel technique (DETT), many diseases that previously would have been treated by surgery are now endoscopically curable by establishing a submucosal tunnel between the mucosa and muscularis propria (MP). Through the tunnel, endoscopic diagnosis or treatment is performed for lesions in the mucosa, in the MP, and even outside the gastrointestinal (GI) tract. At present, the tunnel technique application range covers the following: (1) Treatment of lesions originating from the mucosal layer, e.g., endoscopic submucosal tunnel dissection for oesophageal large or circular early-stage cancer or precancerosis; (2) treatment of lesions from the MP layer, per-oral endoscopic myotomy, submucosal tunnelling endoscopic resection, etc.; and (3) diagnosis and treatment of lesions outside the GI tract, such as resection of lymph nodes and benign tumour excision in the mediastinum or abdominal cavity. With the increasing number of DETTs performed worldwide, endoscopic tunnel therapeutics, which is based on DETT, has been gradually developed and optimized. However, there is not yet an expert consensus on DETT to regulate its indications, contraindications, surgical procedure, and postoperative treatment. The International DETT Alliance signed up this consensus to standardize the procedures of DETT. In this consensus, we describe the definition, mechanism, and significance of DETT, prevention of infection and concepts of DETT-associated complications, methods to establish a submucosal tunnel, and application of DETT for lesions in the mucosa, in the MP and outside the GI tract (indications and contraindications, procedures, pre- and postoperative treatments, effectiveness, complications and treatments, and a comparison between DETT and other operations).

Schistosomiasis japonicum is one of the most severe zoonotic diseases in China. Water buffalo and yellow cattle are important reservoir hosts and the main transmission sources of Schistosoma japonicum in endemic areas. The susceptibility of these two hosts to schistosome infection is different, as water buffaloes are less susceptible to S. japonicum than yellow cattle. In this study, iTRAQ-coupled LC-MS/MS was applied to compare the protein expression profiles of adult schistosomes recovered from water buffalo with those of yellow cattle. A total of 131 differentially expressed proteins (DEPs) were identified, including 46 upregulated proteins and 85 downregulated proteins. The iTRAQ results were confirmed by Western blotting and quantitative real-time PCR. Further analysis indicated that these DEPs were primarily involved in protein synthesis, transcriptional regulation, protein proteolysis, cytoskeletal structure and oxidative stress response processes. The results revealed that some of the differential expression molecules may affect the development and survival of schistosomes in these two natural hosts. Of note, this study provides useful information for understanding the interplay between schistosomes and their final hosts.

Schistosomiasis caused by schsitosomes is a serious global public health concern. The tegument that surrounds the worm is critical to the schistosomes survival. The tegument apical membrane undergoes a continuous process of rupture and repair owing to membranous vacuoles fusing with the plasma membrane. Vesicle-associated membrane protein 2 (VAMP2), a member of soluble N-ethylmaleimide sensitive factor attachment protein receptor (SNAREs) is required for membrane fusion. Here, we used RNA interference (RNAi) to knock down the expression of VAMP2 of Schistosoma japonicum (SjVAMP2), and both real-time PCR and western blot analysis confirmed the suppression of this molecule, as well as the suppression of the transcript levels of schistosome glucose transporters (SGTP1 and SGTP4), and insulin receptors (SjIR1 and SjIR2). SjVAMP2-suppressed worms exhibited a lower viability, and phenotypic alterations were also observed in the tegument. Moreover, the glucose consumption of SjVAMP2-suppressed worms decreased significantly in 4 and 6 days, respectively, as well as a significant reduction in egg production. We also observed a significant reduction in worm burden and hepatic eggs burden in two independent RNAi experiment in vivo, and minor pathological changes in mice treated with SjVAMP2 specific small interfering (si)RNA. These findings reveal that SjVAMP2 may play important roles in the maintenance of tegument, glucose uptake, worm development and egg production in schistosomes.

Parkinson's disease (PD), one of the most common neurodegenerative diseases, is characterized by the loss of dopaminergic neurons in the substantia nigra. Increasing epidemiological evidence has indicated that type 2 diabetes (T2D) may be implicated in the pathogenesis of PD. However, the exact association and the underlying mechanism remain unclear. In the present study, ob/ob and db/db mice, the well accepted T2D models, were acutely treated with MPTP (1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine) to mimic PD-like neural injury. We found that insulin signaling impairment occurred not only in pancreas and livers, but also in the midbrain of ob/ob and db/db mice. Notably, the expressions of monomeric and oligomeric α-synuclein as well as endoplasmic reticulum stress markers (CHOP and GRP78) were significantly upregulated in both pancreas and midbrain of T2D mice, accompanied by the increased activation of NLRP3 inflammasomes to produce excess IL-1β. Furthermore, we found that acute MPTP administration aggravated the loss of dopaminergic neurons and increased the activation of glial cells in the substantia nigra of db/db mice. Collectively, these findings demonstrate that α-synuclein accumulation and neuroinflammation are aggravated in the midbrain of T2D mice and T2D mice are more susceptible to the neurotoxicity induced by MPTP. Our study indicates that metabolic inflammation exacerbates DA neuronal degeneration in the progress of PD, which will provide a novel insight into the etiology of PD.

In this paper, the voltammetric method was used for the first time to study the effect of Cisplatin-liposome on Hela cells. The results showed the voltammetric behavior of Hela cells was irreversible and the peak current had linear relationship with the cell number. With both Cisplatin-liposome concentration and treating time increasing, the peak current decreased. The peak current decreasing was in accordance with the nuclear damage and loss of mitochondrial membrane potential revealed by two-photon laser scanning microscopy and confocal laser scanning microscopy. This voltammetric method may provide a simple way to study the electron-transfer mechanism in drug-treating cells.

Diverse studies have shown that miR-155 is overexpressed in different tumor types. However, the precise molecular mechanism of the ectopic expression of miR-155 in breast cancer is still poorly understood. To further explore the role of miR-155 in breast tumorigenesis, we here assessed the influence of miR-155 antisense oligonucleotide (miR-155 ASO) on MDA-MB-157 cell viability and apoptosis in vitro. Furthermore, the effects of inhibitory effects of miR-155 on the growth of xenograft tumors in vivo were determined with performance of immunohistochemistry to detect expression of caspase-3, a pivotal apoptosis regulatory factor, in xenografts. Transfection efficiency detected by laser confocal microscope was higher than 80%. The level of miR-155 expression was significantly decreased (P

Endoscopic submucosal dissection (ESD) is a well-established treatment for superficial esophageal squamous cell neoplasms (SESCNs) with no risk of lymphatic metastasis. However, for large SESCNs, especially when exceeding two-thirds of the esophageal circumference, conventional ESD is time-consuming and has an increased risk of adverse events. Based on the submucosal tunnel conception, endoscopic submucosal tunnel dissection (ESTD) was first introduced by us to remove large SESCNs, with excellent results. Studies from different centers also reported favorable results. Compared with conventional ESD, ESTD has a more rapid dissection speed and R0 resection rate. Currently in China, ESTD for large SESCNs is an important part of the digestive endoscopic tunnel technique, as is peroral endoscopic myotomy for achalasia and submucosal tunnel endoscopic resection for submucosal tumors of the muscularis propria. However, not all patients with SESCNs are candidates for ESTD, and postoperative esophageal strictures should also be taken into consideration, especially for lesions with a circumference greater than three-quarters. In this article, we describe our experience, review the literature of ESTD, and provide detailed information on indications, standard procedures, outcomes, and complications of ESTD.