Antioxidant and Hepatoprotective Effect of Rosa davurica Pall Seed Oil on CCl4-Induced Acute Liver Injury in Mice.

The liver, being the most metabolically active organ, is highly vulnerable to damage caused by oxidative stress. Rosa davurica Pall. seed oil (RDPO), a novel vegetable oil, and its bioactive components have been extensively researched in the field of antioxidants. In this research, the antioxidant properties and hepatoprotection by RDPO were evaluated. A series of antioxidant evaluation systems and a CCl4-induced acute liver injury model in mice were used to investigate the antioxidant activity and hepatoprotective efficacy of RDPO. The results showed that the extraction rate of RDPO was 11.12% using the optimal extraction process. Three major unsaturated fatty acids of the oil were α-linolenic acid (11.89 ± 0.017%), linoleic acid (18.52 ± 0.072%), and oleic acid (11.54 ± 0.425%). Furthermore, its antioxidant small-molecule compounds were ß-sitosterol (1.429 ± 0.002 µg/g), α-tocopherol (1.273 ± 0.079 µg/g), ß-carotene (0.012 ± 0.001 µg/g), lycopene (0.108 ± 0.002 µg/g), squalene (178.950 ± 0.794 µg/g), total polyphenols (1.114 ± 0.032 µg GAE/mg), and total flavonoids (0.504 ± 0.009 mg RU/g), respectively. In vitro, RDPO significantly inhibited the production of ABTS+•, DPPH•, O2•-, and hydroxyl radicals, as well as Fe3+. In vivo, RDPO significantly reversed the activity of total superoxide-dismutase, catalase, L-glutathione, and the level of malondialdehyde (MDA) in liver tissue. It also obviously inhibited the activity of aspartate transaminase (AST) and the level of MDA in the serum. Therefore, RDPO has demonstrated excellent antioxidant activity and a potential liver protective effect. This effect may be ascribed to its capacity for decreasing AST activity, inhibiting lipid peroxidation, and boosting endogenous antioxidant enzyme activity. Therefore, RDPO has significant application value in the biopharmaceutical industry and as a dietary supplement.

Comparative Efficacy of Drug Interventions on NAFLD Over 24 Weeks: A Traditional and Network Meta-Analysis of Randomized Controlled Trials.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD), currently referred to as metabolic dysfunction-associated steatotic liver disease (MASLD), affects approximately 38% of the world's population, yet no pharmacological therapies have been approved for treatment. We conducted a traditional and network meta-analysis to comprehensively assess the effectiveness of drug regimens on NAFLD, and continued to use the old terminology for consistency. METHODS: Randomized, placebo-controlled trials (RCTs) investigating drug therapy in an adult population diagnosed with NAFLD with or without diabetes mellitus were included. We assessed the quality of RCTs via the Risk of Bias 2 (ROB 2) tool. When I2 < 50%, we chose a random-effects model, otherwise a fixed-effects model was selected. A random effects model was applied in the network meta-analysis. The odds ratio (OR), weighted mean difference (WMD) or standard mean difference (SMD) with 95% confidence interval (CI) were used for outcome evaluation. The primary endpoint was the resolution of nonalcoholic steatohepatitis (NASH) without the worsening of liver fibrosis. Other endpoints included histological findings and metabolic changes. The PROSPERO Registration ID was CRD42023404309. RESULTS: Thiazolidinediones (TZDs), vitamin E plus pioglitazone, glucagon-like peptide-1 (GLP-1) receptor agonists and fibroblast growth factor-21 (FGF-21) analogue had a higher surface under the cumulative ranking curve (SUCRA = 76.6, 73.0, 72.0 and 71.6) regarding NASH resolution. Improvement of liver fibrosis stage (≥ 1) was observed with obeticholic acid 25 mg/day (OR 2.01, 95% CI 1.35-2.98), lanifibranor 1200 mg/day (OR 2.39, 95% CI 1.19-4.82) and silymarin (OR 4.54, 95% CI 1.18-17.43) in traditional meta-analysis. CONCLUSIONS: The results of the comprehensive analysis suggested hypoglycemic drug therapy as an effective intervention for NAFLD, with or without diabetes mellitus. A prioritized selection of TZDs, vitamin E plus pioglitazone, GLP-1 receptor agonists and FGF-21 analogue may be considered for NASH resolution. Obeticholic acid, lanifibranor and silymarin could be considered for the improvement of liver fibrosis. Each medication was relatively safe compared with placebo.

DAHOS Study: Efficacy of dapagliflozin in treating heart failure with reduced ejection fraction and obstructive sleep apnea syndrome - A 3-month, multicenter, randomized controlled clinical trial.

BACKGROUND: The recent discovery of new therapeutic approaches to heart failure with reduced ejection fraction (HFrEF), including sodium-glucose cotransporter-2 (SGLT-2) inhibitors, as well as improved treatment of co-morbidities has provided much needed help to HFrEF. In addition, dapagliflozin, one of the SGLT-2 inhibitors, serves as a promising candidate in treating obstructive sleep apnea (OSA) of HFrEF patients due to its likely mechanism of countering the pathophysiology of OSA of HFrEF. METHODS: This 3-month multicenter, prospective, randomized controlled trial enrolled participants with left ventricular ejection fraction (LVEF) less than 40% and apnea-hypopnea index (AHI) greater than 15. Participants were randomized into two groups: the treatment group received optimized heart failure treatment and standard-dose dapagliflozin, while the control group only received optimized heart failure treatment. The primary endpoint was the difference in AHI before and after treatment between the two groups. Secondary endpoints included oxygen desaturation index (ODI), minimum oxygen saturation, longest apnea duration, inflammatory factors (CRP, IL-6), quality of life score, and LVEF. RESULTS: A total of 107 patients were included in the final analysis. AHI, LVEF and other baseline data were similar for the dapagliflozin and control groups. After 12 weeks of dapagliflozin treatment, the dapagliflozin group showed significant improvements in sleep parameters including AHI, HI, longest pause time, ODI, time spent with SpO2 < 90%, and average SpO2. Meanwhile, the control group showed no significant changes in sleep parameters, but did demonstrate significant improvements in left ventricular end-diastolic diameter, LVEF, and NT-proBNP levels at 12 weeks. In the experimental group, BMI was significantly reduced, and there were improvements in ESS score, MLHFQ score, and EQ-5D-3L score, as well as significant reductions in CRP and IL-6 levels, while the CRP and IL-6 levels were not improved in the control group. The decrease in LVEF was more significant in the experimental group compared to the control group. There were no significant differences in the magnitude of the decreases between the two groups. CONCLUSIONS: Dapagliflozin may be an effective treatment for heart failure complicated with OSA, and could be considered as a potential new treatment for OSA. (Trial registration  www.chictr.org.cn , ChiCTR2100049834. Registered 10 August 2021).

Contamination Status and Acute Dietary Exposure Assessment of Paralytic Shellfish Toxins in Shellfish in the Dalian Area of the Yellow-Bohai Sea, China.

The Yellow-Bohai Sea is an important semi-enclosed continental shelf marginal seas with an intensive aquaculture industry in China. The current study analyzed the contamination status and the time variations of paralytic shellfish toxins (PSTs) in shellfish between 2019 and 2020 from the Yellow-Bohai Sea in the Dalian area and estimated the acute health risks to consumers in China. A total of 199 shellfish samples (including 34 Pacific oysters, 25 Mediterranean blue mussels, 34 Manila clams, 36 bay scallops, 34 veined rapa whelks and 36 bloody clams) were analyzed from four representative aquaculture zones around the Yellow-Bohai Sea in Dalian. Among the samples, scallops and blood clams were the shellfish species with the highest detection rate of PSTs (94.4%), and the highest level of PSTs was detected in scallops with 3953.5 µg STX.2HCl eq./kg (µg STX.2HCL equivalents per kg shellfish tissue), followed by blood clams with 993.4 µg STX.2HCl eq./kg. The contents of PSTs in shellfish showed a time variation trend, and autumn was the season of concern for PST contamination in Dalian. For general Chinese consumers, the probability of acute health risks to shellfish consumers from dietary exposure to PSTs was around 13%. For typical consumers in coastal areas of China, especially those with higher shellfish intake, there was an acute health risk associated with exposure to PSTs through shellfish consumption during the occurrence of harmful algal blooms. It is suggested that the government continue to strengthen the monitoring of the source of PSTs and the monitoring of harmful algal blooms and give reasonable advice on shellfish consumption for consumers in coastal areas, such as not eating scallop viscera.

Vitamin C, vitamin E, ß-carotene and risk of Parkinson's disease: a systematic review and dose-response meta-analysis of observational studies.

OBJECTIVE: This study aimed to explore the relationship between the intake of vitamin C, vitamin E and ß-carotene, and the risk of Parkinson's disease (PD). METHODS: Web of Science, Embase, PubMed, Cochrane library, CNKI, and WanFang databases were searched from inception to 29 August 2022 for observational studies reporting the odds ratios (ORs) or relative risks (RRs) or hazard ratios (HRs) and 95% confidence intervals (CIs) of PD by Vitamin C/Vitamin E/ß-carotene intake. Random-effects models, publication bias assessment, subgroup, sensitivity and dose-response analyses were performed, using.Stata version 12.0. RESULTS: A total of 13 studies were included. There was no significant association between high-dose vitamin C intake and the risk of PD compared with low-dose vitamin C intake (RR = 0.98, 95%CI:0.89,1.08). Compared with low-dose intake, high-dose intake of vitamin E can prevent the risk of PD (RR = 0.87, 95%CI:0.77,0.99). Compared with lower ß-carotene intake, there was a borderline non-significant correlation between higher intake and PD risk (RR = 0.91, 95%CI:0.82,1.01), and high dose ß-carotene intake was found to be associated with a lower risk of PD in women (RR = 0.78, 95%CI:0.64,0.96). CONCLUSION: This study shows that vitamin E intake can reduce the risk of PD and play a preventive role.

The mediating role of AKT/ERK/JNK signaling on the malignant phenotype of microcystin-LR in gastric adenocarcinoma cells.

Microcystin-leucine arginine (MC-LR), a widely distributed and highly toxic environmental pollutant, plays crucial roles in cancer malignancy by activating characteristically toxic signaling pathways. Traditional animal-based toxicity evaluation methods have proven insufficient for identifying the specific role of these signaling pathways. Therefore, this study aimed to uncover the regulatory relationship between the toxic pathways and the progression of gastric cancer (GC). The findings provide novel avenues for conducting in vitro toxicity tests based on the investigated pathways. We found that MC-LR promoted the migration and invasion of SGC-7901 cells while simultaneously inhibiting their apoptosis in a dose-dependent manner. This observed cytotoxicity was primarily mediated through the AKT, JNK, and ERK signaling pathways. By using a mediation analysis model, we determined that AKT and ERK exhibited competitive effects in MC-LR-treated GC malignancy, while AKT and JNK acted independently from one another. This study establishes an in vitro toxicity test model of MC-LR based on toxicity-related pathways and underscores the pivotal roles of AKT, ERK, and JNK signaling in MC-LR toxicity. The findings offer a novel, fundamental framework for conducting chemical toxicity risk assessment.

Automatic epicardial adipose tissue segmentation in pulmonary computed tomography venography using nnU-Net.

Background: Epicardial adipose tissue (EAT) is a key aspect in the investigation of cardiac pathophysiology. We sought to develop a deep learning (DL) model for fully automatic extraction and quantification of EAT through pulmonary computed tomography venography (PCTV) images. Methods: In this retrospective study, we included 128 patients with atrial fibrillation and PCTV from 2 hospitals. A DL model for automated EAT segmentation was developed from a training set of 51 patients and a validation set of 13 patients from hospital A. The algorithm was further validated using an internal test set of 16 patients from hospital A and an external test set of 48 patients from hospital B. The consistency and measurement agreement of EAT quantification were compared between the DL model and the conventional manual protocol using the Dice score coefficient (DSC), Hausdorff distance (HD95), Pearson correlation coefficient, and Bland-Altman plot. Results: In the internal and external test set, automated segmentation with DL was successful in all cases. The total analysis time was shorter for DL than for manual reconstruction (5.43±2.52 vs. 106.20±15.90 min; P<0.001). The EAT segmented with the DL model had good consistency with manual segmentation (the DSC of the internal and external test sets were 0.92±0.02 and 0.88±0.03, respectively). The quantification of EAT evaluated with the 2 methods showed excellent correlation (all correlation coefficients >0.9; all P values <0.001) and minimal measurement difference. Conclusions: The proposed DL model achieved fully automatic quantification of EAT from PCTV images. The yielded results were highly consistent with those of manual quantification.

Single-Dose Rifapentine in Household Contacts of Patients with Leprosy.

BACKGROUND: Previous studies have suggested that a single dose of rifampin has protective effects against leprosy in close contacts of patients with the disease. Rifapentine was shown to have greater bactericidal activity against Mycobacterium leprae than rifampin in murine models of leprosy, but data regarding its effectiveness in preventing leprosy are lacking. METHODS: We conducted a cluster-randomized, controlled trial to investigate whether single-dose rifapentine is effective in preventing leprosy in household contacts of patients with leprosy. The clusters (counties or districts in Southwest China) were assigned to one of three trial groups: single-dose rifapentine, single-dose rifampin, or control (no intervention). The primary outcome was the 4-year cumulative incidence of leprosy among household contacts. RESULTS: A total of 207 clusters comprising 7450 household contacts underwent randomization; 68 clusters (2331 household contacts) were assigned to the rifapentine group, 71 (2760) to the rifampin group, and 68 (2359) to the control group. A total of 24 new cases of leprosy occurred over the 4-year follow-up, for a cumulative incidence of 0.09% (95% confidence interval [CI], 0.02 to 0.34) with rifapentine (2 cases), 0.33% (95% CI, 0.17 to 0.63) with rifampin (9 cases), and 0.55% (95% CI, 0.32 to 0.95) with no intervention (13 cases). In an intention-to-treat analysis, the cumulative incidence in the rifapentine group was 84% lower than that in the control group (cumulative incidence ratio, 0.16; multiplicity-adjusted 95% CI, 0.03 to 0.87; P = 0.02); the cumulative incidence did not differ significantly between the rifampin group and the control group (cumulative incidence ratio, 0.59; multiplicity-adjusted 95% CI, 0.22 to 1.57; P = 0.23). In a per-protocol analysis, the cumulative incidence was 0.05% with rifapentine, 0.19% with rifampin, and 0.63% with no intervention. No severe adverse events were observed. CONCLUSIONS: The incidence of leprosy among household contacts over 4 years was lower with single-dose rifapentine than with no intervention. (Funded by the Ministry of Health of China and the Chinese Academy of Medical Sciences; Chinese Clinical Trial Registry number, ChiCTR-IPR-15007075.).

Evaluation of graphical models for multi-group metabolomics data.

Gaussian graphical model is a strong tool for identifying interactions from metabolomics data based on conditional correlation. However, data may be collected from different stages or subgroups of subjects with heterogeneity or hierarchical structure. There are different integrating strategies of graphical models for multi-group data proposed by data scientists. It is challenging to select the methods for metabolism data analysis. This study aimed to evaluate the performance of several different integrating graphical models for multi-group data and provide support for the choice of strategy for similar characteristic data. We compared the performance of seven methods in estimating graph structures through simulation study. We also applied all the methods in breast cancer metabolomics data grouped by stages to illustrate the real data application. The method of Shaddox et al. achieved the highest average area under the receiver operating characteristic curve and area under the precision-recall curve across most scenarios, and it was the only approach with all indicators ranked at the top. Nevertheless, it also cost the most time in all settings. Stochastic search structure learning tends to result in estimates that focus on the precision of identified edges, while BEAM, hierarchical Bayesian approach and birth-death Markov chain Monte Carlo may identify more potential edges. In the real metabolomics data analysis from three stages of breast cancer patients, results were in line with that in simulation study.

Serum levels of carbohydrate antigen 125 in patients with heart failure and obstructive sleep apnea syndrome: a retrospective analysis.

Background: Obstructive sleep apnea syndrome (OSAS) combined with heart failure (HF) has become a serious disease that threatens human health. Therapeutic interventions targeting OSAS have been shown to improve outcomes in patients with HF, so the identification of severe OSAS in HF is critical. Carbohydrate antigen 125 (CA125) is associated with inflammation and volume overload. The levels of CA125 are elevated in the serum of patients with HF and might be further elevated in patients with HF and OSAS. The aim of this study was to measure CA125 levels in patients with HF with and without OSAS and to analyze affecting factors. Methods: In this single-center retrospective cohort study, a total of 95 patients diagnosed with HF hospitalized in Zhongda Hospital from April 2021 to April 2022 were recruited, including 55 patients with OSAS and 40 patients without OSAS. Participants with a history of central sleep apnea syndrome, severe chronic obstructive pulmonary disease, tumors, severe infection, or who were pregnant were excluded. The histories of the participants were recorded, and laboratory examinations were performed. Binary logistic regression analysis was performed to determine the relationship between serum CA125 levels and OSAS in patients with HF. Results: The serum CA125 levels were higher in the HF + OSAS group than in the HF group (29.60 vs. 9.68 U/mL, P<0.001). According to the univariate analysis, CA125 (>35 U/mL) was significantly related to pleural effusion, acute HF, apnea-hypopnea index (AHI), left ventricular ejection fraction (LVEF) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels. Finally, the AHI demonstrated statistical significance in multiple analyses (OR 1.070, 95% CI: 1.019-1.124, P=0.006). Spearman rank correlation coefficient analysis showed that CA125 was positively correlated with AHI, and Ln(CA125) (Ln is the natural logarithm based on e) gradually increased with increasing AHI (r=0.551, P<0.0001). Conclusions: The levels of CA125 were further increased in patients with HF and OSAS, and CA125 (>35 U/mL) was positively correlated with AHI. As a biomarker associated with inflammation and congestion, serum CA125 may have certain value in the diagnosis of patients with HF combined with OSAS.

Network modeling analysis of depression, Internet addiction and campus bullying in adolescents / 中国学校卫生

Objective@#To explore network relationships among depression, Internet addiction and campus bullying among adolescents, so as to provide a theoretical basis for the comprehensive prevention and control of adolescents psychological status and risky behaviors.@*Methods@#In September 2020, a stratified random cluster sampling method was adopted to select 5 000 middle school students for investigation. A structural equation model was used to analyze depression, Internet addiction and bullying and their related influencing factors in order to clarify the pathway and magnitude of effects.@*Results@#Depression had a positive effect on Internet addiction with adolescents( β=0.35, P <0.01), school bullying had a positive effect on depression and Internet addiction with adolescents( β=0.23, 0.05, P <0.01). Adolescent depression was found to play a partial mediating role with respect to the influence of sleep duration on Internet addiction, and the indirect effect was -0.01, accounting for 63.6% of the total effect. Depression played a partial mediating role regarding the influence of the frequency of moderate and high intensity exercise on Internet addiction in adolescents; the indirect effect was -0.01, accounting for 21.8% of the total effect.@*Conclusion@#Considering the interaction among adolescent depression, Internet addiction, and school bullying, it s important to include associated factors when developing effective prevention and intervention strategies, which can thus promote the physical and mental health of students, and provide scientific and effective protection.

Metabolomic transition trajectory and potential mechanisms of N-nitrosomethylbenzylamine induced esophageal squamous cell carcinoma in rats.

Esophageal squamous cell carcinoma (ESCC) is an environment-relevant malignancy with a high mortality. Nitrosamines, a class of nitrogen-containing environmental carcinogens, are widely suggested as a risk factor for ESCC. However, how nitrosamines affect metabolic regulation to promote ESCC tumorigenesis is largely unknown. In this study, the transition trajectory of serum metabolism in the course of ESCC induced by N-nitrosomethylbenzylamine (NMBA) in rats was depicted by an untargeted metabolomic analysis, and the potential molecular mechanisms were revealed. The results showed that the metabolic alteration in rats was slight at the basal cell hyperplasia (BCH) stage, while it became apparent when the esophageal lesion developed into dysplasia (DYS) or more serious conditions. Moreover, serum metabolism of severe dysplasia (S-DYS) showed more similar characteristics to that of carcinoma in situ (CIS) and invasive cancer (IC). Aberrant nicotinate (NA) and nicotinamide (NAM) metabolism, tryptophan (TRP) metabolism, and sphingolipid metabolism could be the key players favoring the malignant transformation of esophageal epithelium induced by NMBA. More particularly, NA and NAM metabolism in the precancerous stages and TRP metabolism in the cancerous stages were demonstrated to replenish NAD+ in different patterns. Furthermore, both the IDO1-KYN-AHR axis mediated by TRP metabolism and the SPHK1-S1P-S1PR1 axis by sphingolipid metabolism provided an impetus to create the pro-inflammatory yet immune-suppressive microenvironment to facilitate the esophageal tumorigenesis and progression. Together, these suggested that NMBA exerted its carcinogenicity via more than one pathway, which may act together to produce combination effects. Targeting these pathways may open up the possibility to attenuate NMBA-induced esophageal carcinogenesis. However, the interconnection between different metabolic pathways needs to be specified further. And the integrative and multi-level systematic research will be conducive to fully understanding the mechanisms of NMBA-induced ESCC.

Comparison of LPS and MS-induced depressive mouse model: behavior, inflammation and biochemical changes.

Depression is a mental disease involving complex pathophysiological mechanisms, and there are many ways to establish depressive mouse models. The purpose of this study is to comprehensively compare the behavioral changes and its mechanism induced by two different models. This study established two depressive mouse models by maternal separation (MS) or lipopolysaccharide (LPS) administration, and added fluoxetine treatment group respectively for comparison. MS induced more apparent anxiety-like behavior while LPS induced more apparent depressive-like behavior. LPS increased peripheral inflammatory factors more apparent, which were mitigated by fluoxetine. MS inhibited the 5-HT system more obviously and was relieved by fluoxetine. LPS triggered stronger immune response in the hippocampus and prefrontal cortex (PFC). MS significantly reduced the expression of neurotrophic proteins and was alleviated by fluoxetine. Overall, LPS induced stronger system inflammation, while MS impaired the function of HPA axis and 5-HT system. Our results will contribute to a deeper understanding of the pathophysiology of different stress-induced depression and will also help researchers select appropriate models of depression for their own needs.

Evaluation of a multicomponent intervention to shorten thrombolytic door-to-needle time in stroke patients in China (MISSION): A cluster-randomized controlled trial.

BACKGROUND: Rapid intravenous thrombolysis (IVT) for acute ischemic stroke (AIS) is crucial for improving outcomes. However, few randomized trials of interventions aimed at reducing in-hospital delay have been carried out in China. We aimed to evaluate the effect of a multicomponent intervention on thrombolytic door-to-needle time (DNT) of AIS patients via video teleconference based on the Behavior Change Wheel (BCW) method. METHODS AND FINDINGS: This cluster-randomized trial, conducted between January 1, 2019 and December 31, 2019, randomly allocated 22 hospitals equally to PEITEM (Persuasion Environment reconstruction Incentivization Training Education Modeling) intervention or routine care plus stroke registry and subsequently enrolled 1,634 AIS patients receiving IVT within 4.5 hours upon stroke onset from participant hospitals. The PEITEM group received a 1-year PEITEM 6-component intervention based on the behavioral theory monthly via video teleconference. The primary outcome was the proportion of patients with a DNT of 60 minutes or less. A total of 987 patients participated in the PEITEM group (mean age, 69 years; female, 411 [41.6%]) and 647 patients in the control group (mean age, 70 years; female, 238 [36.8%]). Of all participants, the proportion of DNT ≤60 minutes in the PEITEM group was higher than in the control group (82.0% versus 73.3%; adjusted odds ratio, 1.77; 95% confidence interval (CI), 1.17 to 2.70; ICC, 0.04; P = 0.007). Among secondary outcomes, the average DNT was 43 minutes in the PEITEM group and 50 minutes in the control group (adjusted mean difference: -8.83; 95% CI, -14.03 to -3.64; ICC, 0.12; P = 0.001). Favorable functional outcome (score of 0 to 1 on the modified Rankin scale (mRS)) was achieved in 55.6% patients of the PEITEM group and 50.4% of the control group (adjusted odds ratio, 1.38; 95% CI, 1.00 to 1.90; ICC, 0.01; P = 0.049). Main study limitations include non-blinding of clinicians, and that specific interventions component responsible for the observed changes could not be determined. CONCLUSIONS: The teleconference-delivered PEITEM intervention resulted in a moderate but clinically relevant shorter DNT and better functional outcome in AIS patients receiving IVT. TRIAL REGISTRATION: Clinicaltrials.gov NCT03317639.

Ketamine promotes the amyloidogenic pathway by regulating endosomal pH.

Ketamine is an anesthetic and addictive drug that can cause cognitive dysfunction and neuroinflammation. Studies have shown that carboxy-terminal fragment derived from ß-secretase (CTF-ß) and amyloid beta (Aß), the amyloidogenic products of amyloid precursor protein (APP), can also induce neuroinflammation and impair cognitive function. However, it remains unclear whether ketamine regulates the amyloidogenic pathway. In the endosome, APP is cleaved by beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), whose activity is influenced by pH. Endosomal acidification is mainly regulated by sodium hydrogen exchanger 6 (NHE6), which leaks protons out of endosomes, and vacuolar proton translocating ATPases (V-ATPase), which pump protons into endosomes. Therefore, we hypothesized that ketamine lowers the endosomal pH by reducing the endosomal NHE6 protein level, and this hyperacidification promotes the amyloidogenic pathway. We set up C57BL/6 J mouse models using 10, 20, 40, 80, and 100 mg/kg ketamine administration and SH-SY5Y cell models using 1, 10, 100, and 1000 µM ketamine administration to investigate its effects on the amyloidogenic pathway at different doses. Western blotting results showed that 100 mg/kg ketamine treatment in vivo and 1000 µM ketamine treatment in vitro increased endosomal BACE1 and CTF-ß protein levels and reduced endosomal NHE6 and APP protein levels. The endosomal accumulation of BACE1 caused by ketamine administration was also observed using confocal imaging. Moreover, flow cytometry indicated that ketamine treatment lowered the endosomal pH value of SH-SY5Y cells. Later, cells were pretreated with monensin to restore the endosomal pH. Monensin did not affect amyloidogenic-related proteins or NHE6 directly; therefore, ketamine-promoted endosomal amyloidogenic processing and BACE1 accumulation were depleted by restoring endosomal acidity through monensin pretreatment. Finally, knockdown of NHE6 promoted the amyloidogenic pathway similarly and prevented further enhancement by ketamine. These results indicated that the effects of ketamine on the amyloidogenic pathway were dependent on the reduction of NHE6 and endosomal pH.

Association between Dietary Nitrate, Nitrite Intake, and Site-Specific Cancer Risk: A Systematic Review and Meta-Analysis.

BACKGROUND: People consume nitrates, nitrites, nitrosamines, and NOCs compounds primarily through processed food. Many studies have yielded inconclusive results regarding the association between cancer and dietary intakes of nitrates and nitrites. This study aimed to quantify these associations across the reported literature thus far. METHODS: We performed a systematic review following PRISMA and MOOSE guidelines. A literature search was performed using Web of Science, Embase, PubMed, the Cochrane library, and google scholar up to January 2020. STATA version 12.0 was used to conduct meta-regression and a two-stage meta-analysis. RESULTS: A total of 41 articles with 13 different cancer sites were used for analysis. Of these 13 cancer types/sites, meta-regression analysis showed that bladder and stomach cancer risk was greater, and that pancreatic cancer risk was lower with increasing nitrite intakes. Kidney and bladder cancer risk were both lower with increasing nitrate intakes. When comparing highest to lowest (reference) categories of intake, meta-analysis of studies showed that high nitrate intake was associated with an increased risk of thyroid cancer (OR = 1.40, 95% CI: 1.02, 1.77). When pooling all intake categories and comparing against the lowest (reference) category, higher nitrite intake was associated with an increased risk of glioma (OR = 1.12, 95% CI: 1.03, 1.22). No other associations between cancer risk and dietary intakes of nitrates or nitrites were observed. CONCLUSION: This study showed varied associations between site-specific cancer risks and dietary intakes of nitrate and nitrite. Glioma, bladder, and stomach cancer risks were higher and pancreatic cancer risk was lower with higher nitrite intakes, and thyroid cancer risk was higher and kidney cancer risk lower with higher nitrate intakes. These data suggest type- and site-specific effects of cancer risk, including protective effects, from dietary intakes of nitrate and nitrite.

Patterns of Pediatric and Adolescent Gynecologic Problems in China: A Hospital-Based Retrospective Study of 97,252 Patients.

STUDY OBJECTIVE: To describe the pattern and population characteristics of pediatric and adolescent gynecologic (PAG) problems in China DESIGN: A clinic-based retrospective study of gynecologic patients (aged 0-18 years) over a period of 13 years SETTING: Department of PAG in the Children's Hospital, Zhejiang University School of Medicine PARTICIPANT: The final analyses included 97,252 patients with gynecologic problems. INTERVENTIONS/METHODS: Descriptive analysis was conducted to evaluate the pattern of PAG problems. MAIN OUTCOME MEASURES: Spectrum of PAG problems RESULTS AND CONCLUSIONS: The number of first-visit PAG patients increased from 4,582 to 11,876 from 2006 to 2018. Overall, genital inflammation was the most common presentation (57.0%), followed by precocious puberty (18.2%). The disease pattern varied across age groups; the most common problems were genital inflammation for age 0-6 years, genital inflammation and precocious puberty for age 7-9 years, and consultation, genital inflammation, and menstrual disorders for age 10-18 years. Overall, genital inflammation, precocious puberty, consultation, and menstrual disorders were common issues for pediatric and adolescent patients with gynecologic problems in China.

Fresh fruit consumption, physical activity, and five-year risk of mortality among patients with type 2 diabetes: A prospective follow-up study.

BACKGROUND AND AIMS: We explored the associations among fruit consumption, physical activity, and their dose-response relationship with all-cause and cardiovascular disease (CVD) mortality in type 2 diabetic patients. METHODS AND RESULTS: We prospectively followed 20,340 community-dwelling type 2 diabetic patients aged 21-94 years. Information on diets and physical activity was collected using standardized questionnaires. All-cause and CVD mortality were assessed. Hazard ratios (HRs) for all-cause mortality were estimated with Cox regression models, and HRs for CVD mortality were derived from a competing risk model. Restricted cubic spline regression was used to analyze dose-response relationships. We identified 1362 deaths during 79,844 person-years. Compared to non-consumption, fruit consumption >42.9 g/d was inversely associated with all-cause mortality (HR 0.76; 95% CI 0.64-0.88), CVD mortality (HR 0.69, 0.51-0.94) and stroke mortality (HR 0.57, 0.36-0.89), but not with heart disease mortality (HR 0.93, 0.56-1.52). The HRs comparing the top vs bottom physical activity quartiles were 0.44 (0.37-0.53) for all-cause mortality, 0.46 (0.33-0.64) for CVD mortality, 0.46 (0.29-0.74) for stroke mortality and 0.51 (0.29-0.88) for heart disease mortality. Lower fruit consumption combined with a lower physical activity level was associated with a greater mortality risk. A nonlinear threshold of 80 g fruit/day was identified; all-cause mortality risk was reduced by approximately 24% at this value. A physical activity threshold of eight metabolic equivalents (MET) h/day was also identified, after which the risk of mortality did not decrease. CONCLUSIONS: Fruit consumption and physical activity may reduce all-cause, CVD, and stroke mortality in type 2 diabetic patients.

Drinking-water nitrate and cancer risk: A systematic review and meta-analysis.

BACKGROUND: Nitrate is an inorganic compound that occurs naturally in all surface and groundwater, although higher concentrations tend to occur only where fertilizers are used on the land. The regulatory limit for nitrate in public drinking water supplies was set to protect against infant methemoglobinemia, but other health effects were not considered. Risk of specific cancers and congenital disabilities may be increased when the nitrate is ingested, and nitrate is reduced to nitrite, which can react with amines and amides by nitrosation to form N-nitroso compounds which are known animal carcinogens. This study aims to evaluate the association between nitrate ingested through drinking water and the risk of developing cancers in humans. METHODS: We performed a systematic review following PRISMA and MOOSE guidelines. A literature search was performed using PubMed, EMBASE, the Cochrane Library databases, Web of Science and Google Scholars in the time-frame from their inception to January 2020, for potentially eligible publications. STATA version 12.0 was used to conduct meta-regression and a two-stage meta-analysis. RESULTS: A total of 48 articles with 13 different cancer sites were used for analysis. The meta-regression analysis showed stomach cancer had an association with the median dosage of nitrate from drinking water (t = 3.98, p = 0.0001, and adjusted R-squared = 50.61%), other types of cancers didn't show any association. The first stage of meta-analysis showed there was an association only between the risk of brain cancer & glioma (OR = 1.15, 95% CI: 1.06, 1.24) and colon cancer (OR = 1.11, 95% CI: 1.04, 1.17) and nitrate consumption in the analysis comparing the highest ORs versus the lowest. The 2nd stage showed there was an association only between the risk colon cancer (OR = 1.14, 95% CI: 1.04, 1.23) and nitrate consumption in the analysis comparing all combined higher ORs versus the lowest. CONCLUSION: This study showed that there is an association between the intake of nitrate from drinking water and a type of cancer in humans. The effective way of controlling nitrate concentrations in drinking water is the prevention of contamination (water pollution). Further research work on this topic is needed.

Effects of sleep apnea hypopnea syndromes on cardiovascular events: a systematic review and meta-analysis.

PURPOSE: Previous studies suggest that sleep apnea hypopnea syndrome (SAHS) is an independent risk factor that contributes to certain cardiovascular events. However, there are studies arguing that patients with SAHS had lower peak troponin levels when suffering cardiovascular events compared to patients without SAHS, which indicates that there may potentially be a protective effect of SAHS. This meta-analysis aimed to assess the impact of SAHS on cardiovascular events. METHODS: Databases were searched for studies that examined cardiac biomarkers or reported angiographic data when patients with SAHS experienced cardiovascular events. The data about peak cardiac biomarkers and angiographic coronary lesion were extracted and then used to compute the pooled standardized mean difference (SMD) and 95% confidence interval (95% CI). RESULTS: Among 26 studies included in the meta-analysis, there was not a definite difference between the SAHS group and the control group for troponins (SMD, 0.05; 95% CI, [- 0.16, 0.26]), creatine kinase (SMD, - 0.08; 95% CI, [- 0.38, 0.22]), and CK-MB (SMD, - 0.11; 95% CI, [- 0.51, 0.29]). However, patients with SAHS revealed worse coronary lesion condition grading via both Gensini score (SMD, 0.63; 95% CI, [0.31, 0.95]) and SYNTAX score (SMD, 0.99; 95% CI, [0.31-1.67]). CONCLUSIONS: Ischemic preconditioning induced by the intermittent hypoxia at the early stage could generate a cardiac protection effect, which would then benefit SAHS patients encountering a major adverse cardiovascular event.