Correlation between genetic alterations and clinicopathological features of papillary thyroid carcinomas.

OBJECTIVE: To investigate the correlations between multigene alterations and clinicopathological features in papillary thyroid carcinoma (PTC) samples. METHODS: In this retrospective study, 111 cytological specimens of thyroid nodules, including 74 PTC samples and 37 benign samples, were analyzed using a 22-gene mutation assay employing next-generation sequencing. Clinicopathological information was retrospectively collected and analyzed. RESULTS: Gene alterations were associated with a higher rate of lymph node metastasis (LNM) and thyroid capsular invasion, a lower rate of coexisting Hashimoto's thyroiditis, the classical PTC subtype, and younger age (<45 years). Among the 22 genes tested, the BRAF mutation rates showed a significant difference between the PTC and benign groups. In the subgroup analysis, younger age (odds ratio = 12.512, 95% confidence interval: 3.126-50.087) was an independent risk factor for LNM. In further analyses, BRAF mutation was significantly associated with LNM in the older subgroup (age ≥ 45 years), suggesting that the BRAF mutation test has greater value for determining PTC prognosis in the older age group. CONCLUSIONS: Our findings will provide a more comprehensive understanding of the relationship between gene mutations and PTC and may contribute to improved PTC management.

Icariin ameliorates glycolytic dysfunction in Alzheimer's disease models by activating the Wnt/ß-catenin signaling pathway.

It was reported that the Wnt/ß-catenin pathway is involved in the regulation of aerobic glycolysis and that brain glycolytic dysfunction results in the development of Alzheimer's disease (AD). Icariin (ICA), an active component extracted from Epimedii Folium, has been reported to produce neuroprotective effects in multiple models of AD, but its underlying mechanism remains to be fully described. We aimed to investigate the protective effects of ICA on animal and cell models of AD and confirm whether the Wnt/ß-catenin pathway has functions in the neuroprotective function of ICA. The 3 × Tg-AD mice were treated with ICA. HT22 cells, the Aß25-35 peptide and Dickkopf-1 (DKK1) agent (a specific inhibitor of the Wnt/ß-catenin pathway) were used to further explore the underlying mechanism of ICA that produces anti-AD effects. Behavioral examination, western blotting assay, staining analysis, biochemical test, and lactate dehydrogenase (LDH) assays were applied. We first demonstrated that ICA significantly improved cognitive function and autonomous behavior, reduced neuronal damage, and reversed the protein levels and activities of glycolytic key enzymes, and expression of protein molecules of the canonical Wnt signaling pathway, in 3 × Tg-AD mice back to wild-type levels. Next, we further found that ICA increased cell viability and effectively improved the dysfunctional glycolysis in HT22 cells injured by Aß25-35 . However, when canonical Wnt signaling was inhibited by DKK1, the above effects of ICA on glycolysis were abolished. In summary, ICA exerts neuroprotective effects in 3 × Tg-AD animals and AD cellular models by enhancing the function of glycolysis through activation of the Wnt/ß-catenin pathway.

Suppression of hnRNP A1 binding to HK1 RNA leads to glycolytic dysfunction in Alzheimer's disease models.

Objective: To investigate the mechanism of RNA-binding protein hnRNP A1 in mouse hippocampal neurons (HT22) on glycolysis. Methods: RIP and CLIP-qPCR were performed by HT22 in vitro to observe the mechanism of hnRNP A1 regulating the expression of key proteins in glycolysis. The RNA binding domain of hnRNP A1 protein in HT22 was inhibited by VPC-80051, and the effect of hnRNP A1 on glycolysis of HT22 was observed. Lentivirus overexpression of hnRNP A1 was used to observe the effect of overexpression of hnRNP A1 on glycolysis of Aß25-35-injured HT22. The expression of hnRNP A1 in brain tissues of wild-type mice and triple-transgenic (APP/PS1/Tau) AD mice at different ages was studied by Western blot assay. Results: The results of RIP experiment showed that hnRNP A1 and HK1 mRNA were significantly bound. The results of CLIP-qPCR showed that hnRNP A1 directly bound to the 2605-2821 region of HK1 mRNA. hnRNP A1 inhibitor can down-regulate the expression of HK1 mRNA and HK1 protein in HT22 cells. Overexpression of hnRNP A1 can significantly reduce the toxic effect of Aß25-35 on neurons via the hnRNP A1/HK1/ pyruvate pathway. In addition, inhibition of hnRNP A1 binding to amyloid precursor protein (APP) RNA was found to increase Aß expression, while Aß25-35 also down-regulated hnRNP A1 expression by enhancing phosphorylation of p38 MAPK in HT22. They interact to form bidirectional regulation, further down-regulating the expression of hnRNP A1, and ultimately aggravating glycolytic dysfunction. Protein immunoblotting showed that hnRNP A1 decreased with age in mouse brain tissue, and the decrease was greater in AD mice, suggesting that the decrease of hnRNP A1 may be a predisposed factor in the pathogenesis of AD.

The prognostic nutritional index predicts all-cause mortality in critically ill patients with acute myocardial infarction.

BACKGROUND: Malnutrition is common in patients with acute myocardial infarction (AMI) and is associated with a poor prognosis. The prognostic value of the prognostic nutritional index (PNI) in patients with AMI remains controversial. We aimed to explore the relationship between PNI and all-cause mortality in critically ill patients with AMI and evaluate the incremental prognostic value of PNI to commonly used prognostic assessment tools. METHODS: The Medical Information Mart for Intensive Care-IV (MIMIC-IV) database was used to conduct a retrospective cohort analysis on 1180 critically ill patients with AMI. The primary endpoints were defined as 6-month and 1-year all-cause mortality. Cox regression analysis was used to investigate the relationship between admission PNI and all-cause mortality. The effect of adding PNI to sequential organ failure assessment (SOFA) score, or charlson comorbidity index (CCI) on its discriminative ability was assessed using C-statistic, net reclassification improvement (NRI), and integrated discrimination improvement (IDI). RESULTS: Multivariate cox regression analysis demonstrated that the low PNI was regarded as an independent predictor of 1-year all-cause mortality in AMI patients admitted to ICU (adjusted Hazard Ratio: 95% CI = 1.75 (1.22-2.49)). The ROC test showed that admission PNI had a moderate predictive ability to predict all-cause mortality of critically ill patients with AMI. Furthermore, the net reclassification and integrated discrimination of the CCI alone model improved significantly with PNI. [C-statistic increased from 0.669 to 0.752, p < 0.001; NRI = 0.698, p < 0.001; IDI = 0.073, p < 0.001]. When PNI was added to the SOFA score, the C-statistic significantly improved from 0.770 to 0.805 (p < 0.001), and the NRI and IDI were estimated at 0.573 (p < 0.001) and 0.041 (p < 0.001), respectively. CONCLUSION: PNI could be a novel predictor for identifying patients at high risk of 1-year all-cause mortality in critically ill patients with AMI. The addition of PNI to the SOFA score or CCI may be useful for very early risk stratification.

Prognostic impact of in-hospital hemoglobin decline in non-overt bleeding ICU patients with acute myocardial infarction.

BACKGROUND: The prognostic value of in-hospital hemoglobin drop in non-overt bleeding patients with acute myocardial infarction (AMI) admitted to the intensive care unit (ICU) remains insufficiently investigated. METHODS: A retrospective analysis was performed based on the Medical Information Mart for Intensive Care (MIMIC)-IV database. 2,334 ICU-admitted non-overt bleeders diagnosed with AMI were included. In-hospital hemoglobin values (baseline value on admission and nadir value during hospitalization) were available. Hemoglobin drop was defined as a positive difference between admission and in-hospital nadir hemoglobin. The primary endpoint was 180-day all-cause mortality. The time-dependent Cox proportional hazard models were structured to analyze the connection between hemoglobin drop and mortality. RESULTS: 2,063 patients (88.39%) experienced hemoglobin drop during hospitalization. We categorized patients based on the degree of hemoglobin drop: no hemoglobin drop (n = 271), minimal hemoglobin drop (< 3 g/dl; n = 1661), minor hemoglobin drop (≥ 3 g/dl & < 5 g/dl, n = 284) and major hemoglobin drop (≥ 5 g/dl; n = 118). Minor (adjusted hazard ratio [HR] = 12.68; 95% confidence interval [CI]: 5.13-31.33; P < 0.001) and major (adjusted HR = 13.87; 95% CI: 4.50-42.76; P < 0.001) hemoglobin drops were independently associated with increased 180-day mortality. After adjusting the baseline hemoglobin level, a robust nonlinear relationship was observed in the association between hemoglobin drop and 180-day mortality, with 1.34 g/dl as the lowest value (HR = 1.04; 95% CI: 1.00-1.08). CONCLUSION: In non-overt bleeding ICU-admitted patients with AMI, in-hospital hemoglobin drop is independently associated with higher 180-day all-cause mortality.

Stem rot on Adenia globosa caused by Lasiodiplodia theobromae in Jiangsu.

Adenia globosa, as an excellent indoor ornamental plant, is planted in Tropical Botanical Museum, Nanjing Zhongshan Botanical Garden, Jiangsu Province, China. In September 2022, a new stem basal rot disease was observed on A. globosa seedlings, being planted here. Stem basal rot were observed on approximately 80% of A. globosa seedlings. The basal stem of cutting seedlings appeared decayed, and stem tip eventually turned dry due to water loss (Figure S1A). To isolate the pathogen, three diseased stems were collected from three cuttings planted in different pots of the Tropical Botanical Museum. The stem sections (3 to 4 mm) were excised from the margins between healthy and diseased tissues, surface sterilized in 75% ethanol for 30 s and 1.5% NaClO for 90 s, rinsed three times in sterilized distilled water, plated on potato dextrose agar (PDA) and incubated at 25℃ in the dark. Pure cultures were obtained by monosporic isolation. Eight isolates were obtained, and all identified as Lasiodiplodia sp.. The colonies morphology of cultures, growing on PDA were cotton-like, the primary mycelia were black gray after 7 days, and the reverse sides of PDA plates were similar to front sides in color (Figure S1B). A representative isolate, QXM1-2 was selected for the further study. Conidia of QXM1-2 were oval or elliptic, with a mean size of 11.6 µm×6.6 µm (n=35). The conidia are colorless and transparent in the early stage, and become dark brown with one-septum in the later stage (Figure S1C). The conidiophores produced conidia after nearly four weeks of cultivation on PDA plate (Figure S1D). The conidiophore was a transparent cylindrical structure, with a size of (6.4-18.2) µm × (2.3-4.5) µm ( n = 35). These characteristics were consistent with the description of Lasiodiplodia sp. (Alves et al. 2008). The internal transcribed spacer regions (ITS), translation elongation factor 1-alpha (TEF1α) and ß-tubulin (TUB) genes (GenBank Accession No.OP905639, No.OP921005, and No.OP921006, respectively) were amplified and sequenced with the primer pairs ITS1/ITS4 (White et al. 1990), EF1-728F/EF1-986R (Alves et al. 2008) and Bt2a/Bt2b (Glass and Donaldson 1995), respectively. They had 99.8-100% homology to the ITS (504/505 bp) of Lasiodiplodia theobromae strain NH-1 (MK696029), TEF1α (316/316 bp) of strain PaP-3 (MN840491), and TUB (459/459 bp) of isolate J4-1 (MN172230). A neighbor-joining phylogenetic tree was generated by combining all sequenced loci in MEGA7. The isolate QXM1-2 clustered in the L. theobromae clade with 100% bootstrap support (Figure S2). To test pathogenicity, three A. globosa cutting seedlings that previously had been wounded with a sterile needle were inoculated with 20 µL conidia suspension (1×106 conidia/mL) on the stem base. The seedlings inoculated with 20 µL sterile water was used as the control. All plants were covered with clear polyethylene bags to keep moisture in a greenhouse (25℃, 80% relative humidity). The experiment was repeated three times. After 7 days post-inoculation, typical stem rot were found on the treated cutting seedlings and the control seedlings did not have any symptoms (Figure S1E-F). The same fungus, identified by morphological characteristics and sequencing using ITS, TEF1α and TUB genes, was isolated from the diseased tissues of the inoculated stems to complete Koch's postulates. This pathogen has been reported infecting the branch of castor bean (Tang et al. 2021) and root of Citrus (Al-Sadi et al. 2014). For our knowledge, this is the first report of L. theobromae infecting A. globosa in China. This study provides an important reference for the biology, epidemiology of L. theobromae.

Global stability of a tridiagonal competition model with seasonal succession.

In this paper, we investigate a tridiagonal three-species competition model with seasonal succession. The Floquet multipliers of all nonnegative periodic solutions of such a time-periodic system are estimated via the stability analysis of equilibria. Together with the Brouwer degree theory, sufficient conditions for existence and uniqueness of the positive periodic solution are given. We further obtain the global dynamics of coexistence and extinction for three competing species in this periodically forced environment. Finally, some numerical examples are presented to illustrate the effectiveness of our theoretical results.

Icariin ameliorates memory deficits through regulating brain insulin signaling and glucose transporters in 3×Tg-AD mice.

Icariin, a major prenylated flavonoid found in Epimedium spp., is a bioactive constituent of Herba Epimedii and has been shown to exert neuroprotective effects in experimental models of Alzheimer's disease. In this study, we investigated the neuroprotective mechanism of icariin in an APP/PS1/Tau triple-transgenic mouse model of Alzheimer's disease. We performed behavioral tests, pathological examination, and western blot assay, and found that memory deficits of the model mice were obviously improved, neuronal and synaptic damage in the cerebral cortex was substantially mitigated, and amyloid-ß accumulation and tau hyperphosphorylation were considerably reduced after 5 months of intragastric administration of icariin at a dose of 60 mg/kg body weight per day. Furthermore, deficits of proteins in the insulin signaling pathway and their phosphorylation levels were significantly reversed, including the insulin receptor, insulin receptor substrate 1, phosphatidylinositol-3-kinase, protein kinase B, and glycogen synthase kinase 3ß, and the levels of glucose transporter 1 and 3 were markedly increased. These findings suggest that icariin can improve learning and memory impairments in the mouse model of Alzheimer's disease by regulating brain insulin signaling and glucose transporters, which lays the foundation for potential clinical application of icariin in the prevention and treatment of Alzheimer's disease.

Malfilanol C, a new sesquiterpenoid isolated from the deep-sea-derived Aspergillus puniceus A2 fungus.

The chemical examination of the rice solid fermentation products of the deep-sea-derived fungus Aspergillus puniceus A2 resulted in the isolation of one new sesquiterpenoid malfilanol C (1), together with a rare analogue malfilanol B (2). The planar structure of 1 was resolved on the basis of the extensive analyses of the spectroscopic data (HRESIMS and NMR spectra), and its absolute configuration was assigned by quantum chemical calculation of the ECD data. Compound 1, featuring a bicyclo[5.4.0]-undecane nucleus skeleton, was the third example of this subclass sesquiterpenoids found from nature. Additionally, the subclass sesquiterpenoids 1 and 2 were discovered from marine-derived-fungi for the first time. All the isolated metabolites were evaluated the antibacterial activities against Staphylococcus aureus ATCC 29213 and Escherichia coli ATCC 25922. Compound 1 exhibited weak antibacterial activity against S. aureus ATCC 29213.

Phenolic Metabolites from a Deep-Sea-Derived Fungus Aspergillus puniceus A2 and Their Nrf2-Dependent Anti-Inflammatory Effects.

Four undescribed phenolic compounds, namely asperpropanols A-D (1-4), along with two known congeners 5 and 6, were isolated from Aspergillus puniceus A2, a deep-sea-derived fungus. The gross structures of the compounds were established by detailed analyses of the HRESIMS and NMR data, and their absolute configurations were resolved by modified Mosher's method and calculations of ECD data. Compounds 1-6 were found to have excellent anti-inflammatory effect on lipopolysaccharide (LPS)-induced RAW264.7 cells at 20 µM, evidenced by the reduced nitric oxide (NO), tumor necrosis factor α, and interleukin 6 production. Among them, 5 and 6 showed inhibitory effects on NO production comparable with the positive control (BAY11-7083 at 10 µM). Additionally, the LPS-induced mRNA expressions of inducible nitric oxide synthase and cyclooxygenase-2 were also decreased. Interestingly, mRNA expression of nuclear factor erythroid 2-related factor 2 (Nrf2) was downregulated by LPS and recovered by 1-6, suggesting a vital role of Nrf2 in their effect. We further found that pharmacological inhibition of Nrf2 by ML385 largely abrogated the effects of 1-6 on RAW264.7 cells. Therefore, 1-6 may share a common anti-inflammatory mechanism via Nrf2 upregulation and activation.

Development and validation of a nomogram for predicting significant coronary artery stenosis in suspected non-ST-segment elevation acute coronary artery syndrome with low-to-intermediate risk stratification.

Background: Patients with non-ST-segment coronary artery syndrome (NSTE-ACS) have significant heterogeneity in their coronary arteries. A better assessment of significant coronary artery stenosis (SCAS) in low-to-intermediate risk NSTE-ACS patients would help identify who might benefit from invasive coronary angiography (ICA). Our study aimed to develop a multivariable-based model for pretesting SCAS in suspected NSTE-ACS with low-to-intermediate risk. Methods: This prediction nomogram was constructed retrospectively in 469 suspected NSTE-ACS patients with low-to-intermediate risk. Patients were divided into a development group (n = 331, patients admitted to hospital before 1 May 2021) and a temporal validation group (n = 138, patients admitted to hospital since 1 May 2021). The outcome was existing SCAS, including left main artery stenosis ≥50% or any subepicardial coronary artery stenosis ≥70%, all confirmed by invasive coronary angiography. Pretest predictors were selected using Least Absolute Shrinkage and Selection Operator (LASSO) and stepwise logistic regression. Results: Derivation analyses from the development group (n = 331, admitted before 1 May 2021) generated the 7 strongest predictors out of 25 candidate variables comprising smoker, diabetes, heart rate, cardiac troponin T, N-terminal pro-B-type natriuretic peptide, high-density lipoprotein cholesterol, and left atrial diameter. This nomogram model showed excellent discrimination ability with an area under the receiver operating characteristic curve (AUC) of 0.83 in the development set and 0.79 in the validation dataset. Good calibration was generally displayed, although it slightly overestimated patients' SCAS risk in the validation group. Decision curve analysis demonstrated the clinical benefit of this model, indicating its value in clinical practice. Furthermore, an optimal cut-off of prediction probability was assigned as 0.61 according to the Youden index. Conclusion: A prediction nomogram consisting of seven readily available clinical parameters was established to pretest the probability of SCAS in suspected NSTE-ACS patients with low-to-intermediate risk, which may serve as a cost-effective risk stratification tool and thus assist in initial decision making.

Distinct tumor microenvironment landscapes in gastric cancer classified by cuproptosis-related lncRNAs.

Cuproptosis is a newly discovered non-apoptotic form of cell death that may be related to the development of tumors. Nonetheless, the potential role of cuproptosis-related lncRNAs in tumor microenvironment (TME) formation and patient-tailored treatment optimization of gastric cancer (GC) is still unclear. In this study, the six-lncRNA signature was constructed to quantify the molecular patterns of GC using LASSO-Cox regression model. Receiver operating characteristic (ROC) curves, C-index curves, independent prognostic analysis and principal component analysis (PCA) were conducted to verify and evaluate the model. The results showed that this risk model was accurate and reliable in predicting GC patient survival. In addition, two distinct subgroups were identified based on the risk model, which showed significant difference in biological functions of the associated genes, TME scores, characteristics of infiltrating immune cells and immunotherapy responses. We found that the high-risk subgroup was associated with immune activation and tumor-related pathways. Furthermore, compared with the low-risk subgroup, the high-risk subgroup had higher TME scores, richer immune cell infiltration and a better immunotherapy response. To accurately identify immune cold tumors and hot tumors, all samples of GC were divided into four distinct clusters by consensus clustering. Among them, Cluster 3 was identified as an immune hot tumor and was more sensitive to immunotherapy. Overall, this study demonstrates that cuproptosis-related lncRNAs could accurately predict the prognosis of patients with GC, help make a distinction between immune cold tumors and hot tumors and provide a basis for the precision medicine of GC.

Proteinuria is independently associated with carotid atherosclerosis: a multicentric study.

BACKGROUND AND AIMS: Atherosclerosis is a vital cause of cardiovascular diseases. The correlation between proteinuria and atherosclerosis, however, has not been confirmed. This study aimed to assess whether there is a relationship between proteinuria and atherosclerosis. METHODS: From January 2016 to September 2020, 13,545 asymptomatic subjects from four centres in southern China underwent dipstick proteinuria testing and carotid atherosclerosis examination. Data on demography and past medical history were collected, and laboratory examinations were performed. The samples consisted of 7405 subjects (4875 males and 2530 females), excluding subjects failing to reach predefined standards and containing enough information. A multivariate logistic regression model was used to adjust the influence of traditional risk factors for atherosclerosis on the results. RESULTS: Compared with proteinuria-negative subjects, proteinuria-positive subjects had a higher prevalence rate of carotid atherosclerosis. The differences were statistically significant (22.6% vs. 26.7%, χ2 = 10.03, p = 0.002). After adjusting for common risk factors for atherosclerosis, age, sex, BMI, blood lipids, blood pressure, renal function, hypertensive disease, diabetes mellitus and hyperlipidaemia, proteinuria was an independent risk factor for atherosclerosis (OR = 1.191, 95% CI 1.015-1.398, p = 0.033). The Hosmer-Lemeshow test was used to test the risk prediction model of atherosclerosis, and the results showed that the model has high goodness of fit and strong independent variable prediction ability. CONCLUSIONS: Proteinuria is independently related to carotid atherosclerosis. With the increase in proteinuria level, the risk of carotid atherosclerotic plaque increases. For patients with positive proteinuria, further examination of atherosclerosis should not be ignored.

Deep learning-based automated left ventricular ejection fraction assessment using 2-D echocardiography.

Deep learning (DL) has been applied for automatic left ventricle (LV) ejection fraction (EF) measurement, but the diagnostic performance was rarely evaluated for various phenotypes of heart disease. This study aims to evaluate a new DL algorithm for automated LVEF measurement using two-dimensional echocardiography (2DE) images collected from three centers. The impact of three ultrasound machines and three phenotypes of heart diseases on the automatic LVEF measurement was evaluated. Using 36890 frames of 2DE from 340 patients, we developed a DL algorithm based on U-Net (DPS-Net) and the biplane Simpson's method was applied for LVEF calculation. Results showed a high performance in LV segmentation and LVEF measurement across phenotypes and echo systems by using DPS-Net. Good performance was obtained for LV segmentation when DPS-Net was tested on the CAMUS data set (Dice coefficient of 0.932 and 0.928 for ED and ES). Better performance of LV segmentation in study-wise evaluation was observed by comparing the DPS-Net v2 to the EchoNet-dynamic algorithm (P = 0.008). DPS-Net was associated with high correlations and good agreements for the LVEF measurement. High diagnostic performance was obtained that the area under receiver operator characteristic curve was 0.974, 0.948, 0.968, and 0.972 for normal hearts and disease phenotypes including atrial fibrillation, hypertrophic cardiomyopathy, dilated cardiomyopathy, respectively. High performance was obtained by using DPS-Net in LV detection and LVEF measurement for heart failure with several phenotypes. High performance was observed in a large-scale dataset, suggesting that the DPS-Net was highly adaptive across different echocardiographic systems.NEW & NOTEWORTHY A new strategy of feature extraction and fusion could enhance the accuracy of automatic LVEF assessment based on multiview 2-D echocardiographic sequences. High diagnostic performance for the determination of heart failure was obtained by using DPS-Net in cases with different phenotypes of heart diseases. High performance for left ventricle segmentation was obtained by using DPS-Net, suggesting the potential for a wider range of application in the interpretation of 2DE images.

[Analysis of esophageal manometry results and the inflection point of age in 41 volunteers without laryngopharyngeal symptoms].

Objective:This study aimed to explore the differences in esophageal pressure at different ages, and to analyze the possible age inflection points of the physiological degeneration of esophageal motility, and to further evaluate whether the degeneration of esophageal kinetics with age is the only risk factor for the occurrence of throat reflux disease （LPRD）. Methods:A solid-state high-resolution esophageal pressure measurement was performed on 41 volunteers without throat symptoms. The Chicago classification data were compared with the manometry results of all volunteers. In addition, the esophageal manometry results were compared among groups with pre-set age inflection point. Results:Most of the volunteers' esophageal pressure measurements were in line with Chicago standards. When the inflection point of age was 55 years, no significant difference was found between the two groups. However, when the inflection point of age was 65 years, a significant difference in the length of the upper esophageal sphincter and the contractile front velocity was found between the two groups（P=0.021 and 0.046 respectively）. Conclusion:Esophageal dynamics was weakened with increasing age in the volunteers without laryngopharyngeal symptoms, which was more obvious after the age of 65, but still within the normal range. The degeneration of esophageal motility is not the only risk factor for LPRD.

AMPK: A bridge between diabetes mellitus and Alzheimer's disease.

The pathogenesis and etiology of diabetes mellitus (DM) and Alzheimer's disease (AD) share many common cellular and molecular themes. Recently, a growing body of research has shown that AMP-activated protein kinase (AMPK), a biomolecule that regulates energy balance and glucose and lipid metabolism, plays key roles in DM and AD. In this review, we summarize the relevant research on the roles of AMPK in DM and AD, including its functions in gluconeogenesis and insulin resistance (IR) and its relationships with amyloid ß-protein (Aß), Tau and AMPK activators. In DM, AMPK is involved in the regulation of glucose metabolism and IR. AMPK is closely related to gluconeogenesis, which can not only be activated by the upstream kinases liver kinase B1 (LKB1), transforming growth factor ß-activated kinase 1 (TAK1), and Ca2+/calmodulin-dependent protein kinase kinase ß (CaMKKß) but also regulate the downstream kinases glucose-6-phosphatase (G-6-Pase) and phosphoenolpyruvate carboxy kinase (PEPCK), thereby affecting gluconeogenesis and ameliorating DM. Moreover, AMPK can regulate glucose transporter 4 (GLUT4) and free fatty acids to improve IR. In AD, AMPK can ameliorate abnormal brain energy metabolism, not only by reduces Aß deposition through ß-secretase but also reduces tau hyperphosphorylation through sirtuin 1 (SIRT1) and protein phosphatase 2A (PP2A). Therefore, AMPK is a bridge between DM and AD.

A Comparison of Three-Dimensional Speckle Tracking Echocardiography Parameters in Predicting Left Ventricular Remodeling.

Three-dimensional speckle tracking echocardiography (3D STE) is an emerging noninvasive method for predicting left ventricular remodeling (LVR) after acute myocardial infarction (AMI). Previous studies analyzed the predictive value of 3D STE with traditional models. However, no models that contain comprehensive risk factors were assessed, and there are limited data on the comparison of different 3D STE parameters. In this study, we sought to build a machine learning model for predicting LVR in AMI patients after effective percutaneous coronary intervention (PCI) that contains the majority of the clinical risk factors and compare 3D STE parameters values for LVR prediction. We enrolled 135 first-onset AMI patients (120 males, mean age 54 ± 9 years). All patients went through a 3D STE and a traditional transthoracic echocardiography 24 hours after reperfusion. A second echocardiography was repeated at the three-month follow-up to detect LVR (defined as a 20 percent increase in left ventricular end-diastolic volume). Six models were constructed using 15 risk factors. A receiver operator characteristic curve and four performance measurements were used as evaluation methods. Feature importance was used to compare 3D STE parameters. 26 patients (19.3%) had LVR. Our evaluation showed that RF can best predict LVR with the best AUC of 0.96. 3D GLS was the most valuable 3D STE parameters, followed by GCS, global area strain, and global radial strain (feature importance 0.146, 0.089, 0.087, and 0.069, respectively). To sum up, RF models can accurately predict the LVR after AMI, and 3D GLS was the best 3D STE parameters in predicting the LVR.

Study on laryngopharyngeal and esophageal reflux characteristics using 24-h multichannel intraluminal impedance-pH monitoring in healthy volunteers.

OBJECTIVE: We aimed to analyze the results of 24-h multichannel intraluminal impedance and pH-monitoring (MII-pH) of the laryngopharynx and esophagus in asymptomatic volunteers. Moreover, we also aimed to gain insight into and establish a baseline for laryngopharyngeal reflux in the healthy population by quantitatively and qualitatively comparing the reflux and pH distribution in both the laryngopharynx and the esophagus. METHODS: Healthy volunteers were recruited and observed; they underwent 24-h ambulatory combined MII-pH monitoring. The proximal sensor (pH1) was positioned approximately 1 cm above the upper esophageal sphincter with the aid of a solid-state high-resolution esophageal manometer. Laryngopharyngeal reflux events were detected and characterized by the incidence and property of reflux both in the laryngopharynx and the esophagus. RESULTS: Thirty-eight asymptomatic volunteers who completed all the examinations were included in this study. The median pH detected by the proximal sensor was 6.6 (6.2, 7.0), with an average of 6.58 ± 0.74. A total of 814 laryngopharyngeal reflux events were detected, including 722 (89%) in the upright position and 92 (11%) in the supine position with incidence (0%) in the liquid state, 44 (5%) in the mixture, and 769 (95%) in the gaseous state. Furthermore, 5 incidences (1%) of acid reflux and 809 incidences of non-acid reflux (99%) were noted. A total of 5779 esophageal reflux events were detected, including 5020 (87%) in the upright position, 759 (13%) in the supine position, with 2051 (36%) in the liquid state, 2050 (35%) in the mixed condition, and 1678 (29%) in the gaseous state; adding up to 805 incidences (14%) of acid reflux and 4974 incidences (86%) of non-acid reflux. CONCLUSION: Non-acid reflux in the upright position is characteristic of laryngopharyngeal reflux. Acid reflux is almost undetectable in healthy subjects. Hence, the diagnostic indicators of gastroesophageal reflux disease are not suitable for laryngopharyngeal reflux disease.

Exendin­4 reverses endothelial dysfunction in mice fed a high­cholesterol diet by a GTP cyclohydrolase­1/tetrahydrobiopterin pathway.

The present study examined whether exendin­4 (Ex4) can improve the endothelial dysfunction of apolipoprotein E knockout (APOE­KO) mice fed a high­cholesterol diet and the potential mechanism by which it acts. Genetically wild­type (WT) C57BL/6 mice and APOE­KO mice of C57BL/6 background, were each randomly assigned to receive either Ex4 treatment (Ex4­treated, for 8 weeks) or not (control). The 4 groups were fed the same high­cholesterol diet for 8 weeks. The following were measured at the end of the eighth week: Endothelium­dependent vasodilation of the arteries; plasma nitric oxide (NO) and metabolic index; levels of endothelial NO synthase (eNOS); phosphorylated eNOS (p­eNOS; Ser­1,177); guanosine triphosphate cyclohydrolase­1 (GCH1); and tetrahydrobiopterin (THB). Ex4 treatment was associated with higher p­eNOS levels in the WT group and in the APOE­KO group, and higher vascular expression of GCH1 and higher arterial THB content, compared with baseline values. The results of the present study suggested that Ex4 may exert cardioprotective effects by reversing high­cholesterol diet­induced endothelial dysfunction in APOE­KO mice. The protective mechanism is probably associated with the promotion of the expression levels of GCH1 protein and THB that maintain the normal function of eNOS.

Reflux symptom index and reflux finding score in 91 asymptomatic volunteers.

BACKGROUND: The primary goal of this study was to investigating the symptoms, in addition to the reflux-related laryngopharynx inflammation performance of asymptomatic, volunteers, and verified the 'normal point'. METHODS: A total of 91 asymptomatic subjects were recruited for this cross-sectional study between March 2016 and September 2016. Participants completed the reflux symptom index (RSI) assessment and underwent laryngostroboscopic examination using a rigid endoscope. Their RFS were graded according to the laryngeal findings. The distribution and the relationship of the RSI and the RFS were analyzed. RESULTS: The mean RSI of individuals was 2.24 ± 2.34 [95% confidence interval (CI) = 1.75, 2.72], and the mean RFS of individuals was 5.78 ± 1.74 (95% CI = 5.42, 6.15). The Pearson product-moment correlation coefficient of the RSI and RFS scores was -0.084 (n = 91, p = .428). CONCLUSIONS: Asymptomatic people could present relatively high RFS scores, and no linear relationship existed between RSI and RFS.