Prevalence, factors and early outcomes of frailty among hospitalized older patients with valvular heart disease: A prospective observational cohort study.

AIM: The aim was to investigate the prevalence of, and factors related to frailty, together with early clinical outcomes, in hospitalized older patients with valvular heart disease (VHD) in China. DESIGN: A prospective observational cohort study was conducted. METHODS: A validated prospective survey was conducted to assess the prevalence of frailty, factors associated with it, and early clinical outcomes in hospitalized older patients with VHD, utilizing Fried's criterion. A total of 207 consecutive participants aged 65 years and older who underwent cardiac surgery were included in the study, spanning from September 2021 to December 2021. RESULTS: Frailty was detected in 78 patients (37.7%). Patients with multimorbidity, a New York Heart Association (NYHA) class of III/IV, or masticatory dysfunction had a greater incidence of frailty (p < 0.05). Patients with a normal albumin level and a higher frequency of exercise had a lower incidence of frailty (p < 0.05). Patients with frailty had longer hospital and intensive care unit stays and greater hospitalization costs than did those without frailty (p < 0.05). The 30-day adverse event rate of the frail group was also greater (11.5% vs. 3.1%). Therefore, early screening for conditions such as multimorbidity, cardiac dysfunction, and hypoalbuminemia is urgently needed to effectively address frailty, as it has been linked to unfavourable early outcomes. Moreover, promoting exercise and improving masticatory function and nutrition are crucial for preventing and managing frailty in older patients with VHD.

LiOtBu-Promoted Intramolecular 1,3-Dipolar Cycloaddition of the 2'-Alkynyl-biaryl-2-aldehyde N-Tosylhydrazones Approach to 3-Substituted 1H-Dibenzo[e,g]indazoles.

A two-step, one-pot synthesis of 3-substituted 1H-dibenzo[e,g]indazoles in good to high yields via a LiOtBu-promoted intramolecular 1,3-dipolar cyclization of 2'-alkynyl-biaryl-2-aldehyde N-tosylhydrazones was developed. The N-Ts-hydrazones used were prepared in situ via the reactions of 2'-alkynyl-biaryl-2-aldehydes and TsNHNH2(p-methylbenzenesulfonohydrazide). Two types of signals related to the hydrogen bonds, forming in several products, were observed in the 1H NMR spectra recorded in DMSO-d6, assigned to N-H bonds in their dimeric species of product and tautomer.

Clinicopathological and prognostic values of MET expression in pancreatic adenocarcinoma based on bioinformatics analysis.

Pancreatic adenocarcinoma (PAAD) is regarded as one of the most lethiferous cancers worldwide because treatment of pancreatic cancer remains challenging and mostly palliative. Little progress had been made to select certain reliable biomarkers as clinical prognosis. In this context, GSE28735 and GSE16515 were obtained from the Gene Expression Omnibus (GEO). GEO2R tool was used to recognize differentially expressed genes (DEGs). 351 DEGs were screened which included 230 up-regulated genes and 121 down-regulated genes. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to analyze the DEGs and associated signal pathways in the DAVID database. A protein-protein interaction (PPI) network was then constructed to screen 10 hub genes by STRING database and Cityscape software. Analyses of 10 hub genes were performed on GEPIA database and GSCA database, which revealed that MET was high expressed and significantly associated with survival of PAAD patients. Immunohistochemical staining showed that MET was higher expressed in PAAD tissues than adjacent tissues in 20 samples. The clinicopathological analysis revealed that high expression of MET was associated with the degree of differentiation, lymph node metastasis, vascular cancer thrombus and nerve invasion in PAAD tissues (P < .05). Furthermore, the Tumor Immune Estimation Resource (TIMER) database analyzed the correlation between the MET expression level and immune infiltration levels, which elucidated that MET expression was appreciably positively correlated with the infiltration levels of myeloid-derived suppressor cells (MDSCs). Here, these results strongly indicate MET is an unique prognostic biomarker. Its expression level is correlated with certain clinicopathological features and immune cell infiltration.

Serpin Family A Member 1 Is Prognostic and Involved in Immunological Regulation in Human Cancers.

Serpin family A member 1 (SERPINA1) encodes a protease inhibitor participating in many human diseases, but its value in immunoregulation and prognosis of human cancers remains unclear. In this study, through comprehensive analysis of data from The Cancer Genome Atlas (TCGA) datasets, we found that SERPINA1 was dysregulated in many cancers compared with normal tissues. SERPINA1 expression was significantly associated with prognosis, immune subtype, molecular subtype, immune checkpoint (ICP) genes, tumor mutational burden (TMB), microsatellite instability (MSI), and the estimation of stromal and immune cells in malignant tumor tissues using expression data (ESTIMATE) score. There was a strong connection between SERPINA1 expression and tumor-infiltrating lymphocytes, and SERPINA1 showed significant relation to gene markers of immune cells in digestive tumors. Fluorescence-based multiplex immunohistochemistry confirmed that SERPINA1 protein expression was related to clinicopathologic features and immune infiltrates in hepatic cancer. This study suggests that SERPINA can potentially serve as a novel biomarker for cancer prognosis and immunotherapy.

Synthesis of Cyclopenta[c]quinolines by Palladium-Catalyzed Cyclization of 3-Bromoindoles with Internal Alkynes via Spirocyclic Cyclopentadiene Intermediates.

A novel method for the construction of a cyclopenta[c]quinoline ring via cyclization of 3-bromoindoles with internal alkynes in the presence of palladium is described. The formation of the cyclopenta[c]quinoline ring is proposed from a double [1,5] carbon sigmatropic rearrangement of the spirocyclic cyclopentadiene intermediate, which is generated in situ from the cyclization of 3-bromoindoles with internal alkynes involving a sequential double alkyne insertion into the carbon-palladium bond and dearomatization of indole. The present studies have developed a novel ring-expansion reaction of the pyrrole ring to pyridine via one carbon insertion into the C2-C3 bond of indoles and provided a simple and distinct route for the construction of tricyclic fused-quinoline derivatives that are not easy to access with conventional methods.

Copper(I)-Catalyzed Syntheses of Benzo[b]fluorenes by the Cascade Reactions of 2-Alkynylbenzaldehyde N-Tosylhydrazones and Aromatic Terminal Alkynes.

Benzo[b]fluorenes were synthesized via CuI-catalyzed cascade reactions of 2-alkynylbenzaldehyde N-tosylhydrazones and aromatic terminal alkynes in the presence of base including the formation of the benzoenyne-allene intermediate in situ and its Schmittel cyclization. Density functional theory calculation was performed to give the energy difference for the formation of 5-phenyl-11H-benzo[b]fluorene and 1,2-diphenyl-1H-cyclobuta[a]indene from the proposed diradical intermediates.

Effects of Concentrate Levels in Prepartum Diet on Milk Performance, Energy Balance and Rumen Fermentation of Transition Montbéliarde-Holstein Crossbred Cows.

This study was conducted to investigate the effect of three rates of prepartum dietary concentrate feeding on the milk performance, energy balance, and rumen fermentation of Montbéliarde−Holstein crossbred cows. Eighteen transition Montbéliarde−Holstein crossbred cows with similar days of gestation (258 ± 12 day) and body weights (622 ± 44 kg) were selected and randomly divided into three groups. In the prepartum period, the addition of concentrates accounted for 0.3% (low concentrate, LC), 0.6% (medium concentrate, MC), and 0.9% (high concentrate, HC) of the cow's body weight. The forage was corn stover, which was fed to the cows ad libitum with free access to water. Postpartum, all of the cows were fed a common lactation total mixed ration. The experimental period lasted from 21 days prepartum to 28 days postpartum. The energy balance (EB), net energy intake (NEI), and dry matter intake (DMI) of the HC group were greater than those of the other groups (p < 0.05). Likewise, the non-esterified fatty acids (NEFA), ß-hydroxybutyric acid (BHBA), and total bilirubin (TBIL) in the blood of the LC group had significantly higher concentrations than they did in the other groups (p < 0.05). Moreover, the increase in the level of dietary concentrate had no significant effect on the rumen fermentation parameters (p > 0.05), and the total intestinal digestibility of dry matter (DM), crude protein (CP), and ether extract (EE) in the HC group was significantly higher (p < 0.05) than it was in the other groups during the prepartum period. In conclusion, the administration of the MC diet in the prepartum period had no negative effect on the performance and rumen fermentation of postpartum dairy cows and can satisfy the energy needs of prepartum dairy cows. Therefore, under our experimental conditions, the 0.6% prenatal concentrate feeding amount was the most appropriate for Montbéliarde−Holstein crossbred cows.

The specification and function of enteroendocrine cells in Drosophila and mammals: a comparative review.

Enteroendocrine cells (EECs) in both invertebrates and vertebrates derive from intestinal stem cells (ISCs) and are scattered along the digestive tract, where they function in sensing various environmental stimuli and subsequently secrete neurotransmitters or neuropeptides to regulate diverse biological and physiological processes. To fulfill these functions, EECs are specified into multiple subtypes that occupy specific gut regions. With advances in single-cell technology, organoid culture experimental systems, and CRISPR/Cas9-mediated genomic editing, rapid progress has been made toward characterization of EEC subtypes in mammals. Additionally, studies of genetic model organisms-especially Drosophila melanogaster-have also provided insights about the molecular processes underlying EEC specification from ISCs and about the establishment of diverse EEC subtypes. In this review, we compare the regulation of EEC specification and function in mammals and Drosophila, with a focus on EEC subtype characterization, on how internal and external regulators mediate EEC subtype specification, and on how EEC-mediated intra- and interorgan communications affect gastrointestinal physiology and pathology.

Comparison of Ruminal Degradability, Indigestible Neutral Detergent Fiber, and Total-Tract Digestibility of Three Main Crop Straws with Alfalfa Hay and Corn Silage.

Three main crop straws including corn straw (Zea mays, CS), rice straw (Oryza sativa, RS), and wheat straw (Triticum aestivum, WS), and two forages including alfalfa hay (Medicago sativa, AH) and corn silage (Zea mays, CSil) were analyzed in order to compare their ruminal degradability, indigestible neutral detergent fiber (iNDF), intestinal digestibility (ID), and their total-tract digestibility (TTD) of crude protein (CP), neutral detergent fiber (NDF), and acid detergent fiber (ADF) using both an in situ nylon bag technique and a mobile nylon bag technique. The forage samples were incubated in the rumen for 6, 12, 16, 24, 36, 48, 72, and 288 h, respectively, to determine their ruminal degradability. Prior to intestinal incubation, forage samples were incubated in the rumen for 12 h and 24 h to determine the ruminal degradable content of CP, NDF, and ADF, respectively, and for 288 h to determine their iNDF288 content. Residues from the ruminal undegradable fractions (12 h for CP, 24 h for NDF and ADF) were subsequently inserted into the duodenum through a cannula to determine their intestinal digestible content. Here, the TTD of CP, NDF, and ADF were determined as the ruminal degradable content + intestinal digestible content. The results showed that AH had the highest iNDF2.4 (calculated as acid detergent lignin content × 2.4) and iNDF288 values (379.42 and 473.40 g/kg of NDF), while CS and CSil had the lowest iNDF2.4 values (177.44 and 179.43 g/kg of NDF). The ruminal degradability of CP, NDF, and ADF for CS, RS, and WS were lower than those of AH and Csil during the first 48 h of incubation. The potential degradation fraction of CP, NDF, and ADF for CSil was the highest; CS, RS, and WS were intermediate; and AH was the lowest (p < 0.05). CS, RS, and WS had a lower intestinal digestibility with respect to their rumen undegradable content of NDF (p < 0.05), and lower TTD of CP, NDF, and ADF (p < 0.05) compared to AH and CSil. General regression equations with satisfactory accuracy (R2 ≥ 0.828) were derived to predict iNDF288 and TTD based on their chemical compositions and the ruminal degradation kinetics of different forages. Incorporating this information into rations could improve our ability to optimize main crop straws utilization and milk production.

Effects of Paper Mulberry Silage on the Milk Production, Apparent Digestibility, Antioxidant Capacity, and Fecal Bacteria Composition in Holstein Dairy Cows.

Paper mulberry (Broussonetia papyrifera; PM) is an excellent and extensive type of roughage in Asia. This study aimed to evaluate the effects of PM silage on the milk production, apparent digestibility, antioxidant capacity, and fecal bacteria composition in Holstein dairy cows. Forty-five lactating Holstein dairy cows with a similar milk yield and parity were selected and randomly assigned to three groups. The control group was fed a non-PM silage diet, and the PM-treated groups were fed 4.5 and 9.0% PM silage supplementary diets for 28 days. Then, treatment groups were fed diets containing 13.5 and 18.0% PM silage for the next 28 days, respectively. PM silage increased the milk urea nitrogen and decreased the somatic cell count (p < 0.05), but did not affect the dry matter intake, milk yield, apparent digestibility, and energy balance of dairy cows. PM silage can enhance the blood total antioxidant capacity, superoxide dismutase, and immune globulin content (p < 0.05). The PM silage significantly decreased the relative abundance of the genera Ruminococcaceae UCG-013 and Tyzzerella-4 (p < 0.05). In conclusion, PM silage enhanced the antioxidant capacity and immunity of dairy cows, but did not influence the milk yield, dry matter digestibility, and fecal bacteria composition.

The Drosophila Ortholog of Mammalian Transcription Factor Sox9 Regulates Intestinal Homeostasis and Regeneration at an Appropriate Level.

Balanced stem cell self-renewal and differentiation is essential for maintaining tissue homeostasis, but the underlying mechanisms are poorly understood. Here, we identified the transcription factor SRY-related HMG-box (Sox) 100B, which is orthologous to mammalian Sox8/9/10, as a common target and central mediator of the EGFR/Ras and JAK/STAT signaling pathways that coordinates intestinal stem cell (ISC) proliferation and differentiation during both normal epithelial homeostasis and stress-induced intestinal repair in Drosophila. The two stress-responsive pathways directly regulate Sox100B transcription via two separate enhancers. Interestingly, an appropriate level of Sox100B is critical for its function, as its depletion inhibits ISC proliferation via cell cycle arrest, while its overexpression also inhibits ISC proliferation by directly suppressing EGFR expression and additionally promotes ISC differentiation by activating a differentiation-promoting regulatory circuitry composed of Sox100B, Sox21a, and Pdm1. Thus, our study reveals a Sox family transcription factor that functions as a stress-responsive signaling nexus that ultimately controls tissue homeostasis and regeneration.

Base-Promoted SNAr Reactions of Fluoro- and Chloroarenes as a Route to N-Aryl Indoles and Carbazoles.

KOH/DMSO-promoted C-N bond formation via nucleophilic aromatic substitution (SNAr) between chloroarenes or fluoroarenes with indoles and carbazole under transition metal-free conditions affording the corresponding N-arylated indoles and carbazoles has been developed.

Genotoxicity of a Low-Dose Nitrosamine Mixture as Drinking Water Disinfection Byproducts in NIH3T3 Cells.

N-nitrosamines (NAms), which can arise as byproducts of disinfection agents, are reportedly found in drinking water, and their potential carcinogenicity is a concern; however, little research exists regarding the genotoxicity or carcinogenicity of NAms exposure as a low-dose mixture. The three most common NAms components in China's drinking water are N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA) and N-nitrosomethylethylamine (NMEA). Thus, we measured the genotoxic and carcinogenic potential of these compounds and measured the cell cycle and gene expression. The data show that exposure to the NAms-mixture doubled the revertants in the TA98 and TA100 S. typhimurium strains and increased the DNA double-strand breaks and the micronuclear frequency in the NIH3T3 cells compared to a single exposure. After long-term NAms mixture exposure, a malignant transformation of NIH3T3 and a significantly increased G2/M distribution were observed. Furthermore, P53, CDK1, P38, CDC25A and CyclinB expressions were down-regulated in the NAms-mixture exposure group; however, P21 and GADD45A genes were up-regulated. Interestingly, the CHK1/CHK2 and CDC25A genes had two responses, depending on the NAms concentrations. Thus, we observed mutagenic, genotoxic and carcinogenic effects after a low-dose NAms-mixture exposure in drinking water, and DNA repair and apoptosis pathways may contribute to these adverse effects.

Study of GABA in Healthy Volunteers: Pharmacokinetics and Pharmacodynamics.

Preclinical studies show that GABA exerts anti-diabetic effects in rodent models of type 1 diabetes. Because little is known about its absorption and effects in humans, we investigated the pharmacokinetics and pharmacodynamics of GABA in healthy volunteers. Twelve subjects were subjected to an open-labeled, three-period trial involving sequential oral administration of placebo, 2 g GABA once, and 2 g GABA three times/day for 7 days, with a 7-day washout between each period. GABA was rapidly absorbed (Tmax: 0.5 ~ 1 h) with the half-life (t1/2) of 5 h. No accumulation was observed after repeated oral GABA administration for 7 days. Remarkably, GABA significantly increased circulating insulin levels in the subjects under either fasting (1.6-fold, single dose; 2.0-fold, repeated dose; p < 0.01) or fed conditions (1.4-fold, single dose; 1.6-fold, repeated dose; p < 0.01). GABA also increased glucagon levels only under fasting conditions (1.3-fold, single dose, p < 0.05; 1.5-fold, repeated dose, p < 0.01). However, there were no significant differences in the insulin-to-glucagon ratio and no significant change in glucose levels in these healthy subjects during the study period. Importantly, GABA significantly decreased glycated albumin levels in the repeated dosing period. Subjects with repeated dosing showed an elevated incidence of minor adverse events in comparison to placebo or the single dosing period, most notably transient discomforts such as dizziness and sore throat. However, there were no serious adverse events observed throughout the study. Our data show that GABA is rapidly absorbed and tolerated in human beings; its endocrine effects, exemplified by increasing islet hormonal secretion, suggest potential therapeutic benefits for diabetes.