Inhibition of Notch signalling has ability to alter the proximal and distal TCR signalling events in human CD3+ αβ T-cells

The Notch signalling pathway is an important regulator of T cell function and is known to regulate the effector functions of T cells driven by T cell receptor (TCR). However, the mechanism integrating these pathways in human CD3⁺ αβ T cells is not well understood. The present study was carried out to investigate how Notch and TCR driven signalling are synchronized in human αβ T cells. Differential expression of Notch receptors, ligands, and target genes is observed on human αβ T cells which are upregulated on stimulation with α-CD3/CD28 mAb. Inhibition of Notch signalling by GSI-X inhibited the activation of T cells and affected proximal T cell signalling by regulating CD3-ζ chain expression. Inhibition of Notch signalling decreased the protein expression of CD3-ζ chain and induced expression of E3 ubiquitin ligase (GRAIL) in human αβ T cells. Apart from affecting proximal TCR signalling, Notch signalling also regulated the distal TCR signalling events. In the absence of Notch signalling, α-CD3/CD28 mAb induced activation and IFN-γ production by αβ T cells was down-modulated. The absence of Notch signalling in human αβ T cells inhibited proliferative responses despite strong signalling through TCR and IL-2 receptor. This study shows how Notch signalling cooperates with TCR signalling by regulating CD3-ζ chain expression to support proliferation and activation of human αβ T cells.     

Subclinical and clinical atherosclerosis in non-alcoholic fatty liver disease is associated with the presence of hypertension

Background and aimsNon-alcoholic fatty liver disease (NAFLD) is associated with increased cardiovascular (CV) risk. However, it is unclear whether NAFLD contributes independently to the development of CV disease. Our study aimed at assessing the differences in several indices of atherosclerosis, arterial stiffness and cardiac morphology among patients with isolated NAFLD, isolated hypertension (HT) or a combination of the two conditions.Methods and resultsA total of 169 participants (mean age = 50.4 ± 10.2 yrs; males = 73.6%) were divided according to the presence of NAFLD and HT into three groups: only NAFLD (55 patients), only HT (49 patients), and NAFLD + HT (65 patients). Exclusion criteria were a BMI≥35 kg/m² and a diagnosis of diabetes mellitus. Carotid ultrasonography was performed to measure markers of atherosclerosis and arterial stiffness. Cardiac remodeling was analyzed using echocardiography. The prevalence of subclinical and overt atherosclerosis was significantly higher in the NAFLD + HT patients as compared to the other two groups (atherosclerotic plaques: 43.1%, 10.9%, and 22.4% (p < 0.001) in NAFLD + HT, NAFLD, and HT groups, respectively). No differences were found among indices of arterial stiffening and cardiac remodeling across the three groups. In multivariate regression analysis, the coexistence of NAFLD and HT was an independent risk factor for overt atherosclerosis (OR = 4.88, CI 95% 1.14–20.93), while no association was found when either NAFLD or HT was considered alone.ConclusionOvert atherosclerosis was significantly present only in NAFLD + HT patients, but not in patients with isolated NAFLD. This implies that the impact of NAFLD on vascular structure and function could depend on the coexistence of other major CV risk factors, such as HT.     

The accuracy of triglyceride-glucose (TyG) index for the screening of metabolic syndrome in adults: A systematic review and meta-analysis

AimsTo investigate the relationship between the triglyceride-glucose (TyG) index, a novel surrogate index of insulin resistance (IR), and metabolic syndrome (MetS) in a systematic review and meta-analysis.Data synthesisStudies that report the TyG index in adult subjects with and without MetS were included. Thirteen observational articles were included in this study, with a total of 49,325 participants. Two different categories of meta-analyses were performed. First, the means of the TyG index were compared in participants with and without MetS. The pooled mean difference (MD) of the TyG index between groups was 0.83 units (CI 95: 0.74–0.92, I2 = 98, P-value < 0.001), and the subgroup analyses showed MD significantly differed based on the MetS diagnostic criteria. The pooled MD were 0.80 units (CI 95: 0.70–0.91, I2 = %88, P-value < 0.001) and 0.82 units (CI 95: 0.79–0.86, I2 = %0, P-value > 0.767) for studies reported data for males and females individual, respectively. Second bivariate diagnostic test accuracy (DTA) meta-analysis was performed and determined that the TyG index's pooled sensitivity and specificity for screening of MetS were 80% (CI95: 75%–84%, I2 = 87%, P-value < 0.001) and 81% (CI95: 77%–84%, I2 = 90.45%, P-value < 0.001), respectively. Summary receiver-operating characteristics (sROC) curves were also plotted with the area under the sROC curve of 0.87 (CI 95: 0.84–0.90).ConclusionsThe TyG index is a sensitive and specific index for MetS and may be valuable for MetS screening.ProsperoCRD42022316209.     

Laparoscopic versus open pancreatoduodenectomy: an individual participant data meta-analysis of randomized controlled trials

BackgroundRandomized trials have compared laparoscopic pancreatoduodenectomy (LPD) to open pancreatoduodenectomy (OPD) with conflicting results. An IPDMA may give more insight into the differences between LPD and OPD, and could identify high-risk subgroups.MethodsA systematic literature search was performed in the Pubmed, Embase, and the Cochrane library databases (October 2019). Out of 1410 studies, three randomized trials were identified. Primary outcome was major complications (Clavien-Dindo grade ≥ III). Subgroup analyses were performed for high-risk subgroups including patients with BMI of ≥25 kg/m2, pancreatic duct <3 mm, age ≥70 years, and malignancy.ResultsData from 224 patients were collected. After LPD, major complications occurred in 33/114 (29%) patients compared to 34/110 (31%) patients after OPD (adjusted odds ratio (OR) 0.62; 95% confidence interval (CI) 0.3–1.4, P = 0.257). No differences were seen for major complications and 90-day mortality LPD 8 (7%) vs OPD 4 (4%) (adjusted OR 0.2; 95% CI 0.02–1.3, P = 0.080). With LPD, operative time was longer (420 vs 318 min, p < 0.001) and hospital stay was shorter (mean difference ?6.97 days). Outcomes remained stable in the high-risk subgroups.ConclusionLPD did not reduce the rate of major postoperative complications as compared to OPD. LPD increased operative time and shortened hospital stay with 7 days.     

Diets high in glycemic index and glycemic load are associated with an increased risk of metabolic syndrome among Korean women

Background and aimsAccurate estimation of the glycemic index (GI) and glycemic load (GL) of diets is essential when assessing health implications of dietary GI and GL. The present study aimed to estimate dietary GI and GL utilizing the updated GI tables with a large number of new, reliable GI values and assess their associations with metabolic syndrome among Korean adults.Methods and resultsWe analyzed data from 3317 men and 6191 women for this cross-sectional study. Dietary intake was assessed with a validated food frequency questionnaire. Metabolic syndrome and its components were defined based on the harmonized criteria with Korean-specific cutoffs for waist circumference. Multivariate logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Compared with women in the lowest quintiles of energy-adjusted dietary GI and GL, women in the highest quintiles had significantly greater risks of metabolic syndrome (GI, OR = 1.56, 95% CI = 1.18–2.06; GL, OR = 1.80, 95% CI = 1.27–2.57), elevated blood pressure, reduced high-density lipoprotein cholesterol (HDL-C, both GI and GL), elevated triglycerides (GI only), elevated waist circumference, and elevated fasting glucose (GL only). Among men, no significant association was noted except for a higher risk of reduced HDL-C (OR = 1.59, 95% CI = 1.01–2.29) in the highest quintile of energy-adjusted dietary GI than in the lowest quintile.ConclusionOur findings suggest that dietary GI and GL are positively associated with metabolic syndrome risk among women, but not men, in Korea.     

The add-on effect of dengzhan shengmai capsules on secondary prevention of ischemic stroke: A multicentre,randomised, placebo-controlled clinical trial

ObjectiveThe Dengzhan Shengmai (DZSM) capsule is a commercially available type of Chinese herbal medicine frequently administered to improve neurological impairment after stroke. Its ability to prevent recurrent stroke, however, has not been determined. This study therefore evaluated the ability of DZSM as an add-on to conventional secondary preventive agents to prevent recurrent ischemic stroke.MethodsIn this randomised, double-blind, placebo-controlled trial, conducted at 83 hospitals in Mainland China, 3143 patients in 14–180 days after the initial onset of ischemic stroke, were randomly allocated to the DZSM (0.36 g, twice daily for 12 months) or the placebo group. All patients in both groups received standard secondary preventive medications. The primary outcome was the 1-year incidence of stroke. Between group differences were assessed using the Cox proportional hazards model.ResultsIntent-to-treat analysis showed that 58 (3.8%) participants in the DZSM group and 82 (5.4%) in the placebo group experienced new stroke events (hazard ratio = 0.70, 95% confidence interval = 0.50–0.98, P = 0.036). The type and incidence of adverse events were similar in the DZSM and placebo groups.ConclusionsThe addition of DZSM capsules to standard secondary preventive agents provides additional benefits after the initial onset of ischemic stroke, reducing recurrent stroke without increasing severe adverse events. However, further study is needed to elucidate the role of DZSM on the updated practice of conventional secondary prevention for ischemic stroke.     

Chicoric acid alleviates lipopolysaccharide-induced acute lung injury in mice through anti-inflammatory and anti-oxidant activities

Acute lung injury (ALI) is a severe clinical disease with high mortality rates. Chicoric acid (CA), an active component extracted from traditional Chinese medicine, was suggested to have anti-inflammatory and anti-oxidant activities. Inflammation and oxidative damage are implicated in the pathogenesis of ALI. In this study, we explored the protection effect of CA on LPS-induced ALI, and further discussed the possible molecular mechanisms. The results showed that CA could significantly improve the histological changes of LPS-induced acute lung injury. In addition, CA not only decreased LPS-stimulated protein leakage and lung wet/dry ratio but also reduced inflammatory cell infiltration, myeloperoxidase (MPO) activity and the generation of pro-inflammatory cytokines in bronchoalveolar lavage fluid (BALF). Meanwhile, CA lessened the reactive oxygen species (ROS) generation, and malondialdehyde (MDA) formation, and decreased glutathione (GSH) and superoxide dismutase (SOD) depletion, which were caused by LPS challenge. Furthermore, CA dramatically inhibited LPS-stimulated MAPK and NLRP3 activation and increased the expression of NAD (P) H: quinone oxidoreductase (NQO1), and dismutase (SOD), glutamate-cysteine ligase catalytic/modifier (GCLC/GCLM) subunit and heme oxygenase-1 (HO-1), as well as its upstream genes nuclear factor-erythroid 2-related factor 2 (Nrf2), which might be central to the protective effects of CA. In conclusion, these data indicated that the protective effects and mechanisms of CA on LPS-induced ALI and provided new insights for its application.     

Antenatal Rh prophylaxis is unnecessary for “Asia type” DEL women

BackgroundGenerally Rh-negative patients need to be transfused with Rh-negative red blood cells. For pregnant women carrying Rh-positive fetus, the antenatal anti-D detection and Rh immunoglobulin prophylaxis are required worldwide. In East Asia, a RhD variant, termed “Asia type” DEL, was found in approximately 30% of apparent Rh-negative individuals. The antigenic and molecular properties of the DEL were previously defined. Few data discuss whether DEL could be immunized by D antigen clinically although DEL was reported arousing alloimmunization to true Rh-negative patients.Study design and methodsTo determine whether the DEL variant can be immunized to the D antigen, we retrospectively evaluated 104 Rh-negative pregnancies with allo-anti-D antibodies, and we also tracked 199 consecutive apparent Rh-negative pregnant women, with a history of gestations or parturitions but not subject to anti-D gamma-globulin prophylaxis, for evidence of allo-anti-D. The DEL variant was first excluded by ccee phenotypes and then identified through PCR analysis or sequencing.ResultsIn the retrospective study, we expected to find 30 DEL variants, yet none of the anti-D alloimmunized women were DEL-positive. And in the second group, none of 44 DEL-positive women versus 38 of 155 (24.5%) true Rh-negative women (those excluding DEL) formed allo-anti-D.ConclusionThe data indicate that the “Asia type” DEL variant does not appear at risk of alloimmunization to the D antigen. It strongly suggests that the antenatal Rh immune globulin prophylaxis is unnecessary for DEL women. Furthermore, it implicates that the “Asia type” DEL may be deemed Rh-positive safely for clinical transfusion therapy.