Effects of exposure to multiple metallic elements in the first trimester of pregnancy on the risk of preterm birth.

Exposure to certain heavy metals has been demonstrated to be associated with a higher risk of preterm birth (PTB). However, studies focused on the effects of other metal mixtures were limited. A nested case‒control study enrolling 94 PTB cases and 282 controls was conducted. Metallic elements were detected in maternal plasma collected in the first trimester using inductively coupled plasma‒mass spectrometry. The effect of maternal exposure on the risk of PTB was investigated using logistic regression, least absolute shrinkage and selection operator, restricted cubic spline (RCS), quantile g computation (QGC) and Bayesian kernel machine regression (BKMR). Vanadium (V) and arsenic (As) were positively associated with PTB risk in the logistic model, and V remains positively associated in the multi-exposure logistic model. QGC analysis determined V (69.42%) and nickel (Ni) (70.30%) as the maximum positive and negative contributors to the PTB risk, respectively. BKMR models further demonstrated a positive relationship between the exposure levels of the mixtures and PTB risk, and V was identified as the most important independent variable among the elements. RCS analysis showed an inverted U-shape effect of V and gestational age, and plasma V more than 2.18 µg/L was considered a risk factor for shortened gestation length. Exposure to metallic elements mixtures consisting of V, As, cobalt, Ni, chromium and manganese in the first trimester was associated with an increased risk of PTB, and V was considered the most important factor in the mixtures in promoting the incidence of PTB.

Structural basis of HLX10 PD-1 receptor recognition, a promising anti-PD-1 antibody clinical candidate for cancer immunotherapy.

Cancer immunotherapies, such as checkpoint blockade of programmed cell death protein-1 (PD-1), represents a breakthrough in cancer treatment, resulting in unprecedented results in terms of overall and progression-free survival. Discovery and development of novel anti PD-1 inhibitors remains a field of intense investigation, where novel monoclonal antibodies (mAbs) and novel antibody formats (e.g., novel isotype, bispecific mAb and low-molecular-weight compounds) are major source of future therapeutic candidates. HLX10, a fully humanized IgG4 monoclonal antibody against PD-1 receptor, increased functional activities of human T-cells and showed in vitro, and anti-tumor activity in several tumor models. The combined inhibition of PD-1/PDL-1 and angiogenesis pathways using anti-VEGF antibody may enhance a sustained suppression of cancer-related angiogenesis and tumor elimination. To elucidate HLX10's mode of action, we solved the structure of HLX10 in complex with PD-1 receptor. Detailed epitope analysis showed that HLX10 has a unique mode of recognition compared to the clinically approved PD1 antibodies Pembrolizumab and Nivolumab. Notably, HLX10's epitope was closer to Pembrolizumab's epitope than Nivolumab's epitope. However, HLX10 and Pembrolizumab showed an opposite heavy chain (HC) and light chain (LC) usage, which recognizes several overlapping amino acid residues on PD-1. We compared HLX10 to Nivolumab and Pembrolizumab and it showed similar or better bioactivity in vitro and in vivo, providing a rationale for clinical evaluation in cancer immunotherapy.

Anxiety and depression-like behaviours are more frequent in aged male mice conceived by ART compared with natural conception.

The number of children born after assisted reproductive technology (ART) is accumulating rapidly, and the health problems of the children are extensively concerned. This study aims to evaluate whether ART procedures alter behaviours in male offspring. Mouse models were utilized to establish three groups of offspring conceived by natural conception (NC), in vitro fertilization and embryo transfer (IVF-ET), and frozen-thawed embryo transfer (IVF-FET), respectively. A battery of behaviour experiments for evaluating anxiety and depression levels, including the open field test (OFT), elevated plus maze (EPM) test, light/dark transition test (L/DTT), tail suspension test (TST), forced swimming test (FST), and sucrose preference test (SPT) was carried out. Aged (18 months old), but not young (3 months old), male offspring in the IVF-ET and IVF-FET groups, compared with those in the NC group, exhibited increased anxiety and depression-like behaviours. The protein expression levels of three neurotrophins in PFC or hippocampus in aged male offspring from the IVF-ET and IVF-FET groups reduced at different extent, in comparison to NC group. RNA sequencing (RNA-Seq) was performed in the hippocampus of 18 months old offspring to further explore the gene expression profile changes in the three groups. KEGG analyses revealed the coexisted pathways, such as PI3K-Akt signalling pathway, which potentially reflected the similarity and divergence in anxiety and depression between the offspring conceived by IVF-ET and IVF-FET. Our research suggested the adverse effects of advanced age on the psychological health of children born after ART should be highlighted in the future.

Diagnosis and surgical treatment of non-lesional temporal lobe epilepsy with unilateral amygdala enlargement.

OBJECTIVE: Exploring the role of amygdala enlargement (AE) in temporal lobe epilepsy (TLE) without ipsilateral mesial temporal sclerosis (MTS) using comprehensive presurgical workup tools including traditional tools, automatically volumetric analysis, high-density EEG (HD-EEG) source imaging (HD-ESI), and stereoelectroencephalography (SEEG). METHODS: Nine patients diagnosed with TLE-AE who underwent resective surgeries encompassing the amygdala were retrospectively studied. HD-ESI was obtained using 256-channel HD-EEG on the individualized head model. For automatic volumetric analysis, 48 matched controls were enrolled. Diagnosis and surgical strategies were based on a comprehensive workup following the anatomo-electro-clinical principle. RESULTS: At post-operative follow-up (average 30.9 months), eight patients had achieved Engel class I and one Engel class II recovery. HD-ESI yielded unifocal source estimates in anterior mesial temporal region in 85.7% of cases. Automatic volumetric analysis showed the AE sides were consistent with the values determined through other preoperative workup tools. Furthermore, the amygdala volume of the affected sides in AE was significantly greater than that of the larger sides in controls (p < 0.001). Meanwhile, the amygdala volume lateral index (LI) of AE was significantly higher than in controls (p < 0.001). SEEG analysis showed that ictal onsets arose from the enlarged amygdala (and hippocampus) in all cases. CONCLUSION: In addition to traditional workup tools, automatic volumetric analysis, HD-ESI on individualized head model, and invasive SEEG can provide evidence of epileptogenicity in TLE-AE. Resective surgical strategies encompassing the amygdala result in better prognosis. In suspected TLE cases, more attention should be focused on detecting enlargement of amygdala which sometimes is "hidden" in "MR-negative" non-MTS cases.

Predictors of Cognitive Impairment After Stroke: A Prospective Stroke Cohort Study.

BACKGROUND: Post-stroke cognitive impairment (PSCI) significantly affects stroke survivors' quality of life and rehabilitation. A risk model identifying cognitive decline at admission would help to improve early detection and management of post-stroke patients. OBJECTIVE: To develop a new clinical risk score for ischemic stroke survivors in predicting 6-12 months PSCI. METHODS: We prospectively enrolled 179 patients diagnosed with acute ischemic stroke within a 7-day onset. Data were analyzed based on baseline demographics, clinical risk factors, and radiological parameters. Logistic regression and area under the receiver operating curve (AUROC) were used to evaluate model efficiency. RESULTS: One hundred forty-five subjects completed a 6-12-month follow-up visit, and 77 patients (53.1%) were diagnosed with PSCI. Age (ß= 0.065, OR = 1.067, 95% CI = 1.016-1.120), years of education (ß= -0.346, OR = 0.707, 95% CI = 0.607-0.824), periventricular hyperintensity grading (ß= 1.253, OR = 3.501, 95% CI = 1.652-7.417), diabetes mellitus (ß= 1.762, OR = 5.825, 95% CI = 2.068-16.412), and the number of acute nonlacunar infarcts (ß= 0.569, OR = 1.766, 95% CI = 1.243-2.510) were independently associated with 6-12 month PSCI, constituting a model with optimal predictive efficiency (AUC = 0.884, 95% CI = 0.832-0.935). CONCLUSIONS: The optimized risk model was effective in screening stroke survivors at high risk of developing 6-12 months PSCI in a simple and pragmatic way. It could be a potential tool to identify patients with a high risk of PSCI at an early stage in clinical practice after further independent external cohort validation.

White Matter Hyperintensities on Brain Magnetic Resonance Imaging in People with Epilepsy: A Hospital-Based Study.

AIMS: We aim to explore whether people with epilepsy have increased white matter hyperintensities (WMHs). METHODS: Eligible patients were categorized into newly diagnosed epilepsy (NE) and chronic epilepsy (CE); the latter were subdivided to those treated with enzyme-inducing antiepileptic drugs (EIAEDs) with or without non-enzyme-inducing antiepileptic drugs (NEIAEDs) and those with NEIAEDs only. WMHs were measured using age-related white matter changes (ARWMC) scale and compared between patients and healthy control group. Higher scores indicate greater WMH changes. The strengths of associations were estimated as incidence rate ratios (IRRs) with 95% confidence interval (CI). RESULTS: A total of 217 patients were included in the analysis, of whom 67 had NE, 45 had CE treated with NEIAEDs, and 105 had CE treated with EIAEDs. Age was positively associated with ARWMC score (IRR per year, 1.03; 95%CI, 1.03-1.04, P < 0.001). Compared with the healthy control group (n = 23), all patient groups had higher ARWMC score (P < 0.05). The difference was greatest in patients receiving EIAEDs (IRR, 2.13; 95%CI, 1.22-3.70, P = 0.007). CONCLUSIONS: WMHs tended to be observed in people with epilepsy, especially in those treated with EIAEDs. People with epilepsy with white matter changes should be evaluated for stroke risk, particularly if they are receiving EIAEDs.

Early Recanalization Postintravenous Thrombolysis in Ischemic Stroke with Large Vessel Occlusion: A Digital Subtraction Angiography Study.

AIMS: We aimed to evaluate early recanalization postintravenous (i.v.) tissue plasminogen activator (t-PA) by digital subtraction angiography (DSA) in acute ischemic stroke (AIS) with large vessel occlusion (LVO). METHODS: We performed baseline CT angiography to identify LVO in AIS. Recanalization pre- and post-intra-arterial therapy (IAT) was categorized to none, partial, and global recanalization (GR). Modified Rankin Scale score ≤2 at 3 months was considered a favorable outcome. RESULTS: Among 1610 patients with AIS, 286 received IV t-PA. Of these, 55 patients with LVO were included. The median time from IV t-PA to DSA was 120 min (interquartile range, 79-152). Recanalization post-IV t-PA was observed in seven patients (12.7%). By occlusion sites, the recanalization rates were as follows: extracranial internal carotid artery 2 of 14 (14.3%); intracranial internal carotid artery 3 of 24 (12.5%); M1 of middle cerebral artery 3 of 39 (7.7%); M2 of middle cerebral artery 1 of 40 (2.5%); vertebral artery 0 of 4; and basilar artery 0 of 7. GR post-IAT was associated with favorable outcomes (odds ratio: 8.6; 95% confidence interval, 1.5-48.0; P = 0.014). CONCLUSION: Early recanalization assessed by DSA post-IV t-PA is rarely observed in acute ischemic stroke patients with LVO.

Pu-erh Tea Extract Attenuates Nicotine-Induced Foam Cell Formation in Primary Cultured Monocytes: An in Vitro Mechanistic Study.

In this study, the mechanisms by which pu-erh tea extract (PETE) attenuates nicotine-induced foam cell formation were investigated. Monocytes were purified from healthy individuals using commercial antibodies coated with magnetic beads. We found that the nicotine-induced (1-10 µM) expression of oxidized low-density lipoprotein receptors (ox-LDLRs) and α9-nAchRs in monocytes was significantly attenuated by 24 h of PETE (10 µg/mL; ∗, p < 0.05) cotreatment. Nicotine (1 µM for 24 h) significantly induced the expression of the surface adhesion molecule ICAM-1 and the monocyte integrin adhesion molecule (CD11b) by human umbilical vein endothelial cells (HUVECs) and triggered monocytes to differentiate into macrophages via interactions with the endothelium. After treatment with nicotine (0.1-10 µM for 24 h), the HUVECs released chemotactic factors (IL-8) to attract monocytes into the tunica intima of the artery, and the monocytes then transformed into foam cells. We demonstrated that PETE treatment (>1 µg/mL for 24 h; ∗, p < 0.05) significantly attenuates nicotine-induced (1 µM) monocyte migration toward HUVECs and foam cell formation. This study suggests that tea components effectively attenuate the initial step (foam cell formation) of nicotine-induced atherosclerosis in circulating monocytes.

Anti-AMPA receptor encephalitis associated with thymomatous myasthenia gravis.

No thymomatous myasthenia gravis (TMG) has been reported in patients with anti-α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor encephalitis (AMPAR-E). We described clinical presentation and autoimmune profile of the first case with both AMPAR-E and TMG. Clinical information was obtained from original medical records. Antibodies against AMPAR and confounding antigens were examined on transfected human embryonic kidney 293 cells by the indirect immunofluorescence method. In this case, anti-AMPAR antibodies and anti-acetylcholine receptor (AchR) antibodies were both positive and could explain the encephalitis and MG respectively. This report also indicated the complexity of autoimmunity network associated with thymoma. However, the relationships between thymoma, MG and AMPAR-E remained unclear.