ObjectiveBased on the ultrastructure of enteric nervous system （ENS）-platelet-derived growth factor receptor α positive （PDGFRα⁺） cell - smooth muscle cell （SMC） network， the effect and mechanism of Shuwei Decoction （舒胃汤） for rats with functional dyspepsia （FD） of liver-depression and spleen-deficiency syndrome were explored. MethodsFifty SD rats were divided into blank group， model group， low-， medium- and high-dose Shuwei Decoction groups randomly， with 10 rats in each group. The blank group was not set up， and the other 4 groups were set up with the modified composite cause （chronic restraint stress + tail irritation + excessive fatigue + diet disorder） for 21 days， resulting in FD model rats with liver-depression and spleen-deficiency syndrome. After successful modelling， rats in the low-， medium- and high-dose groups were given 3.78， 7.56 and 15.12 g/（kg·d） of Shuwei Decoction by gavage， respectively， while rats in the blank group and the model group were given 10 ml/（kg·d） of saline by gavage； all of them were given gavage once a day for 14 days. Body mass increase were collected before and after gavage， and compared after the experiment； the elevated cross maze experiment was conducted to observe the percentage of staying time and the percentage of times entering the open arm of rats； the gastric emptying rate and small intestinal propulsion rate were measured by black semi-solid paste； HE staining was used to observe histopathology of the gastric antrum； the Western Blotting and RT-qPCR were used to detect the expression levels of PDGFRα， small conductance calcium activated potassium （SK3）， and purinergic G protein-coupled receptor P2Y1 （P2Y1 R）， and mRNA expression in gastric antrum； immunofluorescence double staining was used to detect the co-localization of PDGFRα with receptor tyrosine kinase （C-kit）， protein gene product 9.5 （PGP9.5）， Sk3， and smooth muscle cells （SMCs） in gastric sinusoidal tissues； and transmission electron microscopy was used to observe the ultrastructure of the ENS-PDGFRα⁺ cell-SMC network. ResultsHE staining results showed that the mucosal folds of gastric tissue were clear in all groups， no organic lesions such as bleeding， ulceration and swelling were observed， and the arrangement of gastric glands in the lamina propria of gastric sinusoidal tissues in model group and low-dose Shuwei Decoction group was disordered. The arrangement of gastric glands in lamina propria in medium- and high-dose Shuwei Decoction groups was more orderly， and the lesion degree was less than that in model group and low-dose Shuwei Decoction group. Compared with the blank group， the growth value of body mass， the percentage of open arm retention time， the percentage of times entering the open arm， the small intestine propulsion rate， and the gastric empty rate of rats in the model group significantly decreased after gavage； the expressions of PDGFRα， Sk3， P2Y1 protein and mRNA in gastric sinusoidal tissues decreased； the co-localization expression of PDGFRα with C-kit， Sk3， SMC and PGP9.5 significantly decreased （P＜0.05 or P＜0.01）； the ultrastructure of ENS-PDGFRα⁺ cell-SMC network was damaged without gap junction. Compared with model group and low-dose Shuwei Decoction group， the growth value of body mass， the percentage of open arm retention time， the percentage of times entering the open arm， the small intestine propulsion rate， and the gastric empting rate of rats in medium- and high-dose Shuwei Decoction groups increased after gavage； the expressions of PDGFRα， Sk3， P2Y1 protein and mRNA in gastric sinusoidal tissues increased； the co-localization expression of PDGFRα with C-kit， Sk3， SMC and PGP9.5 significantly increased （P＜0.05 or P＜0.01）； the ultrastructure of ENS-PDGFRα⁺ cell-SMC network was intact. Compared with medium-dose Shuwei Decoction group， the protein expressions of PDGFRα， Sk3 and P2Y1， the mRNA expressions of PDGFRα and Sk3， and the co-localization expressions of PDGFRα and C-kit， Sk3， SMC， and PGP9.5 in high-dose Shuwei Decoction group increased （P＜0.05 or P＜0.01）. ConclusionShuwei Decoction can improve the pathological lesion of the gastric antrum in the FD model rats with liver-depression and spleen-deficiency syndrome and increase the gastric emptying rate as well as the small intestinal propusion rate. The mechanism of Shuwei Decoction on FD rats with liver-depression and spleen-deficiency syndrome is related to the protection of the ultrastructural integrity of ENS-PDGFRα⁺ cell-SMC network.

Objective To investigate how maternal MTR gene polymorphisms and their interactions with periconceptional folic acid supplementation are associated with the incidence of ventricular septal defects(VSD)in offspring.Methods A case-control study was conducted,recruiting 426 mothers of infants with VSD under one year old and 740 mothers of age-matched healthy infants.A questionnaire survey collected data on maternal exposures,and blood samples were analyzed for genetic polymorphisms.Multivariable logistic regression analysis and inverse probability of treatment weighting were used to analyze the associations between genetic loci and VSD.Crossover analysis and logistic regression were utilized to examine the additive and multiplicative interactions between the loci and folic acid intake.Results The CT and TT genotypes of the maternal MTR gene at rs6668344 increased the susceptibility of offspring to VSD(P<0.05).The GC and CC genotypes at rs3768139,AG and GG at rs1050993,AT and TT at rs4659743,GG at rs3768142,and GT and TT at rs3820571 were associated with a decreased risk of VSD(P<0.05).The variations at rs6668344 demonstrated an antagonistic multiplicative interaction with folic acid supplementation in relation to VSD(P<0.05).Conclusions Maternal MTR gene polymorphisms significantly correlate with the incidence of VSD in offspring.Mothers with variations at rs6668344 can decrease the susceptibility to VSD in their offspring by supplementing with folic acid during the periconceptional period,suggesting the importance of periconceptional folic acid supplementation in genetically at-risk populations to prevent VSD in offspring.

Objective To explore the associations of parental smoking and alcohol consumption during the periconceptional period and their interactions with risk of congenital heart disease(CHD)in offspring.Methods The parents of children with simple CHD aged 0 to 1 year(n=683)were recruited as the case group,while the parents of healthy children aged 0 to 1 year(n=740)served as the control group.A case-control study was conducted,and a questionnaire was used to collect information on perinatal exposures.After controlling for relevant confounding factors using multivariate logistic regression analysis and propensity score matching,the associations of parental smoking and alcohol consumption during the periconceptional period and their interactions with CHD were examined,as well as the cumulative effects of smoking and drinking on CHD risk.Results Maternal active smoking(OR=2.91,95%CI:1.60-5.30),passive smoking(OR=1.94,95%CI:1.56-2.42),and alcohol consumption(OR=2.59,95%CI:1.89-3.54),as well as paternal smoking(OR=1.52;95%CI:1.22-1.90)and drinking(OR=1.48,95%CI:1.19-1.84),were associated with an increased risk of CHD in offspring.There was no interaction between parental smoking and drinking behaviors during the periconceptional period concerning the risk of CHD in offspring(P>0.05).The more parents'smoking and drinking behaviors during the perinatal pregnancy,the higher the risk of CHD in their offspring(OR=1.50,95%CI:1.36-1.65).Conclusions Parental smoking and alcohol consumption during the periconceptional period are associated with the occurrence of CHD in offspring,and there is a cumulative effect on CHD risk,suggesting that reducing tobacco and alcohol exposure during the periconceptional period may lower the incidence of CHD.

Aim To investigate the dynamic changes of neuronal cells at different time points following acute cerebral ischemia-reperfusion injury by establishing a model of brain ischemia-reperfusion injury.Methods Thirty male Sprague-Dawley(SD)rats were ran-domly divided into six groups:sham group and cere-bral ischemia-reperfusion injury(IR)groups at differ-ent time points.Focal cerebral ischemia-reperfusion injury model was established using the middle cerebral artery occlusion(MCAO)technique.The Longa sco-ring method was used to assess neurobehavioral scores in rats.After successful model preparation,routine paraffin sections were made,and TUNEL staining and immunohistochemistry staining with NeuN antibody were performed to observe cell apoptosis and neuronal cell survival,respectively.Immunohistochemistry stai-ning was also performed to investigate the changes in glial fibrillary acidic protein(GFAP)as a marker for astrocytes,ionized calcium-binding adapter molecule 1(IBA-1)as a marker for microglia,and CD31 as a marker for endothelial cells at different time points.Results No significant changes were observed in neu-ronal cells of the sham group at different time points.In the cerebral ischemia-reperfusion injury groups,cell apoptosis was activated at IR3h and increased in quan-tity with morphological damage as time progressed.Ne-uN+neurons showed signs of ischemic injury after IR3h,with abnormal cell morphology.From 12 h,Ne-uN+neurons decreased in a time-dependent manner and reached their peak severity at 24 h.GFAP+astro-cytes decreased significantly after IR3h,while poorly labeled GFAP+astrocytes increased at IR 6 h and al-most disappeared in the infarcted area at 24 h and 48 h.The number of IBA-1+microglia-positive cells de-creased at IR3h,and their volume increased at IR6h.Microglial cell death was observed in the infarcted area at IR12h.CD31+endothelial cells around the infarc-ted cortex and striatum increased significantly after IR3h and persisted until 48 h.Conclusions After cerebral ischemia-reperfusion injury,the number of ap-optotic cells increases with the prolongation of time,and NeuN+neurons exhibit the most severe damage at 24 h.GFAP+astrocytes and microglial cells gradually die over time.The number of CD31+endothelial cells increases significantly around the infarcted cortex and striatum after 3 h of reperfusion and persists until 48 h.

This study aimed to evaluate the cost-effectiveness of Chaiyin Granules compared with Oseltamivir Phosphate Capsules in the treatment of influenza(exogenous wind-heat syndrome). Based on a randomized, double-blind, positive drug parallel control clinical trial, this study evaluated the pharmacoeconomics of Chaiyin Granules with cost-effectiveness analysis method. A total of 116 patients with influenza from eight hospitals(grade Ⅱ level A above) in 6 cities were selected in this study, including 78 cases in the experimental group with Chaiyin Granules and Oseltamivir Phosphate Capsules placebo, and 38 cases in the control group with Oseltamivir Phosphate Capsules and Chaiyin Granules placebo. The total cost of this study included direct medical cost, direct non-medical cost, and indirect cost. The remission time of clinical symptoms, cure time/cure rate, antipyretic onset time/complete antipyretic time, viral nucleic acid negative rate, and traditional Chinese medicine(TCM) syndrome curative effect were selected as the effect indicators for cost-effectiveness analysis. Four-quadrant diagram was used to estimate the incremental cost-effectiveness ratio. The results showed that Chaiyin Granules were not inferior to Oseltamivir Phosphate Capsules in the remission time of clinical symptoms of influenza(3.1 d vs 2.9 d, P=0.360, non-inferiority margin was 0.5 d). Compared with Oseltamivir Phosphate Capsules, Chaiyin Granules would delay the remission time of clinic symptoms of influenza for 1 d, but could save 213.9 yuan. 1 d delay in cure time could save 149.3 yuan; 1% reduction in the cure rate could save 8.2 yuan; 1 d delay in antipyretic onset time could save 295.4 yuan; 1 d delay in complete antipyretic time could save 114.3 yuan; 1% reduction in the 5-day cure rate of TCM syndrome could save 19.2 yuan. Different from other indicators, there was no statistically significant difference between two groups in the effect of negative conversion rate of viral nucleic acid, but the cost was lower and the effect was superior, and the pharmacoeconomics was not different from that of Oseltamivir Phosphate Capsules in the field of influenza treatment.
Humans ; Antipyretics/therapeutic use* ; Antiviral Agents/therapeutic use* ; Cost-Effectiveness Analysis ; Influenza, Human/drug therapy* ; Nucleic Acids/therapeutic use* ; Oseltamivir/therapeutic use* ; Phosphates/therapeutic use* ; Treatment Outcome ; Double-Blind Method

We wished to establish an expert consensus on late stage of critical care (CC) management. The panel comprised 13 experts in CC medicine. Each statement was assessed based on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) principle. Then, the Delphi method was adopted by 17 experts to reassess the following 28 statements. (1) ESCAPE has evolved from a strategy of delirium management to a strategy of late stage of CC management. (2) The new version of ESCAPE is a strategy for optimizing treatment and comprehensive care of critically ill patients (CIPs) after the rescue period, including early mobilization, early rehabilitation, nutritional support, sleep management, mental assessment, cognitive-function training, emotional support, and optimizing sedation and analgesia. (3) Disease assessment to determine the starting point of early mobilization, early rehabilitation, and early enteral nutrition. (4) Early mobilization has synergistic effects upon the recovery of organ function. (5) Early functional exercise and rehabilitation are important means to promote CIP recovery, and gives them a sense of future prospects. (6) Timely start of enteral nutrition is conducive to early mobilization and early rehabilitation. (7) The spontaneous breathing test should be started as soon as possible, and a weaning plan should be selected step-by-step. (8) The waking process of CIPs should be realized in a planned and purposeful way. (9) Establishment of a sleep-wake rhythm is the key to sleep management in post-CC management. (10) The spontaneous awakening trial, spontaneous breathing trial, and sleep management should be carried out together. (11) The depth of sedation should be adjusted dynamically in the late stage of CC period. (12) Standardized sedation assessment is the premise of rational sedation. (13) Appropriate sedative drugs should be selected according to the objectives of sedation and drug characteristics. (14) A goal-directed minimization strategy for sedation should be implemented. (15) The principle of analgesia must be mastered first. (16) Subjective assessment is preferred for analgesia assessment. (17) Opioid-based analgesic strategies should be selected step-by-step according to the characteristics of different drugs. (18) There must be rational use of non-opioid analgesics and non-drug-based analgesic measures. (19) Pay attention to evaluation of the psychological status of CIPs. (20) Cognitive function in CIPs cannot be ignored. (21) Delirium management should be based on non-drug-based measures and rational use of drugs. (22) Reset treatment can be considered for severe delirium. (23) Psychological assessment should be conducted as early as possible to screen-out high-risk groups with post-traumatic stress disorder. (24) Emotional support, flexible visiting, and environment management are important components of humanistic management in the intensive care unit (ICU). (25) Emotional support from medical teams and families should be promoted through"ICU diaries"and other forms. (26) Environmental management should be carried out by enriching environmental content, limiting environmental interference, and optimizing the environmental atmosphere. (27) Reasonable promotion of flexible visitation should be done on the basis of prevention of nosocomial infection. (28) ESCAPE is an excellent project for late stage of CC management.
Humans ; Consensus ; Critical Care/methods* ; Intensive Care Units ; Pain/drug therapy* ; Analgesics/therapeutic use* ; Delirium/therapy* ; Critical Illness

Objective: To investigate the effect of CD33-targeted bi-specific and tri-specific T-cell engagers on T-cell proliferation and explore their cytotoxicity on leukemia cells. Methods: The CD33-targeted bi-specific T-cell engager (CD33-BiTE) and tri-specific T-cell engager (CD33-TriTE) expression vectors were successfully constructed and expressed through a eukaryotic cell expression system. CD33-BiTE and CD33-TriTE were purified by affinity chromatography. The effects of CD33-BiTE and CD33-TriTE on T cells were analyzed through in vitro experiments. Results: ① CD33-BiTE and CD33-TriTE were successfully constructed and purified and could compete with flow cytometry antibodies for binding to the target cells. ② After 12 days of co-culture with CD33-BiTE and CD33-TriTE, the number of human T cells were expanded to 33.89±19.46 and 81.56±23.62 folds, respectively. CD33-TriTE induced a stronger proliferation of T cells than CD33-BiTE (P<0.05) . ③ Both CD33-BiTE and CD33-TriTE induced specific dose-dependent cytotoxicity on CD33(+) leukemia cells. ④ Compared to CD33-TriTE, leukemia cells were prone to express PD-L1 when co-cultured with T cells and CD33-BiTE. CD33-TriTE induced powerful cytotoxicity on leukemia cells with high PD-L1 expression. Conclusion: CD33-BiTE and CD33-TriTE expression vectors were constructed, and fusion proteins were expressed in eukaryotic cells. Our results support the proliferative and activating effects of BiTE and TriTE on T cells. Compared to that of CD33-BiTE, CD33-TriTE induced a stronger proliferative effect on T cells and a more powerful cytotoxicity on leukemia cells with high PD-L1 expression.
B7-H1 Antigen/pharmacology* ; Humans ; Leukemia, Myeloid, Acute/metabolism* ; Sialic Acid Binding Ig-like Lectin 3/pharmacology* ; T-Lymphocytes

Objective To investigate the effects of CTNND2 knockout on cerebellar neuronal development and motor function in mice, as well as its possible mechanisms. Methods The mice were divided into two groups (n = 10 in each group), all of them were 7 weeks old : wild-type (WT) C57BL/6J mice were treated as control group, and homozygous of CTNND2 knockout (CTNND2 7) mice were treated as experimental group, the genotype of CTNND2 7 mice were detected with PCR. The motor function of two groups were detected by beam walking test, hanging wire test and gait analysis test. The changes of cerebellar Purkinje cells were detected by immunofluorescence staining and Golgi staining. Western blotting was performed to detect the expression levels of synapse-associated proteins phosphorylated synapsin 1 (p-Synl), synapsin 1 (Synl), ELKS and postsynaptic density protein 95(PSD95), as well as phosphoinositide 3-kinase (PI3K), phosphorylated protein kinase B (p-Akt), protein kinase B (Akt), phosphorylated mammalian target of rapamycin (p-mTOR) and mammalian target of rapamycin (mTOR). Results Compared with the WT mice, except the increase in time to traverse the beam, there was a decrease in the proportion of pass on the beam, or latency to fall from the hanging wire, or score of hanging wire, or fore-stride length and hind-stride length of CTNND2 7 mice. There was also a decrease in numbers of Purkinje cells and its dendritic arborization in cerebellum of CTNND2 7 mice. The ratio of p-Synl/ Synl, p-Akt/Akt and p-mTOR/mTOR, as well as the expression levels of ELKS, PSD95 and PI3K were lower than those of WT mice. Conclusion CTNND2 knockout can affect the number and dendritic architecture of Purkinje cells, as well as synthesis of synapse-associated proteins in cerebellum by down-regulating PI3K/Akt/mT0R signaling pathway, resulting in cerebellar developmental disorder, thereby affecting motor function of mice.

Objective To explore the relationship between sleep duration and different ischemic stroke (IS) subtypes. Methods Participants in the study were recruited from rural communities in Beijing. The survey questionnaires, physical examination and biochemical tests were performed. Sleep duration was categorized into 5 groups, namely ≤5 hours/day, 6 hours/day (5.5-6.5 h/d), 7 hours/day (6.5-7.5 h/d), 8 hours/day (7.5-8.5 h/d) and ≥9 hours/day(≥8.5 h/d). Classification of ischemic stroke was based on Trial of org 10172 in acute stroke treatment(TOAST)classification. Logistic models were used to evaluate the associations between sleep duration and different IS subtypes. Results A total of 6 370 participants were recruited. The average age was (58.34±9.37) years old. Logistic regression analysis showed that after adjusting for age, sex, behavioral lifestyle, socioeconomic status and health status, compared to subjects with 7 hours/day, subjects with sleep duration ≤5 hours/day was significantly associated with increased risk of IS (OR=1.75, 95% CI: 1.42-2.15, P<0.001), large-artery atherosclerosis (OR=1.98, 95% CI:1.46-2.70, P<0.001), small-artery occlusion lacunar (OR=5.73, 95% CI:3.34-9.83, P<0.001) and stroke of undetermined etiology (OR=4.43, 95% CI:1.86-10.53, P=0.001). Subjects with sleep duration 8 hours/day and ≥9 hours/day was only found to be significantly associated with IS and large-artery atherosclerosis (P<0.05). Conclusions Short sleep duration is associated with increased risk of IS, large-artery atherosclerosis, small-artery occlusion lacunar and stroke of undetermined etiology. But long sleep duration is only associated with increased risk of IS and large-artery atherosclerosis.

Objective The aim of this study was to investigate associations of overall obesity (OO) and abdominal obesity (AO) with brachial-ankle pulse wave velocity (baPWV) among type 2 diabetes(T2DM) patients. Methods A community-based study for T2DM patients was conducted in rural communities in Beijing．Every patient completed a questionnaire to collect demography, lifestyle and diseases history, and underwent physical examinations, baPWV assessments and blood biochemical tests. Multivariate linear regression was used to assess the relationship between obesity index and baPWV. Abnormal baPWV was defined as patients with baPWV≥1,700 cm/s. Logistic regression model was performed to explore the risk of abnormal baPWV after adjusting for poetential confounders step by step. Results A total of 2 048 T2DM patients were recruited. The average age was (59.2±8.3) years and total prevalence of abnormal baPWV was 49.7%. After multivariable adjustment, linear regression showed that there was a negative correlation between body mass index(BMI) and baPWV and a positive correlation between waist-to-hip ratio (WHR) and baPWV. Compared to normal weight group, those with BMI≥28 kg/m2 had lower risk of abnormal baPWV (OR=0.59, 95% CI: 0.44-0.78，P<0.001), but there was an increased risk of 46% among patients with obesity in WHR (OR=1.46, 95% CI:1.07-2.00，P=0.018). Compared to those without OO and AO, patients without OO but with AO had a 1.67-fold increasesd risk of abnormal baPWV (OR=1.67, 95% CI: 1.19-2.35，P=0.003). Conclusions Abdominal obesity is related with arterial stiffnening among T2DM patients, and it is critical to evaluate arterial stiffness of T2DM patients with abdmonal obesity and normal BMI in order to reduce future risk of cardiovascular diseases.