ObjectiveTo dynamically observe and evaluate the damage to the pulmonary air-blood barrier in mice during the inflammatory cancer transformation process of ulcerative colitis （UC） based on the "lung-intestine correlation" theory. MethodsSixty-five C57BL/6 mice were divided into a normal group （n=25） and a model group （n=40） using a random number table. Azoxymethane/dextran sodium sulfate （DSS） method was used to establish a mouse model of UC inflammation cancer transformation in the modeling group. According to the tissue collection time points at 5， 8， 11， 13， and 15 weeks， the normal group mice were randomly divided into the normal 5w， 8w， 11w， 13w， and 15w groups. The model group mice， 10 mice of which died after the first cycle of DSS administration， were randomly divided into model 5w， 8w， 11w， 13w， and 15w groups. During the experiment， the general condition of the mice was observed daily， and their body weight was measured weekly. At the corresponding tissue collection time points， the colon length of each group was measured. Histopathology of mouse lung and colon tissues was examined using HE staining. Immunofluorescence was used to detect changes in the positive expression of tight junction protein （ZO-1）， vascular endothelial cadherin （VE-cadherin）， and cytoskeletal protein （F-actin） in lung and colon tissues. RT-PCR was used to detect the mRNA expression of apoptosis regulatory proteins B-cell lymphoma-2 （Bcl-2）， BCL2-associated X protein （Bax）， and Cysteine aspartic acid protease-3 （Caspase-3） in lung tissues. Western Blot was employed to measure protein levels of ZO-1， VE-cadherin， and F-actin in lung tissues. ResultsCompared to the normal group at the same time point， the mice in the model group at each time point generally had poorer conditions， with weight loss and shortened colon length （P＜0.05 or P＜0.01）. In the model 5w group， there was significant inflammatory cell infiltration in the colon tissue； in the model 8w group， there was mild atypical hyperplasia； in the model 11w group， the crypt structure was disordered， and moderate to severe atypical hyperplasia occurred； in the model 13w and 15w groups， tumors appeared. Pulmonary interstitial lesions， inflammation， vasculitis， and fibrosis were observed at all stages of UC inflammation cancer transformation. The protein levels of ZO-1， VE-cadherin， and F-actin， as well as Bcl-2 mRNA expression in lung tissue decreased during the acute inflammatory recovery period， atypical hyperplasia period， and canceration period， while the expressions of Bax and Caspase-3 mRNA increased； the expressions of ZO-1， VE-cadherin， and F-actin proteins in colon tissue decreased during the acute inflammatory recovery period， atypical hyperplasia period， and canceration period （P＜0.01 or P＜0.05）. Compared to the model 5w group， the ZO-1 and F-actin protein levels and Bcl-2 mRNA expression in lung tissue in the other model groups increased in the atypical hyperplasia period and canceration period， while the expressions of Bax and Caspase-3 mRNA decreased； the expression of ZO-1 protein in colon tissue increased in the canceration period， and the expression of VE-cadherin protein decreased in the atypical hyperplasia period （P＜0.01 or P＜0.05）. ConclusionIn the process of "inflammatory response-atypical hyperplasia-carcinogenesis" in UC inflammatory cancer transformation mice， there were damage to air-blood barrier.

OBJECTIVE To establish population pharmacokinetic model of levetiracetam （Lev） for Chinese patients with post- stroke epilepsy （PSE）， and provide reference for formulating individualized dosing regimens for Lev therapy in this specific population. METHODS Blood concentration data and clinical diagnosis and treatment information of PSE patients meeting the inclusion criteria were retrospectively collected and divided into model group and validation group at an 8∶2 ratio using a random number method. Based on the model group data， a population pharmacokinetic model was developed using nonlinear mixed-effects modeling. Internal evaluation was performed through goodness-of-fit tests and bootstrap analysis， while external validation was conducted using the validation group data. RESULTS A total of 75 blood concentration measurements from 70 PSE patients were collected， with 60 measurements from 55 patients used for model development and 15 measurements from 15 patients reserved for external validation. The final model estimated a population typical value of clearance at 2.98 L/h. Estimated glomerular filtration rate， daily dose， and homocysteine level significantly influenced clearance of Lev （P＜0.01）. The model demonstrated satisfactory predictive performance， as evidenced by goodness-of-fit tests， bootstrap analysis， and external validation results. CONCLUSIONS Daily dose， estimated glomerular filtration rate， and homocysteine level are identified as significant covariates influencing Lev clearance in Chinese PSE patients. When making clinical decisions， comprehensive consideration should be given to the patient’s treatment response， physiological and pathological conditions， and the occurrence of adverse reactions， etc. The dosage of Lev should be adjusted based on the results of population pharmacokinetic model.

BACKGROUND: Angiotensin receptor neprilysin inhibitors (ARNIs), angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), β-blockers (BBs), and mineralocorticoid receptor antagonists (MRAs) are the cornerstones in treating heart failure with reduced ejection fraction (HFrEF). Sodium-glucose cotransporter 2 inhibitors (SGLT-2is) are included in HFrEF treatment guidelines. However, the effect of SGLT-2i and the five drugs on HFrEF have not yet been systematically evaluated. METHODS: PubMed, Embase, and the Cochrane Library were searched for randomized controlled trials (RCTs) from inception dates to September 23, 2022. Additional trials from previous relevant reviews and references were also included. The primary outcomes were changes in left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter/dimension (LVEDD), left ventricular end-systolic diameter/dimension (LVESD), left ventricular end-diastolic volume (LVEDV), and left ventricular end-systolic volume (LVESV), left ventricular end-systolic volume index (LVESVI), and left ventricular end-diastolic volume index (LVEDVI). Secondary outcomes were New York Heart Association (NYHA) class, 6-min walking distance (6MWD), B-type natriuretic peptide (BNP) level, and N-terminal pro-BNP (NT-proBNP) level. The effect sizes were presented as the mean difference (MD) with 95% confidence interval (CI). RESULTS: We included 68 RCTs involving 16,425 patients. Compared with placebo, ARNI + BB + MRA + SGLT-2i was the most effective combination to improve LVEF (15.63%, 95% CI: 9.91% to 21.68%). ARNI + BB + MRA + SGLT-2i (5.83%, 95% CI: 0.53% to 11.14%) and ARNI + BB + MRA (3.83%, 95% CI: 0.72% to 6.90%) were superior to the traditional golden triangle ACEI + BB + MRA in improving LVEF. ACEI + BB + MRA + SGLT-2i was better than ACEI + BB + MRA (-8.05 mL/m 2 , 95% CI: -14.88 to -1.23 mL/m 2 ) and ACEI + BB + SGLT-2i (-18.94 mL/m 2 , 95% CI: -36.97 to -0.61 mL/m 2 ) in improving LVEDVI. ACEI + BB + MRA + SGLT-2i (-3254.21 pg/mL, 95% CI: -6242.19 to -560.47 pg/mL) was superior to ARB + BB + MRA in reducing NT-proBNP. CONCLUSIONS: Adding SGLT-2i to ARNI/ACEI + BB + MRA is beneficial for reversing cardiac remodeling. The new quadruple drug "ARNI + BB + MRA + SGLT-2i" is superior to the golden triangle "ACEI + BB + MRA" in improving LVEF. REGISTRATION PROSPERO; No. CRD42022354792.
Humans ; Heart Failure/physiopathology* ; Stroke Volume/physiology* ; Angiotensin Receptor Antagonists/therapeutic use* ; Angiotensin-Converting Enzyme Inhibitors/therapeutic use* ; Sodium-Glucose Transporter 2 Inhibitors/therapeutic use* ; Randomized Controlled Trials as Topic ; Mineralocorticoid Receptor Antagonists/therapeutic use* ; Adrenergic beta-Antagonists/therapeutic use*

Objective To construct an in vitro research model for studying human liver regeneration based on human pluripotent stem cells(hPSCs)-derived hepatocyte-like organoid(HLO).Methods The hPSCs-derived HLO was obtained by inducing differentiation and the regeneration model after liver injury was constructed by adding acetaminophen(APAP)at fixed time points in HLO culture conditions to simulate acute liver injury.Subse-quently,HLO with catenin/cadherin-associated protein beta 1(CTNNB1)knockout,a key gene regulating liver re-generation,was constructed using CRISPR/Cas9 gene editing technology,and regeneration experiments with APAP injury were performed.HLO as a model for liver regeneration studies was further evaluated by morphological observation,RT-qPCR,Western blot and pathological analysis.Results Morphology evidence as well as expres-sion of marker genes showed that hPSCs-derived HLO was able to initiate a post-injury regeneration response after APAP treatment.CTNNB1-deficient HLO showed delayed recovery in dimension and down-regulated or delayed ex-pression of related genes during post-injury regeneration as compared to control HLO.Conclusions A HLO-based hPSCs-derived human liver regeneration model is successfully constructed,which can be used for gene function studies during liver regeneration.

Objective:To investigate the clinical features and prognosis associated risk factors of non-eosinophilic esophagitis eosinophilic gastrointestinal diseases (non-EoE EGID) in children.Methods:A retrospective cohort study was conducted. Clinical data, including symptoms, laboratory test results, endoscopic findings, treatment and prognosis of 48 children diagnosed with non-EoE EGID at Children′s Hospital, Zhejiang University School of Medicine from May 2015 to March 2023 were collected. Patients were grouped according to the eosinophils (EOS) diagnostic threshold of new guideline for non-EoE EGID. Independent sample t tests, Wilcoxon rank-sum test, chi-squared test or Fisher exact test were used for intergroup comparisons. Kaplan-Meier method was used to plot the survival curve of disease recurrence in children with non-EoE EGID. Log-Rank test and the proportional hazards model were respectively used for univariate analysis and multivariate analysis. Results:Of the 48 children with non-EoE EGID, there were 38 males and 10 females. Twenty-six patients (54%) with onset age >6-10 years accounted for the highest proportion. The most common symptom was abdominal pain, occurring in 34 patients (71%). Laboratory test results showed that 32 patients (67%) had increased EOS count in peripheral blood. A total of 35 imaging examination showed thickened intestinal wall in 17 patients (49%) and bowel dilatation in 3 patients (9%). Twenty-five patients (52%) received glucocorticoid treatment. The serum albumin level in the high diagnostic threshold group was lower than that in the low diagnostic threshold group ( Z=2.17, P=0.030), no statistically significant difference was found in other clinical characteristics (all P>0.05). The 1-year, 2-year, and 3-year recurrence-free survival rates for non-EoE EGID children were (81±6)%, (81±6)%, and (44±13)% respectively. Multivariate analysis showed that bowel dilatation ( HR=5.87, 95% CI 1.06-32.48) was an independent predictor of disease recurrence. Conclusions:A higher proportion of non-EoE EGID patients are male. The most common symptom is abdominal pain, and the peripheral blood EOS counts are often elevated. Among children with non-EoE EGID, those with higher pathological EOS counts have lower serum albumin levels. Bowel dilatation is a risk factor for disease recurrence in non-EoE EGID children.

In recent years,there has been a gradual increase in the number of common diseases among children in China,especially younger children.Children are a unique population with distinct differences from adults,such as indications,dosage,accessories,and other characteristics,when it comes to using medication.Long-acting injections,in comparison to regular injections used for long-term treatment in children,can reduce sudden drug side effects and significantly decrease injection frequency.This greatly improves compliance among child patients and enhances clinical outcomes.Long-acting injections offer significant advantages for managing diseases in children.This paper reviews the progress made in basic research on long-acting injectable formulations for children based on interactions between drugs and materials.Additionally,potential future development directions are discussed to guide further advancements in long-acting injections specifically designed for children's needs.

DNA methylation is an important epigenetic modification in mammals, playing a crucial role in various physiological processes, including cell differentiation and the gene expression regulation. The ten-eleven translocation (TET) protein family of DNA demethylases is integral to the regulation of DNA methylation, as it catalyzes the oxidation of 5-methylcytosine to form 5-hydroxymethylcytosine. During early embryonic development, the genome undergoes extensive DNA demethylation, and any aberration in this reprogramming process can result in abnormal embryonic development and physiological defects in offspring. The TET proteins, due to their unique dynamics and multifaceted roles, facilitate DNA demethylation and are involved in development and maturation of germ cells, the establishment of pluripotency, cell lineage differentiation, and transcriptional processes throughout mammalian embryogenesis. Furthermore, these proteins are closely associated with the maintenance of pregnancy and susceptibility of progeny to disease. Factors such as genetic mutations, maternal health conditions, and exposure to adverse environmental influences can impact TET protein activity, resulting in abnormal patterns of DNA demethylation. A comprehensive investigation of the related mechanisms of TET proteins is essential for enhancing our understanding of epigenetic regulation during early life, diagnosing and treating related diseases such as early fetal development retardation, and informing strategies for the prevention and management of pregnancy.This article reviews the regulatory role of DNA demethylation mediated by TET protein in mammalian embryonic development and pregnancy outcomes.

DNA methylation is an important epigenetic modification in mammals, playing a crucial role in various physiological processes, including cell differentiation and the gene expression regulation. The ten-eleven translocation (TET) protein family of DNA demethylases is integral to the regulation of DNA methylation, as it catalyzes the oxidation of 5-methylcytosine to form 5-hydroxymethylcytosine. During early embryonic development, the genome undergoes extensive DNA demethylation, and any aberration in this reprogramming process can result in abnormal embryonic development and physiological defects in offspring. The TET proteins, due to their unique dynamics and multifaceted roles, facilitate DNA demethylation and are involved in development and maturation of germ cells, the establishment of pluripotency, cell lineage differentiation, and transcriptional processes throughout mammalian embryogenesis. Furthermore, these proteins are closely associated with the maintenance of pregnancy and susceptibility of progeny to disease. Factors such as genetic mutations, maternal health conditions, and exposure to adverse environmental influences can impact TET protein activity, resulting in abnormal patterns of DNA demethylation. A comprehensive investigation of the related mechanisms of TET proteins is essential for enhancing our understanding of epigenetic regulation during early life, diagnosing and treating related diseases such as early fetal development retardation, and informing strategies for the prevention and management of pregnancy.This article reviews the regulatory role of DNA demethylation mediated by TET protein in mammalian embryonic development and pregnancy outcomes.

In recent years,there has been a gradual increase in the number of common diseases among children in China,especially younger children.Children are a unique population with distinct differences from adults,such as indications,dosage,accessories,and other characteristics,when it comes to using medication.Long-acting injections,in comparison to regular injections used for long-term treatment in children,can reduce sudden drug side effects and significantly decrease injection frequency.This greatly improves compliance among child patients and enhances clinical outcomes.Long-acting injections offer significant advantages for managing diseases in children.This paper reviews the progress made in basic research on long-acting injectable formulations for children based on interactions between drugs and materials.Additionally,potential future development directions are discussed to guide further advancements in long-acting injections specifically designed for children's needs.

Objective:To investigate the clinical features and prognosis associated risk factors of non-eosinophilic esophagitis eosinophilic gastrointestinal diseases (non-EoE EGID) in children.Methods:A retrospective cohort study was conducted. Clinical data, including symptoms, laboratory test results, endoscopic findings, treatment and prognosis of 48 children diagnosed with non-EoE EGID at Children′s Hospital, Zhejiang University School of Medicine from May 2015 to March 2023 were collected. Patients were grouped according to the eosinophils (EOS) diagnostic threshold of new guideline for non-EoE EGID. Independent sample t tests, Wilcoxon rank-sum test, chi-squared test or Fisher exact test were used for intergroup comparisons. Kaplan-Meier method was used to plot the survival curve of disease recurrence in children with non-EoE EGID. Log-Rank test and the proportional hazards model were respectively used for univariate analysis and multivariate analysis. Results:Of the 48 children with non-EoE EGID, there were 38 males and 10 females. Twenty-six patients (54%) with onset age >6-10 years accounted for the highest proportion. The most common symptom was abdominal pain, occurring in 34 patients (71%). Laboratory test results showed that 32 patients (67%) had increased EOS count in peripheral blood. A total of 35 imaging examination showed thickened intestinal wall in 17 patients (49%) and bowel dilatation in 3 patients (9%). Twenty-five patients (52%) received glucocorticoid treatment. The serum albumin level in the high diagnostic threshold group was lower than that in the low diagnostic threshold group ( Z=2.17, P=0.030), no statistically significant difference was found in other clinical characteristics (all P>0.05). The 1-year, 2-year, and 3-year recurrence-free survival rates for non-EoE EGID children were (81±6)%, (81±6)%, and (44±13)% respectively. Multivariate analysis showed that bowel dilatation ( HR=5.87, 95% CI 1.06-32.48) was an independent predictor of disease recurrence. Conclusions:A higher proportion of non-EoE EGID patients are male. The most common symptom is abdominal pain, and the peripheral blood EOS counts are often elevated. Among children with non-EoE EGID, those with higher pathological EOS counts have lower serum albumin levels. Bowel dilatation is a risk factor for disease recurrence in non-EoE EGID children.