BACKGROUND:Several studies have confirmed the important role of progesterone in fetal and neonatal brain development. Chronic hypoxia in the fetal period may mediate neurodevelopmental and cognitive impairment in offspring by interfering with placental steroid hormone synthesis, but the mechanism is unclear. METHODS:We systematically evaluated the effects of hypoxia on placental endocrine-fetal neuro-cognitive function by constructing a model of chronic hypoxia from fetal to early childhood, combined with progesterone supplementation, multi-omics of placenta and brain samples, microglial morphological analysis, and behavioral testing. RESULTS:Chronic hypoxia significantly inhibited placental steroid synthase, leading to a concurrent decrease of progesterone levels in the fetal circulation and brain. Progesterone deficiency in the brain activates microglia, which in turn drives excessive inflammation under chronic hypoxic conditions, thereby interrupting oligodendrocyte differentiation and causing myelination deficits. Chronic hypoxia could also lead to impairment of spatial memory and learning ability shown by behavioral tests. During hypoxic pregnancy, administration of exogenous progesterone restored the progesterone gradient between the placenta and brain, inhibited abnormal activation of microglia, promoted myelination, and reversed cognitive deficits. CONCLUSION:Chronic hypoxia downregulates placenta-derived progesterone through the "placenta-neural axis", which in turn leads to cognitive impairment through the microglia-myelin pathway. Progesterone supplementation during pregnancy can provide a theoretical basis for clinical intervention.

Chronic hypoxia, common in neonates, disrupts gut microbiota balance, which is crucial for brain development. This study utilized cyanotic congenital heart disease (CCHD) patients and a neonatal hypoxic rat model to explore the association. Both hypoxic rats and CCHD infants exhibited brain immaturity, white matter injury (WMI), brain inflammation, and motor/learning deficits. Through 16s rRNA sequencing and metabolomic analysis, a reduction in B. thetaiotaomicron and P. distasonis was identified, leading to cholic acid accumulation. This accumulation triggered M1 microglial activation and inflammation -induced WMI. Administration of these bacteria rescued cholic acid -induced WMI in hypoxic rats. These findings suggest that gut microbiota-derived cholic acid mediates neonatal WMI and brain inflammation, contributing to brain immaturity under chronic hypoxia. Therapeutic targeting of these bacteria provides a non-invasive intervention for chronic hypoxia patients.

Objective: The objective of this study was to investigate the association between morphological variation and postsurgical pulmonary vein (PV) stenosis (PPVS) in patients with cardiac total anomalous pulmonary venous connection (TAPVC). Methods: This single-center, retrospective study included 168 pediatric patients who underwent surgical repair of cardiac TAPVC from 2013 to 2019 (connection to the coronary sinus [CS], n = 136; connection directly to the right atrium [RA], n = 32). Three-dimensional computed tomography modeling and geometric anal-ysis were performed to investigate the morphological features; their relevance to the PPVS was examined. Results: The connection type had no association with PPVS (CS type: 18% vs right atrial type: 19%; P = .89) but there was a higher incidence of PPVS in patients with a single PV orifice than>1 orifice (P <.001). Confluence-to-total PV area ratio (haz-ard ratio, 4.78, 95% CI, 1.86-12.32; P = .001) and length of drainage route (hazard ratio, 1.22; 95% CI, 1.14-1.31; P < .001) had a 4-and 1-fold increase in the risk for PPVS in the CS type after adjustment for age and preoperative pulmonary venous obstruction. In the right atrial type, those with anomalous PV return to the RA roof were more likely to develop PPVS than to the posterior wall of the RA (P < .001). Conclusions: The number of inter-junction PV orifice correlated with PPVS devel-opment in cardiac TAPVC. The confluence-to-total PV ratio, length of drainage route, and anomalous PV return to the RA roof are important predictors for PPVS. Morphological subcategorization in this clinical setting can potentially assist in surgical decision-making. (J Thorac Cardiovasc Surg 2023;165:449-59)

Background:Studies focused on pregnant women with congenital heart disease (CHD)-associated pulmonary hypertension (PH) are scarce and limited by small sample sizes and single-center design. This study sought to describe the pregnancy outcomes in women with CHD with and without PH. Methods:Outcomes for pregnant women with CHD were evaluated retrospectively from 1993 to 2016 and prospectively from 2017 to 2019 from 7 tertiary hospitals. PH was diagnosed on the basis of echocardiogram or catheterization. The incidence of maternal death, cardiac complications, and obstetric and offspring complications was compared for women with CHD and no PH, mild, and moderate-to-severe PH. Results:A total of 2220 pregnant women with CHD had completed pregnancies. PH associated with CHD was identified in 729 women, including 398 with mild PH (right ventricle to right atrium gradient 30-50 mm Hg) and 331 with moderate-to-severe PH (right ventricle to right atrium gradient >50 mm Hg). Maternal mortality occurred in 1 (0.1%), 0, and 19 (5.7%) women with CHD and no, mild, or moderate-to-severe PH, respectively. Of the 729 patients with PH, 619 (85%) had CHD-associated pulmonary arterial hypertension, and 110 (15%) had other forms of PH. Overall, patients with mild PH had better maternal outcomes than those with moderate-to-severe PH, including the incidence of maternal mortality or heart failure (7.8% versus 39.6%; P<0.001), other cardiac complications (9.0% versus 32.3%; P<0.001), and obstetric complications (5.3% versus 15.7%; P<0.001). Brain natriuretic peptide >100 ng/L (odds ratio, 1.9 [95% CI, 1.0-3.4], P=0.04) and New York Heart Association class III to IV (odds ratio, 2.9 [95% CI, 1.6-5.3], P<0.001) were independently associated with adverse maternal cardiac events in pregnancy with PH, whereas follow-up with a multidisciplinary team (odds ratio, 0.4 [95% CI, 0.2-0.6], P<0.001) and strict antenatal supervision (odds ratio, 0.5 [95% CI, 0.3-0.7], P=0.001) were protective. Conclusions:Women with CHD-associated mild PH appear to have better outcomes compared with women with CHD-associated moderate-to-severe PH, and with event rates similar for most outcomes with women with CHD and no PH. Multimodality risk assessment, including PH severity, brain natriuretic peptide level, and New York Heart Association class, may be useful in risk stratification in pregnancy with PH. Follow-up with a multidisciplinary team and strict antenatal supervision during pregnancy may also help to mitigate the risk of adverse maternal cardiac events.

ObjectiveThe present study objectives were to determine the prevalence of attention-deficit/hyperactivity disorder symptoms (ADHD-like symptoms) in children and adolescent with d-transposition of great artery (D-TGA) after arterial switch operation (ASO) and examine associated risk factors and adverse personal, family dysfunctions.MethodsThis cohort study included 103 patients with D-TGA who underwent ASO in early infancy at Shanghai Children’s Medical Center between 2011 and 2016 and then follow-up. Data analysis was conducted from September 2020 to April 2022. A standardized Swanson, Nolan, and Pelham IV (SNAP-IV) questionnaire is used to evaluate inattention and hyperactivity symptoms. Demographic, preoperative, intraoperative, and postoperative factor were collected. Univariate and multivariable regression analyses were performed with odds ratios (OR) and 95% confidence intervals (CIs).ResultsPrevalence of ADHD-like symptoms was 27.18% (28/103). Attention-deficit (18/28, 64.29%) symptom was the predominant subphenotype. After underwent TGA surgery, 39% of patients with ADHD-like symptoms receive remedial special academic services. There is none had repeated grade. Univariate analysis showed that, positive inotropic drug score (P = 0.03) and delayed sternal closure (P = 0.02) were risk factors of ADHD-like symptoms; increased preoperative oxygen saturation (SpO2) (P = 0.01) and surgical height (P = 0.01) and TGA subtype (VSD) (P = 0.02) were protective factor of ADHD-like symptoms. Multivariable analysis showed that delayed sternal closure (DSC) (OR, 1.50; 95% CI, 1.02–2.18) is a risk factor for the occurrence of ADHD-like symptom while increased preoperative oxygen saturation [odds ratio (OR), 0.95; 95% confidence interval (CI), 0.92–0.99] is a protective factor of ADHD-like symptom.ConclusionThe children and adolescents with D-TGA after ASO were at high risk of ADHD-like symptoms. Preoperative hypoxic status and postoperative DSC became predominant risk factors. Modification of the risk factors may be helpful to relieve ADHD-like symptoms for these patients.

Background Although various surgical techniques have been reported for aortic arch reconstruction for proximal and distal transverse arch (PDTA) hypoplasia, no consensus has been reached on a surgical option for initial arch reconstruction. This study was undertaken to review various arch reconstruction options for PDTA hypoplasia in Chinese infants. Methods A retrospective review of 121 infants who underwent initial arch reconstruction of the proximal and distal aortic arches between 2010 and 2020 was performed. Freedom from recoarctation was analyzed using Kaplan-Meier analysis. Univariate and multivariable Cox regression analyses were performed to determine perioperative data associated with an increased risk of recoarctation after surgery. Results Aortic arch reconstruction was performed by end-to-side anastomosis (ESA) (n=37) or patch repair [autologous pericardial patch (APP), n=53; bovine pericardial patch (BPP), n=20; autologous pulmonary artery patch (APAP), n=11]. The relative diameter of the proximal arch was 0.51±0.07, and the relative diameter of the distal arch was 0.43±0.07. The median follow-up time was 679 (range, 388–1,362) days. Recoarctation was observed in 44 (36.4%) patients. ESA was an independent risk factor for further development of recoarctation after the initial aortic arch reconstruction [hazard ratio (HR) =2.13; P=0.020]. Conclusions Aortic arch reconstruction via ESA was an independent risk factor for late recoarctation of the proximal and distal aortic arches in patients who underwent the initial surgery in infancy. Trial Registration Chinese Clinical Trials Registry ChiCTR2100048212.

目的:探讨近11年维持性血液透析患者的原发病及血管通路应用变迁,为提高其治疗水平和改善预后提供依据.方法:回顾性分析2007年～2018年间上海交通大学附属第一人民医院维持性血液透析超过6月以上患者的流行病学资料,选取2007年01月～ 2018年07月之间的五个时间点,比较维持性血液透析患者的原发病及血管通路使用的变化.结果:(1)原发病构成比中,原发病构成比中糖尿病肾病由11年前的11.14％增加到17.01％(x2 =5.991,P＜0.05),高血压肾病由11年前的10％增加到15.46％(x2 =5.907,P＜0.05),痛风性肾病由11年前的2.10％增加到5.7％(x2=6.352,P＜0.05).而慢性肾小球肾炎由11年前的68.62％下降到51.8％(x2 =23.175,P＜0.01).(2)透析患者平均发病年龄由11年前的(56.48±13.06)岁增加到(61.25±15.91)岁.(3)平均透龄由11年前的(68.91±67.12)个月延长到(74.12±45.17)个月.(4)近11年血管通路仍以自体动静脉内瘘为主(97.16％),其中使用最多为腕部桡动脉-头静脉内瘘(91.7％),其次为肘部内瘘(5.4％).(5)维持性血透患者各类内瘘并发症的发生率均下降,但差异无统计学意义(P＞0.05).血栓形成的发生率仍然最高,其次为动脉瘤样扩张.结论:(1)原发病变迁:终末期肾脏的病因由原发性肾脏疾病向继发性肾脏疾病转变.(2)血管通路变迁:血管通路仍然以自体动静脉内瘘为主,其中使用最多为腕部桡动脉-头静脉内瘘,其次为肘部内瘘.各类内瘘并发症发生率较前有所下降,但无明显差异.

Objectives: This study aims to evaluate the protective effects of progesterone on white matter injury and brain immaturity in neonatal rats with chronic hypoxia. Methods: Three-day old Sprague-Dawley rats were randomly divided into 3 groups: (1) control (n = 48), rats were exposed to normoxia (fraction of inspired oxygen: 21% +/- 0%); (2) chronic hypoxia (n = 48), rats were exposed to hypoxia (fraction of inspired oxygen: 10.5% +/- 1.0%); and (3) progesterone (n = 48), rats were exposed to hypoxia and administrated with progesterone (8 mg/kg/d). Hematoxylin-eosin staining, immunohistochemistry, real-time quantitative polymerase chain reaction, and Western blot analyses were compared on postnatal day 14 in different groups. Motor skill and coordination abilities of rats were assessed via rotation experiments. Results: Increased brain weights (P<.05), narrowed ventricular sizes (P<.01), and rotarod experiment scores (P<.01) were better in the progesterone group than in the chronic hypoxia group. The number of mature oligodendrocytes and myelin basic protein expression increased in the progesterone group compared with the chronic hypoxia group (P<.01). The polarization of M-1 microglia cells in the corpus callosum of chronic hypoxia-induced hypomyelination rats was significantly increased, whereas there were fewer M-2 microglia cells. Conversely, progesterone therapy had an opposite effect and caused an increase in M-2 microglia polarization versus a reduction in M-1 microglia cells. Conclusions: Progesterone could prevent white matter injury and improve brain maturation in a neonatal hypoxic rat model; this may be associated with inducing a switch from M-1 to M-2 in microglia.

Aims: Ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury (AKI), which can lead to poor outcome and increased risk of mortality. Dabrafenib (DAB) is an approved cancer treatment. Little is known about the effect of DAB in prevention or treatment of renal IRI. Methods: For in vivo experiments, C57BL/6 mice were divided into four groups: sham (no IRI, no DAB), IRI, DAB, and DAB + IRI was induced by clamping of bilateral renal pedicles for 30 min. For in vitro experiments, HK-2 cells were used to establish the hypoxia/reoxygenation (H/R) injury model, with four groups: control (no H/R, no DAB), H/R, DAB, and DAB + H/R. Renal function and renal histological changes were recorded. Expression of NGAL and KIM-1 proteins and mRNAs were determined by western blotting and qRT-PCR; secretion of inflammatory cytokines (IL-6 and TNF- alpha) was determined by qRT-PCR; Cell death was determined using the TUNEL assay, measurement of cleaved caspase-3, and flow cytometry. Necroptosis-related proteins were determined by western blotting. Results: In mice, DAB pretreatment improved renal function and also reduced histological injury, inflammation, cell death, and expression of necroptosis-associated proteins. In HK-2 cells, DAB significantly decreased the levels of NGAL and KIM-1, inflammatory cytokines, cell death, and necroptosis-related proteins. Conclusion: Our in vitro and in vivo experiments indicated that DAB appears to alleviate renal IRI by suppressing cell death and inhibiting inflammatory responses. DAB has potential use for the clinical prevention and treatment of AKI-induced IRI. (C) 2019 Elsevier Inc. All rights reserved.

目的 采用双侧肺静脉环缩术建立肺静脉狭窄幼猪动物模型,探讨肺静脉狭窄的病理形态学变化,并与完全性肺静脉异位引流(TAPVC)术后肺静脉狭窄患者标本进行对比.方法 选择6周龄健康幼猪共10头,随机分为2组:假手术组5头,肺静脉环缩组5头.手术分两期,分别在两侧经肋间开胸.环缩组使用生物相容性材料套于肺静脉周围;假手术组使用同样方法开胸,但不环缩肺静脉.术后6周,处死动物取肺静脉,行苏木素-伊红(HE)、免疫荧光染色,观察肺静脉病理形态学变化.取术后肺静脉狭窄患者的增生组织,进行HE、免疫荧光染色观察组织标本.结果 动物实验假手术组和肺静脉环缩组手术均存活,但肺静脉环缩组出现明显的肺静脉狭窄.肺静脉环缩组出现了内膜增生、内皮标志物表达降低和间充质标记物表达增加,且内膜细胞中内皮和间充质标记物共表达.动物模型HE与免疫荧光结果与人标本结果一致.结论 动物模型的症状、病理与临床相符,可以为肺静脉狭窄相关分子机制、药理和临床转化奠定良好的基础.

目的:分析维持性血液透析(maintenance hemodialysis,MHD)患者死亡的主要原因以及心脑血管疾病死亡的危险因素.方法:回顾性分析1997年1月1日 ～2017年1月31日在上海交通大学附属第一人民医院行MHD患者的临床资料,其中病史完整的MHD死亡患者106例,采用Logistic回归分析MHD患者心脑血管疾病死亡的危险因素.结果:106例死亡患者中有59例(55.66％)死于心脑血管疾病,14例(13.21％)死于营养不良,13例(12.26％)死于感染,10例(9.43％)死于肿瘤,10例(9.43％)死于其他.对年龄、体重指数(BMI)及血液检查指标血红蛋白、尿素氮、肌酐、钙、磷、白蛋白、三酰甘油、总胆固醇、低密度脂蛋白、高密度脂蛋白等因素进行Logistic回归分析结果显示,血磷(OR=0.436,95％可信区间0.202～0.941,P=0.034)和总胆固醇(OR=0.347,95％可信区间0.151～0.795,P=0.012)是MHD患者心脑血管疾病死亡的危险因素.结论:MHD患者死亡的主要原因是心脑血管疾病,其次是营养不良、感染以及肿瘤.控制MHD患者的血磷和总胆固醇水平,有助于降低MHD患者心脑血管疾病的死亡率.

目的:探讨达拉菲尼对小鼠肾脏缺血再灌注损伤(IRI)的保护作用及机制. 方法:将24只C57BL/6小鼠随机分为4组:假手术组(sham组);缺血再灌注组(IRI组),夹闭双侧肾蒂30 min再灌注24h;达拉菲尼组(DAB组),仅与IRI组在相同时间灌胃给予相同量的达拉菲尼;达拉菲尼预处理+缺血再灌注组(DAB+IRI组),灌胃给予达拉菲尼2h后进行IRI造模,每组6只.收集小鼠IRI 24h后的血清及肾脏组织.采用相应试剂盒检测各组肾功能血清肌酐(SCr)和血尿素氮(BUN)水平,HE及PAS染色比较各组肾脏病理学改变,Western Blot及qRT-PCR检测肾小管损伤标志物中性粒细胞明胶酶相关脂质运载蛋白(NGAL)和肾损伤分子1(KIM-1)的蛋白及mRNA水平,qRT-PCR检测炎症因子白细胞介素6(IL-6)和肿瘤坏死因子α(TNF-α)的mRNA水平,免疫组织化学染色检测肾脏组织中TNF-α蛋白表达,末端脱氧核苷酸转移酶介导的dUTP缺口末端标记(TUNEL)法检测肾组织细胞死亡情况,Western Blot检测肾脏组织中程序性坏死(necroptosis)通路相关的受体相互作用蛋白1(RIP1)、受体相互作用蛋白3(RIP3)、磷酸化的受体相互作用蛋白3(pRIP3)、混合系列蛋白激酶复合物(MLKL)、磷酸化的混合系列蛋白激酶复合物(pMLKL)蛋白水平. 结果:与sham组相比,IRI组SCr、BUN水平升高(P＜0.05),肾组织病理损伤严重,小管损伤标志物NGAL和KIM-1蛋白和mRNA水平升高,炎症因子IL-6以及TNF-α mRNA含量增加,肾脏组织TNF-α蛋白表达升高,肾脏组织细胞死亡增多,RIP1、RIP3、pRIP3、MLKL以及pMLKL蛋白表达增加;与IRI组比较,DAB+IRI组减轻肾功能、肾组织损伤,减少NGAL、KIM-1的蛋白和mRNA表达水平,下调IL-6和TNF-αmRNA水平,减少肾脏组织中TNF-α蛋白表达,抑制RIP3、pRIP3及pMLKL的蛋白表达(P均＜0.05),而RIP1和MLKL蛋白改变不明显.DAB组与sham组间各指标无统计学差异. 结论:达拉菲尼通过抑制RIP3介导的程序性坏死从而对小鼠肾脏缺血再灌注损伤起保护作用.

Biotechnology and BioengineeringVolume 115, Issue 3 p. 519-523 ISSUE INFORMATIONFree Access Biotechnology and Bioengineering: Volume 115, Number 3, March 2018 First published: 29 January 2018 https://doi.org/10.1002/bit.26414AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Volume115, Issue3March 2018Pages 519-523 RelatedInformation

Biotechnology and BioengineeringVolume 114, Issue 9 p. 1909-1913 Issue Information - TOCFree Access Biotechnology and Bioengineering: Volume 114, Number 9, September 2017 First published: 21 July 2017 https://doi.org/10.1002/bit.26157AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Volume114, Issue9September 2017Pages 1909-1913 RelatedInformation

Biotechnology and BioengineeringVolume 113, Issue 3 p. 459-463 Issue Information - TocFree Access Biotechnology and Bioengineering: Volume 113, Number 3, March 2016 First published: 26 January 2016 https://doi.org/10.1002/bit.25745AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Volume113, Issue3March 2016Pages 459-463 RelatedInformation

Biotechnology and BioengineeringVolume 113, Issue 8 p. 1611-1615 Issue Information - TOCFree Access Biotechnology and Bioengineering: Volume 113, Number 8, August 2016 First published: 27 June 2016 https://doi.org/10.1002/bit.25780AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Volume113, Issue8August 2016Pages 1611-1615 RelatedInformation

Biotechnology and BioengineeringVolume 110, Issue 12 p. fmi-fmv ContentsFree Access Biotechnology and Bioengineering: Volume 110, Number 12, December 2013 First published: 23 October 2013 https://doi.org/10.1002/bit.24705AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinked InRedditWechat Volume110, Issue12December 2013Pages fmi-fmv RelatedInformation