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Isosteviol has been indicated as a cardiomyocyte protector. However, the underlying mechanism remains unclear. Thus, we sought to confirm the protective effect of isosteviol after myocardial infarction in a model of permanent coronary artery occlusion and investigate the potential proangiogenic activity in vitro and in vivo. A 4-week permanent coronary artery occlusion rat model was generated, and the protective effect of isosteviol was evaluated by echocardiographic imaging and hemodynamics assays. The coronary capillary density was tested by immunochemistry and micro-computed tomography (μCT) imaging. The effect of isosteviol on endothelial cells was determined in human umbilical vein endothelial cells (HUVECs) in vitro and Tg (kdrl: EGFP) zebrafish in vivo. We also examined the expression of related transcription factors by real-time polymerase chain reaction (RT-qPCR). Isosteviol increased ejection fraction (EF), fractional shortening (FS), cardiac systolic index (CI), maximum rate of increase of left ventricular pressure (Max dp/dt), and left ventricular systolic pressure (LVSP) by 32%, 40%, 25%, 26%, and 10%, respectively, in permanent coronary artery occlusion rats. Interestingly, it also promoted coronary capillary density by 2.5-fold. In addition, isosteviol promoted the proliferation and branching of HUVECs in vitro. It also rescued intersegmental vessel (ISV) development and improved endothelial cell proliferation by approximately fivefold (4-6) in zebrafish embryos in vivo. Isosteviol also upregulated the expression of hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor A (VEGFA) in zebrafish by fourfold and 3.5-fold, respectively. Our findings suggest that isosteviol is a proangiogenic agent and that this activity is related to its protective effects against myocardial ischemia. After using the permanent coronary artery occlusion model, we demonstrated that isosteviol promotes angiogenesis directly and increases capillary density in myocardial ischemia rats. Isosteviol promotes angiogenesis in zebrafish in vivo and increases vascular endothelial cell proliferation in HUVECs and zebrafish. The angiogenesis activity of isosteviol may be correlated with VEGFA and HIF-1α signaling.

Dynamic or hybrid configurations for extracorporeal membrane oxygenation (ECMO) are needed when patient physiology or clinical conditions change. Dynamic configurations included configurations converting from veno-arterial (V-A) ECMO or veno-venous (V-V) ECMO to other forms. Hybrid configurations included venous-arteriovenous (V-AV) and venovenous-arterial (VV-A) ECMO. This study retrospectively analyzed a total of 3,814 ECMO cases (3,102 adult cases) reported to the Chinese Society of Extracorporeal Life Support from January 1, 2017 to December 31, 2019. Eight-three adult patients had dynamic or hybrid ECMO configurations, whose primary diagnoses included cardiogenic shock (33.7%), cardiac arrest (6.0%), acute respiratory failure (39.8%), septic shock (9.6%), multiple trauma (3.6%), pulmonary hypertension (3.6%), and others (3.6%). Configuration changes occurred in 37 patients with the initial configuration of VA (20 to VV, 13 to V-AV, and 4 to VV-A) and 27 with the initial configuration of VV (7 to VA, and 20 to V-AV). A total of 46 (55.4%) patients received hybrid configurations of V-AV and 10 (12.0%) received VV-A. Patients with the initial configuration of VV who converted to other configurations had higher in-hospital mortality (74.1%) than other initial configurations (VA 45.9%, V-AV 76.9%, VV-A 66.7%, P = 0.021). We concluded that dynamic or hybrid ECMO configurations were used in various underlying diseases, in which V-AV was most commonly used. Patients receiving VV ECMO for respiratory support initially, who then converted to other configurations for both respiratory and circulatory support, had significantly worst outcomes among the groups studied. The initial configuration should be selected carefully after thorough assessment of patient condition.

INTRODUCTION: Coronavirus disease-19 (COVID-19) is a new type of epidemic pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The population is generally susceptible to COVID-19, which mainly causes lung injury. Some cases may develop severe acute respiratory distress syndrome (ARDS). Currently, ARDS treatment is mainly mechanical ventilation, but mechanical ventilation often causes ventilator-induced lung injury (VILI) accompanied by hypercapnia in 14% of patients. Extracorporeal carbon dioxide removal (ECCO2R) can remove carbon dioxide from the blood of patients with ARDS, correct the respiratory acidosis, reduce the tidal volume and airway pressure, and reduce the incidence of VILI. CASE REPORT: Two patients with critical COVID-19 combined with multiple organ failure undertook mechanical ventilation and suffered from hypercapnia. ECCO2R, combined with continuous renal replacement therapy (CRRT), was conducted concomitantly. In both cases (No. 1 and 2), the tidal volume and positive end-expiratory pressure (PEEP) were down-regulated before the treatment and at 1.5 hours, one day, three days, five days, eight days, and ten days after the treatment, together with a noticeable decrease in PCO2 and clear increase in PO2, while FiO2 decreased to approximately 40%. In case No 2, compared with the condition before treatment, the PCO2 decreased significantly with down-regulation in the tidal volume and PEEP and improvement in the pulmonary edema and ARDS after the treatment. CONCLUSION: ECCO2R combined with continuous blood purification therapy in patients with COVID-19 who are criti-cally ill and have ARDS and hypercapnia might gain both time and opportunity in the treatment, down-regulate the ventilator parameters, reduce the incidence of VILI and achieve favorable therapeutic outcomes.

Real-world memories are formed in a particular context and are often not acquired or recalled in isolation1-5. Time is a key variable in the organization of memories, as events that are experienced close in time are more likely to be meaningfully associated, whereas those that are experienced with a longer interval are not1-4. How the brain segregates events that are temporally distinct is unclear. Here we show that a delayed (12-24 h) increase in the expression of C-C chemokine receptor type 5 (CCR5)-an immune receptor that is well known as a co-receptor for HIV infection6,7-after the formation of a contextual memory determines the duration of the temporal window for associating or linking that memory with subsequent memories. This delayed expression of CCR5 in mouse dorsal CA1 neurons results in a decrease in neuronal excitability, which in turn negatively regulates neuronal memory allocation, thus reducing the overlap between dorsal CA1 memory ensembles. Lowering this overlap affects the ability of one memory to trigger the recall of the other, and therefore closes the temporal window for memory linking. Our findings also show that an age-related increase in the neuronal expression of CCR5 and its ligand CCL5 leads to impairments in memory linking in aged mice, which could be reversed with a Ccr5 knockout and a drug approved by the US Food and Drug Administration (FDA) that inhibits this receptor, a result with clinical implications. Altogether, the findings reported here provide insights into the molecular and cellular mechanisms that shape the temporal window for memory linking.

BACKGROUND: Acute kidney injury (AKI) and renal replacement therapy (RRT) are common after heart transplantation (HT). The need for RRT has been reported to be one of the most important predictors of a poor prognosis after HT. Therefore, it is important to early identify risk factors of RRT after HT. However, in the heart transplantation setting, the risk factors are less well studied, and some of the conclusions are controversial. This study aimed to identify the clinical predictors of RRT after HT. METHODS: This single-center, retrospective study from January 2010 to June 2021 analyzed risk factors (pre-, intra-, and postoperative characteristics) of 163 patients who underwent HT. The endpoint of the study was RRT within 7 days of HT. Risk factors were analyzed by multivariable logistic regression models. RESULTS: Fifty-five (33.74%) recipients required RRT within 7 days of HT. Factors independently associated with RRT after HT were as follows: a baseline estimated glomerular filtration rate (eGFR) 10 mg/kg (OR =3.197; 95% CI: 1.290–7.923; P=0.012), the use of mechanical circulatory support (MCS) during surgery (OR =4.903; 95% CI: 1.628–14.766; P=0.005), a cardiopulmonary bypass (CPB) time ≥5 hours (OR =3.929; 95% CI: 1.222–12.634; P=0.022), and postoperative serum total bilirubin (TBIL) ≥60 umol/L (OR =5.105; 95% CI: 1.868–13.952; P=0.001). Protective factors were higher postoperative serum albumin (OR =0.907; 95% CI: 0.837–0.983; P=0.017) and higher postoperative left ventricular ejection fraction (LVEF) (OR =0.908; 95% CI: 0.838–0.985; P=0.020). CONCLUSIONS: A low preoperative eGFR, a high intraoperative dose of methylprednisolone, a long CPB time, the use of mechanical circulatory support, and a high postoperative TBIL were risk factors for RRT after HT. While a high postoperative serum albumin level and a high left ventricular ejection fraction were protective factors. Understanding these risk factors may help us identify high-risk patients and intervene early.

BVES is a transmembrane protein, our previous work demonstrated that single nucleotide mutations of BVES in tetralogy of fallot (TOF) patients cause a downregulation of BVES transcription. However, the relationship between BVES and the pathogenesis of TOF has not been determined. Here we reported our research results about the relationship between BVES and the right ventricular outflow tract (RVOT) stenosis. BVES expression was significantly downregulated in most TOF samples compared with controls. The expression of the second heart field (SHF) regulatory network genes, including NKX2.5, GATA4 and HAND2, was also decreased in the TOF samples. In zebrafish, bves knockdown resulted in looping defects and ventricular outflow tract (VOT) stenosis, which was mostly rescued by injecting bves mRNA. bves knockdown in zebrafish also decreased the expression of SHF genes, such as nkx2.5, gata4 and hand2, consistent with the TOF samples` results. The dual-fluorescence reporter system analysis showed that BVES positively regulated the transcriptional activity of GATA4, NKX2.5 and HAND2 promoters. In zebrafish, nkx2.5 mRNA partially rescued VOT stenosis caused by bves knockdown. These results indicate that BVES downregulation may be associated with RVOT stenosis of non-syndromic TOF, and bves is probably involved in the development of VOT in zebrafish.

Smoke exposure during pregnancy has detrimental effects upon numerous fetal and neonatal outcomes. Nicotine (the main component of tobacco) has been suggested to affect placental development. During placental development, efficient invasion by trophoblasts is required for establishment of the fetus–maternal circulation. In this study we explored the regulation of trophoblast invasion by nicotine. An immortalized first trimester extravillous trophoblast cell line (HTR-8/SVneo cells) was used for all the experiments, which were treated by nicotine, methyllycaconitine, and C-X-C motif chemokine ligand 12 (CXCL12). Total RNA and protein were used to study the expressions of nicotinic acetylcholine receptors (nAChRs), and transwell assay was used to study invasiveness. Changes of RNA expression due to nicotine treatment were detected by RNA sequence. Level of CXCL12 mRNA was verified by quantitative PCR. We showed that HTR-8/SVneo expressed subunits α2–4, α7, α9, β1, and β2 of nAChRs. Nicotine downregulated CXCL12 expression and inhibited trophoblast invasion. Methyllycaconitine, as an antagonist of the α7 homopolymer, blocked the inhibitory effect of nicotine. CXCL12 could rescue the nicotine-induced inhibitory effect on invasion of HTR-8/SVneo cells. These results suggest that the α7 subunit of the nAChR has important roles in modulating trophoblast invasion through CXCL12. Electronic supplementary material The online version of this article (10.1007/s43032-019-00095-4) contains supplementary material, which is available to authorized users.

Background Brain tumors, whether primary or secondary, have limited information about proteomic changes despite advances in the understanding of the driver gene mutations and heterogeneity within tumor cells. In this study, we for the first time systematically analyzed the proteome of tumor tissues from patients with brain metastases (BrMs) and gliomas. Methods We assembled the most common primary tumors as follows: gliomas from WHO grade II to IV with or without IDH1 mutations; and BrMs with a wide range, including lung cancer (L.C), breast cancer (B.C), ovarian cancer (O.C), and colorectal cancer (C.C). A total of 29 tissue samples were analyzed by label free quantitative mass spectrometry-based proteomics. Results In total, 8,370 protein groups were identified, and approximately 4,000 quantified protein groups were adopted for further analysis. Proteomic analysis of metastatic tumors reveals conserved features across multiple cancers. While proteomic heterogeneities were found for discriminating low- and high-grade of gliomas, as well as IDH1 mutant and wild-type gliomas. And distinct pathway-level differences among these two types of brain malignancies were revealed. The characteristic pathways of BrMs focused on proliferation and immunomodulation after colonizing the brain, whereas invasion processes were notably activated in gliomas. Conclusion We elucidated an extensive proteomic landscape of BrMs and gliomas, providing information for the development of potential therapeutic and diagnostic strategies for type-specific brain tumors.

Background: Acute type A aortic dissection (ATAAD) is a cardiovascular emergency and has high mortality and morbidity. We retrospectively compared the effects on outcomes of single arterial cannulation via axillary artery (AAC) with double arterial cannulation via axillary and femoral artery (DAC) in patients who underwent cardiopulmonary bypass (CPB) for ATAAD. Methods: Between January 2017 and May 2021, four hundred 29 patients who underwent aortic arch repair with circulatory arrest for ATAAD were divided into AAC group ( n = 283) and DAC group ( n = 146). The propensity score-matched (PSM) analysis were performed to compare the characteristics and outcomes of the groups. Results: After PSM ( n = 137 in each), the DAC group had a longer duration of CPB (229 vs 244, p = 0.011), aortic cross-clamp time (121 vs 149, p < 0.001), durations of Intensive Care Unit (ICU) stay (7 vs 8, p = 0.014) and hospital stay (19 vs 25, p < 0.001) compared with AAC group. The incidences of dialysis (21% vs. 31%, p = 0.073), postoperative stroke (9% vs 15%, p = 0.143), ECMO support (2% vs 7%, p = 0.077), in-hospital mortality (7% vs 14%, p = 0.071) and follow-up mortality (10% vs 19%, p = 0.059) showed no significant difference between two groups. Multivariate logistic regression analysis showed postoperative ECMO (OR: 16.69, 95% CI: 1.78–156.29; p = 0.014) or stroke (OR: 11.34, 95% CI: 2.64–48.72; p < 0.001) were associated with in-hospital mortality. Univariate Cox regression results showed stroke history (OR: 4.61, 95% CI: 1.90–11.16; p = 0.001), aortic valvuloplasty (OR: 0.21, 95% CI: 0.07–0.59; p = 0.003), postoperative ALT day1 (OR: 1.00, 95% CI: 1.00–1.00; p = 0.008), ECMO (OR: 16.30, 95% CI: 4.78–55.61; p < 0.001), tracheotomy (OR: 3.78, 95% CI: 1.08–13.20; p = 0.037), postoperative stroke (OR: 4.61, 95% CI: 1.90–11.16; p < 0.001) and re-exploration for bleeding (OR: 3.52, 95% CI: 1.01–12.27; p = 0.048) were associated to follow-up mortality. Conclusions: For surgical treatment of ATAAD with CPB when compared to double axillary and femoral artery, single axillary cannulation was associated with shorter durations of CPB and ACC as well as ICU and hospital stays but no with significant difference in mortality.

The novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)...

Background COVID-19 has become a major global threat. The present study aimed to develop a nomogram model to predict the survival of COVID-19 patients based on their clinical and laboratory data at admission. Methods COVID-19 patients who were admitted at Hankou Hospital and Huoshenshan Hospital in Wuhan, China from January 12, 2020 to March 20, 2020, whose outcome during the hospitalization was known, were retrospectively reviewed. The categorical variables were compared using Pearson’s χ2-test or Fisher’s exact test, and continuous variables were analyzed using Student’s t-test or Mann Whitney U-test, as appropriate. Then, variables with a P-value of ≤0.1 were included in the log-binomial model, and merely these independent risk factors were used to establish the nomogram model. The discrimination of the nomogram was evaluated using the area under the receiver operating characteristic curve (AUC), and internally verified using the Bootstrap method. Results A total of 262 patients (134 surviving and 128 non-surviving patients) were included in the analysis. Seven variables, which included age (relative risk [RR]: 0.905, 95% confidence interval [CI]: 0.868–0.944; P P P = 0.0029), platelets (RR: 1.008, 95% CI: 1.003–1.012; P = 0.001), C-reaction protein (RR: 0.982, 95% CI: 0.973–0.991; P P P Conclusions A nomogram based on age, CHD, Lym%, platelets, C-reaction protein, LDH and D-dimer was established to accurately predict the prognosis of COVID-19 patients. This can be used as an alerting tool for clinicians to take early intervention measures, when necessary.

Aim: This study aimed to evaluate the efficacy of the resin hemoperfusion device (HA380 hemoperfusion cartridge) on inflammatory responses during adult cardiopulmonary bypass (CPB). Methods: Sixty patients undergoing surgical valve replacement were randomized into the HP group (n = 30) with an HA380 hemoperfusion cartridge in the CPB circuit or the control group (n = 30) with the conventional CPB circuit. The results of routine blood tests, blood biochemical indexes, and inflammatory factors were analyzed at V0 (pre-CPB), V1 (CPB 30 min), V2 (ICU 0 h), V3 (ICU 6 h), and V4 (ICU 24 h). Results: The HP group had significantly lower levels of IL-6, IL-8, and IL-10. Significant estimation of group differences in the generalized estimating equation (GEE) models was also observed in IL-6 and IL-10. The HP group had significantly lower levels of creatinine (Cr), aminotransferase (AST), and total bilirubin (TBil) compared to the control group. The estimation of differences of Cr, AST, and TBil all reached statistical significance in GEE results. The HP group had significantly less vasopressor requirement and shorter mechanical ventilation time and ICU stay time as compared to the control group. Conclusion: The HA380 hemoperfusion cartridge could effectively reduce the systemic inflammatory responses and improve postoperative recovery of patients during adult CPB.

Smoke exposure during pregnancy has detrimental effects upon numerous fetal and neonatal outcomes. Nicotine (the main component of tobacco) has been suggested to affect placental development. During placental development, efficient invasion by trophoblasts is required for establishment of the fetus-maternal circulation. In this study we explored the regulation of trophoblast invasion by nicotine. An immortalized first trimester extravillous trophoblast cell line (HTR-8/SVneo cells) was used for all the experiments, which were treated by nicotine, methyllycaconitine, and C-X-C motif chemokine ligand 12 (CXCL12). Total RNA and protein were used to study the expressions of nicotinic acetylcholine receptors (nAChRs), and transwell assay was used to study invasiveness. Changes of RNA expression due to nicotine treatment were detected by RNA sequence. Level of CXCL12 mRNA was verified by quantitative PCR. We showed that HTR-8/SVneo expressed subunits α2-4, α7, α9, β1, and β2 of nAChRs. Nicotine downregulated CXCL12 expression and inhibited trophoblast invasion. Methyllycaconitine, as an antagonist of the α7 homopolymer, blocked the inhibitory effect of nicotine. CXCL12 could rescue the nicotine-induced inhibitory effect on invasion of HTR-8/SVneo cells. These results suggest that the α7 subunit of the nAChR has important roles in modulating trophoblast invasion through CXCL12.

Pulmonary stenosis (PS) is a congenital heart disease characterized by a dynamic or fixed anatomic obstruction of blood flow from the right ventricle to the pulmonary arterial vasculature. In the present study, extracellular vesicle long RNAs (EVLRs) from pregnant females who had healthy infants or PS infants were analyzed by RNA sequencing, and their diagnostic potential for PS during pregnancy was evaluated. A method for the selection of genes that could be considered as informative for the prediction PS based on extracellular vesicles (EVs) from pregnant females using long‑read RNA sequencing was developed. Blood samples were collected from females carrying fetuses with PS and females carrying unaffected fetuses (n=6 in each group). Physical characterization of EVs was performed using nanoparticle tracking analysis, transmission electron microscopy and western blotting. EVLRs from plasma were profiled by RNA sequencing and mRNA co‑expression modules were constructed by weighted gene co‑expression network analysis (WGCNA). Gene Ontology (GO) enrichment analysis was used to predict the function of the genes in each module. Hub genes were filtered out based on WGCNA and visualized using Cytoscape. EVLRs consisted of mRNAs, microRNAs and long non‑coding RNA. Overall, 26 modules were identified containing 16,394 genes. All modules were independent of each other. One particular module, referred to as the blue module, was markedly different between the two groups. A total of 735 hub genes in the blue module were identified, of which 33 were visualized, demonstrating the connection between these hub genes. GO enrichment analysis demonstrated that the analyzed hub genes were enriched in 'glucose transport', 'ATP‑dependent chromatin remodeling', 'histone deacetylation', 'histone H3‑K4 methylation', 'DNA methylation', 'apoptotic signaling pathway' and 'glucocorticoid receptor signaling pathway'. The hub genes identified in this module may provide a genetic framework for prenatal PS diagnosis. Furthermore, functional analysis of these associated genes may provide a theoretical basis for further research on PS pathogenesis.

The objective of this study was to compare the effects of different shunt diameters and pulmonary artery (PA) stenosis grades on the hemodynamics of central shunts to determine an optimal surgical plan and improve the long-term outcomes of the operation. A 3D anatomical model was reconstructed based on the patient’s clinical CT data. 3D computational fluid dynamics models were built with varying degrees of stenosis (the stenosis ratio α was represented by the ratio of blood flow through the main pulmonary artery to cardiac output, ranging from 0 to 30%; the smaller the value of α, the more severe the pulmonary artery stenosis) and varying shunt diameters (3, 3.5, 4, 4.5, and 5 mm). Our results show that the asymmetry of pulmonary artery flow increased with increasing shunt diameter and α, which will be more conducive to the development of the left pulmonary artery. Additionally, the pulmonary-to-systemic flow ratio (QP/QS) increases with the shunt diameter and α, and all the values exceed 1. When the shunt diameter is 3 mm and α = 0%, QP/QS reaches the minimum value of 1.01, and the oxygen delivery reaches the maximum value of 205.19 ml/min. However, increasing shunt diameter and α is beneficial to reduced power loss and smoother PA flow. In short, for patients with severe PA stenosis (α is small), a larger-diameter shunt may be preferred. Conversely, when the degree of PA stenosis is moderate, a smaller shunt diameter can be considered.

Fulminant myocarditis (FM) is a life-threatening disease in children. With a rapid, progressive course of deterioration, it causes refractory cardiorespiratory failure even with optimal clinical intervention. We present the case of a 9-year-old girl with FM complicated by cardiogenic shock, malignant arrhythmia, and refractory cardiac arrest. She received effective cardiopulmonary resuscitation, therapeutic hypothermia, and other supportive treatments. However, the patient rapidly worsened into pulseless ventricular tachycardia and refractory cardiac arrest. Therefore, we performed extracorporeal membrane oxygenation (ECMO) to establish spontaneous circulation after the failure of standard resuscitation measures. The girl recovered with intact cardiac and neurocognitive functions after continued ECMO treatment for 221 hours. Therefore, ECMO is an effective rescue therapeutics for FM, especially when complicated with refractory cardiac arrest.

Introduction Placental dysfunction characterized by vascular endothelial inflammation is one of the most notable responses to fetal cardiac bypass. Regulator of calcineurin 1 (RCAN1) is an important regulator of inflammatory responses. MicroRNAs (miRNAs) are essential post-transcriptional modulators of gene expression, and miRNA-34a (miR-34a) was showed to activate vascular endothelial inflammation. We hypothesized that miR-34a may be a key regulator of placental dysfunction after fetal cardiac bypass. Methods We evaluated miRNA expression in goat placentas via small RNA sequencing, quantitative real-time polymerase chain reaction (qRT-PCR) and in situ hybridization. Expression of miRNA target genes was determined via bioinformatics analyses and dual luciferase reporter assays. Furthermore, human umbilical vein endothelial cells (HUVECs) were transfected with miR-34a or a control sequence. The RCAN1, nuclear factor of activated T-cells (NFATC1) and nuclear factor kappa-B (NF-κB) levels in HUVECs and placentas were evaluated via Western blot and qRT-PCR. Results We demonstrated that miR-34a was highly enriched in goat placenta after cardiopulmonary bypass. Moreover, RCAN1 was identified as a novel direct target of miR-34a. Transfection of miR-34a led to decreased RCAN1 expression and increased NFATC1 and NF-κB expression in HUVECs. Conversely, inhibition of miR-34a rescued RCAN1 expression and reduced NFATC1 and NF-κB expression in HUVECs. Conclusions We demonstrated a remarkable role of miR-34a as a regulator of NFATC1-associated placental inflammation through direct targeting of RCAN1. MiR-34a could serve as a novel therapeutic target for limiting the progression of placental inflammation after fetal cardiac bypass.

Background To report our initial experience of fetal pulmonary valvuloplasty (FPV) in fetuses with pulmonary atresia with intact ventricular septum (PA/IVS) or critical pulmonary stenosis (CPS), including the experiences of case selection, technical feasibility, post-FPV effects in utero and the postnatal outcome. Methods Two cases with fetal PA/IVS and three cases with fetal CPS were enrolled between September 2016 and April 2018, and all cases were diagnosed with severe right ventricular dysplasia and growth arrest by fetal echocardiogram. Parameters of right heart structure development and hemodynamics from echocardiography included tricuspid /mitral annulus ratio (TV/MV), right ventricle/left ventricle long-axis ratio (RV/LV), tricuspid valve inflow duration/cardiac cycle ratio (TVI/CC), degree of tricuspid regurgitation (TR), blood flow direction of arterial duct and ductus venosus. FPV procedure was performed trans-abdominally under ultrasound-guidance. Echocardiography was performed post-procedure immediately and every 2-4 weeks until delivery. Results Seven FPV have been performed in the five fetuses with PA/IVS or CPS. The median gestational age at the time of FPV was 28 weeks. From technical perspective, pulmonary balloon valvuloplasty was successfully performed in all cases. The opening of pulmonary valve improved in these five cases in 2-4 weeks. However, progressive restenosis was detected in four fetuses during advancing gestation and re-atresia occurred in two PA/IVS cases at 36 weeks and 37 weeks gestation, respectively. The growth trajectories of TV/MV, RV/LV, and TVI/CC improved in the first weeks, and then slowed down along with the pulmonary valve restenosis. All fetuses were born alive and underwent postnatal interventions, including pulmonary balloon valvuloplasty in 3 cases and surgical procedures in 2 cases. During the follow-up, three fetuses became biventricular, one case became one and a half ventricular at one year of age and the other one died of neonatal infection. Conclusion FPV is feasible and safe for fetuses during the second and third trimester of pregnancy. PV restenosis may occur as pregnancy advances, but overall, FPV still improved the growth trajectories of fetal right heart structures and has the potential to alter the natural history of PA/IVS and CPS.

Background and objective Studying the hemodynamic effects of nonclosure of patent ductus arteriosus (PDA) on the modified Blalock-Taussig shunt (MBTS) is beneficial for surgical PDA management. In the present study, the effect of PDA on MBTS was investigated numerically. A series of parameters including energy loss, wall shear stress (WSS), and left/right Pulmonary artery (LPA/RPA) flow ratio were computed from simulations to analyze the hemodynamic effects of PDA on MBTS. Methods To ensure the universality of the research conclusions, three typical models, including models with a well-developed RPA, a symmetrically-developed pulmonary artery(PA) and a well-developed LPA, were constructed based on patient-specific pre-surgery clinical data sets. A commercial CFD solver ANSYS-Fluent software was adopted for this study. A pressure-based solver for incompressible Newtonian flows, the K-omega based shear-stress-transport model and a second-order accurate numerical discretization scheme were employed for simulation. Results Our results show that MBTS with nonclosure of PDA is accompanied by lower blood velocity, energy loss and WSS values at the MBT shunt; smaller vortex regions; higher oxygen content(Sao2) and PA flow; and more uniform velocity distribution in the LPA and RPA than MBTS with closure of PDA. If the PDA was not closed when performing primary MBTS, a series of hemodynamic changes occurs during PDA closure in postoperative recovery: the energy loss, PA flow and Sao2 decrease, while the oxygen delivery(Do2) and WSS values at the MBT shunt increase. Conclusion Nonclosure of PDA could provide a better hemodynamic environment and play an active role in preventing early acute shunt failure. It could be preferred for cases with very low PA overflow risk and may benefit patients with an underdeveloped myocardium due to its lower energy dissipation than PDA closure. However, excessive PA flow induced by nonclosure of PDA may result in a series of complications. Surgeon's decision-making process with respect to PDA management should consider the individual patient to achieve optimal postoperative recovery.

Additional pulmonary blood flow (APBF) can provide better pulsating blood flow and systemic arterial oxygen saturation, while low blood pulsation and low oxygen saturation are defects of the Fontan and Glenn procedure. Studying the hemodynamic effect of APBF is beneficial for clinical decisions. This study aimed to explore the effect on particle washout, as well as the differences among the sensitivities of both different hemodynamic parameters and different procedures to APBF. The patient-specific clinical datasets of a patient who underwent bilateral bidirectional Glenn (BBDG) with APBF were enrolled in this study, and using these datasets, Glenn- and Fontan-type artery models were reconstructed. A series of parameters, including the total caval flow pulsatility index (TCPI), indexed energy loss (iPL), wall shear stress (WSS), systemic arterial oxygen saturation (Satart), particle washout time (WOT), pressure in the right superior vena cava (PRSVC), pulmonary flow distribution (PFD) and hepatic flow distribution (HFD), were computed from computational fluid dynamic (CFD) simulation to evaluate the hemodynamic effect of APBF. The result showed that APBF led to better iPL and Satart but worse PRSVC and heart load accompanied by a great impact on HFD, making hepatic flow easier to perfuse the side without MPA and APBF. The increase in the APBF rate also effectively results in larger flow pulsation, region velocity, and wall shear stress and lower WOT, and this effect may be more effective for patients with persistent left superior vena cava (PLSVC). However, APBF might have little effect on PFD. Furthermore, APBF might affect WOT, iPL and HFD more significantly than PRSVC and has a greater improvement effect in patients with poorer iPL and WOT. Moderate APBF is not only a measure to promote pulmonary artery growth and systemic arterial oxygen saturation but also an effective method against endothelial dysfunction and thrombosis. However, moderate APBF is patient-specific and should be determined based on hemodynamic preference that leads to desired patient outcomes, and care should be taken to prevent PRSVC and heart load from being too high as well as an imbalance in HFD.

Studies have implied that the circadian oscillation of mitogen-activated protein kinase (MAPK) signal pathways is crucial for hippocampus-dependent memory. NF1 mouse models (Nf1 heterozygous null mutants; Nf1 +/−) displayed enhanced MAPK activity in the hippocampus and resulted in memory deficits. We assumed a link between MAPK pathways and hippocampal rhythmic oscillations, which have never been explored in Nf1 +/− mice. We demonstrated that the level of extracellular signal–regulated kinases 1 and 2 (ERK1/2) phosphorylation in Nf1 +/− mice were significantly higher at nighttime than at daytime. Moreover, the in vivo recording revealed that for the Nf1 +/− group, the power spectral density of theta rhythm significantly decreased and the firing rates of pyramidal neurons increased. Our results indicated that the hippocampal MAPK oscillation and theta rhythmic oscillations in Nf1 +/− mice were disturbed and hinted about a possible mechanism for the brain dysfunction in Nf1 +/− mice. Electronic supplementary material The online version of this article (doi:10.1186/s13041-017-0309-8) contains supplementary material, which is available to authorized users.

In vivo recording in CA1 demonstrates alterations in hippocampal rhythmic oscillations and firing rates in Nf1 +/− mice. a The local field potentials (LFPs) recordings in CA1(WT mice). First trace- unfiltered LFPs, second trace- alpha oscillations (filtered 7–12 Hz). b Histograms show the averaged power spectral density of the neuronal rhythmic oscillations (alpha). Data are expressed as mean ± SEM (WT, n = 5; Nf1 +/− , n = 5). Two-way analysis of variance with repeated measures and post hoc Bonferroni tests was used to evaluate differences in local field potential power spectrum density in day and night recordings in Nf1 +/− and WT groups. ***p

The correlation is shown between theta oscillation and MAPK level in hippocampus. The averaged power spectral density of the neuronal rhythmic oscillations (theta) was shown. The pErk1/2 expression in Nf1 +/â mice and littermates WT mice were evaluated by western blot analysis at day and night. (PDF 421Â kb)

Rationale: Extracorporeal membrane oxygenation (ECMO) is a well-known technique to provide cardio-pulmonary support. Although continuous renal replacement therapy (CRRT) is frequently indicated, the need for faster fluid removal as the primary indication for ECMO is uncommon. Experiences on concomitant applications of ECMO, peritoneal dialysis (PD) and CRRT in neonates are relatively limited. Patient concerns: We report a 2-day-old male neonate with life-threatening hyaline membrane disease (HMD), accompained by severe systemic fluid retention, sepsis and abdominal compartment syndrome. Diagnosis: Hyaline membrane disease (HMD), neonatal respiratory distress syndrome, sepsis, capillary leakage syndrome, and abdominal compartment syndrome. Intervention: Veno-arterial ECMO, CRRT, and PD were synchronously initiated for the sake of faster fluid removal possible. Outcomes: The infant was successfully weaned from ECMO circuit and fluid overload was greatly improved four days after extracorporeal life support (ECLS), without major complications. Lessons: Initiation of CRRT and PD during ECMO therapy is effective and safe to release fluid overload in neonates, and severe complications are absent. When a neonate requires dialysis of urgency, ECMO offers assured vascular access to hemodialysis, allowing faster fluid removal.

Objective Increasing evidence shows that some cardiac defects may benefit from fetal interventions, including fetal cardiac surgery. We attempted to develop an in vivo animal model of fetal cardiopulmonary bypass with cardioplegic arrest. Methods Operations were performed on 14 pregnant goats. The extracorporeal circulation circuit consisted of a centrifugal pump, silicone tubings with an inner diameter of 6 mm, a roller pump, and a reservoir. The placenta was the sole oxygenator. Cardiopulmonary bypass was maintained at a mean flow rate of 344 ± 68 mL/kg/min, including 30 minutes of cardiac arrest and 15 minutes of reperfusion. Mean arterial blood pressure and heart rate were monitored. Arterial blood samples were analyzed. The pulse index and resistance index of the fetal umbilical artery were monitored. Results Experiments were completed in 11 cases (79%), with the fetuses weighing 0.65 to 1.8 kg. Fetal mean arterial blood pressure and heart rate remained stable throughout the experiments. A decrease in partial pressure of oxygen with concomitant increase in carbon dioxide partial pressure was noted, but trends were relatively stable. Metabolic acidosis was recognized during and after cardiac bypass. The pulse index and resistance index of the umbilical artery increased significantly after 2 hours off bypass. Conclusions We confirmed the technical feasibility of establishing an in vivo model of fetal cardiac bypass with cardioplegic arrest. This fetal goat model provides reproducible data and is suitable to study clinically relevant problems related to fetal cardiopulmonary bypass, myocardial protection, and hemodynamics.

The aim of this study is to evaluate the effect of fetal cardiac bypass on the production and secretion of fetal atrial natriuretic peptide (ANP) in the goat. Eighteen pregnant goats, at days 120 to 140 of gestation, were randomly divided into control (n = 8) and bypass (n = 10) groups. The control group underwent a sham procedure involving fetal sternotomy and cannulation. The bypass group underwent fetal cardiac bypass using a centrifugal pump for 30 min. Fetuses in the bypass group exhibited hypoxia, hypercapnia, and acidosis during and after cardiac bypass. The pulse index (PI) of the umbilical artery in the bypass group increased significantly after cardiac bypass compared with the control group. Tei indices of the left and right ventricles in the bypass group increased remarkably after cardiac bypass. Plasma troponin I levels in the bypass group increased significantly compared with that of the control group. Plasma ANP levels increased markedly in the bypass group after cardiac bypass, and the difference between two groups was significant. Transcriptional levels of ANP mRNA in the fetal heart elevated remarkably in the bypass group compared with the control group at 2 h after the bypass. A significant positive correlation between plasma ANP levels and Tei indices of the ventricles, plasma troponin I was observed (left ventricular Tei index, r = 0.606, P < 0.01; right ventricular Tei index, r = 0.581, P < 0.01; plasma troponin I, r = 0.275, P < 0.05). In conclusion, fetal cardiac bypass promoted the production and secretion of ANP and was associated with fetal cardiac dysfunction.

Background To evaluate the effects of leukocyte-depleting filtration on myocardial and pulmonary protection and the inflammatory response in patients undergoing valve surgery. Methods Fifty-two patients who underwent mitral valve or mitral and aortic valve replacement were randomized into two groups with or without a leukocyte-depleting filter during surgery. The filter was used from 10 minutes before the release of the aortic cross-clamp to the end of cardiopulmonary bypass. Results Total leukocyte and neutrophil counts showed a short-term reduction in patients undergoing leukocyte filtration, but there was no significant difference between the two groups during the study. Serum levels of cardiac troponin I were lower than that of the control group (p=0.030). Leukocyte depletion resulted in a significantly higher oxygenation index (p=0.002) and a lower respiratory index (p=0.003) compared with the control group. Serum levels of interleukin-8 were significantly elevated in patients undergoing leukocyte filtration compared with patients without leukocyte filtration (p=0.001). There were no statistically significant differences between the two groups with regards to the concentration of interleukin-6 and TNFα, or the duration of intensive care and hospital stay. Conclusions Leukocyte depletion is associated with improved myocardial and lung protection but does not appear to attenuate the inflammatory response in valve surgery.

To study the hormonal and metabolic responses of fetal lamb during cardiopulmonary bypass.Six pregnant ewes underwent fetal cardiopulmonary bypasses with artificial oxygenators and roller pumps for 30 minutes, which maintained the blood gas value at the fetal physiological level. The fetal blood pressure, heart rate, pH value and blood lactate levels were monitored. The levels of catecholamine, cortisol and insulin were measured pre-bypass and then again 30 minutes later. The blood glucose and free fatty acid levels were monitored continuously during the bypass. Fetal hepatic PAS staining was also carried out.There were no changes before and during the bypass in fetal blood pressure, heart rate and blood gas. However, pH values decreased and blood lactate levels increased (P0.05). The fetal catecholamine and cortisol levels increased significantly (P0.01), while the levels of insulin did not change. The blood glucose and free fatty acid levels increased at the beginning of the bypass (P0.01), and then gradually slowed down during the bypass. The fetal hepatic PAS staining showed that hepatic glycogen was consumed in large amounts. After 30 minutes of bypass, the fetal lamb would not survive more than 1 hour.The fetal lamb has a strong negative reaction to cardiopulmonary bypass.

Objective One of the most significant responses to fetal cardiac bypass is severe placental dysfunction characterized by increased vascular resistance. We tested the hypothesis that fetal cardiac bypass triggers the activation of nuclear factor kappa-B (NF-KB), a major regulator of inflammatory response, and that pharmacologic inhibition of NF-KB activation by pyrrolidine dithiocarbamate alleviates fetal cardiac bypass–induced placental dysfunction. Methods Fifteen pregnant goats at 120 to 140 days' gestation were equally divided into the control group with a sham procedure of fetal sternotomy and cannulation (CG), the fetal bypass group (FB), and the fetal bypass group with 300 mg pyrrolidine dithiocarbamate before sternotomy (FP). Fetal cardiac bypass was performed for 30 minutes. Umbilical arterial flow rate was measured by ultrasonic flowmeter and placental vascular resistance was calculated. Fetal plasma levels of nitric oxide (NO), endothlin-1 (ET-1), 6-keto-prostaglandin F1α (6-K), thromboxane B 2 (TXB2), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α) were assayed. IL-6 and TNF-α mRNA were analyzed by real-time polymerase chain reaction. NF-KB activation was evaluated by electrophoretic mobility shift assay. Results Placental vascular resistance significantly increased in the FB and FP groups compared with the CG group. Increases in plasma levels of NO were observed in all 3 groups. Plasma levels of ET-1 rose significantly in the FB and FP groups without noticeable difference between them. Plasma levels of 6-K, TXB 2 , IL-6, and TNF-α increased significantly in the FB group compared with the CG and FP groups. The transcription levels of IL-6 and TNF-α mRNA in the placental tissues of the FB group were significantly higher than in the FP and CG groups. The amount of activated NF-KB in the placental tissues of the FB group was also significantly higher than that in the FP and CG groups. Conclusions Fetal cardiac bypass–induced inflammatory response possibly mediated by NF-KB caused placental dysfunction. Pharmacologic inhibition of NF-KB activation and decrease in the inflammatory response did not alleviate the placental dysfunction.