Clinical Symptoms Affect Treatment and Prognosis in Pediatric Patients with Congenital Pulmonary Airway Malformation: A Propensity Score Matching Retrospective Cohort Study.

OBJECTIVES: Surgery for asymptomatic congenital pulmonary airway malformation patients is still debatable at this time. This study aims to investigate the safety and efficacy of surgery for asymptomatic patients, as well as the factors influencing the symptoms of this group of patients. METHODS: An institutional database was sampled for congenital pulmonary airway malformation patients. Patients were divided into the symptomatic group and the asymptomatic group. Propensity score matching (PSM) analysis selected patients in each group to compare perioperative outcomes. A multivariable logistic regression analysis was performed to investigate the potential influences on symptomatic lesions. RESULTS: The asymptomatic group had better perioperative results than the symptomatic group, including shorter operating times (119.39 ± 49.42 min vs 100.73 ± 23.09 min, P = 0.031), shorter postoperative mechanical ventilation (2 h [0.5-46] vs 1 h [0.5-5], P = 0.002), shorter chest tube durations (4d [2-29] vs 3d [2-10], P = 0.007), and shorter postoperative hospital stays (10d [6-36] vs 8d [6-16], P < 0.001). With the conversion to thoracotomy and postoperative complications, there was no statistically significant difference between the two PSM-matched groups (P > 0.05). Age (p = 0.037), postnatal diagnosis (p = 0.018), and maximum cyst diameter (p = 0.032) were found to be independent variables associated with symptomatic lesions by multivariable logistic regression. CONCLUSIONS: Patients with congenital pulmonary airway malformation appear to have better perioperative outcomes before the beginning of symptoms. Symptomatic pulmonary lesions were associated with age, postnatal diagnosis, and maximum cyst diameter. LEVEL OF EVIDENCE: Level III.

Association of increased risk of cardiovascular diseases with higher levels of perfluoroalkylated substances in the serum of adults.

Evidence showing the association of perfluoroalkylated substance (PFAS) exposure with CVD risk is scarce. The objective of this study was to explore the relationships of CVD risk with mixed or individual serum PFAS levels among general adults. We analyzed combined data of 7904 adults who participated in the National Health and Nutrition Examination Survey 2003-2012 with a Bayesian kernel machine regression (BKMR) to examine the relationships of individual or mixed PFAS exposure with total CVD risk. A logistic regression model and restricted cubic spline (RCS) regression with multivariate adjustment were conducted to assess the relationships between individual serum PFAS levels and the risk of total CVD or its subtypes. A mediation model was applied to investigate how C-reactive protein (CRP) levels mediate the strength of the association. The BKMR results indicated a positive relationship between mixed PFAS exposure and total CVD risk; among the PFASs, perfluorooctane sulfonic acid (PFOS) had the highest posterior inclusion probability. As determined by logistic regression, a log-unit change in PFOS levels was positively related to a higher risk of heart attack and stroke in males (both P < 0.05). A nonlinear relationship was found between PFOS levels and stroke risk (P for nonlinearity = 0.04), as illustrated in the RCS plot. The mediation analysis showed that CRP levels mediated 8% and 1.2% of the relationship between serum PFOS and PFNA levels, respectively, and the prevalence of stroke. A significant relationship between higher serum PFAS concentrations and an increased risk of CVD was observed, mainly in males.

Joint association of polycyclic aromatic hydrocarbons and heavy metal exposure with pulmonary function in children and adolescents aged 6-19 years.

Studies have reported associations between polycyclic aromatic hydrocarbon (PAH) or heavy metal (HM) exposure and respiratory diseases. However, evidence of their joint associations with pulmonary function, especially in children and adolescents aged 6-19 years, is lacking. We utilized cross-sectional data from 1,734 children and adolescents aged 6-19 years collected in the National Health and Nutrition Examination Survey 2007-2012 and analysed mixed PAH and mixed HM exposures and their joint association with pulmonary function by applying weighted quantile sum (WQS) regression and Bayesian kernel machine regression (BKMR). Multivariate linear regressions were carried out to determine the relationships between individual urinary PAH metabolites or blood HM levels and pulmonary function indices. We found that mixed PAHs and HMs were negatively related to forced expiratory volume in 1 s (FEV1) in subjects aged 6-12 years (all p values < 0.05). We found synergistic associations of PAH and HM exposure on pulmonary function impairment, mainly in children; lead (Pb) was the most damaging. In the analysis of individual PAH metabolites or HMs, Pb exposure was negatively associated with FEV1 values in all subgroups (all p values < 0.05). Thus, our findings indicate that increased PAH or HM exposure is associated with impairments to pulmonary function and that this association is more pronounced in children.

Low-level plasticizer exposure and all-cause and cardiovascular disease mortality in the general population.

BACKGROUND: Plasticizers, also called phthalates, are a group of chemicals widely used in daily life. A previous report showed no significant association between phthalate metabolite concentrations and mortality. We investigated the association of urinary phthalate levels and individual phthalate metabolite levels with all-cause and cardiovascular disease (CVD) mortality after standardizing the phthalate concentration. METHODS: A total of 6,625 participants were recruited from a nationally representative sample of adults aged 40 years or older who were enrolled in the National Health and Nutrition Examination Survey (NHANES) between 2003 and 2014 and were followed up through December 31, 2015. Data were analyzed from January 2021 to June 2021. NHANES-linked updated National Death Index public access files were used to acquire information on mortality status and cause of death. The present study conducted extended follow-up of an earlier analysis. Cox proportional hazard models were performed to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) of covariate-adjusted creatinine standardization urinary phthalate concentrations with all-cause and CVD mortality after adjusting for demographics, lifestyle factors and comorbidity variables. RESULTS: The mean ± standard deviation age of all participants in the final study was 59.9±12.6 years old, and 49.6% of the participants were male. The median follow-up time was 73 months (range 1-157 months). At the censoring date of December 31, 2015, 3,023 participants were identified as deceased (13.4%). A fully adjusted Cox model showed that a urinary di(2-ethylhexyl) phthalate (DEHP) concentration >= 83.4 ng/mL was associated with a slight increase in all-cause mortality (HR 1.27, 95% CI 1.03, 1.57, P for trend= 0.014) and CVD mortality (HR 2.19, 95% CI 1.35, 3.54, P for trend= 0.002). Similarly, urinary mono-2-ethyl-5-carboxypentyl phthalate (MECPP) levels >= 39.2 ng/mL were associated with increased CVD mortality (HR 2.33, 95% CI 1.45, 3.73, P for trend < 0.001). Restricted cubic spline analyses suggested linear associations of DEHP and MECPP levels with all-cause and CVD mortality. CONCLUSION: In this large nationally representative sample of American adults, high urinary DEHP and MECPP were significantly associated with all-cause and CVD mortality after adjusting for demographics, lifestyle factors and comorbidity variables.

The relationship between multiple perfluoroalkyl substances and cardiorespiratory fitness in male adolescents.

Exposure to perfluoroalkyl substances (PFASs) is associated with a number of adverse health outcomes. However, the relationship between mixed and individual PFAS exposure and cardiorespiratory fitness (CRF) in adolescents remains unclear. We used cross-sectional data from 491 teenagers (aged 13-19 years) from the 2003-2004 National Health and Nutrition Examination Survey (NHANES) and examined the association between mixed PFAS exposure and CRF via weighted quantile sum (WQS) regression. Maximal oxygen consumption (VO2max) was used to evaluate CRF. Multivariate linear regression was performed to investigate the relationship between each PFAS and VO2max as well as the relationship between PFAS exposure and the inflammation parameters and blood lipid content. Mediation analyses were performed to investigate possible explanations of the risk of low CRF due to PFAS exposure. The results showed that for males, mixed PFAS exposure was negatively related to VO2max (beta = - 0.80, 95% CI: - 1.53 to - 0.10, P = 0.028) and that of the PFASs, perfluorononanoic acid (PFNA) had the greatest influence on VO2max. In the individual PFAS analysis, PFNA was negatively related to VO2max in male adolescents (beta = - 1.49, 95% CI: - 2.65 to - 0.32, P = 0.013). Additionally, significant relationships among serum PFNA levels and total cholesterol and the white blood cell (WBC) count were found. Mediation analyses revealed that WBC count accounted for 24.18% of the variation between PFNA level and CRF. The present results provide epidemiological evidence that exposure to PFASs, mainly PFNA, is negatively associated with CRF, possibly via alterations in WBC count.

Urinary levels of Phthalate metabolite mixtures and pulmonary function in adolescents.

Although an association between urinary phthalate (PAE) metabolites and respiratory symptoms and diseases has been reported, knowledge regarding its effect on pulmonary function is limited, especially in adolescents. Using cross-sectional data from 1389 adolescents (aged 10-19 years) in the 2007-2012 National Health and Nutrition Examination Survey, the association of mixed urinary PAE metabolites with pulmonary function was evaluated using the weighted quantile sum. Moreover, multivariate linear regression was performed to investigate associations between each urinary PAE metabolite and pulmonary function indicators and to estimate the interaction effects between urinary PAE metabolites and demographic characteristics. We found that mixed urinary PAE metabolites were negatively associated with forced expiratory volume at the 1 s (FEV1, p < 0.001) and forced vital capacity (FVC, p = 0.008) levels. In individual PAE metabolite analyses, mono (carboxynonyl) pthalate (MCNP), mono-n-butyl pthalate (MnBP), mono-isobutyl pthalate (MiBP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) and mono-benzyl phthalate (MBzP) correlated negatively with both FVC and FEV1 values (Holm-Bonferroni corrected p < 0.05). Mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) was negatively associated with the FVC value. Significant interactions between sex and urinary MnBP or MBzP levels for the risk of FEV1 decrease in girls were found (p = 0.005), as was a significant interaction between sex and urinary MBzP level for the risk of FVC decline. Our findings suggest that higher PAE exposure is associated with respiratory dysfunction; the association is more pronounced among girls.

Associations of exposure to secondhand smoke with hypertension risk and blood pressure values in adults.

BACKGROUND: The effects of environmental chemical exposure on blood pressure (BP) have been confirmed, but the association between exposure to secondhand smoke (SHS) and hypertension risk and BP in the general population remains unknown. METHODS: Cross-sectional associations between SHS exposure and hypertension risk and BP values were evaluated using data for subjects who participated in the National Health and Nutrition Examination Survey (NHANES), 1999-2016. Logistic regression and linear regression were performed after adjusting for age, sex, race, alcohol consumption, poverty-to-income ratio (PIR), body mass index (BMI), estimated glomerular filtration rate, physical activity, diabetes, cardiovascular disease, and NHANES cycle. Restricted cubic spline models were created to display the potential nonlinear association between SHS and BP levels. RESULTS: Higher risk of hypertension was found at the highest SHS concentrations (OR = 1.13, 95% CI 1.04, 1.24, P for trend = 0.007). Additionally, SHS exposure had a strong positive association with systolic blood pressure (SBP) but was negatively associated with diastolic blood pressure (DBP). Furthermore, the nonlinear model result showed a significant association between SHS and SBP (P = 0.017); however, the nonlinear model result was not significant for SHS or DBP. CONCLUSIONS: Our results suggest a potential association between high SHS exposure and the risk of hypertension. Further research is needed to elucidate the underlying mechanisms.

Association between blood ethylene oxide levels and the risk of cardiovascular diseases in the general population.

Ethylene oxide (EtO) is a highly reactive organic compound that is mainly used as a sterilizing agent. However, to date, the effects of EtO on the cardiovascular system are not clear. We aimed to explore the association between blood EtO levels and the risk of cardiovascular disease (CVD) in the general US population. We obtained information on blood levels of EtO and CVD outcomes in 3,410 participants from the National Health and Nutritional Examination Survey (NHANES) 2013-2014 and 2015-2016. Logistic regression models were applied to calculate the odds ratios (ORs) and 95% confidence intervals (95% CIs) for the association between EtO and risk of all CVD as well as subtypes of CVD. Linear regression analyses were used to estimate the associations of EtO with potential mechanistic parameters of CVD, including blood pressure, blood lipid levels and inflammatory parameters. Higher blood levels of EtO were associated with an increased risk of all CVD (p for trend = 0.003), with an adjusted OR (95% CI) in the highest quartile of 1.94 (1.24, 3.02) compared with the lowest quartile as a reference. Higher concentrations of EtO were positively associated with the risk of angina (p for trend = 0.04) and heart attack (p for trend = 0.011). In addition, the concentration of EtO was positively associated with the levels of triglycerides, white blood cells, lymphocytes, monocytes, neutrophils and eosinophils (p = 0.003 for eosinophils and p < 0.001 for the others) and negatively associated with the level of high-density lipoprotein cholesterol (p < 0.001). We found that exposure to EtO was associated with angina, heart attack and all CVD in a large representative US population. Furthermore, EtO may induce CVD through the inflammatory response and abnormal fatty acid metabolism.

Correction: High-aspect-ratio water-dispersed gold nanowires incorporated within gelatin methacrylate hydrogels for constructing cardiac tissues in vitro.

Correction for 'High-aspect-ratio water-dispersed gold nanowires incorporated within gelatin methacrylate hydrogels for constructing cardiac tissues in vitro' by Xiao-Pei Li et al., J. Mater. Chem. B, 2020, 8, 7213-7224, DOI: .

High-aspect-ratio water-dispersed gold nanowires incorporated within gelatin methacrylate hydrogels for constructing cardiac tissues in vitro.

The field of cardiac tissue engineering has made significant strides in therapeutic and pharmaceutical applications, highlighted by the development of smart biomaterials. Scaffolds with appropriate properties mimicking the nature of a heart matrix will be highly beneficial for cardiac tissue engineering. In this study, high-aspect-ratio water-dispersed gold nanowires (AuNWs) were synthesized and incorporated into gelatin methacrylate (GelMA) hydrogels, demonstrating enhanced electrical conductivity and mechanical properties of the biomaterial scaffolds. Cardiac cells cultured on GelMA-AuNW hybrid hydrogels exhibited better biological activities such as cell viability and maturation state compared to those cultured on GelMA hydrogels. Moreover, cardiomyocytes showed synchronous beating activity and a faster spontaneous beating rate on GelMA-AuNW hybrid hydrogels. Our strategy of integrating high-aspect-ratio water-dispersed gold nanowires within gelatin methacrylate hydrogels provides a favorable biomaterial scaffold to construct functional cardiac tissue for further applications in cardiac tissue engineering and drug screening.

Small-molecule-based generation of functional cardiomyocytes from human umbilical cord-derived induced pluripotent stem cells.

The purpose of this study was to investigate the cardiac-differentiation potential of induced pluripotent stem cells (iPSCs) generated from human umbilical cord-derived mesenchymal cells. Spontaneous beating colonies were observed at day 7 after the sequential addition of CHIR99021 and IWP-4. The combined use of CHIR99021 and IWP-4 downregulated the expression of pluripotency markers while upregulating cardiac transcription factors and cardiomyocyte-specific markers. The derived cardiomyocytes demonstrated typical sarcomeric structures and action-potential features; most importantly, the derived cells exhibited responsiveness to ß-adrenergic and muscarinic stimulations. The analyses of molecular, structural, and functional properties revealed that the derived cardiomyocytes were similar to cardiomyocytes derived from BJ foreskin fibroblast cells. In summary, our results demonstrate that functional cardiomyocytes can be generated from human umbilical cord-derived cells. The methodology described here has potential as a means for the production of functional cardiomyocytes from discarded human umbilical cord tissue.

Efficient generation of functional cardiomyocytes from human umbilical cord-derived virus-free induced pluripotent stem cells.

We have previously demonstrated that human umbilical cord-derived mesenchymal stem cells (UC-MSCs) can differentiate into cardiomyocyte-like cells. However, no contracting cells were observed during differentiation. In this study, we generated induced pluripotent stem cells (iPSCs) from UC-MSCs using mRNA reprogramming and focused on the differentiation of reprogrammed iPSCs into functional cardiomyocytes. For cardiac differentiation, the spontaneously contracting cell clusters were present on day 8 of differentiation. Immunostaining studies and cardiac-specific gene expression confirmed the cardiomyocyte phenotype of the differentiated cells. Electrophysiology studies indicated that iPSCs derived from UC-MSCs had a capacity for differentiation into nodal-, atrial-, and ventricular-like phenotypes based on action potential characteristics, and the derived cardiomyocytes exhibited responsiveness to ß-adrenergic and muscarinic stimulations. Moreover, the derived cardiomyocytes displayed spontaneous intracellular Ca2+ transients. These results demonstrate that functional cardiomyocytes can be generated from reprogrammed UC-MSCs, and the methodology described here will serve as a useful protocol to obtain functional cardiomyocytes from human mesenchymal stem cells.

MicroRNA-34a modulates the Notch signaling pathway in mice with congenital heart disease and its role in heart development.

The objective of the study was to elucidate the mechanism by which microRNA-34a (miR-34a) influences heart development and participates in the pathogenesis of congenital heart disease (CHD) by targeting NOTCH-1 through the Notch signaling pathway. Forty D7 pregnant mice were recruited for the purposes of the study and served as the CHD (n=20, successfully established as CHD model) and normal (n=20) groups. The positive expression of the NOTCH-1 protein was evaluated by means of immunohistochemistry. Embryonic endocardial cells (ECCs) were assigned into the normal, blank, negative control (NC), miR-34a mimics, miR-34a inhibitors, miR-34a inhibitors+siRNA-NOTCH-1, siRNA-NOTCH-1, miR-34a mimics+NOTCH-1 OE and miR-34a mimics+crispr/cas9 (mutant NOTCH-1) groups. The expressions of miR-34a, NOTCH-1, Jagged1, Hes1, Hey2 and Csx in cardiac tissues and ECCs were determined by both RT-qPCR and western blotting methods. MTT assay and flow cytometry were conducted for cell proliferation and apoptosis measurement. A dual luciferase reporter assay was applied to demonstrate that NOTCH-1 was the target gene of miR-34a. In comparison to the normal group, the expressions of miR-34a, Jagged1, Hes1 and Hey2 displayed up-regulated levels, while the expressions of NOTCH-1 and Csx were down-regulated in the CHD group. Compared with the blank and NC groups, the miR-34a mimics and siRNA-NOTCH-1 groups displayed reduced expressions of NOTCH-1 and Csx as well as a decreased proliferation rate, higher miR-34a, Jagged1, Hes1 and Hey2 expressions and an increased rate of apoptosis; while an reverse trend was observed in the miR-34a inhibitors group. The expressions of MiR-34a recorded increased levels in the miR-34a mimics+NOTCH-1 OE and miR-34a mimics+crispr/cas9 (mutant NOTCH-1) groups, however no changes in the expressions of NOTCH-1, Jagged1, Hes1, Hey2, Csx, as well as cell proliferation and apoptosis were observed when compared to the blank and NC groups. The results of our study demonstrated that miR-34a increases the risk of CHD through its downregulation of NOTCH-1 by modulating the Notch signaling pathway.

Isolation, characterization and cardiac differentiation of human thymus tissue derived mesenchymal stromal cells.

Mesenchymal stromal cells (MSCs) are promising candidate donor cells for replacement of cardiomyocyte loss during ischemia and in vitro generation of myocardial tissue. We have successfully isolated MSCs from the discarded neonatal thymus gland during cardiac surgery. The thymus MSCs were characterized by cell-surface antigen expression. These cells have high ability for proliferation and are able to differentiate into osteoblasts and adipocytes in vitro. For cardiac differentiation, the cells were divided into 3 groups: untreated control; 5-azacytidine group and sequential exposure to 5-azacytidine, bone morphogenetic protein 4, and basic fibroblast growth factor. Thymus MSCs showed a fibrolast-like morphology and some differentiated cells increased in size, formed a ball-like appearance over time and spontaneously contracting cells were observed in sequential exposure group. Immunostaining studies, cardiac specific genes/protein expression confirmed the cardiomyocyte phenotype of the differentiated cells. These results demonstrate that thymus MSCs can be a promising cellular source for cardiac cell therapy and tissue engineering.

Cardiac cell therapy: pre-conditioning effects in cell-delivery strategies.

Stem-cell therapy holds great promise for the treatment of ischemic heart disease. However, the benefit of cardiac cell therapy has not yet been proven in long-term clinical trials. Poor engraftment and survival of transplanted cells is one of the major concerns for the successful application of stem cells in cardiac cell therapy. Cell and cardiac pre-conditioning are now being explored as new approaches to support cell survival and enhance the therapeutic efficacy. In this paper, we summarize the state-of-the-art methods of cell delivery and cell survival post-delivery, with a focus on the pre-conditioning approaches that have been attempted to support the survival of transplanted cells.

Cell delivery in cardiac regenerative therapy.

There is a growing interest in the clinical application of stem cells as a novel therapeutic approach for treatment of myocardial infarction and prevention of subsequent heart failure. Transplanted stem cells improve cardiac functions through multiple mechanisms, which include but are not limited to promoting angiogenesis, replacing dead cardiomyocytes, modulating cardiac remodeling. Most of the results obtained so far are exciting and very promising, spawning an increasing number of clinical trials recently. However, many problems still remain to be resolved such as the best delivery method for transplantation of cells to the injured myocardium and the issue of how to optimize the delivery of targeted cells is of exceptional clinical relevance. In this review, we focus on the different delivery strategies in cardiac regenerative therapy, as well as provide a brief overview of current clinical trials utilizing cell-based therapy in patients with ischemic heart disease.

Thymosin beta 4 treatment after myocardial infarction does not reprogram epicardial cells into cardiomyocytes.

Myocardial infarction (MI) is one of the leading causes of morbidity and mortality world-wide. Whether endogenous repair and regenerative ability could be augmented by drug administration is an important issue for generation of novel therapeutic approach. Recently it was reported that in mice pretreated with thymosin beta 4 (TB4) and subsequently subjected to experimental MI, a subset of epicardial cells differentiated into cardiomyocytes. In clinical settings, epicardial priming with TB4 prior to MI is impractical. Here we tested if TB4 treatment after MI could reprogram epicardium into cardiomyocytes and augment the epicardium's injury response. Using epicardium genetic lineage trace line Wt1(CreERT2/+) and double reporter line Rosa26(mTmG/+), we found post-MI TB4 treatment significantly increased the thickness of epicardium and coronary capillary density. However, epicardium-derived cells did not adopt cardiomyocyte fate, nor did they migrate into myocardium to become coronary endothelial cells. Our result thus indicates that TB4 treatment after MI does not alter epicardial cell fate to include the cardiomyocyte lineage, providing both cautions and insights for the full exploration of the potential benefits of TB4 in the clinical settings. This article is part of a Special Issue entitled 'Possible Editorial'.

Stem cell engraftment and survival in the ischemic heart.

Cellular therapy has emerged as a potentially novel treatment for severe ischemic heart disease, and there is increasing evidence that stem cell transplantation may improve the perfusion and contractile function of ischemic myocardium. However, the problem of poor donor cell engraftment and survival in ischemic myocardium limits the successful use of cellular therapy for treating ischemic heart disease. This review discusses the state-of-the-art understanding of the low level of cell engraftment and cell survival after transplantation into the ischemic heart, with a focus on the approaches that have been investigated for supporting and improving the survival and engraftment of transplanted cells in this setting.

Cardiac potential of stem cells from whole human umbilical cord tissue.

We investigated the role of stem cells from human umbilical cord tissue in cardiomyocyte regeneration. The umbilical cord stem cells were initially characterized and differentiated in a myocardial differentiation medium containing 5-azacytidine for 24 h. Differentiation into cardiomyocytes was determined by expression of cardiac specific markers, like cardiac alpha-actin, connexin43, myosin, Troponin T, and ultrastructural analysis. In vivo, the transplanted umbilical cord stem cells were sprouting from local injection and differentiated into cardiomyocyte-like cells in a rat myocardial infarction model. Echocardiography revealed increasing left ventricular function after umbilical cord stem cell transplantation. These results demonstrate that umbilical cord stem cells can differentiate into cardiomyocyte-like cells both in vitro and in vivo. Therefore, human umbilical cord might represent a source of stem cells useful for cellular therapy and myocardial tissue engineering. Future studies are required to determine the molecular signaling mechanisms responsible for this phenomenon.