Publications by authors named "Xiaobin Wang"

418 Publications

Prospective association between baseline plasma zinc concentration and development of proteinuria in Chinese hypertensive patients.

J Trace Elem Med Biol 2021 Apr 2;66:126755. Epub 2021 Apr 2.

Division of Nephrology, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangdong Provincial Clinical Research Center for Kidney Disease, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, 510515, China. Electronic address:

Objective: We aimed to evaluate the association between baseline plasma zinc and the development of proteinuria as well as possible effect modifiers in hypertensive patients.

Methods: This is a subset of the China Stroke Primary Prevention Trial (CSPPT) Renal Sub-Study. In the CSPPT, participants were randomized to receive a daily oral dose of 1 tablet containing 10 mg enalapril and 0.8 mg folic acid or 1 tablet containing 10 mg enalapril only. A total of 783 participants with plasma zinc measurements and without proteinuria at baseline were included in the current study. The study outcome was the development of proteinuria during the follow-up, defined as a urine dipstick reading of trace or ≥1+ at the exit visit.

Results: During a median follow-up duration of 4.4 years, the development of proteinuria occurred in 93 (11.9 %) participants. There was an inverse relation of baseline plasma zinc with the development of proteinuria (per SD increment; OR, 0.74, 95 % CI: 0.55-0.99), p for trend of quartiles = 0.005.

Conclusions: In Chinese hypertensive patients, there was a significant inverse association between baseline plasma zinc and the development of proteinuria, although plasma zinc remained in the reference range.
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http://dx.doi.org/10.1016/j.jtemb.2021.126755DOI Listing
April 2021

A multi-magneto-inductive sensor array system for real-time magnetic field imaging of ferromagnetic targets.

Rev Sci Instrum 2021 Mar;92(3):035113

School of Automation, China University of Geosciences, Wuhan, Hubei 430074, China.

In this Note, we develop a real-time magnetic field imaging system by employing a multi-magneto-inductive (MI) sensor array. The sensor array consists of 3 × 3 tri-axial MI sensors, which we constructed by using three sensor coils. Outputs from several rows of sensors are routed to a master-controller responsible for data pre-processing and data reconstruction. The data are streamed to a host computer via a universal serial bus interface, and the image can be generated and displayed at a rate of several frames per second. The magnetic field imaging is implemented on a knowledge of the MI sensors' response, magnetic field perturbations, and the nature of the ferromagnetic object respecting permeability and conductivity. The performance of the system has been further evaluated by extensive numerical modeling of magnetic field distribution patterns with partial differential equation solution. The proposed magnetic field imaging system can be employed in many potential applications, for instance, medicine, security screening, quality assurance, and other areas of nondestructive evaluation, designs associated with magnetic fields, teaching, and research.
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http://dx.doi.org/10.1063/5.0039894DOI Listing
March 2021

Systematic Profiling of Alternative Splicing Events in Ovarian Cancer.

Front Oncol 2021 8;11:622805. Epub 2021 Mar 8.

Cancer Center, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.

Alternative splicing (AS) is significantly related to the development of tumor and the clinical outcome of patients. In this study, our aim was to systematically analyze the survival-related AS signal in ovarian serous cystadenocarcinoma (OV) and estimate its prognostic validity in 48,049 AS events out of 21,854 genes. We studied 1,429 AS events out of 1,125 genes, which were significantly related to the overall survival (OS) in patients with OV. We established alternative splicing features on the basis of seven AS events and constructed a new comprehensive prognostic model. Kaplan-Meier curve analysis showed that seven AS characteristics and comprehensive prognostic models could strongly stratify patients with ovarian cancer and make them distinctive prognosis. ROC analysis from 0.781 to 0.888 showed that these models were highly efficient in distinguishing patient survival. We also verified the prognostic characteristics of these models in a testing cohort. In addition, uni-variate and multivariate Cox analysis showed that these models were superior independent risk factors for OS in patients with OV. Interestingly, AS events and splicing factor (SFs) networks revealed an important link between these prognostic alternative splicing genes and splicing factors. We also found that the comprehensive prognosis model signature had higher prediction ability than the mRNA signature. In summary, our study provided a possible prognostic prediction model for patients with OV and revealed the splicing network between AS and SFs, which could be used as a potential predictor and therapeutic target for patients with OV.
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http://dx.doi.org/10.3389/fonc.2021.622805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982604PMC
March 2021

LC-MS/MS-Based Quantitative Proteomics Analysis of Different Stages of Non-Small-Cell Lung Cancer.

Biomed Res Int 2021 26;2021:5561569. Epub 2021 Feb 26.

Department of Dermatology, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, China.

Lung cancer has a higher incidence rate and mortality rate than all other cancers. Early diagnosis and treatment of lung cancer remain a major challenge, and the 5-year survival rate of its patients is only 15%. Basic and clinical research, especially the discovery of biomarkers, is crucial for improving the diagnosis and treatment of lung cancer patients. To identify novel biomarkers for lung cancer, we used the iTRAQ8-plex labeling technology combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) to analyze the serum and urine of patients with different stages of lung adenocarcinoma and healthy individuals. A total of 441 proteins were identified in the serum, and 1,161 proteins were identified in the urine. The levels of elongation factor 1-alpha 2, proteasome subunit alpha type, and spermatogenesis-associated protein increased significantly in the serum of patients with lung cancer compared with those in healthy controls. The levels of transmembrane protein 143, cadherin 5, fibronectin 1, and collectin-11 decreased significantly in the serum of patients with metastases compared with those of nonmetastatic lung cancer patients. In the urine of stage III and IV lung cancer patients, the prostate-specific antigen and prostatic acid phosphatase decreased significantly, whereas neutrophil defensin 1 increased significantly. The results of LC-MS/MS were confirmed by enzyme-linked immunosorbent assay (ELISA) for transmembrane protein 143, cadherin 5, fibronectin 1, and collectin-11 in the serum. These proteins may be a potential early diagnosis and metastasis biomarkers for lung adenocarcinoma. Furthermore, the relative content of these markers in the serum and urine could be used to determine the progression of lung adenocarcinoma and achieve accurate staging and diagnosis.
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http://dx.doi.org/10.1155/2021/5561569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937045PMC
February 2021

Plasma lipidomics profile in pregnancy and gestational diabetes risk: a prospective study in a multiracial/ethnic cohort.

BMJ Open Diabetes Res Care 2021 Mar;9(1)

Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, USA

Introduction: Disruption of lipid metabolism is implicated in gestational diabetes (GDM). However, prospective studies on lipidomics and GDM risk in race/ethnically diverse populations are sparse. Here, we aimed to (1) identify lipid networks in early pregnancy to mid-pregnancy that are associated with subsequent GDM risk and (2) examine the associations of lipid networks with glycemic biomarkers to understand the underlying mechanisms.

Research Design And Methods: This study included 107 GDM cases confirmed using the Carpenter and Coustan criteria and 214 non-GDM matched controls from the National Institute of Child Health and Human Development Fetal Growth Studies-Singleton cohort, untargeted lipidomics data of 420 metabolites (328 annotated and 92 unannotated), and information on glycemic biomarkers in maternal plasma at visit 0 (10-14 weeks) and visit 1 (15-26 weeks). We constructed lipid networks using weighted correlation network analysis technique. We examined prospective associations of lipid networks and individual lipids with GDM risk using linear mixed effect models. Furthermore, we calculated Pearson's partial correlation for GDM-related lipid networks and individual lipids with plasma glucose, insulin, C-peptide and glycated hemoglobin at both study visits.

Results: Lipid networks primarily characterized by elevated plasma diglycerides and short, saturated/low unsaturated triglycerides and lower plasma cholesteryl esters, sphingomyelins and phosphatidylcholines were associated with higher risk of developing GDM (false discovery rate (FDR) <0.05). Among individual lipids, 58 metabolites at visit 0 and 96 metabolites at visit 1 (40 metabolites at both time points) significantly differed between women who developed GDM and who did not (FDR <0.05). Furthermore, GDM-related lipid networks and individual lipids showed consistent correlations with maternal glycemic markers particularly in early pregnancy at visit 0.

Conclusions: Plasma lipid metabolites in early pregnancy both individually and interactively in distinct networks were associated with subsequent GDM risk in race/ethnically diverse US women. Future research is warranted to assess lipid metabolites as etiologic markers of GDM.
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http://dx.doi.org/10.1136/bmjdrc-2020-001551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7939004PMC
March 2021

DNA methylation mediates the effect of maternal smoking on offspring birthweight: a birth cohort study of multi-ethnic US mother-newborn pairs.

Clin Epigenetics 2021 Mar 4;13(1):47. Epub 2021 Mar 4.

Department of Biostatistics, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, 21205, USA.

Background: Maternal smoking affects more than half a million pregnancies each year in the US and is known to result in fetal growth restriction as measured by lower birthweight and its associated long-term consequences. Maternal smoking also has been linked to altered fetal DNA methylation (DNAm). However, what remains largely unexplored is whether these DNAm alterations are merely markers of smoking exposure or if they also have implications for health outcomes. This study tested the hypothesis that fetal DNAm mediates the effect of maternal smoking on newborn birthweight.

Methods: This study included mother-newborn pairs from a US predominantly urban, low-income multi-ethnic birth cohort. DNAm in cord blood were determined using the Illumina Infinium MethylationEPIC BeadChip. After standard quality control and normalization procedures, an epigenome-wide association study (EWAS) of maternal smoking was performed using linear regression models, controlling for maternal age, education, race, parity, pre-pregnancy body mass index, alcohol consumption, gestational age, maternal pregestational/gestational diabetes, child sex, cord blood cell compositions and batch effects. To quantify the degree to which cord DNAm mediates the smoking-birthweight association, the VanderWeele-Vansteelandt approach for single mediator and structural equational model for multiple mediators were used, adjusting for pertinent covariates.

Results: The study included 954 mother-newborn pairs. Among mothers, 165 (17.3%) ever smoked before or during pregnancy. Newborns with smoking exposure had on average 258 g lower birthweight than newborns without exposure (P < 0.001). Using a false discovery rate (FDR) < 0.05 as the significance cutoff, the EWAS identified 38 differentially methylated CpG sites associated with maternal smoking. Of those, 17 CpG sites were mapped to previously reported genes: GFI1, AHRR, CYP1A1, and CNTNAP2; 8 of those, located in the first three genes, were Bonferroni significantly associated with newborn birthweight and mediated the smoking-birthweight association. The combined mediation effect of the three genes explained 67.8% of the smoking-birthweight association.

Conclusions: Our study not only lends further support that maternal smoking alters fetal DNAm in a multiethnic population, but also suggests that fetal DNAm substantially mediates the maternal smoking-birthweight association. Our findings, if further validated, indicate that DNAm modification is likely an important pathway by which maternal smoking impairs fetal growth and, perhaps, even long-term health outcomes.
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http://dx.doi.org/10.1186/s13148-021-01032-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931602PMC
March 2021

GASC1 promotes glioma progression by enhancing NOTCH1 signaling.

Mol Med Rep 2021 May 2;23(5). Epub 2021 Mar 2.

Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, P.R. China.

Recent studies have reported that gene amplified in squamous cell carcinoma 1 (GASC1) is involved in the progression of several types of cancer. However, whether GASC1 promotes glioma progression remains unknown. Therefore, the present study aimed to investigate the effect of GASC1 exposure on glioma tumorigenesis. The western blot demonstrated that grade III and IV glioma tissues exhibited a higher mRNA and protein expression of GASC1. Moreover, CD133+ U87 or U251 cells from magnetic cell separation exhibited a higher GASC1 expression. Invasion Transwell assay, clonogenic assay and wound healing assay have shown that GASC1 inhibition using a pharmacological inhibitor and specific short hairpin (sh)RNA suppressed the invasive, migratory and tumorsphere forming abilities of primary culture human glioma cells. Furthermore, GASC1‑knockdown decreased notch receptor (Notch) responsive protein hes family bHLH transcription factor 1 (Hes1) signaling. GASC1 inhibition reduced notch receptor 1 (NOTCH1) expression, and a NOTCH1 inhibitor enhanced the effects of GASC1 inhibition on the CD133+ U87 or U251 cell tumorsphere forming ability, while NOTCH1 overexpression abrogated these effects. In addition, the GASC1 inhibitor caffeic acid and/or the NOTCH1 inhibitor DAPT (a γ‑Secretase Inhibitor), efficiently suppressed the human glioma xenograft tumors. Thus, the present results demonstrated the importance of GASC1 in the progression of glioma and identified that GASC1 promotes glioma progression, at least in part, by enhancing NOTCH signaling, suggesting that GASC1/NOTCH1 signaling may be a potential therapeutic target for glioma treatment.
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http://dx.doi.org/10.3892/mmr.2021.11949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7974312PMC
May 2021

A unique photoswitch: intrinsic photothermal heating induced reversible proton conductivity of a HKUST-1 membrane.

Dalton Trans 2021 Mar;50(8):2731-2735

State Key Laboratory of Silicon Materials, School of Materials Science and engineering, Zhejiang University Hangzhou, 310027, P.R. China.

In this work, a unique photoswitch is reported based on the intrinsic photothermal properties of a HKUST-1 metal-organic framework (MOF) membrane. The HKUST-1 membrane is synthesized through a solid conversion process at room temperature. It exhibits excellent reversible photoswitchable proton conductivity owing to its intrinsic localized photothermal effect with an optimal on/off ratio of 299 at 55 °C under 95% RH. This may have potential application in remote controlled smart devices.
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http://dx.doi.org/10.1039/d0dt04332jDOI Listing
March 2021

Antenatal and neonatal factors contributing to extra uterine growth failure (EUGR) among preterm infants in Boston Birth Cohort (BBC).

J Perinatol 2021 Feb 15. Epub 2021 Feb 15.

Center on the Early Life Origins of Disease, Department of Population Family and Reproductive Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.

Objective: Identify antenatal and neonatal factors associated with primary outcome of EUGR.

Methods: 1063 preterm infants from a subset of the BBC were included in this prospective cohort study. Regression analysis was carried out to evaluate associations of EUGR with antenatal factors and neonatal factors.

Results: 6.1% of the infants had in-utero growth restriction (IUGR) at birth and 21.7% of infants had EUGR. The adjusted odds ratio for EUGR status were significant for birth weight (OR 0.99, p = 0.00, CI 0.99-0.99), for GA at birth (OR 4.58, p = 0.00, CI 3.25-6.44), for PDA (OR 2.9, p = 0.02, CI 1.17-7.1), for NEC (OR 5.14, p = 0.012, CI 1.44-18.3) and for day of life of reaching full feeds (OR 1.04, p = 0.001, CI 1.01-1.06).

Conclusion: This study highlights important factors associated with EUGR. Additional studies are needed to gain further insight.
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http://dx.doi.org/10.1038/s41372-021-00948-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883994PMC
February 2021

Bioaugmentation by AAF1-5 Improves the Bacterial Activity and Diversity of Cereal Vinegar Under Solid-State Fermentation.

Front Microbiol 2020 28;11:603721. Epub 2021 Jan 28.

State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Fermentation Microbiology, College of Biotechnology, Ministry of Education, Tianjin University of Science and Technology, Tianjin, China.

Bioaugmentation technology may be an effective strategy to improve the solid-state fermentation rate and utilization of raw materials for traditional vinegar production. The relationship between bacteria and fermentation process was analyzed to rationally design and perform bioaugmented solid-state fermentation of the Tianjin Duliu mature vinegar (TDMV). Fermentation process was highly correlated with , and contents, which were the core functional microorganisms in TDMV fermentation. AAF1-5 was selected from 20 strains to fortify the fermentation due to its acidity and thermal tolerance. Bioaugmentation was performed in the upper layer of TDMV fermentation. AAF1-5 colonized and then spread into the lower layer to improve the fermentation. Result showed that the fermentation period was 5 days less than that of the control. Meanwhile, the non-volatile acid, lactic acid, amino nitrogen, and reducing sugar contents in the bioaugmented TDMV increased by 53%, 14%, 32%, and 36%, respectively, compared with those in the control. Bioaugmentation with AAF1-5 not only improved the utilization of starch from 79% to 83% but also increased the bacterial community diversity.
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http://dx.doi.org/10.3389/fmicb.2020.603721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876233PMC
January 2021

Neutrophil counts and the risk of first stroke in general hypertensive adults.

Hypertens Res 2021 Feb 9. Epub 2021 Feb 9.

National Clinical Research Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.

We aimed to investigate the association between neutrophil counts and first stroke and examine possible effect modifiers among treated hypertensive adults. This is a post hoc analysis of the China Stroke Primary Prevention Trial (CSPPT). A total of 11,878 hypertensive adults with data on neutrophil counts at baseline were included in the current study. The primary outcome was first stroke. During a median follow-up of 4.5 years, 414 (3.5%) participants experienced a first stroke, including 358 with ischemic stroke, 55 with hemorrhagic stroke and one with uncertain type of stroke. Compared with participants in quartile 1 (<2.9 × 10/L) of neutrophil counts, those in the upper quartiles (quartile 2-4 [≥2.9 × 10/L]) had a significantly higher risk of first stroke (HR, 1.35; 95% CI: 1.02, 1.78) or first ischemic stroke (HR, 1.38; 95% CI: 1.02, 1.86). Moreover, a strong positive association between neutrophil counts and first ischemic stroke was found in participants with total homocysteine (tHcy) levels <15 μmol/L (HR, 1.74; 95% CI: 1.17, 2.58; vs. ≥15 μmol/L; HR, 0.91; 95% CI: 0.57, 1.46, P interaction = 0.042) at baseline or time-averaged mean arterial pressure (MAP) ≥102 mmHg (median) (HR, 1.92; 95% CI: 1.27, 2.89; vs. <102 mmHg; HR, 0.89; 95% CI: 0.57, 1.41, P interaction = 0.015) during the treatment period. However, no such association between neutrophil counts and first hemorrhagic stroke was found. In summary, high baseline neutrophil counts were associated with an increased risk of first ischemic stroke among hypertensive patients, especially in those with low tHcy at baseline or high time-averaged MAP during the treatment period.
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http://dx.doi.org/10.1038/s41440-021-00625-1DOI Listing
February 2021

Relationship of Preeclampsia With Maternal Place of Birth and Duration of Residence Among Non-Hispanic Black Women in the United States.

Circ Cardiovasc Qual Outcomes 2021 Feb 10;14(2):e007546. Epub 2021 Feb 10.

Department of Population, Family and Reproductive Health (Y.A.K., X.H., Y.J., A.A.C., X.W.), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.

Background: Preeclampsia is one of the leading causes of maternal mortality in the United States. It disproportionately affects non-Hispanic Black (NHB) women, but little is known about how preeclampsia and other cardiovascular disease risk factors vary among different subpopulations of NHB women in the United States. We investigated the prevalence of preeclampsia by nativity (US born versus foreign born) and duration of US residence among NHB women.

Methods: We analyzed cross-sectional data from the Boston Birth Cohort (1998-2016), with a focus on NHB women. We performed multivariable logistic regression to investigate associations between preeclampsia, nativity, and duration of US residence after controlling for potential confounders.

Results: Of 2697 NHB women, 40.5% were foreign born. Relative to them, US-born NHB women were younger, in higher percentage current smokers, had higher prevalence of obesity (body mass index ≥30 kg/m) and maternal stress, but lower educational level. The age-adjusted prevalence of preeclampsia was 12.4% and 9.1% among US-born and foreign-born women, respectively. When further categorized by duration of US residence, the prevalence of all studied cardiovascular disease risk factors except for diabetes was lower among foreign-born NHB women with <10 versus ≥10 years of US residence. Additionally, the odds of preeclampsia in foreign-born NHB women with duration of US residence <10 years was 37% lower than in US-born NHB women. In contrast, the odds of preeclampsia in foreign-born NHB women with duration of US residence ≥10 years was not significantly different from that of US-born NHB women after adjusting for potential confounders.

Conclusions: The prevalence of preeclampsia and other cardiovascular disease risk factors is lower in foreign-born than in US-born NHB women. The healthy immigrant effect, which typically results in health advantages for foreign-born women, appears to wane with longer duration of US residence (≥10 years). Further research is needed to better understand these associations.
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http://dx.doi.org/10.1161/CIRCOUTCOMES.120.007546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887058PMC
February 2021

Relationship of several serum folate forms with the risk of mortality: A prospective cohort study.

Clin Nutr 2021 Jan 27. Epub 2021 Jan 27.

Division of Nephrology, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, 510515, China. Electronic address:

Objective: We aim to examine the relation of several folate forms (5-methyltetrahydrofolate [5-mTHF], unmetabolized folic acid [UMFA], non-methyl folate, and MeFox [pyrazino-s-triazine derivative of 4α-hydroxy-5-methyltetrahydrofolate]) with the risk of mortality.

Methods: Using data from National Health and Nutrition Examination Survey 2011-2014, a total of 10,661 people with folate forms data were recruited. Death information was obtained from the National Death Index until 2015. Cox proportional hazards regression models were developed to evaluate the relationship between folate forms and mortality.

Results: During 2.99 years of follow-up, 344 (2.6%) deaths occurred. Overall, significantly higher risks of all-cause mortality were found in participants with higher level of serum 5-mTHF (≥51.3 nmol/L [quartile 4] vs. 23.9-51.3 nmol/L [quartile 2-3]; HR, 1.61; 95% CI: 1.03-2.53), UMFA (≥1.1 nmol/L [quartile 4] vs. <1.1 nmol/L [quartile 1-3]; HR, 1.55; 95% CI: 1.15-2.09), non-methyl folate (≥1.7 nmol/L [quartile 4] vs. 1.2-1.7 nmol/L [quartile 3]; HR, 1.62; 95% CI: 1.06-2.48), or MeFox (≥2.5 nmol/L [quartile 4] vs. <2.5 nmol/L [quartile 1-3]; HR, 1.54; 95% CI: 1.11-2.12). In addition, there was an increased risk of all-cause mortality for those with low level of serum 5-mTHF (<23.9 nmol/L [quartile 1] vs. 23.9-51.3 nmol/L [quartile 2-3]; HR, 1.66; 95% CI: 1.12-2.47). Most importantly, none of any folate forms significantly modified the association between other folate forms and mortality (all P for interactions >0.05).

Conclusion: Higher levels of serum folate forms (5-mTHF, UMFA, non-methyl folate, and MeFox) were associated with higher risk of mortality while 5-mTHF insufficiency also showed a negative impact on mortality. Our findings emphasized the importance of monitoring the folate forms concentrations and may help counsel future related clinical trials.
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http://dx.doi.org/10.1016/j.clnu.2021.01.025DOI Listing
January 2021

FATC Domain Deletion Compromises ATM Protein Stability, Blocks Lymphocyte Development, and Promotes Lymphomagenesis.

J Immunol 2021 Mar 3;206(6):1228-1239. Epub 2021 Feb 3.

Institute for Cancer Genetics, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032;

Ataxia-telangiectasia mutated (ATM) kinase is a master regulator of the DNA damage response, and loss of ATM leads to primary immunodeficiency and greatly increased risk for lymphoid malignancies. The FATC domain is conserved in phosphatidylinositol-3-kinase-related protein kinases (PIKKs). Truncation mutation in the FATC domain (R3047X) selectively compromised reactive oxygen species-induced ATM activation in cell-free assays. In this article, we show that in mouse models, knock-in ATM-R3057X mutation (⁠ ⁠, corresponding to R3047X in human ATM) severely compromises ATM protein stability and causes T cell developmental defects, B cell Ig class-switch recombination defects, and infertility resembling ATM-null. The residual ATM-R3057X protein retains minimal yet functional measurable DNA damage-induced checkpoint activation and significantly delays lymphomagenesis in ⁠ ⁠ mice compared with ⁠ ⁠. Together, these results support a physiological role of the FATC domain in ATM protein stability and show that the presence of minimal residual ATM-R3057X protein can prevent growth retardation and delay tumorigenesis without restoring lymphocyte development and fertility.
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http://dx.doi.org/10.4049/jimmunol.2000967DOI Listing
March 2021

Association between plasma copper levels and first stroke: a community-based nested case-control study.

Nutr Neurosci 2021 Feb 3:1-10. Epub 2021 Feb 3.

Department of Cardiovascular Medicine, the Second Affiliated Hospital of Nanchang University, Nanchang of Jiangxi, People's Republic of China.

Background And Aims: Uncertainty remains regarding the association between the risk of stroke and plasma copper levels in population with copper mostly in normal range due to limited data. We examined the association between baseline plasma copper and risk of first stroke in Chinese community-dwelling population.

Methods: We conducted a nested case control study from 'H-type Hypertension and Stroke Prevention and Control Project'. A total of 1255 first stroke cases and 1255 controls matched for age, sex and study site were included in the analysis. Conditional logistic regression analyses were performed to evaluate the association between plasma copper and first stroke.

Results: The overall mean of copper was 15.90 (2.66) μmol/L. In total, 94.26% participants' copper concentration was in the normal range by Mayo Clinic laboratory reference values. Smoothing curve showed that the associations of plasma copper with first stroke and its subtypes were linear. Each standard deviation (SD) increment of plasma copper was independently and positively associated with risk of first stroke [odds ratio (OR): 1.17, 95% confidence interval (CI): 1.07-1.28]. The multivariable ORs with 95% CIs for total stroke, ischemic stroke and hemorrhagic stroke in the highest versus the lowest quartile of plasma copper were 1.49 (1.16-1.90; -trend = 0.001), 1.46 (1.12-1.92; -trend = 0.004) and 2.05 (0.95-4.38; -trend = 0.050), respectively.

Conclusions: Baseline plasma copper was positively associated with risk of first ischemic stroke in an approximately linear fashion among Chinese community population (80.32% hypertensives), although their copper levels were mostly within the normal range according to current reference values. Our findings warrant additional investigation.
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http://dx.doi.org/10.1080/1028415X.2021.1875299DOI Listing
February 2021

Spectrum analysis of inborn errors of metabolism for expanded newborn screening in a northwestern Chinese population.

Sci Rep 2021 Jan 29;11(1):2699. Epub 2021 Jan 29.

Center of Neonatal Disease Screening, Department of Clinical Genetics, Northwest Women's and Children's Hospital, 1616 Yanxiang Road, Xi'an, Shaanxi Province, China.

Expanded newborn screening facilitates early identification and intervention of patients with inborn errors of metabolism (IEMs), There is a lack of disease spectrum data for many areas in China. To determine the disease spectrum and genetic characteristics of IEMs in Xi'an city of Shaanxi province in northwest China, 146152 newborns were screening by MSMS from January 2014 to December 2019 and 61 patients were referred to genetic analysis by next generation sequencing (NGS) and validated by Sanger sequencing. Seventy-five newborns and two mothers were diagnosed with IEMs, with an overall incidence of 1:1898 (1:1949 without mothers). There were 35 newborns with amino acidemias (45.45%, 1:4176), 28 newborns with organic acidurias (36.36%, 1:5220), and 12 newborns and two mothers with FAO disorders (18.18%; 1:10439 or 1:12179 without mothers). Phenylketonuria and methylmalonic acidemia were the two most common disorders, accounting for 65.33% (49/75) of all confirmed newborn. Some hotspot mutations were observed for several IEMs, including PAH gene c.728G>A for phenylketonuria; MMACHC gene c.609G>A and c.567dupT, MMUT gene c.323G>A for methylmalonic acidemia and SLC25A13 gene c.852_855del for citrin deficiency. Our study provides effective clinical guidance for the popularization and application of expanded newborn screening, genetic screening, and genetic counseling of IEMs in this region.
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http://dx.doi.org/10.1038/s41598-021-81897-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846761PMC
January 2021

A Rat Model with Multivalve Calcification Induced by Subtotal Nephrectomy and High-Phosphorus Diet.

Kidney Dis (Basel) 2020 Sep 10;6(5):346-354. Epub 2020 Jul 10.

Institute of Nephrology, Zhong Da Hospital, School of Medicine, Southeast University, Nanjing, China.

Background: Chronic kidney disease (CKD) with known valve calcification (VC) places individuals at high risk of cardiovascular disease. The study of VC in CKD is challenging due to the lack of a suitable research model. Here, we established a rat model of multivalve calcification induced by subtotal nephrectomy and a high-phosphate (HP) diet and analyzed the valve characteristics.

Methods: We established a CKD model in Sprague-Dawley rats by performing 5/6 nephrectomy (5/6Nx) followed by feeding with chow containing different phosphate concentrations for 8, 12, or 16 weeks. The rats were divided into 4 groups: sham+normal phosphate (NP, 0.9% P), sham+high phosphate (HP, 2.0% P), 5/6Nx+NP, and 5/6Nx+HP. Serum creatinine (Scr), blood urea nitrogen (BUN), parathyroid hormone (PTH), calcium, phosphorus, and 24-h urine protein levels were investigated. Pathological examinations included histological characterization, safranin staining, Alcian blue staining, and von Kossa staining at different time points. Using nanoanalytical electron microscopy, we examined valves from rats in the 5/6Nx+HP and sham+HP groups and detected spherical particles using energy-dispersive spectroscopy (EDS) to observe microscopic changes in the valves. In addition, the calcified tissues were analyzed for phase and crystallization properties using an X-ray powder diffractometer.

Results: The rats in the 5/6Nx+HP and 5/6Nx+NP groups presented with increased levels of Scr, BUN, and 24-h urine protein compared with those of the rats in the sham+HP and sham+NP groups. High levels of PTH were observed, and hematoxylin and eosin staining and immunohistochemistry for proliferating cell nuclear antigen showed parathyroid hyperplasia in rats in the 5/6Nx+HP group but not in the 5/6Nx+NP group. In rats in the 5/6Nx+HP group, extracellular matrix glycosylation was observed in the aortic valve in the 12th week and the mitral valve in the 16th week. In the 16th week, chondrocytes appeared in the aortic valve, as confirmed by immunofluorescence and Western blotting. Calcified particles mainly composed of phosphorus and calcium were observed in both the aortic and mitral valves by transmission electron microscopy and scanning electron microscopy (SEM). The main mineral component of the calcified aortic valve particles was hydroxyapatite [Ca(PO)(OH)], as shown by X-ray diffraction. However, there were no obvious differences in heart function between rats in the 5/6Nx+HP and sham+HP groups.

Conclusions: Our findings demonstrate that multivalve calcification is involved in CKD following 16-week HP and that hydroxyapatite [Ca(PO)(OH)] is the main component of the calcified aortic valve particles of rats in the 5/6Nx+HP group.
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http://dx.doi.org/10.1159/000506013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745662PMC
September 2020

Relation of BMI and waist circumference with the risk of new-onset hyperuricemia in hypertensive patients.

QJM 2021 Jan 24. Epub 2021 Jan 24.

Institute of Biomedicine, Anhui Medical University, Hefei, China.

Background: We aimed to evaluate the relationship of body mass index (BMI) and waist circumference (WC) with the risk of new-onset hyperuricemia, and examine possible effect modifies in general hypertensive patients.

Methods: A total of 10,611 hypertensive patients with normal uric acid (UA) concentrations (<357μmol/L) at baseline were included from the UA Sub-study of the China Stroke Primary Prevention Trial (CSPPT). The primary outcome was new-onset hyperuricemia, defined as a UA concentration ≥417μmol/L in men or ≥ 357μmol/L in women at the exit visit.

Results: During a median follow-up duration of 4.4 years, 1663 (15.7%) participants developed new-onset hyperuricemia. When analyzed separately, increased BMI (≥25 kg/m2, quartile 3-4; OR, 1.46; 95% CI: 1.29-1.65), or increased WC (≥85cm for females, quartile 3-4; OR, 1.24; 95% CI: 1.08-1.42; and ≥84cm for males, quartile 3-4; OR, 1.30; 95% CI: 1.01-1.67) were each significantly associated with higher risk of new-onset hyperuricemia. When WC was forced into the model with BMI simultaneously, its significant association with new-onset hyperuricemia disappeared in females (<85 versus ≥85cm; OR, 0.96, 95% CI: 0.81-1.13) or males (≥84 versus <84cm; OR, 1.13; 95%CI: 0.84-1.52); however, BMI was still significantly related with new-onset hyperuricemia (≥25 versus <25kg/m2; OR, 1.48; 95%CI: 1.27-1.73). Moreover, the positive BMI & new-onset hyperuricemia association was more pronounced in participants with higher time-averaged on-treatment SBP (median: <138.3 versus ≥138.3 mmHg; P-interaction = 0.041).

Conclusions: Higher BMI, but not WC, is significantly and independently associated with an increased risk of new-onset hyperuricemia among hypertensive patients.
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http://dx.doi.org/10.1093/qjmed/hcaa346DOI Listing
January 2021

Role of neddylation in neurological development and diseases.

Biotechnol Appl Biochem 2021 Jan 19. Epub 2021 Jan 19.

Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People's Republic of China.

Neddylation, a posttranslational protein modification, refers to the specific conjugation of NEDD8 to substrates, which is of great significance to various biological processes. Besides members of the cullin protein family, other key proteins can act as a substrate for neddylation modification, which remarkably influences neurodevelopment and neurodegenerative diseases. Normal levels of protein neddylation contribute to nerve growth, synapse strength, neurotransmission, and synaptic plasticity, whereas overactivation of protein neddylation pathways lead to apoptosis, autophagy of neurons, and tumorigenesis. Furthermore, impaired neddylation causes neurodegenerative diseases. These facts suggest that neddylation may be a target for treatment of these diseases. This review focuses on the current understanding of neddylation function in neurodevelopment as well as neurodegenerative diseases. Meanwhile, the recent view that different level of neddylation pathway may contribute to the opposing disease progression, such as neoplasms and Alzheimer's disease, is discussed. The review also discusses neddylation inhibitors, which are currently being tested in clinical trials. However, potential drawbacks of these drugs are noted, which may benefit the development of new pharmaceutical strategies in the treatment of nervous system diseases.
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http://dx.doi.org/10.1002/bab.2112DOI Listing
January 2021

A Nonlinear Relation Between Maternal Red Blood Cell Manganese Concentrations and Child Blood Pressure at Age 6-12 y: A Prospective Birth Cohort Study.

J Nutr 2021 Mar;151(3):570-578

Center on the Early Life Origins of Disease, Department of Population, Family and Reproductive Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA.

Background: Although manganese (Mn) is an essential trace element and a common component of most multivitamins on the market, an adverse effect on blood pressure (BP) has been reported in adults. In addition, the longitudinal relation between prenatal Mn status and childhood BP is still unknown.

Objective: This study investigated the association between prenatal Mn concentrations and risk of elevated BP at ages 3-12 y.

Method: The analyses included 1268 mother-child dyads who were enrolled at birth and followed prospectively at the Boston Medical Center. Maternal RBC Mn concentrations were measured by inductively coupled plasma mass spectrometry, using RBCs collected within 1-3 d after delivery (reflecting late-pregnancy Mn exposure). Child elevated BP was defined as systolic or diastolic BP ≥90th percentile for a given age, sex and height. Multivariate logistic regression models were conducted. Path analysis was applied to mediation estimation.

Results: The median (IQR) maternal RBC Mn concentration was 37.5 (29.2-48.5) μg/L. The rate of child elevated BP at ages 3-12 y was 25%. Both the lowest and highest quartiles of maternal RBC Mn concentrations were associated with higher risk of elevated BP among children aged 6-12 y (OR: 1.52; 95% CI: 1.04, 2.21 and OR: 1.65; 95% CI: 1.13, 2.40, respectively) compared with those in the second and third quartiles. Gestational age and fetal growth mediated the association between low maternal RBC Mn (first quartile) and child elevated BP, explaining 25% of the association, but not for high (fourth quartile) maternal RBC Mn concentrations. No association was found between maternal RBC Mn concentrations and BP among children aged 3-5 y.

Conclusion: We found a nonlinear association between maternal RBC Mn concentrations and elevated BP among children aged 6-12 y from a high-risk, predominantly minority population. Our findings warrant further investigation.
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http://dx.doi.org/10.1093/jn/nxaa368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948198PMC
March 2021

Predictive formulae of ideal lumbar lordosis determined by individual pelvic incidence and thoracic kyphosis in asymptomatic adults.

J Orthop Sci 2021 Jan 5. Epub 2021 Jan 5.

Department of Spine Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China. Electronic address:

Background: The precise prediction of ideal lumbar lordosis (LL) has become increasingly important in clinical practice. The aim of this study was to explore the regulatory mechanisms of sagittal spinopelvic alignment and to predict ideal LL based on individual pelvic incidence (PI) and thoracic kyphosis (TK) parameters in asymptomatic adults.

Methods: A total of 233 asymptomatic subjects older than 18 years were consecutively enrolled in our study between April 2017 and December 2019. A full-spine, standing X-ray was performed for each subject. The following parameters were measured in the sagittal plane: the apex of lumbar lordosis (LLA), the distance between the plumb line of the lumbar apex (LAPL) and the gravity plumb line, the inflection point (IP), LL, the upper arc and lower arc of lumbar lordosis (LLUA and LLLA, respectively), PI and TK. Stepwise multiple linear regressions were conducted, and the statistical significance level was P < 0.05.

Results: Both PI and TK were two important predictive variables for LLA, LAPL, IP and LL. In addition, the LLUA was mainly explained by TK, while the LLLA was explained by PI. The corresponding predictive models are listed as follows: LLA = 17.110 - 0.040∗PI + 0.023∗TK (R = 0.380), LAPL = 31.296 + 0.467∗PI - 0.126∗TK (R = 0.309), IP = 10.437 + 0.091∗TK - 0.029∗PI (R = 0.227), LL = 2.035 + 0.618∗PI + 0.430∗TK (R = 0.595), LLUA = 0.893 + 0.418∗TK (R = 0.598), LLLA = 3.543 + 0.576∗PI (R = 0.433).

Conclusion: The specific sagittal lumbar profile should be regulated by both pelvic and thoracic morphology. Such predictive models for lumbar parameters determined by individual PI and TK parameters have been established, which are meaningful for surgeons to better understand the regulatory mechanisms of sagittal spinopelvic alignment and reconstruct a satisfactory lumbar alignment.
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http://dx.doi.org/10.1016/j.jos.2020.11.022DOI Listing
January 2021

Simultaneous measurement of the absolute and relative time delay of a tiled-aperture coherent beam combination via the double-humped spectral beam interferometry.

Opt Express 2020 Nov;28(24):35498-35505

Coherent beam combination (CBC) is a promising technology for achieving several hundred petawatts and even EW-level lasers. However, the measurement of the synchronization error and the time jitter of CBC is one of key technical issues, especially in the few-cycle PW-level laser facilities. In this paper, we demonstrate that the absolute time delay (ATD) and the relative time delay (RTD) for a tiled-aperture CBC can simultaneously be measured by using the double-humped spectral beam interferometry. The experimental study also was demonstrated. A root-mean-square deviation of approximately λ/38 (70 as) and a combining efficiency of 87.3% at 1 Hz closed feedback loop was obtained, respectively. Due to the wide adjustment range and a vast resisting beam energy disturbance capacity, this technique provide an effective and practical solution for measuring simultaneously the ATD and the RTD in the few-cycle PW-level laser pulses CBC.
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http://dx.doi.org/10.1364/OE.405430DOI Listing
November 2020

Prenatal exposure to mercury and precocious puberty: a prospective birth cohort study.

Hum Reprod 2021 Feb;36(3):712-720

Department of Population, Family and Reproductive Health, Center on the Early Life Origins of Disease, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA.

Study Question: Is in utero exposure to mercury associated with the risk of precocious puberty?

Summary Answer: Prenatal exposure to high levels of mercury was associated with increased risk of precocious puberty, which was strengthened by concomitant maternal cardiometabolic conditions and adverse birth outcomes.

What Is Known Already: The developing fetus is sensitive to mercury, a well-known endocrine disruptor which impacts the endocrine and reproductive system.

Study Design, Size, Duration: This study included 1512 mother-child pairs from the Boston Birth Cohort, a longitudinal cohort which recruited at birth and followed prospectively up to 21 years of age.

Participants/materials, Setting, Methods: Mother-child pairs, from a predominantly urban minority population, were enrolled from 2002 to 2013. Prenatal exposure was assessed by maternal mercury concentration in red blood cells (RBCs) collected at 1-3 days after delivery. Precocious puberty was defined based on International Classification of Disease codes. Cox proportional hazards models were applied to the association between maternal mercury concentrations and the risk of precocious puberty.

Main Results And The Role Of Chance: The median (interquartile range) of maternal mercury concentrations among children with and without precocious puberty were 3.4 (1.9-4.6) µg/l and 2.0 (1.0-3.7) µg/l, respectively. Compared to those in the lowest tertile for mercury, the highest tertile was associated with increased risk of precocious puberty, with an adjusted hazard ratio (HR) of 2.41, 95% CI: 1.16-5.03. In addition, concomitant maternal cardiometabolic conditions and adverse birth outcomes strengthened the effects of mercury on the risk of precocious puberty. The highest risk of precocious puberty was observed among children who had adverse birth outcomes and whose mothers had high RBC-mercury concentrations along with cardiometabolic conditions, with an HR of 4.76 (95% CI: 1.66-13.60) compared to children with favorable profiles of all three risk factors.

Limitations, Reasons For Caution: Precocious puberty was defined based on medical records, not on a direct assessment, which may have led to underdiagnosis and the inability to make a subclassification. The study included a predominately urban, low-income, minority population and as such our findings may not be widely generalizable.

Wider Implications Of The Findings: Prenatal Hg exposure was associated with an increased risk of precocious puberty. This risk was strengthened by concomitant maternal cardiometabolic conditions during pregnancy and adverse birth outcomes.

Study Funding/competing Interest(s): This study was funded by the NIH/National Institute of Environmental Health Sciences, NIH/Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Health Resources and Services Administration of the U.S. Department of Health and Human Services. The authors declare no conflicts of interest.

Trial Registration Number: N/A.
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http://dx.doi.org/10.1093/humrep/deaa315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891807PMC
February 2021

Joint Associations of Maternal-Fetal APOL1 Genotypes and Maternal Country of Origin With Preeclampsia Risk.

Am J Kidney Dis 2020 Dec 22. Epub 2020 Dec 22.

Molecular Genetic Epidemiology Section, Frederick National Laboratory for Cancer Research in the Basic Research Laboratory, National Cancer Institute, Frederick, MD. Electronic address:

Rationale & Objectives: Preeclampsia, which disproportionately affects Black women, is a leading cause of preterm delivery and risk for future hypertension and chronic kidney disease (CKD). Apolipoprotein L1 (APOL1) kidney risk alleles, common among Black individuals, contribute substantially to CKD disparities. Given the strong link between preeclampsia and CKD, we investigated whether maternal and fetal APOL1 risk alleles can jointly influence preeclampsia risk, and explored potential modifiers of the association between APOL1 and preeclampsia.

Study Design: Nested case-control study.

Setting & Participants: 426 Black mother-infant pairs (275 African Americans and 151 Haitians) from the Boston Birth Cohort.

Exposure: Maternal and fetal APOL1 risk alleles.

Outcomes: Preeclampsia.

Analytical Approach: Logistic regression models with adjustment for demographic characteristics were applied to analyze associations between fetal and maternal APOL1 risk alleles and risk of preeclampsia and to investigate the effects of modification by maternal country of origin.

Results: Fetal APOL1 risk alleles tended to be associated with an increased risk of preeclampsia, which was not statistically significant in the total genotyped population. However, this association was modified by maternal country of origin (P<0.05 for interaction tests): fetal APOL1 risk alleles were significantly associated with an increased risk of preeclampsia among African Americans under recessive (odds ratio [OR], 3.6 [95% CI, 1.3-9.7]; P=0.01) and additive (OR, 1.7 [95% CI, 1.1-2.6]; P=0.01) genetic models but not in Haitian Americans. Also, maternal-fetal genotype discordance at the APOL1 locus was associated with a 2.6-fold higher risk of preeclampsia (P<0.001) in African Americans.

Limitations: Limited sample size in stratified analyses; self-reported maternal country of origin; pre-pregnancy estimated glomerular filtration rate (eGFR) and proteinuria data in mothers were not collected; unmeasured confounding social and/or environmental factors; no replication study.

Conclusions: This study supports the hypothesis that fetal APOL1 kidney risk alleles are associated with increased risk for preeclampsia in a recessive mode of inheritance in African Americans and suggests that maternal-fetal genotype discordance is also associated with this risk. These conclusions underscore the need to better understand maternal-fetal interaction and their genetic and environmental factors as contributors to ethnic disparities in preeclampsia.
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http://dx.doi.org/10.1053/j.ajkd.2020.10.020DOI Listing
December 2020

Folic Acid Supplementation and the Association between Maternal Airborne Particulate Matter Exposure and Preterm Delivery: A National Birth Cohort Study in China.

Environ Health Perspect 2020 12 18;128(12):127010. Epub 2020 Dec 18.

Environmental and Spatial Epidemiology Research Center, National Human Genetic Resources Center, Beijing, China.

Background: Potential modification of the association between maternal particulate matter (PM) exposure and preterm delivery (PTD) by folic acid (FA) supplementation has not been studied.

Objective: We examined whether FA supplementation could reduce the risk of PTD associated with maternal exposure to PM in ambient air during pregnancy.

Method: In a cohort study covering 30 of the 31 provinces of mainland China in 2014, 1,229,556 primiparas of Han ethnicity were followed until labor. We collected information on their FA supplementation and pregnancy outcomes and estimated each participant's exposure to PM with diameters of (), (), and () using satellite remote-sensing based models. Cox proportional hazard regression models were used to examine interactions between FA supplementation and PM exposures, after controlling for individual characteristics.

Results: Participants who initiated FA prior to pregnancy (38.1%) had a 23% [hazard ratio (95% CI: 0.76, 0.78)] lower risk of PTD than women who did not use preconception FA. Participants with PM concentrations in the highest quartile had a higher risk of PTD [ (95% CI: 1.26, 1.32) for , 1.52 (95% CI: 1.46, 1.58) for , and 1.22 (95% CI: 1.17, 1.27) for ] than those with exposures in the lowest PM quartiles. Estimated associations with a increase in and were significantly lower among women who initiated FA prior to pregnancy [ (95% CI: 1.08, 1.10) for both exposures] than among women who did not use preconception FA [ (95% CI: 1.11, 1.13) for both exposures; ]. The corresponding association was also significantly lower for a increase in [ (95% CI: 1.02, 1.03) for FA before pregnancy vs. 1.04 (95% CI: 1.03, 1.04) for no preconception FA; ].

Conclusion: Our findings require confirmation in other populations, but they suggest that initiating FA supplementation prior to pregnancy may lessen the risk of PTD associated with PM exposure during pregnancy among primiparas of Han ethnicity. https://doi.org/10.1289/EHP6386.
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http://dx.doi.org/10.1289/EHP6386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747880PMC
December 2020

Degree of blood pressure control and the risk of new-onset hyperuricemia in treated hypertensive patients.

Ann Transl Med 2020 Nov;8(21):1434

Division of Nephrology, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Guangzhou, China.

Background: The relationship between blood pressure (BP) control and the risk of new-onset hyperuricemia remains uncertain. We aimed to examine the association between degree of time-averaged on-treatment BP control and new-onset hyperuricemia in general hypertensive patients.

Methods: A total of 10,617 hypertensive patients with normal uric acid (UA) concentrations (<357 µmol/L) at baseline were included from the UA Sub-study of the China Stroke Primary Prevention Trial (CSPPT). Participants were randomized to receive a double-blind daily treatment of enalapril 10 mg and folic acid 0.8 mg or enalapril 10 mg alone. BP measurements were taken every three months after randomization. The primary outcome was new-onset hyperuricemia, defined as a UA concentration ≥417 µmol/L in men or ≥357 µmol/L in women at the exit visit.

Results: Over a median of 4.4 years, 1,664 (15.7%) participants developed new-onset hyperuricemia. Overall, there was a significantly positive association between time-averaged on-treatment diastolic BP (DBP) and new-onset hyperuricemia (per 10 mmHg increment; OR 1.13; 95% CI: 1.02-1.26). Consistently, a significantly higher risk of new-onset hyperuricemia was found in participants with time-averaged on-treatment DBP ≥82.9 mmHg (median) (. <82.9 mmHg; 17.3% . 14.1%; OR 1.25; 95% CI: 1.10-1.44). Furthermore, the lowest new-onset hyperuricemia risk (12.1%) was found in those with both time-averaged on-treatment SBP (median: 138.3 mmHg) and DBP below the median (P-interaction=0.023). The results were similar for time-averaged DBP during the first 12- or 24-month treatment period, or in the analysis using propensity scores. Furthermore, a non-significant higher risk of new-onset hyperuricemia was observed in participants with time-averaged on-treatment SBP ≥120 mmHg (. <120 mmHg; OR 1.61; 95% CI: 0.88-2.97).

Conclusions: A tight DBP control of <82.9 mmHg was associated with lower risk of new-onset hyperuricemia among hypertensive patients without hyperuricemia.
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http://dx.doi.org/10.21037/atm-20-3017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723605PMC
November 2020

Plasma 25-Hydroxyvitamin D3 Concentrations and Risk of New-Onset Proteinuria in Patients With Hypertension.

J Ren Nutr 2020 Dec 9. Epub 2020 Dec 9.

Division of Nephrology, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, China. Electronic address:

Objective: We aimed to evaluate the relationship of plasma 25-hydroxyvitamin D3 (25[OH]D3) with the risk of new-onset proteinuria and examine the possible effect modifiers in patients with hypertension and without chronic kidney disease at baseline.

Methods: This is a post hoc analysis of the renal substudy of the China Stroke Primary Prevention Trial. A total of 1655 patients with hypertension, who had plasma 25(OH)D3 measurements, as well as without proteinuria and with an estimated glomerular filtration rate of ≥60 mL/min/1.73 m at baseline, were included in the present study. The main outcome was new-onset proteinuria, defined as a urine dipstick reading of ≥1+ at the exit visit.

Results: The mean (standard deviation) 25(OH)D3 level at baseline was 18.6 (7.5) ng/mL. The median follow-up duration was 4.4 years. Overall, there was a significant inverse association between plasma 25(OH)D3 and the risk of new-onset proteinuria (per standard deviation increment; [odds ratio] OR: 0.70; 95% confidence interval [CI]: 0.50, 0.97). Accordingly, when 25(OH)D3 was assessed as quartiles, a significantly lower risk of new-onset proteinuria was found in participants in quartiles 3-4 (≥17.8 ng/mL; OR: 0.45; 95% CI: 0.23, 0.87), compared with those in quartile 1 (<13.1 ng/mL). Furthermore, a stronger inverse relationship of plasma 25(OH)D3 and new-onset proteinuria was observed in nondiabetic participants (per standard deviation increment; OR: 0.57; 95% CI: 0.39, 0.83; vs. diabetics: OR: 1.48; 95% CI: 0.67, 3.28; P for interaction = 0.028).

Conclusion: There was a significant inverse association between plasma 25(OH)D3 and the risk of proteinuria in patients with hypertension, especially in those without diabetes.
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http://dx.doi.org/10.1053/j.jrn.2020.09.005DOI Listing
December 2020

Interaction of neutrophil counts and folic acid treatment on new-onset proteinuria in hypertensive patients.

Br J Nutr 2020 Dec 14:1-8. Epub 2020 Dec 14.

National Clinical Research Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou510515, People's Republic of China.

We aimed to examine whether baseline neutrophil counts affected the risk of new-onset proteinuria in hypertensive patients, and, if so, whether folic acid treatment is particularly effective in proteinuria prevention in such a setting. A total of 8208 eligible participants without proteinuria at baseline were analysed from the renal substudy of the China Stroke Primary Prevention Trial. Participants were randomised to receive a double-blind daily treatment of 10 mg of enalapril and 0·8 mg of folic acid (n 4101) or 10 mg of enalapril only (n 4107). The primary outcome was new-onset proteinuria, defined as a urine dipstick reading of ≥1+ at the exit visit. The mean age of the participants was 59·5 (sd, 7·4) years, 3088 (37·6 %) of the participants were male. The median treatment duration was 4·4 years. In the enalapril-only group, a significantly higher risk of new-onset proteinuria was found among participants with higher neutrophil counts (quintile 5; ≥4·8 × 109/l, OR 1·44; 95 % CI 1·00, 2·06), compared with those in quintiles 1-4. For those with enalapril and folic acid treatment, compared with the enalapril-only group, the new-onset proteinuria risk was reduced from 5·2 to 2·8 % (OR 0·49; 95 % CI 0·29, 0·82) among participants with higher neutrophil counts (≥4·8 × 109/l), whereas there was no significant effect among those with neutrophil counts <4·8 × 109/l. In summary, among hypertensive patients, those with higher neutrophil counts had increased risk of new-onset proteinuria, and this risk was reduced by 51 % with folic acid treatment.
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http://dx.doi.org/10.1017/S000711452000505XDOI Listing
December 2020

HHIP gene overexpression inhibits the growth, migration and invasion of human liver cancer cells.

J BUON 2020 Sep-Oct;25(5):2424-2429

Department of Ninth Liver Disease, Qingdao Sixth People's Hospital, No.9, Qingdao, Shandong, 266033, China.

Purpose: Currently ranked as 5th most prevalent cancer type, liver cancer causes significant mortality across the globe. Additionally, the emergence of drug resistance and the alarming increase in the incidence of liver cancer has further worsened the situation. Therefore, development of effective chemotherapy, identification of molecular markers and therapeutic targets for proper treatment of liver cancer is the need of the hour. This study was undertaken to investigate the expression profile of hedgehog-interacting protein (HHIP) in liver cancer. Additionally, this study also investigated the effect of HHIP on the proliferation, migration and invasion of the human liver cancers.

Methods: The expression analysis was done qRT-PCR. The cell viability was determined by MTT assay. Apoptosis was detected by annexin V/propidium iodide (PI) assay. Wound healing and transwell assays were used to monitor cell migration and invasion. Protein expression was determined by western blot analysis.

Results: The results showed a significant (6.8-fold) downregulation of HHIP in human liver cancer cells relative to the normal AML12 cells. Next, overexpression of HHIP resulted in significant (p<0.05) and time-dependent decrease in the growth of the HepG2 cells. The decrease in growth of the HepG2 cells was found to be mainly due to induction of apoptosis which was accompanied by increase in Bax and decrease in Bcl-2 expression. The wound healing assay showed that HHIP overexpression caused a remarkable decrease in the migration of the HepG2 cells. Furthermore, the transwell assay showed that the invasion of the HepG2 cells decreased by 65% upon HHIP overexpression.

Conclusion: Taken together, HHIP may serve as potential molecular marker and therapeutic target for liver cancer management.
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December 2020

Plasma Magnesium Concentrations and Risk of Incident Cancer in Adults with Hypertension: A Nested Case-Control Study.

Ann Nutr Metab 2020 3;76(5):304-312. Epub 2020 Dec 3.

Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China.

Objective: The association between plasma magnesium and risk of incident cancer remains inconclusive in previous studies. We aimed to investigate the prospective relationship of baseline plasma magnesium concentrations with the risk of incident cancer and to examine possible effect modifiers.

Methods: A nested case-control study with 228 incident cancer cases and 228 matched controls was conducted using data from the China Stroke Primary Prevention Trial (CSPPT), a randomized, double-blind, controlled trial, conducted from May 2008 to August 2013. Study outcomes included incident cancer and its subtypes.

Results: When plasma magnesium concentrations were assessed as quartiles, a significantly higher incident risk of total cancer was found in participants in quartile 1 (<0.76 mmol/L; odds ratio [OR] = 2.70; 95% CI: 1.33-5.49) and quartile 4 (≥0.89 mmol/L; OR = 2.05; 95% CI: 1.12-3.76), compared with those in quartile 3 (0.83 to <0.89 mmol/L). In cancer site-specific analyses, similar trends were found for gastrointestinal cancer, esophageal cancer, gastric cancer, breast cancer, lung cancer, and other cancers. Furthermore, none of the variables, including age, sex, current smoking status, current alcohol intake, BMI, systolic blood pressure, and total cholesterol levels at baseline significantly modified the association between plasma magnesium and cancer risk.

Conclusions: Both low and high plasma magnesium concentrations were significantly associated with an increased incident risk of cancer, compared with the reference concentrations of 0.83 to <0.89 mmol/L among hypertensive adults.
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http://dx.doi.org/10.1159/000510214DOI Listing
December 2020