Publications by authors named "Liming Guo"

37 Publications

Field-applied biochar-based MgO and sepiolite composites possess CO capture potential and alter organic C mineralization and C-cycling bacterial structure in fertilized soils.

Sci Total Environ 2022 Mar 27;813:152495. Epub 2021 Dec 27.

College of Resources and Environment, Fujian Agriculture and Forestry University, Fuzhou 350002, Fujian Province, China; Key Research Laboratory of Soil Ecosystem Health and Regulation in Fujian Provincial University, Fuzhou 350002, Fujian Province, China; Fujian Colleges and Universities Engineering Research Institute of Conservation and Utilization of Natural Bioresources, College of Forestry, Fujian Agriculture and Forestry University, Fuzhou 350002, Fujian Province, China. Electronic address:

Agricultural soils contribute a significant amount of anthropogenic CO emission, a greenhouse gas of global environmental concern. Hence, discovering sustainable materials that can capture CO in cultivated soils is paramount. Since the effect of biochar on C mineralization/retention in fertilized soils is unclear, we produced biochar-based MgO and sepiolite-nanocomposites with CO capture potential. The field-scale impacts of the modified-biochars were evaluated on net C exchange rate (NCER) periodically for 3 months in fertilized plots. The effects of the modified-biochar on organic-C mineralization, the activities, and dynamics of C-cycling-related 16S rRNA which are unknown, were investigated. Results revealed an initial rapid and higher cumulative CO emission from the sole fertilizer treatment (F). Unlike the biochar treatment (BF), the successful incorporation of MgO/Mg(OH) nanoparticles into the matrix and surface of biochar, and the potential formation of MgCO with soil CO, mitigated CO emission, especially in the MgO-modified biochar (MgOBF), compared to the sepiolite-biochar treatment (SBF). Compared to F and BF, the higher C retention as MgCO in the modified biochar treatments led to an increase in cellulase activity, stimulation of key C-cycling-related bacteria, and the expression of genes associated with starch, sucrose, amino sugar, nucleotide sugar, ascorbate, aldarate, cellulose, and chitin degradation, thus, increasing organic C mineralization. Among the modified-biochar treatments, higher C mineralization was recorded in SBF, resulting in increased cumulative CO emission, despite its initial capture for up to 42 days. However, MgOBF was effective in capturing soil-derived CO, despite the increased C mineralization compared to biochar. The changes in soil moisture and temperature significantly regulated NCER. Also, the modified biochars positively influenced the distribution of C-cycling-related bacteria by improving soil pH and available nutrients. Among the modified biochars, the observed higher mitigation effect of MgOBF on NCER indicated that it could be preferably applied in agricultural soils.
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http://dx.doi.org/10.1016/j.scitotenv.2021.152495DOI Listing
March 2022

Re-exploring α-Cyano-4-Hydroxycinnamic Acid as a Reactive Matrix for Selective Detection of Glutathione via MALDI-MS.

J Am Soc Mass Spectrom 2021 Dec 11;32(12):2837-2841. Epub 2021 Nov 11.

State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun 130012, China.

Herein, we re-explored α-cyano-4-hydroxycinnamic acid (CHCA) as a reactive matrix for selective and sensitive analysis of glutathione (GSH) by matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). CHCA efficiently reacted with GSH, and the resulting CHCA-GSH conjugate was readily detected by MALDI-MS without interferences. The detection limit of the CHCA-GSH conjugate decreased to 200 pmol μL, which was 2 orders of magnitude lower than that of pure GSH.Forapplication, CHCA was successfully applied for the detection of GSH, present in HepG2 cell lysates. The results demonstrated detection advantages of simple, high-throughput, and selective and screening of GSH in biological samples by MALDI-MS.
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http://dx.doi.org/10.1021/jasms.1c00261DOI Listing
December 2021

A dual-mode reactive matrix for sensitive and quantitative analysis of carbohydrates by MALDI-TOF MS.

Talanta 2021 Dec 8;235:122792. Epub 2021 Aug 8.

State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun, 130012, China; Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, College of Life Science, Jilin University, Changchun, 130012, China. Electronic address:

Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) is a widely used tool for the analysis of carbohydrates. However, the detection of carbohydrates by MALDI-TOF MS is often limited by the unsatisfactory ionization efficiency, instability and the matrix interference in low molecular weight region. Here, we demonstrate that a reactive matrix, 2-hydrazinoquinoline (2-HQ), can be used to detect neutral, sialic and low molecular weight carbohydrates sensitively both in the positive and negative ion mode. Since 2-HQ reacts efficiently with the reducing end of carbohydrate to form stable hydrazone, the ionization efficiency of derived carbohydrates is significantly enhanced. Using 2-HQ, the sensitivity for analyzing glycans has been improved 10-fold and 100-fold compared with those using 3-aminquinoline (3-AQ) and 2,5-dihydroxybenzoic acid (DHB) as matrix, respectively. Moreover, quantitative analysis of neutral, acidic and low molecular weight carbohydrates has been achieved because of the good reproducibility by using 2-HQ as matrix. As a result, up to 50 glycans in a single sample spot of human fresh serum without any prior purification and enrichment have been successfully detected. Therefore, 2-HQ as a new reactive matrix has shown great potentials in widespread applications for sensitive, selective, quantitative, high speed and high throughput analysis of carbohydrates in complex samples by MALDI-TOF MS.
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http://dx.doi.org/10.1016/j.talanta.2021.122792DOI Listing
December 2021

Neurocognitive disorders amongst patients with congenital heart disease undergoing procedures in childhood.

Int J Cardiol 2021 08 18;336:47-53. Epub 2021 May 18.

McGill Adult Unit for Congenital Heart Disease Excellence, McGill University, Montreal, QC, Canada. Electronic address:

Background: Amongst children with congenital heart disease (CHD), earlier age of repair improves cardiovascular outcomes. The effects of early intervention on neurodevelopment remains unclear. We assessed the association between early life repair, cardiopulmonary bypass (CPB) and the incidence of neurocognitive disorders (NCD) amongst CHD patients.

Methods: We created two retrospective cohorts from the Quebec CHD Database; with data from 1988 to 2010. Complexity of reparative procedures for CHD lesions were used as the proxy of CPB exposure with more complex procedure means longer exposure to CPB. Study Population 1 included pediatric patients with a single reparative procedure and compared patients with complex (long CBP) versus isolated shunt (short CBP) lesions. To assess the effects of CPB alone in Study Population 2 we compared patients with isolated atrial septal defects (ASD) who had surgical (short CBP) versus percutaneous (no CBP) repairs. The primary endpoint for both cohorts was development of an NCD.

Results: In Study population 1, 1174 patients underwent complex surgical repair and 1620 had a shunt closure. The incidence of NCDs was 2.45/100 person-years in the complex surgery group, and 2.08/100 person-years in the shunt closure group. The following were associated with increased risk of developing a NCD: surgical complexity (Hazard Ratio [HR] = 1.20, 95% Confidence Interval [CI]: 1.01-1.42), younger age at intervention (AAI) (HR = 1.20, 95% CI: 1.16-1.25), male sex (HR = 1.91, 95% CI: 1.61-2.27), and later calendar year at intervention (HR = 1.06, 95% CI: 1.04-1.07). Study population 2 had 527 isolated ASD patients; 202 underwent surgical repair and 325 had percutaneous closure. The incidence of NCDs was not statistically different between groups. Male sex (HR = 1.77, 95% CI: 1.08-2.89) and younger AAI (HR = 1.15, 95% CI: 1.06-1.25) were associated with increased NCD risk.

Conclusion: Increased surgical complexity, male sex and younger AAI were associated with increased risk of NCDs in pediatric CHD patients. Surveillance protocols should be considered to identify NCDs in CHD patients after cardiac intervention.
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http://dx.doi.org/10.1016/j.ijcard.2021.05.001DOI Listing
August 2021

Sarcopenia in Fontan patients: a sign of frailty-associated premature ageing?

Cardiol Young 2021 05 6;31(5):696-698. Epub 2021 May 6.

McGill Adult Unit for Congenital Heart Disease Excellence, McGill University Health Centre, Montreal, Quebec, Canada.

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http://dx.doi.org/10.1017/S1047951121001748DOI Listing
May 2021

Recurrent disease progression networks for modelling risk trajectory of heart failure.

PLoS One 2021 6;16(1):e0245177. Epub 2021 Jan 6.

School of Computer Science, McGill University, Montreal, Canada.

Motivation: Recurrent neural networks (RNN) are powerful frameworks to model medical time series records. Recent studies showed improved accuracy of predicting future medical events (e.g., readmission, mortality) by leveraging large amount of high-dimensional data. However, very few studies have explored the ability of RNN in predicting long-term trajectories of recurrent events, which is more informative than predicting one single event in directing medical intervention.

Methods: In this study, we focus on heart failure (HF) which is the leading cause of death among cardiovascular diseases. We present a novel RNN framework named Deep Heart-failure Trajectory Model (DHTM) for modelling the long-term trajectories of recurrent HF. DHTM auto-regressively predicts the future HF onsets of each patient and uses the predicted HF as input to predict the HF event at the next time point. Furthermore, we propose an augmented DHTM named DHTM+C (where "C" stands for co-morbidities), which jointly predicts both the HF and a set of acute co-morbidities diagnoses. To efficiently train the DHTM+C model, we devised a novel RNN architecture to model disease progression implicated in the co-morbidities.

Results: Our deep learning models confers higher prediction accuracy for both the next-step HF prediction and the HF trajectory prediction compared to the baseline non-neural network models and the baseline RNN model. Compared to DHTM, DHTM+C is able to output higher probability of HF for high-risk patients, even in cases where it is only given less than 2 years of data to predict over 5 years of trajectory. We illustrated multiple non-trivial real patient examples of complex HF trajectories, indicating a promising path for creating highly accurate and scalable longitudinal deep learning models for modeling the chronic disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245177PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787457PMC
May 2021

Diagnostic value of VDBP and miR-155-5p in diabetic nephropathy and the correlation with urinary microalbumin.

Exp Ther Med 2020 Nov 11;20(5):86. Epub 2020 Sep 11.

Department of Nephrology, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, Zhejiang 315000, P.R. China.

This study explored the diagnostic and therapeutic significance of vitamin D binding protein (VDBP) and miR-155-5p for diabetic nephropathy and the correlation with urinary microalbumin. A total of 145 patients with type 2 diabetes who attended the Hwamei hospital were selected as research objects and assigned to diabetic nephropathy group (DN group) and diabetes group according to whether they suffered from diabetic nephropathy (DN). The expression levels of urine VDBP and serum miR-155-5p in the two groups were detected, and the correlation between urinary microalbumin (mAlb), serum cystatin C (Cys C) and 24-h urinary protein was analyzed. The predictive value of single and joint detection of urinary VDBP and serum miR-155-5p for DN onset and poor prognosis was analyzed. In DN patients, urine VDBP and serum miR-155-5p were highly expressed, and urine VDBP, serum miR-155-5p and mAlb, Cys C and 24-h urine protein were positively correlated (P<0.05). Moreover, the joint detection of urine VDBP and serum miR-155-5p was more valuable in diagnosis and poor prognosis prediction of DN patients than its single detection. Urine VDBP and serum miR-155-5p have good diagnostic value for DN, but their joint diagnostic value is higher, and their expression levels are all related to mAlb of DN patients, which may be used as new biological indicators for diagnosis and disease assessment.
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http://dx.doi.org/10.3892/etm.2020.9214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500046PMC
November 2020

Risk prediction models for heart failure admissions in adults with congenital heart disease.

Int J Cardiol 2021 01 14;322:149-157. Epub 2020 Aug 14.

McGill Adult Unit for Congenital Heart Disease Excellence, Montréal, Québec, Canada; iCACH Net Group (Canadian Adult Congenital Heart Disease Network Investigators' Group), Canada. Electronic address:

Background: Heart failure (HF) is the leading cause of death in adult patients with congenital heart disease (ACHD). No risk prediction model exists for HF hospitalization (HFH) for ACHD patients. We aimed to develop a clinically relevant one-year risk prediction system to identify ACHD patients at high risk for HFH.

Methods: Data source was the Quebec CHD Database. A retrospective cohort including all ACHD patients aged 18-64 (1995-2010) was constructed for assessing the cumulative risk of HFH adjusting for competing risk of death. To identify one-year predictors of incident HFH, multivariable logistic regressions were employed to a nested case-control sample of all ACHD patients aged 18-64 in 2009. The final model was used to create a risk score system based on adjusted odds ratios.

Results: The cohort included 29,991 ACHD patients followed for 648,457 person-years. The cumulative HFH risk by age 65 was 12.58%. The case-control sample comprised 26,420 subjects, of whom 189 had HFHs. Significant one-year predictors were age ≥ 50, male sex, CHD lesion severity, recent 12-month HFH history, pulmonary arterial hypertension, chronic kidney disease, coronary artery disease, systemic arterial hypertension, and diabetes mellitus. The created risk score ranged from 0 to 19. The corresponding HFH risk rose rapidly beyond a score of 8. The risk scoring system demonstrated excellent prediction performance.

Conclusions: One eighth of ACHD population experienced HFH before age 65. Age, sex, CHD lesion severity, recent 12-month HFH history, and comorbidities constructed a risk prediction model that successfully identified patients at high risk for HFH.
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http://dx.doi.org/10.1016/j.ijcard.2020.08.039DOI Listing
January 2021

Inferring multimodal latent topics from electronic health records.

Nat Commun 2020 05 21;11(1):2536. Epub 2020 May 21.

Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, 32 Vassar St, Cambridge, MA, 02139, USA.

Electronic health records (EHR) are rich heterogeneous collections of patient health information, whose broad adoption provides clinicians and researchers unprecedented opportunities for health informatics, disease-risk prediction, actionable clinical recommendations, and precision medicine. However, EHRs present several modeling challenges, including highly sparse data matrices, noisy irregular clinical notes, arbitrary biases in billing code assignment, diagnosis-driven lab tests, and heterogeneous data types. To address these challenges, we present MixEHR, a multi-view Bayesian topic model. We demonstrate MixEHR on MIMIC-III, Mayo Clinic Bipolar Disorder, and Quebec Congenital Heart Disease EHR datasets. Qualitatively, MixEHR disease topics reveal meaningful combinations of clinical features across heterogeneous data types. Quantitatively, we observe superior prediction accuracy of diagnostic codes and lab test imputations compared to the state-of-art methods. We leverage the inferred patient topic mixtures to classify target diseases and predict mortality of patients in critical conditions. In all comparison, MixEHR confers competitive performance and reveals meaningful disease-related topics.
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http://dx.doi.org/10.1038/s41467-020-16378-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242436PMC
May 2020

Downregulation of TNFRSF19 and RAB43 by a novel miRNA, miR-HCC3, promotes proliferation and epithelial-mesenchymal transition in hepatocellular carcinoma cells.

Biochem Biophys Res Commun 2020 04 23;525(2):425-432. Epub 2020 Feb 23.

Tianjin Life Science Research Center and Tianjin Key Laboratory of Inflammation Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China. Electronic address:

Tumor necrosis factor receptor superfamily 19 (TNFRSF19) is a transmembrane protein involved in tumorigenesis. RAB43 is a small molecule GTP-binding protein contributing to the occurrence and development of tumors. However, TNFRSF19/RAB43 dysregulation and their role in hepatocellular carcinoma cells are unknown. Herein, we found that TNFRSF19 and RAB43 were downregulated in hepatocellular carcinoma tissues. TNFRSF19/RAB43 overexpression suppressed, whereas TNFRSF19/RAB43 knockdown promoted cell proliferation and epithelial-mesenchymal transition (EMT) of hepatocellular carcinoma cells. Previously, using deep sequencing technology, a new miRNA, miR-HCC3, was identified and found to suppress the expression of TNFRSF19 and RAB43 by binding to their 3'untranslated regions (3'UTRs) directly. miR-HCC3 was upregulated in hepatocellular carcinoma (HCC) tissues compared with adjacent noncancerous tissues and promoted proliferation and epithelial-mesenchymal transition in HCC cells. Furthermore, TNFRSF19/RAB43 suppressed but miR-HCC3 promoted tumor growth in vivo. Collectively, our results indicated that downregulation of TNFRSF19 and RAB43 by miR-HCC3 contributes to oncogenic activities in HCC, which sheds light on tumorigenesis and might provide potential therapeutic targets for HCC.
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http://dx.doi.org/10.1016/j.bbrc.2020.02.105DOI Listing
April 2020

Dihydromyricetin promotes autophagy and attenuates renal interstitial fibrosis by regulating miR-155-5p/PTEN signaling in diabetic nephropathy.

Bosn J Basic Med Sci 2020 Aug 3;20(3):372-380. Epub 2020 Aug 3.

Department of Nephrology, HwaMei Hospital, University of Chinese Academy of Sciences, Zhejiang, China.

Diabetic nephropathy (DN) is the most common complication of diabetes and is prone to kidney failure. Dihydromyricetin (DHM) has been reported to have a variety of pharmacological activities. This study aims to explore the effect of DHM on DN and the underlying molecular mechanism. An in vivo DN rat model was established. The degree of renal interstitial fibrosis (RIF) was detected by hematoxylin-eosin (HE) staining, Masson's trichrome staining, and immunohistochemistry (IHC). In vitro, NRK-52E cells were divided into four groups: normal glucose (NG), high glucose (HG), HG+DHM, and HG+rapamycin (autophagy inhibitor). The levels of autophagy- and fibrosis-related proteins were analyzed by western blotting. The expression of miR-155-5p and phosphatase and tensin homolog deleted on chromosome ten (PTEN) and their relationship were assessed by quantitative reverse transcription (qRT)-PCR and dual luciferase reporter gene assay. Our results showed that RIF was increased in DN rat model and in HG-induced NRK-52E cells. DHM treatment attenuated the increased RIF and also increased autophagy. MiR-155-5p expression was increased, while PTEN expression was decreased in DN rat and cell model, and DHM reversed both effects. Dual luciferase assay showed that PTEN was the target gene of miR-155-5p. DHM inhibited HG-induced fibrosis and promoted autophagy by inhibiting miR-155-5p expression in NRK-52E cells. In addition, DHM promoted autophagy by inhibiting the PI3K/AKT/mTOR signaling pathway. In conclusion, DHM promotes autophagy and attenuates RIF by regulating the miR-155-5p/PTEN signaling and PI3K/AKT/mTOR signaling pathway in DN.
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http://dx.doi.org/10.17305/bjbms.2019.4410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416184PMC
August 2020

Rapidly quantitative analysis of γ-glutamyltranspeptidase activity in the lysate and blood via a rational design of the molecular probe by matrix-assisted laser desorption ionization mass spectrometry.

Talanta 2019 Dec 9;205:120141. Epub 2019 Jul 9.

State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun, 130012, China; Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, College of Life Science, Jilin University, Changchun, 130012, China. Electronic address:

Gamma-glutamyl transpeptidase (GGT) plays an important role in cellular glutathione/cysteine homeostasis and is a potential tumor biomarker. Herein, we report a rationally designed molecular probe (Aq-ECG) for rapid and quantitative analysis of GGT activities via matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). The probe is a water-soluble molecule consisting of an UV-absorptive aromatic anthraquinone (Aq) and a GGT cleavable glutathione (ECG) via one-step thiol-ene reaction covalently linked together. The function of anthraquinone part is not only to increase molecular mass of the target ions after GGT catalyzed cleavage enabling the report ions appearing in higher m/z region avoiding matrix ion interference, but also to remarkably enhance the report ions ionization efficiency. Additionally, the aromatic Aq part can be selectively captured by home-made magnetic graphene oxide materials and separated the targets from complex mixtures. Under optimized conditions, when employing an Aq linked methylated-glutathione (Aq-ECA) as the internal standard, the GGT activity amount can be quantified in a linear range of 1-50 U/L with r > 0.99. Applying this probe the GGT levels in human serum samples from both healthy and liver cancer patients have been readily detected; the results were consistent with those determined by an enzyme-linked immunosorbent assay. This method was also successfully applied for the detection of endogenous GGT amounts in different tumor/normal cells and the inhibition capability of sodium butyrate (an anticancer drug) to GGT activity. Thus, a simple, sensitive and cost/time economic method has been demonstrated for accurately quantitative GGT activity assay and screening of its inhibitors/anticancer drugs via the using of a functional molecular probe. This method is also widely applicable for other protease activity analysis by the replacement of reaction/report part of the probe.
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http://dx.doi.org/10.1016/j.talanta.2019.120141DOI Listing
December 2019

2-Phenyl-3-(-aminophenyl) Acrylonitrile: A Reactive Matrix for Sensitive and Selective Analysis of Glycans by MALDI-MS.

Anal Chem 2019 07 3;91(14):8801-8807. Epub 2019 Jul 3.

State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry , Jilin University , Changchun 130012 , China.

Analysis of glycans by matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) is usually limited by the intrinsically low abundance and low ionization efficiency of glycans. Aiming to enhance the ionization efficiency of glycans and simplify the sample preparation procedure during MALDI-MS analysis, we reported herein a novel reactive matrix, 2-phenyl-3-(-aminophenyl) acrylonitrile (PAPAN), for sensitive and selective detection of glycans. PAPAN is a derivative of α-cyanocinnamic acid, which possesses high ionization efficiency in MALDI-MS. The PAPAN can react with the terminal aldehyde of glycans and thereby enable the significant enhancement of ionization efficiency of glycans. As a result, using PAPAN as a reactive matrix, the detection sensitivity for glycans was improved 100-fold compared with that using 2,5-dihydroxybenzoic acid (DHB) as the matrix. Meanwhile, the ionization of peptides can be significantly suppressed using PAPAN as the matrix, which allowed the selective detection of -glycans from a deglycosylated tryptic digest of glycoprotein without any prepurification. Moreover, the PAPAN matrix also endowed the analysis of glycans with enhanced fragmentation during MS/MS analysis, which could facilitate glycan structure interpretation. Finally, PAPAN was successfully used for the analysis of -glycome in human serum. Thus, a simple, sensitive, and selective method for the analysis of glycans has been achieved by using a novel reactive matrix, PAPAN.
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http://dx.doi.org/10.1021/acs.analchem.9b01434DOI Listing
July 2019

Secular trends in pregnancy rates, delivery outcomes, and related health care utilization among women with congenital heart disease.

Congenit Heart Dis 2019 Sep 17;14(5):735-744. Epub 2019 Jun 17.

McGill Adult Unit for Congenital Heart Disease Excellence (MAUDE Unit), McGill University Health Center, Montreal, Quebec, Canada.

Background: The number of women with congenital heart disease (CHD) of reproductive age is increasing, yet a description of trends in pregnancy and delivery outcomes in this population is lacking.

Objective: To assess secular trends in pregnancy rates, delivery outcomes, and related health care utilization in the adult female CHD population in Quebec, Canada.

Methods: The Quebec CHD database was used to construct a cohort with all women with CHD aged 18-45 years between 1992 and 2004. Pregnancy and delivery rates were determined yearly and compared to the general population. Secular trends in pregnancy and delivery rates were assessed with linear regression. The cesarean delivery rate in the CHD population was compared to the general population. Predictors of cesarean section were determined with multivariable logistic regression. Cox regression, adjusted for comorbidities, was used to analyze the impact of cesarean sections on 1-year health care use following delivery.

Results: About 14 878 women were included. A total of 10 809 pregnancies were identified in 5641 women, of whom 4551 (80%) and 2528 (45%) experienced at least one delivery and/or abortion, respectively. Absolute yearly numbers and rates of pregnancies and deliveries increased during the study period (P < .05). The increment in cesarean section rates was more pronounced among women with CHD than among the general population. Gestational diabetes (OR 1.50, 95% CI [1.13, 1.99]), gestational hypertension (OR 1.81, 95% CI [1.27, 2.57]), and preeclampsia (OR 1.59, 95% CI [1.11, 2.8]) were independent predictors of cesarean delivery. Cesarean sections were associated with postpartum cardiac-hospitalization within 1 year following delivery (HR = 2.35, 95% CI [1.05, 5.28]).

Conclusions: Yearly numbers and rates of pregnancies and deliveries in adult females with CHD rose significantly during the study period. Cesarean sections led to increased health care utilization. Further research is required to determine causes of high cesarean section rates in this patient population.
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http://dx.doi.org/10.1111/chd.12811DOI Listing
September 2019

Flexible Modeling of the Association Between Cumulative Exposure to Low-Dose Ionizing Radiation From Cardiac Procedures and Risk of Cancer in Adults With Congenital Heart Disease.

Am J Epidemiol 2019 08;188(8):1552-1562

Department of Epidemiology, Biostatistics and Occupational Health, Faculty of Medicine, McGill University, Montréal, Quebec, Canada.

Adults with congenital heart disease are increasingly being exposed to low-dose ionizing radiation (LDIR) from cardiac procedures. In a recent study, Cohen et al. (Circulation. 2018;137(13):1334-1345) reported an association between increased LDIR exposure and cancer incidence but did not explore temporal relationships. Yet, the impact of past exposures probably accumulates over years, and its strength may depend on the amount of time elapsed since exposure. Furthermore, LDIR procedures performed shortly before a cancer diagnosis may have been ordered because of early symptoms of cancer, raising concerns about reversal causality bias. To address these challenges, we combined flexible modeling of cumulative exposures with competing-risks methodology to estimate separate associations of time-varying LDIR exposure with cancer incidence and all-cause mortality. Among 24,833 patients from the Quebec Congenital Heart Disease Database, 602 had incident cancer and 500 died during a follow-up period of up to 15 years (1995-2010). Initial results suggested a strong association of cancer incidence with very recent LDIR exposures, likely reflecting reverse causality bias. When exposure was lagged by 2 years, an increased cumulative LDIR dose from the previous 2-6 years was associated with increased cancer incidence, with a stronger association for women. These results illustrate the importance of accurate modeling of temporal relationships between time-varying exposures and health outcomes.
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http://dx.doi.org/10.1093/aje/kwz114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6670051PMC
August 2019

A pyrene linked peptide probe for quantitative analysis of protease activity via MALDI-TOF-MS.

Talanta 2019 Aug 14;200:236-241. Epub 2019 Mar 14.

State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun 130012, China; Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, College of Life Science, Jilin University, Changchun 130012, China. Electronic address:

We report herein a rationally designed pyrene linked substrate for quantitative protease activity assay via matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). In this proof-of-concept study, a trypsin-specific peptide with the sequence of GGGGRG was selected to conjugate with pyrene forming a pyrene linked peptide probe, Py-GGGGRG. In the presence of trypsin, the Py-GGGGRG probe can be specifically hydrolyzed into Py-GGGGR. The introduction of pyrene greatly increased ionization efficiency of Py-peptides, and Py-peptides could be selectively captured from complex mixtures by a facially fabricated polystyrene coated MALDI plate through hydrophobic and π-π stacking interactions. As a result, trypsin activity can be directly quantified by relative intensity ratio of product and substrate via MALDI-TOF-MS without the use of external internal standard. A linear range of 0.1-10 μg/mL and a relatively low detection limit of 29 ng/mL were obtained. This method has also been successfully used for quantification of trypsin activity in urine and screening the inhibitors of trypsin. Besides, the proposed strategy was also validated for another protease, chymotrypsin, by using the probe Py-GGGGGGYG. Therefore, owing to simplicity, high-throughput capacity and quantificational accuracy, the proposed method shows great potential for activity assay of various proteases and screening their inhibitors via application of specific peptide sequences.
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http://dx.doi.org/10.1016/j.talanta.2019.03.055DOI Listing
August 2019

Quantitation of Glutathione by Quinoline-5, 8-Dione-Based Tag Strategy Using MALDI Mass Spectrometry.

J Am Soc Mass Spectrom 2019 Apr 11;30(4):625-633. Epub 2019 Feb 11.

State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun, 130012, China.

In the present work, we developed an UV-absorptive and highly reactive tag aromatic molecule, quinoline-5,8-dione (QLD), for robust quantitative analysis of GSH by matrix-assisted laser desorption/ionization (MALDI) mass spectrometry. The QLD could react with GSH with high efficiency at room temperature, and the resultant QLD-GSH conjugate could be readily detected by MALDI MS without interferences. By using the QLD tag, the detection limit of GSH was lowered to 10 fmol μL, which was four orders of magnitude higher than that detected without using the QLD tag. Furthermore, accurate quantitative measurements of GSH in solution were successfully demonstrated by using glutamic acid-cysteine-alanine (ECA) as an internal standard. By properly adjusting the ECA concentrations, the intensity ratio value of QLD-tagged GSH (QLD-GSH) to QLD-tagged ECA (QLD-ECA) displayed a good linearity with GSH concentrations in a broad range from 4 to 4000 μM. Finally, the GSH level in HeLa cell lysates was also successfully detected, and the results are consistent with that obtained by a colorimetric assay. In summary, the proposed QLD-based tag method should be a rapid, cost-/time-effective, and sensitive new method for quantitative determination of GSH by MALDI MS. Graphical Abstract.
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http://dx.doi.org/10.1007/s13361-019-02135-4DOI Listing
April 2019

DBDA as a Novel Matrix for the Analyses of Small Molecules and Quantification of Fatty Acids by Negative Ion MALDI-TOF MS.

J Am Soc Mass Spectrom 2018 04 18;29(4):704-710. Epub 2018 Jan 18.

State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun, 130012, China.

Matrix interference ions in low mass range has always been a concern when using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) to analyze small molecules (<500 Da). In this work, a novel matrix, N1,N4-dibenzylidenebenzene-1,4-diamine (DBDA) was synthesized for the analyses of small molecules by negative ion MALDI-TOF MS. Notably, only neat ions ([M-H]) of fatty acids without matrix interference appeared in the mass spectra and the limit of detection (LOD) reached 0.3 fmol. DBDA also has great performance towards other small molecules such as amino acids, peptides, and nucleotide. Furthermore, with this novel matrix, the free fatty acids in serum were quantitatively analyzed based on the correlation curves with correlation coefficient of 0.99. In addition, UV-Vis experiments and molecular orbital calculations were performed to explore mechanism about DBDA used as matrix in the negative ion mode. The present work shows that the DBDA matrix is a highly sensitive matrix with few interference ions for analysis of small molecules. Meanwhile, DBDA is able to precisely quantify the fatty acids in real biological samples. Graphical Abstract ᅟ.
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http://dx.doi.org/10.1007/s13361-017-1881-yDOI Listing
April 2018

Exposure to Low-Dose Ionizing Radiation From Cardiac Procedures and Malignancy Risk in Adults With Congenital Heart Disease.

Circulation 2018 03 21;137(13):1334-1345. Epub 2017 Dec 21.

McGill Adult Unit for Congenital Heart Disease Excellence, Montreal, Quebec, Canada (S.C., A.L., L.G., J.T., A.J.M.)

Background: Adults with congenital heart disease (CHD) are exposed to increasing amounts of low-dose ionizing radiation (LDIR) from cardiac procedures. Cancer prevalence in this population is higher than in the general population. This study estimates the association between LDIR exposure from cardiac procedures and incident cancer in adult patients with CHD.

Methods: The study population derived from the Quebec Congenital Heart Disease Database. We measured cumulative numbers of LDIR-related cardiac procedures for each patient until 1 year before the time of cancer diagnosis or administrative censoring. To assess the association between LDIR exposure and cancer risk, we conducted a nested case-control study and matched cancer cases with controls on sex, CHD severity, birth year, and age.

Results: The study included 24 833 adult patients with CHD aged 18 to 64 years from 1995 to 2009. In >250 791 person-years of follow-up, 602 cancer cases were observed (median age, 55.4 years). The cumulative incidence of cancer estimated up to 64 years of age was 15.3% (95% confidence interval [CI], 14.2-16.5). Cases had more LDIR-related cardiac procedures than controls (1410 versus 921 per 1000 adult patients with CHD, <0.0001). Cumulative LDIR exposure was independently associated with cancer (odds ratio [OR], 1.08 per procedure; 95% CI, 1.04-1.13). Similar results were obtained by using dose estimates for LDIR exposure (OR, 1.10 per 10 mSv; 95% CI, 1.05-1.15) with a possible dose-related response. The effect measure was in the same direction, and the association was persistent for exposure from ≥6 procedures in all sensitivity analyses: after excluding most smoking-related cancer cases (OR, 1.10 per procedure; 95% CI, 1.05-1.16 and OR when exposure from ≥6 procedures, 3.08; 95% CI, 1.77-5.37), and after applying a 3-year lag period (OR, 1.09 per procedure; 95% CI, 1.03-1.14 and OR when exposure from ≥6 procedures: 2.58; 95% CI, 1.43-4.69).

Conclusions: To our knowledge, this is the first large population-based study to analyze and document the association between LDIR-related cardiac procedures and incident cancer in the population of adults with CHD. Confirmations of these findings by prospective studies are needed to reinforce policy recommendations for radiation surveillance in patients with CHD where no regulation currently exists. Physicians ordering and performing cardiac imaging should ensure that exposure is as low as reasonably achievable without sacrificing quality of care.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.117.029138DOI Listing
March 2018

Repeated blood transfusions: Identification of a novel culprit of early graft failure in children.

Int J Cardiol 2018 03 5;254:90-95. Epub 2017 Dec 5.

McGill Adult Unit for Congenital Heart Disease Excellence, Montreal, Canada.

Background: The attrition of right ventricle to pulmonary artery (RV-PA) grafts has been attributed in part to the body's immunologic response. We hypothesized that antibodies developed through blood transfusion, directed against the grafts, may result in accelerated degeneration and the need for re-intervention.

Methods: This is a population-based study of the province of Quebec. We included children born between January 1, 1987 to December 31, 2006 who were diagnosed with a cono-truncal anomaly and had an RV-PA graft. The patients were followed for transfusion exposure and RV-PA graft re-intervention. Time to re-intervention in those exposed versus non-exposed was analyzed using Cox regression. Analysis was done in two time periods, before and after the calendar year 2000, given the change in blood preparation in the province of Quebec.

Results: There were 413 patients who met the inclusion criteria of a cono-truncal disorder. Of the whole study population, 69% received a blood transfusion. Cox regression analysis showed that among patients who had the initial graft performed (n=181) before year 2000, having 2 or more blood transfusion was associated with an nearly tripled risk of a re-intervention comparing to no blood transfusion (hazard ratio of 2.88; 95% confidence interval 1.05-7.91). In patients who had the initial graft performed after year 2000 (n=232), the associated risk increase was 7-fold (hazard ratio of 7.01; 95% confidence interval 3.06-16.02). Kaplan-Meier analyses confirmed the significant difference in the re-intervention free survival probabilities between those who received 2 or more blood product transfusion and those who did not as well: prior to year 2000 (67.9% vs. 88.0% at 5years, p=0.0201) as well as after year 2000 (39.7% vs. 82.8% at 5years, p<0.0001).

Conclusion: In this population-based analysis, repeated blood product transfusion was associated with a significant increased risk of a need for RV-PA graft re-intervention. This data strongly suggest that repeated blood transfusion may adversely impact graft longevity.
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http://dx.doi.org/10.1016/j.ijcard.2017.11.112DOI Listing
March 2018

Incidence, Predictors, and Mortality of Infective Endocarditis in Adults With Congenital Heart Disease Without Prosthetic Valves.

Am J Cardiol 2017 Dec 14;120(12):2278-2283. Epub 2017 Oct 14.

McGill Adult Unit for Congenital Heart Disease Excellence, McGill University Health Centre, Montreal, Quebec, Canada; Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada. Electronic address:

Congenital heart disease (CHD) increases the risk of infective endocarditis (IE), though the lesion-specific risk and mortality are poorly defined. Using the population-based Quebec CHD database, we sought to describe the predictors of IE and to evaluate if IE was associated with mortality among adult CHD (ACHD) patients without prior valve replacement surgery. We extracted data on ACHD patients with IE and assessed the lesion-specific incidence of IE, risk factors for IE acquisition, and all-cause 1-year mortality. Among 29,866 ACHD patients, 285 (0.95%) developed IE during follow-up period of 378,901 patient-years, from 1988-2010. The highest and lowest lesion-specific incidences of IE were observed with left-sided lesions (1.61/1000 patient-years) and patent ductus arteriosus (0.24/1000 patient-years), respectively. The following predicted the risk of IE acquisition (odds ratio (OR), 95% confidence interval [CI]): cardiac surgery in the previous 6 months (9.07, 3.98-20.67), endocardial cushion defects (6.65, 3.84-11.53), left-sided lesions (5.11, 3.60-7.25), cyanosis at birth (4.82, 3.12-7.46), ventricular septal defect (2.81, 1.87-4.21), diabetes mellitus (1.65, 1.10-2.48), and recent medical interventions (12.52, 5.23-29.97). Twenty-five (8.77%) patients died within 1-year of IE diagnosis, a substantially elevated rate compared to patients without IE (OR 31.07, 95%CI 16.23-59.49). The risk of death following IE diagnosis was similarly elevated among patients with left-sided, cyanotic and other CHD lesions. In conclusion, the risk of IE in ACHD patients is lesion-specific and is greatest in the context of recent medical interventions. IE is associated with increased 1-year mortality, irrespective of broad CHD lesion grouping.
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http://dx.doi.org/10.1016/j.amjcard.2017.08.051DOI Listing
December 2017

Preliminary experimental investigation of an X-band Cerenkov-type high power microwave oscillator without guiding magnetic field.

Rev Sci Instrum 2017 Feb;88(2):024708

College of Optoelectronic Science and Engineering, National University of Defense Technology, Changsha 410073, People's Republic of China.

Among high power microwave (HPM) generators without guiding magnetic field, Cerenkov-type oscillator is expected to achieve a relatively high efficiency, which has already been realized in X-band in our previous simulation work. This paper presents the preliminary experimental investigations into an X-band Cerenkov-type HPM oscillator without guiding magnetic field. Based on the previous simulation structure, some modifications regarding diode structure were made. Different cathode structures and materials were tested in the experiments. By using a ring-shaped graphite cathode, microwave of about one hundred megawatt level was generated with a pure center frequency of 9.14 GHz, and an efficiency of about 1.3%. As analyzed in the paper, some practical issues reduce the efficiency in experiments, such as real features of the electron beam, probable breakdown regions on the cathode surface which can damage the diode, and so forth.
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http://dx.doi.org/10.1063/1.4975831DOI Listing
February 2017

Prevalence of Cancer in Adults With Congenital Heart Disease Compared With the General Population.

Am J Cardiol 2016 Dec 31;118(11):1742-1750. Epub 2016 Aug 31.

McGill Adult Unit for Congenital Heart Disease Excellence, McGill University, Montreal, Québec, Canada. Electronic address:

The prevalence rate of cancer among adult patients with congenital heart disease (CHD) in North America has not been previously described. The Quebec adult CHD database was used to determine the prevalence rate of cancer among adult patients with CHD measured as the number of adults with CHD and cancer alive in 2005 per 1,000 adults with CHD. This prevalence rate was compared with the prevalence rate of cancer in the general population of adults in Canada. Types of cancer among the CHD group were described by gender and age. Adult patients with CHD had a 1.6 to 2 times higher prevalence of cancer at 2, 5, and 10 years for both men and women. Overall, men had a greater prevalence of total cancers in all-time durations than did women. Breast, colon, and prostate cancer were the most common cancers reported in adults with CHD. In conclusion, we observed an increased prevalence of cancer among the adult CHD population of Quebec compared with the general Canadian population.
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http://dx.doi.org/10.1016/j.amjcard.2016.08.057DOI Listing
December 2016

Cardiac output as a predictor in congenital heart disease: Are we stating the obvious?

Int J Cardiol 2016 May 8;210:143-8. Epub 2016 Feb 8.

McGill Adult Unit for Congenital Heart Disease Excellence (MAUDE Unit), McGill University Health Center, Montréal, Canada; Beth Raby Adult Congenital Heart Disease Clinic, Jewish General Hospital, Montréal, Canada. Electronic address:

Background: Significant pulmonary regurgitation, declining right-sided ejection fraction, increased right ventricular (RV) volumes as well as left ventricular (LV) dysfunction have all been identified as predictors of poor outcomes in patients with congenital heart disease (CHD). The prognostic value of the cardiac output (CO) in these patients however has never been studied.

Methods: All consecutive ambulatory adult patients with CHD referred for magnetic resonance imaging (MRI) at the Montreal Children's Hospital between June 2007 and May 2009 were included. Right ventricular (RV) and left ventricular (LV) variables including end diastolic and end systolic volumes (EDV, ESV respectively), ejection fractions (EF) and regurgitant volumes were obtained. Cardiac index (CI) was calculated. Patients were followed for cardiac-related hospitalizations and cardiac interventions.

Results: Ninety-six patients were included. Median follow up was 3.9 ± 1.4 years. Nineteen percent of patients had a systemic CI<2.4 l/min/m(2). LVEDV, LVEF and RVEF were significantly diminished in the low CI group with a significant increase in RVESV and total regurgitant volume. Best predictors of low CI were LVEF (AUC=0.74), RVEF (AUC=0.71), total RV regurgitant volume (AUC=0.64) and RVESV (AUC=0.563). Low systemic CI was the best predictor of cardiac-related hospitalizations (hazard ratio 3.5, 95% confidence interval 1.5-8.5) and cardiac interventions (hazard ratio 2.2, 95% confidence interval 1.3-4.0), superior to LVEF, RVEF, total regurgitant volume and RVESV parameters.

Conclusions: In patients with congenital heart disease, cardiac index is the best predictor of cardiac hospitalizations and cardiac interventions.
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http://dx.doi.org/10.1016/j.ijcard.2016.02.071DOI Listing
May 2016

Stroke in Adults With Congenital Heart Disease: Incidence, Cumulative Risk, and Predictors.

Circulation 2015 Dec 23;132(25):2385-94. Epub 2015 Nov 23.

From the McGill Adult Unit for Congenital Heart Disease Excellence, Montreal, Québec, Canada (J.L., J.T., M.K., L.G., A.J.M.); Department of Medicine, McGill University Health Centre, Montreal, Québec, Canada (J.M.B., A.J.M.); and Division of Cardiology, Jewish General Hospital, Montreal, Québec, Canada (J.T.).

Background: Stroke is an important cause of morbidity and mortality, although there is a lack of comprehensive data on its incidence, cumulative risk, and predictors in patients with adult congenital heart disease.

Methods And Results: This retrospective study of 29 638 Quebec patients with adult congenital heart disease aged 18 to 64 years between 1998 and 2010 was based on province-wide administrative data. The cumulative risk of ischemic stroke estimated up to age 64 years was 6.1% (95% confidence interval [CI], 5.0-7.0%) in women and 7.7% (95% CI, 6.4-8.8%) in men; the risk of hemorrhagic stroke was 0.8% (95% CI, 0.4-1.2%) and 1.3% (95% CI, 0.8-1.8%), respectively. Compared with rates reported for the general Quebec population, age-sex standardized incidence rates of ischemic stroke were 9 to 12 times higher below age 55 years and 2 to 4 times higher in the age group 55 to 64 years; hemorrhagic stroke rates were 5 to 6 times (age <55 years) and 2 to 3 times higher. Using a combination of stepwise model selection and Bayesian model averaging, the strongest predictors of ischemic stroke were heart failure (odds ratio for age group 18-49 years, 5.94 [95% CI, 3.49-10.14], odds ratio for age group 50-64 years, 1.68 [95% CI, 1.06-2.66]), diabetes mellitus (odds ratio, 2.33 [95% CI, 1.66-3.28]), and recent myocardial infarction (odds ratio, 8.38 [95% CI, 1.77-39.58]).

Conclusions: Among patients with adult congenital heart disease, 1 in 11 men and 1 in 15 women experienced a stroke between ages 18 and 64 years. Stroke incidence was considerably higher than in the general population, especially at a younger age. The most important predictors of ischemic stroke were heart failure, diabetes mellitus, and recent myocardial infarction. Additional research is required to see whether advances in the management of adult congenital heart disease may reduce this substantial stroke rate.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.115.011241DOI Listing
December 2015

Exposure to Low-Dose Ionizing Radiation From Cardiac Procedures in Patients With Congenital Heart Disease: 15-Year Data From a Population-Based Longitudinal Cohort.

Circulation 2016 Jan 4;133(1):12-20. Epub 2015 Nov 4.

From Department of Cardiology, Children's Hospital Boston, Harvard Medical School, MA (V.B.L., M.G.); Department of Pediatrics, Montreal Children's Hospital, McGill University, QC, Canada (V.B.L.); Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (P.R.L.); Department of Medicine, McGill University Health Center, Montreal, QC, Canada (P.R.L., L.P.); and Division of Cardiology, Jewish General Hospital (M.J.E.) and McGill Adult Unit for Congenital Heart Disease Excellence (R.I.-I., L.G., A.J.M.), McGill University, Montreal, QC, Canada.

Background: The burden of low-dose ionizing radiation (LDIR) exposure from medical procedures among individuals with congenital heart disease (CHD) is unknown. In this longitudinal population-based study, we sought to determine exposure to LDIR-related cardiac imaging and therapeutic procedures in children and adults with CHD.

Methods And Results: In an analysis of the Quebec CHD database, exposure to the following LDIR-related cardiac procedures was recorded: catheter-based diagnostic procedures, structural heart interventions, coronary interventions, computed tomography scans of the chest, nuclear procedures, and pacemaker/implantable cardioverter-defibrillator insertion and repair. From 1990 to 2005, there were 16 253 LDIR-exposed patients with CHD with 317 988 patient-years of available follow-up. The total number of LDIR-related procedures increased from 18.5 to 51.9 per 1000 CHD patients per year (P<0.0001). This increase was attributable to increases in rates per 1000 CHD patients in diagnostic cardiac catheterizations (11.7 to 13.7 per 1000), structural heart interventions (1.0 to 5.2 per 1000), coronary interventions (1.0 to 2.4 per 1000), pacemaker/implantable cardioverter-defibrillator insertions (1.6 to 4.4 per 1000), nuclear procedures (4.2 to 13.8 per 1000), and computed tomography scans of the chest (2.5 to 12.3 per 1000). Over time, among children with CHD, the median age at first LDIR procedure decreased from 5.0 years to 9.6 months. Severity of CHD significantly predicted extent of exposure.

Conclusions: From 1990 to 2005, patients with CHD were exposed to increasing numbers of LDIR-emitting cardiac procedures. This exposure occurred at progressively younger ages. These findings provide an important perspective on longitudinal LDIR exposure in this at-risk population.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.115.019137DOI Listing
January 2016

The REC domain mediated dimerization is critical for FleQ from Pseudomonas aeruginosa to function as a c-di-GMP receptor and flagella gene regulator.

J Struct Biol 2015 Oct 8;192(1):1-13. Epub 2015 Sep 8.

State Key Laboratory of Microbial Technology, School of Life Sciences, Shandong University, Jinan 250100, Shandong, China. Electronic address:

FleQ is an AAA+ ATPase enhancer-binding protein that regulates both flagella and biofilm formation in the opportunistic pathogen Pseudomonas aeruginosa. FleQ belongs to the NtrC subfamily of response regulators, but lacks the corresponding aspartic acid for phosphorylation in the REC domain (FleQ(R), also named FleQ domain). Here, we show that the atypical REC domain of FleQ is essential for the function of FleQ. Crystal structure of FleQ(R) at 2.3Å reveals that the structure of FleQ(R) is significantly different from the REC domain of NtrC1 which regulates gene expression in a phosphorylation dependent manner. FleQ(R) forms a novel active dimer (transverse dimer), and mediates the dimerization of full-length FleQ in an unusual manner. Point mutations that affect the dimerization of FleQ lead to loss of function of the protein. Moreover, a c-di-GMP binding site deviating from the previous reported one is identified through structure analysis and point mutations.
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http://dx.doi.org/10.1016/j.jsb.2015.09.002DOI Listing
October 2015

Crystal structure of PnpCD, a two-subunit hydroquinone 1,2-dioxygenase, reveals a novel structural class of Fe2+-dependent dioxygenases.

J Biol Chem 2015 Oct 24;290(40):24547-60. Epub 2015 Aug 24.

From the State Key Laboratory of Microbial Technology, School of Life Sciences, Shandong University, Jinan, Shandong 250100,

Aerobic microorganisms have evolved a variety of pathways to degrade aromatic and heterocyclic compounds. However, only several classes of oxygenolytic fission reaction have been identified for the critical ring cleavage dioxygenases. Among them, the most well studied dioxygenases proceed via catecholic intermediates, followed by noncatecholic hydroxy-substituted aromatic carboxylic acids. Therefore, the recently reported hydroquinone 1,2-dioxygenases add to the diversity of ring cleavage reactions. Two-subunit hydroquinone 1,2-dioxygenase PnpCD, the key enzyme in the hydroquinone pathway of para-nitrophenol degradation, catalyzes the ring cleavage of hydroquinone to γ-hydroxymuconic semialdehyde. Here, we report three PnpCD structures, named apo-PnpCD, PnpCD-Fe(3+), and PnpCD-Cd(2+)-HBN (substrate analog hydroxyenzonitrile), respectively. Structural analysis showed that both the PnpC and the C-terminal domains of PnpD comprise a conserved cupin fold, whereas PnpC cannot form a competent metal binding pocket as can PnpD cupin. Four residues of PnpD (His-256, Asn-258, Glu-262, and His-303) were observed to coordinate the iron ion. The Asn-258 coordination is particularly interesting because this coordinating residue has never been observed in the homologous cupin structures of PnpCD. Asn-258 is proposed to play a pivotal role in binding the iron prior to the enzymatic reaction, but it might lose coordination to the iron when the reaction begins. PnpD also consists of an intriguing N-terminal domain that might have functions other than nucleic acid binding in its structural homologs. In summary, PnpCD has no apparent evolutionary relationship with other iron-dependent dioxygenases and therefore defines a new structural class. The study of PnpCD might add to the understanding of the ring cleavage of dioxygenases.
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http://dx.doi.org/10.1074/jbc.M115.673558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4591834PMC
October 2015

Expression, purification and preliminary crystallographic analysis of a haem-utilizing protein, HutX, from Vibrio cholerae.

Acta Crystallogr F Struct Biol Commun 2015 Feb 28;71(Pt 2):141-4. Epub 2015 Jan 28.

State Key Laboratory of Microbial Technology, School of Life Science, Shandong University, 27 Shanda Nanlu, Jinan, Shandong 250100, People's Republic of China.

Vibrio cholerae, the causative agent of cholera, has developed a variety of mechanisms to obtain the limited-availability iron from human hosts. One important method for iron acquisition is through haem-uptake systems. Although the transport of haem has been widely studied, the fate of haem once it enters the cytoplasm remains an open question. Here, preliminary X-ray crystallographic analysis was performed on HutX, a member of the conserved haem-utilization operon from V. cholerae strain N16961. The crystals of HutX were found to belong to the orthorhombic space group C2221, with unit-cell parameters a = 50.1, b = 169.0, c = 81.8 Å. There are two protein molecules in the asymmetric unit, with a corresponding Matthews coefficient VM of 2.06 Å(3) Da(-1) and a solvent content of 40.28%.
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http://dx.doi.org/10.1107/S2053230X14027666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4321465PMC
February 2015
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