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1.
Hongchao Zhou Xinyuan Dong Rafi Kabarriti Yong Chen Yesim Avsar Xia Wang Jianqiang Ding Laibin Liu Ira J. Fox Jayanta Roy-Chowdhury Namita Roy-Chowdhury Chandan Guha 《PloS one》2012,7(10)
Background and Aims
Preparative hepatic irradiation (HIR), together with mitotic stimulation of hepatocytes, permits extensive hepatic repopulation by transplanted hepatocytes in rats and mice. However, whole liver HIR is associated with radiation-induced liver disease (RILD), which limits its potential therapeutic application. In clinical experience, restricting HIR to a fraction of the liver reduces the susceptibility to RILD. Here we test the hypothesis that repopulation of selected liver lobes by regional HIR should be sufficient to correct some inherited metabolic disorders.Methods
Hepatocytes (107) isolated from wildtype F344 rats or Wistar-RHA rats were engrafted into the livers of congeneic dipeptidylpeptidase IV deficient (DPPIV−) rats or uridinediphosphoglucuronateglucuronosyltransferase-1A1-deficient jaundiced Gunn rats respectively by intrasplenic injection 24 hr after HIR (50 Gy) targeted to the median lobe, or median plus left liver lobes. An adenovector expressing hepatocyte growth factor (1011 particles) was injected intravenously 24 hr after transplantation.Results
Three months after hepatocyte transplantation in DPPIV− rats, 30–60% of the recipient hepatocytes were replaced by donor cells in the irradiated lobe, but not in the nonirradiated lobes. In Gunn rats receiving median lobe HIR, serum bilirubin declined from pretreatment levels of 5.17±0.78 mg/dl to 0.96±0.30 mg/dl in 8 weeks and remained at this level throughout the 16 week observation period. A similar effect was observed in the group, receiving median plus left lobe irradiation.Conclusions
As little as 20% repopulation of 30% of the liver volume was sufficient to correct hyperbilirubinemia in Gunn rats, highlighting the potential of regiospecific HIR in hepatocyte transplantation-based therapy of inherited metabolic liver diseases. 相似文献2.
Background
Patellar tendinopathy (PT) is one of the most common knee disorders among athletes. Changes in morphology and elasticity of the painful tendon and how these relate to the self-perceived pain and dysfunction remain unclear.Objectives
To compare the morphology and elastic properties of patellar tendons between athlete with and without unilateral PT and to examine its association with self-perceived pain and dysfunction.Methods
In this cross-sectional study, 33 male athletes (20 healthy and 13 with unilateral PT) were enrolled. The morphology and elastic properties of the patellar tendon were assessed by the grey and elastography mode of supersonic shear imaging (SSI) technique while the intensity of pressure pain, self-perceived pain and dysfunction were quantified with a 10-lb force to the most painful site and the Victorian Institute of Sport Assessment-patella (VISA-P) questionnaire, respectively.Results
In athletes with unilateral PT, the painful tendons had higher shear elastic modulus (SEM) and larger tendon than the non-painful side (p<0.05) or the dominant side of the healthy athletes (p<0.05). Significant correlations were found between tendon SEM ratio (SEM of painful over non-painful tendon) and the intensity of pressure pain (rho = 0.62; p = 0.024), VISA-P scores (rho = −0.61; p = 0.026), and the sub-scores of the VISA-P scores on going down stairs, lunge, single leg hopping and squatting (rho ranged from −0.63 to −0.67; p<0.05).Conclusions
Athletes with unilateral PT had stiffer and larger tendon on the painful side than the non-painful side and the dominant side of healthy athletes. No significant differences on the patellar tendon morphology and elastic properties were detected between the dominant and non-dominant knees of the healthy control. The ratio of the SEM of painful to non-painful sides was associated with pain and dysfunction among athletes with unilateral PT. 相似文献3.
Liesbeth Van Huffel Charles R. V. Tomson Johannes Ruige Ionut Nistor Wim Van Biesen Davide Bolignano 《PloS one》2014,9(11)
Background
Obesity and sedentary lifestyle are major health problems and key features to develop cardiovascular disease. Data on the effects of lifestyle interventions in diabetics with chronic kidney disease (CKD) have been conflicting.Study Design
Systematic review.Population
Diabetes patients with CKD stage 3 to 5.Search Strategy and Sources
Medline, Embase and Central were searched to identify papers.Intervention
Effect of a negative energy balance on hard outcomes in diabetics with CKD.Outcomes
Death, cardiovascular events, glycaemic control, kidney function, metabolic parameters and body composition.Results
We retained 11 studies. There are insufficient data to evaluate the effect on mortality to promote negative energy balance. None of the studies reported a difference in incidence of Major Adverse Cardiovascular Events. Reduction of energy intake does not alter creatinine clearance but significantly reduces proteinuria (mean difference from −0.66 to −1.77 g/24 h). Interventions with combined exercise and diet resulted in a slower decline of eGFR (−9.2 vs. −20.7 mL/min over two year observation; p<0.001). Aerobic and resistance exercise reduced HbA1c (−0.51 (−0.87 to −0.14); p = 0.007 and −0.38 (−0.72 to −0.22); p = 0.038, respectively). Exercise interventions improve the overall functional status and quality of life in this subgroup. Aerobic exercise reduces BMI (−0.74% (−1.29 to −0.18); p = 0.009) and body weight (−2.2 kg (−3.9 to −0.6); p = 0.008). Resistance exercise reduces trunk fat mass (−0,7±0,1 vs. +0,8 kg ±0,1 kg; p = 0,001−0,005). In none of the studies did the intervention cause an increase in adverse events.Limitations
All studies used a different intervention type and mixed patient groups.Conclusions
There is insufficient evidence to evaluate the effect of negative energy balance interventions on mortality in diabetic patients with advanced CKD. Overall, these interventions have beneficial effects on glycaemic control, BMI and body composition, functional status and quality of life, and no harmful effects were observed. 相似文献4.
Hung-Chieh Chou Chiang-Ting Chien Po-Nien Tsao Wu-Shiun Hsieh Chien-Yi Chen Mei-Hwei Chang 《PloS one》2014,9(1)
Background
We hypothesized that cord blood hydrogen peroxide (H2O2) could be utilized to predict the severity of neonatal hyperbilirubinemia.Methods
We prospectively enrolled term or near-term healthy neonates. Cord blood and capillary blood at three days of age were measured for hydrogen peroxide and bilirubin concentrations. For newborns with hyperbilirubinemia, further blood samples were obtained at five and seven days of age. Newborns were divided into severe or less severe hyperbilirubinemic groups (peak bilirubin ≥17 mg/dL or not). The sensitivity, specificity, and negative predictive values were determined.Results
There were 158 neonates enrolled. The incidence of neonatal hyperbilirubinemia was 30.5% for a concentration ≥15 mg/dl. The rising patterns were similar among bilirubin concentrations and hydrogen peroxide levels during the first few days of life. There was a strong positive correlation between bilirubin concentrations and hydrogen peroxide levels after correlation analysis. The rate of severe hyperbilirubinemia was 13.3%. It revealed that a cord blood hydrogen peroxide signal level of 2500 counts/10 seconds was an appropriate cut-off for predicting severe hyperbilirubinemia. Sensitivity and the negative predictive value were 76.2% and 93.3%, respectively.Conclusions
Our findings confirm that hydrogen peroxide levels and bilirubin concentrations in cord and neonatal blood are closely related. A cord blood hydrogen peroxide level above 2500 counts/10 seconds associated with a high predictive value for severe hyperbilirubinemia. This method provides information about which neonate should be closely followed after discharge from the nursery. 相似文献5.
Daniel P. Bailey Lynne M. Boddy Louise A. Savory Sarah J. Denton Catherine J. Kerr 《PloS one》2013,8(2)
Background
It is unknown whether using different published thresholds (PTs) for classifying physical activity (PA) impacts upon activity-health relationships. This study explored whether relationships between PA (sedentary [SED], light PA [LPA], moderate PA [MPA], moderate-to-vigorous PA, vigorous PA [VPA]) and health markers differed in children when classified using three different PTs.Methods
104 children (63 girls) aged 10–14 years wore an RT3 triaxial accelerometer for seven days and measures of adiposity and cardiometabolic risk markers were taken.Results
Significant associations (p< .05) in boys were found between LPA and body mass index z-score and waist circumference z-score for the Rowlands et al PT only (β = .459 and.401, respectively) and body fat% (BF%) for the Chu et al PT only (β = .322) and in girls with BF% for the Rowlands et al PT only (β = .303) and systolic BP and blood glucose for the Vanhelst et al PT only (β = −.298 and −.283, respectively). MPA was significantly (p<.05) associated with BF%, diastolic BP, and cardiorespiratory fitness (CRF) for the Chu et al PT only in girls (β = −.436, −.529, and .446, respectively). SED was significantly (p<.05) associated with triglycerides (β = .492) for the Rowlands et al PT only in boys and VPA with CRF (p<.05) for the Rowlands et al and Vanhelst et al PTs only in girls (β = .416 and .352, respectively).Conclusions
The choice of PT impacted upon activity-health relationships. A consensus on appropriate accelerometer thresholds for quantifying PA intensity and sedentary behaviour is needed in order to make accurate evidence-based recommendations for health promotion. 相似文献6.
Debbie A. Lawlor Marianne Benn Luisa Zuccolo N. Maneka G. De Silva Anne Tybjaerg-Hansen George Davey Smith B?rge G. Nordestgaard 《PloS one》2014,9(12)
Background
The effect of alcohol consumption on liver function is difficult to determine because of reporting bias and potential residual confounding. Our aim was to determine this effect using genetic variants to proxy for the unbiased effect of alcohol.Methods
We used variants in ADH1B and ADH1C genes as instrumental variables (IV) to estimate the causal effect of long-term alcohol consumption on alanine aminotransferase (ALT), γ-glutamyl-transferase (γ-GT), alkaline phosphatase (ALP), bilirubin and prothrombin action. Analyses were undertaken on 58,313 Danes (mean age 56).Results
In both confounder adjusted multivariable and genetic-IV analyses greater alcohol consumption, amongst those who drank any alcohol, was associated with higher ALT [mean difference per doubling of alcohol consumption: 3.4% (95% CI: 3.1, 3.7) from multivariable analyses and 3.7% (−4.5, 11.9) from genetic-IV analyses] and γ-GT [8.2% (7.8, 8.5) and 6.8% (−2.8, 16.5)]. The point estimates from the two methods were very similar and statistically the results from the two methods were consistent with each other for effects with ALT and γ-GT (both pdiff>0.3). Results from the multivariable analyses suggested a weak inverse association of alcohol with ALP [−1.5% (−1.7, −1.3)], which differed from the strong positive effect found in genetic-IV analyses [11.6% (6.8, 16.4)] (pdiff<0.0001). In both multivariable and genetic-IV analyses associations with bilirubin and protrombin action were weak and close to the null.Conclusions
Our results suggest that greater consumption of alcohol is related to poorer liver function as indicated by higher ALT, γ-GT and ALP, but not to clotting or bilirubin. 相似文献7.
Sally H. Vitali S. Alex Mitsialis Olin D. Liang Xiaoli Liu Angeles Fernandez-Gonzalez Helen Christou Xinqi Wu Francis X. McGowan Stella Kourembanas 《PloS one》2009,4(6)
Background
Hypoxia and pressure-overload induce heme oxygenase-1 (HO-1) in cardiomyocytes and vascular smooth muscle cells (VSMCs). HO-1−/− mice exposed to chronic hypoxia develop pulmonary arterial hypertension (PAH) with exaggerated right ventricular (RV) injury consisting of dilation, fibrosis, and mural thrombi. Our objective was to indentify the HO-1 product(s) mediating RV protection from hypoxic injury in HO-1−/− mice.Methodology/Principal Findings
HO-1−/− mice were exposed to seven weeks of hypoxia and treated with inhaled CO or biliverdin injections. CO reduced right ventricular systolic pressure (RVSP) and prevented hypoxic pulmonary arteriolar remodeling in both HO-1−/− and control mice. Biliverdin had no significant effect on arteriolar remodeling or RVSP in either genotype. Despite this, biliverdin prevented RV failure in the hypoxic HO-1−/− mice (0/14 manifested RV wall fibrosis or thrombus), while CO-treated HO-1−/− mice developed RV insults similar to untreated controls. In vitro, CO inhibited hypoxic VSMC proliferation and migration but did not prevent cardiomyocyte death from anoxia-reoxygenation (A-R). In contrast, bilirubin limited A-R-induced cardiomyocyte death but did not inhibit VSMC proliferation and migration.Conclusions/Significance
CO and bilirubin have distinct protective actions in the heart and pulmonary vasculature during chronic hypoxia. Moreover, reducing pulmonary vascular resistance may not prevent RV injury in hypoxia-induced PAH; supporting RV adaptation to hypoxia and preventing RV failure must be a therapeutic goal. 相似文献8.
Eugenia Ulzurrun Camilla Stephens Francisco Ruiz-Cabello Mercedes Robles-Diaz Pablo Saenz-López Hacibe Hallal German Soriano Eva Roman M. Carmen Fernandez M. Isabel Lucena Raúl J. Andrade 《PloS one》2014,9(4)
Background and Aims
Flawed ABC transporter functions may contribute to increased risk of drug-induced liver injury (DILI). We aimed to analyse the influence of genetic variations in ABC transporters on the risk of DILI development and clinical presentations in a large Spanish DILI cohort.Methods
A total of ten polymorphisms in ABCB1 (1236T>C, 2677G>T,A, 3435T>C), ABCB4 (1954A>G) and ABCC2 (−1774G>del, −1549A>G, −24C>T, 1249G>A, 3972C>T and 4544G>A) were genotyped using Taqman 5′ allelic discrimination assays or sequencing in 141 Spanish DILI patients and 161 controls. The influence of specific genotypes, alleles and haplotypes on the risk of DILI development and clinical presentations was analysed.Results
None of the individual polymorphisms or haplotypes was found to be associated with DILI development. Carriers homozygous for the ABCC2 −1774del allele were however only found in DILI patients. Hence, this genotype could potentially be associated with increased risk, though its low frequency in our Spanish cohort prevented a final conclusion. Furthermore, carriers homozygous for the ABCC2 −1774G/−1549A/−24T/1249G/3972T/4544G haplotype were found to have a higher propensity for total bilirubin elevations when developing DILI.Conclusions
Our findings do not support a role for the analysed polymorphisms in the ABCB1, ABCB4 and ABCC2 transporter genes in DILI development in Spanish patients. The ABCC2 −1774deldel genotype was however restricted to DILI cases and could potentially contribute to enhanced DILI susceptibility. 相似文献9.
Teresa Cobo Marian Kacerovsky Ctirad Andrys Marcela Drahosova Ivana Musilova Helena Hornychova Bo Jacobsson 《PloS one》2013,8(7)
Objective
To evaluate umbilical cord interleukin (IL)-6 and funisitis as independent predictors of early-onset neonatal sepsis (EONS) in preterm prelabor rupture of membranes (PPROM).Design
Prospective cohort study.Setting
Evaluation of umbilical cord IL-6 and funisitis as predictors of early-onset neonatal sepsis in PPROM.Population
176 women with PPROM between 23+0−36+6 weeks of gestation.Methods
Umbilical cord IL-6 was assayed by ELISA. Funisitis was defined according to the Salafia classification. Data was adjusted by gestational age at delivery and prenatal administration of corticosteroids and antibiotics.Main Outcome Measures
Binary logistic regression was performed to assess the independence of umbilical cord IL-6 and funisitis to predict EONS in women complicated with PPROM.Results
The rate of EONS was 7%. Funisitis was present in 18% of women. Umbilical cord IL-6 was significantly higher in women complicated with EONS than without [median (range) 389.5 pg/mL (13.9–734.8) vs 5.2 (0.1–801–4), p<0.001]. Umbilical cord IL-6 was the only independent predictor of early-onset neonatal sepsis (odds ratio 13.6, p = 0.004).Conclusion
Umbilical cord IL-6 was the only predictor of early-onset neonatal sepsis in PPROM. Contrary to what is reported, funisitis was not. 相似文献10.
Jung Pyo Lee Do Hyoung Kim Seung Hee Yang Jin Ho Hwang Jung Nam An Sang Il Min Jongwon Ha Yun Kyu Oh Yon Su Kim Chun Soo Lim 《PloS one》2014,9(4)
Background
Oxidative stress is a major mediator of adverse outcome after kidney transplantation. Bilirubin is produced by heme oxygenase-1 (HO-1), catalyzed by UDP-glucuronosyltransferase (UGT1A1), and has potential as an antioxidant. In this study, we investigated the effects of HO-1 and UGT1A1 sequence variations on kidney allograft outcomes.Methods
Clinical data were collected from 429 Korean recipients who underwent kidney transplantation from 1990–2008. Genotyping for UGT1A1*28 and HO-1 (A−413T) was performed. Acute rejection and graft survival were monitored as end-points.Results
Serum levels of total bilirubin were significantly increased after transplantation (0.41±0.19 mg/dL to 0.80±0.33 mg/dL, P<0.001). Post-transplant 1-year bilirubin level was higher in 6/7 or 7/7 carriers compared with 6/6 homozygotes in terms of the UGT1A1*28 polymorphism (6/6 vs. 6/7 vs. 7/7: 0.71±0.27 vs. 1.06±0.36 vs. 1.10±0.45 mg/dL, P<0.001). According to an additive model of genotype analysis, the 7-allele genotype had a protective effect on the development of acute rejection compared with the 6-allele (odds ratio 0.43, 95% CI 0.25–0.73, P for trend = 0.006). Multivariate Cox regression analysis revealed that individuals carrying the 7-allele had a decreased risk of graft loss, by a factor of 0.36 (95% CI 0.15–0.85, P = 0.019). The HO-1 (A−413T) polymorphism had no effect on serum bilirubin levels or graft outcomes.Conclusions
The UGT1A1*28 polymorphism is associated with changes in serum bilirubin and with graft outcome after kidney transplantation. 相似文献11.
Yu Lu Zhitong Wu Qiliu Peng Liping Ma Xiaolian Zhang Jiangyang Zhao Xue Qin Shan Li 《PloS one》2014,9(10)
Background
Interleukin-4 (IL-4) is best known as an important mediator and modulator of immune and inflammatory responses. Hepatocellular carcinoma (HCC) is a typical inflammation-related cancer, and genetic variations in the IL-4 gene may be associated with the risk of hepatitis B virus (HBV)-related HCC. However, few studies have been conducted on their association.Objectives
To clarify the effects of IL-4 gene polymorphisms on the risk of HBV-related HCC, two common variants, −590C/T (rs2243250) and −33C/T (rs2070874), and their relationship with HBV-related disease risk were investigated in a Chinese population.Methods
IL-4 −590C/T and −33C/T polymorphisms were examined in 154 patients with HBV-related HCC, 62 patients with HBV-induced liver cirrhosis (LC), 129 patients with chronic hepatitis B (CHB), and 94 healthy controls, using the polymerase chain reaction-restriction fragment length polymorphism method and DNA sequencing.Results
Overall, no significant differences were observed regarding the IL-4 −590C/T and −33C/T polymorphism genotypes, alleles, or haplotypes between the patient groups and the healthy controls. However, the CC genotypes of IL-4 −590C/T and −33C/T polymorphisms were observed to be significantly associated with CHB in subgroup analysis in males [CC versus TT (OR: 4.193, 95% CI: 1.094–16.071, P = 0.037; and OR: 3.438, 95% CI: 1.032–11.458, P = 0.044) and CC versus TT+CT (OR: 4.09, 95% CI: 1.08–15.49, P = 0.038; and OR: 3.43, 95% CI: 1.04–11.28, P = 0.042)].Conclusions
These findings suggest that genetic variants in IL-4 −590C/T and −33C/T polymorphisms may be a risk factor for CHB in Chinese males but not for HBV-related LC or HCC. 相似文献12.
Background
Kernicterus still occurs around the world; however, the mechanism of bilirubin neurotoxicity remains unclear, and effective treatment strategies are lacking. To solve these problems, several kernicterus (or acute bilirubin encephalopathy) animal models have been established, but these models are difficult and expensive. Therefore, the present study was performed to establish a novel kernicterus model that is simple and affordable by injecting unconjugated bilirubin solution into the cisterna magna (CM) of ordinary newborn Sprague-Dawley (SD) rats.Methods
On postnatal day 5, SD rat pups were randomly divided into bilirubin and control groups. Then, either bilirubin solution or ddH2O (pH = 8.5) was injected into the CM at 10 µg/g (bodyweight). For model characterization, neurobehavioral outcomes were observed, mortality was calculated, and bodyweight was recorded after bilirubin injection and weaning. Apoptosis in the hippocampus was detected by H&E staining, TUNEL, flow cytometry and Western blotting. When the rats were 28 days old, learning and memory ability were evaluated using the Morris water maze test.Results
The bilirubin-treated rats showed apparently abnormal neurological manifestations, such as clenched fists, opisthotonos and torsion spasms. Bodyweight gain in the bilirubin-treated rats was significantly lower than that in the controls (P<0.001). The early and late mortality of the bilirubin-treated rats were both dramatically higher than those of the controls (P = 0.004 and 0.017, respectively). Apoptosis and necrosis in the hippocampal nerve cells in the bilirubin-treated rats were observed. The bilirubin-treated rats performed worse than the controls on the Morris water maze test.Conclusion
By injecting bilirubin into the CM, we successfully created a new kernicterus model using ordinary SD rats; the model mimics both the acute clinical manifestations and the chronic sequelae. In particular, CM injection is easy to perform; thus, more stable models for follow-up study are available. 相似文献13.
Maarten van Vliet Mark van den Boogaard J. Peter Donnelly Andrea W. M. Evers Nicole M. A. Blijlevens Peter Pickkers 《PloS one》2014,9(1)
Objective
Long-term health-related quality of life (HRQoL) was determined for patients admitted to the haematology ward who needed intensive care treatment (H-IC+) and compared with those who did not (H-IC−) as well as with that for patients admitted to the general ICU (nH-IC+).Methods
A cross-sectional study was carried out median 18 months after admission by employing the short form-36, checklist for individual strength, cognitive failure questionnaire and hospital anxiety and depression scale.Results
27 (79%) of the 34 H-IC+ patients approached, and 93 (85%) of the 109 H-IC− patients approached replied. Data were adjusted for relevant covariates and matched with those of 149 patients in the general ICU. Apart from the lower role-physical functioning score for H-IC+ (P = 0.04) no other differences were found between H-IC+ and H-IC−. Groups H-IC+ and nH-IC+ evaluated their HRQoL on SF-36 similarly, except for the lower aggregated physical component summary (PCS) for H-IC+ (P<0.0001). After adjusting for PCS, no significant differences in CIS, CFQ and HADS were observed between the groups.Conclusions
Eighteen months after admission, patients treated for haematological malignancies reported similar HRQoL, whether or not they had received intensive care treatment, but reported a lower PCS than those of patients in the general ICU. Hence, there is no reason to assume that admission to the ICU has a negative impact on long-term HRQoL, so this should not affect the decision whether or not to transfer patients with haematological malignancies to the ICU. 相似文献14.
Background
The relationship between passive smoking exposure (PSE) and breast cancer risk is of major interest.Objective
To evaluate the relationship between PSE from partners and breast cancer risk stratified by hormone-receptor (HR) status in Chinese urban women population.Design
Hospital-based matched case control study.Setting
Chinese urban breast cancer patients without current or previous active smoking history in China Medical University 1st Hospital, Liaoning Province, China between Jan 2009 and Nov 2009.Patients
Each breast cancer patient was matched 1∶1 with healthy controls by gender and age (±2 years) from the same hospital.Measurements
The authors used unconditional logistic regression analyses to estimate odds ratio for women with PSE from partners and breast cancer risk.Results
312 pairs were included in the study. Women who endured PSE had significantly increased risk of breast cancer (adjusted OR: 1.46; 95% CI: 1.05–2.03; P = 0.027), comparing with unexposed women. Women who exposed to >5 cigarettes/day also had significant increased risk (adjusted OR: 1.99; 95% CI: 1.28–3.10; P = 0.002), as were women exposed to passive smoke for 16–25 years (adjusted OR: 1.87 95% CI: 1.22–2.86; P = 0.004), and those exposed to > 4 pack-years (adjusted OR: 1.71 95% CI: 1.17–2.50; P = 0.004). Similar trends were significant for estrogen receptor (ER)/progesterone receptor (PR) double positive subgroup(adjusted OR: 1.71; 2.20; 1.99; 1.92, respectively), but not for ER+/PR−, ER−/PR+, or ER−/PR− subgroups.Limitations
limitations of the hospital-based retrospective study, lack of information on entire lifetime PSE and low statistical power.Conclusions
Our findings provide further evidence that PSE from partners contributes to increased risk of breast cancer, especially for ER/PR double positive breast cancer, in Chinese urban women. 相似文献15.
16.
《PloS one》2012,7(9)
Rationale
Asthma has substantial morbidity and mortality and a strong genetic component, but identification of genetic risk factors is limited by availability of suitable studies.Objectives
To test if population-based cohorts with self-reported physician-diagnosed asthma and genome-wide association (GWA) data could be used to validate known associations with asthma and identify novel associations.Methods
The APCAT (Analysis in Population-based Cohorts of Asthma Traits) consortium consists of 1,716 individuals with asthma and 16,888 healthy controls from six European-descent population-based cohorts. We examined associations in APCAT of thirteen variants previously reported as genome-wide significant (P<5x10−8) and three variants reported as suggestive (P<5×10−7). We also searched for novel associations in APCAT (Stage 1) and followed-up the most promising variants in 4,035 asthmatics and 11,251 healthy controls (Stage 2). Finally, we conducted the first genome-wide screen for interactions with smoking or hay fever.Main Results
We observed association in the same direction for all thirteen previously reported variants and nominally replicated ten of them. One variant that was previously suggestive, rs11071559 in RORA, now reaches genome-wide significance when combined with our data (P = 2.4×10−9). We also identified two genome-wide significant associations: rs13408661 near IL1RL1/IL18R1 (P Stage1+Stage2 = 1.1x10−9), which is correlated with a variant recently shown to be associated with asthma (rs3771180), and rs9268516 in the HLA region (P Stage1+Stage2 = 1.1x10−8), which appears to be independent of previously reported associations in this locus. Finally, we found no strong evidence for gene-environment interactions with smoking or hay fever status.Conclusions
Population-based cohorts with simple asthma phenotypes represent a valuable and largely untapped resource for genetic studies of asthma. 相似文献17.
Zheng-hui Liu Yuan-lin Ding Liang-chang Xiu Hai-yan Pan Yan Liang Shou-qiang Zhong Wei-wei Liu Shao-qi Rao Dan-li Kong 《PloS one》2013,8(3)
Objective
A meta-analysis was applied to evaluate the associations between tumor necrosis factor-α (TNF-α) −308G>A (rs1800629) polymorphism and type 2 diabetes mellitus (T2DM).Methods
Hardy-Weinberg equilibrium (HWE) was employed to test genetic equilibrium among the genotypes of the selected literature. Power analysis was performed with the Power and Sample Size Calculation (PS) program. A fixed or random effect model was used on the basis of heterogeneity. Publication bias was quantified and examined with the Begg''s funnel plot test and Egger''s linear regression test. The meta-analysis was performed with Review Manager 5.1 and Stata 11.0.Results
There were 10 studies including 1425 T2DM patients and 1116 healthy control subjects involved in this meta-analysis. No significant publication bias was found in the studies. The pooled ORs (95% CIs) for TNF-α −308G>A of A vs. G allele and GA+AA vs. GG genotype were 1.63 (1.17–2.25) and 1.47 (1.17–1.85), respectively.Conclusion
This meta-analysis result suggested that TNF-α −308G>A polymorphism was strongly associated with T2DM risk, and A allele at this locus might be a susceptibility allele for the development of T2DM in Han Chinese population. 相似文献18.
Background
Jaundice is one of the most common problems encountered in newborn infants, due to immaturity of hepatic conjugation and transport processes for bilirubin. Although the majority of neonatal jaundice is benign, some neonates with severe hyperbilirubinemia develop bilirubin encephalopathy or kernicterus. Accumulation of unconjugated bilirubin (UCB) in selected brain regions may result in temporary or permanent impairments of auditory, motor, or cognitive function; however, the molecular mechanisms by which UCB elicits such neurotoxicity are still poorly understood. The present study is undertaken to investigate whether prolonged exposure of rat organotypic hippocampal slice cultures to UCB alters the induction of long-term synaptic plasticity.Methodology/Principal Findings
Using electrophysiological recording techniques, we find that exposure of hippocampal slice cultures to clinically relevant concentrations of UCB for 24 or 48 h results in an impairment of CA1 long-term potentiation (LTP) and long-term depression (LTD) induction in a time- and concentration-dependent manner. Hippocampal slice cultures stimulated with UCB show no changes in the secretion profiles of the pro-inflammatory cytokines, interleukin-1β and tumor necrosis factor-α, or the propidium ioide uptake. UCB treatment produced a significant decrease in the levels of NR1, NR2A and NR2B subunits of N-methyl-D-aspartate (NMDA) receptors through a calpain-mediated proteolytic cleavage mechanism. Pretreatment of the hippocampal slice cultures with NMDA receptor antagonist or calpain inhibitors effectively prevented the UCB-induced impairment of LTP and LTD.Conclusion/Significance
Our results indicate that the proteolytic cleavage of NMDA receptor subunits by calpain may play a critical role in mediating the UCB-induced impairment of long-term synaptic plasticity in the hippocampus. These observations provide new insights into the molecular mechanisms underlying UCB-induced impairment of hippocampal synaptic plasticity which, in turn, might provide opportunities for the development of novel therapeutic strategies that targets these pathways for treatment. 相似文献19.
Tao Qin Yuan-Yuan Sun Wen-Wu Bai Bo Wang Yi-Fan Xing Yan Liu Rui-Xue Yang Yu-Xia Zhao Jian-Min Li 《PloS one》2014,9(9)
Background
In the clinic, variations in circadian rhythm are evident in patients with cardiovascular disease, and the risk of cardiovascular events increases when rhythms are disrupted. In this study, we focused on the role of the circadian gene period2 (per2) in mobilization and function of endothelial progenitor cells (EPCs) in vitro and in vivo after myocardial infarction (MI) in mice.Methods and Results
MI was produced by surgical ligation of the left anterior descending coronary artery in mice with and without per2 deficiency. Trans-thoracic echocardiography was used to evaluate cardiac function in mice. Per2−/− mice with MI showed decreased cardiac function and increased infarct size. The number of CD34+ cells and capillary density were decreased in the myocardium of per2−/− mice on immunohistochemistry. Flow cytometry revealed decreased number of circulating EPCs in per2−/− mice after MI. In vitro, per2−/− EPCs showed decreased migration and tube formation capacity under hypoxia. Western blot analysis revealed inhibited activation of extracellular signal-regulated kinase and Akt signaling in the bone marrow of per2−/− mice and inhibited PI3K/Akt expression in per2−/− EPCs under hypoxia.Conclusions
Per2 modulates EPC mobilization and function after MI, which is important to recovery after MI in mice. 相似文献20.
Alan Winston Alejandro Arenas-Pinto Wolfgang St?hr Martin Fisher Chloe M. Orkin Kazeem Aderogba Andrew De Burgh-Thomas Nigel O'Farrell Charles JN. Lacey Clifford Leen David Dunn Nicholas I. Paton for the PIVOT Trial Team 《PloS one》2013,8(4)