Epithelial lining fluid free IGF-I-to-PAPP-A ratio is associated with bronchopulmonary dysplasia in preterm infants

Preterm newborns developing retinopathy of prematurity (ROP) and bronchopulmonary dysplasia (BPD) show persistently low levels of insulin-like growth factor-I (IGF-I) in sera. They also present higher free IGF-I concentrations in epithelial lining fluids (ELFs) and lung tissues. Pregnancy-associated plasma protein-A (PAPP-A) is a metalloproteinase that dissociates three binding proteins from the active form of IGF-I, namely free IGF-I. The present study analyzes the ELF concentrations of free IGF-I, PAPP-A, and their ratios in preterm newborns developing or not BPD, defined as O(2) dependence at 36 wk postmenstrual age. Bronchoalveolar lavage fluids of 41 infants (34 without and 7 with BPD) were analyzed on the 2nd and 4th day after birth. Infants developing BPD showed increased ELF free IGF-I and decreased PAPP-A concentrations on both days 2 and 4 compared with newborns without BPD. A nonsignificant trend between these 2 days was observed for free IGF-I (increasing) and PAPP-A (decreasing). On the same days, the free IGF-I-to-PAPP-A ratio was always significantly higher in patients developing BPD. These differences were more significant than those of IGF-I or PAPP-A when individually evaluated. A multivariate analysis confirmed the significance for free IGF-I on day 4, whereas the ratio was confirmed on both days 2 and 4. The same ratio was significantly correlated with some indexes of disease severity, such as hours of oxygen administration, days of hospitalization, and ROP severity scores. Finally, the ratio between ELF free IGF-I and PAPP-A appears to be a useful marker for lung injury of premature newborns.     

Nutrition of preterm infants in relation to bronchopulmonary dysplasia

Background

The pathogenesis of bronchopulmonary dysplasia (BPD) is multifactorial. In addition to prenatal inflammation, postnatal malnutrition also affects lung development.

Methods

A retrospective study was performed to analyse during the first two weeks of life the total, enteral and parenteral nutrition of premature infants (<31 weeks, birth weight ≤1500 g) born between 08/04 and 12/06.

Results

Ninety-five premature infants were analysed: 26 with BPD (27 ± 1 weeks) and 69 without BPD (28 ± 1 weeks). There was no statistical significant difference in the total intake of fluids, calories, glucose or protein and weight gain per day in both groups. The risk of developing BPD was slightly increased in infants with cumulative caloric intake below the minimal requirement of 1230 kcal/kg and a cumulative protein intake below 43.5 g/kg. Furthermore, the risk of developing BPD was significantly higher when infants had a cumulative fluid intake above the recommended 1840 ml/kg. In infants who developed BPD, the enteral nutrition was significantly lower than in non-BPD infants [456 ml/kg (IQR 744, 235) vs. 685 (IQR 987, 511)]. Infants who did not develop BPD reached 50% of total enteral feeding significantly faster [9.6 days vs. 11.5].

Conclusions

Preterm infants developing BPD received less enteral feeding, even though it was well compensated by the parenteral nutrient supply. Data suggest that a critical minimal amount of enteral feeding is required to prevent development of BPD; however, a large prospective clinical study is needed to prove this assumption.

     

Plasma and erythrocyte selenium and glutathione peroxidase activity in preterm infants at risk for bronchopulmonary dysplasia

The purpose of this study was to examine the relationships between selenium status, as measured by plasma and erythrocyte selenium and glutathione peroxidase (GPx) activity, and other postnatal factors, including selenium intake, gestational age, and oxygen dependence in preterm infants at risk for bronchopulmonary dysplsia. Eighteen preterm infants of 30 wk gestational age or less were included. At postnatal wk 1 and 4, selenium concentrations and GPx activity were measured and oxygen dependence and daily selenium intakes were determined from the medical chart. Plasma and erythrocyte selenium concentrations decreased from wk 1 to wk 4, whereas erythrocyte GPx activity increased. Increased selenium intakes during wk 1 were associated with increased erythrocyte GPx activity at both time-points, as well as a decreased need for supplemental oxygen on d 28. Preterm infants display increasing erythrocyte GPx activity despite declines in plasma and erythrocyte selenium. GPx activity might be enhanced by very early selenium supplementation.     

Common polymorphisms (rs2241766 and rs1501299) in the ADIPOQ gene are not associated with hypertension susceptibility among the Chinese

The ADIPOQ gene has been implicated in the etiology of hypertension. However, the results have been inconsistent. In this study, a meta-analysis was performed to assess the associations of ADIPOQ polymorphisms with hypertension risk among the Chinese. Published literature from PubMed, CNKI and Wanfang Data were retrieved. Pooled odds ratio (OR) with 95 % confidence interval (CI) was calculated using fixed- or random-effects model. Six studies (1,812 cases and 2,631 controls) for rs2241766 polymorphism and four studies (1,449 cases and 2,175 controls) for rs1501299 polymorphism were identified. A marginally significant association was observed for rs2241766 polymorphism under recessive genetic model (GG vs. GT+TT: OR = 1.22, 95 % CI 1.01-1.48) and for rs1501299 polymorphism under heterogeneous co-dominant model (TG vs. GG: OR = 0.86, 95 % CI 0.75-0.99) and dominant model (TT+TG vs. GG: OR = 0.85, 95 % CI 0.74-0.98). In addition, under other genetic models, there was no significant association for rs2241766 polymorphism (GG vs. TT: OR = 1.20, 95 % CI 0.98-1.48; GT vs. TT: OR = 0.97, 95 % CI 0.85-1.10; GG+GT vs. TT: OR = 1.01, 95 % CI 0.90-1.15) and for rs1501299 polymorphism (TT vs. GG: OR = 0.82, 95 % CI 0.62-1.08; TT vs. TG+GG: OR = 0.87, 95 % CI 0.66-1.14). However, the associations above were not robust by sensitivity analysis. The present meta-analysis indicated the limited evidence of the significant associations between ADIPOQ gene polymorphisms and hypertension susceptibility among the Chinese.     

Association Between HOTAIR rs920778 and H19 rs3741219 Polymorphisms with Hashimoto’s Thyroiditis (HT) and Graves’ Disease (GD)

Background:Graves’ disease (GD) and Hashimoto’s thyroiditis (HT) are two autoimmune thyroid diseases (AITDs). The current study aimed to assess possible association between HOTAIR rs920778 and H19 rs3741219 polymorphisms with GD and HT.Methods:We recruited 248 patients with autoimmune thyroid disease (133 HT patients and 115 GD patients) and 135 age- and sex-matched controls. The PCR-RFLP method was applied for genotyping of HOTAIR rs920778, and H19 rs3741219 polymorphisms.Results:The HOTAIR rs920778 GA frequency was significantly higher in control compared to HT group. The Overdominant model showed a significant association with the risk of HT. However, no significant association was observed between this polymorphism and HT susceptibility in dominant and recessive models. The H19 rs3741219 GA was more repeated in HT patients compared to control group, but the difference was not significant. There was no association between HOTAIR rs920778 and H19 rs3741219 polymorphisms with GD in all genetic models.DiscussionOur findings indicated that HOTAIR rs920778 polymorphism decreased the risk of HT. Since, this the first study, further studies with different races are required to confirm our results.Key Words: Hashimoto’s thyroiditis, Graves’ disease, HOTAIR, H19, Polymorphism     

Polymorphisms of DNA base‐excision repair genes APE/Ref‐1 and XRCC1 are not associated with the risk for Graves' disease

Oxidative stress has been implicated in etiopathogenesis of Graves' disease (GD). Increased lipid peroxidation and oxidative DNA damage have been found in GD patients. Oxidative DNA damage is mainly repaired by the base‐excision repair (BER) pathway. Polymorphisms in DNA‐repair genes have been associated with the increased risk of various diseases and could also be related to the etiology of GD. Therefore, we conducted a study including 197 patients with GD and age‐ and sex‐matched 303 healthy subjects to examine the role of single‐nucleotide polymorphisms of BER genes, APE/Ref‐1 (codon 148) and XRCC1 (codons 194 and 399) as a risk factor for GD. These polymorphisms were determined by quantitative real‐time PCR and melting curve analysis using LightCycler. No significant association was observed between the variant alleles of APE/Ref‐1 codon 148 [odds ratio (OR) = 0.89, 95% confidence interval (CI) = 0.69–1.17], XRCC1 codon 194 (OR = 1.24, 95% CI = 0.79–1.94), and XRCC1 codon 399 (OR = 1.12, 95% CI = 0.86–1.46) and GD. These preliminary results suggest that APE/Ref‐1 (codon 148) and XRCC1 (codons 194 and 399) polymorphisms are not significant risk factors for developing GD. Copyright © 2009 John Wiley & Sons, Ltd.     

Polymorphisms in an obesity-related gene (PCSK1) are associated with fat deposition and production traits in Italian heavy pigs

The proprotein convertase subtilisin/kexin type 1 (PCSK1) gene encodes the prohormone convertase 1/3 enzyme that processes prohormones into functional hormones that, in turn, regulate central and peripheral energy metabolism. Mutations in the human PCSK1 gene cause severe monogenic obesity or confer risk of obesity. We herein investigated the porcine PCSK1 gene with the aim of identifying polymorphisms associated with fat deposition and production traits in Italian heavy pigs. By re-sequencing about 5.1 kb of this gene in 21 pigs of different breeds, we discovered 14 polymorphisms that were organized in nine haplotypes, clearly distributed in two clades of putative European and Asian origin. Then we re-mapped this gene on porcine chromosome 2 and analysed its expression in several tissues including gastric oxyntic mucosa of weanling pigs in which PCSK1 processes the pre-pro-ghrelin into ghrelin, which in turn is involved in the control of feed intake and energy metabolism. Association analyses between PCSK1 single-nucleotide polymorphisms (SNPs) and production, carcass and several other traits were conducted on five groups of pigs from three different experimental designs, for a total of 1221 animals. Results indicated that the analysed SNPs were associated (P < 0.01 or P < 0.05) with several traits including backfat thickness and visible intermuscular fat in Italian Duroc (ID) and growth performances in Italian Large White (ILW) and in ILW × Italian Landrace pigs. However, the effects estimated in the ILW were opposite to the effects reported in the ID pigs. Suggestive association (P < 0.10) was observed with muscle cathepsin B activity, opening, if confirmed, potential applications to reduce the excessive softness defect of the green hams that is of particular concern for the processing industry. The results obtained supported the need to further investigate the PCSK1 gene to fully exploit the value of its variability and apply this information in pig breeding programmes.     

Gelatinase activities in the airways of premature infants and development of bronchopulmonary dysplasia

Matrix-degrading metalloproteinases may play a role in the pathophysiology of bronchopulmonary dysplasia (BDP). We, therefore, evaluated correlations between gelatinase activities [metalloproteinase (MMP)-2 and MMP-9] or tissue inhibitor of metalloproteinase (TIMP)-1 levels present in the airways during the initial phase of hyaline membrane disease and the onset of BPD. Tracheal aspirates were obtained within 6 h of birth (day 0) from 64 intubated neonates with a gestational age < or =30 wk. Forty-five neonates were resampled on day 3 or 5. Total MMP-2 level measured by zymography fell with time, whereas total MMP-9 level and TIMP-1 levels, assayed by ELISA, increased; the MMP-9 increase correlated with the increase in airway inflammatory cell numbers. Among the parameters measured on day 0, 3, or 5, lower total MMP-2 level, lower birth weight, and higher fraction of inspired oxygen on day 0 were significantly and independently associated with the development of BPD. In conclusion, MMP-9 level and TIMP-1 levels increased after birth but are not linked to BPD outcome. In contrast, low MMP-2 level at birth is strongly associated with the development of BPD.     

Polymorphisms in NAT2 and GSTP1 are associated with survival in oral and oropharyngeal cancer

Introduction: Functional polymorphisms in drug metabolizing enzymes (DMEs) may be determinants of survival in oral and oropharyngeal squamous cell carcinoma (OOSCC). Methods: OOSCC cases (N = 159) with a history of either tobacco or alcohol use were genotyped for polymorphisms in eight DMEs. Overall and disease-specific survival were analyzed using Kaplan–Meier plots and the log-rank test. Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) in exploratory analyses of patient subgroups. Results: Kaplan–Meier analyses showed N-acteyltransferase-2 (NAT2) fast acetylators experienced a 19.7% higher 5-year survival rate than slow acetylators (P = 0.03) and this association was similar in oropharyngeal and oral cancer. After multiple adjustment, including tumor site and stage, the NAT2 fast acetylator phenotype was associated with improved overall survival (vs. slow acetylators) provided chemotherapy or radiation were not used (HR, 0.26; 95% CI, 0.10–0.66). However, NAT2 phenotype was unrelated to survival in patients treated with chemoradiotherapy (HR, 1.21; 95% CI, 0.54–2.73) or radiotherapy (HR, 0.67; 95% CI, 0.31–1.59) (P-for-NAT2/treatment-interaction = 0.04). Normal activity GSTP1 was associated with a 19.2% reduction in 5-year disease-specific survival relative to reduced activity GSTP1 (P = 0.04) but this association was not modified by treatment. Conclusions: Our results suggest that functional polymorphisms in NAT2 and GSTP1 are associated with OOSCC survival. Confirmation of these results in larger studies is required.     

Polymorphisms of the FTO gene are associated with variation in energy intake, but not energy expenditure

The FTO gene has significant polymorphic variation associated with obesity, but its function is unknown. We screened a population of 150 whites (103F/47M) resident in NE Scotland, United Kingdom, for variants of the FTO gene and linked these to phenotypic variation in their energy expenditure (basal metabolic rate (BMR) and maximal oxygen consumption VO(2)max) and energy intake. There was no significant association between the FTO genotype and BMR or VO(2)max. The FTO genotype was significantly associated (P = 0.024) with variation in energy intake, with average daily intake being 9.0 MJ for the wild-type TT genotype and 10.2 and 9.5 MJ for the "at risk" AT and AA genotypes, respectively. Adjusting intake for BMR did not remove the significance (P = 0.043). FTO genotype probably affects obesity via effects on food intake rather than energy expenditure.     

Surfactant disaturated phosphatidylcholine kinetics in infants with bronchopulmonary dysplasia measured with stable isotopes and a two-compartment model.

We previously found a shorter surfactant disaturated phosphatidylcholine palmitate (DSPC-PA) half-life in infants with bronchopulmonary dysplasia (BPD) by using a single stable isotope tracer and simple formulas based on a one-exponential fit of the final portion of the enrichment decay curve. The aim of this study was to apply noncompartmental and compartmental analysis on the entire enrichment decay curve of DSPC-PA and to compare the kinetic data with our previous results. We analyzed 10 preterm newborns with BPD (gestational age 26 +/- 0.6 wk, weight 777 +/- 199 g) and 6 controls (gestational age 26 +/- 1.4 wk, weight 787 +/- 259 g). All took part in our previous study. Endotracheal 13C-labeled dipalmitoyl phosphatidylcholine was administered, and the 13C-enrichment of surfactant DSPC-PA was measured from serial tracheal aspirates by gas chromatography-mass spectrometry. Noncompartmental and compartmental models were numerically identified from the tracer-to-tracee ratio and kinetic parameters related to the accessible (pool accessible to sampling, likely to be the lung alveolar pool) and to the nonaccessible pools (pools not accessible to samplings, likely to be the intracellular storage pool) were estimated in the two study groups. Comparison was performed by Mann-Whitney test. A two-compartment model provided the most reliable assessment of DSPC-PA kinetics. In BPD vs. controls, mean +/- SE residence time of DSPC-PA in the accessible was 17.5 +/- 2.6 vs. 32.2 +/- 6.4 h (P < 0.05), whereas it was 49.7 +/- 3.5 vs. 54.4 +/- 3.9 h (NS, not significant) in the nonaccessible pool; DSPC-PA recycling was 0.26 +/- 0.05 vs. 0.43 +/- 0.04% (NS), respectively. A two-compartment model of surfactant DSPC-PA kinetics allowed a thorough assessment of DSPC-PA kinetics, including masses, synthesis, and fluxes between pools. The most important findings of this study are that in BPD infants DSPC-PA loss from the alveolar pool was higher and recycling through the intracellular pool lower than in controls.     

Serum selenium levels of the very low birth weight premature newborn infants with bronchopulmonary dysplasia

BackgroundThe selenium (Se) is an essential trace element that has a critical role in synthesis and activity of a number of selenoproteins with protective properties against free radical damage. This study was conducted to detect the serum Se concentration in very low birth weight (VLBW) preterm infants and its association with bronchopulmonary dysplasia (BPD).Materials and methodsCord blood Se concentration was determined in 54 neonates with gestation age 30 week or less. Another sample was obtained from these infants at day 28 of birth and serum Se levels were measured by atomic absorption spectrophotometer. All neonates were followed for oxygen dependency at 28 day after birth and 36 week postmenstrual age.ResultsThe mean cord blood Se concentration in studied neonates was 64.78 ± 20.73 μg L^?1. Serum Se concentration was 60.33 ± 26.62 μg L^?1 at age 28-day. No significant correlation was observed for serum Se concentration at birth and at one month after birth (r = ?0.04, p = 0.72). BPD was diagnosed in 25 neonates (46%). The mean serum Se concentration at one month was 57.16 ± 29.68 μg L^?1 in patients with BPD (25 cases) and 63.27 ± 23.6 μg L^?1 in 29 patients without BPD (p = 0.40).ConclusionIn our study, serum Se concentration at 28 day of birth was lower than cord blood levels in preterm neonates, but we have not found significant difference among patients who had BPD or not with respect to serum Se concentrations at this age.     

Polymorphisms in calpastatin and mu‐calpain genes are associated with beef iron content

The objective of this study was to assess the association of markers in the calpastatin and mu‐calpain loci with iron in beef cattle muscle. The population consisted of 259 cross‐bred steers from Beefmaster, Brangus, Bonsmara, Romosinuano, Hereford and Angus sires. Total iron and heme iron concentrations were measured. Markers in the calpastatin (referred to as CAST) and mu‐calpain (referred to as CAPN4751) genes were used to assess their association with iron levels. The mean and standard error for iron and heme iron content in the population was 35.6 ± 1.3 μg and 27.1 ± 1.4 μg respectively. Significant associations (P < 0.01) of markers were observed for both iron and heme iron content. For CAST, animals with the CC genotype had higher levels of iron and heme iron in longissimus dorsi muscle. For CAPN4751, individuals with the TT genotype had higher concentrations of iron and heme iron than did animals with the CC and CT genotypes. Genotypes known to be associated with tougher meat were associated with higher levels of iron concentration.     

Polymorphisms in cinnamoyl CoA reductase (CCR) are associated with variation in microfibril angle in Eucalyptus spp

Linkage disequilibrium (LD) mapping using natural populations results in higher resolution of marker-trait associations compared to family-based quantitative trait locus (QTL) studies. Depending on the extent of LD, it is possible to identify alleles within candidate genes associated with a trait. Analysis of a natural mutant in Arabidopsis has shown that mutations in cinnamoyl CoA reductase (CCR), a key lignin gene, affect physical properties of the secondary cell wall such as stiffness and strength. Using this gene, we tested whether LD mapping could identify alleles associated with microfibril angle (MFA), a wood quality trait affecting stiffness and strength of wood. We identified 25 common single-nucleotide polymorphism (SNP) markers in the CCR gene in Eucalyptus nitens. Using single-marker and haplotype analyses in 290 trees from a E. nitens natural population, two haplotypes significantly associated with MFA were found. These results were confirmed in two full-sib families of E. nitens and Eucalyptus globulus. In an effort to understand the functional significance of the SNP markers, we sequenced the cDNA clones and identified an alternatively spliced variant from the significant haplotype region. This study demonstrates that LD mapping can be used to identify alleles associated with wood quality traits in natural populations of trees.     

The CYP17-MspA1 rs743572 polymorphism is not associated with gender dysphoria

Gender dysphoria is commonly thought to arise from discrepant cerebral and genital sexual differentiation. Increasing evidence supports the idea of genetic vulnerability. The purpose of this paper was to investigate whether the polymorphism CYP17-MspA1 rs743572 is associated with gender dysphoria. Fragments that included the rs743572 polymorphism were PCR amplified and digested with MspA1 in 317 MtFs, 223 FtMs, 358 control men and 264 control women. The allele/genotype frequencies were compared between groups, with the 1000 Genomes Data Base and with international literature. Allele and genotype frequencies did not differ significantly between the FtM and female control groups (χ² = 0.631; p = 0.43 and χ² = 2.767; p = 0.25), or between the MtF and male control groups (χ² = 0.105; p = 0.74 and χ² = 0.789; p = 0.67). A2 frequency was higher in the FtM (0.43) than the female control group (0.41), male control group (0.40), or MtF group (0.39), but this difference did not reach statistical significance. Genotype frequencies did not differ significantly between groups (p = 0.66), between genotypes (p = 0.4) or between sexes (p = 0.66). Our data contradict previous findings about the CYP17-MspA1 rs743572 polymorphism and gender dysphoria and concur with the 1000 Genomes Data Base, which shows that the allele frequencies vary between countries and ethnicities but not between sexes. Our data do not support a hypothetical involvement of the rs743572 polymorphism in the genetic basis of gender dysphoria.     

Polymorphisms within the C-reactive protein (CRP) promoter region are associated with plasma CRP levels

Elevated plasma levels of C-reactive protein (CRP), an inflammation-sensitive marker, have emerged as an important predictor of future cardiovascular disease and metabolic abnormalities in apparently healthy men and women. Here, we performed a systematic survey of common nucleotide variation across the genomic region encompassing the CRP gene locus. Of the common single-nucleotide polymorphisms (SNPs) identified, several in the CRP promoter region are strongly associated with CRP levels in a large cohort study of cardiovascular risk in European American and African American young adults. We also demonstrate the functional importance of these SNPs in vitro.     

Polymorphisms in mitochondrial ribosomal protein S5 (MRPS5) are associated with leprosy risk in Chinese

Leprosy is an infectious disease caused by Mycobacterium leprae (M. leprae), with about 210,000 new cases per year worldwide. Although numerous risk loci have been uncovered by genome-wide association studies, the effects of common genetic variants are relatively modest. To identify possible new genetic locus involved in susceptibility to leprosy, whole exome sequencing was performed for 28 subjects including 14 patients and 12 unaffected members from 8 leprosy-affected families as well as another case and an unrelated control, and then the follow-up SNP genotyping of the candidate variants was studied in case-control sample sets. A rare missense variant in mitochondrial ribosomal protein S5 (MRPS5), rs200730619 (c. 95108402T>C [p. Tyr137Cys]) was identified and validated in 369 cases and 270 controls of Chinese descent (P_adjusted = 0.006, odds ratio [OR] = 2.74) as a contributing factor to leprosy risk. Moreover, the mRNA level of MRPS5 was downregulated in M. leprae sonicate-stimulated peripheral blood mononuclear cells. Our results indicated that MRPS5 may be involved in leprosy pathogenesis. Further studies are needed to determine if defective MRPS5 could lead to impairment of energy metabolism of host immune cells, which could further cause defect in clearing M. leprae and increase susceptibility to infection.