Late arterial hypertension has been identified as a major predictor for morbidity and mortality in aortic coarctation (AoC) patients. Few data are available about efficacy and tolerability of ...angiotensin converting enzyme inhibitors vs beta-blockers in young AoC patients. This study aimed to evaluate the tolerability and efficacy on 24-h blood pressure (BP) and left ventricular mass/height(2.7) (LVMI), of atenolol vs enalapril. We enrolled consecutive AoC hypertensive patients with (a) no history of BP treatment or after >48 h of withdrawn, (b) aged 6-20 years, (c) body mass index (BMI) <90th percentile for age and sex, (d) >12 months from a successful AoC repair and (e) no major associated cardiovascular abnormalities. All patient were evaluated with 24-h ambulatory BP monitoring, standard echocardiography, strain-strain rate imaging, at enrolment, 3, 6 and 12 months of treatment. We studied 51 AoC patients (13±3.9 years, BMI: 21.4±4.3 kg m(-2)). Patients were randomly assigned at atenolol treatment (n=26), or enalapril treatment (n=25). The mean follow-up duration was 11±2 months. Both drugs were able to significantly reduce 24-systolic BP (SBP; atenolol: 133±11 mm Hg vs 124±16 mm Hg, P=0.016; enalapril: 135±6 mm Hg vs 127±7 mm Hg, P=0.001). Only enalapril was able to significantly reduce LVMI (47±12 vs 39.6±10 g m(-)(2.7), P=0.016). Only in atenolol group in two cases (7.7%) drug withdrawal was needed because of adverse events. Enalapril and atenolol are similarly effective in reducing SBP. However, only enalapril demonstrated a significant reduction of LVMI. In no case, enalapril was stopped because of adverse events.
Human height is considered highly heritable and correlated with certain disorders, such as type 2 diabetes and cancer. Despite environmental influences, genetic factors are known to play an important ...role in stature determination. A number of genetic determinants of adult height have already been established through genome wide association studies.
To examine 51 single nucleotide polymorphisms (SNPs) corresponding to the 46 previously reported genomic loci for height in 8,184 European American children with height measurements. We leveraged genotyping data from our ongoing GWA study of height variation in children in order to query the 51 SNPs in this pediatric cohort.
Sixteen of these SNPs yielded at least nominally significant association to height, representing fifteen different loci including EFEMP1-PNPT1, GPR126, C6orf173, SPAG17, Histone class 1, HLA class III and GDF5-UQCC. Other loci revealed no evidence for association, including HMGA1 and HMGA2. For the 16 associated variants, the genotype score explained 1.64% of the total variation for height z-score.
Among 46 loci that have been reported to associate with adult height to date, at least 15 also contribute to the determination of height in childhood.
Longevity has a strong genetic component evidenced by family-based studies. Lipoprotein metabolism, FOXO proteins, and insulin/IGF-1 signaling pathways in model systems have shown polygenic ...variations predisposing to shorter lifespan. To test the hypothesis that rare variants could influence lifespan, we compared the rates of CNVs in healthy children (0-18 years of age) with individuals 67 years or older. CNVs at a significantly higher frequency in the pediatric cohort were considered risk variants impacting lifespan, while those enriched in the geriatric cohort were considered longevity protective variants. We performed a whole-genome CNV analysis on 7,313 children and 2,701 adults of European ancestry genotyped with 302,108 SNP probes. Positive findings were evaluated in an independent cohort of 2,079 pediatric and 4,692 geriatric subjects. We detected 8 deletions and 10 duplications that were enriched in the pediatric group (P=3.33×10(-8)-1.6×10(-2) unadjusted), while only one duplication was enriched in the geriatric cohort (P=6.3×10(-4)). Population stratification correction resulted in 5 deletions and 3 duplications remaining significant (P=5.16×10(-5)-4.26×10(-2)) in the replication cohort. Three deletions and four duplications were significant combined (combined P=3.7×10(-4)-3.9×10(-2)). All associated loci were experimentally validated using qPCR. Evaluation of these genes for pathway enrichment demonstrated ~50% are involved in alternative splicing (P=0.0077 Benjamini and Hochberg corrected). We conclude that genetic variations disrupting RNA splicing could have long-term biological effects impacting lifespan.
Increasing feed efficiency is an important goal for improving sustainable pork production and profitability for producers. To study feed efficiency, genetic selection based on residual feed intake ...(RFI) was used to create 2 divergent lines. Low-RFI pigs consume less feed for equal weight gain compared to their less efficient, high-RFI counterparts. Therefore, our objective was to assess how a pig's behavioral reactivity toward fear-eliciting stimuli related to RFI selection and improvement of feed efficiency. In this study, behavioral reactivity of pigs divergently selected for RFI was evaluated using human approach (HAT) and novel object (NOT) tests. Forty low-RFI and 40 high-RFI barrows and gilts ( = 20 for each genetic line; 101 ± 9 d old) from ninth-generation Yorkshire RFI selection lines were randomly selected and evaluated once using HAT and once using NOT over a 2-wk period utilizing a crossover experimental design. Each pig was individually tested within a 4.9 × 2.4 m test arena for 10 min; behavior was evaluated using live and video observations. The test arena floor was divided into 4 zones; zone 1 being oral, nasal, and/or facial contact with the human (HAT) or orange traffic cone (NOT) and zone 4 being furthest from the human or cone and included the point where the pig entered the arena. During both HAT and NOT, low-RFI pigs entered zone 1 less frequently compared to high-RFI pigs ( ≤ 0.03). During NOT, low-RFI pigs changed head orientation more frequently ( = 0.001) but attempted to escape less frequently (low-RFI = 0.97 ± 0.21 vs. high-RFI = 2.08 ± 0.38; = 0.0002) and spent 2% less time attempting to escape compared to high-RFI pigs ( = 0.04). Different barrow and gilt responses were observed during HAT and NOT. During HAT, barrows spent 2% more time within zone 1 ( = 0.03), crossed fewer zone lines ( < 0.0001), changed head orientation less frequently ( = 0.002), and froze less frequently compared to gilts ( = 0.02). However, during NOT, barrows froze more frequently ( = 0.0007) and spent 2% longer freezing ( = 0.05). When the behavior and RFI relationship was examined using odds ratios, decreasing RFI by 1 kg/d decreased the odds of freezing by 4 times but increased the odds of attempting to escape by 5.26 times during NOT ( ≤ 0.04). These results suggest that divergent selection for RFI resulted in subtle behavioral reactivity differences and did not impact swine welfare with respect to responses to fear-eliciting stimuli.
Genetic analysis of the κ-casein gene (CSN3) promoter regions of 42 cattle representing 9 different breeds revealed that 2 distinct haplotypes (A and B) exist at this locus, differing from each other ...by single base changes at positions −514 (T/G), −426 (T/C), and −384 (T/C), where haplotype A has bases T, T, and T and haplotype B has bases G, C, and C. The AA and AB haplotypes were found to occur at a higher frequency in the animals tested, with 69.0 and 21.4% being homozygous and heterozygous, respectively. The sequences that include these polymorphisms are potentially important in transcriptional regulation of the κ-casein gene, because they contain putative sites for binding of many transcription factors. Linkage disequilibrium between the κ-casein promoter haplotype and either one of the 2 major κ-casein coding sequence haplotypes was not evident. The A allele is dominant in all groups (dairy, beef, and dual purpose) with an allele frequency of 80% and is higher among high-yielding dairy animals (88.9%) than among beef animals (75%). The AB haplo-type is comparatively rare in the dairy cattle (11.1%) compared with both beef and dual-purpose animals. The BB haplotype, though rare overall (9.5%), is much higher in dual-purpose animals (18.8%) than dairy (5.6%) animals. In contrast, the B allele is much more representative of the κ-casein promoters from other ruminants.
4-vinylcyclohexene diepoxide (VCD) is an ovotoxicant that specifically destroys primordial and small primary follicles in the ovaries of mice and rats. In contrast, 7,12-dimethylbenzaanthracene ...(DMBA) is ovotoxic to all ovarian follicle classes. This study investigated phosphatidylinositol-3 kinase signaling involvement in VCD- and DMBA-induced ovotoxicity. Postnatal day (PND) 4 Fischer 344 (F344) rat whole ovaries were cultured for 2–12 days in vehicle control, VCD (30 μM), or DMBA (1 μM), ±
PI3 kinase inhibitor LY294002 (20 μM) or its inactive analog LY303511 (20 μM). Following culture, ovaries were histologically evaluated, and healthy follicles were classified and counted. PI3 kinase inhibition had no effect on primordial follicle number, but reduced (
P
<
0.05) small primary and larger follicles beginning on day 4. VCD caused primordial and small primary follicle loss (
P
<
0.05) beginning on day 6. With PI3 kinase inhibition, VCD did not affect primordial follicles (
P
>
0.05) at any time, but did cause loss (
P
<
0.05) of small primary follicles. DMBA exposure caused primordial and small primary follicle loss (
P
<
0.05) on day 6. Further, DMBA-induced primordial and small primary follicle loss was greater with PI3 kinase inhibition (
P
<
0.05) than with DMBA alone. These results support that (1) PI3 kinase mediates primordial to small primary follicle recruitment, (2) VCD, but not DMBA, enhances ovotoxicity by increasing primordial to small primary follicle recruitment, and (3) in addition to xenobiotic-induced ovotoxicity, VCD is also a useful model chemical with which to elucidate signaling mechanisms involved in primordial follicle recruitment.
Preterm infants often need red blood cell (RBC) transfusions. The aim of this study was to determine whether haemoglobin levels before transfusion were associated with regional cerebral tissue oxygen ...saturation (r(c)SO(2)) and fractional tissue oxygen extraction (FTOE) and whether RBC transfusions were associated with r(c)SO(2) and FTOE during the 24-h period thereafter.
Prospective observational cohort study.
Third level neonatal intensive care unit.
Thirty-three preterm infants (gestational age 25-34 weeks, birth weight 605-2080 g) were included.
None.
R(c)SO(2) was measured during a 1-h period, before, 1 h after and 24 h after a 15 ml/kg RBC transfusion in 3 h. Using r(c)SO(2) and transcutaneous arterial oxygen saturation (tcSaO(2)) values, FTOE was calculated: FTOE=(tcSaO(2)-r(c)SO(2))/tcSaO(2). Results Forty-seven RBC transfusions were given. R(c)SO(2) and FTOE correlated strongly with haemoglobin before transfusion (r=0.414 and r=-0.462, respectively, p<0.005). TcSaO(2) did not correlate with haemoglobin before transfusion. 24 h after transfusion, r(c)SO(2) increased from a weighted mean of 61% to 72% and FTOE decreased from a weighted mean of 0.34 to 0.23. The decrease in FTOE was strongest in the group with haemoglobin below 6.0 mmol/l (97 g/l). The decrease in FTOE was already present 1 h after transfusion and remained unchanged at 24 h after transfusion.
Following RBC transfusion, cerebral tissue oxygen saturation increases and FTOE decreases. The data suggest that cerebral oxygenation in preterm infants may be at risk when haemoglobin decreases under 6 mmol/l (97 g/l).
•A LEFM approach was implemented to estimate the fatigue life of a riveted girder.•The effect of thermal clamping stresses on fatigue life was quantified and analyzed.•The effect of plate thickness ...on the thermal clamping stress was discussed.•Variable amplitude loading due to heavy railroad cars traversing a bridge was considered.•Crack growth due to remote tension in a riveted plate was discussed and analyzed.
A linear-elastic Fracture Mechanics approach is used to estimate the fatigue life of riveted connections present in railroad bridge built-up steel girders under variable amplitude loading. Special care has been taken to analyze the effect of thermal clamping stresses on fatigue life. The analysis is developed using the variable amplitude stresses generated due to a traversing heavy axle train on a simply supported girder. Stress intensity factors for quarter elliptical corner crack emanating from a through-thickness (rivet) hole under remote tension were used. Thermal clamping stress, typically generated during the installation process, was quantified through a finite element simulation. Superposition principle was utilized to account for localized clamping stress present on the base material along with remote tension. Fatigue life estimations calculated using a linear-elastic Fracture Mechanics approach with and without considering clamping stress are compared. Finally, crack growth proved to be different under the effect of localized clamping stresses when compared to a crack growth emanating from a hole with no clamping stress.
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