Longitudinal transcriptional immune profiles and persistent wheezing in moderate-to-late preterm infants.

Ionizing radiation (IR) is used in a wide variety of medical and nonmedical applications and poses a potential threat to human health. Knowledge of changes in gene expression in irradiated cells may be helpful for the establishment of effective paradigms for radiation protection. IR-induced DNA damage triggers a complex cascade of signal transduction. Recently, genome-wide approaches have allowed the detection of alterations in gene expression across a wide range of radiation doses. However, the delayed or long-term biological effects of mild-doses of IR remain largely unknown. The main objective of the present study was to investigate the effects of a moderate dose of gamma-rays (50 cGy) on gene expression 6 days post-irradiation. Gene expression using cDNA microarrays revealed statistically significant changes in the expression of 59 genes (FDR < 0.07), whose functions are related to cell-cycle control, protein trafficking, ubiquitin cycle, Rho-GTPAse pathway, protein phosphatase signalization, oxidoreductase control, and stress response. A set of 464 genes was also selected by a less stringent approach, and we demonstrate that this broader set of genes can efficiently distinguish the irradiated samples from the unirradiated, defining a long-term IR signature in human primary fibroblasts. Our findings support the existence of persistent responses to mild doses of IR detectable by changes in gene expression profiles. These results provide insight into delayed effects observed in human primary cells as well as the role of long-term response in neoplastic transformation. Environ.

Late-preterm infants are known to have greater morbidity and costs compared with term infants during the neonatal period, but less is known about whether these differences continue beyond this period. The purpose of this study was to examine the most common causes and costs of rehospitalization and other health care use among late-preterm and term infants throughout the first year of life. We conducted a retrospective cohort study of late-preterm (33-36 weeks' gestation) and term infants born in 2004 with > or =1 year of enrollment in a large national US database of commercially insured members. All of the reported health care services and costs were examined from the birth hospitalization through the first year of life. We evaluated 1683 late-preterm and 33 745 term infants. The average length of stay of the birth hospitalization for term infants was 2.2 days, and the average cost was $2061. Late-preterm infants had a substantially longer average stay of 8.8 days and average cost of $26 054. Total first-year costs after birth discharge were, on average, 3 times as high among late-preterm infants ($12 247) compared with term infants ($4069). Late-preterm infants were rehospitalized more often than term infants (15.2% vs 7.9%). A subset of late-preterm infants that were discharged late from their birth hospitalization had the highest rates of rehospitalization and total health care costs. Higher costs during rehospitalization of late-preterm infants, especially those with a late discharge, indicate their propensity to have more severe illness. Late-preterm infants have greater morbidity and total health care costs than term infants, and these differences persist throughout the first year of life. Management strategies and guidelines to reduce morbidity and costs in late-preterm infants should be investigated.

The preterm birth rate has increased markedly in recent decades, mainly because of the increase in late preterm (LP) births. Late preterm infants are those born between 34+0 and 36+6 weeks’ gestation and account for more than 70% of all prematurely born infants in the United States. Moderately preterm (MP) (32+0–33+6 weeks) and LP infants together comprise more than 80% of all preterm births. Late preterm infants may have poor neurodevelopmental outcomes, and one relatively common disorder is cerebral palsy (CP), diagnosed based on medical history, imaging data, and clinical multidisciplinary evaluations. Cerebral palsy incidence also depends on gestational age (GA) in very preterm (VP) infants. Risk factors for CP have been identified for term infants, but not as thoroughly for MP and LP infants. This Finnish national-register study was performed to compare the CP incidence among LP and MP infants to that in VP and term infants and to identify risk factors for CP. The study population included all 1,039,263 infants born in Finland from 1991 to 2008. Data on baseline and pregnancy/infant characteristics, live births, deaths, and congenital anomalies were collected from several national registries. After exclusions, the final cohort included 1,018,302 infants. Infants were followed up to age 7 years or to 2009. Gestational age categories were classified as VP (≤32+0 weeks, n = 6347), MP (32+0–33+6 weeks, n = 6799), LP (34+0–36+6 weeks, n = 39,932), and term (≥37 weeks, n = 965,224). Time periods were 1991 to 1995, 1996 to 2001, and 2002 to 2008. Pregnancy-related risk factors were the number of fetuses and their order, timing of birth, in vitro fertilization, and cervical cerclage. Resuscitation at birth included intubation, mechanical ventilation, or chest compressions. Late preterm and MP infants accounted for 75% and 13%, respectively, of all premature infants born during the study period. The proportion of all preterm births was 5.02% in 1991 to 1995, 5.43% in 1996 to 2001, and 5.18% in 2002 to 2008. Moderately preterm infants accounted for 0.63% to 0.69% and LP infants for 3.82% to 4.08% of all births. Cerebral palsy was diagnosed in 2242 cases. The incidence of CP was 0.22%, and this rate decreased nonlinearly with increasing GA and time. The proportion of diplegia cases was greatest in the VP group and of hemiplegia cases in the term group. Birth during 1991 to 1995, 1-minute Apgar score of less than 7, and intracranial hemorrhage predicted CP in all GA categories in the logistic regression model. Resuscitation at birth was associated with an increased risk in the MP, LP, and term groups. Small for GA and antibiotic treatment during the first hospitalization seemed to predict an increased risk of CP in the LP and the term groups. Premature rupture of membranes was associated with an increased risk and antenatal steroid treatment with a decreased risk of CP in the MP group. In the analysis for 2004 to 2008, the odds ratio for CP in the MP group with antenatal steroids was 0.24 (95% confidence interval [CI], 0.08–0.76). Respiratory distress syndrome predicted a decreased risk of CP in the LP group. Independent odds ratios for CP in premature groups compared with the full-term group were 9.37 in the VP group (95% CI, 7.34–11.96), 5.12 in the MP group (95% CI, 4.13–6.34), and 2.35 in the LP group (95% CI, 1.99–2.77). The incidence and risk for CP were higher in MP and LP infants compared with term infants. The medical expense burden of CP to the families of the MP and LP children was comparable to term-born babies. The need for disability allowance was significantly less common in the MP and LP groups than in the VP cases. These results could be used to counsel parents and to plan for follow-up with of MP and LP newborns. Future studies should create and evaluate guidelines for management, and risk assessment should be established for LP and MP infants.

Protein kinase C (PKC) isozymes are key signal transducers involved in normal physiology and disease and have been widely implicated in cancer progression. Despite our extensive knowledge of the signaling pathways regulated by PKC isozymes and their effectors, there is essentially no information on how individual members of the PKC family regulate gene transcription. Here, we report the first PKC isozyme-specific analysis of global gene expression by microarray using RNAi depletion of diacylglycerol/phorbol ester-regulated PKCs. A thorough analysis of this microarray data revealed unique patterns of gene expression controlled by PKCα, PKCδ, and PKCε, which are remarkably different in cells growing in serum or in response to phorbol ester stimulation. PKCδ is the most relevant isoform in controlling the induction of genes by phorbol ester stimulation, whereas PKCε predominantly regulates gene expression in serum. We also established that two PKCδ-regulated genes, FOSL1 and BCL2A1, mediate the apoptotic effect of phorbol esters or the chemotherapeutic agent etoposide in prostate cancer cells. Our studies offer a unique opportunity for establishing novel transcriptional effectors for PKC isozymes and may have significant functional and therapeutic implications.

Introduction: Worldwide major proportion of preterm births is late preterm infants. Preterm infants are deprived of optimal in-utero nutrition leading to immediate consequences of growth failure and long-term complications like adverse neurodevelopment outcomes whereas preterm infants with fast catch up growth after birth have health consequences like obesity and hypertension in adulthood. Aim: To assess growth of late preterm infants at their term equivalent Gestational Age (GA) and compare their growth and body composition with term infants. Materials and Methods: This was a cohort study of late preterm (34 0/7 to 36 6/7 weeks) infants that were Appropriate for Gestational Age (AGA) and controls that were AGA term infants (39 0/7 to 40 6/7 weeks). All enrolled late preterm infants were followed-up at term equivalent (39 0/7 to 40 6/7 weeks). Growth plotted on Fenton’s chart and body composition were calculated using pre-defined formula for total mid-upper arm area (cm2), mid-upper arm muscle area (cm2), mid-upper arm fat area (cm2), and the Arm Fat Index (AFI) (%). The data was analysed using Epi info (version 7.2) with student t-test for continuous variables and chi-square test for dichotomous variables. A p-value of &lt;0.05 was considered statistically significant. Results: Out of the 135 infants enrolled, 45 were late preterm and 90 were term born infants. Median GA of the case cohort was 35 (IQR 35-36) weeks and in the control cohort it was 39 (IQR 39-40) weeks. Total 45.7% (N=35) of the late preterm infants (after excluding loss to follow-up) were below 10th percentile (EUGR) at term GA. At term follow-up, mean weight and length of late preterm infants compared to term born infants was less and statistically significant. The mean Skin Fold Thickness (SKT) (cm) at triceps level 0.55 (SD 0.07) vs. 0.49 (SD 0.06), mean of calculated AFI (%) 31.25 (SD 3.08) vs. 28.19 (SD 2.5) and among late preterm infants at follow-up was more than in term infants and was statistically significant. Conclusion: Failure to thrive is common among the late preterm infants at term equivalent GA. Late preterm infants show postnatal growth characterised by predominant fat mass accretion and less lean mass.

Effects of Home Visiting and Maternal Mental Health on Use of the Emergency Department among Late Preterm Infants

Expression profiling: Opportunities and pitfalls and impact on the study and management of allergic diseases

Using next-generation, transcriptome-wide RNA sequencing (RNA-Seq) technology we assessed the effects of exercise training on transcriptional profiles in skeletal muscle arterioles isolated from the soleus and gastrocnemius muscles of Otsuka Long Evans Tokushima Fatty (OLETF) rats that underwent an endurance exercise training program (EX; n = 13), interval sprint training program (SPRINT; n = 14), or remained sedentary (Sed; n = 12). We hypothesized that the greatest effects of exercise would be in the gastrocnemius arterioles. Results show that EX caused the largest number of changes in gene expression in the soleus and white gastrocnemius 2a arterioles with little to no changes in the feed arteries. In contrast, SPRINT caused substantial changes in gene expression in the feed arteries. IPA canonical pathway analysis revealed 18 pathways with significant changes in gene expression when analyzed across vessels and revealed that EX induces increased expression of the following genes in all arterioles examined: Shc1, desert hedgehog protein (Dhh), adenylate cyclase 4 (Adcy4), G protein binding protein, alpha (Gnat1), and Bcl2l1 and decreased expression of ubiquitin D (Ubd) and cAMP response element modulator (Crem). EX increased expression of endothelin converting enzyme (Ece1), Hsp90b, Fkbp5, and Cdcl4b in four of five arterioles. SPRINT had effects on expression of Crem, Dhh, Bcl2l1, and Ubd that were similar to EX. SPRINT also increased expression of Nfkbia, Hspa5, Tubb 2a and Tubb 2b, and Fkbp5 in all five arterioles and increased expression of Gnat1 in all but the soleus second-order arterioles. Many contractile and/or structural protein genes were increased by SPRINT in the gastrocnemius feed artery, but the same genes exhibited decreased expression in red gastrocnemius arterioles. We conclude that training-induced changes in arteriolar gene expression patterns differ by muscle fiber type composition and along the arteriolar tree.

Changes in gene expression in human renal proximal tubule cells exposed to low concentrations of S-(1,2-dichlorovinyl)-l-cysteine, a metabolite of trichloroethylene

ObjectiveTo explore the association between breastfeeding support and breastfeeding among late preterm (gestation 34–36 weeks) and term (gestation ≥37 weeks) infants.MethodsSecondary analysis of the UK 2010 Infant Feeding Survey. Logistic...

Chapter 9 - Changes in cortical gene expression in major depressive disorders: More evidence implicating inflammatory-related pathways in disease etiology

Systemic immune checkpoint blockade and intraperitoneal chemo-immunotherapy in recurrent ovarian cancer: An interim analysis (317)

BackgroundMicroRNAs (miRNAs) are a class of small RNAs that have been linked to a number of diseases including cancer. The potential application of miRNAs in the diagnostics and therapeutics of ovarian and other cancers is an area of intense interest. A current challenge is the inability to accurately predict the functional consequences of exogenous modulations in the levels of potentially therapeutic miRNAs.MethodsIn an initial effort to systematically address this issue, we conducted miRNA transfection experiments using two miRNAs (miR-7, miR-128). We monitored the consequent changes in global patterns of gene expression by microarray and quantitative (real-time) polymerase chain reaction. Network analysis of the expression data was used to predict the consequence of each transfection on cellular function and these predictions were experimentally tested.ResultsWhile ~20% of the changes in expression patterns of hundreds to thousands of genes could be attributed to direct miRNA-mRNA interactions, the majority of the changes are indirect, involving the downstream consequences of miRNA-mediated changes in regulatory gene expression. The changes in gene expression induced by individual miRNAs are functionally coordinated but distinct between the two miRNAs. MiR-7 transfection into ovarian cancer cells induces changes in cell adhesion and other developmental networks previously associated with epithelial-mesenchymal transitions (EMT) and other processes linked with metastasis. In contrast, miR-128 transfection induces changes in cell cycle control and other processes commonly linked with cellular replication.ConclusionsThe functionally coordinated patterns of gene expression displayed by different families of miRNAs have the potential to provide clinicians with a strategy to treat cancers from a systems rather than a single gene perspective.

The regulation of human cytomegalovirus (hCMV) and human immunodeficiency virus (HIV) gene expression has been studied in single intact mammalian cells. Viral promoters were placed upstream of the firefly luciferase reporter gene and the resulting hybrid reporter constructs were stably integrated into the HeLa cell genome. A highly sensitive photon-counting camera system was used to study the level of gene expression in single intact cells. Luciferase expression was studied in the absence of activators of viral gene expression, in the presence of the HIV-1 TAT transactivator protein, or in the presence of sodium butyrate, a non-viral activator of gene expression. In the absence of any activator of gene expression, while expression was undetectable in most cells, significant levels of basal luciferase activity were observed in a few cells, indicating heterogeneity in gene expression in the cell population. In the presence of the general activator of viral gene expression, sodium butyrate, transcriptional activation from the viral promoters gave rise to significant and relatively homogeneous levels of luciferase expression in a majority of cells. The luciferase imaging technology was used for the real-time analysis of changes of gene expression within a single cell. This non-invasive reporter assay should become important for studies of the temporal regulation of gene expression in single cells.

Over the past 100 years, changes in the food supply in Western nations have resulted in alterations in dietary fatty acid consumption, leading to a dramatic increase in the ratio of omega-6 (omega6) to omega3 polyunsaturated fatty acids (PUFA) in circulation and in tissues. Increased omega6/omega3 ratios are hypothesized to increase inflammatory mediator production, leading to higher incidence of inflammatory diseases, and may impact inflammatory gene expression. To determine the effect of reducing the omega6/omega3 ratio on expression of inflammatory pathway genes in mononuclear cells, healthy humans were placed on a controlled diet for 1 week, then given fish oil and borage oil for an additional 4 weeks. Serum and neutrophil fatty acid composition and ex vivo leukotriene B(4) production from stimulated neutrophils were measured at the start and end of the supplementation period and after a 2-week washout. RNA was isolated from mononuclear cells and expression of PI3K, Akt, NFkappaB, and inflammatory cytokines was measured by real-time PCR. A marked increase was seen in serum and neutrophil levels of long-chain omega3 PUFA concomitant with a reduction in the omega6/omega3 PUFA ratio (40%). The ex vivo capacity of stimulated neutrophils to produce leukotriene B(4) was decreased by 31%. Expression of PI3Kalpha and PI3Kgamma and the quantity of PI3Kalpha protein in mononuclear cells was reduced after supplementation, as was the expression of several proinflammatory cytokines. These data reveal that PUFA may exert their clinical effects via their capacity to regulate the expression of signal transduction genes and genes for proinflammatory cytokines.