The Diverse Major Histocompatibility Complex Haplotypes of a Common Commercial Chicken Line and Their Effect on Marek's Disease Virus Pathogenesis and Tumorigenesis.

The major histocompatibility complex (MHC) is crucial for appropriate immune responses against invading pathogens. Chickens possess a single predominantly-expressed class I molecule with strong associations between disease resistance and MHC haplotype. For Marek's disease virus (MDV) infections of chickens, the MHC haplotype is one of the major determinants of genetic resistance and susceptibility. VALO specific pathogen free (SPF) chickens are widely used in biomedical research and vaccine production. While valuable findings originate from MDV infections of VALO SPF chickens, their MHC haplotypes and associated disease resistance remained elusive. In this study, we used several typing systems to show that VALO SPF chickens possess MHC haplotypes that include B9, B9:02, B15, B19 and B21 at various frequencies. Moreover, we associate the MHC haplotypes to MDV-induced disease and lymphoma formation and found that B15 homozygotes had the lowest tumor incidence while B21 homozygotes had the lowest number of organs with tumors. Finally, we found transmission at variable levels to all contact birds except B15/B21 heterozygotes. These data have immediate implications for the use of VALO SPF chickens and eggs in the life sciences and add another piece to the puzzle of the chicken MHC complex and its role in infections with this oncogenic herpesvirus.

Seizures in Pre-term Infants Less than 29 Weeks: Incidence, Etiology, and Response to Treatment.

INTRODUCTION: Seizures are neurological emergencies with short-and long-term adverse effects in pre-term infants. They may present with or without abnormal movements (clinical versus subclinical). Thus, the true incidence of seizures may be under-reported. Current research indicates that most seizures occur in the first few days of life, are associated with intraventricular hemorrhage (IVH), and show low response to anticonvulsant drugs. The purpose of this study was to evaluate incidence, etiology, clinical antecedents, mortality, and response to treatment of seizures in extremely pre-term infants. METHODS: This is a retrospective cohort study of pre-term infants < 29 weeks gestation from January 2011 to December 2013. Presence or absence of seizure was the outcome. Data extraction included demographics, medications, co-morbidities, mortality, and details of seizures. A multivariable prediction model was developed to evaluate risk for seizures. RESULTS: Analysis included 269 pre-term infants. Incidence of EEG-confirmed seizures was 40% (108/269); 49% were clinical and 51% were subclinical. Seizures occurred in 72% of infants ≤ 24 weeks, 57% of those 25-26 weeks, and 23% of those 27-28 weeks. Most seizures (85%) occurred after day eight of life. Mortality was 14% in those with seizures versus 5% in those without (p = 0.019). The model showed seizures were associated significantly with gestational age and medications, while controlling for sex, APGAR score, and co-morbidities, including IVH. At discharge, anticonvulsants were continued in 66% (72/108) of infants with seizures. CONCLUSION: The incidence of seizures was highest in infants born most premature. Contrary to previous research, nearly two-thirds of pre-term infants with seizures did not have IVH or cystic periventricular leukomalacia; apnea of prematurity was a common presentation of subclinical seizures; and the majority of treated infants responded to Phenobarbital. These findings need be explored in future research.

A systematic review of the validity of dietary assessment methods in children when compared with the method of doubly labeled water.

Measuring dietary intake in children enables the assessment of nutritional adequacy of individuals and groups and can provide information about nutrients, including energy, food, and eating habits. The aim of this review was to determine which dietary assessment method(s) provide a valid and accurate estimate of energy intake by comparison with the gold standard measure, doubly labeled water (DLW). English-language articles published between 1973 and 2009 and available from common nutrition databases were retrieved. Studies were included if the subjects were children birth to age 18 years and used the DLW technique to validate reported energy intake by any other dietary assessment method. The review identified 15 cross-sectional studies, with a variety of comparative dietary assessment methods. These included a total of 664 children, with the majority having <30 participants. The majority of dietary assessment method validation studies indicated a degree of misreporting, with only eight studies identifying this to a significant level (P<0.05) compared to DLW estimated energy intake. Under-reporting by food records varied from 19% to 41% (n=5 studies) with over-reporting most often associated with 24-hour recalls (7% to 11%, n=4), diet history (9% to 14%, n=3), and food frequency questionnaires (2% to 59%, n=2). This review suggested that the 24-hour multiple pass recall conducted over at least a 3-day period that includes weekdays and weekend days and uses parents as proxy reporters is the most accurate method to estimate total energy intake in children aged 4 to 11 years, compared to total energy expenditure measured by DLW. Weighed food records provided the best estimate for younger children aged 0.5 to 4 years, whereas the diet history provided better estimates for adolescents aged≥16 years. Further research is needed in this area to substantiate findings and improve estimates of total energy expenditure in children and adolescents.

Hypoxia-inducible factor-1alpha suppresses squamous carcinogenic progression and epithelial-mesenchymal transition.

Hypoxia-inducible factor-1 (HIF-1) is a known cancer progression factor, promoting growth, spread, and metastasis. However, in selected contexts, HIF-1 is a tumor suppressor coordinating hypoxic cell cycle suppression and apoptosis. Prior studies focused on HIF-1 function in established malignancy; however, little is known about its role during the entire process of carcinogenesis from neoplasia induction to malignancy. Here, we tested HIF-1 gain of function during multistage murine skin chemical carcinogenesis in K14-HIF-1alpha(Pro402A564G) (K14-HIF-1alphaDPM) transgenic mice. Transgenic papillomas appeared earlier and were more numerous (6 +/- 3 transgenic versus 2 +/- 1.5 nontransgenic papillomas per mouse), yet they were more differentiated, their proliferation was lower, and their malignant conversion was profoundly inhibited (7% in transgenic versus 40% in nontransgenic mice). Moreover, transgenic cancers maintained squamous differentiation whereas epithelial-mesenchymal transformation was frequent in nontransgenic malignancies. Transgenic basal keratinocytes up-regulated the HIF-1 target N-myc downstream regulated gene-1, a known tumor suppressor gene in human malignancy, and its expression was maintained in transgenic papillomas and cancer. We also discovered a novel HIF-1 target gene, selenium binding protein-1 (Selenbp1), a gene of unknown function whose expression is lost in human cancer. Thus, HIF-1 can function as a tumor suppressor through transactivation of genes that are themselves targets for negative selection in human cancers.

HIF-1alpha regulates epithelial inflammation by cell autonomous NFkappaB activation and paracrine stromal remodeling.

Hypoxia inducible factor-1 (HIF-1) is a master regulatory transcription factor controlling multiple cell-autonomous and non-cell-autonomous processes, such as metabolism, angiogenesis, matrix invasion, and cancer metastasis. Here we used a new line of transgenic mice with constitutive gain of HIF-1 function in basal keratinocytes and demonstrated a signaling pathway from HIF-1 to nuclear factor kappa B (NFkappaB) activation to enhanced epithelial chemokine and cytokine elaboration. This pathway was responsible for a phenotypically silent accumulation of stromal inflammatory cells and a marked inflammatory hypersensitivity to a single 12-O-tetradecanoylphorbol-13-acetate (TPA) challenge. HIF-1-induced NFkappaB activation was composed of 2 elements, IkappaB hyperphosphorylation and phosphorylation of Ser276 on p65, enhancing p65 nuclear localization and transcriptional activity, respectively. NFkappaB transcriptional targets macrophage inflammatory protein-2 (MIP-2/CXCL2/3), keratinocyte chemokine (KC/CXCL1), and tumor necrosis factor [alfa] (TNFalpha) were constitutively up-regulated and further increased after TPA challenge both in cultured keratinocytes and in transgenic mice. Whole animal KC, MIP-2, or TNFalpha immunodepletion each abrogated TPA-induced inflammation, whereas blockade of either VEGF or placenta growth factor (PlGF) signaling did not affect transgenic inflammatory hyper-responsiveness. Thus, epithelial HIF-1 gain of function remodels the local environment by cell-autonomous NFkappaB-mediated chemokine and cytokine secretion, which may be another mechanism by which HIF-1 facilitates either inflammatory diseases or malignant progression.