Background: Trisomy 21 (TS21) is a condition with a high risk for sleep apnea. In the pediatric population, the risk also includes central breathing disorders. The aim of this study was to define the clinical and polysomnographic characteristics of central apnea in infants, children, and adolescents with TS21. Methods: Retrospective review of baseline polysomnograms (PSGs) in children with TS21 in the sleep center at Children's National Medical Center in Washington DC. Results: We included a total of 158 infants, children, and adolescents (0-18 years) with TS21 in this study. The median age was 4.82 years and 62% were male. The primary findings of the study are that (1) 12% of all pediatric subjects with TS21 included had a central apnea index (CAI) > 2/h; (2) the proportion of TS21 individuals with central breathing abnormalities progressively decreased with age being common in young individuals (≤2 years of age) but rare after 10 years of age; (3) additional sleep breathing disturbances (e.g., OSA and/or hypoxemia) are often present in children with TS21 and central apnea; and (4) the prevalence of central breathing abnormalities in TS21 is influenced by sex, being more likely to persist beyond early childhood (>2 years of age) in females than in males. Conclusion: Central breathing abnormalities are common in TS21 among young children (≤2 years of age) and in females older than 2 years of age. Central apnea is often associated with concomitant obstructive sleep apnea and/or hypoxemia in children with TS21.

Background Epidemiological studies indicate that disruption of circadian rhythm by shift work increases the risk of breast and prostate cancer. Our studies demonstrated that carcinogens disrupt the circadian expression of circadian genes (CGs) and circadian-controlled genes (CCGs) during the early stages of rat mammary carcinogenesis. A chemopreventive regimen of methylselenocysteine (MSC) restored the circadian expression of CGs and CCGs, including PERIOD 2 (PER2) and estrogen receptor β (ERS2), to normal. The present study evaluated whether changes in CG and CCG expression in whole blood can serve as indicators of circadian disruption in shift workers. Methods Fifteen shift workers were recruited to a crossover study. Blood samples were drawn before (6 PM) and after (8 AM) completing a night shift after at least 7 days on floating night-shift rotation, and before (8 AM), during (1 PM), and after (6 PM) completing 7 days on day shift. The plasma melatonin level and messenger RNA (mRNA) expression of PER2, nuclear receptor subfamily 1, group d, member 1 (NR1D1), and ERS2 were measured, and the changes in levels of melatonin and gene expression were evaluated with statistical analyses. Results The mRNA expression of PER2 was affected by shift (p = 0.0079); the levels were higher in the evening for the night shift, but higher in the morning for the day shift. Increased PER2 expression (p = 0.034) was observed in the evening on the night versus day shifts. The melatonin level was higher in the morning for both day shifts (p = 0.013) and night shifts (p < 0.0001). Conclusion Changes in the level of PER2 gene expression can serve as a biomarker of disrupted circadian rhythm in blood cells. Therefore, they can be a useful intermediate indicator of efficacy in future MSC-mediated chemoprevention studies.

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Rat strains differ dramatically in their susceptibility to mammary carcinogenesis. On the assumption that susceptibility genes are conserved across mammalian species and hence inform human carcinogenesis, numerous investigators have used genetic linkage studies in rats to identify genes responsible for differential susceptibility to carcinogenesis. Using a genetic backcross between the resistant Copenhagen (Cop) and susceptible Fischer 344 (F344) strains, we mapped a novel mammary carcinoma susceptibility (Mcs30) locus to the centromeric region on chromosome 12 (LOD score of ∼8.6 at the D12Rat59 marker). The Mcs30 locus comprises approximately 12 Mbp on the long arm of rat RNO12 whose synteny is conserved on human chromosome 13q12 to 13q13. After analyzing numerous genes comprising this locus, we identified Fry, the rat ortholog of the furry gene of Drosophila melanogaster, as a candidate Mcs gene. We cloned and determined the complete nucleotide sequence of the 13 kbp Fry mRNA. Sequence analysis indicated that the Fry gene was highly conserved across evolution, with 90% similarity of the predicted amino acid sequence among eutherian mammals. Comparison of the Fry sequence in the Cop and F344 strains identified two non-synonymous single nucleotide polymorphisms (SNPs), one of which creates a putative, de novo phosphorylation site. Further analysis showed that the expression of the Fry gene is reduced in a majority of rat mammary tumors. Our results also suggested that FRY activity was reduced in human breast carcinoma cell lines as a result of reduced levels or mutation. This study is the first to identify the Fry gene as a candidate Mcs gene. Our data suggest that the SNPs within the Fry gene contribute to the genetic susceptibility of the F344 rat strain to mammary carcinogenesis. These results provide the foundation for analyzing the role of the human FRY gene in cancer susceptibility and progression.