Identification of tissue-specific cell death using methylation patterns of circulating DNA

Minimally invasive detection of cell death could prove an invaluable resource in many physiologic and pathologic situations. Cell-free circulating DNA (cfDNA) released from dying cells is emerging as a diagnostic tool for monitoring cancer dynamics and graft failure. However, existing methods rely on differences in DNA sequences in source tissues, so that cell death cannot be identified in tissues with a normal genome. We developed a method of detecting tissue-specific cell death in humans based on tissue-specific methylation patterns in cfDNA. We interrogated tissue-specific methylome databases to identify cell type-specific DNA methylation signatures and developed a method to detect these signatures in mixed DNA samples. We isolated cfDNA from plasma or serum of donors, treated the cfDNA with bisulfite, PCR-amplified the cfDNA, and sequenced it to quantify cfDNA carrying the methylation markers of the cell type of interest. Pancreatic β-cell DNA was identified in the circulation of patients with recently diagnosed type-1 diabetes and islet-graft recipients; oligodendrocyte DNA was identified in patients with relapsing multiple sclerosis; neuronal/glial DNA was identified in patients after traumatic brain injury or cardiac arrest; and exocrine pancreas DNA was identified in patients with pancreatic cancer or pancreatitis. This proof-of-concept study demonstrates that the tissue origins of cfDNA and thus the rate of death of specific cell types can be determined in humans. The approach can be adapted to identify cfDNA derived from any cell type in the body, offering a minimally invasive window for diagnosing and monitoring a broad spectrum of human pathologies as well as providing a better understanding of normal tissue dynamics

Welfare Families\u27 Use Of Early Childhood Care And Education Programs, And Implications For Their Children\u27s Development

With recent legislation placing a strong emphasis on the transition of welfare mothers into the workforce, it becomes increasingly important to understand whether and how participation in early childhood care and education programs has implications for the development of children from welfare families. This study focused on a sample of 182 African-American families, all of whom had applied for or were receiving Aid to Families With Dependent Children, and each with a child of between 3 and 5 years of age. We first examined which of a wide range of background characteristics predicted participation in early childhood care and education programs. We then examined whether measures of the children\u27s school readiness and social maturity were predicted by current participation in an early childhood program, above and beyond the background characteristics associated with the use of such a program. Our results indicate that participation in an early childhood program is associated with significantly higher scores on the measure of school readiness

How Well Are They Faring?: AFDC Families With Preschool-Aged Children In Atlanta At The Outset Of The JOBS Evaluation

The centerpiece of the 1988 Family Support Act (FSA) is the Job Opportunities and Basic Skills Training (JOBS) Program, which requires eligible recipients of Aid to Families with Dependent Children (AFDC) to participate in educational, job training and work experience, or job search activities, in order to reduce welfare dependency and promote self-sufficiency. Although most services offered through JOBS are aimed at meeting the needs of adults, there are numerous reasons to expect that JOBS may also affect children in families that receive AFDC. The purposes of this report are to describe the lives and circumstances of this sample of AFDC families with preschool-aged children in Fulton County, Georgia and to inform policymakers about the mothers\u27 goals and the development of their children. In addition, the study provides a context within which we will examine later impacts of the JOBS program on children

Extremely high maternal alkaline phosphatase serum concentration with syncytiotrophoblastic origin

An extremely high alkaline phosphatase (AP) concentration (3609 IU/litre) was found in a 20 year old primigravida at 37 week’s gestation, prompting an examination of its histological and cellular origin. Immunohistochemistry and western blots using antibodies against AP, Ki-67, phospho-protein kinase B (Akt), phospho-p44/42 mitogen activated protein kinase/extracellular signal regulated kinase 1/2 (MAPK/Erk1/2), phospho-glycogen synthase kinase-3β (GSK-3β), phospho-stress activated protein kinase/c-Jun N-terminal kinase, total-Akt, total-GSK-3β, and phospho-p38-MAPK were carried out on index and control placental samples of the same gestational age. Compared with controls, staining of the index placenta showed minimal AP labelling of the brush border and remarkable positivity of the intervillous space. Cytotrophoblastic proliferation was 8–10% in the index placenta compared with 1–2% in controls. The index placenta also had raised concentrations of protein kinases with important roles in cell differentiation. The proliferation and differentiation rates of the cytotrophoblasts were found to be five times higher in index samples than in controls. It is hypothesised that loss of syncytial membranes in immature villi led to increased AP concentrations in the maternal circulation and decreased AP staining of the placenta. Loss of the syncytium might also stimulate increased proliferation of villous cytotrophoblasts, which would then fuse and maintain the syncytium

Bidder Gains and Losses of Firms Involved in Many Acquisitions

We examine shareholders' wealth effects (both in the short- and the long-run) of UK frequent bidders acquiring public, private, and/or subsidiary targets with alternative methods of payment between 1987 and 2004. We find that, in the short-run, bidders break even when acquiring public targets and gain significantly when buying private and subsidiary targets. This result is robust after controlling for relative size, bidder's book-to-market ratio, target origin, and industry diversification. Our long-run evidence, however, reveals that acquirers experience, significant wealth losses regardless of the target type acquired, indicating that markets may initially overreact to the acquisition announcement. As a result, we argue that contrary to Fuller et al. (2002) who suggest that acquiring private and subsidiary firms creates value for bidding firms, a reliable conclusion on bidders' shareholders wealth effects cannot be based solely on a short-run event study