Early parenting intervention: Family risk and first-time parenting related to intervention effectiveness

The effects of cumulative risk and parity on the effectiveness of a home based parenting intervention were tested in a randomized controlled trial with 237 families with 1- to 3-year-old children screened for high levels of externalizing behavior. The intervention was aimed at enhancing positive parenting and decreasing externalizing behaviors. The results showed that cumulative risk was not associated with either change in child externalizing behaviors or change in positive parenting. When intervention effectiveness was compared for primiparas (i.e., first-time mothers) versus multiparas (i.e., mothers with more than one child), we found that intervention mothers of first-born children displayed an increase in their use of positive discipline strategies as compared to first-time mothers in the control group, whereas a similar effect for multiparas was absent. Among multiparas we found an intervention effect on sensitivity, with control group mothers showing an increase in sensitivity, whereas the intervention group showed a constant level of sensitivity over time. These results suggest that parity may be a moderator of intervention effectiveness. Implications for investigating moderators of intervention effectiveness are discussed. © 2007 Springer Science+Business Media, LLC

Predicting growth curves of early childhood externalizing problems: Differential susceptibility of children with difficult temperament

Using an accelerated longitudinal design, the development of externalizing problems from age 2 to 5 years was investigated in relation to maternal psychopathology, maternal parenting, gender, child temperament, and the presence of siblings. The sample consisted of 150 children selected at age 2-3 years for having high levels of externalizing problems. Parenting was measured using observational methods, and maternal reports were used for the other variables. Overall, mean levels of externalizing problems decreased over time, and higher initial levels (intercept) were related to a stronger decrease (negative slope) in externalizing problems. Results showed that higher levels of maternal psychopathology were related to less decrease in early childhood externalizing problems. Parental sensitive behavior predicted a stronger decrease in externalizing problems, but only for children with difficult temperaments. A stronger decrease of externalizing problems in children with older siblings also pertained only to children with difficult temperaments. Thus, temperamentally difficult children appear to be more susceptible to environmental influences on the development of externalizing behaviors. Our results indicate that the role of siblings in early childhood externalizing problems deserves more research attention, and that intervention efforts need to take into account temperamental differences in children's susceptibility to environmental influences. © 2009 Springer Science+Business Media, LLC

Sensitive Monogenic Noninvasive Prenatal Diagnosis by Targeted Haplotyping

During pregnancy, cell-free DNA (cfDNA) in maternal blood encompasses a small percentage of cell-free fetal DNA (cffDNA), an easily accessible source for determination of fetal disease status in risk families through non-invasive procedures. In case of monogenic heritable disease, background maternal cfDNA prohibits direct observation of the maternally inherited allele. Non-invasive prenatal diagnostics (NIPD) of monogenic diseases therefore relies on parental haplotyping and statistical assessment of inherited alleles from cffDNA, techniques currently unavailable for routine clinical practice. Here, we present monogenic NIPD (MG-NIPD), which requires a blood sample from both parents, for targeted locus amplification (TLA)-based phasing of heterozygous variants selectively at a gene of interest. Capture probes-based targeted sequencing of cfDNA from the pregnant mother and a tailored statistical analysis enables predicting fetal gene inheritance. MG-NIPD was validated for 18 pregnancies, focusing on CFTR, CYP21A2, and HBB. In all cases we could predict the inherited alleles with >98% confidence, even at relatively early stages (8 weeks) of pregnancy. This prediction and the accuracy of parental haplotyping was confirmed by sequencing of fetal material obtained by parallel invasive procedures. MG-NIPD is a robust method that requires standard instrumentation and can be implemented in any clinic to provide families carrying a severe monogenic disease with a prenatal diagnostic test based on a simple blood draw

Relevant Market and Pricing Behavior of Regional Newspapers in the Netherlands

The aim of this study is to investigate the effect of market structure and area characteristics on the subscription prices and advertising rates for regional newspapers in the Netherlands. The price-market structure analysis in this study shows that there exists a negative relationship between concentration and prices. The results also show that advertising rates, differently to subscription prices, are significantly influenced by regional income and particularly by population density in the specific area. Furthermore, the evidence indicates that the relevant market for regional newspapers in the Netherlands is a market which encompasses regional newspapers, national newspapers and other media sources. Zusammenfassung Ziel der vorliegenden Untersuchung ist es, den Einfluss von Marktstruktur und anderen regionalen Einflussgrößen auf die Preise der Zeitungen für Abonnements und Anzeigen zu analysieren. Im Ergebnis zeigt sich insbesondere eine negative Korrelation von Konzentration und Zeitungspreisen. Die Preise für Anzeigen hängen – anders als die für Abonnements – signifikant vom Einkommensniveau und der Bevölkerungsdichte in der jeweiligen Region ab. Weiterhin deutet die empirische Evidenz darauf hin, dass zu den relevanten Märkten für Regionalzeitungen in den Niederlanden auch die überregionalen Zeitungen und andere Medien gehören

Skeletal muscle capillary density and microvascular function are compromised with aging and type 2 diabetes

Background: Adequate muscle perfusion is required for the maintenance of skeletal muscle mass. Impairments in microvascular structure and/or function with aging and type 2 diabetes have been associated with the progressive loss of skeletal muscle mass. Objective: To compare muscle fiber type specific capillary density and endothelial function between healthy young, older men and age-matched type 2 diabetes patients. Design: 15 healthy young men (24+/-1 y), 15 healthy older men (70+/-2 y), and 15 age-matched type 2 diabetes patients (70+/-1 y) were selected to participate in the present study. Whole-body insulin sensitivity, muscle fiber type specific capillary density, sublingual microvascular density and dimension of the erythrocyte perfused boundary region were assessed to evaluate the impact of aging and/or type 2 diabetes on microvascular structure and function. Results: Whole body insulin sensitivity was significantly lower at a more advanced age, with lowest values reported in the type 2 diabetic patients. In line, skeletal muscle capillary contacts were much lower in the older and older type 2 diabetic patients when compared with the young. Sidestream darkfield imaging showed a significantly greater thickness of the erythrocyte perfused boundary region in the type 2 diabetic patients compared with the young. Conclusions: Skeletal muscle capillary density is reduced with aging and type 2 diabetes and accompanied by impairments in endothelial glycocalyx function, which is indicative of compromised vascular function

Measurement of International and Product Diversification in the Publishing Industry

Corporate diversification has become an integral part of the strategy of many publishing companies. These diversification strategies may include both product diversification and international geographic diversification. This study demonstrates the diversification strategy of large-sized publishing companies. A number of measures and techniques are used to measure the diversification of these companies. We construct an additional measure to show the international diversification of the publishing companies. The findings indicate the existence of a set of common underlying dimensions or factors between a few measures, although no evidence of unidimensionality amongst all diversification measures exists. The various diversification indicators measure different aspects of diversification of publishing companies. Our data show that the publishing companies diversify into related activities and businesses and that, in particular, North American publishing companies do not diversify internationally.

Ongoing chromosomal instability and karyotype evolution in human colorectal cancer organoids

Chromosome segregation errors cause aneuploidy and genomic heterogeneity, which are hallmarks of cancer in humans. A persistent high frequency of these errors (chromosomal instability (CIN)) is predicted to profoundly impact tumor evolution and therapy response. It is unknown, however, how prevalent CIN is in human tumors. Using three-dimensional live-cell imaging of patient-derived tumor organoids (tumor PDOs), we show that CIN is widespread in colorectal carcinomas regardless of background genetic alterations, including microsatellite instability. Cell-fate tracking showed that, although mitotic errors are frequently followed by cell death, some tumor PDOs are largely insensitive to mitotic errors. Single-cell karyotype sequencing confirmed heterogeneity of copy number alterations in tumor PDOs and showed that monoclonal lines evolved novel karyo-types over time in vitro. We conclude that ongoing CIN is common in colorectal cancer organoids, and propose that CIN levels and the tolerance for mitotic errors shape aneuploidy landscapes and karyotype heterogeneity

Enhancer hubs and loop collisions identified from single-allele topologies

Chromatin folding contributes to the regulation of genomic processes such as gene activity. Existing conformation capture methods characterize genome topology through analysis of pairwise chromatin contacts in populations of cells but cannot discern whether individual interactions occur simultaneously or competitively. Here we present multi-contact 4C (MC-4C), which applies Nanopore sequencing to study multi-way DNA conformations of individual alleles. MC-4C distinguishes cooperative from random and competing interactions and identifies previously missed structures in subpopulations of cells. We show that individual elements of the β-globin superenhancer can aggregate into an enhancer hub that can simultaneously accommodate two genes. Neighboring chromatin domain loops can form rosette-like structures through collision of their CTCF-bound anchors, as seen most prominently in cells lacking the cohesin-unloading factor WAPL. Here, massive collision of CTCF-anchored chromatin loops is believed to reflect 'cohesin traffic jams'. Single-allele topology studies thus help us understand the mechanisms underlying genome folding and functioning