Sibship and dispensing patterns of asthma medication in young children : a population based study

Purpose: Our aim was to study the association between sibship and dispensing patterns of asthma medication in young children, focusing on incidence and persistence, and taking sibship status, asthma diagnoses, and siblings’ medication into account. Methods: A register-based cohort study including all children (n=50,546) born in Stockholm, Sweden 2006–2007, followed up during 2006–2014. Exposure was sibling status; outcome was incidence of dispensed asthma medication and persistence over time. A Cox-model was used to study the association between sibship and asthma medication. Persistence was defined using two different time windows (4- and 18-months) in a refill sequence model including siblings’ and unrelated control children’s medication. Results: After one year of age, the adjusted hazard ratio of dispensed asthma medication was 0.85 (95%CI 0.80–0.90) among children with siblings compared to singletons. The estimated proportion of children with persistent controller medication was 7.2% (4-month model) and 64.5% (18-month model). When including the siblings’ controller medication, the estimated proportion was 8.8% (4-months) and 7.8% for control children (relative risk, RR 0.89, 95%CI 0.81-0.98). The persistence was lower for those with siblings compared to singletons (adj. RR 0.72, 95%CI 0.62-0.85 for 4-months) with similar estimates for older, younger, and full siblings and regardless of asthma diagnoses. Conclusions: Siblings have different dispensing patterns of asthma medications compared to singletons regardless of asthma diagnoses. After including the siblings’ asthma medication and compared with control children, the proportion of children with persistent medication increased which may indicate that siblings share asthma medications.Swedish Research Council for Health, Working Life and WelfareStrategic Research Program in EpidemiologyStockholm County CouncilSwedish Heart Lung FoundationSwedish Research CouncilAccepte

Local Destabilization of the Metal-Binding Region in Human Copper−Zinc Superoxide Dismutase by Remote Mutations Is a Possible Determinant for Progression of ALS

More than 100 distinct mutations in the gene CuZnSOD encoding human copper–zinc superoxide dismutase (CuZnSOD) have been associated with familial amyotrophic lateral sclerosis (fALS), a fatal neuronal disease. Many studies of different mutant proteins have found effects on protein stability, catalytic activity, and metal binding, but without a common pattern. Notably, these studies were often performed under conditions far from physiological. Here, we have used experimental conditions of pH 7 and 37 °C and at an ionic strength of 0.2 M to mimic physiological conditions as close as possible in a sample of pure protein. Thus, by using NMR spectroscopy, we have analyzed amide hydrogen exchange of the fALS-associated I113T CuZnSOD variant in its fully metalated state, both at 25 and 37 °C, where ^(15)N relaxation data, as expected, reveals that CuZnSOD I113T exists as a dimer under these conditions. The local dynamics at 82% of all residues have been analyzed in detail. When compared to the wild-type protein, it was found that I113T CuZnSOD is particularly destabilized locally at the ion binding sites of loop 4, the zinc binding loop, which results in frequent exposure of the aggregation prone outer β-strands I and VI of the β-barrel, possibly enabling fibril or aggregate formation. A similar study (Museth, A. K., et al. (2009) Biochemistry, 48, 8817–8829) of amide hydrogen exchange at pH 7 and 25 °C on the G93A variant also revealed a selective destabilization of the zinc binding loop. Thus, a possible scenario in ALS is that elevated local dynamics at the metal binding region can result in toxic species from formation of new interactions at local β-strands

Play-Responsive Teaching in Early Childhood Education

This open access book develops a theoretical concept of teaching that is relevant to early childhood education, and based on children’s learning and development through play. It discusses theoretical premises and research on playing and learning, and proposes the development of play-responsive didaktik. It examines the processes and products of learning and development, teaching and its phylogenetic and ontogenetic development, as well as the ‘what’ of learning and didaktik. Next, it explores the actions, objects and meaning of play and provides insight into the diversity of beliefs about the practices of play. The book presents ideas on how combined research and development projects can be carried out, providing incentive and a model for practice development and research. The second part of the book consists of empirical studies on teacher’s playing skills and examples of play with very young as well as older children

Relationship Between Ljungan Virus Antibodies, HLA-DQ8, and Insulin Autoantibodies in Newly Diagnosed Type 1 Diabetes Children

Environmental factors, including viral infections, may explain an increasing and fluctuating incidence of childhood type 1 diabetes (T1D). Ljungan virus (LV) isolated from bank voles have been implicated, but it is unclear whether LV contributes to islet autoimmunity, progression to clinical onset, or both, of T1D. The aim was to test whether LV antibodies (LVAb) were related to HLA-DQ and islet autoantibodies in newly diagnosed T1D patients (n = 676) and controls (n = 309). Patients, 0-18 years of age, diagnosed with T1D in 1996-2005 were analyzed for LVAb, HLA-DQ genotypes, and all seven known islet autoantibodies (GADA, IA-2A, IAA, ICA, ZnT8RA, ZnT8WA, and ZnT8QA). LVAb at 75th percentile, defined as cut off, was 90 (range 6-3936) U/mL and 4th quartile LVAb were found in 25% (170/676) of which 64% were < 10 (n = 108, p < 0.0001), and 27% were < 5 (n = 45; p < 0.0001) years old. The 4th quartile LVAb in children < 10 years of age correlated to HLA DQ2/8, 8/8, and 8/X (p < 0.0001). Furthermore, in the group with 4th quartile LVAb, 55% were IAA positive (p = 0.01) and correlation was found between 4th quartile LVAb and IAA in children < 10 years of age (p = 0.035). It is concluded that 1) LVAb were common among the young T1D patients and LVAb levels were higher in the younger age groups; 2) 4th quartile LVAb correlated with IAA; and 3) there was a correlation between 4th quartile LVAb and HLA-DQ8, particularly in the young patients. The presence of LVAb supports the notion that prior exposure to LV may be associated with T1D

The Effect of Schooling on Basic Cognition in Selected Nordic Countries

The present study investigated schooling effects on cognition. Cognitive data were collected as part of a research project (ProMeal) that investigated school meals and measured the intake of school lunch in relation to children’s health, cognitive function, and classroom learning in four Nordic countries, among children between 10–11 years of age. It was found that Finnish pupils attending 4th grade were not, on any measure, outperformed by Norwegian and Icelandic pupils attending 5th and Swedish pupils attending 4th grade on a task measuring working memory capacity, processing speed, inhibition, and in a subsample on response- and attention control. Moreover, boys were found to perform superior to girls on tasks measuring processing speed. However, girls were found to perform better on tasks related to attention and self-control. The results are discussed in relation to the reciprocal association between cognition and schooling and whether these results reflect quality differences between schools in the four Nordic countries; most notably in comparison to Finland.</p

Thiopurine Enhanced ALL Maintenance (TEAM) : study protocol for a randomized study to evaluate the improvement in disease-free survival by adding very low dose 6-thioguanine to 6-mercaptopurine/methotrexate-based maintenance therapy in pediatric and adult patients (0-45 years) with newly diagnosed B-cell precursor or T-cell acute lymphoblastic leukemia treated according to the intermediate risk-high group of the ALLTogether1 protocol

Background: A critical challenge in current acute lymphoblastic leukemia (ALL) therapy is treatment intensification in order to reduce the relapse rate in the subset of patients at the highest risk of relapse. The year-long maintenance phase is essential in relapse prevention. The Thiopurine Enhanced ALL Maintenance (TEAM) trial investigates a novel strategy for ALL maintenance. Methods: TEAM is a randomized phase 3 sub-protocol to the ALLTogether1 trial, which includes patients 0-45 years of age with newly diagnosed B-cell precursor or T-cell ALL, and stratified to the intermediate risk-high (IR-high) group, in 13 European countries. In the TEAM trial, the traditional methotrexate (MTX)/6-mercaptopurine (6MP) maintenance backbone (control arm) is supplemented with low dose (2.5-12.5 mg/m(2)/day) oral 6-thioguanine (6TG) (experimental arm), while the starting dose of 6MP is reduced from 75 to 50 mg/m(2)/day. A total of 778 patients will be included in TEAM during similar to 5 years. The study will close when the last included patient has been followed for 5 years from the end of induction therapy. The primary objective of the study is to significantly improve the disease-free survival (DFS) of IR-high ALL patients by adding 6TG to 6MP/MTX-based maintenance therapy. TEAM has 80% power to detect a 7% increase in 5-year DFS through a 50% reduction in relapse rate. DFS will be evaluated by intention-to-treat analysis. In addition to reducing relapse,TEAM may also reduce hepatotoxicity and hypoglycemia caused by high levels of methylated 6MP metabolites. Methotrexate/6MP metabolites will be monitored and low levels will be reported back to clinicians to identify potentially non-adherent patients. Discussion: TEAM provides a novel strategy for maintenance therapy in ALL with the potential of improving DFS through reducing relapse rate. Potential risk factors that have been considered include hepatic sinusoidal obstruction syndrome/nodular regenerative hyperplasia, second cancer, infection, and osteonecrosis. Metabolite monitoring can potentially increase treatment adherence in both treatment arms.Peer reviewe

Prevalence of osteoporosis and incidence of hip fracture in women - secular trends over 30 years

<p>Abstract</p> <p>Background</p> <p>The number of hip fractures during recent decades has been reported to be increasing, partly because of an increasing proportion of elderly women in the society. However, whether changes in hip fracture annual incidence in women are attributable to secular changes in the prevalence of osteoporosis is unclear.</p> <p>Methods</p> <p>Bone mineral density was evaluated by single-photon absorptiometry at the distal radius in 456 women aged 50 years or above and living in the same city. The measurements were obtained by the same densitometer during three separate time periods: 1970-74 (n = 106), 1987-93 (n = 175) and 1998-1999 (n = 178), and the age-adjusted prevalence of osteoporosis in these three cohorts was calculated. Additionally, all hip fractures sustained in the target population of women aged 50 years or above between 1967 and 2001 were registered, whereupon the crude and the age-adjusted annual incidence of hip fractures were calculated.</p> <p>Results</p> <p>There was no significant difference in the age-adjusted prevalence of osteoporosis when the three cohorts were compared (P = 1.00). The crude annual incidence (per 10,000 women) of hip fracture in the target population increased by 110% from 40 in 1967 to 84 in 2001. The overall trend in the crude incidence between 1967 and 2001 was increasing (1.58 per 10,000 women per year; 95 percent confidence interval, 1.17 to 1.99), whereas the age-adjusted incidence was stable over the same period (0.22 per 10,000 women per year; 95 percent confidence interval, -0.16 to 0.60).</p> <p>Conclusions</p> <p>The increased number of hip fracture in elderly women is more likely to be attributable to demographic changes in the population than to secular increase in the prevalence of osteoporosis.</p

CD44 isoforms are heterogeneously expressed in breast cancer and correlate with tumor subtypes and cancer stem cell markers

<p>Abstract</p> <p>Background</p> <p>The CD44 cell adhesion molecule is aberrantly expressed in many breast tumors and has been implicated in the metastatic process as well as in the putative cancer stem cell (CSC) compartment. We aimed to investigate potential associations between alternatively spliced isoforms of CD44 and CSCs as well as to various breast cancer biomarkers and molecular subtypes.</p> <p>Methods</p> <p>We used q-RT-PCR and exon-exon spanning assays to analyze the expression of four alternatively spliced CD44 isoforms as well as the total expression of CD44 in 187 breast tumors and 13 cell lines. ALDH1 protein expression was determined by IHC on TMA.</p> <p>Results</p> <p>Breast cancer cell lines showed a heterogeneous expression pattern of the CD44 isoforms, which shifted considerably when cells were grown as mammospheres. Tumors characterized as positive for the CD44⁺/CD24<it>^-</it>phenotype by immunohistochemistry were associated to all isoforms except the CD44 standard (CD44S) isoform, which lacks all variant exons. Conversely, tumors with strong expression of the CSC marker ALDH1 had elevated expression of CD44S. A high expression of the CD44v2-v10 isoform, which retain all variant exons, was correlated to positive steroid receptor status, low proliferation and luminal A subtype. The CD44v3-v10 isoform showed similar correlations, while high expression of CD44v8-v10 was correlated to positive EGFR, negative/low HER2 status and basal-like subtype. High expression of CD44S was associated with strong HER2 staining and also a subgroup of basal-like tumors. Unsupervised hierarchical cluster analysis of CD44 isoform expression data divided tumors into four main clusters, which showed significant correlations to molecular subtypes and differences in 10-year overall survival.</p> <p>Conclusions</p> <p>We demonstrate that individual CD44 isoforms can be associated to different breast cancer subtypes and clinical markers such as HER2, ER and PgR, which suggests involvement of CD44 splice variants in specific oncogenic signaling pathways. Efforts to link CD44 to CSCs and tumor progression should consider the expression of various CD44 isoforms.</p