Findings from the Hvidøre Study Group on Childhood Diabetes: metabolic control and quality of life

The study involved 2,101 adolescents, aged 10-18 years, from 21 centres in 17 countries in Europe, Japan and North America. Adolescent quality of life (QOL) was assessed by a previously developed Diabetes Quality of Life Questionnaire for adolescents (DQOL), measuring impact of diabetes, worries about diabetes, satisfaction with life and health perception. Parents and health professionals assessed 'family burden' using newly constructed questionnaires. Mean HbA1c was 8.7% (range 4.8-17.4%). Lower HbA1c was associated with lower impact (p < 0.0001), fewer worries (p < 0.05), greater satisfaction (p < 0.0001) and better health perception (p < 0.0001) for adolescents. Girls showed increased worries (p < 0.01), less satisfaction and poorer health perception (p < 0.01) earlier than boys. Parent and health professional perceptions of burden decreased with age of adolescent (p < 0.0001). Lower HbA(1c) was significantly associated with better adolescent-rated QOL on all four subscales and with lower perceived family burden as assessed by parents and health professionals.     

Rapid changes in bird community composition at multiple temporal and spatial scales in response to recent climate change

Although climate change is acknowledged to affect population dynamics and species distribution, details of how community composition is affected are still lacking. We investigate whether ongoing changes in bird community composition can be explained by contemporary changes in summer temperatures, using four independent long‐term bird census schemes from Sweden (up to 57 yr); two at the national scale and two at local scales. The change in bird community composition was represented by a community temperature index (CTI) that reflects the balance in abundance between low‐ and high‐temperature dwelling species. In all schemes, CTI tracked patterns of temperature increase, stability or decrease remarkably well, with a lag period of 1–3 yr. This response was similar at both the national and local scale. However, the communities did not respond fast enough to cope with temperature increase, suggesting that community composition lags behind changes in temperature. The change in CTI was caused mainly by changes in species’ relative abundances, and less so by changes in species composition. We conclude that ongoing changes in bird community structure are driven to a large extent by contemporary changes in climate and that CTI can be used as a simple indicator for how bird communities respond.     

Candidate states of Helicobacter pylori's genome-scale metabolic network upon application of "loop law" thermodynamic constraints

Constraint-based modeling has proven to be a useful tool in the analysis of biochemical networks. To date, most studies in this field have focused on the use of linear constraints, resulting from mass balance and capacity constraints, which lead to the definition of convex solution spaces. One additional constraint arising out of thermodynamics is known as the "loop law" for reaction fluxes, which states that the net flux around a closed biochemical loop must be zero because no net thermodynamic driving force exists. The imposition of the loop-law can lead to nonconvex solution spaces making the analysis of the consequences of its imposition challenging. A four-step approach is developed here to apply the loop-law to study metabolic network properties: 1), determine linear equality constraints that are necessary (but not necessarily sufficient) for thermodynamic feasibility; 2), tighten V(max) and V(min) constraints to enclose the remaining nonconvex space; 3), uniformly sample the convex space that encloses the nonconvex space using standard Monte Carlo techniques; and 4), eliminate from the resulting set all solutions that violate the loop-law, leaving a subset of steady-state solutions. This subset of solutions represents a uniform random sample of the space that is defined by the additional imposition of the loop-law. This approach is used to evaluate the effect of imposing the loop-law on predicted candidate states of the genome-scale metabolic network of Helicobacter pylori.     

Quantitative Phosphoproteomics Analysis of ERBB3/ERBB4 Signaling

The four members of the epidermal growth factor receptor (EGFR/ERBB) family form homo- and heterodimers which mediate ligand-specific regulation of many key cellular processes in normal and cancer tissues. While signaling through the EGFR has been extensively studied on the molecular level, signal transduction through ERBB3/ERBB4 heterodimers is less well understood. Here, we generated isogenic mouse Ba/F3 cells that express full-length and functional membrane-integrated ERBB3 and ERBB4 or ERBB4 alone, to serve as a defined cellular model for biological and phosphoproteomics analysis of ERBB3/ERBB4 signaling. ERBB3 co-expression significantly enhanced Ba/F3 cell proliferation upon neuregulin-1 (NRG1) treatment. For comprehensive signaling studies we performed quantitative mass spectrometry (MS) experiments to compare the basal ERBB3/ERBB4 cell phosphoproteome to NRG1 treatment of ERBB3/ERBB4 and ERBB4 cells. We employed a workflow comprising differential isotope labeling with mTRAQ reagents followed by chromatographic peptide separation and final phosphopeptide enrichment prior to MS analysis. Overall, we identified 9686 phosphorylation sites which could be confidently localized to specific residues. Statistical analysis of three replicate experiments revealed 492 phosphorylation sites which were significantly changed in NRG1-treated ERBB3/ERBB4 cells. Bioinformatics data analysis recapitulated regulation of mitogen-activated protein kinase and Akt pathways, but also indicated signaling links to cytoskeletal functions and nuclear biology. Comparative assessment of NRG1-stimulated ERBB4 Ba/F3 cells revealed that ERBB3 did not trigger defined signaling pathways but more broadly enhanced phosphoproteome regulation in cells expressing both receptors. In conclusion, our data provide the first global picture of ERBB3/ERBB4 signaling and provide numerous potential starting points for further mechanistic studies.     

Extensive linkage disequilibrium in small human populations in Eurasia

The extent of linkage disequilibrium (LD) was studied in two small food-gathering populations—Evenki and Saami—and two larger food-producing populations—Finns and Swedes—in northern Eurasia. In total, 50 single-nucleotide polymorphisms (SNPs) from five genes were genotyped using real-time pyrophosphate DNA sequencing, whereas 14 microsatellites were genotyped in two X-chromosomal regions. In addition, hypervariable region I of the mtDNA was sequenced to shed light on the demographic history of the populations. The SNP data, as well as the microsatellite data, reveal extensive levels of LD in Evenki and Saami when compared to Finns and Swedes. mtDNA-sequence variation is compatible with constant population size over time in Evenki and Saami but indicates population expansion in Finns and Swedes. Furthermore, the similarity between Finns and Swedes in SNP allele- and haplotype-frequency distributions indicate that these two populations may share a recent common origin. These findings suggest that populations such as the Evenki and the Saami, rather than the Finns, may be particularly suited for the initial coarse mapping of common complex diseases.     

Plant species richness in grasslands: the relative importance of contemporary environment and land-use history since the Iron Age

The richness of vascular plants in all patches of dry semi-natural grassland within a landscape was investigated. The patch level richness was scaled up to the level of parish to match data on land-use intensity from Iron Age through historical time. Three measures of diversity were obtained: the local species pool, an area-independent diversity measure (the slope of the species number vs log area regression line), and the β-diversity, A gradient through the study area in the density of grassland and a corresponding clinal variation in grassland plant species diversity were found. Explanatory models were built by partial least squares regression and conventional stepwise multiple regression. Data on contemporary environmental conditions in the grassland patches and in the parish as a whole were added first, and then data on continuously older times in sequence. In the stepwise regression analyses the variables were also added in the opposite sequence. The results show that contemporary conditions are able to explain the major part of the variation in all diversity measures. Variables concerning former land-use do, however, add significantly to the explanation of variation in local species pool and in the area-independent diversity, but not in β-diversity. It is concluded that patterns of land-use intensity from the Iron Age and onwards have contributed significantly to the shaping of local species pools, and thereby the richness of grassland communities.     

RVX-208, an Inducer of ApoA-I in Humans,Is a BET Bromodomain Antagonist

Increased synthesis of Apolipoprotein A-I (ApoA-I) and HDL is believed to provide a new approach to treating atherosclerosis through the stimulation of reverse cholesterol transport. RVX-208 increases the production of ApoA-I in hepatocytes in vitro, and in vivo in monkeys and humans, which results in increased HDL-C, but the molecular target was not previously reported. Using binding assays and X-ray crystallography, we now show that RVX-208 selectively binds to bromodomains of the BET (Bromodomain and Extra Terminal) family, competing for a site bound by the endogenous ligand, acetylated lysine, and that this accounts for its pharmacological activity. siRNA experiments further suggest that induction of ApoA-I mRNA is mediated by BET family member BRD4. These data indicate that RVX-208 increases ApoA-I production through an epigenetic mechanism and suggests that BET inhibition may be a promising new approach to the treatment of atherosclerosis.     

Serial fine needle cytology in the diagnosis of esophageal cancer

OBJECTIVE: To describe a method of registering local spread of cancer in the esophageal wall through serial endoscopic fine needle aspiration (FNA), to evaluate FNA as a diagnostic tool as compared to histologic biopsies and brush cytology, and to investigate cytologic appearances of aspirates and correlate them with survival STUDY DESIGN: Fifty-two patients with esophageal cancer were investigated with serial FNA every second centimeter from the upper esophageal sphincter aborally down to the level of macroscopic tumor. Histologic biopsies and brush cytologies were then performed. RESULTS: Of investigated cases, 33% showed malignant or suspect malignant cells from macroscopic tumor, at > or = 4 cm orally, as did 3 of 12 patients at 14 cm. FNA was more sensitive than brush cytology in establishing the diagnosis. A high ratio between the numbers of benign and malignant cells in aspirates from gross tumor tissue correlated with shorter survival (P < .03). CONCLUSION: Serial FNA can demonstrate local microscopic tumor spread in the wall of the esophagus in vivo in esophageal cancer patients. FNA is also a useful adjunct in establishing the diagnosis. Finally, evaluations of tumor cytology may have prognostic value.     

7β-hydroxycholesterol induces natural killer cell death via oxidative lysosomal destabilization

Peripheral natural killer (NK) cells are reduced in patients with coronary artery disease and highly susceptible to apoptosis induced by oxidized lipids including 7β-hydroxycholesterol (7βOH) in vitro. The present study aimed to further explore the mechanisms behind 7βOH-mediated cytotoxicity to human NK cells. Human NK cells were purified and treated with 7βOH in different concentrations and times. Cell death, lysosomal and mitochondrial permeabilization and reactive oxygen species (ROS) production were then analysed. The 7βOH induced time and dose dependent apoptosis and necrosis in human NK cells, which was preceded by loss of lysosomal integrity and enhanced ROS production. At later time points, the mitochondrial membrane permeability in 7βOH-treated cells was significantly increased. The findings indicate that 7βOH induces human NK cell death through early lysosomal permeabilization and consequent oxidative stress. The data further suggest that 7βOH may induce immune disturbances in clinical settings such as atherosclerosis.