Risk faktors for fracture in middle-aged men and women

The number of fractures is increasing worldwide, and fractures frequently cause long-term disability, impaired quality of life and sometimes death. The Malmö Preventive Project, a population-based, prospective study, consisting of 22 444 men, mean age 44 and 10 902 women, mean age 50 years, provides data for evaluation of common public health conditions, such as fracture and diabetes. The follow-up was 19 and 15 years for men and women, respectively. Multiple risk factors for fracture were identified. In women, the most important risk factors were advancing age (relative risk RR 1.56, Confidence Interval 95% 1.45-1.68), previous fracture (RR 2.00, CI 95% 1.56-2.58) and diabetes (RR 1.87, CI 95% 1.26-2,79). In men, advancing age (RR 1.19, CI 95% 1.12-1.26), mental health problems (RR 1.92, CI 95% 1.47-2.51), increased levels of ? glutamyl transferase (RR 1.24, CI 95% 1.18-1.31) and diabetes (RR 2.38, CI 95% 1.65-3.42) were major risk contributors. Impaired glucose tolerance, evaluated through an oral glucose tolerance test, was in both genders associated with a substantially decreased risk of fractures, independent of age, BMI and smoking. This thesis has identified multiple risk factors for low-energy fracture, in both men and women, highlighting diabetes and mental health problems as major contributors in this age group. Current management strategies and therapeutic guidelines are not addressing a number of the identified risk factors. Subsequently, risk assessment can be substantially improved by adding these risk factors to intervention algorithms for middle-aged individuals

Three Different Types of Galaxy Alignment within Dark Matter Halos

Using a large galaxy group catalogue based on the Sloan Digital Sky Survey Data Release 4 we measure three different types of intrinsic galaxy alignment within groups: halo alignment between the orientation of the brightest group galaxies (BGG) and the distribution of its satellite galaxies, radial alignment between the orientation of a satellite galaxy and the direction towards its BGG, and direct alignment between the orientation of the BGG and that of its satellites. In agreement with previous studies we find that satellite galaxies are preferentially located along the major axis. In addition, on scales r < 0.7 Rvir we find that red satellites are preferentially aligned radially with the direction to the BGG. The orientations of blue satellites, however, are perfectly consistent with being isotropic. Finally, on scales r < 0.1 \Rvir, we find a weak but significant indication for direct alignment between satellites and BGGs. We briefly discuss the implications for weak lensing measurements.Comment: 4 pages, 4 figures, ApJL accepte

Spatial and kinematic alignments between central and satellite halos

Based on a cosmological N-body simulation we analyze spatial and kinematic alignments of satellite halos within six times the virial radius of group size host halos (Rvir). We measure three different types of spatial alignment: halo alignment between the orientation of the group central substructure (GCS) and the distribution of its satellites, radial alignment between the orientation of a satellite and the direction towards its GCS, and direct alignment between the orientation of the GCS and that of its satellites. In analogy we use the directions of satellite velocities and probe three further types of alignment: the radial velocity alignment between the satellite velocity and connecting line between satellite and GCS, the halo velocity alignment between the orientation of the GCS and satellite velocities and the auto velocity alignment between the satellites orientations and their velocities. We find that satellites are preferentially located along the major axis of the GCS within at least 6 Rvir (the range probed here). Furthermore, satellites preferentially point towards the GCS. The most pronounced signal is detected on small scales but a detectable signal extends out to 6 Rvir. The direct alignment signal is weaker, however a systematic trend is visible at distances < 2 Rvir. All velocity alignments are highly significant on small scales. Our results suggest that the halo alignment reflects the filamentary large scale structure which extends far beyond the virial radii of the groups. In contrast, the main contribution to the radial alignment arises from the adjustment of the satellite orientations in the group tidal field. The projected data reveal good agreement with recent results derived from large galaxy surveys. (abridged)Comment: accepted for publication in Ap

Correction: The Endocytic Adaptor Eps15 Controls Marginal Zone B Cell Numbers.

Eps15 is an endocytic adaptor protein involved in clathrin and non-clathrin mediated endocytosis. In Caenorhabditis elegans and Drosophila melanogaster lack of Eps15 leads to defects in synaptic vesicle recycling and synapse formation. We generated Eps15-KO mice to investigate its function in mammals. Eps15-KO mice are born at the expected Mendelian ratio and are fertile. Using a large-scale phenotype screen covering more than 300 parameters correlated to human disease, we found that Eps15-KO mice did not show any sign of disease or neural deficits. Instead, altered blood parameters pointed to an immunological defect. By competitive bone marrow transplantation we demonstrated that Eps15-KO hematopoietic precursor cells were more efficient than the WT counterparts in repopulating B220⁺ bone marrow cells, CD19⁻ thymocytes and splenic marginal zone (MZ) B cells. Eps15-KO mice showed a 2-fold increase in MZ B cell numbers when compared with controls. Using reverse bone marrow transplantation, we found that Eps15 regulates MZ B cell numbers in a cell autonomous manner. FACS analysis showed that although MZ B cells were increased in Eps15-KO mice, transitional and pre-MZ B cell numbers were unaffected. The increase in MZ B cell numbers in Eps15 KO mice was not dependent on altered BCR signaling or Notch activity. In conclusion, in mammals, the endocytic adaptor protein Eps15 is a regulator of B-cell lymphopoiesis

Prostate-specific antigen patterns in US and European populations:Comparison of six diverse cohorts

Objective: To determine whether there are differences in prostate-specific antigen (PSA) levels at diagnosis or changes in PSA levels between US and European populations of men with and without prostate cancer (PCa). Subjects and Methods: We analysed repeated measures of PSA from six clinically and geographically diverse cohorts of men: two cohorts with PSA-detected PCa, two cohorts with clinically detected PCa and two cohorts without PCa. Using multilevel models, average PSA at diagnosis and PSA change over time were compared among study populations. Results: The annual percentage PSA change of 4-5% was similar between men without cancer and men with PSA-detected cancer. PSA at diagnosis was 1.7 ng/mL lower in a US cohort of men with PSA-detected PCa (95% confidence interval 1.3-2.0 ng/mL), compared with a UK cohort of men with PSA-detected PCa, but there was no evidence of a different rate of PSA change between these populations. Conclusion: We found that PSA changes over time are similar in UK and US men diagnosed through PSA testing and even in men without PCa. Further development of PSA models to monitor men on active surveillance should be undertaken in order to take advantage of these similarities. We found no evidence that guidelines for using PSA to monitor men cannot be passed between US and European studies

Haptoglobin Genotype Does Not Confer a Risk of Stroke in Type 1 Diabetes

The exon copy number variant in the haptoglobin gene is associated with cardiovascular and kidney disease. For stroke, previous research is inconclusive. We aimed to study the relationship between haptoglobin Hp1/2 genotype and stroke in individuals with type 1 diabetes from the Finnish Diabetic Nephropathy Study. We included two partially overlapping cohorts: one with haptoglobin genotypes determined using genotyping for 179 stroke cases and 517 matched controls, and the other using haptoglobin genotype imputation for a larger cohort of 500 stroke cases and 3,806 controls. We observed no difference in the Hp1-1, Hp2-1, and Hp2-2 genotype frequencies between the stroke cases and controls, neither in the genotyping nor the imputation cohorts. Haptoglobin genotypes were also not associated with the ischemic or hemorrhagic stroke subtypes. In our imputed haptoglobin cohort, 61% of individuals with stroke died during follow-up. However, the risk of death was not related to the haptoglobin genotype. Diabetic kidney disease and cardiovascular events were common in the cohort, but the haptoglobin genotypes were not associated with stroke when stratified by these complications. To conclude, the Hp1/2 genotypes did not affect the risk of stroke or survival after stroke in our type 1 diabetes cohort.Peer reviewe

Sociodemographic variation in the use of chemotherapy and radiotherapy in patients with stage IV lung, oesophageal, stomach and pancreatic cancer: evidence from population-based data in England during 2013-2014.

BACKGROUND: Sociodemographic inequalities in cancer treatment have been generally described, but there is little evidence regarding patients with advanced cancer. Understanding variation in the management of these patients may provide insights into likely mechanisms leading to inequalities in survival. METHODS: We identified 50,232 patients with stage IV lung, oesophageal, pancreatic and stomach cancer from the English national cancer registry. A generalised linear model with a Poisson error structure was used to explore variation in radiotherapy and chemotherapy within 6 months from diagnosis by age, sex, deprivation, ethnicity, cancer site, comorbidity and, additionally, performance status. RESULTS: There was substantial variation by cancer site, large gradients by age, and non-trivial associations with comorbidity and deprivation. After full adjustment, more deprived patients were consistently least likely to be treated with chemotherapy alone or chemotherapy and radiotherapy combined compared with less deprived patients with equally advanced disease stage (treatment rate ratio: 0.82 95% CI (0.78, 0.87) for CT, 0.78 95% CI (0.71, 0.85) for CTRT p < 0.0001). CONCLUSIONS: There was marked variation in the management of patients with stage IV cancer. Routinely collected data could be used for surveillance across all cancers to help reduce treatment variation and optimise outcomes among patients with advanced cancer

Unagreement is an illusion

This is the author accepted manuscript. The final version is available from Springer via http://dx.doi.org/10.1007/s11049-015-9311-yThis paper proposes an analysis of unagreement, a phenomenon involving an apparent mismatch between a definite third person plural subject and first or second person plural subject agreement observed in various null subject languages (e.g. Spanish, Modern Greek and Bulgarian), but notoriously absent in others (e.g. Italian, European Portuguese). A cross-linguistic correlation between unagreement and the structure of adnominal pronoun constructions suggests that the availability of unagreement depends on whether person and definiteness are hosted by separate heads (in languages like Greek) or bundled on a single head (i.e. pronominal determiners in languages like Italian). Null spell-out of the head hosting person features high in the extended nominal projection of the subject leads to unagreement. The lack of unagreement in languages with pronominal determiners results from the interaction of their syntactic structure with the properties of the vocabulary items realising the head encoding both person and definiteness. The analysis provides a principled explanation for the cross-linguistic distribution of unagreement and suggests a unified framework for deriving unagreement, adnominal pronoun constructions, personal pronouns and pro

Modeling of Human Prokineticin Receptors: Interactions with Novel Small-Molecule Binders and Potential Off-Target Drugs

The Prokineticin receptor (PKR) 1 and 2 subtypes are novel members of family A GPCRs, which exhibit an unusually high degree of sequence similarity. Prokineticins (PKs), their cognate ligands, are small secreted proteins of ∼80 amino acids; however, non-peptidic low-molecular weight antagonists have also been identified. PKs and their receptors play important roles under various physiological conditions such as maintaining circadian rhythm and pain perception, as well as regulating angiogenesis and modulating immunity. Identifying binding sites for known antagonists and for additional potential binders will facilitate studying and regulating these novel receptors. Blocking PKRs may serve as a therapeutic tool for various diseases, including acute pain, inflammation and cancer.Ligand-based pharmacophore models were derived from known antagonists, and virtual screening performed on the DrugBank dataset identified potential human PKR (hPKR) ligands with novel scaffolds. Interestingly, these included several HIV protease inhibitors for which endothelial cell dysfunction is a documented side effect. Our results suggest that the side effects might be due to inhibition of the PKR signaling pathway. Docking of known binders to a 3D homology model of hPKR1 is in agreement with the well-established canonical TM-bundle binding site of family A GPCRs. Furthermore, the docking results highlight residues that may form specific contacts with the ligands. These contacts provide structural explanation for the importance of several chemical features that were obtained from the structure-activity analysis of known binders. With the exception of a single loop residue that might be perused in the future for obtaining subtype-specific regulation, the results suggest an identical TM-bundle binding site for hPKR1 and hPKR2. In addition, analysis of the intracellular regions highlights variable regions that may provide subtype specificity

Speech Communication

Contains table of contents for Part V, table of contents for Section 1, reports on six research projects and a list of publications.C.J. Lebel FellowshipDennis Klatt Memorial FundNational Institutes of Health Grant R01-DC00075National Institutes of Health Grant R01-DC01291National Institutes of Health Grant R01-DC01925National Institutes of Health Grant R01-DC02125National Institutes of Health Grant R01-DC02978National Institutes of Health Grant R01-DC03007National Institutes of Health Grant R29-DC02525National Institutes of Health Grant F32-DC00194National Institutes of Health Grant F32-DC00205National Institutes of Health Grant T32-DC00038National Science Foundation Grant IRI 89-05249National Science Foundation Grant IRI 93-14967National Science Foundation Grant INT 94-2114