The value of some Corsican sub-populations for genetic association studies

<p>Abstract</p> <p>Background</p> <p>Genetic isolates with a history of a small founder population, long-lasting isolation and population bottlenecks represent exceptional resources in the identification of disease genes. In these populations the disease allele reveals Linkage Disequilibrium (LD) with markers over significant genetic intervals, therefore facilitating disease locus identification. In a previous study we examined the LD extension on the Xq13 region in three Corsican sub-populations from the inner mountainous region of the island. On the basis of those previous results we have proposed a multistep procedure to carry out studies aimed at the identification of genes involved in complex diseases in Corsica. A prerequisite to carry out the proposed multi-step procedure was the presence of different degrees of LD on the island and a common genetic derivation of the different Corsican sub-populations. In order to evaluate the existence of these conditions in the present paper we extended the analysis to the Corsican coastal populations.</p> <p>Methods</p> <p>Samples were analyzed using seven dinucleotide microsatellite markers on chromosome Xq13-21: DXS983, DXS986, DXS8092, DXS8082, DXS1225, DXS8037 and DXS995 spanning approximately 4.0 cM (13.3 Mb). We have also investigated the distribution of the DXS1225-DXS8082 haplotype which has been recently proposed as a good marker of population genetic history due to its low recombination rate.</p> <p>Results</p> <p>the results obtained indicate a decrease of LD on the island from the central mountainous toward the coastal sub-populations. In addition the analysis of the DXS1225-DXS8082 haplotype revealed: 1) the presence of a particular haplotype with high frequency; 2) the derivation from a common genetic pool of the sub-populations examined in the present study.</p> <p>Conclusion</p> <p>These results indicate the Corsican sub-populations useful for the fine mapping of genes contributing to complex diseases.</p

Mechanical ventilation modulates TLR4 and IRAK-3 in a non-infectious, ventilator-induced lung injury model

<p>Abstract</p> <p>Background</p> <p>Previous experimental studies have shown that injurious mechanical ventilation has a direct effect on pulmonary and systemic immune responses. How these responses are propagated or attenuated is a matter of speculation. The goal of this study was to determine the contribution of mechanical ventilation in the regulation of Toll-like receptor (TLR) signaling and interleukin-1 receptor associated kinase-3 (IRAK-3) during experimental ventilator-induced lung injury.</p> <p>Methods</p> <p>Prospective, randomized, controlled animal study using male, healthy adults Sprague-Dawley rats weighing 300-350 g. Animals were anesthetized and randomized to spontaneous breathing and to two different mechanical ventilation strategies for 4 hours: high tidal volume (V_T) (20 ml/kg) and low V_T(6 ml/kg). Histological evaluation, TLR2, TLR4, <it>IRAK3 </it>gene expression, IRAK-3 protein levels, inhibitory kappa B alpha (IκBα), tumor necrosis factor-alpha (<it>TNF-α</it>) and interleukin-6 (<it>IL6</it>) gene expression in the lungs and TNF-α and IL-6 protein serum concentrations were analyzed.</p> <p>Results</p> <p>High V_Tmechanical ventilation for 4 hours was associated with a significant increase of TLR4 but not TLR2, a significant decrease of <it>IRAK3 </it>lung gene expression and protein levels, a significant decrease of IκBα, and a higher lung expression and serum concentrations of pro-inflammatory cytokines.</p> <p>Conclusions</p> <p>The current study supports an interaction between TLR4 and IRAK-3 signaling pathway for the over-expression and release of pro-inflammatory cytokines during ventilator-induced lung injury. Our study also suggests that injurious mechanical ventilation may elicit an immune response that is similar to that observed during infections.</p

Kidney size in relation to ageing, gender, renal function, birthweight and chronic kidney disease risk factors in a general population

Background: The relationship of kidney size to ageing, kidney function and kidney disease risk factors is not fully understood. Methods: Ultrasound length and parenchymal kidney volume were determined from a population-based sample of 3972 Sardinians (age range 18-100 years). We then identified the subset of 2256 'healthy' subjects to define age- and sex-specific reference ranges (2.5-97.5 percentile) of kidney volume. Logistic regression (accounting for family clustering) was used to identify the clinical characteristics associated with abnormally large kidneys or abnormally small kidneys. Results: In the healthy subset, kidney volume and length increased up to the fourth to fifth decade of life followed by a progressive decrease in men, whereas there was a gradual kidney volume decrease throughout the lifespan of women. In the whole sample, independent predictors of lower kidney volume (97.5 percentile for age and sex) were younger age, female sex, diabetes, obesity, high height, high waist:hip ratio and lower SCr. Estimated heritability for kidney volume was 15%, and for length 27%; kidney volume correlated strongly with birthweight. Conclusions: Overall, in a general healthy population, kidney measures declined with age differently in men and women. The determinants of kidney parenchymal volume include genetic factors and modifiable clinical factors

Serum IgE Reactivity Profiling in an Asthma Affected Cohort

BACKGROUND: Epidemiological evidence indicates that atopic asthma correlates with high serum IgE levels though the contribution of allergen specific IgE to the pathogenesis and the severity of the disease is still unclear. METHODS: We developed a microarray immunoassay containing 103 allergens to study the IgE reactivity profiles of 485 asthmatic and 342 non-asthmatic individuals belonging to families whose members have a documented history of asthma and atopy. We employed k-means clustering, to investigate whether a particular IgE reactivity profile correlated with asthma and other atopic conditions such as rhinitis, conjunctivitis and eczema. RESULTS: Both case-control and parent-to-siblings analyses demonstrated that while the presence of specific IgE against individual allergens correlated poorly with pathological conditions, particular reactivity profiles were significantly associated with asthma (p<10E-09). An artificial neural network (ANN)-based algorithm, calibrated with the profile reactivity data, correctly classified as asthmatic or non-asthmatic 78% of the individual examined. Multivariate statistical analysis demonstrated that the familiar relationships of the study population did not affect the observed correlations. CONCLUSIONS: These findings indicate that asthma is a higher-order phenomenon related to patterns of IgE reactivity rather than to single antibody reactions. This notion sheds new light on the pathogenesis of the disease and can be readily employed to distinguish asthmatic and non-asthmatic individuals on the basis of their serum reactivity profile

Developmentally regulated expression and localization of fibroblast growth factor receptors in the human muscle.

Fibroblast growth factors (FGFs) are believed to play a key role in tissue differentiation and maturation. Thus, the expression of the four members of the high-affinity tyrosine kinase FGF receptor family (FGFRs) and of the low-affinity heparan sulphate proteoglycan binding sites, syndecan-1 and perlecan, was studied in the human skeletal muscle during development. Northern blot analysis demonstrated a developmentally regulated expression of the mRNAs for FGFR-1, FGFR-3, FGFR-4, whereas only traces of FGFR-2 mRNA were found. Each receptor type had a different developmental pattern, suggesting an independent regulation. Signal for FGFR-3 was retained only in the adult muscle. Among the low-affinity FGF binding sites, perlecan was absent, whereas RNA transcript for syndecan-1 peaked at week 13 of gestation, after which a significant decrease was observed. Immunohistochemistry for FGFRs revealed that their localization changed with muscle maturation. At early embryonic stages, FGFR-3 and FGFR-4 had a scattered distribution in the tissue, and FGFR-1 was found on myotube and myofiber plasma membranes. At later stages, FGFR-1 positivity decreased and was found in a few areas of the muscle, FGFR-3 was concentrated in the nuclei of some, but not all, muscle fibers, and FGFR-4 maintained an association with plasma membrane. In adult tissue, weak positivity for FGFR-3 and FGFR-4 was observed in the connective tissue only. When immunocytochemistry was performed on human fetal myoblasts in culture, confocal microscope analysis revealed a nonhomogeneous cell membrane distribution of FGFRs. Taken together, the data strongly suggest that developmentally regulated expression and cell distribution of FGFRs play a role during muscle maturation

Differential expression of fibroblast growth factor receptors by human neurones, astrocytes and microglia.

Expression of fibroblast-growth factor receptors (FGFRs) was studied in human fetal neurones, astrocytes and microglia in culture. Northern blot analysis showed that neurones and microglia expressed the mRNAs for FGFR-1, FGFR-2, FGFR-3, FGFR-4 at different levels, whereas astrocytes expressed only FGFR-1 and FGFR-4 mRNAs. Immunocytochemical localization of FGFR-1 revealed that this receptor was predominantly localized on the axon hillock membrane in neurones, and was associated with the plasma membrane of ameboid, activated microglia and of glial-fibrillar acidic protein positive astrocytes. The expression of various members of the FGFR family in all the cell types investigated implicates FGFs in human brain development and functions