Invasive aspergillosis has become a major cause of infection-related mortality in nonneutropenic patients after allogeneic stem cell transplantation (SCT). To assess the potential role of Aspergillusspecific T-cell responses for the successful control of invasive aspergillosis, lymphoproliferative responses to Aspergillus fumigatus antigens were studied in healthy individuals, patients with evidence of invasive aspergillosis, and patients late after allogeneic SCT.

Age-related hearing impairment (ARHI) is the most prevalent sensory impairment in the elderly. ARHI is a complex disease caused by an interaction between environmental and genetic factors. The contribution of various environmental factors has been relatively extensively studied. In contrast, investigations to identify the genetic risk factors have only recently been initiated. In this paper we describe the results of an association study performed on 2418 ARHI samples derived from nine centers from seven European countries. In 70 candidate genes, a total of 768 tag single nucleotide polymorphisms (SNPs) were selected based on HAPMAP data. These genes were chosen among the monogenic hearing loss genes identified in mice and men in addition to several strong functional candidates. After genotyping and data polishing, statistical analysis of all samples combined resulted in a P-value that survived correction for multiple testing for one SNP in the GRHL2 gene. Other SNPs in this gene were also associated, albeit to a lesser degree. Subsequently, an analysis of the most significant GRHL2 SNP was performed separately for each center. The direction of the association was identical in all nine centers. Two centers showed significant associations and a third center showed a trend towards significance. Subsequent fine mapping of this locus demonstrated that the majority of the associated SNPs reside in intron 1. We hypothesize that the causative variant may change the expression levels of a GRHL2 isoform.

Reconstitution of human cytomegalovirus (HCMV)-specific cytotoxic T lymphocytes (CTLs),

Background: Age-related hearing impairment (ARHI) is the most common sensory impairment in older people, affecting 50% of those aged 80 years. The proportion of older people is increasing in the general population, and as a consequence, the number of people affected with ARHI is growing. ARHI is a complex disorder, with both environmental and genetic factors contributing to the disease. The first studies to elucidate these genetic factors were recently performed, resulting in the identification of the first two susceptibility genes for ARHI, NAT2 and KCNQ4. Methods: In the present study, the association between ARHI and polymorphisms in genes that contribute to the defence against reactive oxygen species, including GSTT1, GSTM1 and NAT2, was tested. Samples originated from seven different countries and were combined into two test population samples, the general European population and the Finnish population. Two distinct phenotypes for ARHI were studied, Z low and Z high , representing hearing in the low and high frequencies, respectively. Statistical analysis was performed for single polymorphisms (GSTM1, GSTT1, NAT2*5A, NAT2*6A, and NAT2*7A), haplotypes, and geneenvironment and gene-gene interactions. Results: We found an association between ARHI and GSTT1 and GSTM1 in the Finnish population sample, and with NAT2*6A in the general European population sample. The latter finding replicates previously published data. Conclusion: As replication is considered the ultimate proof of true associations in the study of complex disorders, this study provides further support for the involvement of NAT2*6A in ARHI.

Age-related hearing impairment (ARHI), or presbycusis, is a very common multifactorial disorder. Despite the knowledge that genetics play an important role in the etiology of human ARHI as revealed by heritability studies, to date, its precise genetic determinants remain elusive. Here we report the results of a cross-sectional family-based genetic study employing audiometric data. By using principal component analysis, we were able to reduce the dimensionality of this multivariate phenotype while capturing most of the variation and retaining biologically important features of the audiograms. We conducted a genome-wide association as well as a linkage scan with high-density SNP microarrays. Because of the presence of genetic population substructure, association testing was stratified after which evidence was combined by meta-analysis. No association signals reaching genome-wide significance were detected. Linkage analysis identified a linkage peak on 8q24.13-q24.22 for a trait correlated to audiogram shape. The signal reached genome-wide significance, as assessed by simulations. This finding represents the first locus for an ARHI trait.

An efficient and robust method to measure vitamin D (25-hydroxy vitamin D 3 (25(OH)D 3 ) and 25-hydroxy vitamin D 2 in dried blood spots (DBS) has been developed and applied in the pan-European multi-centre, internet-based, personalised nutrition intervention study Food4Me. The method includes calibration with blood containing endogenous 25(OH)D 3 , spotted as DBS and corrected for haematocrit content. The methodology was validated following international standards. The performance characteristics did not reach those of the current gold standard liquid chromatography-MS/MS in plasma for all parameters, but were found to be very suitable for status-level determination under field conditions. DBS sample quality was very high, and 3778 measurements of 25(OH)D 3 were obtained from 1465 participants. The study centre and the season within the study centre were very good predictors of 25(OH)D 3 levels (P < 0·001 for each case). Seasonal effects were modelled by fitting a sine function with a minimum 25(OH)D 3 level on 20 January and a maximum on 21 July. The seasonal amplitude varied from centre to centre. The largest difference between winter and summer levels was found in Germany and the smallest in Poland. The model was cross-validated to determine the consistency of the predictions and the performance of the DBS method. The Pearson's correlation between the measured values and the predicted values was r 0·65, and the SD of their differences was 21·2 nmol/l. This includes the analytical variation and the biological variation within subjects. Overall, DBS obtained by unsupervised sampling of the participants at home was a viable methodology for obtaining vitamin D status information in a large nutritional study.

Mutations in GJB2, a gene encoding the gap junction protein connexin 26 (Cx26), are a major cause for inherited and sporadic non-syndromic hearing loss, albeit with highly variable clinical effects. To determine new mutations and their frequencies in a Southern Egyptian population restriction fragment length polymorphism, gene sequencing, and single strand conformational polymorphism revealed only 2 mutations for GJB2: c.35delG and p.I71N. The allelic frequency of the c.35delG mutation was 8.7% (found in 27 out of 310 investigated alleles) resulting in a relatively low carrier frequency (1.6%) in Upper Egypt. The new mutation, a substitution of isoleucin (I) (a non-polar amino acid) by the polar amino acid asparagin (N), was localized within the conserved Cx26 structure. The functional significance of p.I71N was tested by injection of cRNA into Xenopus laevis oocytes. Cx26 hemi-channel activity was measured by depolarization activated conductance in non-coupled oocytes. As a result, the p.I71N mutated channel was non-functional. The study discloses a novel, functionally relevant GJB2 mutation and defines the contribution of Cx26 alterations to the hearing loss in the Southern Egyptian population.

These results implicate the participation of NK cells and gammadelta T cells, especially CD8(+)/gammadelta T cells, in the pathogenesis of BD and may explain one mechanism by which IFN-alpha2a exerts therapeutic effects. Alternatively, they may result indirectly from remission induction by IFN-alpha2a. The reduced expression of HLA class I on monocytes in HLA-B*51-positive patients might reflect an impaired expression of and antigen presentation by HLA-B*51.