| Uudet artikkelit 28.11.2005 - ISI
Web of Knowledge & PubMed Search Alert Cannon, T. D., W. Hennah, T. G. M. van Erp, P. M. Thompson, J. Lonnqvist, M. Huttunen, T. Gasperoni, A. Tuulio-Henriksson, T. Pirkola, A. W. Toga, J. Kaprio, J. Mazziotta and L. Peltonen. Archives of General Psychiatry. 2005; 62(11): 1205-1213. Context: Chromosome 1q42 is among several genomic regions showing replicated evidence of linkage with schizophrenia, but the specific susceptibility mechanisms underlying this relationship remain to be identified. Objective: To examine a series of haplotype blocks of single-nucleotide polymorphic markers from a segment of 1q42 spanning the disrupted-in-schizophrenia 1 (DISC1) and translin-associated factor X (TRAX) genes for association with schizophrenia and several endophenotypic traits thought to be involved in disease pathogenesis. Design: Population-based twin cohort study. Setting: Finland. Participants: Two hundred thirty-six subjects, consisting of 7 twin pairs concordant for schizophrenia (6 monozygotic [MZ] and I dizygotic [DZ]), 52 pairs discordant for schizophrenia (20 MZ and 32 DZ), and 59 demographically balanced normal pairs (28 MZ and 31 DZ), were drawn from a twin cohort consisting of all of the same-sex twins born in Finland from 1940 through 1957. Main Outcome Measures: Psychiatric diagnosis, performance on neurocognitive tests of short- and long-term memory, and gray matter volume measurements taken from high-resolution magnetic resonance images. Results: A common haplotype incorporating 3 single-nucleotide polymorphic markers near the translocation break point of DISC1 (odds ratio, 2.6 [P=.02]) and a rare haplotype incorporating 4 markers from the DISC1 and TRAX genes (odds ratio, 13.0 [P=.001]) were significantly overrepresented among individuals with schizophrenia. These haplotypes were also associated with several quantitative endophenotypic traits previously observed to covary with schizophrenia and genetic liability to schizophrenia, including impairments in short- and long-term memory functioning and reduced gray matter density in the prefrontal cortex, as demonstrated using a population-based brain atlas method, with a trend toward association with reduced hippocampal volume. Conclusions: Specific alleles of the DISC1 and TRAX genes on 1q42 appear to contribute to genetic risk for schizophrenia through disruptive effects on the structure and function of the prefrontal cortex, medial temporal lobe, and other brain regions. These effects are consistent with their production of proteins that play roles in neuritic outgrowth, neuronal migration, synaptogenesis, and glutamatergic neurotransmission. Lehto, M., R. Haapakoski, H. Wolff, M. L. Majuri, M. J. Makela, M. Leino, T. Reunala, K. Turjanmaa, T. Palosuo and H. Alenius. Journal of Investigative Dermatology. 2005; 125(5): 962-968. As respiratory symptoms are common in addition to skin reactions in natural rubber latex allergy, we investigated the significance of different allergen exposure routes in the development of lung inflammation and airway hyperreactivity (AHR). Both intracutaneous (IC) and intraperitoneal (IP) exposure followed by airway challenge with latex proteins induced an influx of mononuclear cells and eosinophils to the lungs. AHR and lung mucus production increased significantly after IC and IP but not after intranasal (IN) exposure. Infiltration of inflammatory cells was associated with the induction of T-helper type 2 (Th2) cytokines and several CC chemokines. Only a marginal induction of these mediators was found after IN exposure. On the contrary, increased levels of transforming growth factor-beta 1 and forkhead box 3 mRNA, markers of regulatory activities, were found in the lungs after IN but not after IC exposure. Finally, IC and IP, but not IN, latex exposure induced a striking increase in specific immunoglobulin E (IgE) levels. Cutaneous latex exposure in the absence of adjuvant followed by airway challenge induces a local Th2-dominated lung inflammation and a systemic IgE response. Cutaneous exposure to proteins eluting from latex products may therefore profoundly contribute to the development of asthma in latex allergy. Lehtonen, A., V. Veckman, T. Nikula, R. Lahesmaa, L. Kinnunen, S. Matikainen and I. Julkunen. Journal of Immunology. 2005; 175(10): 6570-6579. In vitro human monocyte differentiation to macrophages or dendritic cells (DCs) is driven by GM-CSF or GM-CSF and IL-4, respectively. IFN regulatory factors (IRFs), especially IRF1 and IRF8, are known to play essential roles in the development and functions of macrophages and DCs. In the present study, we performed cDNA microarray and Northern blot analyses to characterize changes in gene expression of selected genes during cytokine-stimulated differentiation of human monocytes to macrophages or DCs. The results show that the expression of IRF4 mRNA, but not of other IRFs, was specifically up-regulated during DC differentiation. No differences in IRF4 promoter histone acetylation could be found between macrophages and DCs, suggesting that the gene locus was accessible for transcription in both cell types. Computer analysis of the human IRF4 promoter revealed several putative STAT and NF-kappa B binding sites, as well as an IRF/Ets binding site. These sites were found to be functional in transcription factor-binding and chromatin immunoprecipitation experiments. Interestingly, Stat4 and NF-kappa B p50 and p65 mRNAs were expressed at higher levels in DCs as compared with macrophages, and enhanced binding of these factors to their respective IRF4 promoter elements was found in DCs. IRF4, together with PU.1, was also found to bind to the IRF/Ets response element in the IRF4 promoter, suggesting that IRF4 protein provides a positive feedback signal for its own gene expression in DCs. Our results suggest that IRF4 is likely to play an important role in myeloid DC differentiation and gene regulatory functions. In utero and lactational exposure to TCDD; Steroidogenic outcomes differ in male and female rat pups Myllymaki, S. A., T. E. Haavisto, L. J. S. Brokken, M. Viluksela, J. Toppari and J. Paranko. Toxicological Sciences. 2005; 88(2): 534-544. TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) has a potency to induce decreased fertility and structural reproductive anomalies in male and female mammals. While the activity profile of sex steroid hormone production distinctly differs in developing males and females, we wanted to analyze sex-specific effects of TCDD introduced in utero and via lactation on gonadal steroidogenesis and gonadotropin levels in male and female rat infant pups. One oral dose of TCDD (0, 0.04, 0.2, or 1.0 mu g/kg) was given to dams on gestational day (GD) 13. Plasma testosterone, estradiol, progesterone, follicle stimulating hormone (FSH), luteinizing hormone (LH), and gonadal mRNA levels for steroid acute regulatory protein (StAR), cytochrome P-450 cholesterol side-chain cleavage (P450scc), 3 beta-hydroxy-steroid-dehydrogenase/Delta(5)-Delta(4) isomerase type I (3 beta-HSD1), P-450 17 alpha-hydroxylase/17,20-lyase (P450-17 alpha), and cytochrome P-450 aromatase (P450arom) were determined on postnatal days (PND) 10-16. TCDD 1.0 mu g/kg reduced body weights but did not affect relative testis weight or alter testicular and ovarian histology. Plasma estradiol levels in dams and female pups were reduced on PND 14 and 16. Progesterone levels remained unaltered, and FSH levels were increased in female pups. In males, testosterone levels were elevated on PND 10. Gonadal mRNA levels for StAR and steroidogenic enzymes increased during the postnatal growth. TCDD caused no changes in relatively low testicular mRNA levels. However, significant reductions in StAR and P450arom mRNA levels were seen in PND 14 ovaries, and P450arom activity was decreased in isolated ovarian follicles. We conclude that developing testis and male gonadotropin secretion are resistant to TCDD-induced toxicity. In female pups, reduced estradiol, ovarian P450arom expression and enzyme activity levels, and elevated FSH levels may have a role in the development of ovarian dysfunction reported in TCDD-exposed females. Molecular identification of PAL-E, a widely used endothelial-cell marker Niemela, H., K. Elima, T. Henttinen, H. Irjala, M. Salmi and S. Jalkanen. Blood. 2005; 106(10): 3405-3409. The pathologische anatomie Leiden-endothelium (PAL-E) antibody has been used for almost 20 years as a specific marker for vascular endothelial cells. Due to the fact that this antibody works only in very limited applications, the molecular identity of PAL-E has remained unknown. In this work, we demonstrate by double stainings, cross-immunoprecipitations, and transfectants that the PAL-E antigen is identical with a protein designated PV-1 (plasmalemmal vesicle 1) or FELS (fenestrated endothelial-linked structure protein) and is not vimentin, as reported earlier. As the expression of this molecule is by no means restricted to fenestrated endothelium, we suggest the use of the name PLVAP for this protein. Molecular identification of PLVAP should help in the production of new tools for the identification of vascular as opposed to lymphatic endothelium and to elucidate the function of this protein. Economic evaluation of pneumococcal conjugate vaccination in Finland Salo, H., H. Sintonen, J. Pekka Nuorti, M. Linna, H. Nohynek, J. Verho and T. Kilpi. Scand J Infect Dis. 2005; 37(11): 821-832. The aim of this study was to evaluate cost-effectiveness of pneumococcal conjugate vaccine (PCV7) in children < 5 y of age. A Markov simulation model was used to compare the cost-effectiveness of 4 doses (assumed € 50.5 per dose) of PCV7 with no intervention. Only direct effects of the vaccine were taken into account. In Finland, vaccination of a birth cohort of 57,500 healthy infants would potentially prevent annually 60 cases of invasive PD, 1,400 cases of pneumococcal pneumonia, 15,000 episodes of acute otitis media, 3,000 otological surgery procedures and 0.9 deaths in children aged <5 y. Investing € 12.0 million to vaccinate a birth cohort would save annually € 6.3 million in medical, and € 2.0 million in productivity and other, costs. Therefore, investing € 1 in a vaccination programme would return € 0.53 in medical costs and € 0.70 in societal costs. In the base case, vaccination would cost society € 139,986 per life y gained. To achieve cost savings from a health care provider (societal) perspective, without considering herd effects or replacement phenomenon, the price of PCV7 should be 50% (70%) of the price used in the base case. Sing, A., D. Reithmeier-Rost, K. Granfors, J. Hill, A. Roggenkamp and J. Heesemann. Proceedings of the National Academy of Sciences of the United States of America. 2005; 102(44): 16049-16054. The virulence antigen LcrV of Yersinia enterocolitica 0:8 induces IL-10 in macrophages via Toll-like receptor 2 (TLR2). The TLR2-active region of LcrV is localized within its N-terminal amino acids (aa) 31-57. Sequencing of codons 25-92 of the lcrV gene from 59 strains of the three pathogenic Yersinia species revealed a hypervariable hotspot within as 40-61. According to these sequence differences, seven LcrV groups were identified, with Y. pestis and Y. pseudotuberculosis represented in group I and the other six distributed within Y. enterocolitica. By testing LcrV sequence-derived synthetic oligopeptides of all seven LcrV groups in CD14/TLR2-transfected human embryonic kidney 293 cells, we found the highest TLR2 activity with a peptide derived from group IV comprising exclusively Y. enterocolitica 0:8 strains. These findings were verified in murine peritoneal macrophages by using recombinant LcrV truncates representing as 1-130 from different Yersinia spp. By systematically replacing charged as residues by glutamine in synthetic oligopeptides, we show that the K42Q substitution leads to abrogation of TLR2 activity in both in vitro cell systems. This K42Q substitution was introduced in the lcrV gene from Y. enterocolitica 0:8 WA-C(pYV), resulting in WA-C(pYVLcrV(K42Q)), which turned out to be less virulent for C57BL/6 mice than the parental strain. This difference in virulence was not observed in TLR2(-/-) or IL-10(-/-) mice, proving that LcrV contributes to virulence by TLR2-mediated IL-10 induction. LcrV is a defined bacterial virulence factor shown to target the TLR system for evasion of the host's immune response. |