| Uudet artikkelit 12.12.2005 - ISI
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Bäckström, P. and Hyytiä, P. Eur J Pharmacol. 2005. Glutamatergic neurotransmission has been suggested to modulate cue-induced drug-seeking behavior. Here we examined the effects of metabotropic glutamate receptor agonists on alcohol self-administration and cue-induced reinstatement. Rats were trained to self-administer 10% w/v ethanol under an FR1 schedule of reinforcement during 30-min sessions. In the reinstatement experiments, ethanol and a non-rewarding quinine solution (available on alternating days) were paired with olfactory stimuli (S(+)/S(-)) as well as light (CS(+)) or tone (CS(-)) stimuli. Following extinction training, reinstatement of responding was induced by the ethanol-associated stimuli (S(+)/CS(+)). The mGlu2/3 receptor agonist LY379268 (0, 1, 3 and 5 mg/kg i.p.) and the mGlu8 receptor agonist (S)-3,4-DCPG (0, 5, 10 and 15 mg/kg i.p.) attenuated alcohol self-administration and reinstatement at doses that decreased also spontaneous locomotor activity. The results suggest that metabotropic glutamate receptors may have a role in the modulation of alcohol seeking and self-administration. However, further studies with ligands with fewer motor-suppressant side effects are needed. Cardiovascular stress responses in late life are predicted by gestational age at birth Feldt, K., Raikkonen, K., Eriksson, J., Andersson, S., Osmond, C., Parker, D. J. P., Phillips, D. I. W. and Kajantie, E. Pediatric Research. 2005; 58(5): 1037-1037. Meeting Abstract Genetic component of noise sensitivity Heinonen-Guzejev, M., Vuorinen, H. S., Mussalo-Rauhamaa, H., Heikkila, K., Koskenvuo, M. and Kaprio, J. Twin Research and Human Genetics. 2005; 8(3): 245-249. We investigated the genetic component of noise sensitivity using a twin-study design. The study sample consisted of 573 same-sexed twin pairs from the Finnish Twin Cohort. The 131 monozygotic (MZ) and 442 dizygotic (DZ) twin pairs with an age range of 31 to 88 years replied to a questionnaire on noise and health-related items in 1988. The noise sensitivity of respondents was defined as high, quite high, quite low or low. MZ pairs were more similar with regards noise sensitivity than DZ pairs, and quantitative genetic modeling indicated significant familiality. The best z-fitting genetic model provided an estimate of heritability of 36% (95% CI = .20-.50) and when hearing impaired subjects were excluded this rose to 40% (95% CI = .24-.54). In conclusion, noise sensitivity does aggregate in families and probably has a genetic component. Hennah, W., Tuulio-Henriksson, A., Paunio, T., Ekelund, J., Varilo, T., Partonen, T., Cannon, T. D., Lonnqvist, J. and Peltonen, L. Molecular Psychiatry. 2005; 10(12): 1097-1103. We have previously reported evidence of linkage and association between markers on 1q42 and schizophrenia in a study sample of 498 multiply affected Finnish nuclear families, leading to the recent identification of four significantly associated haplotypes that specifically implicate the Translin- Associated Factor X ( TRAX) and Disrupted in Schizophrenia 1 and 2 ( DISC1 and DISC2) genes in the genetic etiology of schizophrenia. Previously, the DISC genes were found to be disrupted by a balanced translocation ( 1; 11)( q42.1; q14.3) that cosegregated with schizophrenia and related disorders in a large Scottish pedigree. Interestingly, we also reported earlier suggestive linkage between endophenotypic quantitative traits of visual and verbal memory and microsatellite markers in close proximity to TRAX/ DISC, on 1q41. Here, we tested if the identified allelic haplotypes of TRAX/ DISC would be associated with visual and/ or verbal memory function impairments that are known to aggregate with schizophrenia in families. One haplotype of DISC1, HEP3, displayed association with poorer performance on tests assessing short- term visual memory and attention. Analysis of affected and unaffected offspring separately revealed that both samples contribute to the observed association to visual working memory. These results provide genetic support to the view that the DISC1 gene contributes to sensitivity to schizophrenia and associated disturbances and affects short- term visual memory functions. This finding should stimulate studies aiming at the molecular characterization of how the specific alleles of DISC1 affect the visual memory functions and eventually participates in the development of schizophrenia. AUTOGSCAN: Powerful tools for automated genome-wide linkage and linkage disequilibrium analysis Hiekkalinna, T., Terwilliger, J. D., Sammalisto, S., Peltonen, L. and Perola, M. Twin Research and Human Genetics. 2005; 8(1): 16-21. Genome-wide linkage analysis using multiple traits and statistical software packages is a tedious process which requires a significant amount of manual file manipulation. Different linkage analysis programs require different input file formats, making the task of analyzing data with multiple methods even more time-consuming. We have developed a software tool, AUTOGSCAN, that automates file formatting, the running of statistical analyses, and the summarizing of resulting statistics for whole genome scans with a push of a button using several independent, and often idiosyncratic statistical software packages such as MERLIN, SOLAR and GENEHUNTER. We also describe a program, ANALYZE, designed to run qualitative linkage analysis with several different statistical strategies and programs to efficiently screen for linkage and linkage disequilibrium for a given discrete trait. The ANALYZE program can also be used by AUTOGSCAN in a genome-wide sense. Aberrant glucose tolerance in adults with birth weight below 1500g Hovi, P., Andersson, S., Eriksson, J. G., Jarvenpaa, A. L., Strang, S. and Kajantie, E. Pediatric Research. 2005; 58(5): 1065-1066. Meeting Abstract. Hu, G., Sarti, C., Jousilahti, P., Peltonen, M., Qiao, Q., Antikainen, R. and Tuomilehto, J. Stroke. 2005; 36(12): 2538-2543. Background and Purpose - Both hypertension and diabetes are strong predictors of stroke, but very few studies have assessed their joint effect on stroke risk. We evaluated prospectively the joint association of history of hypertension and type 2 diabetes on the incidence of stroke and stroke mortality. Methods - We prospectively followed 49 582 Finnish subjects aged
25 to 74 years without a history of stroke and coronary heart
disease at baseline. Hazards ratios (HRs) for stroke risk were
estimated by the hypertension and diabetes status. Results - During a mean follow-up of 19.1 years, 2978 incident stroke events were recorded, of which 924 were fatal. Age-, sex-, and study year-adjusted HRs of stroke incidence were 1.35 (95% CI, 1.21 to 1.51), 1.98 ( 95% CI, 1.79 to 2.19), 2.54 (95% CI, 1.61 to 4.01), 3.51 (95% CI, 2.40 to 5.14), and 4.50 (95% CI, 3.60 to 5.61), respectively, among subjects with hypertension I (blood pressure 140 to 159/90 to 94 mm Hg) only, with hypertension II (blood pressure >= 160/ 95 mm Hg, or using antihypertensive drugs) only, with diabetes only, with both hypertension I and diabetes, and with both hypertension II and diabetes compared with the subjects without either of the diseases. The corresponding HRs of stroke mortality were 1.47, 2.62, 3.06, 5.59, and 9.27, respectively. Additional adjustments for body mass index, cholesterol, education, smoking, alcohol consumption, and physical activity did not appreciably change these risk estimates. Blood pressure affected the risk of stroke similarly in diabetic and nondiabetic subjects. Conclusions - Hypertension and type 2 diabetes increase stroke risk independently, and their combination increases the risk drastically. A significant proportion of the risk of stroke assumed to be related to hypertension may be attributable to concomitant diabetes. Early life origins of spontaneous hypothyroldism in adult women Kajantie, E., Phillips, D. I. W., Osmond, C., Barker, D. J. P., Forsen, T. and Eriksson, J. G. Pediatric Research. 2005; 58(5): 1029-1029. Meeting Abstract. Longitudinal study of leisure physical activity in twins from age 16 to young adulthood Kaprio, J., Kujala, U., Viken, R. J. and Rose, R. J. Behavior Genetics. 2005; 35(6): 830-831. Meeting Abstract. Kerttula, A. M., Lyytikäinen, O., Vuopio-Varkila, J., Ibrahem, S., Agthe, N., Broas, M., Jagerroos, H. and Virolainen, A. J Clin Microbiol. 2005; 43(12): 6161-6163. Our point-prevalence survey followed an outbreak of methicillin-resistant Staphylococcus aureus (MRSA) in a long-term care facility and identified five MRSA strains, of which two possessed an outbreak genotype not encountered previously and three had another profile. All of them possessed SCCmec type V. Six methicillin-sensitive S. aureus strains were genotypically related to the epidemic strains. Small body size at birth in term infants predicts behavioural symptoms of ADHD in preschoolers Lahti, J., Raikkonen, K., Kajantie, E., Pesonen, A., Heinonen, K., Jarvenpaa, A. L. and Strandberg, T. Pediatric Research. 2005; 58(5): 1014-1014. Meeting Abstract. Laitinen, A., Koskinen, S., Harkanen, T., Reunanen, A., Laatikainen, L. and Aromaa, A. Ophthalmology. 2005; 112(12): 2227-37. PURPOSE: To estimate the prevalence rates of habitual visual acuity (VA) levels and visual impairment in Finland and to assess their correlation with self-reported visual function. DESIGN: Cross-sectional population-based study. PARTICIPANTS: Subjects were selected randomly from the Finnish population aged 30 years or older. Of 7979 eligible people, 7393 (93%) were interviewed, 6771 (85%) were examined, and 6663 (84%) had distance VA assessed. METHODS: Participants underwent a home interview and a comprehensive examination including measuring binocular VA for distance and for near with the participants' current spectacles, if any. MAIN OUTCOME MEASURES: The level of VA for distance and for near with current spectacle correction. The self-reported capability to read newsprint and television text and the ability to move about without being restricted by reduced vision. RESULTS: The prevalence of good to moderate VA for distance (VA> or =0.5 [> or =20/40]) measured with current spectacles was 95.9%, and 87.4% had a VA level of 0.8 (20/25) or better. The prevalence of habitual visual impairment (VA< or =0.25 [< or =20/80]) was 1.6%, and 0.5% were blind (VA<0.1 [<20/200]). The prevalence of visual impairment increased significantly with age (P<0.001), especially in the age group of 65 to 74 years and upward. There was no gender difference in VA for distance, but decreased near vision (VA< or =0.25 [< or =20/80]) was significantly more common in men than in women (P<0.01). By applying the imputated numbers of visually impaired and blind participants to the Finnish population (approximately 3 million aged 30 years or older), there were approximately 65000 (2.1%) visually impaired and 17000 (0.6%) blind adult persons in the country in 2000. The correlation between self-reported visual ability and measured visual function was moderate but statistically significant (r = 0.27-0.40; P<0.0001). The proportion of people with reading difficulties or who were unable to read newsprint has decreased 7% during the last 2 decades. CONCLUSIONS: Functional visual impairment increased with age especially in the age group of 65 to 74 years and upward and was as prevalent in women as in men. The prevalence of people with reading difficulties has decreased considerably since 1980. Fas costimulation of naive CD4 T cells is controlled by NF-{kappa}B signaling and caspase activity Maksimow, M., Soderstrom, T. S., Jalkanen, S., Eriksson, J. E. and Hanninen, A. J Leukoc Biol. 2005. Fas ligation induces apoptosis of activated T cells via the caspase cascade but can also mediate costimulatory signals to naive T cells at the time of activation. We have previously shown that Fas ligation of naive CD4 T cells activated by dendritic cells induces death or accelerates their proliferation and increases interferon-gamma (IFN-gamma) production. To understand this costimulation, we investigated the roles of caspases and nuclear factor (NF)-kappaB in survival and proliferation of responding T cells. Fas ligation increased caspase-3 and -8 activities during T cell activation, irrespective of cell fate. The accelerated proliferation induced by Fas ligation could be reduced by selective inhibition of both caspases. It is interesting that inhibition of NF-kappaB simultaneously with Fas ligation inhibited the increased IFN-gamma production and caused uniform death of all responding T cells. Thus, Fas-mediated costimulation of naive CD4 T cells is driven by active caspases, and NF-kappaB acts as a dominant survival-supporting factor of Fas-costimulated cells containing high levels of activated caspase-8 and -3. Mentula, S., Virtanen, T., Kanervo-Nordstrom, A., Harmoinen, J., Westermarck, E., Rautio, M., Huovinen, P. and Kononen, E. Int J Antimicrob Agents. 2005. The aim of this study was to investigate the effects of ampicillin treatment on selection and diversity of ampicillin-resistant intestinal Escherichia coli in beagles treated with ampicillin, ampicillin+beta-lactamase (targeted to degrade antibiotic residues in the gut) or placebo. Selected faecal (n=339) and jejunal (n=63) E. coli isolates with known resistance patterns were typed using pulsed-field gel electrophoresis (PFGE). Among the 25 detected PFGE types, ampicillin resistance was detected in 6, none of which was dominant over others among the dogs. The resistant types increased especially in the ampicillin group, whilst beta-lactamase inhibited their emergence. Selection of genetically unrelated resistant strains rather than emerging resistance among previously susceptible strains accounts for increasing resistance rates during ampicillin treatment. Paajanen, L., Korpela, R., Tuure, T., Honkanen, J., Jarvela, I., Ilonen, J., Knip, M., Vaarala, O. and Kokkonen, J. Am J Clin Nutr. 2005; 82(6): 1327-1335. BACKGROUND: Gastrointestinal hypersensitivity to cow milk (CM) may be more common among school-aged children and young adults than previously thought. OBJECTIVE: The objective was to study various gastrointestinal complaints and the immunologic mechanisms associated with food-related, especially CM-related, gastrointestinal disorders in young adults. DESIGN: Of 827 subjects aged 16-21 y who completed a questionnaire on food-related gastrointestinal symptoms, 49 symptomatic subjects agreed to a clinical examination, including an interview, blood tests, a lactose-maldigestion test, a blinded CM challenge and, in severely symptomatic subjects (n = 12), an endoscopic examination. Twenty-nine subjects served as controls. RESULTS: Approximately 10% of the subjects reported having major gastrointestinal symptoms, mainly food-related (n = 70 of 86), during the preceding year. Specific organic disease was found in 2 symptomatic subjects: 1 case of celiac disease and 1 of colitis. The result of the lactose-maldigestion test was positive in 16 of the remaining 47 symptomatic subjects, but only 4 carried the C/C(-13910) genotype for adult-type hypolactasia. The symptomatic subjects had restricted their consumption of certain foods, particularly CM. However, in a blinded challenge, CM-induced symptoms were rare. The symptomatic subjects had higher plasma soluble intercellular adhesion molecule 1 (P = 0.007) and lower granzyme A (P = 0.001) concentrations than did the control subjects. Duodenal biopsy samples tended to have higher intraepithelial CD3(+) cell counts (P = 0.065) and a higher expression of transforming growth factor beta (P = 0.073) and interleukin 12p35 messenger RNA (P = 0.075) than did the control subjects. CONCLUSIONS: In an unselected cohort of young adults, 8% reported food-related gastrointestinal symptoms. The finding of immunologic activity implied the existence of a food-related gastrointestinal syndrome but not one induced by CM. Pajala, S., Era, P., Koskenvuo, M., Kaprio, J., Alen, M., Tolvanen, A., Tiainen, K. and Rantanen, T. Journals of Gerontology Series a-Biological Sciences and Medical Sciences. 2005; 60(10): 1299-1303. Background. Among older people, distraction while walking may increase the risk of falls. Factors underlying individual differences in dual tasking are not fully understood. Our aim was to study the effect of a second task on maximal walking speed and to examine whether individual differences in walking speed measured with and without a second task are accounted for by genetic and environmental influences shared across tasks or specific to each task. Methods. The data were collected from the 101 monozygotic and 116 dizygotic twin pairs aged 63-76 years recruited from the Finnish Twin Cohort. Maximal walking speed (MWS) over 10 m was measured on a laboratory corridor and timed with photocells. The test was repeated while subjects performed, first, a manual task (MWSmanual) and, second, a verbal task (MWSverbal). Results. Mean walking speed without a simultaneous task was 1.72 m/s (standard deviation [SD] 0.33), with a manual task it was 1.52 m/s (SD 0.26), and with a verbal task it was 1.36 m/s (SD 0.27). Multivariate genetic analysis showed that an additive genetic factor in common accounted for 17% of individual differences in MWS, 19% in MWSmanual, and 12% in MWSverbal. In addition, MWSverbal had a genetic factor specific to it accounting for 10% of the variance. Shared environmental influences, common to all three traits, accounted for 39%, 27%, and 21% of the individual differences, respectively. Conclusion. Approximately half of the individual differences in walking with or without another task were accounted for by genetic and nongenetic familial effects in common, and the rest of the variation was accounted for by unique environmental factors in common and factors specific to walking tests. Penninkilampi-Kerola, V., Kaprio, J., Moilanen, I. and Rose, R. J. Twin Research and Human Genetics. 2005; 8(3): 232-244. The role of co-twin dependence (twins' closeness or reliance on the co-twin) was examined as a moderator of genetic and environmental influences on alcohol use in adolescence and early adulthood in a large longitudinal population-based study of Finnish twins (FinnTwin 16). The associations between co-twin dependence and alcohol use were studied first at an individual level in adolescence (n = 3362) and early adulthood (n = 2912). Then, maximum likelihood models were fit to the two waves of data from same-sex twin pairs to assess the differences and changes in genetic and environmental influences on alcohol use (abstinence, drinking frequency, intoxication frequency); N = 1342 pairs in adolescence, and N = 1078 pairs in early adulthood. Overall, no significant associations were found between co-twin dependence and individual alcohol use. However, co-twin dependence importantly modulated genetic effects on drinking habits, especially in adolescence, but also in early adulthood. Co-twin-dependent twins reported greater similarity in their alcohol-related behavior across all alcohol-use measures at both time points, and the role of genes and environments varied according to co-twin dependence. Shared environmental factors explained most of the variation in drinking among co-twin-dependent twins in adolescence and contributed to drinking to intoxication during early adulthood. In contrast, among co-twin-independent twin pairs, genetic variance contributed significantly to all alcohol-use measures at both time-points. An interdependent sibling relationship is an important modifier of drinking habits, and it appears to reduce the impact of inherited liabilities on alcohol-related behavior especially in adolescence. Raikkonen, K., Pesonen, A. K., Kajantie, F., Heinonen, K., Forsen, T., Phillips, D. I. W., Osmond, C., Barker, D. J. P. and Eriksson, J. G. Pediatric Research. 2005; 58(5): 1061-1061. Meeting Abstract. Roivainen, M., Alakulppi, N., Ylipaasto, P., Eskelinen, M., Paananen, A., Airaksinen, A. and Hovi, T. Journal of Virological Methods. 2005; 130(1-2): 108-116. Coxsackievirus A9 (CAV-9) infects human rhabdomyosarcoma (RD) cells using an unidentified RGD-independent receptor. Monoclonal antibodies were prepared by immunizing mice with intact RD cells and by selecting cells from the cytopathic effect of CAV-9 for protection, Here we describe a monoclonal antibody that binds to host cell plasma membrane and protects cells from virus infection. In addition, binding of the virus to cell monolayers was more efficient in the presence of the antibody, suggesting that the antibody is also capable of recognizing virus particles. Immunoprecipitation and electron microscopy studies with highly purified virus preparations verified binding of the monoclonal antibody to the virus particles. The antibody also recognized coxsackievirus A21 and all three serotypes of poliovirus, but without affecting their infectivity. The amino acid sequence of CAV-9 recognized by the monoclonal antibody was identified by peptide mapping and by producing escape mutants in the presence of the antibody. (c) 2005 Elsevier B.V. All rights reserved. Tuuma vai toimi? Alkoholihaittojen ehkäisyn mahdollisuudet terveyskeskuksessa. Seppä K, Aalto M. Kunnallislääkäri 2005; 20(4B): 33-36. Silander, K., Komulainen, K., Ellonen, P., Jussila, M., Alanne, M., Levander, M., Tainola, P., Kuulasmaa, K., Salomaa, V., Perola, M., Peltonen, L. and Saarela, J. Twin Research and Human Genetics. 2005; 8(4): 368-375. The amount of available DNA is often a limiting factor in pursuing genetic analyses of large-scale population cohorts. An association between higher DNA yield from blood and several phenotypes associated with inflammatory states has recently been demonstrated, suggesting that exclusion of samples with very low DNA yield may lead to biased results in statistical analyses. Whole genome amplification (WGA) could present a solution to the DNA concentration-dependent sample selection. The aim was to thoroughly assess WGA for samples with low DNA yield, using the multiply-primed rolling circle amplification method. Fifty-nine samples were selected with the lowest DNA yield (less than 7.5 mu g) among 799 samples obtained for one population cohort. The genotypes obtained from two replicate WGA samples and the original genomic DNA were compared by typing 24 single nucleotide polyrnorphisms (SNPs). Multiple genotype discrepancies were identified for 13 of the 59 samples. The largest portion of discrepancies was due to allele dropout in heterozygous genotypes in WGA samples. Pooling the WGA DNA replicates prior to genotyping markedly improved genotyping reproducibility for the samples, with only 7 discrepancies identified in 4 samples. The nature of discrepancies was mostly homozygote genotypes in the genomic DNA and heterozygote genotypes in the WGA sample, suggesting possible allele dropout in the genomic DNA sample due to very low amounts of DNA template. Thus, WGA is applicable for low DNA yield samples, especially if using pooled WGA samples. A higher rate of genotyping errors requires that increased attention be paid to genotyping quality control, and caution when interpreting results. Blood pressure in young adults with birth weight below 1500g Strang, S., Hovi, P., Andersson, S., Jarvenpaa, A. L., Eriksson, J. and Kajantie, E. Pediatric Research. 2005; 58(5): 1066-1067. Meeting Abstract. Analysis of four neuroligin genes as candidates for autism. Ylisaukko-oja, T., Rehnstrom, K., Auranen, M., Vanhala, R., Alen, R., Kempas, E., Ellonen, P., Turunen, J. A., Makkonen, I., Riikonen, R., von Wendt, T. N., von Wendt, L., Peltonen, L. and Jarvela, I. European Journal of Human Genetics. 2005; 13(12): 1285-1292. Neuroligins are cell-adhesion molecules located at the postsynaptic side of the synapse. Neuroligins interact with beta-neurexins and this interaction is involved in the formation of functional synapses. Mutations in two X-linked neuroligin genes, NLGN3 and NLGN4, have recently been implicated in pathogenesis of autism. The neuroligin gene family consists of five members (NLGN1 at 3q26, NLGN2 at 17p13, NLGN3 at Xq13, NLGN4 at Xp22, and NLGN4Y at Yq11), of which NLGN1 and NLGN3 are located within the best loci observed in our previous genome-wide scan for autism in the Finnish sample. Here, we report a detailed molecular genetic analysis of NLGN1, NLGN3, NLGN4, and NLNG4Y in the Finnish autism sample. Mutation analysis of 30 probands selected from families producing linkage evidence for Xq13 and/or 3q26 loci revealed several polymorphisms, but none of these seemed to be functional. Family-based association analysis in 100 families with autism spectrum disorders yielded only modest associations at NLGN1 (rs1488545, P = 0.002), NLGN3 (DXS7132, P = 0.014), and NLGN4 (DXS996, P = 0.031). We conclude that neuroligin mutations most probably represent rare causes of autism and that it is unlikely that the allelic variants in these genes would be major risk factors for autism. |