The interval of linkage disequilibrium (LD) detected with microsatellite and SNP markers in chromosomes of Finnish populations with different histories

Linkage disequilibrium (LD) has been an efficient tool for fine mapping of monogenic disease genes in population isolates. Its usefulness for identification of predisposing loci for common, polygenic diseases has been challenged on the basis of anticipated allelic and locus heterogeneity. We compared the extent of LD among marker loci in Finnish subpopulations with divergent but well-characterized histories. One study sample represents the early settlement Finnish population, descended from two immigration events 4,000 and 2,000 years ago. The second sample represents the geographically large late settlement region, populated 15 generations ago by several small immigrant groups from the early settlement region. The third is a restricted regional subpopulation in northeastern Finland which was founded 12 generations ago by 39 immigrant families from the late settlement region. We genotyped 243 microsatellite markers and 68 single nucleotide polymorphisms (SNPs) on chromosomes 1q and 5q. The genealogy of the families from the early (n=16) and late settlements (n=54) and the isolated settlement (n=54) was studied in detail back to the 1800s. Microsatellite data revealed greater LD in the young, founder subpopulation than was seen in either of the older populations. Observed linkage disequilibrium correlated not only with physical distance between markers but also with the information content of the markers. Using biallelic SNP markers, significant LD could only be detected up to 0.1 cM. Our results demonstrate the complexity of the concept of 'detectable LD' and emphasize the importance of understanding population history when designing a strategy for disease gene mapping.     

Reproductive factors and risk of meningioma and glioma

Female sex hormones have previously been suggested as possible risk factors for brain tumors, but published studies have reported conflicting results. We conducted a population-based case-control study of glioma (n=626) and meningioma (n=906) cases and randomly selected controls stratified on age and geographic region (n=1,774) in Denmark, Finland, Norway, Sweden, and the United Kingdom. Unconditional logistic regression was used to estimate odds ratios (OR) for glioma and meningioma in relation to reproductive factors. A decreased glioma risk was associated with ever-pregnancy compared with never-pregnancy [OR, 0.8; 95% confidence interval (95% CI), 0.6-1.0]. Meningioma risk among women ages <50 years was increased in relation to number of pregnancies leading to a live birth (OR, 1.8; 95% CI: 1.1-2.8 for giving birth to 3 children compared with nulliparous women; P(trend) among parous women=0.01). This relation was not found for older women. Breast-feeding among parous women increased the glioma risk (OR, 2.2; 95% CI, 1.3-3.9 for breast-feeding 36 months or more compared with breast-feeding 3 months or less). Menopausal status and age at menopause were not associated with meningioma or glioma risk. Our findings imply that reproductive hormones may influence the occurrence of meningioma and glioma.     

Herpes simplex virus and risk of cervical cancer: a longitudinal,nested case-control study in the nordic countries

Human papillomaviruses (HPVs) play the major role in cervical carcinogenesis. The authors reevaluated the role of herpes simplex virus type 2 (HSV-2) in this multistage process by conducting a longitudinal, nested case-control study using 1974-1993 data and comparing the results with those from a meta-analysis of studies. A Nordic cohort of 550,000 women was followed up for an average of 5 years, after which 178 cervical carcinoma cases and 527 controls were identified. HSV-2; HPV-16, HPV-18, and HPV-33; and Chlamydia trachomatis antibodies were determined at baseline by HSV-2 glycoprotein gG-2 and HPV virus-like-particle enzyme immunoassays and by using the microimmunofluorescence method. The relative risk of cervical carcinoma was calculated by conditional logistic regression. Longitudinal studies on HSV-2 and cervical neoplasia were identified through MEDLINE (National Library of Medicine, Bethesda, Maryland), and weighted mean relative risks were calculated. Smoking (relative risk = 1.6, 95% confidence interval (CI): 1.1, 2.3) and HPV-16/HPV-18/HPV-33 (relative risk = 2.9, 95% CI: 1.9, 4.3) were both associated with cervical carcinoma. The smoking- and HPV-16/HPV-18/HPV-33-adjusted relative risks for HSV-2 were 1.0 (95% CI: 0.6, 1.7) and 0.7 (95% CI: 0.3, 1.6), respectively, for HPV seropositives. In the meta-analysis, the relative risk for HSV-2 was 0.9 (95% CI: 0.6, 1.3). In both sets of data, HSV-2 did not play a role in cervical carcinogenesis.     

Mercury in saliva and the risk of exceeding limits for sewage in relation to exposure to amalgam fillings

The concentration of total mercury in stimulated saliva was studied in humans with dental amalgam fillings and in 2 nonamalgam groups. The probability of exceeding the limits of mercury permitted in wastewater increased proportionally as the number of amalgam-filled surfaces increased. The mercury limit for sewage is 0.05 mg/l (= 250 nmol/l) effluent, according to the Council of European Communities directive 84/156/EEC. In neither of the nonamalgam groups was this limit exceeded, but 20.5% in the amalgam group exceeded the limit (p < .001). The risk of exceeding the limit increased 2-fold for every 10 additional amalgam-filled surfaces (odds ratio = 2.0; 95% confidence interval = 1.3, 3.3). These results demonstrate that humans, especially in populated areas, can be a significant source of mercury pollutants. As a consequence of mercury release, bacteria may acquire mercury resistance, as well as resistance to other antimicrobial agents, thus resulting in failure of antibiotic treatment.     

Cerebral lateralization and cognitive deficits after congenital hemiparesis

The purpose of this study was to investigate whether and how handedness is related to the processes of cerebral lateralization and cognitive performance in children with congenital insult. Fifty-six children (31 males and 25 females) with congenital hemiparesis and 14 control subjects were investigated. Of these children, 32 had a left hemisphere lesion, and 24 children had a right hemisphere lesion. There were 30 right-handed, 23 left-handed, and three ambidextrous children in the study group. The neuropsychologic assessment was performed using the NEPSY (a developmental neuropsychological assessment of child development) test battery. We found that 41% of the hemiparetic children and 72% of the children with a left hemisphere lesion were left-handed. In children contralateral to lesion handedness (no evidence of interhemispheric transfer of functions), we found diffuse cognitive deficits with impaired language abilities and poor visuomotor and narrative memory processing. In contrast, children with ipsilateral to brain lesion handedness (interhemispheric transfer of functions) demonstrated minimal or moderate side-specific cognitive dysfunction. Right-handed children with a right hemisphere lesion had attention, spatial, and short-term memory problems; left-handed children with a left hemisphere lesion had receptive language and visuomotor difficulties. Handedness combined with neuropsychologic assessment is a reliable indicator of the processes of cerebral reorganization after early brain insult.     

Interaction modification among decomposers impairs ecosystem processes in lead-polluted soil

Environmental pollution by toxicants is generally believed to lead both to direct toxic effects and indirect effects via altered species interactions in a stressed community. We examined how contamination of a coniferous forest soil floor by lead (from an abandoned shooting range area) may alter trophic interactions and decomposition processes. We constructed laboratory microcosms containing microbial-based food webs with various trophic structures: microbes alone; microbes with microbivorous-detritivorous enchytraeid worms (Cognettia sphagnetorum, a potential keystone species of boreal forest soil); and microbes, worms, and predatory mites (Lysigamasus spp.) together. The direct toxic effect of lead and the effectiveness of the predators in preying upon the worms were studied in separate experiments. Polluted humic soil (acid-extractable lead concentration was 2,720 +/- 349 mg/kg of dry soil [mean +/- standard error]) was toxic to enchytraeids, and predators effectively reduced worm populations. Positive density-dependent effects of worms on microbes and a trophic cascade from predatory mites to microbes, observed in the unpolluted humus, were not observed in the polluted humus, indicating pollution-induced interaction modification among organisms. Concomitantly, lead pollution altered the process of nutrient mineralization in the humic soil. However, causality and relative importance of direct toxicity and indirect effects of lead on the dynamics of the decomposer food web could not be pointed out. Examination of our results indicates that traditional food web models are incapable of predicting mechanisms that alter dynamics of pollution-stressed belowground food webs.     

Concurrent LOH at multiple loci in human malignant mesothelioma with preferential loss of NF2 gene region

Human malignant mesothelioma (MM) is a highly aggressive neoplasm related to occupational asbestos exposure and characterised by a long latency period between the exposure and onset of disease. Previous studies indicate that losses at different genomic regions are present in MM. We examined allele loss at three known tumour suppressor gene regions (22q/NF2 gene, 9p/p16 gene, and 3p/FHIT gene) and at two other frequently deleted areas (14q and 6q) in MM. Loss of heterozygosity (LOH) was investigated in cell cultures and primary tumours with several highly polymorphic markers for each site. To study if LOH of the NF2 gene is a consistent feature in MM, we performed a more detailed analysis of chromosome 22q that included a NF2 marker (NF2CA3). We observed a high frequency of LOH occurring simultaneously at multiple loci. In particular, 100% of the cultured MM cells exhibited LOH at the NF2 gene region. From the other chromosomal sites analysed, recurrent allele loss was detected at 9p (5/7; 71%), 3p (4/7; 57%), 14q (3/7; 43%), and 6q (3/7; 43%). Of the 32 tumours, even those trimmed to exclude normal tissue, few showed LOH, suggesting consielment by normal cells within MM tumours, whereas tumour cells in primary cultures showed LOH already in passages 1-2. In conclusion, our present LOH data indicate that MM cells exhibit allele losses at multiple tumour suppressor gene sites concurrently, involving NF2 gene preferentially. This supports the view that the accumulation of multiple genetic hits is characteristic to malignant transformation of MM cells.     

Critical role for GALR1 galanin receptor in galanin regulation of neuroendocrine function and seizure activity

The GALR1 galanin receptor is expressed at high levels within the central nervous system. To determine which specific actions of galanin are mediated by GALR1, we have developed mice with an insertional inactivating mutation within the gene encoding GALR1 (Galr1). Homozygous Galr1-/- mice are viable and capable of breeding. They exhibit no significant difference in growth rate relative to Galr1+/+ controls but have reduced circulating levels of insulin-like growth factor-I (IGF-I) and exhibit spontaneous tonic-clonic seizures. The phenotype of these mice identifies a critical role for GALR1 in neuroendocrine regulation and in mediating the anti-seizure activity of galanin.     

Conducting case study research in occupational therapy

Background:  Case study research has been used increasingly in psychology and sociology in recent years. It provides researchers with an opportunity to explore a situation involving one individual or several individuals over time from multiple points of view.
Methods:  This literature review explains case study research as a method and summerises its scientific merit, also providing an example of its use.
Results:  Case study research offers occupational therapists a scientific methodology that can be used to understand and develop occupational therapy practice.
Conclusion:  This paper argues that case study research should be used more extensively by occupational therapists as the method respects the basic principles of occupational therapy.