Increasing prevalence of coeliac disease over time

BACKGROUND: The number of coeliac disease diagnoses has increased in the recent past and according to screening studies, the total prevalence of the disorder is around 1%. AIM: To establish whether the increased number of coeliac disease cases reflects a true rise in disease frequency. METHODS: The total prevalence of coeliac disease was determined in two population-based samples representing the Finnish adult population in 1978-80 and 2000-01 and comprising 8000 and 8028 individuals, respectively. Both clinically-diagnosed coeliac disease patients and previously unrecognized cases identified by serum endomysial antibodies were taken into account. RESULTS: Only two (clinical prevalence of 0.03%) patients had been diagnosed on clinical grounds in 1978-80, in contrast to 32 (0.52%) in 2000-01. The prevalence of earlier unrecognized cases increased statistically significantly from 1.03% to 1.47% during the same period. This yields a total prevalence of coeliac disease of 1.05% in 1978-80 and 1.99% in 2000-01. CONCLUSIONS: The total prevalence of coeliac disease seems to have doubled in Finland during the last two decades, and the increase cannot be attributed to the better detection rate. The environmental factors responsible for the increasing prevalence of the disorder are issues for further studies.     

Functional significance and clinical phenotype of nontruncating mismatch repair variants of MLH1

BACKGROUND & AIMS: Germline mutations in mismatch repair genes are associated with hereditary nonpolyposis colorectal cancer. A significant proportion of mutations are nontruncating and associated with a variability of clinical phenotype and microsatellite instability and with occasional presence of residual protein in tumor tissue that suggests impaired functional activity but not total lack of mismatch repair. To address pathogenic significance and mechanism of pathogenicity, we studied the functionality of 31 nontruncating MLH1 mutations found in clinically characterized colorectal cancer families and 3 other variations listed in a mutation database. METHODS: Mutations constructed by site-directed mutagenesis were studied for protein expression/stability, subcellular localization, protein-protein interaction, and repair efficiency. The genetic and biochemical data were correlated with clinical data. Finally, comparative sequence analysis was performed to assess the value of sequence homology as a tool for predicting functional results. RESULTS: Altogether, 22 mutations were pathogenic in more than one assay, 2 variants were impaired in one assay, and 10 variants acted like wild-type protein. Twenty of 34 mutations affected the quantity of MLH1 protein, whereas only 15 mainly amino-terminal mutations were defective in an in vitro repair assay. Comparative sequence analysis correctly predicted functional studies for 82% of variants. CONCLUSIONS: Pathogenic nontruncating alterations in MLH1 may interfere with different biochemical mechanisms but generally more than one. The severe biochemical defects are mirrored by phenotypic characteristics such as early age at onset and high microsatellite instability, whereas variants with no or mild defects in functionality are associated with variable clinical phenotypes.     

Prognosis of unrecognized coeliac disease as regards mortality: A population-based cohort study

Background and aim. Clinically diagnosed coeliac disease patients carry an increased risk of mortality. As coeliac disease is markedly underdiagnosed, we aimed to quantify the risk of mortality in subjects with unrecognized and thus untreated coeliac disease.

Method. Blood samples from 6,987 Finnish adults were drawn in 1978–80, and sera were tested for immunoglobulin A (IgA)-class tissue transglutaminase antibodies (Eu-tTG) in 2001. Positive sera were further analysed for endomysial (EMA) and tissue transglutaminase antibodies by another test (Celikey tTG). EMA- and Celikey tTG-positive cases were compared to negatives as regards mortality in up to 28 years of surveillance, yielding a total follow-up of 147,646 person years. Dates and causes of death were extracted from the nation-wide database.

Results. Altogether 74 (1.1%) of the participants were EMA- and 204 (2.9%) Celikey tTG-positive. The age- and sex-adjusted relative risk of overall mortality was not increased in either EMA (0.78, 95% CI 0.52–1.18) or Celikey tTG (1.19, 95% CI 0.99–1.42) -positive subjects. However, antibody-positive cases evinced a tendency to die from lymphoma, stroke, and diseases of the respiratory system.

Conclusions. The prognosis of unrecognized coeliac disease was good as regards overall mortality, which does not support screening of asymptomatic coeliac disease cases.     

Shorter adult stature increases the impact of risk factors for cognitive impairment: a comparison of two Nordic twin cohorts

We analyzed the association between mean height and old age cognition in two Nordic twin cohorts with different childhood living conditions. The cognitive performance of 4720 twin individuals from Denmark (mean age 81.6 years, SD = 4.59) and Finland (mean age 74.4 years, SD = 5.26) was measured using validated cognitive screens. Taller height was associated with better cognitive performance in Finland (beta-estimates 0.18 SD/10cm, p value < .001, for men and 0.13 SD, p = .008, for women), but this association was not significant in Denmark (beta-estimates 0.0093 SD, p value = .16, for men and 0.0075 SD, p value = .016, for women) when adjusted for age and education/social class. Among Finnish participants higher variability of cognitive performance within shorter height quintiles was observed. Analysis using gene-environment interaction models showed that environmental factors exerted a greater impact on cognitive performance in shorter participants, whereas in taller participants' it was explained mainly by genetic factors. Our results suggest that shorter participants with childhood adversity are more vulnerable to environmental risk factors for cognitive impairment.     

Segregation of point mutation heteroplasmy in the control region of dog mtDNA studied systematically in deep generation pedigrees

Heteroplasmy, the presence of two or more variants in an organism, may render mitochondrial DNA (mtDNA)-based individual identification challenging in forensic analysis. However, the variation of heteroplasmic proportions and the segregation of heteroplasmic variants through generations and within families have not been systematically described at a large scale in animals such as the domestic dog. Therefore, we performed the largest study to date in domestic dogs and screened a 582-bp-long fragment of the mtDNA control region in 180 individuals in 58 pedigrees for signs of heteroplasmy. We identified three pedigrees (5.17%) with heteroplasmic point mutations. To follow the segregation of the point mutations, we then analyzed 131 samples from these three independent pedigrees and found significant differences in heteroplasmy between generations and among siblings. Frequently (10% of cases), the proportion of one base changed from 0–10% to 80–90% (as judged from Sanger electropherograms) between generations and varied to a similar extent among siblings. We included also a literature review of heteroplasmic and potential mutational hot spot positions in the studied region which showed that all heteroplasmic positions appear to be mutational hot spots. Thus, although heteroplasmy may be used to increase the significance of a match in forensic case work, it may also cause erroneous exclusion of related individuals because of sharp switches from one state to the other within a single generation or among siblings especially in the presented mutational hot spots.     

Childhood bullying as a predictor for becoming a teenage mother in Finland

The aim of this study is to examine the association between bullying behaviour at the age of 8 and becoming a mother under the age of 20. This birth cohort study included 2,867 Finnish girls at baseline in 1989. Register-based follow-up data on births was collected until the end of 2001. Information, both on the main exposure and outcome, was available for 2,507 girls. Both bullies and victims had an increased risk of becoming a teenage mother independent of family-related risk factors. When controlled for childhood psychopathology, however, the association remained significant for bullies (OR 2.2, 95% CI 1.2–4.1) and bully-victims (OR 1.8, 95% CI 1.05–3.2), but not for pure victims. Reports of bullying and victimisation from the girls themselves, their parents and their teachers were all associated with becoming a teenage mother independent of each other. There is a predictive association between being a bully in childhood and becoming a mother in adolescence. It may be useful to target bullies for teenage pregnancy prevention.     

The preattentive processing of major vs. minor chords in the human brain: An event-related potential study

Western music has two classifications that are highly familiar to all Western listeners: the dichotomy between the major and minor modalities and consonance vs. dissonance. We aimed at determining whether these classifications already take place at the level of the elicitation of the change-related mismatch negativity (MMN) component of the event-related potential (ERP). To this end, we constructed an oddball-paradigm with root minor, dissonant and inverted major chords in a context of root major chords. These stimuli were composed so that the standard and deviant chords did not include a physically deviant frequency which could cause the MMN. The standard chords were transposed into 12 different keys (=pitch levels) and delivered to the participants while they were watching a silent movie (ignore condition) or detecting softer target sounds (detection condition). In the ignore condition, the MMN was significant for all but inverted major chords. In the detection condition, the MMN was significant for dissonant chords and soft target chords. Our results indicate that the processes underlying MMN are able to make discriminations which are qualitative by nature. Whether the classifications between major and minor modalities and consonance vs. dissonance are innate or based on implicit learning remains a question for the future.