Regional differences in birth size: a comparison between the Helsinki Birth Cohort Study and contemporaneous births on the Åland Islands.

The Åland Islands were recently ranked as Finland's healthiest region with lower prevalence of several non-communicable diseases compared with the national mean. We have compared birth characteristics of 1697 individuals born on the Åland Islands between 1937 and 1944 with contemporaneous data from the Helsinki Birth Cohort Study (HBCS; n=11,808). This is a first step towards a potential future analysis of Ålandic health from a life-course perspective. Mean birth weight and length were calculated for both cohorts. Birth weight was entered into a multiple linear regression model with sex, maternal age, marital status and birth year as predictors. Mean birth weight in the Åland cohort was 3499 g, 87 g (95% CI 62; 111) higher compared with the HBCS. Sex and maternal marital status were the strongest predictors of birth weight. More detailed studies are needed to explore the potential effects of this difference in average birth weight between cohorts.

Regional, temporal, and seasonal variations in births and deaths: the effects of famines.

A knowledge of the seasonal variation in births and deaths during normal years is important for analyses of the effects of wars, famines, epidemics or similar privations on these two variables. In studies of seasonality, multiple trigonometric regression models are more flexible than the simple sine curve. The seasonal variation in mortality in Iceland, 1856-1990, shows a strong secular decrease, and a connection between this and the epidemiological transition is considered. As a consequence of the severe famine in Finland in 1867-68, the mortality for the whole year 1868 was almost four times as high as during normal years, and the seasonality of the mortality was even more accentuated. The birth rate in Finland during 1868 was about 70 percent of that during normal years and showed an aberrant seasonality, with a strong trough from October 1868 to February 1869 (fewer conceptions between January and May 1868, when the food shortage was severe).

Statistical analysis of the seasonal variation in demographic data.

There has been little agreement as to whether reproduction or similar demographic events occur seasonally and, especially, whether there is any universal seasonal pattern. One reason is that the seasonal pattern may vary in different populations and at different times. Another reason is that different statistical methods have been used. Every statistical model is based on certain assumed conditions and hence is designed to identify specific components of the seasonal pattern. Therefore, the statistical method applied should be chosen with due consideration. In this study we present, develop, and compare different statistical methods for the study of seasonal variation. Furthermore, we stress that the methods are applicable for the analysis of many kinds of demographic data. The first approaches in the literature were based on monthly frequencies, on the simple sine curve, and on the approximation that the months are of equal length. Later, "the population at risk" and the fact that the months have different lengths were considered. Under these later assumptions the targets of the statistical analyses are the rates. In this study we present and generalize the earlier models. Furthermore, we use trigonometric regression methods. The trigonometric regression model in its simplest form corresponds to the sine curve. We compare the regression methods with the earlier models and reanalyze some data. Our results show that models for rates eliminate the disturbing effects of the varying length of the months, including the effect of leap years, and of the seasonal pattern of the population at risk. Therefore, they give the purest analysis of the seasonal pattern of the demographic data in question, e.g., rates of general births, twin maternities, neural tube defects, and mortality. Our main finding is that the trigonometric regression methods are more flexible and easier to handle than the earlier methods, particularly when the data differ from the simple sine curve.

Seasonal variation of livebirths, stillbirths, extramarital births and twin maternities in Switzerland.

A study was made of the seasonal variation in all births, and births according to marital status, multiplicity and birth status (live and still) in Switzerland recorded between 1876 and 1990. To obtain seasonal variation in as pure as possible form, our analyses are based on rates. When comparing the seasonality in data sets showing markedly different levels, standardised indices were used. Assuming the length of pregnancies with twins to be about one month shorter than for pregnancies with singletons, lagged twinning rates were calculated but, in comparison with actual twinning rates, the general seasonal variation remained. Therefore, this study was based on actual twinning rates. A monotonic increase in the amplitude of the seasonal variation in general births was noted for the period 1876-1930, with strong seasonal variation holding for 1921-1980. After that, a marked decline in the amplitude can be observed. Seasonality of both all births and twin maternities showed very similar pattern for the periods 1876-1930 and 1969-1990, with maxima in the spring (March-May) and troughs in late autumn (October-December). Twin maternities showed a strong seasonality for the period 1876-1930, being about 20% higher in March than in October. The twinning rate in the period 1876-1930 was about 2.6 per thousand units higher than in the period 1969-90. For twin maternities there was also a stronger seasonal variation during the earlier period than during the later one. The pattern of the seasonal variation for extramarital births, showing a maximum in February (conceptions in May-June) and a minimum in August (conceptions in November-December) with a difference of no less than 24% was more marked than for the marital births. It seems likely that this seasonality of extra-marital maternities was due mainly to seasonal variation of coital rates and multiple ovulation in the early summer months coinciding with optima of light, temperature and food supply. A strong reduction in the rate of stillbirths (gestational age more than 29 weeks) was observed during the twentieth century. The stillbirth rate declined from about 40 per 1000 in the 1870s to fewer than 5 per 1000 in the 1980s. Irrespective of this strong decline in the stillbirth rate, the same seasonal rhythm was noticed throughout the period with high stillbirth rates among births around March and low rates during the summer and autumn.

Gene mapping in isolated populations: new roles for old friends?

Population isolates are increasingly being used in attempts to map genes underlying complex diseases. To further explore the utility of isolates for this purpose, we explore linkage disequilibrium patterns in polymorphisms from two regions (VWF and NF1) in three isolated populations from Finland. At the NF1 locus, the Finnish populations have greater pairwise disequilibrium than populations from Africa, Asia, or northern Europe. However, populations from 'New Finland' and 'Old Finland' do not differ in their disequilibrium levels at either the NF1 or the VWF locus. In addition, disequilibrium patterns and haplotype diversity do not differ between a sample from the Aland Islands, Finland, and a collection of outbred Centre d'Etude du Polymorphisme Humain families. These results show that linkage disequilibrium patterns sometimes differ among populations with different histories and founding dates, but some putative isolated populations may not significantly differ from larger admixed populations. We discuss factors that should be considered when using isolated populations in gene-mapping studies.

Statistical analysis of the seasonal variation in the twinning rate.

There have been few secular analyses of the seasonal variation in human twinning and the results are conflicting. One reason for this is that the seasonal pattern of twinning varies in different populations and at different periods. Another reason is that the statistical methods used are different. The changing pattern of seasonal variation in twinning rates and total maternities in Denmark was traced for three periods (1855-69, 1870-94, and 1937-84). Two alternative methods of analysis are considered. The method of Walter and Elwood and a trigonometric regression model give closely similar results. The seasonal distribution of twin maternities for the periods in the 19th century showed highly significant departures. For both twin and general maternities, the main peaks can be seen from March to June and a local peak in September. During the spring-summer season the twinning rates were higher than the total birth rates, indicating a stronger seasonal variation for the twin maternities than for the general maternities. For 1937-84, there was a similar, but less accentuated, pattern. Studies of other populations are compared with the Danish results. The more accentuated seasonal variation of twinning in the past indicate that some factors in the past affected women during summer-autumn and around Christmas time, making them more fecund and particularly to be more prone to polyovulation and/or more able to complete a gestation with multiple embryos.

Time-dependent changes to lipids and antioxidants in plasma and aortas of apolipoprotein E knockout mice.

Oxidation of lipoproteins is thought to be an early event in atherogenesis. To evaluate whether aortic lipoprotein lipid (per)oxidation contributes to atherosclerosis, we investigated the time-dependent changes to lipids and antioxidants in plasma and aortas of apolipoprotein E gene knockout (apoE-/-) mice receiving a high fat diet, and compared these changes with lesion development. Circulating buoyant lipoproteins and associated cholesterol (C), cholesteryl esters (CE), and alpha-tocopherol (alpha-TOH) increased within 1 month then remained largely constant up to 6 months. Coenzyme Q (CoQ) remained unchanged for the first 3 months and increased marginally after 6 months. With increasing duration of the diet, plasma lipids showed an increased propensity to undergo peroxyl radical-induced (per)oxidation. Absolute concentrations of aortic C, hydroperoxides and hydroxides of CE (CE-O(O)H) and alpha-TOH increased gradually while aortic CE increased more markedly with changes to cholesteryl linoleate being most pronounced. Aortic CoQ remained largely unchanged. Overall, the extent of aortic CE (per)oxidation remained low (

Inhibition by a coantioxidant of aortic lipoprotein lipid peroxidation and atherosclerosis in apolipoprotein E and low density lipoprotein receptor gene double knockout mice.

Antioxidants can inhibit atherosclerosis in animals, though it is not clear whether this is due to the inhibition of aortic lipoprotein lipid (per)oxidation. Coantioxidants inhibit radical-induced, tocopherol-mediated peroxidation of lipids in lipoproteins through elimination of tocopheroxyl radical. Here we tested the effect of the bisphenolic probucol metabolite and coantioxidant H 212/43 on atherogenesis in apolipoprotein E and low density lipoprotein (LDL) receptor gene double knockout (apoE-/-;LDLr-/-) mice, and how this related to aortic lipid (per)oxidation measured by specific HPLC analyses. Dietary supplementation with H 212/43 resulted in circulating drug levels of approximately 200 microM, increased plasma total cholesterol slightly and decreased plasma and aortic alpha-tocopherol significantly relative to age-matched control mice. Treatment with H 212/43 increased the antioxidant capacity of plasma, as indicated by prolonged inhibition of peroxyl radical-induced, ex vivo lipid peroxidation. Aortic tissue from control apoE-/-;LDLr-/- mice contained lipid hydro(pero)xides and substantial atherosclerotic lesions, both of which were decreased strongly by supplementation of the animals with H 212/43. The results show that a coantioxidant effectively inhibits in vivo lipid peroxidation and atherosclerosis in apoE-/-;LDLr-/- mice, consistent with though not proving a causal relationship between aortic lipoprotein lipid oxidation and atherosclerosis in this model of the disease.

Autosomal recessive cornea plana. A clinical and genetic study of 78 cases in Finland.

PURPOSE: To review the literature of autosomal recessive cornea plana (RCP) and to perform a clinical and genetic study on this disorder in Finland. The 78 Finnish RCP patients represent the majority of RCP cases worldwide; outside Finland only 35 cases have been reported. METHODS: Families with RCP, particularly in northern Finland, have been followed up by the senior author since the 1950s and extensive genealogical studies have been made. RESULTS: The most typical symptoms are greatly reduced corneal refraction, 25-35 dioptres, causing strong hyperopia, slight microcornea, an extended limbus zone, a central, deep corneal opacity and a marked arcus senilis, seen even before the age of 20. We present a pedigree comprising 33 affected persons with cornea plana. We have mapped the two genes for the dominantly and the recessively inherited type of cornea plana to the same region on the long arm of chromosome 12, (12q21). CONCLUSIONS: In northern Finland RCP has a higher frequency than elsewhere, probably as a result of a strong founder effect in the population that arrived in these regions approx. 400 years ago. The strong accumulation of this rare disease in these isolated areas and the strong genealogical connections between different families with RCP, suggest that probably all the Finnish RCP cases are caused by the same mutation.

High rate of twins among offspring of mothers with the Järvi-Hakola-Nasu disease and with comments on disorders associated with twinning.

Finnish mothers with Jrvi-Hakola-Nasu disease, progressive dementia with lipomembranous polycystic osteodysplasia (McKusick 221770) have a high rate of twin maternities, 128.2/1000. The exact 99% confidence intervals are 28.7-322.2/1000, thus above the average twinning rate in Finland, i.e. 15/1000. This eightfold increase in twinning may be an indication of a disturbed cortico-hypothalmic-hypophyseal axis or an other premorbid hormonal imbalance. It is concluded that even if dizygotic twinning is as a rule an event in itself, not only iatrogenic factors, as ovulation inducers, etc., but also some genetic disorders may be associated with twinning. More studies are needed to elucidate the incidence of twinning in families with these disorders.

Autosomal recessive Sorsby fundus dystrophy revisited: molecular evidence for dominant inheritance.

Sorsby fundus dystrophy (SFD) originally was characterized as an autosomal dominant disorder in which patients lose central vision during the 4th or 5th decade of life. Since Sorsby's initial description, interfamilial phenotypic variations have been noted and have given rise to controversy as to whether SFD constitutes more than one nosologic entity. In addition, several reports have proposed the existence of a recessively inherited form of SFD. The recent identification of the tissue inhibitor of metalloproteinases-3 (TIMP3) as the disease-causing gene in SFD has made it possible to address the questions of clinical and genetic heterogeneity. In this study, we reinvestigated a large, highly consanguineous Finnish family previously diagnosed as having early-onset autosomal recessive SFD. We identified a novel heterozygous Gly166Cys mutation in TIMP3 in all affected individuals and provide strong evidence for an autosomal dominant inheritance of the SFD phenotype in this family. Our results, in conjunction with a critical review of the reported cases, render the existence of a recessive mode of inheritance in SFD questionable. Considering all available data, we suggest that SFD is a genetically homogeneous, autosomal dominant condition.

Linkage disequilibrium patterns vary with chromosomal location: a case study from the von Willebrand factor region.

Linkage disequilibrium analysis has been used as a tool for analyzing marker order and locating disease genes. Under appropriate circumstances, disequilibrium patterns reflect recombination events that have occurred throughout a population's history. As a result, disequilibrium mapping may be useful in genomic regions of < 1 cM where the number of informative meioses needed to detect recombinant individuals within pedigrees is exceptionally high. Its utility for refining target areas for candidate disease genes before initiating chromosomal walks and cloning experiments will be enhanced as the relationship between linkage disequilibrium and physical distance is better understood. To address this issue, we have characterized linkage disequilibrium in a 144-kb region of the von Willebrand factor gene on chromosome 12. Sixty CEPH and 12 von Willebrand disease families were genotyped for five PCR-based markers, which include two microsatellite repeats and three single-base-pair substitutions. Linkage disequilibrium and physical distance between polymorphisms are highly correlated (rm = -.76; P < .05) within this region. None of the five markers showed significant disequilibrium with the von Willebrand disease phenotype. The linkage disequilibrium/physical distance relationship was also analyzed as a function of chromosomal location for this and eight previously characterized regions. This analysis revealed a general trend in which linkage disequilibrium dissipates more rapidly with physical distance in telomeric regions than in centromeric regions. This trend is consistent with higher recombination rates near telomeres.

Temporal trends in migration in the Aland Islands: effects of population size and geographic distance.

Using a model developed by Relethford (1992), we assess temporal trends (1750-1949) in marital migration in the Aland Islands, Finland, in relation to both geographic distance and population size. The 200-year time period was divided into four 50-year periods. For all time periods both geographic distance and population size are important determinants of migration among 15 Lutheran parishes. The geographic distance parameter of the model decreases significantly over time, and the population size parameter fluctuates slightly but shows no significant change over time. For all time periods migration is negative density dependent, indicating that there is greater relative flow from larger to smaller subdivisions. Even though both the geographic distance and population size parameters are statistically significant, the analysis suggests that geographic distance has a greater relative effect on migration than population size. There is a clear indication of isolate breakdown during the last two time periods (1850-1899 and 1900-1949). Residual analysis indicated that the smallest parish (Sottunga) was a major outlier that showed greater exogamy (less endemicity) than expected from the model.

Negative-configuration electroretinogram in Oregon eye disease. Consistent phenotype in Xp21 deletion syndrome.

OBJECTIVE: To determine whether abnormal configurations on electroretinogram were a consistent finding in patients with Xp21 deletion and to characterize the associated ophthalmologic phenotype. DESIGN: Case series. SETTING: University hospitals and eye institutes. PATIENTS: Five patients with complex glycerol kinase deficiency (Duchenne-type or Becker's muscular dystrophy, glycerol kinase deficiency, and congenital adrenal hypoplasia) and demonstrated chromosomal deletions at Xp21. Control patients were matched by age. MAIN OUTCOME MEASURES: Clinical information was obtained from medical records. Complete ophthalmologic examinations were performed. Electroretinography was performed using a Ganzfeld technique and chloral hydrate sedation. RESULTS: We report the clinical features and abnormal configurations on electroretinograms of five patients with complex glycerol kinase deficiency, including follow-up studies on a previously described patient. The original patient had ocular hypopigmentation; four, strabismus; two, myopia; three, astigmatism; and one, symptomatic night blindness. All had negative configurations on scotopic electroretinograms showing a reduced-amplitude B wave in the dark-adapted state. CONCLUSIONS: Our original report suggested a diagnosis of Aland Island eye disease, which appears to be an incomplete form of congenital stationary night blindness. Linkage data place Aland Island eye disease and congenital stationary night blindness at Xp11, whereas our patients had deletions at Xp21. The phenotype reported here may represent the effects of a single gene defect or the compound effects of the Xp21 contiguous gene syndrome (complex glycerol kinase deficiency). The phenotype is referred to as Oregon eye disease.

Population relationships of Lapps as reflected by quantitative dermatoglyphics.

Relationships and divergence among five Lapp samples were assessed using finger and palm interdigital ridge counts. Lapp relationships to other Uralic speakers were also assessed. Multivariate minimum FST values expressing differentiation among Lapps are 0.012. These values are higher than those for most European populations and show the importance of isolation and genetic drift in Lapp populations. Skolt Lapps and Lapps of the Kola Peninsula are generally more similar to each other and are differentiated from Mountain and Fisher Lapps. When Lapps are placed within the context of Uralic speakers in general, they show a marked affinity for the Finnic speakers and are differentiated from the Samoyedic speakers of Siberia. The ridge counts support the hypothesis of a European origin for the Lapps.

Epidemiological and birth weight characteristics of triplets: a study from the Dutch twin register.

From 112 triplet sets, born in The Netherlands from the end of 1986 to the beginning of 1991 and registered in the Dutch Twin Register, several details such as birth weight, gestational age, zygosity, and etiology were assessed by questionnaire, which was filled out by the mother. For 33 triplet sets, zygosity was also assessed by blood typing. Maternal smoking during pregnancy was also noted. Results show a very strong increase in number of triplets caused by artificial fertility enhancing techniques and consequently a shift in the relative contribution of zygosity types to the total number of triplets. Birth weight is predominantly influenced by gestational age. Other effects on birth weight are controlled for possible confounding with gestational age. First born triplets weigh more than later born triplets; boys weigh more than girls; nearly 25% of all individual triplets weigh less than 1500 g, i.e. belong to the category very low birth weight (VLBW); regular maternal smoking produces a 14% birth weight reduction; ovulation induction seems to decrease the sex ratio, i.e. hormonal treatment with ovulation inducing substances increases the probability of female offspring.

Biometric analysis of the multiple maternities in Finland, 1881-1990, and in Sweden since 1751.

Hellin's law states that if the twinning rate is w, then the triplet rate is w2, the quadruplet rate is w3, and so forth. The opinion of today is that Hellin's law holds only approximately. In this study the inaccuracy of Hellin's law is studied and the discrepancies are explained mathematically. In our earlier studies we built linear models for the twinning rate. Because most of the mothers are younger than 40 years of age and because in this age interval the twinning rate depends linearly on age, linear regression methods have been applied. Hellin's law suggests using the square-root transformation of the triplet rate r. Statistical arguments speak in favor of using the arcsin square root of r transformation. We discuss both transformations. Despite the fact that Hellin's law is only approximate, the arcsin transformation proves valuable. The transformed triplet rate can be modeled in a way similar to the twinning rate. We consider secular data from Finland for 1881-1990 and from Sweden since 1751. Using Hellin's law, we compare the triplet rates and the twinning rates and study the time trends of the observed twinning and triplet rates. The data are standardized. Our theoretical results are applied to multiple maternity data for Finland. Using maternal age as the regressor, we build a linear model for the twinning rate and for the arcsin-transformed triplet rate. This analysis shows a decreasing linear time trend in the triplet series for the period 1881-1950 but not in the twinning series. The triplet rate has an increasing trend after 1960, which seems to be mainly caused by artificial induction of ovulation.

Gastric chief cell-specific transcription of the pepsinogen A gene.

The molecular mechanisms underlying the regulation of pepsinogen A (PGA) gene expression in mammalian cells are poorly understood. In this paper we describe the structural and functional analysis of the pepsinogen A gene promoter in the pig. By genomic Southern analyses we demonstrate that, in contrast with human PGA genes which are amplified and organized in haplotypes, only a single PGA gene is present per haploid porcine genome. With the aim of identifying promoter elements mediating the gastric mucosa cell-specific transcription of the PGA gene in pig, we isolated a PGA gene from a porcine genomic library. The nucleotide sequence of the first exon and 1.7 kb of the upstream DNA region were determined and compared with the corresponding regions of the human PGA gene encoding isozymogen Pg5. In order to study the promoter activity of the PGA gene a functional assay was developed: we succeeded in obtaining primary monolayer cultures of porcine gastric mucosal chief cells, suitable for transfection. Fragments of 5'-flanking and noncoding first exon sequences of the porcine and human PGA genes were linked to the chloramphenicol acetyltransferase (CAT) gene. The transcriptional activity of these hybrid genes was assessed in transient expression assays upon transfection (lipofection) of gastric and nongastric cells. Whereas PGA 5'-flanking sequences showed no promoter activity in nongastric cell types, the DNA region from -205 to +21 was found to be sufficient to direct expression of the porcine PGA constructs in a cell-specific manner. Further deletion analysis of the proximal promoter fragment identified several regions (-205 to -167, -127 to -67 and +2 to +21) acting synergistically in the transcriptional regulation of the PGA gene. In contrast, all human PGA-CAT constructs used failed to show promoter activity in porcine gastric chief cells, indicating species-specific control of PGA gene expression. In addition, the transcriptional activity of the porcine PGA promoter in chief cells from pig was completely abolished by in vitro CpG methylation. Footprint analyses of the proximal promoter fragment using nuclear extracts from either porcine gastric mucosal chief cells or liver revealed some notable differences between both extracts, which might reflect the interaction with (a) cell-specific factor(s).