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Background: Germline mutations of the REarranged during Transfection (RET) proto-oncogene cause multiple endocrine neoplasia 2 (MEN2). It is unclear whether the distribution of RET mutations varies among populations. The first nationwide study of the distribution of RET mutations was conducted, and the results were compared to those of other populations.Methods: This retrospective cohort study included 1583 patients who underwent RET gene testing in one of three centers covering all of Denmark between September 1994 and December 2014. Primary testing method was Sanger sequencing, which included exons 8–11 and 13–16. Mutations were defined according to the ARUP database July 1, 2016.Results: RET mutations were identified in 163 patients from 36 apparently unrelated families. Among the 36 families 13 (36.1%) carried mutations in codon 611, four (11.1%) in codon 618, three (8.3%) in codon 620, one (2.8%) in codon 631, six (16.7%) in codon 634, one (2.8%) in codon 790, one (2.8%) in codon 804, one (2.8%) in codon 852, one (2.8%) in codon 883, and five (13.9%) in codon 918. Among the 13 families with codon 611 mutations, 12 had the p.C611Y mutation.Conclusions: The distribution of RET mutations in Denmark appears to differ from that of other populations. Mutations in codon 611 were the most prevalent, followed by more frequently reported mutations. This might be due to a possible founder effect for the p.C611Y mutation. However, further studies are needed to find possible explanations for the skewed mutational spectrum in Denmark.

SUMMARY In stereological studies analysis of sampling variances is used for optimizing the sampling design. In organs with a heterogeneous distribution of the phase of interest the analysis of sampling variances can be undertaken only if the observed variance between sections is distributed into the fraction which is due to random variation and the fraction which is due to the heterogeneity. In the present example (pancreatic islet volume estimated by light microscopic point‐counting) the density of islets showed a linear increase along the axis of the organ. By analysis of sampling variances it was calculated that the most efficient number of sections (cut perpendicular to the organ) was considerably lower when the isolated contribution from the random variation was considered. The total islet volume was obtained by the product of the fractional islet volume and the pancreatic weight. Analysis of sampling variances of the total islet volume was performed by including the variance contribution from the individual pancreatic weights to the variance of the group mean total islet volume. Due to a negative correlation between the fractional volume and organ weight the total islet volume in the group of animals was more precisely estimated than the fractional islet volume. The methods used for dealing with the heterogeneity of the organ and for estimating sampling variances of total structural quantities generalize to a large number of stereological studies in biology.

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Studies of the glomerular structure in diabetes mellitus have helped to elucidate the basis for some functional abnormalities. The decline in glomerular filtration occurring in many long-term diabetics is a functional disorder of great clinical importance. Quantitative structural studies of the glomeruli in diabetics at different stages of disease are necessary to learn about the development of structural changes leading to the end-stage kidney disease. Preliminary results of a study of glomeruli from long-term diabetics with clinical nephropathy are compared with those obtained in control subjects and in diabetics within the first 5 yr of disease. In the long-term diabetics the peripheral basement membrane thickness was doubled. On the average, mesangial regions occupied nearly 60% of the total tuft volume as compared with 33% in the early stages. A marked accumulation of basement membrane material in the mesengial regions had taken place so that 85% of the total basement membrane material of the tufts (i.e., peripheral basement membrane in the capillary walls plus mesangial basement membrane-like material) was localized within the mesangial regions. In the early stages equal amounts were found at these two different sites. The distribution of the lesions within the kidney is under investigation in a light microscopic study of autopsy material from long-term diabetics with varying degrees of glomerulopathy. The severity of the diabetic glomerulopathy was quantitated separately within the superficial and the deep cortical zones. The results showed that there was no tendency toward increased severity in the deep glomeruli.(ABSTRACT TRUNCATED AT 250 WORDS)