An exhaustive study of erythropoietic protoporphyria in the Netherlands led to the discovery of 200 patients with this disorder in 91 families. In 46 of these families a single patient occurred. A study of parents, sibs and children led to the conclusion that the disease of erythropoietic protoporphyria is inherited as an autosomal recessive disorder. The presence of an occasional fluorescent red blood cell combined with normal protoporphyrin levels was observed in half of the children and sibs of patients and one of their parents; this phenomenon is therefore inherited as an autosomal dominant character. From an analysis of the findings in the 91 families we put forward the hypothesis of a 3-allele system.

By isoelectric focusing of delipidated sera followed by immunoblotting we studied the apolipoprotein (apo) E polymorphism in 2018 randomly selected 35-years-old males from three different areas in the Netherlands. Comparison of the APOE allele (E*2, E*3, and E*4) frequencies estimated in this study with those reported for several other population samples showed that there are marked differences between the Dutch population and the populations of Japan, New Zealand, Finland, and the United States. These differences in APOE allele frequencies appeared to be mainly due to differences in frequencies of the E*2 allele (decreased in Japan and Finland; increased in New Zealand) and the E*4 allele (increased in Finland; decreased in Japan and the United States). No difference in APOE allele frequencies was found between the Dutch population and the populations of West Germany and Scotland. Measurements of plasma cholesterol and apo B and E concentrations showed that the E*4 allele is associated with elevated plasma cholesterol and apo B levels and with decreased apo E concentrations, whereas the opposite is true for the E*2 allele. In the Dutch population, the sum of average allelic effects of the common APOE alleles on plasma cholesterol and apo B levels is 6.8% and 14.2%, respectively, of the total population mean. The total average allelic effect on plasma apo E concentrations was more pronounced (50.1%), suggesting that the APOE alleles primarily affect apo E concentrations rather than plasma cholesterol and apo B levels. This hypothesis is sustained by the observation that for plasma apo E levels the genetic variance associated with the APOE gene locus contributed about 18% to the total phenotypic variance. For plasma cholesterol and apo B this contribution was only 1.4% and 2.3% and is relatively low as compared with that reported for other population samples.

A variant of apolipoprotein E, denoted apo E3-Leiden, has been identified in a 41-year-old male suffering from type III hyperlipoproteinemia with xanthomatosis. Apo E3-Leiden focus in the E3 position. In contrast with normal apo E3, apo E3-Leiden is defective in binding to the low density lipoprotein (LDL) receptor and does not contain cysteine as evaluated by cysteamine treatment of very low density lipoprotein followed by isoelectric focusing and conventional protein staining and by amino acid analysis. On sodium dodecyl sulfate polyacrylamide gel electrophoresis, apo E3-Leiden displays an electrophoretic mobility intermediate to that of normal apo E3 and apo E2 (Arg158----Cys). The mother and four siblings of the proband also have apo E3-Leiden and hyperlipoproteinemia type III; three of them with xanthomatosis. Two siblings do not show apo E3-Leiden in their VLDL fraction and do not have hyperlipoproteinemia type III. In the VLDL fractions of all affected family members only the presence of apo E3-Leiden could be detected after cysteamine treatment and isoelectric focusing followed by conventional protein staining. However, isoelectric focusing of cysteamine-treated sera followed by immunoblotting, using anti-apo E antiserum as first antiserum, demonstrates the presence of low amounts of normal apo E3 in addition to apo E3-Leiden in serum of the affected family members. These results indicate that all affected family members are heterozygotes E3/E3-Leiden and suggest that in this family type III hyperlipoproteinemia is transmitted as a dominant trait.

The molecular defect has been elucidated in the alpha-1-antitrypsin (PI) gene of a patient with a serum level of only 5 mg/100 ml and a PI M-like phenotype, designated PI MHeerlen. The restriction fragment patterns obtained by probes covering the whole gene and flanking sequences were normal, suggesting no major rearrangements. The nucleotide sequence of the exons, intron/exon junctions, and a part of the promoter region is similar to that of a PI M1(Ala213) gene except for an C----T mutation in codon 369, causing a Pro----Leu substitution. Haplotype analysis and oligonucleotide hybridization studies demonstrated the homozygous state of the mutation in the index case. It is most likely that the Pro369----Leu substitution is responsible for the low serum alpha-1-antitrypsin concentration of the patient because this mutation is solely confined to the PI MHeerlen allele and no other relevant mutations could be revealed. As proline is important for the secondary and tertiary structure of proteins, the mutation may cause an abnormal processing of the nascent polypeptide. The same mutation was observed in two unrelated subjects known to carry a PI allele giving a low serum alpha-1-antitrypsin level.

The last decade has seen the evaluation of health research pay more and more attention to societal use and benefits of research in addition to scientific quality, both in qualitative and quantitative ways. This paper elaborates primarily on a quantitative approach to assess societal output and use of research performed by health research groups (societal quality of research). For this reason, one of the Dutch university medical centres (i.e. the Leiden University Medical Center (LUMC)) was chosen as the subject of a pilot study, because of its mission to integrate top patient care with medical, biomedical and healthcare research and education. All research departments were used as units of evaluation within this university medical centre.The method consisted of a four-step process to reach a societal quality score per department, based on its (research) outreach to relevant societal stakeholders (the general public, healthcare professionals and the private sector). For each of these three types of stakeholders, indicators within four modes of communication were defined (knowledge production, knowledge exchange, knowledge use and earning capacity). These indicators were measured by a bottom-up approach in a qualitative way (i.e. all departments of the LUMC were asked to list all activities they would consider to be of societal relevance), after which they were converted into quantitative scores. These quantitative scores could then be compared to standardised scientific quality scores that are based on scientific publications and citations of peer-reviewed articles.Based on the LUMC pilot study, only a weak correlation was found between societal and scientific quality. This suggests that societal quality needs additional activities to be performed by health research groups and is not simply the consequence of high scientific quality. Therefore we conclude that scientific and societal evaluation should be considered to be synergistic in terms of learning for the future, accountability and advocacy.This quantitative approach to assess societal quality in a quantitative sense is based on indicators that function as proxies for society quality on different levels, based on the communication of researchers with their societal stakeholders (i.e. knowledge production, knowledge exchange and knowledge use). The methodology presented is just a first attempt to compare scientific quality scores (publication and citation scores) with societal quality scores in a quantitative way. This comparison can be used by organisations (e.g. university medical centres) in their planning and control cycle.