The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal dominant genes underlying these common neurodegenerative diseases. We have previously shown that a founder haplotype, covering the MOBKL2b, IFNK and C9ORF72 genes, is present in the majority of cases linked to this region. Here we show that there is a large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 on the affected haplotype. This repeat expansion segregates perfectly with disease in the Finnish population, underlying 46.0% of familial ALS and 21.1% of sporadic ALS in that population. Taken together with the D90A SOD1 mutation, 87% of familial ALS in Finland is now explained by a simple monogenic cause. The repeat expansion is also present in one third of familial ALS cases of outbred European descent making it the most common genetic cause of these fatal neurodegenerative diseases identified to date.

Increased release of oxidants has been implicated in the pathogenesis of pulmonary fibrosis. Previous work in the rat showed that formation of the early fibrotic lesion is associated with increased expression of inducible nitric oxide synthase (iNOS) in pulmonary fibroblasts. The aim of this study was to test the hypothesis that NO is involved in the activation of pulmonary fibroblasts. The effects of endogenous and exogenous NO on proliferation of human pulmonary fibroblasts were investigated by administration of cytomix or SNAP, respectively. At low concentrations, both treatments increased cell numbers, an effect attenuated by iNOS inhibitor or NO scavenger. Induction of iNOS was confirmed by measurement of nitrate/nitrite production and by immunodetection. Quantitative RT-PCR showed an increase in iNOS mRNA as early as 3 h after stimulation. These results support the hypothesis and show that upregulation of the iNOS gene is an early event in the proliferative response of human lung fibroblasts to inflammatory stimuli.

SUMMARY Debrisoquine and sparteine tests were carried out in 215 random white British subjects. There is a high degree of correlation between the urinary 'metabolic ratios' of the two drugs. New A polymorphism has also been described for the metabolism of sparteine, an alkaloid which has been used as an anti-arrhythmic and oxytocic drug. One phenotype with a frequency of 0-05 in the German population was unable to metabolise the compound. The other phenotype produced two substances thought to result from N-oxidation. The limited amount of pedigree information previously available suggested that 'non-metabolisers' might be autosomal recessives, homozygous for an allele with a frequency of 0-22.23 This paper presents information to show (1) the manner of inheritance of sparteine metabolism, (2) the relationship between the genetic control of 4-hydroxylation of debrisoquine and the metabolism of sparteine, and (3) the use of improved methods for the analysis of bimodal (and trimodal) frequency distributions. MethodsThe debrisoquine phenotyping test' and the analytical procedure5 were carried out as previously described.Received for publication 10 September 1982. Accepted for publication 19 February 1983. The sparteine phenotyping test2 was carried out as follows. Subjects who had fasted overnight ingested a 100 mg capsule of sparteine sulphate. They remained in the fasting state for a further 2 hours thereafter and were then allowed normal food and drink. The urine excreted 11 to 13 hours after drug ingestion was collected for analysis. The analytical procedure3 was carried out as described previously. The areas of the gas liquid chromatography peaks for sparteine, 2-dehydrosparteine, and 5-dehydrosparteine were measured. The 'metabolic ratio' was calculated as: area of sparteine peak sum of areas of peaks of 2-dehydrosparteine and 5-dehydrosparteine. POPULATION SURVEY OF UNRELATED WHITE BRITISH SUBJECTSA total of 215 healthy unrelated adult subjects (who had given informed consent) were tested with both compounds, with intervals of at least 4 days being allowed between the two tests.The families studied whose members were tested with the two drugs were obtained by two methods of ascertainment. (1) Some of the families published in a previous report1 were studied because they contained a debrisoquine 'poor metaboliser', found in the population survey of unrelated white British adult subjects. (2) Other families were investigated because they contained a proband who was found in the present population sample of unrelated British 321 on 11 May 2018 by guest. Protected by copyright.

Background: Low density arrays (LDAs) have recently been introduced as a novel approach to gene expression profiling. Based on real time quantitative RT-PCR (QRT-PCR), these arrays enable a more focused and sensitive approach to the study of gene expression than gene chips, while offering higher throughput than more established approaches to QRT-PCR. We have now evaluated LDAs as a means of determining the expression of multiple genes simultaneously in human tissues and cells.

SUMMARY Thirty-eight healthy white British Caucasian subjects were hydroxylator phenotyped with sparteine and acetylator phenotyped with sulphadimidine. The results showed that there was no significant difference in the mean sparteine metabolic ratio between eight rapid acetylator extensive hydroxylators and 27 slow acetylator extensive hydroxylators. ResultsThe acetylator phenotyping information is shown in