In this study we have established the frequencies of the DRB1-DQA1-DQB1 haplotypes in a large cohort of Sardinian new-borns and found that the most frequent haplotypes were detected at frequencies unique to the Sardinians. Other haplotypes, common in other Caucasian populations, are rare or absent across the island. Next, the DRB1-DQA1-DQB1 haplotype frequencies obtained in Sardinians and those reported in other human populations were used to compute genetic distances and construct phylogenetic trees. A clear-cut pattern appeared with a split between the three major human groups: Caucasians, Asians and Blacks. Among the Caucasians there were three major clusters: a group representing the North-Africans, a group including most of the European-derived populations and a group encompassing Bulgaria, Greece and Sardinia. When we increased the resolution of the tree using the genetic distances calculated from both DRB1-DQA1-DQB1 haplotypes and class I HLA A, B, C allelic frequencies, the Sardinians clearly emerged as the major outlier among the various European populations considered in this study. These results indicate that the genetic structure of the present Sardinian population is the result of a fixation of haplotypes, which are very rare elsewhere, and are most likely to have originated from a relatively large group of founders.

Coeliac disease (CD) is a malabsorptive disorder of the small intestine resulting from ingestion of gluten. The HLA risk factors involved in CD are well known but do not explain the whole genetic susceptibility. Several regions of potential linkage on chromosomes 3q, 5q, 10q, 11q, 15q and 19q have already been reported in the literature. These six regions were analyzed with the Maximum Lod Score method on a dense set of markers. A new sample of 89 Italian sibpairs was available for study. There was no evidence for linkage for any of the regions tested, except for chromosome 5q. For this region, our data, as well as a sample of 93 sibpairs from our first genome screen (Greco et al. 1998), are compatible with the presence of a risk factor for CD with a moderate effect. Coeliac disease (CD) is a permanent glutensensitive enteropathy characterized by malabsorption and mucosal injury of the small bowel. The existence of a genetic predisposition is clearly established. A strong predisposing factor lies in the HLA class II region. 80-95 % of

SUMMARY High doses of intravenous desferrioxamine infused over a short period of time induce a large faecal and urinary iron excretion but also produce retinal abnormalities that are characterised by decreased amplitude on electroretinography and defective dark adaptation. This regimen also results in high faecal iron, zinc, and copper excretion, and reduced granulocyte zinc concentrations and alkaline phosphatase activity. The retinal abnormalities may be related to the zinc and copper deficiency and/or iron depletion 'per se' which interferes negatively with critical iron dependent enzymes.Subcutaneous infusion of desferrioxamine is the most efficient method for reducing the iron burden in patients with thalassaemia major who are transfusion dependent. 1 The daily infusion of 40-60 mg/kg over 12 hours for six days a week is usually sufficient to obtain iron balance.'v Because some patients fail to comply with this regimen the additional administration of large doses by intravenous infusion has been proposed.3 High doses of desferrioxamine, either by intravenous or subcutaneous administration, however, may result in optic neuropathy or high frequency sensorineural hearing loss, or both.7 8 Likewise, in rabbits anaesthetised with urethane, the intravenous infusion of large doses of desferrioxamine produced a reversible reduction in the amplitude of the electroretinogram.9 Toxic concentrations are probably reached when the dose of desferrioxamine administered is disproportionately high in relation to the amount of iron available for chelation. In these conditions desferrioxamine may chelate critical trace elements such as copper and zinc,10 the depletion of these elements may be responsible for the neurotoxic effect of the drug.In this study we monitored the development of ocular abnormalities and possible zinc or copper depletion, or both, in a group of patients with thalassaemia major who were chelated with desferrioxamine by a combination of traditional daily subcutaneous infusion and monthly intravenous administration of large doses because of failure to comply with the regimen of subcutaneous administration. Patients and methodsFifteen children, aged from 9 to 16 years, with transfusion dependent thalassaemia major and moderate iron overload (serum ferritin concentrations from 1100 to 2000 [tg/l), because of low compliance with daily infusion of subcutaneous desferrioxamine, were treated by a combination of traditional daily subcutaneous infusion and monthly intravenous administration of very large doses according to a previously published scheme.11 Each patient was treated for 10 consecutive months but the balance study (see later) was carried out only once.The dose of desferrioxamine for subcutaneous infusion was 40-60 mg/kg over a period of 12 hours each night for six days a week. The intravenous infusion was given over a period of 24 hours at the dosage of 10-12 g (200-450 mg/kg) dissolved in 750 ml of 5% glucose solution. Urinary and faecal iron concentrations, zinc and copper excretion, serum zinc pat...

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