The influence of different environmental oxygen concentrations on vascularization was studied in the yolk sac blood vessel system of chick embryos. The eggs were incubated at normoxic (20.9% oxygen, n = 29), hypoxic (10% oxygen, n = 36) or hyperoxic (100% oxygen, n = 26) conditions and evaluated on day 4 of incubation. In vivo photographs were taken of the vascularized part of the yolk sac membrane (area vasculosa). Prints of a given enlargement were evaluated by histometrical methods to measure the extension of the area vasculosa, the density and the total area of blood vessels. Hypoxia induced an increase in vascular density, in area occupied by blood vessels (44.4%, normoxia = 40.6%) and an enlargement of the area vasculosa (441 ± 78.6 mm2, normoxia = 380 ± 68.7 mm2). Hyperoxia also induced an increase in vascular density and in the area occupied by blood vessels (45.9%), but a decline in the extension of the vascularized area (287 ± 48.8 mm2). Thus the total number of blood vesels as well as the total exchange surface decrease in hyperoxia. Our results indicate that in the area vasculosa of the early chick embryo hypoxia possibly causes an upregulation of vascular growth factors. From the present results it cannot be decided whether vasculogenesis or angiogenesis is stimulated.

In previous studies, it has been demonstrated that adverse reactions during aurothiomalate therapy for rheumatoid arthritis (RA) might have a genetic basis. Thus, Panayi et al (1) and Wooley et a1 (2) showed that patients who were positive for HLA-B8 and DR3 had a significantly increased risk of developing toxic kidney manifestations during sodium aurothiomalate or D-penicillamine therapy. These studies were confirmed (3) and extended by Bardin et a1 (4) who observed a correlation between gold salt intolerance and the HLA-A1 Cw7 B8 DR3 haplotype and a possible association between the renal side effects of D-penicillamine and the haplotype HLA-AI B8 DR3.Further possible correlations between gold salt induced adverse reactions and HLA antigens in two studies (5,6) suggest an association between HLA-DR3 and thrombocytopenia.In this study, we describe a characteristic dissociation of HLA correlations with mucocutaneous le- sions and nephropathy in RA patients being treated with sodium aurothiomalate. In addition, we confirm the previously published data on the association of nephropathy with the presence of the phenotypic combination HLA-A1 B8 DR3. PATIENTS AND METHODSPatients. Seventy-four patients with rheumatoid arthritis as defined by the criteria of the American Rheumatism Association (7) were retrospectively selected for the study. There were 61 women and 13 men with an age range from 29-75 years. All patients had received parenteral gold salt therapy with sodium aurothiomalate for various periods. Retrospectively, 16 patients manifested renal and 33 patients manifested mucocutaneous lesions, while both adverse reactions were observed in only 2 patients. Lichenoid, maculopapular, eczematous, or nonspecific skin reactions, and aphthous stomatitis were regarded as druginduced mucocutaneous adverse reactions which rapidly improved after the therapy was stopped. Twenty of the patients showed dermatitis solely, 6 of them had stomatitis, and 8 presented both types of mucocutaneous manifestations. Nephropathy was noted when persistent proteinuria was present, confirmed by a 24-hour urinalysis which showed a protein loss of more than 0.5 mg and normalized when drug treatment was abrogated. Twenty-five patients without toxic reactions, who had been treated for a minimum of 8 months with sodium aurothiomalate, served as controls. None of the patients with adverse reactions from gold therapy developed thrombocytopenia, toxic liver reactions, hyperthermia, or leukopenia.HLA typing. HLA typing was performed ac-

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