Radioiodine treatment is a significant risk factor for development of TAO in Graves' hyperthyroidism. Smokers run the highest risk for worsening or development of TAO irrespective of treatment modality.

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Tumor necrosis factor (TNF) is a pleiotropic mediator of inflammatory responses. A cysteine-rich, highly glycosylated 30-kD TNF-binding protein (TNF-BP) purified from urine may have a role in regulation because it protects in vitro against the biological effects of TNF. The cytotoxic effect of TNF on the fibrosarcoma cell line WEHI 164 was inhibited by-50% at a 10-fold excess of TNF-BP. The binding of TNF to the receptor was partially reversed after the addition of TNF-BP. Results from biosynthetic labeling of cells with 35S-cysteine followed by immunoprecipitation with anti-TNF-BP indicated that TNF-BP is formed and released at the cell surface by cleavage because no corresponding cellular polypeptide was observed. A cellular 60-kD polypeptide, which was immunoprecipitated with anti-TNF-BP, may correspond to the transmembrane TNF-receptor molecule and be the precursor of TNF-BP. Thus, TNF-BP appears to be a soluble form of a transmembrane TNF-receptor. Moreover our results demonstrate that the production of TNF-BP is increased when the TNF receptor is downregulated in cells by treatment with TNF or by activation of protein kinase C with phorbol esters. TNF-BP may be an important agent that blocks harmful effects of TNF, and, therefore, useful in clinical applications. (J. Clin.

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Graves' disease (GD) is an autoimmune condition with elevated thyroid hormone levels and symptoms suggesting an affected brain. These symptoms often resolve with treatment but, for some patients, GD results in a long period of reduced wellbeing. The overall aim of this thesis is to characterize the consequences of GD with a special focus on the brain. Three studies were conducted with data from questionnaires and clinical assessments of patients with GD in both the hyperthyroid and the euthyroid phase. Paper I was a longitudinal cohort study that assessed long-term treatment results 6 10 years after the onset of GD. Among 1186 included patients, the 774 who were initially treated with antithyroid drugs had a 40% chance of being euthyroid without thyroid medication at follow-up. One in four patients did not feel fully recovered. Paper II was a longitudinal case-control study designed to characterize affective and cognitive symptoms in 65 premenopausal women with newly diagnosed untreated GD. At onset of GD, the patients were significantly more affected with depression, anxiety, and mental fatigue compared to controls. At follow-up after 15 months, these symptoms remained in a significant proportion of patients. Patients with eye symptoms or a history of psychiatric conditions were more likely to be affected with brain-related symptoms. Paper III was a longitudinal case-control study of 65 premenopausal women with newly diagnosed untreated GD designed to investigate the effect of GD on hippocampal volumes. At onset of GD, hippocampus and amygdala volumes of the patients were smaller compared to controls. These brain structures became larger with treatment and, after 15 months, only the left amygdala remained smaller than in controls. At inclusion, there was an inverse correlation between thyroid-stimulating hormone receptor antibody (TRAb) and the volumes of both amygdalae and the right hippocampus. There were also inverse correlations between TRAb and free triiodothyronine recovery and the recovery of most of the four assessed brain volumes. GD is a condition where a minority of patients can hope for a long-lasting restored thyroid function. A large proportion of GD patients do not feel recovered after 8 years. Mental fatigue is an important concept for understanding the brain-derived symptoms in GD. In summary, the studies demonstrate that Graves' hyperthyroidism has unexpected long-term consequences for many patients, provide extensive new data on the serious and chronic nature of GD, and show for the first time that GD is accompanied by reversible brain changes.

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Tumor necrosis factor (TNF), a protein released by activated macrophages, is a central mediator of the host response to infection and inflammation. The TNF-binding protein I (TNF-BP-I) is a soluble fragment of the p60 transmembrane TNF receptor and an antagonist to TNF. The level of serum TNF-BP-I was found to be increased in patients with renal insufficiency as a result of a decrease in the glomerular filtration rate. During hemodialysis of patients with renal failure there was a rapid but transient increase in serum TNF-BP-I. This increase was found to be caused by heparin given before dialysis and a similar dose-dependent response to heparin was observed also in healthy individuals. The finding of a repeated release of TNF-BP-I into the circulation with intermittent injections of heparin indicates that TNF-BP-I is present both in a storage pool and in a circulating pool. The mechanism for the heparinmediated release of TNF-BP-I was not explained; TNF-BP did not show affinity for heparin. On the other hand, TNF was found to have affinity for heparin and it could also be dissociated from heparin by TNF-BP-I. It is suggested that heparinlike molecules of the extracellular matrix can retain TNF in physical proximity with target cells and restrict the actions of TNF and protect against systemic harmful manifestations. (J.