Lessons from mouse models of Graves' disease.

Graves' disease (GD) is an autoimmune condition with the appearance of anti-TSH receptor (TSHR) autoantibodies in the serum. The consequence is the development of hyperthyroidism in most of the patients. In addition, in the most severe cases, patients can develop orbitopathy (GO), achropachy and dermopathy. The central role of the TSHR for the disease pathology has been well accepted. Therefore immunization against the TSHR is pivotal for the creation of in vivo models for the disease. However, TSHR is well preserved among the species and therefore the immune system is highly tolerant. Many differing attempts have been performed to break tolerance and to create a proper animal model in the last decades. The most successful have been achieved by introducing the human TSHR extracellular domain into the body, either by injection of plasmid or adenoviruses. Currently available models develop the whole spectrum of Graves' disease-autoimmune thyroid disease and orbitopathy and are suitable to study disease pathogenesis and to perform treatment studies. In recent publications new immunomodulatory therapies have been assessed and also diseaseprevention by inducing tolerance using small cyclic peptides from the antigenic region of the extracellular subunit of the TSHR.

In-vitro stimulation of the rat epitrochlearis muscle. I. Contractile activity per se affects myofibrillar protein degradation and amino acid metabolism.

The influence of contractile activity on protein degradation and amino acid metabolism in skeletal muscle was investigated by utilizing an in-vitro electrical stimulation model with the rat epitrochlearis muscle preparation. Graded decreases in contraction force and in the muscle content of ATP and PCr, and increases in lactate were recorded with different rates of stimulation (1 h) and with both isometric twitches and tetanic contractions. 3-Methylhistidine and phenylalanine were chosen as indicators of myofibrillar and total protein degradation, respectively. The release of 3-methylhistidine was significantly stimulated by contractile activity, but a significant increase in the total amount of this amino acid (released amount + tissue content) occurred only at the most intense contraction rates. The release rate, tissue content and total amount of phenylalanine were not influenced by the contractions. Glutamate formation was generally inhibited, but its release was increased. Alanine synthesis was increased in moderately and intensely stimulated muscles. Glutamine and glycine were not influenced by the contractions, however. Inhibition of protein synthesis did not significantly influence protein degradation or amino acid release. The data suggest that in the absence of anabolic factors in the medium, myofibrillar protein degradation is increased in heavily activated muscle. This takes place without total protein breakdown being affected.

Abnormal free fatty acids and cortisol concentrations in the serum of AIDS patients.

The serum free fatty acid (FFA), cortisol and urinary creatinine, 17-hydzoxycorticosteroid and 17-oxosteroid concentrations of acquired immunedeficiency syndrome (AIDS-I: beginning and AIDS-II: end phase) and AIDS-related complex (ARC) patients were determined. Both groups were compared to a control group (healthy men). ARC and AIDS-I patients. The ratios of stearic (C18:0) to oleic (C18:1) acid were 75%, P less than 0.01 (ARC) and 45%, P less than 0.05 (AIDS-I) greater than normal, due to a decrease in the relative percentage of monounsaturated fatty acids by 25%, P less than 0.001 (ARC) and 20%, P less than 0.01 (AIDS-I). In contrast, the relative percentage of polyunsaturated fatty acids was 85% greater than normal (P less than 0.001) in ARC and 100% greater than normal (P less than 0.001) in AIDS-I patients. Total FFA levels did not differ from controls. Serum cortisol levels were 35% (P less than 0.01) above normal in ARC and 60% (P less than 0.001) above normal in AIDS-I patients. Urinary 17-hydroxycorticosteroids and 17-oxosteroids were very low (2-3-fold lower than normal values, P less than 0.001) in both groups of patients. Urinary creatinine did not differ from controls. In AIDS-II patients the total FFA concentration was below normal 35% (P less than 0.01) and the stearic/oleic acid ratio was 50% above normal (P less than 0.05). The relative percentages of monounsaturated and polyunsaturated fatty acids in this group were similar to those of controls. Serum cortisol concentrations were significantly higher, 50% (P less than 0.001), but the urinary 17-hydroxycorticosteroids and 17-oxosteroids were 2-fold lower (P less than 0.001) than those of controls. Urinary creatinine did not differ from controls. These significant differences from normal may be implicated in the pathophysiology of AIDS and could represent not only a good index of diagnosis and prognosis, but also indicate new therapeutic approach to the disease.

[The minimal freezing temperature for a necrosis of the epidermis and the influence of cryoprotective agents (author's transl)]. / Die Mindestgefriertemperatur für eine Hautnekrose und ihre Beeinflussung durch Kälteschutzsubstanzen

The sensitiveness to cold of the epidermis (cold threshold) is determined on the auricular skin of 24 rabbits, using freezing temperatures of -10, -15, -20, -25, -30, and -40 degrees C and a freezing time of 30 sec. The experiments are performed with and without application of cryoprotective agents (DMSO, glycerol and aethanol in a 10% solution) before cryosurgery. Only at -20 degrees C a necrosis of the epidermis is seen whereas after application of cryoprotective agents before freezing a necrosis of the epidermis first appears at -30 degrees C. Following these experiments clinically it might be possible to protect the epidermis in the periphery of the freezing area up to a certain degree with the use of cryoprotective agents, so that a topographically more concentrated epidermis-necrosis and therefore a limitation of the cryoeffect to the epidermis to a certain degree could be possible.

[Method of rapid separation of free, sulfoconjugated and glucuronoconjugated fractions of plasma steroids]. / Méthode de séparation rapide des fractions libre, sulfoconjuguée et glucuroconjuguée des stéroïdes plasmatiques

A method for the separation of serum conjugated steroids, sulfates and glucuronides, is described. It is based on the fact that methylene blue forms complexes with ester-sulfates which can be quantitatively and specifically extracted by chloroform from aqueous phase. The quantitative determination of the conjugated fractions thus obtained can be done after solvolysis followed by hydrolysis by beta-glucuronidase from Helix pomatia.