[The 65th birthday of Professor Hans Petzold].
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Biomedical subjects
Publications and source records attributed to H Kohler.
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Autoradiographs of thyroid glands of aging mice demonstrate the gradual appearance of "cold" follicles which fail to iodinate the intraluminar iodoproteins even after intense exogeneous or endogeneous TSH stimulation. "Cold" follicles first appear at the age of 5 months. They may account for 80% of all thyroid follicles in 13-month-old mice. Morphologically, the "cold" follicles are characterized by a larger than normal colloid volume and a comparatively flat epithelium for any given follicle size. Old thyroids are twice as large as young ones. They contain twice as much normally iodinated thyroglobulin/mg wet weight. The total number of cells per gland remains constant throughout the life time. This is probably also true for the total number of follicles. The iodide pump, as judged by the tissue to serum ratio, remains normal and TSH-responsive. Yet, it is not established whether this is due to a higher activity of the pump in normal follicles or to preservation of inorganic iodide transport in "cold" follicles. Pinocytosis is defective in "cold" follicles and is poorly responsive to TSH stimulation. Furthermore, diffusion of iodocompounds is severely impaired in the colloid of "cold" follicles. It is suggested that the primary defect in the pathogenesis of "cold" follicles in old mice is the gradual failure of endocytosis to respond to normal TSH stimulation. Because exocytosis and iodination would first proceed normally, the follicular lumina would become overdistended up to a point where the apical membrane is functionally impaired. With this sequence of events, "cold" follicles would have impaired iodination while being metabolically as active as hot ones. Thus, several puzzling reports on high metabolic activity of "cold" tissue could possibly be interpreted.
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Analyses were made of the scalp and hair lipids of 67 test persons. These were the most important results: 1. Seborrhoea is caused on one hand by a high secretion performance of the sebaceous glands. A further cause is that a longer period of time passes before a constant lipid amount is established. 2. There was an average of 19.32% of free fatty acids in the scalp and hair lipids on the 1st day after the hair was washed, and 38.68% on the 10th day. These results allow an assessment of the physiological significance of microbial lipolysis outside the secretory ducts of the sebaceous glands. 3. On the hairy head the percentage of free fatty acids in the scalp and hair lipids is independent of the amount of lipids. Such a difference in the concentration of fatty acids as is found between seborrhoea oleosa and seborrhoea sicca on hairless skin can not be found on the hairy head.
Free cholesterol in lipids from the scalp and hair is predominantly a constituent of epidermal lipids. Therefore, a reduction in cholesterol content induced by a drug indicates a reduction in cell turnover in the epidermis. As, according to the literature, increased cell turnover in the epidermis results in formation of dandruff, a reduction in the proportion of cholesterol should indicate inhibition of the formation of dandruff. Conversely, an increase in free cholesterol should generally indicate a "keratolytic" effect. So unequivocal an interpretation has not so far been possible in persons with dandruff, as it was not known whether free cholesterol was increased or decreased. In addition, this interpretation was not possible after use of antimicrobial substances, as in vitro investigations had failed to exclude microbial esterification of cholesterol on the scalp. The present investigation has shown that correlation of free cholesterol level with cell turnover is permissible in patients with dandruff, even if antimicrobial drugs are being tested.
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Lithium and excess iodide inhibit the release of thyroid hormone from preformed stores. We thus tested the hypothesis that this was due to an inhibition of thyroglobulin breakdown. Rats were pre-treated with propyl-thiouracil (PTU) for 3 weeks in order to deplete their thyroids of thyroglobulin. While the PTU was continued, lithium chloride (0.25 mEq./100 g weight) or potassium iodide (3 mg per rat) were injected every 12 h for d days. Thereafter the thyroglobulin content in thyroid gland homogenates was measured. PTU pre-treatment lowered the thyroglobulin content from 4.21 to 0.22 mg/100 mg gland. Lithium caused a marked re-accumulation of thyroglobulin to 0.60 mg/100 mg within 3 days. While iodide alone had only a borderline effect, it markedly potentiated the action of lithium and a combination of the two drugs increased the thyroglobulin content to 1.04 mg/100 mg. Thyroxine was injected into similarly pre-treated animals to suppress secretion of thyrotrophic hormone. This markedly inhibited the proteolysis of thyroglobulin and 1.3 mg/100 mg gland accumulated after 3 days. Excess iodide, given in addition to thyroxine, decreased the amount of thyroglobulin accumulated to 0.75 mg/100 mg gland. To study whether this could be explained by an inhibitory action of iodide on thyroglobulin biosynthesis, thyroid glands from animals treated with excess iodide were incubated in vitro in the presence of 0.2 mM iodide for 3 h. Iodide decreased the incorporation of radioactive leucine into total thyroidal protein and into thyroglobulin by 25 and 35% respectively. Iodide did not inhibit protein synthesis in the kidney, liver or muscle tissue. Thus, large doses of iodide selectively inhibit thyroglobulin biosynthesis.
Small doses of iodide (2 times 3.2 mug at 12 h interval), below those capable of inducing Wolff-Chaikoff effect, were injected into rats kept on a moderately low iodine diet. By means of a 125I equilibration technique as well as by direct measurement of cold T4, it was demonstrated that the level of circulating PB125I (representing iodothyronines as confirmed by column chromatography) increased by a mean of 40% within 24 h following the first iodide injection. The serum TSH concentration (measured by radioimmunoassay) was simultaneously depressed. Thus, in stimulated thyroid glands, a biologically significant fraction of an iodide load escapes autoregulatory control of iodothyronine synthesis. A small, transient increase of hormone release is likely to represent the physiological response of a normal gland to a sudden supplement of iodide supply. The ensuing depression of TSH secretion may be necessary for final adjustment of thyroid function. It is considered to be the last step in a cascade of mechanisms whose interaction keeps the thyroidal hormone output within narrow limits in the face of a fluctuating iodide supply. Failure of one or several of these mechanisms in the goitrous human gland could conceivable explain the phenomenon of "Jod Basedow".
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In response to the question when radioactive isotopes (radionuclides) are necessary or superfluous in the diagnostic workup of thyroid disease, the following observations can be made: 1. Radionuclides are almost ubiquitously used for the specific and relevant in-vitro tests for measuring the circulating thyroid hormones (T4 und T3, etc.) and necessitate a very small quantity of serum. They lead in approximately 90% of cases of the correct diagnosis, especially when supported by careful clinical workup. 2. The use of radionuclides is of unquestionable value for scanning the thyroid gland and thus permitting the localization of normal vs. ectopic thyroid tissue, and the recognition of active ("warm" or "hot") vs. inactive ("cold") areas, especially in nodular goiter. 3. As the best screening tests for hypo- or hyperthyroidism are those related to the level of circulating thyroid hormones (see above), thyroid radionuclide uptake tests have lost much of their diagnostic value. However, the measurement of thyroidal radionuclide uptake remains valuable whenever radioiodine treatment is considered and in detailed thyroid function studies, and its also useful in the follow-up of drug-treated hyperthyroid patients. Thyroid uptake measurements may be of particular interest in so-called dynamic tests (e.g. TSH-stimulation, T3-suppression). 4. Finally, attention is drawn to the fact that, according to AITCHISON et al. (1), our capacity to interpret multidimensional information properly is limited. Thus, experience and precise knowledge help to economize the use of radionuclides and permit minimal application with maximal output.
In addition to thyroglobulin, several low molecular wt iodinated glycopeptides are present in the thyroid gland. Some of these compounds are considered to be slowly metabolized remnants of intracellular lysis of engulfed colloid droplets. In this paper we present autoradiographic evidence obtained by light microscopy, suggesting that breakdown products of thyroglobulin digestion can indeed be located within the thyroid cells. The thyroid glands of rats were labeled with 125I to approach isotopic equilibrium. The tracer was then withdrawn from the otherwise unchanged high-iodine diet, and thyroidal radioactivity was washed out for 80 days. Autoradiographs of glands containing 10% or less of the tracer present at equilibrium showed the bulk of 125I within the follicular cells while the colloid was only slightly labeled. An additional finding was the presence of dense radioactive inclusions in the lumina of many follicles. They are assumed to represent clusters of thyroglobulin molecules not readily available to pinocytosis. In addition to autoradiographic evidence, the identity of intracellularly located radioactivity with slow-turnover enzyme-resistant iodocompounds is supported by double labeling experiments, using 125I as the "old" tracer, accumulating within the cells, and 131I as the "new" label representing intraluminal 19 S thyroglobulin. Experimental manipulations which tended to deplete the thyroid of thyroglobulin, increased the 125I/131I ratio in the gland as predicted by the working hypothesis. Thus, this paper describes a new kind of autoradiographic ring reaction due to a hitherto barely considered intracellular organic iodine pool.
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