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Preliminary Communication
918 obvious scarring. Adipose infiltration of the right ventricle and some fine-droplet fatt,y change in the myocardium were seen.
The liver, when fixed, weighed 2510 g. The capsule showed very fine cirrhotic change over both lobes. A cut section revealed much autolytic change ; the fine cirrhosis was confirmed, and the liver lobules appeared distinctly dusky brown. Prussian-blue stain showed iron. Histologically all the sections showed the typical changes ofhsemochromatosis a
(fig 3). CONCLUSIONS
Fig. 3-Liver, showing islands of liver tissue separated by strands of fibrosis in which proliferating bile-ducts can be seen. (Haematoxylin and eosin.
x
32.)
the ventricles. The granules tended to be adjacent to the muscle nuclei and were closely associated with the granules of lipochrome or brown-atrophy pigment. There was some apparent hypertrophy of fibres in the left ventricle but no
Preliminary
Communication
SITE OF ACCUMULATION OF IODIDE THE IN THYROID OF RATS TREATED WITH
THE
THIOURACIL THE hormone of the mammalian thyroid gland is formed in two distinct stages : (1) inorganic iodide is accumulated within the gland at a much higher concentration than it occurs in blood ; and (2) this iodide is oxidised and enters into organic combinations. The two stages can be artificially separated by the administration of anti-thyroid drugs of the thiouracil series which inhibit the second but not the first stage, and permit study of the iodide-concentrating function in isolation. All that is so far known of this function is that the iodide is retained within the gland in a loosely bound form, from which it can readily be released by drugs such as thiocyanate and perchlorate. It is not known whether the concentration of iodide is effected by an enzymic mechanism in the cells lining the acini, or by
The case is remarkable for the rapid cardiac death: nine days previously the patient had played thirty-six holes of golf. The reason for the absence of previous symptoms seems to have been that the myocardial changes were balanced between the left and the right ventricles, with the result that there was no upset between the normal relation between the systemic and pulmonary circulations. During the final illness the failure involved the right ventricle more than the left, which explained the absence of excessive dyspncea or symptoms and signs of pulmonary congestion. In this respect the case appears to be analogous to those cases of severe anemia in which the patients live a normal life until near the end and die quickly, necropsy revealing a widespread fatty degeneration of the heart muscle. REFERENCES Sheldon. J. H. (1935) Hæmochromatosis. London. Swan, W. G. A., Dewar, H. A. (1952) Brit. Heart J. 14, 117. on a constituent of the colloid within the In the hope of demonstrating the site of the acini. iodide concentration an attempt was made to prepare autoradiographs of the thyroids of rats which had been treated with an anti-thyroid drug.
adsorption
Male hooded rats, each weighing about 80 g., were all treated with propylthiouracil 4 mg. given subcutaneously or intraperitoneally in2 mg. doses with an hour’s interval. Fifteen minutes after the second dose, 200 .c of carrier-free 131I was injected intraperitoneally. The rats were killed by a blow on the head fifteen minutes later, and the thyroid was immediately dissected out. One lobe was dissolved in dilute sodium-hydroxide solution and examined on a one-dimensional paper chromatogram with butanol-dioxan-ammonia (Gross and Leblond 1) ; an autoradiograph of the chromatogram was subsequently made to reveal the location of the radioactive iodine. In all the experiments done the 1311 in the gland was found to be iodide ; none had been organically bound. The other lobe was immediately dropped intoFreon 12’ The frozen thyroid which had been cooled in liquid air. lobe was then transferred to a freeze-drying apparatus modified from that of Stowell,2 and it lay on a platform of paraffin wax, which was kept at -40°C for forty-eight hours. The condensing surface was 2-5 em. above the specimen and was cooled by a mixture of solid carbon dioxide and alcohol. The interior of the apparatus was maintained at a pressure of less than 10-3 mm. Hg. At the end of the drying period the paraffin wax was heated to its melting-point with an electric coil, and the thyroid lobe was allowed to sink into the wax, which was resolidified while still in vacuo. The impregnated specimen was cut with a microtome into 4 [L sections; these were laid flat on photographic film, which was exposed in the dark for about three days and subsequently developed in the usual way.
thyroids of normal rats preunsatisfactory because the contrast between thyroid and non-thyroid tissue was not striking enough. After the first few experiments all the rats were pretreated with 0-1% thiouracil in their drinking-water for one or two weeks. The thyroids from these animals were hyperplastic, and their iodide
Autoradiographs
of the
pared in this way
were
level relative to that in the blood can be presumed to be greater than that of normal thyroids by a factor Autoradiograph
of
thyroid gland of rat after intraperitoneal injection of 131 1 (X 100).
1.
Gross, J., Leblond, C. P.
2. Stowell, R. E.
Stain
Endocrinology, 1951, 48, 714.
Technology, 1951, 26,
105.
919 of about 10. This enabled autoradiographs to be made which showed a sharp contrast between the thyroid and the surrounding tissues. Attempts were made to stain the sections as they lay on the photographic plate after exposure and development ; but, as any staining method involves rehydration, the configuration of the tissue was necessarily altered and the results were not satisfactory. The tissue was therefore examined by phase-contrast microscopy ; since this involved removal of the wax with xylol, the tissue may have been somewhat distorted in this also. An autoradiograph of a section of rat’s thyroid containing only radioactive iodide is shown in the accompanying illustration. It will be seen that the radioactivity is mostly in clumps. Examination by phasecontrast microscopy (with the sections in place) and inspection of stained adjacent sections showed that the radioactive areas corresponded in position with acini ; as with conventional autoradiography of the thyroid, some acini were apparently inactive at the time of examination. It seems that iodide is present either in the colloid alone or in both cells and colloid ; the definition of the radioactive areas is not sharp enough to If radiodistinguish between the two possibilities. activity were present in the cells but not in the colloid, the blackening on the autoradiographs would occur in rings ; these, however, have not been seen. It therefore appears case
Reviews of Books Clinical Endocrinology ALLAN W. SrENCE, M.A., M.D. Camb., F.R.c.P., physician, St. Bartholomew’s Hospital, London. London : Cassell. 1953. Pp. 696. 50s.
IN recent years there has been a rapid growth in understanding of endocrine diseases, and a spread of interest in them-partly evoked by the dramatic and unexpected effects of giving cortisone in a number of
ill-understood diseases. As a result, several new books on clinical endocrinology have appeared : some are purely clinical, others are texts of applied physiology, while one or two from the United States have managed to combine the logical and critical approach of the investigator with an adequate clinical treatment of the subject. The latest British book, by Dr. A. W. Spence, is addressed to the general physician and to those aspiring to become clinical endocrinologists. Dr. Spence has made a serious attempt to provide the needed physiological background, but the clarity and the interest of the clinical sections have not thereby gained as much as one might have hoped. Albright, in his cautionary introduction to the study of endocrinology in Cecil’s Textbook of Medicine, laments that, as endocrine diseases such as diabetes become understood, they are Dr. removed to the section on metabolic diseases. Spence leaves diabetes out, perhaps justifiably ; but he has not taken full advantage of the metabolic aspects of other endocrine conditions when explaining them, or when giving guidance on their management. Thus, for the diagnosis of hyperparathyroidism the aspirant will need more explicit information than is here provided : surely we are not going to turn these problems over to another specialist, the chemical pathologist ? Many conditions are discussed where there is no evidence of a metabolic disturbance and where an endocrine origin is doubtful ; but this is an advantage, for, as Albright pointed out, these patients with the grotesque syndromes of medicine are more likely to be referred to an endocrinologist than elsewhere. The book is easy to read but difficult to learn from, and the reader is sometimes left with the impression that he is being offered collected notes. Occasionally, where the results of a treatment are controversial, a more explicit statement of Dr. Spence’s own views, based on his exceptional experience, would be welcome. The bibliography is extensive but hardly goes beyond 1950, and some of the more recent advances-such as the rôle of cortisone in the treatment
that the greater part of the concentrated iodide is rapidly passed into the colloid. In one rat an autoradiograph was prepared of the submaxillary salivary gland as well as of the thyroid. This showed no localised radioactivity, even after exposure for a month. Since salivary glands can concentrate iodide from the blood to about the same degree as the thyroid, it seems that in this instance the iodide had passed with great rapidity into the saliva and had not remained concentrated within the cells. Our observations would be compatible with the hypothesis that in the thyroid also iodide passes rapidly through the secreting cells into the secretion (in this case the colloid). These conclusions do not necessarily apply to the thyroid glands of untreated rats ; in such animals, however, the demonstration of radioactivity from 131 iodide is very difficult, and it has not yet been found
possible
to
get good autoradiographs.
The early part of this work was done with Dr. Jack Gross. We wish to thank Mr. M. R. Young for many helpful suggestions and for the autoradiographs and photomicrographs ; we also thank Mr. A. Brownstone for the preparation of the tissue and Mr. F. Higginson for cutting the sections.
ROSALIND PITT-RIVERS
M.Sc., National Institute for Medical Research, Mill Hill, London *In
receipt of
a
Ph.D. Lond.
W. R. TROTTER* D.M.
Oxfd, M.R.C.P.
grant from the Sir Halley Stewart Trust.
of hypopituitarism and of adrenogenital virilism-get little notice. Monographs may have different functions. A few bring together a large amount of original work from one centre. Others provide a comprehensive review for the specialist in the field. Others seek to make a new subject easily available to the general reader. In spite of minor criticisms we are grateful to Dr. Spence for performing this last labour for the subject of clinical endocrinology. Food
Poisoning and Food Hygiene HOBBS, B.SC., PH.D., DIP. BACT., Food Hygiene Laboratory, Central Public Health Laboratory, Colindale. BETTY C.
London:
Edward Arnold.
1953.
Pp.
174.
14s.
WHETHER the increase in notifications of food-poisoning from 83 in 1939 to 3347 in 1951 reflects an increased number of infections or a greater awareness of them we shall never know. One result has been the publication of several books on the subject intended for the sanitary inspector or other layman whose duties or interests are concerned with the prevention of these infections. This is one of the best of them, and none the worse for being compressed within a small compass. Of its two parts the first begins with some elementary bacteriology, clearly expounded, and is supported by good pictures. The chapters on epidemiology show an eye for essentials: many people who should know better are apt to talk about the risks of unwrapped bread on a par with those arising from sausages and faggots, but, as Dr. Hobbs points out, more than half the outbreaks of food-poisoning in which the cause can be traced are due to made-up " meat. On the other hand, her argument that because 0’4% of 750 unspecified cattle harboured species of salmonella, 32,000 out of a cattle population of 2 million do so, is good arithmetic but pure guesswork. Not only is the sample minute, but there is good evidence that the distribution of Salmonella dublin, at any rate, is patchy. This part of the book ends with the histories of some typical outbreaks, which are illustrative and to the point. In the second part Dr. Hobbs has had the help of a sanitary Kluth. It deals with personal hygiene, the inspector, Mr. storage and preservation of food, the cleaning of utensils, and the design of kitchens and shops. The chapter on vermin discusses not only the lethal agents but some sensible ways by which premises may be made as ratproof as possible. All this advice is clear and, disregarding cost, could be carried out ; though it would have been well to mention certain problems, such as a mechanical mixer for sausages containing rusk, which are still unsolved. Similarly there are valid objections, hygienic or financial, to all the methods of drying the hands which are "
The liver, when fixed, weighed 2510 g. The capsule showed very fine cirrhotic change over both lobes. A cut section revealed much autolytic change ; the fine cirrhosis was confirmed, and the liver lobules appeared distinctly dusky brown. Prussian-blue stain showed iron. Histologically all the sections showed the typical changes ofhsemochromatosis a
(fig 3). CONCLUSIONS
Fig. 3-Liver, showing islands of liver tissue separated by strands of fibrosis in which proliferating bile-ducts can be seen. (Haematoxylin and eosin.
x
32.)
the ventricles. The granules tended to be adjacent to the muscle nuclei and were closely associated with the granules of lipochrome or brown-atrophy pigment. There was some apparent hypertrophy of fibres in the left ventricle but no
Preliminary
Communication
SITE OF ACCUMULATION OF IODIDE THE IN THYROID OF RATS TREATED WITH
THE
THIOURACIL THE hormone of the mammalian thyroid gland is formed in two distinct stages : (1) inorganic iodide is accumulated within the gland at a much higher concentration than it occurs in blood ; and (2) this iodide is oxidised and enters into organic combinations. The two stages can be artificially separated by the administration of anti-thyroid drugs of the thiouracil series which inhibit the second but not the first stage, and permit study of the iodide-concentrating function in isolation. All that is so far known of this function is that the iodide is retained within the gland in a loosely bound form, from which it can readily be released by drugs such as thiocyanate and perchlorate. It is not known whether the concentration of iodide is effected by an enzymic mechanism in the cells lining the acini, or by
The case is remarkable for the rapid cardiac death: nine days previously the patient had played thirty-six holes of golf. The reason for the absence of previous symptoms seems to have been that the myocardial changes were balanced between the left and the right ventricles, with the result that there was no upset between the normal relation between the systemic and pulmonary circulations. During the final illness the failure involved the right ventricle more than the left, which explained the absence of excessive dyspncea or symptoms and signs of pulmonary congestion. In this respect the case appears to be analogous to those cases of severe anemia in which the patients live a normal life until near the end and die quickly, necropsy revealing a widespread fatty degeneration of the heart muscle. REFERENCES Sheldon. J. H. (1935) Hæmochromatosis. London. Swan, W. G. A., Dewar, H. A. (1952) Brit. Heart J. 14, 117. on a constituent of the colloid within the In the hope of demonstrating the site of the acini. iodide concentration an attempt was made to prepare autoradiographs of the thyroids of rats which had been treated with an anti-thyroid drug.
adsorption
Male hooded rats, each weighing about 80 g., were all treated with propylthiouracil 4 mg. given subcutaneously or intraperitoneally in2 mg. doses with an hour’s interval. Fifteen minutes after the second dose, 200 .c of carrier-free 131I was injected intraperitoneally. The rats were killed by a blow on the head fifteen minutes later, and the thyroid was immediately dissected out. One lobe was dissolved in dilute sodium-hydroxide solution and examined on a one-dimensional paper chromatogram with butanol-dioxan-ammonia (Gross and Leblond 1) ; an autoradiograph of the chromatogram was subsequently made to reveal the location of the radioactive iodine. In all the experiments done the 1311 in the gland was found to be iodide ; none had been organically bound. The other lobe was immediately dropped intoFreon 12’ The frozen thyroid which had been cooled in liquid air. lobe was then transferred to a freeze-drying apparatus modified from that of Stowell,2 and it lay on a platform of paraffin wax, which was kept at -40°C for forty-eight hours. The condensing surface was 2-5 em. above the specimen and was cooled by a mixture of solid carbon dioxide and alcohol. The interior of the apparatus was maintained at a pressure of less than 10-3 mm. Hg. At the end of the drying period the paraffin wax was heated to its melting-point with an electric coil, and the thyroid lobe was allowed to sink into the wax, which was resolidified while still in vacuo. The impregnated specimen was cut with a microtome into 4 [L sections; these were laid flat on photographic film, which was exposed in the dark for about three days and subsequently developed in the usual way.
thyroids of normal rats preunsatisfactory because the contrast between thyroid and non-thyroid tissue was not striking enough. After the first few experiments all the rats were pretreated with 0-1% thiouracil in their drinking-water for one or two weeks. The thyroids from these animals were hyperplastic, and their iodide
Autoradiographs
of the
pared in this way
were
level relative to that in the blood can be presumed to be greater than that of normal thyroids by a factor Autoradiograph
of
thyroid gland of rat after intraperitoneal injection of 131 1 (X 100).
1.
Gross, J., Leblond, C. P.
2. Stowell, R. E.
Stain
Endocrinology, 1951, 48, 714.
Technology, 1951, 26,
105.
919 of about 10. This enabled autoradiographs to be made which showed a sharp contrast between the thyroid and the surrounding tissues. Attempts were made to stain the sections as they lay on the photographic plate after exposure and development ; but, as any staining method involves rehydration, the configuration of the tissue was necessarily altered and the results were not satisfactory. The tissue was therefore examined by phase-contrast microscopy ; since this involved removal of the wax with xylol, the tissue may have been somewhat distorted in this also. An autoradiograph of a section of rat’s thyroid containing only radioactive iodide is shown in the accompanying illustration. It will be seen that the radioactivity is mostly in clumps. Examination by phasecontrast microscopy (with the sections in place) and inspection of stained adjacent sections showed that the radioactive areas corresponded in position with acini ; as with conventional autoradiography of the thyroid, some acini were apparently inactive at the time of examination. It seems that iodide is present either in the colloid alone or in both cells and colloid ; the definition of the radioactive areas is not sharp enough to If radiodistinguish between the two possibilities. activity were present in the cells but not in the colloid, the blackening on the autoradiographs would occur in rings ; these, however, have not been seen. It therefore appears case
Reviews of Books Clinical Endocrinology ALLAN W. SrENCE, M.A., M.D. Camb., F.R.c.P., physician, St. Bartholomew’s Hospital, London. London : Cassell. 1953. Pp. 696. 50s.
IN recent years there has been a rapid growth in understanding of endocrine diseases, and a spread of interest in them-partly evoked by the dramatic and unexpected effects of giving cortisone in a number of
ill-understood diseases. As a result, several new books on clinical endocrinology have appeared : some are purely clinical, others are texts of applied physiology, while one or two from the United States have managed to combine the logical and critical approach of the investigator with an adequate clinical treatment of the subject. The latest British book, by Dr. A. W. Spence, is addressed to the general physician and to those aspiring to become clinical endocrinologists. Dr. Spence has made a serious attempt to provide the needed physiological background, but the clarity and the interest of the clinical sections have not thereby gained as much as one might have hoped. Albright, in his cautionary introduction to the study of endocrinology in Cecil’s Textbook of Medicine, laments that, as endocrine diseases such as diabetes become understood, they are Dr. removed to the section on metabolic diseases. Spence leaves diabetes out, perhaps justifiably ; but he has not taken full advantage of the metabolic aspects of other endocrine conditions when explaining them, or when giving guidance on their management. Thus, for the diagnosis of hyperparathyroidism the aspirant will need more explicit information than is here provided : surely we are not going to turn these problems over to another specialist, the chemical pathologist ? Many conditions are discussed where there is no evidence of a metabolic disturbance and where an endocrine origin is doubtful ; but this is an advantage, for, as Albright pointed out, these patients with the grotesque syndromes of medicine are more likely to be referred to an endocrinologist than elsewhere. The book is easy to read but difficult to learn from, and the reader is sometimes left with the impression that he is being offered collected notes. Occasionally, where the results of a treatment are controversial, a more explicit statement of Dr. Spence’s own views, based on his exceptional experience, would be welcome. The bibliography is extensive but hardly goes beyond 1950, and some of the more recent advances-such as the rôle of cortisone in the treatment
that the greater part of the concentrated iodide is rapidly passed into the colloid. In one rat an autoradiograph was prepared of the submaxillary salivary gland as well as of the thyroid. This showed no localised radioactivity, even after exposure for a month. Since salivary glands can concentrate iodide from the blood to about the same degree as the thyroid, it seems that in this instance the iodide had passed with great rapidity into the saliva and had not remained concentrated within the cells. Our observations would be compatible with the hypothesis that in the thyroid also iodide passes rapidly through the secreting cells into the secretion (in this case the colloid). These conclusions do not necessarily apply to the thyroid glands of untreated rats ; in such animals, however, the demonstration of radioactivity from 131 iodide is very difficult, and it has not yet been found
possible
to
get good autoradiographs.
The early part of this work was done with Dr. Jack Gross. We wish to thank Mr. M. R. Young for many helpful suggestions and for the autoradiographs and photomicrographs ; we also thank Mr. A. Brownstone for the preparation of the tissue and Mr. F. Higginson for cutting the sections.
ROSALIND PITT-RIVERS
M.Sc., National Institute for Medical Research, Mill Hill, London *In
receipt of
a
Ph.D. Lond.
W. R. TROTTER* D.M.
Oxfd, M.R.C.P.
grant from the Sir Halley Stewart Trust.
of hypopituitarism and of adrenogenital virilism-get little notice. Monographs may have different functions. A few bring together a large amount of original work from one centre. Others provide a comprehensive review for the specialist in the field. Others seek to make a new subject easily available to the general reader. In spite of minor criticisms we are grateful to Dr. Spence for performing this last labour for the subject of clinical endocrinology. Food
Poisoning and Food Hygiene HOBBS, B.SC., PH.D., DIP. BACT., Food Hygiene Laboratory, Central Public Health Laboratory, Colindale. BETTY C.
London:
Edward Arnold.
1953.
Pp.
174.
14s.
WHETHER the increase in notifications of food-poisoning from 83 in 1939 to 3347 in 1951 reflects an increased number of infections or a greater awareness of them we shall never know. One result has been the publication of several books on the subject intended for the sanitary inspector or other layman whose duties or interests are concerned with the prevention of these infections. This is one of the best of them, and none the worse for being compressed within a small compass. Of its two parts the first begins with some elementary bacteriology, clearly expounded, and is supported by good pictures. The chapters on epidemiology show an eye for essentials: many people who should know better are apt to talk about the risks of unwrapped bread on a par with those arising from sausages and faggots, but, as Dr. Hobbs points out, more than half the outbreaks of food-poisoning in which the cause can be traced are due to made-up " meat. On the other hand, her argument that because 0’4% of 750 unspecified cattle harboured species of salmonella, 32,000 out of a cattle population of 2 million do so, is good arithmetic but pure guesswork. Not only is the sample minute, but there is good evidence that the distribution of Salmonella dublin, at any rate, is patchy. This part of the book ends with the histories of some typical outbreaks, which are illustrative and to the point. In the second part Dr. Hobbs has had the help of a sanitary Kluth. It deals with personal hygiene, the inspector, Mr. storage and preservation of food, the cleaning of utensils, and the design of kitchens and shops. The chapter on vermin discusses not only the lethal agents but some sensible ways by which premises may be made as ratproof as possible. All this advice is clear and, disregarding cost, could be carried out ; though it would have been well to mention certain problems, such as a mechanical mixer for sausages containing rusk, which are still unsolved. Similarly there are valid objections, hygienic or financial, to all the methods of drying the hands which are "