CALCIFICATION OF THE SUPRARENAL GLANDS OF CATS

Calcification of the fascicular zone of the cortex has been observer in 64 of 257 cats. It is always calcification and never ossification It is more common in young animals and in our experience is associated with distemper. In its severe forms it may be recognized clinically. The symptoms resemble those seen in cats surviving double suprarenalectomy for 2 to 3 weeks. The toxin producing the focal degeneration is dearly a very specific one since attempts to produce such lesions by several types of experimental injury have failed. The sequence of events appears to be similar to that present in other degenerative processes associated with calcification, namely cell injury and necrosis, deposition of calcium at first as fatty compounds which later change to carbonate and phosphate. It is suggested that this lesion should be considered in interpreting experiments in which cats are used.     

STUDIES ON THE SUPRARENAL CORTEX : IV. THE EFFECT OF SODIUM SALTS IN SUSTAINING THE SUPRARENALECTOMIZED DOG

1. A group of experiments is reported in which bilaterally suprarenalectomized adult male dogs have been maintained in apparently normal condition over prolonged periods, up to 5 months, without the use of any suprarenal gland preparation or extract and by the administration of sodium chloride and sodium bicarbonate alone. Withdrawal of the salts then produced typical suprarenal insufficiency. 2. The relation of the absence of free hydrochloric acid in the gastric juice of suprarenalectomized animals, in addition to, or independent of the factor of dehydration, for the production of anorexia and hypoglycemia, is discussed. 3. Further evidence is presented in these experiments in support of the view that the suprarenal cortical hormone in the adult male dog is concerned with the regulation of sodium excretion by the kidney, and thus eventually with the proper maintenance of water balance in the organism. It has no direct influence on carbohydrate metabolism. 4. The reciprocal changes in the plasma concentrations of urea and of potassium which take place as the concentrations of plasma sodium and chlorides vary, are pointed out as furnishing a mechanism whereby abrupt alterations in osmotic pressure are dampened, and the volumes of fluids in extracellular and intracellular compartments more efficiently stabilized.     

EPINEPHRINE CONTENT OF THE SUPRARENAL GLANDS IN ANAPHYLAXIS

The epinephrine store of the suprarenal glands remains unaltered in guinea pigs and rabbits which have been sensitized to ox serum, or subjected to varying degrees of anaphylactic shock by the reinjection of the foreign protein.     

STUDIES ON THE SUPRARENAL CORTEX : III. PLASMA ELECTROLYTES AND ELECTROLYTE EXCRETION DURING SUPRARENAL INSUFFICIENCY IN THE DOG

A characteristic alteration in the electrolyte structure of the blood plasma of the suprarenalectomized dog occurs when injections of cortical extract are stopped. This alteration progresses during the course of the suprarenal insufficiency, parallel with the hemoconcentration and the loss in weight. When injections of cortical extract are resumed, the electrolyte structure returns to its original form, the alterations paralleling the dilution of the blood and the return of the body weight to its original level. The hemoconcentration, with the resulting physiological changes which take place in the suprarenalectomized dog after the cessation of cortical extract injections, is associated with a loss of sodium and chloride, accompanied by their proper complement of body water, by way of the kidney. Since this effect is produced in the suprarenalectomized animal, well nourished and in excellent condition, solely by cessation of injections of the cortical hormone, and since the reverse process of repair of the electrolyte and water losses can be effected solely by resumption of extract injections, it follows that all of the observed phenomena are due to this cause, and to this alone. It can be concluded that one function of the cortical extract in the suprarenalectomized dog is that of participation in the regulation of the sodium and chloride metabolism, and consequently, of the balance and distribution of water. The loss of water, in the absence of the cortical hormone, is sustained partly by the blood plasma, but to a far greater extent by the interstitial body fluid. The available evidence points to the kidney as the locus of this regulatory function of the cortical hormone.     

EFFECTS OF INSULIN ON THE WEIGHT OF THE RABBIT'S SUPRARENAL GLANDS

There is no gross hypertrophy of the adrenals in rabbits after long continued, daily doses of insulin.     

THE INFLUENCE OF THE ADRENAL GLANDS ON RESISTANCE : II. THE TOXIC EFFECT OF KILLED BACTERIA IN ADRENALECTOMIZED RATS.

1. The resistance of rats to bacterial intoxication is greatly decreased after double adrenalectomy. 2. This decreased resistance is dependent upon a functional insufficiency of the adrenal cortex. 3. A dose of killed streptococci or staphylococci can be obtained that is invariably fatal to adrenalectomized rats, before hypertrophy of cortical accessories, but never kills control rats.     

THE ADRENALIN INDEX OF THE SUPRARENAL GLANDS IN HEALTH AND DISEASE

The adrenalin index as used in this paper means the amount of adrenalin in milligrams per gram of gland. As in our hands the chemical colorimetric method has proved more accurate, these values rather than the physiological values will be given in the final analysis. The two adrenal glands in the same individual as a rule contain about the same amount of adrenalin per gram, but variations of 10 to 20 per cent. are not unusual. Normal dogs show an index which may vary from 1.2 to 1.8 milligrams. The dogs were killed by short ether anesthesia and bleeding from the carotid. Normal human beings, dying from trauma, rupture of aneurysm, etc., show an index of 0.35 to 0.50 of a milligram, when autopsy takes place a few hours after death. Deterioration of uncut glands or of a gland hash kept on ice in the dark is not rapid and rarely exceeds 10 per cent. in twenty-four hours. Acute intoxication in dogs shows a low adrenalin index, especially the intoxication associated with intestinal obstruction and the closed intestinal loop. Intravenous injection of the poison found in closed duodenal loops sufficient to cause fatal shock causes a great drop in the adrenalin index, at times to one fourth normal or even lower. After recovery from a sublethal toxic dose the adrenalin index may rise rapidly to a point considerably above normal. The same may hold for recovery after chloroform poisoning. Anesthesia by chloroform or ether causes a drop in the adrenalin index depending upon the length of anesthesia and probably in part on the depth of anesthesia. Liver poisons (chloroform, phosphorus, hydrazine) cause a drop in the adrenal index to a low level, perhaps one half normal in acute cases. Pancreas extirpation with prolonged glycosuria and death produces a great drop in the adrenalin index (cat). There is evidence that this may hold in some cases of human diabetes. In man disease of one adrenal (tuberculosis) may be associated with an adrenalin index of double the normal value in the intact adrenal. Pernicious anemia is the only disease so far found to present an abnormally high adrenalin index, and the single case shows an index at least twice normal. This is of interest especially in relation to the views recently put forward to indicate that the spleen and adrenal may be concerned in the lipoid metabolism which is thought to be profoundly disturbed in this disease. Secondary anemia due to repeated hemorrhage or the intoxication of cancer or tuberculosis causes a fall in the adrenalin index. Cachexia due to neoplasm or tuberculosis may cause a marked fall in the adrenalin index, perhaps to less than one half of normal. Acute infections (typhoid fever), septicemia, peritonitis, and similar conditions may be associated with a normal adrenalin index or one somewhat below normal. Diseases of the kidneys, heart, or blood vessels associated with elevated blood pressure show no constant variation in the adrenalin index, which may be normal or slightly subnormal.     

STUDIES ON THE SUPRARENAL CORTEX : I. CORTICAL SUPRARENAL INSUFFICIENCY AND THE ACTION OF THE CORTICAL HORMONE UPON THE NORMAL AND SUPRARENALECTOMIZED DOG

1. The methods used in the operation and care of suprarenalectomized dogs are given. 2. The effect of injections of the cortical hormone upon normal and suprarenalectomized dogs is described. 3. Symptoms and chemical studies of suprarenal insufficiency in the dog, following extract withdrawal are described, together with the effects produced by its readministration. 4. The phenomena associated with experimental suprarenal insufficiency are contrasted with those seen in patients with Addison''s disease. The identity of the acute symptoms with those of "shock" is pointed out.     

QUANTITATIVE STUDIES OF PROSTATIC SECRETION : II. THE EFFECT OF CASTRATION AND OF ESTROGEN INJECTION ON THE NORMAL AND ON THE HYPERPLASTIC PROSTATE GLANDS OF DOGS

Cystic hyperplasia of the prostate occurs spontaneously in senile dogs only when they possess physiologically effective amounts of androgenic hormone. The cysts are closely grouped and radially arranged in a conical manner with the base of the cone at the periphery of the gland. Flattened and columnar epithelium, varying from about 5 to 25µ are seen in each cyst. The cysts communicate with the urethra by way of ducts. Both normal and cystic prostates undergo marked atrophy when the testes are removed, the chief difference 3 months after orchiectomy being the persistence of slightly dilated clefts and spaces at the site of the former cysts in the senile state. In the castrate dog whose prostate gland is being reconstructed as result of the influence of daily injections of androgen, certain doses of estrogen prevent increase of secretion and still larger doses greatly depress the output of the gland. In dogs so treated by daily injections of testosterone propionate, 10 mg., the amount of secretion is maintained from day to day at a level by daily injections of stilbestrol, 0.4 to 0.6 mg. and greatly depressed by doses of 1 to 1.5 mg. When the larger amounts of estrogen are used, together with androgen, squamous metaplasia occurs in the posterior lobe of the prostate while the epithelium of the acini decreases in height to cuboidal or low columnar form; these histological signs of activity of both androgen and estrogen on the prostate show that inhibition of the male hormone by stilbestrol is incomplete at these ratios. In dogs with either normal or cystic prostate glands, the prostate decreases in size when estrogen is injected in amounts to depress prostatic secretion profoundly. The gland is maintained in an atrophic state and overdosage avoided by controlled periodic injections of stilbestrol until secretion is reduced to the minimum, followed by free intervals, the estrogen being again administered when secretion measurably increases. The shrinkage is related to depression of male hormone production. Overdosage of estrogen causes the prostate gland of dogs to enlarge, and structures of the posterior lobe and utriculus respond first and most markedly with metaplasia caused by this material. The prostatic enlargement does not resemble the common cystic hyperplasia of senile dogs. Metaplasia rapidly disappears from the prostate, and the epithelial structures quickly return to normal when estrogen is discontinued and androgen is administered.     

THE INFLUENCE OF THE SUPRARENAL GLAND ON THE THYMUS : I. REGENERATION OF THE THYMUS FOLLOWING DOUBLE SUPRARENALECTOMY IN THE RAT.

Experimental evidence has been presented showing that the thymus gland of the rat enlarges rapidly in those animals surviving double suprarenalectomy. The enlargement has been observed to follow bilateral ablation with such constancy that it may be said to occur in all rats which survive double suprarenalectomy in good condition for from 3 to 5 weeks. The thymus enlarges even though the animal loses some weight after operation. Our data, though inconclusive, would seem to indicate a sex difference, the secondary hyperplasia of the thymus being more marked in the female than in the male. This difference, we believe, may shed some light on the mechanism of thymus enlargement following double suprarenalectomy. In the rat there is a definite sex difference in the weight of the suprarenals (20), the glands being much larger in the female than in the male. This weight difference becomes greater as the rat grows, and it appears at an early period of life; indeed, it is obvious at about 35 days of age, in spite of the fact that sexual maturity is seldom attained before 60 to 90 days. This difference in the suprarenals is independent of pregnancy. It is highly probable that the suprarenal glands stand in closer relation to the sex organs of the females than in the male, and that removal of these glands disrupts the sex interrelationships between gonads, suprarenals, and thymus, this disturbance being more definitely expressed in the female than in the male. The great majority of the rats were operated on when they were between 6 and 7 months of age; that is, after thymus involution would normally have set in. Thymuses examined when they had reached their largest size resembled both grossly and microscopically the growing thymuses of much younger animals, the only evidence of previous involutionary change being the presence of thickening of the vessels. We assume, therefore, from indirect, but statistical data, that regeneration of the involuted thymus must have taken place. The regeneration following bilateral ablation describes a curve which reaches its height between the 3rd and 5th weeks after operation. After the height of enlargement is attained, there is a gradual decline in the size of the gland, but involutionary changes may be retarded for months. Pregnancy prior to suprarenalectomy does not prevent thymus regeneration following this operation. Thymic enlargement does not ordinarily take place following a unilateral ablation. Severe chronic infections may sometimes bring about such a pronounced pathological involution of the thymus that the hyperplasia may be prevented. There can as yet be only speculation as to the mechanism involved in the regeneration of the thymus which follows suprarenalectomy. This secondary thymic hyperplasia may be one manifestation of the generalized lymphoid hyperplasia that follows sublethal but sufficient suprarenal injury, and which is characterized by the appearance of prominent lymphoid foci in the various organs, particularly in the thyroid, a generalized hyperplasia of the lymph nodes and bone marrow, and the appearance of a lymphocytosis in the blood. The evidence at present available would suggest that both the thymic and general lymphoid hyperplasia may be effected through the gonads and parasex tissues and that the thymus especially regenerates because of a disruption of the interrelations between the interrenal gland, the gonads, and the thymus. The close association between the gonads and the suprarenals (21) is well known. The latter undergo enlargement in pregnancy, ovulation, and castration, and the ovaries hypertrophy after suprarenalectomy. Tumors of the suprarenals are associated frequently with sex perversion and precocity both in the male and female. The interrelation between the gonads and thymus is classical, castration before puberty delaying thymus involution for a long time. A number of diseases present thymus enlargement among the major pathological findings at autopsy. The most outstanding of these are Addison''s disease, status lymphaticus, and Graves'' disease. It is now generally recognized that the suprarenal glands play an important r61e in the etiology both of Addison''s disease and status lymphaticus. Whether the interrenal or the chromophil system is primarily involved or whether disturbances in function of both systems are at the basis of these diseases is still undetermined. The newer evidence, including our own work on lymphoid regeneration following suprarenalectomy supports the view that the lymphoid hyperplasia occurring in both Addison''s disease and status lymphaticus is dependent upon insufficiency of the interrenal system (suprarenal cortex). While anatomical studies have not disclosed any constant lesions in the suprarenals in Graves'' disease, evidence is being accumulated which would indicate that functionally these glands also play an important if not a primary role in the production of the clinical syndrome of Graves'' disease (14, 18, 19). We are of the belief that the persistence of the thymus which occurs in status lymphaticus, and the regeneration which occurs in Addison''s and Graves'' diseases, are brought about by the same disturbances in glandular interrelations which bring about regeneration of the thymus in the experimental animal after suprarenalectomy.     

THE INFLUENCE OF RESISTANCE ON THE CHARACTER OF DISEASE IN EXPERIMENTAL RESPIRATORY INFECTION

An organism of the Pasteurella group (Pasteurella avicida) has been shown to possess considerable pathogenicity for rabbits when injected into the trachea. 1 cc. of bouillon containing 1/100 cc. of a 24 hour bouillon culture introduced by means of a curved metal tube passed through the larynx gives rise to a rapidly fatal septicemia in which the lungs are not particularly involved. Rabbits may be made completely resistant to this intratracheal infection by means of intratracheal, intraperitoneal, or subcutaneous injections of killed cultures. Vaccination and subsequent injection of living culture beneath the skin resulted in extensive abscess formation about the site of inoculation. Vaccines sprayed on the mucous membranes of the nose and throat failed to raise appreciably the resistance against subsequent intratracheal injection. Rabbits whose resistance has been stimulated within narrow limits by a small dose of vaccine beneath the skin become more resistant to the experimental respiratory infection. The character of the disease is changed from a rapidly fatal septicemia without lung involvement to a more prolonged pneumonia. The blood remains sterile for varying periods. Consolidations of the more dependent lobes occur with considerable regularity. In two instances a characteristic empyema developed in the course of the experiments.     

THE INFLUENCE OF PROTEIN-FREE LIVER AND SPLEEN EXTRACTS ON THE BLOOD REGENERATION AND RESPIRATORY EXCHANGE OF ANEMIC RABBITS

1. Respiratory exchange measurements may be used for gaining further evidence concerning the body changes during anemia, and are complementary to the hematological and histological data. 2. The heat production during anemia was slightly decreased. At the 3rd week it began to rise. 3. A protein-free liver extract has accelerated blood regeneration and at the same time increased the respiratory exchange of anemic animals. 4. A protein-free spleen extract has distinctly lowered the respiratory exchange of normal animals. The metabolism of anemic animals thus treated was practically the same as before bleeding and treatment. The recovery of the spleen extract-treated animals was not complete during the period of observation. This extract may have been somewhat toxic. In spite of this disturbing factor we are not inclined to accept the view of C. D. and E. W. Leake (15) and Thalhimer (16) that the spleen takes part in the stimulating effect upon blood regeneration when given in combination with red bone marrow by mouth.     

THE INFLUENCE OF THE SUPRARENAL CORTEX ON THE GONADS OF RABBITS : I. THE EFFECTS OF SUPRARENAL INJURY (BY REMOVAL OR FREEZING) ON THE INTERSTITIAL CELLS OF THE OVARY.

1. Moderate or marked ovarian enlargement has been observed in 76 per cent of rabbits which survived double suprarenalectomy over 30 days. 2. The ovarian enlargement consists essentially of an hypertrophy of the interstitial cells. 3. The hypertrophy of the interstitial cells is a compensatory reaction and adds further data to the functional interrelation between the suprarenal cortex and the interstitial cells.     

IMMUNOLOGICAL STUDIES IN RELATION TO THE SUPRARENAL GLAND : III. THE EFFECT OF INJECTIONS OF EPINEPHRINE ON THE HEMOLYSIN FORMATION IN NORMAL RATS.

The effect of subcutaneous injections of varying amounts of epinephrine on the hemolysin formation of normal adult albino rats was studied. In one group of experiments the rats received 0.4 mg. per kilo per day in two injections during 3 days prior and 4 days subsequent to the injection of sheep cells. Another series received the same daily amounts but only during 4 days subsequent to the injection of antigen. A third series received the same daily amounts only during 1 day prior and 2 days subsequent to the injection of sheep cells. In a second group of experiments smaller amounts of epinephrine were given during 3 days prior and 4 days subsequent to the injection of antigen. The amounts used were 1/5th, 1/20th, 1/40th, and 1/60th the daily quantity of epinephrine injected in the first group of experiments.     

THE INFLUENCE OF THE SUPRARENAL GLAND ON THE THYMUS : III. STIMULATION OF THE GROWTH OF THE THYMUS GLAND FOLLOWING DOUBLE SUPRARENALECTOMY IN YOUNG RATS.

1. Double suprarenalectomy in growing rats is an additional stimulus for thymic growth and brings about marked prepubertal hyperplasia of this gland. 2. Our results on young rats suggest that the suprarenal cortex may be a factor in the excessive thymic hyperplasias seen in infants and children.     

THE INFLUENCE OF THE SUPRARENAL GLAND ON THE THYMUS : II. DIRECT EVIDENCE OF REGENERATION OF THE INVOLUTED THYMUS FOLLOWING DOUBLE SUPRARENALECTOMY IN THE RAT.

1. Regeneration of involuted thymuses of old rats follows double suprarenalectomy in this species with great constancy. 2. Partial thymectomy alone does not induce compensatory secondary hyperplasia in involuting glands. 3. Regeneration of the thymus following suprarenalectomy would appear to be completed in most rats in about 2 weeks; and it probably begins in the medulla.     

STUDIES ON THE SUPRARENAL CORTEX : V. THE INFLUENCE OF THE CORTICAL HORMONE UPON THE EXCRETION OF WATER AND ELECTROLYTES IN THE SUPRARENALECTOMIZED DOG

1. The withdrawal of maintenance injections of the cortical hormone from the suprarenalectomized dog during balance experiments, in which a constant meat diet is given, with constant fluid and salt intake, is followed by increased urinary loss of sodium and chloride, and by retention of potassium and nitrogen. 2. Where the water intake is low, a definite diuresis usually accompanies this excretion of sodium and chloride, but where fluids are forced, no diuresis may be observed. 3. The reinjection of the cortical hormone in suprarenal insufficiency causes an active renal excretion of potassium which is greatly in excess of the probable extra accumulation of this component in the extracellular fluids during the period when insufficiency is developing. This potassium excretion is surmised to be sufficient to account for such an accumulation, if diffusible potassium is present in like concentration equally throughout all of the body water, intracellular as well as extracellular. The excretion of potassium is accompanied by a. corresponding excretion of phosphate and of nitrogen. 4. The excretion of electrolytes which is associated with withdrawal and with subsequent reinjection of suprarenal cortical hormone differs from the effects produced with various diuretic agents regarding which data are available. The effects produced by injection of the cortical hormone during suprarenal insufficiency, however, do resemble those produced with pituitrin, particularly in the greatly increased excretion of potassium relative to sodium, and in the coincidental dilution of the circulating blood. They suggest the possibility that the two similar effects may be ascribable to a common cause.