Theodore B. Schwartz

Dynamics of plasma triglyceride turnover in man

Plasma free fatty acid (FFA) and triglyceride(TG) influx rates were determined in 17 patients with wide range of plasma triglyceride levels. No significant correlation was found between plasma FFA or TG influx rates and the plasma TG level in these patients. Alterations in the plasma TG levels were induced by various treatments, but plasma TG influx rates were not significantly or concordantly changed. It is concluded that plasma FFA and TG influx rates do not exert primary control of plasma TG levels. Rather, the data are compatible with the thesis that TG clearance is a major determinant of plasma TG concentration.

New Tactics for Hyperthyroidism: Sympathetic Blockade

Excerpt The similarity between signs and symptoms of hyperthyroidism and of excessive adrenergic activity is well known. Though it is clear that the thyroid hormones have many direct metabolic effe...

Fibrous dysplasia of bone with Vitamin D resistant rickets: A case study

Abstract A patient with the unusual combination of fibrous dysplasia of bone and Vitamin D resistant rickets is described. Studies performed provide evidence for normal gastrointestinal absorption of calcium, low renal tubular maximum of phosphate reabsorption (TmP), and elevated phosphate clearance responsive to alterations in serum calcium level. Possible mechanisms underlying these disorders are discussed.

The Occurrence of Carcinoma in Hot Thyroid Nodules: Report of Two Cases

Excerpt When the physician finds a patient with nodular goiter, he must consider the possibility of malignancy and decide whether surgery is indicated. Surgeons, generally, have found that the inci...

Outpatient Treatment of Paget's Disease of Bone with Mithramycin

Abstract Mithramycin is a cytotoxic antibiotic that causes hypocalcemia and diminishes the elevated osteoclastic activity characteristic of Pagets disease. Previous inpatient studies have shown th...

The Effect of Glucola, Diet Cola and Water Ingestion on Blood Glucose and Plasma Insulin

Summary A study was undertaken to investigate the effect of neurogenic influences on carbohydrate metabolism. Four normal subjects were given a cola flavored glucose preparation, a diet cola containing saccharin, and water. Only the glucose preparation produced significant changes in blood glucose and plasma insulin levels.

Propranolol-induced Insulin Release in Isolated Rat Islets of Langerhans

Immunoreactive insulin was measured in the medium following incubation of isolated rat islets of Langerhans in different concentrations of propranolol and propranolol plus glucose. Pretreatment with propranolol (20 μg./ml.) prevented glucose (3 mg./ml.)-mediated insulin release. Propranolol alone in concentrations up to 25 μg./ml. did not cause insulin release; however, at 50 μg./ml. this drug had strong beta-cytotrophic activity.

Serum Immunoreactive Insulin Levels During Glucose Tolerance and Intensive Islet Stimulation

Glucose tolerance and intensive islet stimulation tests were done on eighty-seven subjects who covered a broad range of age and glucose tolerance. The data suggest decreasing glucose tolerance with increasing age compatible with the observations of others. Over a broad range of glucose tolerance there was seen such a broad spread of serum immunoreactive insulin levels (IRI) that it was not possible to relate them directly to the degree of glucose tolerance seen. This suggested that multiple factors, including variations in peripheral resistance to insulin not attributable to known factors, are operative in determining glucose tolerance. Only when glucose tolerance was very abnormal or fasting blood sugar was elevated was there apparent decrease in serum IRI response to the stimuli used, making it difficult to attribute mild-to-moderate degrees of glucose intolerance to lack of capacity for IRI release. A close correlation between the two-hour IRI in a glucose tolerance test and the levels obtained after the stimulus of glucagon and tolbutamide suggested that the former may be an adequate reflection of islet secretory capacity.

How To Learn from Patients: Fuller Albright's Exploration of Adrenal Function

The charm of Dr. Albrights presentations is that he not only presents some of the facts that they have discovered, but he also tells us how they may be interpreted. Kenneth Thompson Fuller Albright (1900-1969) is known, if known at all, among the present generation of medical students as the first to describe a rare form of bone disease, Albright osteodystrophy. Knowledgeable residents and junior faculty may also be aware of his pioneering descriptions of parathyroid diseases. However, few recognize how far his interests ranged across the then new and fertile field of endocrinology and metabolism and how monumental were his achievements. In a brief introductory note to his bibliography [1], Albright wrote, In my opinion, my contributions divide themselves into two groups: (a) clinical descriptions and (b) elucidations of pathological physiology. In category (a), by my count, he, along with his students and associates, described de novo or made definitive contributions to the delineation of an astonishing 14 major syndromes over a 20-year period [2]. In category (b), Dr. Albright excelled as well. He was one of the pioneers in the burgeoning sciences of human physiology and pathophysiology. Characteristically, he would identify some measuring stick, either in the laboratory or at the bedside, and then use it to test some pathophysiologic hypothesis. I have elected to single out and to describe in some detail his exploration of the workings of the adrenal cortex because his efforts in this area serve to illuminate the synergistic interactions between bedside medicine and basic science. At the same time, these studies provide elegant and instructive examples of how an astute clinical observer can unravel complex hormonal and metabolic interactions. The Cushing Syndrome Albrights strongly held concept of parathyroid action was based on his investigation of a single patient with idiopathic hypoparathyroidism [3]. In contrast, Albright cast a wide net in initiating his studies of adrenocortical abnormalities. He and his associates measured something in a spectrum of patients with endocrine disorders and then focused on those in whom there was an unexpected aberrant result. Their findings were reported in three papers, all published in 1941. In the first of these [4], a survey of changes in carbohydrate metabolism in several endocrine diseases, Albright and his colleagues showed that the Cushing syndrome was characterized by impaired glucose tolerance and decreased insulin sensitivity, the latter measured by the glucose-insulin tolerance test. In the second paper [5], the Boston group surveyed the changes in the 24-hour urinary excretion of neutral 17-ketosteroids, which was thought to be a rough measure of androgen secretion, in a similarly wide variety of endocrine abnormalities. One hundred thirty-five patients were tested and more that 1500 assays were done. By simply examining mean 17-ketosteroid values in pertinent disease states, Albright adduced convincing evidence that urinary 17-ketosteroids were the end-products of secretions from not only the testes but also the adrenal glands. He reasoned that because normal 17-ketosteroid excretion averaged 14 mg in men and only 9 mg in women, it was likely that 9 mg was secreted from the adrenal glands and 5 mg from the testes. He predicted correctly that among patients with Addison disease, women would excrete essentially no 17-ketosteroids and men would excrete only about 5 mg per 24 hours. Similarly, he found that patients with panhypopituitarism and loss of both adrenal and gonadal function showed negligible urinary 17-ketosteroid excretion. He concluded, again correctly, that the contribution of the ovaries to 17-ketosteroid excretion must be small because he found no change from normal urinary excretion values in patients who were surgically castrated or had undergone natural menopause. Albright also clearly asserted that all forms of the Cushing syndrome were caused by hyperfunction of the adrenal cortex. Although this assertion is for us an endocrinologic truism, in 1941 it was a bold effort to dispel a decade of confusion. Cushing, in his ground-breaking report of 1932 [6], tentatively concluded that the syndrome was due to pituitary basophilism because 2 of his 12 patients had shown only pituitary basophilic adenomas at autopsy. Whether the adrenal cortex was also involved was uncertain, although 1 patient had an adrenal adenoma and another had adrenal hyperplasia. Cushings view was challenged 3 years later by Oppenheimer and colleagues [7], who concluded that adrenal changes are practically essential for the development of the clinical features of basophilism. Others did not clarify matters when they suggested that the adrenal overactivity might stimulate the growth of pituitary basophils, and the waters were muddied further by the conclusion of Heinbecker [8] that either an adrenal tumor or hypofunction of paraventricular hypothalamic nuclei may be primary causes of the basophil degeneration which in turn is the immediate cause of Cushings syndrome. Still another confounding factor was the variation in histologic findings in the adrenal glands. These findings included tumors, both adenomas and carcinomas, bilateral hyperplasia, and, most puzzling, instances in which the adrenal glands were found to be histologically normal. Albright maintained that normal or not, such adrenal glands were hyperfunctioning. (At the time of these discussions it was not known that the Cushing syndrome could also result from ectopic adrenocorticotropic hormone [ACTH] production, although Albright must be credited with proposing the concept of tumoral ectopic hormone production in his description of a patient with hypercalcemia accompanying a hypernephroma [9].) Although contemporary investigators [10-12] agreed that some cases of the Cushing syndrome were attributable to adrenal hyperfunction it was Albright who cut the Gordian knot by insisting that all cases were caused by adrenal overactivity regardless of whether histologic abnormalities of the adrenal glands were shown or whether a pituitary tumor was present. Several years later [13], Albright happily accepted the suggestion of Kessel that the term Cushings disease is reserved for those cases in which a basophil tumor of the pituitary is present, whereas the term Cushings syndrome is used for the syndrome as a whole. Having cleared the etiologic air, at least to his own satisfaction, Albright turned his attention to his favorite preoccupation: pathophysiology. The third paper, published in 1941 [14], was devoted to the treatment of the Cushing syndrome with testosterone. Albright pointed out that although the 24-hour urinary excretion of 17-ketosteroids was greatly elevated in patients with adrenocortical carcinoma, it was only slightly elevated in patients with adrenal hyperplasia and, finally, that the measurement of urinary cortin in J.S.L. Brownes laboratory showed definite elevations. (It is unusual that Albright, such a sharp-eyed clinician, never recorded the differentiating observation that patients with pituitary adenoma showed typical Addisonian pigmentation of the skin but that patients with adrenocortical tumor did not.) When considering the pathogenesis of the Cushing syndrome, Albright drew heavily on the seminal studies of Long [15], who showed with irrefutable clarity that adrenocortical hormone enhanced protein catabolism through a process of gluconeogenesis from protein, with a resulting impairment of carbohydrate metabolism. Albright asked the rhetorical question, Are not many features of the Cushing syndrome the result of protein shortage? He responded with a resounding Yes, singling out muscular weakness, thinning of the skin, easy bruisability and osteoporosis. If the Cushing syndrome were indeed a state of hypergluconeogenesis, Albright reasoned that patients would improve when treated with an anabolic hormone. Again, his conjecture was found to be correct; long-term testosterone therapy was clearly efficacious: All the patients gained in weight and strength, their abdomens became less protuberant, the skin noticeably thicker and, with the disappearance of the reddish hue, they bruise less easily. The salutary effect of testosterone in the treatment of the Cushing syndrome was confirmed in the laboratory of J.S.L. Browne [13], but this form of therapy never gained much acceptance; surgical approaches remain predominant. Albright reviewed his findings on the Cushing syndrome in a 1943 Harvey lecture [13]. He credited Long with the importance of adreno-cortical hormone. in converting proteins and hence tissues into sugar (gluconeogenesis). Albright suggested the term S hormone (todays cortisol) to designate this sugar hormone. He pointed out that osteoporosis was the result of protein depletion rather than a disease of calcium metabolism and that an excess of S hormone would therefore lead to a decrease in bone density by depleting the proteinaceous bone matrix. He emphasized the fact that testosterone was more than just a stimulator of sexual organ growth; it promoted a generalized somatic anabolic effect. He was struck by Brownes observations of a patient with an interstitial cell testicular cancer. This individual had a 17 ketosteroid excretion of over 1000 mgs. per 24 hours and (failed) right up to his death, to lose weight or to become debilitated in spite of extensive metastases. Finally, Albright showed, using the elegant but arduous metabolic balance studies for which he was famous, that treatment with testosterone resulted in both the production of a strikingly positive nitrogen balance in these patients with the Cushing syndrome and the previously mentioned considerable improvement in their clinical state. He went on to speculate about the mode of action of the S hormone. He rejected the obvious possibility that the S hormone provoked a direct protein catabolic effect because baseli

Mithramycin and long remission of Paget's disease of bone.

Excerpt To the editor: Slightly more than a decade has passed since we reported the effects of mithramycin on Pagets disease of bone (1). During that interval we have used mithramycin in the treat...