"Medical informatics in a medical research facility. An interactive multimedia presentation". Diabetes as a model.

This interactive demonstration provides a model for integrating information in a medical facility. By the use of networking computers, diagnostic data and scientific data are shared between geographically-separated clinical and research units. Data collected in a patient database in the outpatient clinic is sorted on specified qualifying criteria and the resulting subset further analyzed for research studies. To show the process of patient selection from a general database to a diabetes database, and further selection to a subset of diabetes, i.e., Diabetic Neuropathy, the authors used HyperCard. Firstly, HyperCard provided us with a flexible design allowing for both vertical and horizontal progressions. Because we wanted to include an educational component on diabetes and its complications, this flexibility was important. At any point in the demonstration, the viewer is able to access more information nested in several levels. Secondly, we wanted to be able to import a variety of programs that are used to translate diagnostic data into scientific data that is analyzed and prepared for publication in a medical textbook or journal. According to Douglas Adams, author of "Pathways and Relationships", HyperCard occupies the same niche in the evolution of software as human beings do in the evolution of life. "It's the fact that we are unspecialized but infinitely adaptable that has been our success as a species. In the same way, HyperCard is unspecialized but can turn its hand to any kind of task. And if the task is beyond it, HyperCard can use the phone, go for a ride on Excel, or go out and find a powerful graphics tool or sophisticated wordprocessing program!"

Fasting decreases thyrotropin responsiveness to thyrotropin-releasing hormone: a potential cause of misinterpretation of thyroid function tests in the critically ill.

We have previously reported that caloric deprivation inhibits peripheral T4 metabolism and blunts the TSH response to TRH in euthyroid obese subjects. To determine whether these phenomena also occur in hypothyroid subjects, T4, T3, rT3, and the TSH response to TRH were measured initially and after a 60-h fast in seven hypothyroid patients. Short term fasting caused a 29% decrement in the maximum serum TSH increment and a 32% decrement in the integrated TSH response to TRH (P less than 0.01). In two subjects with mild hypothyroidism, basal TSH as well as the TSH response to TRH were reduced to levels within the normal range. Specifically, basal TSH values decreased from 7.6 to 3.5 microU/ml and from 11 to 4.1 microU/ml. In the seven subjects, mean serum T3 decreased significantly from 88 to 60 ng/dl, (P less than 0.05) and rT3, initially undetectable in six of seven subjects, rose to detectable or low normal values in four of seven subjects, serum T4 remained at 2.7 micrograms/dl during both study periods. We conclude that 1) fasting induces changes in both peripheral thyroid hormone metabolism and the hypothalamic-pituitary axis in hypothyroid individuals which are qualitatively similar to those that occur in euthyroid subjects; and 2) in certain hypothyroid subjects, fasting alone can decrease basal TSH values to within the normal range. If these data can be extrapolated to critically ill subjects whose caloric intake may be diminished, they suggest that basal TSH concentrations in moderately and severely hypothyroid critically ill subjects will accurately reflect the biochemically hypothyroid state. However, mild degrees of hypothyroidism in critically ill subjects might be overlooked due to the lowering effect of fasting or poor caloric intake alone on basal TSH concentrations.

T3 may be a better agent than T4 in the critically ill hypothyroid patient: evaluation of transport across the blood-brain barrier in a primate model.

Thyroid hormone transport across the blood brain barrier in hypothyroid patients is clinically important yet poorly understood. To study this question, 200 micrograms of thyroxine (T4), 100 micrograms of 3,5,3'-triiodothyronine (T3) and 100 micrograms of 3,3',5'-triiodothyronine (reverse T3) were administered separately to 3 baboons, first iv and at a later date intrathecally (IT). Six animals were used. Three received the iv injections and three received the IT injections. In each of the 18 experiments, cerebrospinal fluid (CSF) and serum specimens were collected serially for 6 h after injection. Mean maximal elevations from baseline in CSF iodothyronine levels were 100 +/- 10 ng/dl after iv T4, 3921 +/- 293 ng/dl after iv T3 and 31 +/- 17 ng/dl after iv reverse T3. When given IT in the same dosages, the mean maximal increases in serum iodothyronine concentrations were: 1670 +/- 600 ng/dl for T4, 806 +/- 405 ng/dl for T3, and 210 +/- 43 ng/dl for reverse T3. In every animal studied, rapid bidirectional transfer of T3 from serum to CSF and CSF to serum occurred, whereas iv T4 resulted in delayed minimal increments in CSF T4 concentration. Isotopic experiments were also performed and the results analyzed using a kinetic model. When 125I-T3 was given iv, the equilibrium point in CSF was observed within 90 min with 1.7% of the administered dose/L able to be counted in CSF at any moment in time. When labeled T4 was given iv, only 0.6% of the administered dose/L was counted in CSF and the equilibrium point was not reached until 360 min. These data suggest: (a) T4, T3, and reverse T3 are all capable of bidirectional transfer across the blood brain barrier, (b) T3 may be a better agent than T4 in treating patients with myxedema coma because T3 crosses more rapidly and more completely from serum to CSF.

Adaptation to hypocaloric feeding: physiologic significance of the fall in serum T3 as measured by the pulse wave arrival time (QKd).

We have investigated the physiologic significance of the decline in serum triiodothyronine (T3) occurring during hypocaloric feeding by measurement of changes in cardiovascular function. The QKd interval, the interval between the Q wave of the electrocardiogram and the onset of Korotkoff sounds at diastolic pressure at the brachial artery, is the sum of the preejection period and pulsetransmission time, and has proven to be a sensitive and effective measure of the effect of thyroid hormones on the cardiovascular system. Fifteen euthyroid obese volunteers underwent successive 2 wk periods of hypocaloric feeding (200-400 calories per day) interspersed with periods of at least 2 wk of re-feeding on a weight-maintaining diet (1500 calories). In a later phase subjects received oral supplementation of triiodothyronine (T3) in addition to the diet to prevent the fall in serum T3. In the last study phase, subjects on the diet received supplementation with oral thyroxine (T4), which prevented the fall in serum T3 and resulted in a slight increase in serum T4. During the first 2 wk period of hypocaloric feeding, there was a statistically significant increase in QKd, and a decrease in pulse rate, compatible with a hypothyroid state relative to initial measurements. When oral T3 supplementation was given, the rise in QKd and fall in pulse rate were prevented. Likewise, with oral T4 supplementation, the changes in QKd and pulse were prevented. Thus, the fall in serum T3 occurring during hypocaloric feeding is associated with changes in the cardiovascular system which are qualitatively similar to those observed during hypothyroidism. The present data, taken with other data in the literature, suggest that the decline in serum T3 during hypocaloric feeding may be an adaptive mechanism to conserve energy during caloric deprivation.

Malignant pheochromocytoma. Severe clinical exacerbation and release of stored catecholamines during lymphoma chemotherapy.

The association of malignant pheochromocytoma and poorly differentiated lymphocytic lymphoma has not previously been reported. A case is presented of a 58-year old man with a 20-year history of malignant pheochromocytoma well controlled on Dibenzyline who was found to have poorly differentiated lymphocytic lymphoma. During lymphoma chemotherapy with cyclophosphamide, vincristine and prednisone (VCP) he developed tachycardia and syncope accompanied by severe hypertension. During the next course of chemotherapy one month later, 24-hour urinary VMA, metanephrine and catecholamine values were determined before, during and after the chemotherapy and were found to have increased two- to ten-fold. This suggests that VCP caused tumor lysis with release of catecholamines into the circulation.

Euthyroid familial hyperthyroxinemia due to abnormal thyroid hormone-binding protein.

A family is described in which three members had an elevated total serum thyroxine level and free thyroxine index. Each affected subject was clinically euthyroid and had a normal pulse wave arrival time (QKd), serum triiodothyronine and free thyroxine levels, and a normal serum thyroxine-binding globulin (TBG) concentration. Electrophoresis of their serum with 125I-labeled thyroxine revealed increased thyroxine binding in the albumin region. In addition, this abnormal protein, like thyroxine-binding globulin, bound 125I-labeled triiodothyronine and 125I-labeled reverse triiodothyronine. However, electrophoresis of serum treated by sialidase (neuraminidase) digestion suggested that this abnormal protein is not an anomalous form of thyroxine-binding globulin "buried" in the albumin area. These cases of euthyroid familial hyperthyroxinemia due to an abnormal thyroid hormone-binding protein show that an elevated serum thyroxine level or free thyroxine index is not always sufficient to confirm the presence of thyrotoxicosis.

Familial elevations of total and free thyroxine in healthy, euthyroid subjects without detectable binding protein abnormalities.

Elevations of serum thyroxine without thyrotoxicosis or binding protein abnormalities have been documented in 8 of 13 family members, representing 4 generations. This syndrome appears to represent an elevated threshold for the amount of free thyroxine substrate required to maintain adequate T3 production form the peripheral monodeiodination of T4. It reiterates the need for a prudent re-evaluation of all clinically euthyroid patients with elevated serum thyroxine concentrations before concluding that they are indeed thyrotoxic.

Secondary adrenal insufficiency after intrathecal steroid administration.

A 38-year-old man developed secondary adrenal insufficiency as a consequence of intrathecal methylprednisolone administration. Evidence in support of this diagnosis included an absent plasma cortisol response to insulin-induced hypoglycemia, an inadequate adrenal response to exogenous corticotropin stimulation, a typical delayed response to prolonged corticotropin infusion over 3 days, and the findings of an elevated level of prednisolone in the cerebrospinal fluid a full 2 months after its administration. It is therefore recommended that patients receiving intrathecal steroids be carefully observed for the possible development of secondary adrenal insufficiency.

Thyroid hormone homeostasis in states of relative caloric deprivation.

Starvation is accomplished by significant changes in the hypothalamic-pituitary-thyroid axis and in peripheral thyroid hormone metabolism. Less well studied, however, are the effects on thyroid hormone economy produced by hypocaloric feeding. We explored these changes in obese patients fed 200, 400, or 600 cal/day of either carbohydrate of protein for 28 days. T4' T3' reverse T3 and the TSH response to TRH were measured at frequent intervals. Each patient demonstrated a transient rise in reverse T3 and a fall in T2 that returned to near basal levels by the end of the study period. The TSH response to TRH on the other hand, declined to approximately 50% of control values and remained at that level throughout the course of study, regardless of the type of substrate or calorie level chosen. The results indicated that hypocaloric feeding is associated with changes in thyroid hormone economy similar to those in starvation and that peripheral (changes in T3 and rT3) and central (TRH response) events are controlled by separate mechanisms.

Somatostatin effects on lower esophageal sphincter function.

The effect of somatostatin (GH-RIH) infusion (2 microgram/min) on lower esophageal sphincter pressure (LESP) responses to various stimuli was evaluated in adult male baboons. GH-RIH infusion did not affect basal LESP, but did cause a significant suppression of mean immunoreactive insulin (IRI) to 5.8% of basal values (P less than 0.05). Pentagastrin IV caused dose-related increases in LESP that were unaffected by GH-RIH. Abdominal compression caused a threefold rise in LESP (P less than 0.005) both without and with GH-RIH. However, atropine (20 microgram/kg iv bolus) completely blocked this cholinergic LES pressure response. Intragastric alkali as well as intragastric glycine caused significant increases in LESP (P less than 0.05). These LESP responses to alkali and to glycine were totally abolished by GH-RIH. In conclusion, GH-RIH infusion in the baboon does not affect basal LESP, LES smooth muscle response to exogenous stimulation, nor a cholinergically mediated LES response. GH-RIH does inhibit the response of LESP both to intragastric alkali and to glycine by the apparent suppression of a hormonally mediated mechanism.

Plasma testosterone, luteinizing hormone and follicle-stimulating hormone one day after vasectomy.

Plasma testosterone, LH and FSH were measured in 20 healthy subjects prior to and one day after bilateral vasectomy. No significant change in these hormones was noted after surgery. These data suggest that the decrease in free testosterone index and FSH reported by others at one week post-vasectomy is probably not related to the effects of psychological stress, local anesthesia or surgical stress, either singularly or in concert. Further studies are indicated to evaluate the transient hormonal changes reported within the first few weeks following vasectomy.

PIP: In the attempt to clarify the stress effect of vasectomy, the plasma testosterone -- luteinizing hormone (LH) and follicle stimulating hormone (FSH) was measured before and 1 day following bilateral transcrotal vasectomy performed on 20 men between the ages of 24 and 53 years. Plasma testosterone -- LH and FSH -- were measured by radioimmunoassay. All measurements were performed in duplicate and samples from each individual were measured in the same assay. All values were in the normal range, and there was no signficant change after surgery (compared to basal values) in any of the parameters measured. The data suggest that the decrease in free testosterone index and FSH reported by others at 1-week post-vasectomy is probably not related to the effects of psychological stress, local anesthesia or surgical stress, either singularly or in combination.

A radioimmunoassay for 3',5'-diiodothyronine.

The present report describes a RIA for 3',5'-diiodothyronine (T2) that can be performed on unextracted serum and which has a lower limit of detectability of 2 ng/dl. Cross-reactivity with other iodothyronines was negligible, except for rT3 which began to demonstrate cross-reactivity when rT3 levels were elevated to 180 ng/dl. Employing this RIA for T2, we have determined that 83 healthy individuals had a mean (+/-SE) serum T2 concentration of 5.0 +/- 0.3 ng/dl, thyrotoxic subjects (n = 12) had a mean T2 level that was elevated to 10.8 +/- 0.8 ng/dl, and each of 6 hypothyroid subjects had undetectable (less than 2 ng/dl) concentrations. Athyreotic patients (n = 8), receiving 0.4 mg T4 daily, had serum T2 concentrations of 15.0 +/- 3.0 ng/dl. Fasting in obese subjects was associated with an increase in serum T2 to 6.9 +/- 0.6 ng/dl from a basal level of 4.4 +/- 0.4 ng/dl in the fed state (P less than 0.01). Despite the fact that rT3 levels may be elevated in amniotic fluid and that rT3 is expected to represent the major source from which extrathyroidal T2 arises, T2 levels were low in amniotic fluid, being undetectable (less than 2 ng/dl) in 9 of 19 samples; the mean (+/-SE) T2 concentration in the 10 detectable samples was 5.4 +/- 1 ng/dl. These data indicate T2 is a normal component of serum and that the majority of serum T2 is probably derived from peripheral conversion. Furthermore, these observations suggest that situations associated with elevated rT3 levels (e.g. thyrotoxicosis and fasting) may also have increased T2 values.

Exercise tolerance test. Single-sample screening technique to rule out growth-hormone deficiency.

Parent-directed vigorous exercise was evaluated as a screening test for adequacy of pituitary growth-hormone release in 57 short-statured children. This method obviated the need for pharmacologic provocative testing in all but the four children with growth-hormone deficiency. In 92% of the euendocrine children, the immediate postexercise venous sample demonstrated an adequate growth-hormone level. Vigorous physical exercise after an 8- to 12- hour fast with a single postexercise serum growth-hormone sample is a reliable, safe, and cost-effective screening test for growth-hormone deficiency.

Premature craniosynostosis: A common complication of juvenile thyrotoxicosis.

Cranial vault suture opacification (apparent closure) and bone age were evaluated roentgenographically in ten children with thyrotoxicosis. The bone age was advanced greater than 2 SD in only one. In comparison to 96 control children of similar age, craniosynostosis was present in each of the patients with thyrotoxicosis. Children with advanced bone age, nine due to virilizing adrenal hyperplasia and three with precocious puberty, had normal radiographic patterns of cranial suture closure. Thyrotoxic premature craniosynostosis did not interfere with continued head circumference growth nor did it result in clinical or radiographic evidence of increased intracranial pressure. We conclude that premature craniosynostosis appears to be a common feature of juvenile thyrotoxicosis. Investigation of the possible long-term adverse effects of this entity on central nervous system function is advocated.

Total body retention of orally administered 47-calcium in primary hyperparathyroidism.

Using a whole body radiation detector, we have measured the total body retention of 47-Ca 7 days after oral administration of the isotope to patients with various disorders of calcium metabolism. The percent retention of 47-Ca given with 90 mg of unlabeled (carrier) calcium varied with the calcium metabolic status as follows: normals (n equals 14), 33-43 percent (mean 38); primary hyperparathyroidism (n equals 28), 32-74 percent (mean 52); idiopathic hypercalciuria (n equals 9), 34-49 percent (mean 42); and hypercalcemia of other etiology (n equals 3), 23-26 percent (mean 25). Almost half (13/28) of those with hyperparathyroidism showed a retention above 55 percent, distinguishing them from subjects with idiopathic hypercalciuria. Retention of 47-Ca correlated poorly with clinical measures of severity of hyperparathyroidism. When isotope was diluted with a smaller amount of carrier calcium (20 mg), retention was increaseed in normals (n equals 5) to 46-54 percent (mean 50) and in hyperparathyroidism (n equals 5) to 64-87 percent (mean 73). After surgical cure of hyperparathyroidism retention of isotope returned toward normal in 5 of 7 subjects. Whole body retention of orally administered 47-Ca may prove useful in detecting hyperparathyroidism in subjects with mild hypercalcemia or hypercalciuria.

Metabolic effects of propranolol in thyrotoxicosis. I. Nitrogen, calcium, and hydroxyproline.

The effect of propranolol on the hypermetabolism of thyrotoxicosis was investigated in eight subjects with diffuse toxic goiter. After equilibration on a constant nitrogen, calcium, and hydroxproline intake, nitrogen balance was determined before and during propranolol therapy prior to subtotal thyroidectomy and compared to similar data obtained in seven of the patients following surgically induced euthyroidism. Propranolol administration was associated with clinical amelioration and a rapid, statistically significant, improvement in nitrogen retention. A slight additional improvement in retention was noted in the postoperative euthyroid state. Oxygen consumption, measured serially in four patients, was not significantly changed by propranolol. Urinary loss of calcium, phosphorus, and hydroxyproline was unaffected by propranolol, but excretion of these substances was sharply reduced in the subjects restudied postoperatively. These data offer a evidence of a previously unreported nitrogen sparing effect of oral propranolol during its short-term administration in thyrotoxic man.