Biomedical subjects
Publications and source records attributed to M K Elson.
Dynorphin is a potent opioid peptide. Using a highly sensitive radioimmunoassay we have measured the levels of immunoreactive (ir) dynorphin in the cortex, hypothalamus, anterior and posterior pituitary in hyperthyroid and hypothyroid rats. Ir dynorphin levels were increased in the cortex of hypothyroid animals and decreased in the hypothalamus of hyperthyroid rats.
Endotoxin-induced fever in rabbits causes a rapid decrease in serum T3, a reciprocal rise of 3,3',5'-tri-iodothyronine (rT3), and a less marked reduction in T4 with a rebound at 24 hr. To answer the question whether the alteration in hormone levels was the result of a decrease in T3 or T4 production and release or of an increase in T3 and T4 metabolism, we measured the disappearance of [125I]T4 and [125I]T3 during endotoxin-induced fever and externally applied heat. Results showed no significant difference in disappearance of [125I]T4 or [125I]T3. This suggests that the rapid change in T3 levels associated with endotoxin fever is due to an inhibition of thyroid production and peripheral conversion, and not to increased metabolism of hormones.
Two indices of free thyroxine (T4) and four methods of free T4 measurement were compared in 85 patients with acute illness, hospitalized in intensive care units. All of the methods of free T4 measurement in critical illness were nonspecific, and two of the methods failed to suggest hypothyroidism in two patients with primary hypothyroidism and another associated critical illness. Since the ideal screening test should be both sensitive and specific, all tests for free T4 used in this study should be interpreted with caution in severely ill patients.
Thyroid function was measured in 86 patients hospitalized in an intensive care unit. Two patients were found to have primary hypothyroidism and were excluded from the study. Hypothyroxinemia with normal thyroid-stimulating hormone (TSH) levels was found in 22% of the patients and was associated with a high mortality (thyroxine [T4] levels less than 3.0 micrograms/dL, 84% mortality; T4 levels of 30 to 5.0 micrograms/dL, 50% mortality; and T4 levels greater than 5.0 micrograms/dL, 15% mortality). There was a high correlation between low T4 levels and mortality.
The accumulation of false neurotransmitters such as octopamine and depletion of true neurotransmitters such as dopamine have been purported to play a pathogenetic role in portal systemic encephalopathy (PSE). Therefore, we measured plasma prolactin, a known sensitive indicator of functional dopamine activity in man, in an attempt to evaluate dopaminergic function in 21 patients with alcoholic liver disease and PSE and several control groups. Subjects with PSE had markedly elevated prolactin levels (P less than 0.01) when compared to all control groups. Moreover, patients with PSE were divisible into two groups, 12 having mildly increased prolactin levels and 9 having markedly elevated levels. Although the degree of PSE was similar in both groups, those PSE patients with the higher prolactin values had significantly greater derangement of serum albumin, bilirubin, prothrombin time, and also had a higher mortality (100%). These data: (1) provide evidence consistent with the hypothesis of altered neurotransmitter function in individuals with chronic alcoholic liver disease, particularly those manifesting evidence of PSE; (2) suggest that altered dopamine function in chronic liver disease may have pathophysiologic significance as judged by altered hormone release; (3) demonstrate that a markedly elevated plasma prolactin level in individuals with PSE carries an ominous prognosis; and (4) suggest a possible role for the plasma prolactin in the selection and monitoring of PSE patients who are to be treated with agents aimed at correcting neurotransmitter abnormalities.
Serum was obtained from 11 patients with nonthyroidal illness (NTI) and from 9 control subjects. Patients with NTI demonstrated decreased total T4 and T3 levels; increased rT3, T3 resin uptake, and percent free (dialyzable) T4 levels; and normal TSH and free T4 concentrations in vitro. In addition, the effects of control and patient sera on the first pass extraction of labeled T4 and T3 by rat liver was measured with a tissue sampling-single injection technique. The percent of total serum T4 and T3 that was transported into liver on one pass was 17 +/- 2% and 77 +/- 5%, respectively, in the case of NTI, and these values were no different from control estimates. The concentrations of total serum T4 and T3 available for transport into liver in vivo were 0.69 +/- 0.13 micrograms/100 ml and 21 +/- 2 ng/100 ml, respectively, in NTI, and these values were 46% and 18% of control values, respectively. Therefore, in contrast to in vitro estimates of free T4, in vivo measurements indicate the amount of circulating T4 or T3 that is available for transport into liver cells in NTI is reduced in proportion to the decrease in total plasma hormone.
Osteomyelitis of maxillofacial bones is difficult to differentiate from the results of trauma or malignancy, yet successful management is dependent upon early diagnosis and appropriate therapy. To determined if gallium-67 could differentiate infection from trauma or malignancy, 61 Tc-99m phosphate scans and 52 gallium-67 scans were made in 42 patients with maxillofacial disease. In all patients, definitive diagnosis was determined by surgery and/or clinical followup. Bone scans were positive in 37 patients. Gallium-67 scans were positive in 16 patients. Subsequent surgery and/or clinical followup demonstrated active osteomyelitis in 15 patients. From the data we conclude that: (a) the addition of Ga-67 scanning to the bone scans in evaluation of maxillofacial disease contributes significantly to differentiating trauma from osteomyelitis; (b) radiographic changes do not accurately reflect bone activity or differentiate osteomyelitis from trauma or malignancy; and (c) reduction in accumulation of gallium-67 in followup scans is a useful indicator for the termination of therapy in osteomyelitis.
Four patients had high serum thyroxine (T4) concentrations during periods of heavy amphetamine abuse. After amphetamine was withdrawn, serum T4 returned to normal. Administration of amphetamine to monkeys induced a rise in serum T4; in this model the high T4 level appeared to be caused by increased serum thyrotropin. The mechanism of this effect is unclear but is presumably mediated via the hypothalamus. Awareness of transient hyperthyroxinemia due to amphetamine may allow the physician to avoid confusion with true thyrotoxicosis.
Thyroid hormones in man are affected by acute and chronic febrile states. To define these acute changes, we used a previously described rabbit model. Serum levels of T3, rT3, and T4 were measured at 0, 2, 4, 6, and 24 hr following injection of 1 microgram E. coli endotoxin, and during heat-induced hyperthermia. All rabbits receiving endotoxin developed fever with peaks at one hour (delta T = 1.1 degrees C) and three hours (delta T = 1.4 degrees C); they then defervesced to base levels at 6 hr. Similar temperature elevations occurred with heat-induced hyperthermia. Results show that endotoxin-induced fever produces changes similar to those reported during infections to man, and more rapidly than previously recognized. These include a prompt decrease in T3, reciprocal rise in rT3, and an initially reduced T4 that rebounds above basal levels. These findings may represent suppressed TSH release, alteration of peripheral monodeiodination of T4 from T3 to rT3, or enchanced clearance of T3. Heat-induced hyperthermia, except for slight decrease in T4 at 6 and 24 hr, had little effect on thyroid hormones.
Recently two radioimmunoassays have been independently developed for determination of bleomycin levels. In this study these assays are compared with each other and with a standard microbiologic assay for bleomycin. Bleomycin levels were determined in serum and urine samples obtained at varying intervals following intramuscular bleomycin injection. There were systematic differences between the assays. One radioimmunoassay indicated bleomycin levels lower than the levels indicated by the microbiologic assay with serum samples. With urine samples, both radioimmunoassays indicated bleomycin levels greater than the microbiologic assay.
Prolactin responses to provocative thyrotropin releasing hormone (TRH) stimulation were evaluated in 20 cirrhotic men with gynecomastia. Fifteen of these cirrhotic men had normal responses with a minimum doubling of the prolactin concentration above basal in response to TRH. Five had abnormal (autonomous) responses in that they failed to double their basal level or had a paradoxical decrease from basal in response to TRH. Moreover, these same five men failed to have a sleep-related increase in plasma prolactin. Three of them also failed to respond to chlorpromazine stimulation. Such abnormal responses are generally associated with the presence of a prolactin secreting pituitary tumor. Basal plasma levels of prolactin were measured in all 20 men studied. The five men who failed to respond to TRH had significantly greater basal prolactin concentrations (80.5 +/- 18.7 ng/ml) than did the 15 men who responded normally (33.7 +/- 4.3 ng/ml) (p less than 0.01), although all 20 had increased prolactin levels relative to that of controls (10.8 +/- 0.9 ng/ml) (both p less than 0.01).
Prolactin responses to provocative thyrotropin-releasing factor (TRH) stimulation were evaluated in 43 chronic alcoholic men were divided into groups for analysis based on the presence or absence of gynecomastia and the histologic appearance of their livers as determined by percutaneous liver biopsy. Compared to the normal volunteers, alcoholics with reversible liver disease (fatty liver) had reduced basal prolactin levels and exaggerated TRH responses. In contrast, alcoholics with cirrhosis and gynecomastia had markedly elevated basal prolactin levels and reduced responses to TRH. The results of this study combined with previously reported findings in cirrhotic men provide a basis for a possible explanation for the signs of feminization frequently found in alcoholic men.
Fetal and adult bovine serum albumin were purified by standard techniques and then treated with activated charcoal at pH 2.75 to remove small molecular weight legands. The two proteins were compared and found to be identical by the following criteria: isoelectric focusing, electrophoresis on cellulose acetate and polyacrylamide gel, by the binding of bromcresol green, salicylic acid, diphenylhydantoin, and six different fatty acids (palmitic, stearic, oleic, elaidic, linoleic, and arachidonic). Reports of marked differences in the capacities of fatal and ault plasma to bind bilirubin and various drugs have usually been attributed to the presence of a "fetal" albumin. Our results, however, are consistent with the view that there is no difference between adult and fetal albumin and that the observed altered binding properties of fetal plasma are due to the tight binding of a ligand to fetal albumin in blood, which modifies the protein's affinity for lipophilic compounds.
A radioimmunoassay for bleomycin, suitable for monitoring serum and urine drug levels, has been developed. Antisera were obtained from rabbits immunized with a conjugate of bleomycin and human serum albumin.Bleomycin labeled with 57Co was used as the tracer. Antibody-bound and free bleomycin were separated by precipitation with polyethylene glycol. The assay could determine bleomycin levels down to 0.025 mug/ml. The assay was precise, with a coefficient of variation of 2.8% Other drugs likely to be administered in combination with bleomycin did not interfere with the radioimmunoassay.
Because skeletal images obtained with a commercial lyophilized preparation of 99mTc-Sn-pyrophosphate were occasionally degraded by liver and spleen uptake, a method for preparing 99mTc-Sn-pyrophosphate and a system for in-house quality assurance were developed. Control of the age of the stannous chloride solution and the final pH of the 99mTc-Sn-pyrophosphate eliminated the undesirable uptake. The quality and body distribution of the in-house preparation were compared to those of the radiopharmaceutical from a commercial kit.
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Dynorphin is an opioid peptide distributed throughout the central nervous system. Using a highly specific and sensitive radioimmunoassay for dynorphin we have examined the effect of stress on ir-dynorphin levels in the cortex and hypothalamus of the rat. Stresses related to food ingestion, i.e. starvation (72 hr), mild tail-pinch and insulin (10 U/kg) induced hypoglycemia all produced alterations in ir-dynorphin levels in the cortex. In contrast, restraint stress and 10-minute swim stress produced no changes in ir-dynorphin levels in either the hypothalamus or the cortex. Two hour exposure at 4 degrees C resulted in a fall in ir-dynorphin levels in the hypothalamus. Taken together with previously reported pharmacological effects of dynorphin-(1-13), these results suggest a possible physiological role for dynorphin in appetite and temperature regulation.