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Biomedical subjects

R C Smallridge

Publications and source records attributed to R C Smallridge.

121 records · Page 7Linked to original sources
PubMed1980

Solubilized nuclear thyroid hormone receptors in circulating human mononuclear cells.

In order to assess iodothyronine receptor interactions in man, we have developed a receptor assay for T3 and T4 in solubilized nuclear extracts from circulating mononuclear cells. This assay utilizes the technique of salt solubilization to isolate nuclear receptors and employs standard saturation analysis for T3 and T4 to determine maximal binding capacity (MBC) and equilibrium dissociation constants (Kd). We have determined that 11 normal subjects had a MBC for T3 of 1.20 +/- 0.20 pmol/mg DNA (+/- SE) and a Kd of 3.4 +/- 0.2 X 10(-10) M; the T4 MBC was 8.44 +/- 1.22 pmol/mg DNA and the Kd was 2.7 +/- 0.3 X 10(-10) M. Hypothyroid patients had a mean T3 MBC of 7.32 +/- 2.28 pmol/mg DNA and a mean T4 MBC of 40.04 +/- 21.36 pmol/mg DNA (P less than 0.05 compared to normal). Obese subjects (n = 12) had a basal fed MBC that was 0.66 +/- 0.13 pmol/mg DNA for T3 (P less than 0.05 compared to normal) and was 3.58 +/- 0.56 pmol/mg DNA for T4 (P less than 0.01 compared to normal). During fasting, the average T3 MBC increased to 1.43 +/- 0.31 pmol/mg DNA and the average T4 MBC increased to 9.63 +/- 2.46 pmol/mg DNA, values that are both significantly higher than those in the fed period; the dissociation constants were unaltered in obese subjects (compared to normals) in fed and fasting states. Gel filtration with 0.5 M agarose was employed to ascertain if the physicochemical properties of the solubilized mononuclear human cell receptor were similar to those previously observed in rat and human liver and kidney receptors. The elution profile obtained was similar to that reported earlier. The major binding activity has an estimated Stokes radius of 35 A and a molecular weight ratio of approximately 50,000 daltons. These studies indicate that: 1) high affinity T3 and T4 receptors exist in human mononuclear cells and have properties similar to those for T3 and T4 described previously in rat liver; 2) T3 and T4 receptor number tends to increase in hypothyroid subjects and tend to be lower in obese patients than in normal weight control subjects; 3) fasting is associated with an increase in both T3 and T4 MBC; and 4) despite their apparent physicochemical similarity, T3 receptors in rat liver and human mononuclear cells may be regulated differently, at least during fasting since hepatic T3 receptors decrease in the fasted rat. Collectively, these observations support the concept that human white cell T3 nuclear receptor binding is capable of rapid fluctuations, suggesting a mechanism for homeostatic regulation of T3 action.

Adult↗
PubMed1980

Glucagon kinetics in fasting: physiological elevations in serum 3,5,3'-triiodothyronine increase the metabolic clearance rate of glucagon.

We have attempted to determine if the elevated plasma glucagon concentration and delayed MCR of glucagon (MCRg) observed during caloric restriction are related to the decreased serum T3 that also occurs during fasting. Twelve obese subjects received a 3-h iv glucagon infusion during a 4-day fed period (1000 kCal/day) and again on approximately the third fasting day. Five patients fasted without receiving exogenous T3 (control group), whereas seven subjects fasted but also received 5 micrograms T3 orally every 4 h (T3 group) to maintain approximately the same serum T3 levels in the fed and fasting periods. Glucagon production rates (GPR) were derived by multiplying the MCRg by the respective basal plasma glucogon concentrations. In the control group, the MCRg was 442 +/- 55 ml/m2 . min in the postabsorptive state and decreased to 312 +/- 49 ml/m2 . min (P < 0.025) during fasting, whereas in the T3-treated group, the postabsorptive MCRg was 304 +/- 22 ml/m2 . min and increased during fasting to 417 +/- 47 ml/m2 . min (P < 0.025). The GPRs in the control group were statistically unaltered between the fed (27.7 +/- 3.0 ng/m2 . min) and fasted (22.9 +/- 1.8 ng/m2 . min) intervals, but GPR increased from 37.9 +/- 6.1 ng/m2 . min during fasting to 49.2 +/- 9.1 ng/m2 . min when T3 was administered (5 micrograms every 4 h). The net plasma glucose increment in response to glucagon decreased from 18 mg/dl (fed) to 5 mg/dl (fast) in the control patients and from 10 mg/dl (fed) to 7 mg/dl (fast) in the T3-treated subjects. In the T3-treated patients, serum T3 averaged 124 ng/dl during both feeding and fasting, and rT3 was 55 +/- 6 ng/dl during feeding and 49 +/- 5 ng/dl during fasting. In summary, the results from this study indicate that during fasting 1) slight physiological alterations in serum T3 influence the MCRg, and 2) T3 increases the GPR and blocks the customary fasting-induced rise in rT3. Conceivably, decreased T3 is an early event in the fasting state which serves to decrease the MCRg, a process which subsequently regulates glucose homeostasis.

Adult↗
PubMed1979

Acromegaly and the heart. An echocardiographic study.

Twenty-seven patients with acromegaly had echocardiograms performed to delineate the ventricular septum, left ventricular posterior wall and mitral valve. Left ventricular function was assessed by calculating the systolic internal dimensional shortening of the left ventricle. Six patients met the criteria for asymmetric septal hypertrophy and eight had concentric left ventricular hypertrophy. The remaining 13 patients were categorized as "normal," although six had septal measurements greater than 11 mm. The group with asymmetric septal hypertrophy had significantly greater percentage of internal dimensional shortening during systole than either the normal group (p less than 0.05) or the group with left ventricular hypertrophy (p less than 0.01). Initial mean growth hormone levels were considerably higher in the group with left ventricular hypertrophy than in the normal group (93 versus 34 ng/ml). Thus, echocardiographic abnormalities are common in acromegaly, and patients with asymmetric septal hypertrophy and acromegaly appear to have significantly increased ventricular ejection. Many of the patients with left ventricular hypertrophy have no evidence of clinical cardiovascular disease, and their left ventricular hypertrophy may be related to higher initial growth hormone levels.

Acromegaly↗
PubMed1978

Inherited medullary thyroid carcinoma: a final monoclonal mutation in one of multiple clones of susceptible cells.

Inherited medullary thyroid carcinomas contain one form of glucose-6-phosphate dehydrogenase (G6PD) in black female patients who are mosaic in normal tissues for G6PD types A and B. The same individual may have several tumors each containing either G6PD A or G6PD B. The data suggest that the inherited defect is an initial mutation producing multiple clones of defective cells; each tumor then arises as a final mutation in one clone of these cells.

Black People↗
PubMed1978

Metabolic clearance and production rates of 3,3',5-triiodothyronine in hyperthyroid, euthyroid, and hypothyroid subjects.

To further elucidate the peripheral metabolism of rT3 and to determine if rT3 production rates vary directly with thyroid function, we measured the disappearance of [125I]rT3 in thyrotoxic and hypothyroid subjects as well as in athyreotic patients maintained eumetabolic on exogenous T4. Kinetic parameters were determined by noncompartmental analysis, and serum concentrations of rT3 and T4 were determined by specific RIAs. In six hyperthyroid, seven euthyroid, and six hypothyroid subjects, the MCRs were 190.7 +/- 15.7, 111.7 +/- 13.2, and 71.8 +/- 7.0 liters/day kg, respectively (mean +/- SE). Production rates (PR) for these same groups were 271.3 +/- 40.5, 51.7 +/- 9.1, and 4.3 +/- 0.6 micrograms/day/70 kg. The observed differences in MCR and PR among the three study groups were highly significant (P less than 0.002). These data indicate that in comparison to euthyroid subjects, rT3 PR and MCR are increased in thyrotoxic and decreased in hypothyroid individuals.

Adult↗
PubMed1978

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.

Amniotic Fluid↗
PubMed1975

Inherited antithrombin-III deficiency causing mesenteric venous infarction: a new clinical entity.

Primary superior mesenteric venous thrombosis is sometimes preceded by peripheral thrombophlebitis. Inherited antithrombin-III deficiency is a recently recognized autosomal dominant trait, which is characterized by thrombophlebitis and pulmonary embolism. This case report illustrates many features of both entities and strongly suggest a causal relationship. While long-term therapy has yet to be established, prophylactic therapy is recommended when asymptomatic individuals with known antithrombin-III deficiency are at increased risk of thrombosis. The efficacy of heparin alone has been unreliable, whereas Coumadin has been encouraging. Antithrombin-III concentrates are being developed and theoretically should be helpful. Patients with thrombophlebitis or pulmonary embolism should be suspected of having antithrombin-III deficiency. Such individuals also represent one mechanism to explain "primary" mesenteric venous thrombosis.

Adult↗
PubMedDate not supplied

Sodium ipodate increases triiodothyronine action in vivo.

Sodium ipodate (IPO) has been shown to bind nuclear T3 receptors (NT3R) in vitro, but previous studies have conflicted in regard to demonstration of this interaction in vivo. We sought evidence for IPO-NT3R binding in vivo by giving large doses of IPO to thyroidectomized (TDX) rats replaced with low doses of T3. We predicted that IPO-NT3R binding would inhibit T3 induced increases in mitochondrial alpha glycerophosphate dehydrogenase activity (alpha-GPDH) in kidney, heart and liver. Three groups of ten euthyroid rats each received 13 daily injections of vehicle, or 6 or 12 mg/100 g body weight of IPO, respectively. Both doses of IPO resulted in decreases in serum T3 and increases in serum TSH. Liver and kidney alpha-GPDH, however, were decreased only in the group receiving 6 mg IPO. In addition, three groups of 30 TDX rats were implanted with osmotic minipumps that contained T3 in the following concentrations: 33, 69 and 96 ng/ul. Ten rats in each group received 13 daily injections of vehicle, or IPO (vide supra). The alpha-GPDH responses were complex in that there was significant interaction between T3 and IPO effects in the kidney (AxB F ratio 5.13, p less than 0.001) and liver (AxB F ratio 2.85, p less than 0.05). The major finding, however, was that alpha-GPDH was not significantly reduced by IPO in any T3 replaced group. Rather, in all three organs, alpha GPDH was significantly increased above that produced by T3 alone by at least one combination of IPO and T3. Changes in serum TSH also suggested that IPO could enhance T3 effects. We conclude that IPO-NT3R binding is not a prominent mechanism via which the drug attenuates T3 effects in vivo. The data suggest that IPO may enhance T3 effects at the cellular level and that this enhancement may not be reflected by routinely monitored serum TSH. The latter observation may have clinical importance.

Analysis of Variance↗
PubMedDate not supplied

Effects of soman on neuroendocrine and immune function.

We have previously reported that plasma growth hormone (GH) and prolactin levels were markedly decreased in rats two weeks following a single dose (100 micrograms/kg, SC) of soman. We have now conducted additional experiments to attempt to determine whether neuroendocrine responses to physiological or pharmacological challenge are altered in rat survivors of soman exposure, and whether immune function, which can be affected by circulating hormones, is altered in the soman-exposed rats. In the present study, basal prolactin levels were not significantly lower in the soman-treated rats although prolactin increases in response to physiological or pharmacological challenge were attenuated. Also, basal growth hormone levels in soman survivors were similar to control levels in 2 of 3 experiments in the present report. In the third experiment, growth hormone levels were lower in soman-treated animals. Endocrine abnormalities appeared to be related to the severity of soman insult as assessed by changes in body weight following exposure. Both ACTH and prolactin responses to stress were impaired in a severely affected subpopulation of soman survivors. The thymus, an important immune organ, was decreased in weight in severely affected soman survivors, but other tests of immune function did not show differences between control and soman-exposed rats.

Adrenocorticotropic Hormone↗