Biomedical subjects

S Refetoff

Publications and source records attributed to S Refetoff.

At least 127 records · Page 7Linked to original sources

PubMed1991

Sequence of the variant thyroxine-binding globulin (TBG) in a Montreal family with partial TBG deficiency.

The variant thyroxine-binding globulin in a family from Montreal (TBG-M) has a reduced affinity for thyroxine, shows a slight cathodal shift on isoelectric focusing, and has an increased susceptibility to inactivation by heat and acid. We present the molecular basis for TBG-M, deduced by sequencing the entire 1245-bp coding regions and intron/exon junctions of the TBG gene of an affected hemizygous male. A single nucleotide substitution in the codon for amino acid 113 of the mature protein (GCC to CCC) was found, resulting in the replacement of alanine by proline. The mutation was confirmed by allele-specific amplification of genomic DNA from the propositus and three other affected family members. Since point mutations throughout the molecule have been shown to alter the properties of variant TBGs, and because amino acid substitutions with proline are known to impair stability and function of proteins, the replacement of alanine 113 by proline provides a logical explanation for the observed properties of TBG-M.

Amino Acid Sequence↗

PubMed1991

Complete thyroxine-binding globulin (TBG) deficiency caused by a single nucleotide deletion in the TBG gene.

Thyroxine-binding globulin (TBG) is the major thyroid hormone transport protein. Several inherited TBG variants resulting in partial and complete TBG deficiency have been shown to be caused by one or two nucleotide replacements in the coding regions of the TBG gene. Each manifests as a different change in the physical properties and/or biological function of the mature TBG protein. We now report sequencing of the entire coding region and exon-intron junctions of a TBG allele of a subject with inherited complete TBG deficiency, previously classified as TBG-CD6. A single nucleotide deletion was found in the codon for amino acid 165 of the normal TBG molecule. The shift in the reading frame due to this nucleotide deletion results in downstream encoding of two different amino acids followed by an early stop codon. This results in a mature protein of only 167 residues, as compared with the normal 395. Nine members of the TBG-CD6 family were tested for the presence of this mutation by allele-specific amplification. Seven of them were found to be carriers of the defect, with five hemizygous subjects manifesting complete TBG deficiency. The mutant allele correlated with the results of TBG analysis in serum. This defect was not present in affected subjects of any of seven unrelated families with complete TBG deficiency tested.

Base Sequence↗

PubMed1991

Sleep deprivation in the rat: XIII. The effect of hypothyroidism on sleep deprivation symptoms.

Previous studies of rats subjected to total sleep deprivation by the disk-over-water method had shown a large increase in energy expenditure (EE) and an initial increase followed by a later decrease in body temperature (Tb). It had been proposed that the increase in Tb resulted from regulation toward a higher temperature or setpoint, that the later decline in Tb resulted from excessive heat loss, and that the increase in EE supported both of these thermoregulatory changes. To evaluate this proposed role of the increase in EE, we examined whether blunting the EE rise in sleep-deprived rats by making them hypothyroid attenuated and/or shortened the initial increase in Tb and accelerated the later decline in Tb. Rats made hypothyroid by propylthiouracil administration (TxD rats) were totally sleep deprived and compared to hypothyroid yoked control (TxC) rats and to previously studied, untreated, totally sleep-deprived (TSD) rats. Neither TxD nor TxC rats showed large increases in EE like those of TSD rats. TxD rats did not initially increase Tb, as TSD rats had. Presumably, TSD rats had been able to support an initially elevated Tb, in spite of excessive heat loss, by large increases in EE, although even these increases were eventually insufficient. TxD rats showed much earlier and greater declines in Tb than TxC and TSD rats, eventually becoming severely hypothermic. These results support the interpretation that the large increase in EE previously seen in TSD rats had been compensatory for deprivation-induced thermoregulatory deficits. TxD rats survived an average of 17.1 days, which was not significantly different from survival time in TSD rats. However, there were differences in mortal processes between the two groups. TxD rats died or were sacrificed after chronic, severe hypothermia without observable signs of other morbid pathology. TSD rats had not shown similarly low Tb until just prior to death, but had shown signs of severe pathology, including severely debilitated appearance, disheveled fur, and severe lesions on their tails and on the plantar surfaces of their paws. These signs were diminished or absent in TxD rats, possibly due to blunted EE, lower Tb, or other effects of hypothyroidism. Because the skin changes seen in TSD rats were minimal in TxD rats, they could not have been responsible for the excessive heat loss.

Adipose Tissue, Brown↗

PubMed1991

Screening of nineteen unrelated families with generalized resistance to thyroid hormone for known point mutations in the thyroid hormone receptor beta gene and the detection of a new mutation.

Generalized resistance to thyroid hormone (GRTH) is a syndrome characterized by impaired tissue responsiveness to thyroid hormone. Two distinct point mutations in the hormone binding domain of the thyroid hormone receptor (TR) beta have recently been identified in two unrelated families with GRTH. One, Mf, involves a replacement of the normal glycine-345 for arginine in exon 7 and another, Mh, replaces the normal proline-453 for histidine in exon 8. To probe for the presence of the Mf and Mh defect in 19 unrelated families with GRTH, we applied separate polymerase chain reactions using allele-specific oligonucleotide primers containing the normal and each of the two mutant nucleotides at the 3'-position. A total of 24 affected subjects and 13 normal family members were studied. The mode of inheritance was dominant in 13 families, was unknown in 5 families, and was clearly recessive in 1 family in which only the consanguineous subjects were affected. Primers containing the substitutions specific for Mf and Mh amplified exons 7 and 8, respectively, only in affected members of each of the two index families. Primers containing the normal sequences amplified exons 7 and 8 of the TR beta gene in all subjects except affected members of one family. In this family with recessively inherited GRTH, neither exon could be amplified using any combinations of primers and DNA blot revealed absence of all coding exons. These results indicate a major deletion of the TR beta gene, including both DNA and hormone binding domains. Since heterozygous members of this family are not affected, the presence of a single normal allele is sufficient for normal function of the TR beta. These data also support the hypothesis that in the dominant mode of GRTH inheritance the presence of an abnormal TR beta interferes with the function of the normal TR beta. Distinct mutations are probably responsible for GRTH in unrelated families.

Alleles↗

PubMed1991

Modulation of glucose regulation and insulin secretion by circadian rhythmicity and sleep.

To define the roles of circadian rhythmicity (intrinsic effects of time of day independent of the sleep or wake condition) and sleep (intrinsic effects of the sleep condition, irrespective of the time of day) on the 24-h variation in glucose tolerance, eight normal men were studied during constant glucose infusion for a total of 53 h. The period of study included 8 h of nocturnal sleep, 28 h of continuous wakefulness, and 8 h of daytime sleep. Blood samples for the measurement of glucose, insulin, C-peptide, cortisol, and growth hormone were collected at 20-min intervals throughout the entire study. Insulin secretion rates were derived from C-peptide levels by deconvolution. Sleep was polygraphically monitored. During nocturnal sleep, levels of glucose and insulin secretion increased by 31 +/- 5% and 60 +/- 11%, respectively, and returned to baseline in the morning. During sleep deprivation, glucose levels and insulin secretion rose again to reach a maximum at a time corresponding to the beginning of the habitual sleep period. The magnitude of the rise above morning levels averaged 17 +/- 5% for glucose and 49 +/- 8% for calculated insulin secretion. Serum insulin levels did not parallel the circadian variation in insulin secretion, indicating the existence of an approximate 40% increase in insulin clearance during the night. Daytime sleep was associated with a 16 +/- 3% rise in glucose levels, a 55 +/- 7% rise in insulin secretion, and a 39 +/- 5% rise in serum insulin. The diurnal variation in insulin secretion was inversely related to the cortisol rhythm, with a significant correlation of the magnitudes of their morning to evening excursions. Sleep-associated rises in glucose correlated with the amount of concomitant growth hormone secreted. These studies demonstrate previously underappreciated effects of circadian rhythmicity and sleep on glucose levels, insulin secretion, and insulin clearance, and suggest that these effects could be partially mediated by cortisol and growth hormone.

Adult↗

PubMed1991

Low serum free thyroxine index in ambulating elderly is due to a resetting of the threshold of thyrotropin feedback suppression.

Subnormal free T4 index (FT4I) values (less than 80) with inappropriately normal serum TSH concentrations that could not be attributed to illness or drugs were found in 2.5% of ambulating elderly clinic patients. Six such individuals (three men and three women, aged 68.8 +/- 4.8 yr) were selected for their persistent thyroid test abnormalities and were sex and age matched to six subjects (67.7 +/- 4.9 yr) with normal FT4I (greater than 90) and TSH levels. The former also had low serum total T4 (TT4) and rT3 (TrT3) concentrations, but total T3 (TT3) and basal TSH values were normal and did not differ between the groups. Responses of ACTH, LH, FSH, TSH, and PRL to stimulation with CRH, GnRH, and TRH showed no differences between the two groups, indicating that the normal TSH concentration, inappropriate for the low FT4I level, is not due to generalized hypothalamic or pituitary dysfunction. Administration of 3 g iopanoic acid (IOP) daily for 3 days produced significant increases in the TT4 and TrT3 concentrations to the same degree in both groups. Also, in both groups the IOP-induced suppression of T4 to T3 conversion in the pituitary gland provoked similar increases in basal TSH (280 +/- 47% and 288 +/- 33%) and TSH secretion in response to TRH (173 +/- 7% and 156 +/- 13%). These results indicate that the low FT4I is not the consequence of reduced pituitary TSH reserve. In addition, evidence for normal thyroid gland reserve and the secretion of TSH of normal biological activity was obtained by comparing the acute iodothyronine responses to TRH-induced TSH release in both groups. It is concluded that the normal serum TSH concentration, inappropriate for the low FT4I value in some elderly subjects, is due to an apparent resetting of the thyroid hormone feedback regulation threshold of TSH secretion. It may, in turn, be the result of enhanced pituitary conversion of T4 to T3 or increased T4 uptake by the thyrotrophs.

Adrenocorticotropic Hormone↗

PubMed1991

Sequencing of the variant thyroxine-binding globulin (TBG)-Quebec reveals two nucleotide substitutions.

Thyroxine-binding globulin (TBG) is a liver glycoprotein that transports thyroid hormone in serum. In 1987 a variant TBG was discovered in an infant born in Quebec, following an investigation prompted by the finding of low blood thyroxine (T4) level on screening for neonatal hypothyroidism. This variant, TBG-Quebec, has cathodal shift on isoelectric focusing, reduced affinity for thyroxine, and markedly reduced stability. The latter property of the variant molecule is probably responsible for the partial TBG deficiency. We now report the results of sequencing of the entire coding region and exon-intron junctions of TBG-Quebec, which revealed two nucleotide substitutions; one, located in exon 3, changes the normal codon 283 of TTG (leucine) to that of TTT (phenylalanine), and the other, in exon 4, results in the replacement of the normal histidine-331 (CAT) by tyrosine (TAT). Allele-specific amplification (ASA) confirmed the cosegregation of the two nucleotide substitutions with the TBG-Quebec phenotype in individual members of this family. The substitution in codon 283, but not that in codon 331, has been previously described and, when occurring alone, does not alter the properties of the gene product. Thus, it appears that the replacement of histidine-331 by tyrosine is responsible for the observed altered properties of TBG-Quebec. However, the question of whether substitution of both amino acids is necessary for expression of the variant phenotype has yet to be answered.

Alleles↗

PubMed1991

Identification of a serum protein polymorphism via two-dimensional electrophoresis. Family and population studies in two genetically isolated groups: North American Hutterites and Australian aborigines.

We report the identification and initial family and population studies of a previously undescribed serum protein polymorphism with two allelic forms. It was discovered in Hutterites, a reproductively isolated religious sect, and is also present in Australian aborigines and a sample of Chicago residents. A two-allele model is consistent with the segregation pattern observed in five kindreds within our initial study group. This polymorphism, provisionally designated SPPM-158, appears as a horizontal (charge-based) doublet in silver-stained ISO-DALT high-resolution two-dimensional electrophoresis gels. It is a low-concentration polypeptide (approximately 1 mg/dL) that has an apparent MWSDS of 43.6 kD and an isoelectric point of approximately 5.5. We infer that it circulates as a multimer or in a high-molecular-weight (greater than 200 kD) complex with other proteins because it is not observed in normal body fluids derived from physiologically ultrafiltered plasma such as amniotic fluid, urine, or cerebrospinal fluid; however, it is present in urine of patients with glomerular proteinuria. The high heterozygosity rates imply utility of this new serum protein marker for both forensic and population studies.

Australia↗

PubMed1990

Neonatal detection of generalized resistance to thyroid hormone.

Generalized resistance to thyroid hormone (GRTH) is an inherited disease that is usually suspected when elevated serum thyroid hormone levels are associated with nonsuppressed thyrotropin. Often these test results are obtained because of short stature, decreased intelligence, and/or hyperactivity with learning disability noted in childhood and adolescence, or because of goiter in adulthood. We detected GRTH at birth by analysis of blood obtained during routine neonatal screening. The proposita, born to a mother with GRTH, had a thyrotropin level of 26 mU/L and a corresponding thyroxine concentration of 656 nmol/L (normal, 84 to 232 nmol/L). Administration of thyroid hormone in doses eightfold to 10-fold above replacement levels (liothyronine sodium, 21 micrograms/kg per day, and levothyroxine sodium, 44 micrograms/kg per day) were required to reduce serum thyrotropin to normal levels without induction of hypermetabolism. This case, and the retrospective finding of high thyroxine levels in five newborns subsequently diagnosed as having GRTH, suggest that measurement of thyroxine at birth, in conjunction with thyrotropin, could allow the early detection of GRTH.

Basal Metabolism↗

PubMed1990

Molecular basis for the properties of the thyroxine-binding globulin-slow variant in American blacks.

Thyroxine-binding globulin-slow (TBG-S), a variant found in 4-12% of Black and Pacific Island populations, is inherited as an X-chromosome linked trait. This variant is detected on isoelectric focusing by the characteristic cathodal shift of all its isoforms, suggesting that the difference resides in the core protein. In addition, TBG-S is slightly more thermolabile, which explains why subjects expressing TBG-S have on the average lower serum TBG, and thus reduced T4, concentrations. We now report the molecular basis for this TBG variant, deduced from sequencing the TBG-S gene of an American Black man. Sequencing of the four coding regions and all intron/exon junctions revealed a single nucleotide substitution in the codon for amino acid 171 of the mature protein. The resulting change of the codon GAC to AAC results in replacement of the normal aspartic acid by asparagine. Since the negative charge provided by the aspartic acid is lost when replaced by the neutral asparagine, this substitution seems responsible for the cathodal shift on isoelectric focusing and slower electrophoretic mobility of TBG-S. An identical nucleotide substitution was identified in an unrelated American Black man expressing TBG-S. Whether the TBG-S phenotype observed in populations from the Pacific Islands is caused by the same mutation remains to be determined.

Amino Acid Sequence↗

PubMed1990

Sleep deprivation in the rat: XI. The effect of guanethidine-induced sympathetic blockade on the sleep deprivation syndrome.

In earlier studies, rats totally deprived of sleep by a disk-over-water apparatus (TSD rats) had shown an increase in energy expenditure (EE) that could not be explained by increased motor activity or the metabolic expense of wakefulness. Excessive activation of a calorigenic mediator was a possibility, and norepinephrine-mediated sympathetic activation was the most likely candidate, because plasma norepinephrine (NE) levels had risen sharply in TSD rats. To determine whether this activation was necessary for increased EE in sleep deprived rats, the peripheral sympathetic blocking agent guanethidine (GU) was administered to six sleep-deprived (GD) rats and their yoked control (GC) rats. GU attenuated the increase in NE previously seen in TSD rats, but the increase in EE was not attenuated. Apparently, NE-mediated sympathetic activation was not critical for increased EE in sleep-deprived rats. On the other hand, plasma epinephrine (EPI) levels were significantly increased in GD (but not in GC) rats above those previously seen in TSD rats, suggesting the substitution of one calorigenic mediator for another in response to an abnormally elevated need for EE. Temperature data suggest that increased need for EE could arise from an elevated temperature setpoint and an inability to retain body heat. GD (but not GC) rats also showed other effects previously seen in TSD rats, including debilitated appearance; severe ulcerative and hyperkeratotic lesions on the tails and plantar surfaces; initially increased and later decreased body temperature; decreased plasma thyroxine; increased triiodothyronine-thyroxine ratio; and eventual death. Evidently, NE-mediated sympathetic activation was not critical to any of these effects, although a role for catecholamines cannot be ruled out.

Animals↗

PubMed1990

Effect of total sleep deprivation on 5'-deiodinase activity of rat brown adipose tissue.

Prolonged sleep deprivation of the rat produces a progressive increase in energy expenditure and an eventual decrease in body temperature, which suggests a profound derangement in thermoregulation. Because increased thermogenic activity in brown adipose tissue (BAT) is a likely mechanism mediating the observed increase in energy expenditure, we focused our attention on the effect of total sleep deprivation on BAT type II 5'-deiodinase (5'D-II), since its activation indicates BAT stimulation and is essential for full BAT thermogenic response. Five euthyroid rats were subjected to total (92%) sleep deprivation (euD-rats). Sharing the sleep deprivation apparatus, yoked control rats (euC-rats) received the same degree of physical stimulation as the D-rats, but were only partially (25%) sleep deprived. Additional cage controls (euCC-rats) were housed in the same room. Since during sleep deprivation the animals undergo a reduction in plasma T4 concentration and inability to maintain body temperature heralds death, an identical study was performed in five trios of hyperthyroid rats (hyperD-, hyperC-, and hyper CC-rats) given daily ip injections of 15 micrograms T4/100 g BW, 10 days before and throughout the deprivation period. Experiments were carried out at an ambient temperature of 29 C, close to thermoneutrality for rats. Sleep deprivation in hyperD-rats was maintained until death seemed imminent (9-14 days), and in euD-rats for 12-15 days. Sleep deprivation induced a significant increase in BAT 5'D-II activity in both hyperD- and euD-rats compared with that in euCC-rats (P less than 0.01). BAT 5'D-II in euC-rats was also significantly higher than that in euCC-rats (P less than 0.05), probably because they were partially sleep deprived. BAT 5'D-II activity in hyperD-rats was increased compared to that in both hyperC- and hyperCC-rats (P less than 0.05), in which the activity was slightly but not significantly lower than that in euCC-rats. No significant differences were observed in liver and kidney type I 5'-D (5'D-I) and in pituitary 5'D-II among euD-rats, euC-rats, and euCC-rats. As expected, the hyperthyroid groups (hyperD-rats, hyperC-rats, and hyperCC-rats) had significantly higher kidney 5'D-I and lower pituitary 5'D-II than the euCC-rats. Liver 5'D-I was also significantly increased in the hyperC-rats and hyperCC-rats, but not in the hyperD-rats. These observations indicate that total sleep deprivation is associated with a marked increase in BAT 5'D-II activity in both euthyroid and hyperthyroid rats.(ABSTRACT TRUNCATED AT 400 WORDS)

Acclimatization↗

PubMed1990

Replacement of Leu227 by Pro in thyroxine-binding globulin (TBG) is associated with complete TBG deficiency in three of eight families with this inherited defect.

The T4-binding globulin (TBG) gene is a single copy located on the X-chromosome. Previous studies have failed to elucidate the molecular defect in individuals with complete TBG deficiency (TBG-CD). Indeed, no major deletions, insertions, or other rearrangements were observed in the TBG gene of six unrelated males with this defect. To clarify the molecular basis of TBG-CD, we have cloned and sequenced the TBG gene of an affected male (CD5) of French Canadian origin. The sequence of the exons encoding the mature protein, adjacent introns, and the promoter region revealed two nucleotide substitutions: CTA(Leu)----CCA(Pro) at codon 227 and TTG(Leu)----TTT(Phe) at codon 283. The Leu----Phe substitution, a relatively conservative replacement, is a TBG polymorphism present in 16% (3 of 19) of French Canadian males. It has no effect on the serum concentration or properties of the common type TBG (TBG-C). The new Leu----Pro substitution, which is predicted to alter the higher order of TBG structure, is probably responsible for the TBG-CD phenotype of the individual studied and two other families with TBG-CD. It possibly impairs TBG biosynthesis or secretion or perhaps alters TBG structure to such a degree that the molecule is not recognized by antibodies against native or denatured TBG and does not bind T4.

Adult↗

PubMed1990

Serum thyrotropin and prolactin in the syndrome of generalized resistance to thyroid hormone: responses to thyrotropin-releasing hormone stimulation and short term triiodothyronine suppression.

Serum TSH and PRL levels and their response to TRH were measured in 11 patients with generalized resistance to thyroid hormone (GRTH), 6 euthyroid subjects, and 6 patients with primary hypothyroidism. TSH and PRL levels and their response to TRH were also measured after the consecutive administration of 50, 100, and 200 micrograms T3 daily, each for a period of 3 days. Using a sensitive TSH assay, all GRTH patients had TSH values that were elevated or within the normal range. On the basis of a normal or elevated TSH level, GRTH patients were classified as GRTH-N1 TSH (5 patients) or GRTH-Hi TSH (6 patients), respectively. Only GRTH patients with previous thyroid ablative therapy had basal TSH values greater than 20 mU/L. TSH responses, in terms of percent increment above baseline, were appropriate for the basal TSH level in all subjects. No GRTH patient had an elevated basal PRL level. PRL responses to TRH were significantly increased only in the hypothyroid controls compared to values in all other groups. On 50 micrograms T3, 7 of 12 (58%) nonresistant (euthyroid and hypothyroid) and 1 of 11 (9%) resistant subjects had a greater than 75% suppression of the TSH response to TRH. On the same T3 dose, 2 of 12 (17%) nonresistant and 4 of 11 (36%) resistant subjects had a greater than 50% suppression of the PRL response to TRH. On 200 micrograms T3, all subjects, except for 1 with GRTH, had a greater than 75% suppression of the TSH response to TRH. On the same T3 dose, while 11 of 12 (92%) nonresistant subjects had a greater than 50% reduction of the PRL response to TRH, only 3 of 10 (30%) resistant patients showed this degree of suppression (P less than 0.005). Without previous ablative therapy, serum TSH in patients with GRTH is usually normal or mildly elevated. The TSH response to TRH is proportional to the basal TSH level and is suppressed by exogenous T3. However, on 200 micrograms T3 basal TSH was not detectable (less than 0.1 mU/L) in all euthyroid subjects, but it was measurable in three of four GRTH patients with normal TSH levels before T3 treatment. PRL levels in GRTH are normal even when TSH is elevated. The PRL response to TRH is not increased in GRTH. In all subjects, exogenous T3 suppresses the PRL response to TRH to a lesser degree than the TSH response, but this difference is much greater in patients with GRTH.

Adult↗

PubMed1990

Dominant negative transcriptional regulation by a mutant thyroid hormone receptor-beta in a family with generalized resistance to thyroid hormone.

An abnormal human thyroid hormone beta-receptor (hTR beta-Mf), which has a glycine to arginine substitution in the hormone-binding domain, has been identified in affected members of one family with generalized resistance to thyroid hormone. To better understand the mechanism by which this mutation produces the observed abnormality, expression vectors for the wild-type and mutant thyroid hormone receptors (TRs) were prepared to test hormone-binding activity and trans-activation function. Nuclear extracts of COS-7 cells transfected with wild-type TRs showed specific T3-binding activity, while mutant receptor-transfected COS-7 nuclear extract failed to bind T3. On the other hand, in a avidin-biotin complex DNA-binding assay, in vitro translated hTR beta-Mf showed high binding activity to the thyroid hormone response element, which was indistinguishable from that of wild-type TRs. In a transient expression study, only the wild-type TRs activated a rat GH gene promoter-chloramphenicol acetyltransferase fusion gene in a T3-dependent manner. Additionally, when wild-type TR and hTR beta-Mf were cotransfected, hTR beta-Mf inhibited gene activation regulated by wild-type TRs. From these results we conclude that 1) hTR beta-Mf has no demonstrable T3 binding and appears to have minimal, if any, ability to activate a thyroid hormone-responsive gene in spite of its preserved ability to bind to a TRE in DNA; 2) hTR beta-Mf inhibits the transcriptional activation of a thyroid hormone-responsive gene by the wild-type TRs in a dominant manner; and 3) the dominant negative regulatory function of hTR beta-Mf appears to explain the clinical manifestations of thyroid hormone resistance produced by this mutation when present in the heterozygous state.

Animals↗

PubMed1989

Leukocyte alkaline phosphatase in hypothyroidism and hyperthyroidism. Response to initiation of thyroxine replacement therapy.

Leukocyte alkaline phosphatase (LAP) activity was determined in normal subjects, and in untreated, symptomatic patients with primary hypothyroidism or thyrotoxicosis. The means +/- 1 SD of (n) subjects were, respectively: 61.7 +/- 27.5 (16), 149.9 +/- 56.3 (9) and 96.9 +/- 27.7 (9). The mean LAP values of the hypothyroid and thyrotoxic groups were significantly different from that of the normal group (P less than .01). Values were above the normal range (20 to 120) in seven of the nine hypothyroid patients. LAP values were in the upper half of the normal range in eight of the nine thyrotoxic patients. In the two hypothyroid patients studied at 24-hour intervals, LAP activity was altered markedly within 48 hours of initiation of thyroxine therapy, 25 micrograms daily. In five hypothyroid patients followed for several months after initiating thyroxine replacement, LAP levels were essentially normal within 1 to 2 months. In the thyrotoxic patients, LAP values declined within the first month of medical management, but tended to remain within the normal range.

Alkaline Phosphatase↗

PubMed1989

Generalized resistance to thyroid hormone associated with a mutation in the ligand-binding domain of the human thyroid hormone receptor beta.

The syndrome of generalized resistance to thyroid hormone is characterized by elevated circulating levels of thyroid hormone in the presence of an overall eumetabolic state and failure to respond normally to triiodothyronine. We have evaluated a family with inherited generalized resistance to thyroid hormone for abnormalities in the thyroid hormone nuclear receptors. A single guanine----cytosine replacement in the codon for amino acid 340 resulted in a glycine----arginine substitution in the hormone-binding domain of one of two alleles of the patient's thyroid hormone nuclear receptor beta gene. In vitro translation products of this mutant human thyroid hormone nuclear receptor beta gene did not bind triiodothyronine. Thus, generalized resistance to thyroid hormone can result from expression of an abnormal thyroid hormone nuclear receptor molecule.

Alleles↗

PubMed1989

Sleep deprivation in the rat: V. Energy use and mediation.

We investigated the use and possible mechanisms mediating the increased energy expenditure (EE) previously described for rats subjected to total or paradoxical sleep deprivation. Bomb calorimetry of wastes showed that during deprivation the efficiency of energy utilization was not reduced. Estimates of CO2 production by the doubly labelled water method of indirect calorimetry correlated with EE estimated from the caloric value of food, weight change, and wastes and confirmed an increase in EE during deprivation. Core temperatures decreased during the later stages of deprivation, suggesting the hypothesis that excessive heat loss may have required increased EE to protect body temperature. The increased EE could not be explained by the metabolic cost of increase wakefulness, water exposure, or motor activity; an increase in resting EE was indicated. The contribution of the hypothalamic-pituitary-adrenal axis, thyroid gland, and sympathoadrenal system to the mediation of the EE increases was evaluated by measuring the plasma levels of their hormones. Results appear to rule out the first as a mediator. Evidence for the other two was equivocal.

Adrenal Cortex Hormones↗