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M C Sheppard

Publications and source records attributed to M C Sheppard.

At least 73 records · Page 4Linked to original sources

The use of a neural network to detect upper airway obstruction caused by goiter.

Goiter is a common condition and can cause upper airway obstruction (UAO), which may be difficult to detect. We have studied maximal expiratory and inspiratory flow volume loops using a neural network to see if this offers a better way to identify patients with UAO. The flow-volume loops from 155 patients with goiter were assessed by a human expert and sorted into those with and without UAO. The reliability of this assessment was judged by using two observers who repeated the sorting 8 wk apart. A set of 46 patients with loops suggesting UAO and a set of 51 patients with normal flow loops were taken from these 155, and the loops from a further 50 subjects with airflow limitation caused by chronic obstructive pulmonary disease were used for training and testing the neural network. Novel and standard indices were derived from the loops and used by the neural network. The kappa score for agreement between each of the observers and the original classification were 0.5 and 0.46, respectively, with the agreement between the observers at each reading of 0.58 and 0.68. The neural network found that a combination of four novel scores for flatness of the expiratory loop, the moment ratio, and the FEV1/PEF ratio was best at identifying UAO with a kappa score of 0.81, a sensitivity of 88%, specificity of 94% and an accuracy of 92%. We conclude that a neural network using only six indices taken from the expiratory limb of a flow-volume loop was better than human experts at identifying flow loops with UAO.

Adult↗

Linkage disequilibrium between the human leukocyte antigen class II region of the major histocompatibility complex and Graves' disease: replication using a population case control and family-based study.

Early case control studies found association of the DRB1 allele, DR3, with Graves' disease (GD). Recent reports, claim the DQA1 allele, DQA1*0501, to be the primary susceptibility determinant within the human leukocyte antigen (HLA) class II region. We typed 228 GD patients, 364 controls, and 98 families (parents, GD, and unaffected sibling) at the DRB1, DQB1, and DQA1 loci. The case control study showed an increased frequency in GD, compared to controls, of DRB1*0304 (47% vs. 24%; pc < 1.4 x 10(-5)), DQB1*02 (58% vs. 46%; pc < 0.035), DQB1*0301/4 (42% vs. 28%; pc < 3.5 x 10(-3)) and DQA1*0501 (67%, vs. 39%; pc < 7 x 10(-6)). The DRB1*0304-DQB1*02-DQA1*0501 haplotype was increased in GD (47%) vs. controls (24%; pc < 1.8 x 10(-5); odds ratio = 2.72). No independent association of these alleles was observed. Preferential transmission of DRB1*0304-DQB1*02-DQA1*0501 from parents heterozygous for the haplotype to GD siblings (72%) was seen in the families (chi2 = 11.95; 1 d.f.; P = 0.0005). Lack of preferential transmission to unaffected siblings (53%; chi2 = 0.19; 1 d.f.; P = NS) excluded segregation distortion. These results show that linkage disequilibrium between GD and the HLA class II region is due to the extended haplotype DRB1*0304-DQB1*02-DQA1*0501.

Alleles↗

Fibroblast growth factors 1 and 2 and fibroblast growth factor receptor 1 are elevated in thyroid hyperplasia.

We have previously reported increased expression of fibroblast growth factor (FGF-1 and FGF-2) in benign and malignant human thyroid neoplasia. To determine the role of these factors in thyroid hyperplasia we have examined their expression in multinodular goiter and compared findings with those in normal thyroid tissue. Because the effects of FGF-1 and FGF-2 are predominantly mediated through the FGF receptor-1 (FGFR-1), its expression has also been examined. Immunocytochemistry was performed on sections from multinodular goiters (n = 18) and normal thyroid (n = 7). Cytoplasmic staining for FGF-1, FGF-2, and FGFR-1 was scored on a scale of 0 (no staining) to 3 (heavy staining) and expressed as a percentage of total cells stained. Confocal microscopy of immunofluorescent staining for FGF-1, FGF-2, and FGFR-1 in sections of multinodular goiter (n = 3) and normal thyroid (n = 3) provided quantitation of immunostaining. FGF-1 expression was significantly increased in multinodular goiter when compared with normal. A mean of 74% of follicular cells in multinodular goiter compared with 9% of follicular cells in normal thyroid expressed FGF-1 (P < 0.0001). When expression of FGF-2 was examined, 77% of the follicular cells in multinodular goiter compared with 5% in normal thyroids were immunopositive (P < 0.0001). Confocal microscopy revealed that the intensity was 160 times greater in follicular cells in sections of multinodular goiters when compared with normal. When expression of FGFR-1 was analyzed, 89% of the follicular cells in multinodular goiter stained positively, compared with 15% of follicular cells in sections of normal thyroid. Confocal microscopy revealed a 6-fold increase in intensity of FGFR-1 expression in follicular cells of multinodular goiter (P < 0.05). In addition, there was significant nuclear expression of FGFR-1 in multinodular goiter contrasting with negligible expression in normal thyroid. These data show that enhanced expression of FGF-1, FGF-2, and FGFR-1 accompany thyroid hyperplasia and are not exclusively associated with the neoplastic state. These factors may be involved in the pathogenesis of uncontrolled thyroid growth observed in these conditions.

Case-Control Studies↗

Characterization of aromatase and 17 beta-hydroxysteroid dehydrogenase expression in rat osteoblastic cells.

Postmenopausal loss of 17 beta-estradiol (E2) in women is associated with decreased bone mineral density and increased susceptibility to osteoporotic bone fracture. These changes in bone status are assumed to be due to circulating levels of the hormone; therapeutic replacement of E2 can alleviate the bone disease. However, recent reports have shown that human osteoblastic (OB) cells are able to synthesize estrogens locally, via expression of the enzyme aromatase. In this study, we have characterized the expression and activity of aromatase and 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) in rat OB cell lines. Aromatase activity in ROS 17/2.8, ROS 25/1, and UMR 106 cells was similar to that shown in human OB cells, with the highest levels of activity observed in the more differentiated ROS 17/2.8 cells (Vmax = 45 pmol/h/mg of protein). The rat OB cells also showed 17 beta-HSD activity, with the predominant metabolism in all three cell lines being estrone (E1) to E2. As with aromatase, the highest activity was observed in ROS 17/2.8 cells (Vmax = 800 pmol/h/mg of protein). Northern analyses indicated the variable presence of transcripts corresponding to the type 1, 2, 3, and 4 isoforms of 17 beta-HSD. Further analysis of androstenedione metabolism indicated that the net effect of aromatase and 17 beta-HSD activity varied with cell type and culture treatment. All three OB cell lines were able to synthesize E1, E2, and testosterone from androstenedione, although activity varied between OB cell types. Regulatory effects were observed with 1,25-dihydroxyvitamin D3 (positive) and dexamethasone (negative). These data suggest that local synthesis of sex hormones is an important function of OB cells and may play a key role in the modulation of bone turnover independent of circulating hormone concentrations.

17-Hydroxysteroid Dehydrogenases↗

Hormone-induced changes in nuclear receptor stoichiometry in HL60 cells correlate with induction of monocyte or neutrophil differentiation.

HL60 cells differentiate to monocytes or neutrophils in response to 1 alpha,25(OH)2-vitamin D3 (D3) and retinoids respectively. D3 and retinoid actions converge since their receptors (VDR, RAR) heterodimerise with a common partner, RXR, which also interacts with thyroid hormone (T3) receptors (T3R). HL60 cells were treated with combinations of D3 and retinoids to induce differentiation and to investigate whether increased VDR or RAR expression correlated with monocyte or neutrophil differentiation and whether altered receptor concentrations affected DNA-binding specificity. As assessed by Western blotting, VDR and RXR expression was unchanged in monocytes relative to controls but levels of RAR and T3R were reduced. In contrast, only VDR expression was reduced in neutrophils. T3 did not promote differentiation or influence its induction by D3 or retinoids and did not affect expression of any receptor. Gel mobility-shift analysis revealed that nuclear extracts from undifferentiated cells, monocytes and neutrophils interacted differently with VDRE-, RARE- and RXRE-binding sites. Monocyte nuclear protein/DNA complexes contain readily detectable VDR and RXR whereas neutrophil complexes contain RAR and RXR. Thus hormone-induced changes in receptor stoichiometry favour either VDR/RXR or RAR/RXR heterodimerisation and correlate with hormone-induced differentiation of HL60 cells to monocytes or neutrophils respectively.

Blotting, Western↗

Inflammatory cytokines and type I 5'-deiodinase expression in phi1 rat liver cells.

Administration of tumour necrosis factor-alpha (TNF alpha), interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) to animals and humans results in changes in circulating thyroid hormone concentrations similar to those seen in non-thyroidal illness (NTI). Inflammatory cytokines have been postulated as mediators of the euthyroid sick syndrome by inhibiting type 1 5'-deiodinase (5'D-I) enzyme activity. We have investigated direct effects of cytokines upon 5'D-I expression, measuring changes in 5'D-I enzyme activity and mRNA in phi1 rat liver cells. All three cytokines stimulated 5'D-I enzyme activity: TNF alpha 326 +/- 43% (100% in controls, mean + S.E.M., n = 9, P < 0.01 by ANOVA), IL-1beta 297 +/- 8% and IL-6 272 +/- 25%. Co-incubation with cycloheximide abolished stimulation by each cytokine. Kinetic analysis revealed that stimulation of 5'D-I enzyme activity was a result of significantly increased Vmax, (P < 0.01 by ANOVA) with Km relatively unchanged. 5'D-I mRNA abundance was not significantly changed following treatment by any of the three cytokines. These findings do not support the hypothesis that inflammatory cytokines may mediate the euthyroid sick syndrome by causing inhibition of 5'D-I activity.

Animals↗

Differential expression of oestrogen receptor and oestrogen inducible genes in gastric mucosa and cancer.

BACKGROUND: Evidence exists for a role for oestrogen in gastric cancer. The incidence of gastric cancer is much higher in men than in woman, and a similar sex difference is also seen in a rat experimental model of gastric cancer. AIMS: Evidence for a functional oestrogen receptor in normal gastric mucosa and cancer has been sought. METHODS: Oestrogen receptor and the oestrogen inducible genes pS2 and ERD5 were sought by northern blot analysis and in situ hybridisation and immunohistochemistry. Oestrogen receptor protein was studied by enzyme immunoassay. RESULTS: mRNA for oestrogen receptor was detected in cancer and normal gastric mucosa. Enzyme immunoassay for oestrogen receptor showed a mean of 1.8 fmol/mg protein in cancer and 13.7 fmol/mg in paired normal mucosa. The oestrogen inducible genes pS2 and ERD5 were also detected in both cancer and normal mucosa, with expression localised to epithelium. Expression of pS2 was lower in cancer compared with normal mucosa, whereas ERD5 expression was higher in cancer. CONCLUSIONS: Significant amounts of oestrogen receptor were expressed in gastric mucosa with a lower amount in cancer. Oestrogen inducible genes were also expressed differentially but were not found to correlate closely with oestrogen receptor. Oestrogen receptor functionality remains to be demonstrated in the stomach.

Blotting, Northern↗

Thyroid hormone and estrogen receptor expression in normal pituitary and nonfunctioning tumors of the anterior pituitary.

Nonfunctioning tumors (NFTs) of the anterior pituitary often express elevated levels of the glycoprotein hormone alpha-subunit, which, under normal physiological conditions, is under negative feedback control by thyroid and gonadal steroid hormones. We postulate that inappropriately elevated levels of expression of alpha-subunit in the face of normal levels of these target organ hormones may reflect an abnormality of thyroid hormone receptors (TRs) and/or gonadal steroid receptors in NFTs. Using immunocytochemistry and Western blotting we have examined TR and estrogen receptor (ER) protein expression in normal human anterior pituitary glands and NFTs. Pretranslational expression of these receptors was examined using semiquantitative reverse transcriptase-PCR. Expression of all TR variant and ER proteins was reduced in pituitary tumors compared with that in normal pituitaries. The expression of messenger ribonucleic acids encoding the TR beta1 and TR beta2 isoforms and ER was also significantly reduced in tumors compared with normal tissues, although there was no difference between tumors and normals in the level of expression of TR alpha1 and alpha2 messenger ribonucleic acids. We suggest that reduced expression of TRs and ER may account for inappropriate expression of the glycoprotein hormone alpha-subunit gene in some NFTs and may contribute to uncontrolled tumor growth.

Female↗

Thyroid hormone, vitamin D and retinoid receptor expression and signalling in primary cultures of rat osteoblastic and immortalised osteosarcoma cells.

3,5,3'-Tri-iodothyronine (T3), 1 alpha,25(OH)2-vitamin D3 (D3) and retinoids activate related nuclear receptors which interact by heterodimerisation to regulate gene expression. Actions of each hormone are discrete and may be specified by changes in the relative concentrations of their receptors (T3R, vitamin D receptor (VDR), retinoic acid receptor (RAR), retinoid X receptor (RXR)). T3, D3 and retinoids are essential for skeletal development and maintenance and we have previously shown complex interactions amongst their signalling pathways in osteosarcoma cells. In these studies we demonstrate that similar T3R, VDR, RAR and RXR proteins are co-expressed in both osteoblast lineage cell primary cultures and osteosarcoma cells by Western blotting. We investigated whether hormone interactions in bone result from changes in receptor stoichiometry. Cells were treated with combinations of T3, D3, 9-cis retinoic acid (9-cis RA) and all-trans retinoic acid (RA) that are known from previous studies to produce complex cell specific responses. No alteration in expression of any receptor protein was seen in response to any hormone combination in three phenotypically distinct osteosarcoma cell lines. Thus, in contrast to studies of overexpressed receptors in vitro, changes in the physiological concentrations of endogenous T3R, VDR, RAR and RXR do not specify discrete hormone actions in osteoblastic cells. Other unidentified factors are likely to modulate hormone action in these bone cells.

Animals↗

Expression of oestrogen receptor and oestrogen-inducible genes in pancreatic cancer.

BACKGROUND: Previous studies have not been able to demonstrate convincingly whether the human pancreas expresses oestrogen receptor and whether there is any benefit from antioestrogen therapy in advanced pancreatic cancer. METHODS: Oestrogen receptor expression was assessed in normal human pancreas and pancreatic cancer tissue by enzyme immunoassay, Northern blot analysis, in situ hybridization and immunohistochemistry. The expression of the oestrogen-inducible proteins, progesterone receptor, pS2 and ERD5 was also examined. RESULTS: A mean of 1.0 (range 0-2.4) fmol oestrogen receptor per mg protein was detected in normal pancreas and 0.5 (range 0-1.2) fmol mg-1 in pancreatic cancer. Messenger RNA for oestrogen receptor was detected in both normal and cancerous pancreas. In situ hybridization and immunohistochemistry, however, failed to localize oestrogen receptor expression. Mean (range) expression of progesterone receptor in normal and neoplastic pancreas was 1.9 (0.5-3.5) and 2.5 (0.3-9.3) fmol mg-1 respectively. pS2 and ERD5 were also expressed in normal tissue and pancreatic cancer, and expression was localized to ductular epithelium. CONCLUSION: The amount of oestrogen receptor detected in pancreatic tissue was small, and may account for previous difficulties in its detection. The extent to which it is functional in both the normal and malignant pancreas warrants further investigation.

Adult↗

Thyroid-stimulating hormone rapidly stimulates inositol polyphosphate formation in FRTL-5 thyrocytes without activating phosphoinositidase C.

The thyroid-stimulating hormone (TSH) receptor is widely regarded as one of a limited number of G-protein-coupled receptors that activate both adenylate cyclase and phosphoinositidase C (PIC) via G-proteins, but the existing experimental evidence for TSH-stimulated PtdIns(4,5)P2 hydrolysis remains inconclusive. We have compared the effects of TSH and of ATP (acting via P2-purinergic receptors) on the inositol lipids and polyphosphates of [2-3H]inositol-labelled FRTL-5 rat thyroid cells. ATP initiated a rapid decrease in 3H-labelled PtdIns4P and PtdIns(4,5)P2, whereas TSH did not. Stimulation with ATP and, less consistently, with noradrenaline (acting via alpha-adrenergic receptors) provoked rapid formation of Ins(1,4,5)P3, Ins(1,3,4,5)P4, Ins(1,3,4)P3 and Ins(1,4)P2, confirming activation of PtdIns(4,5)P2 hydrolysis. No concentration of TSH provoked detectable accumulation of Ins(1,4,5)P3 or Ins(1,4)P2 during the first few minutes of stimulation. However, an InsP3 [with the chromatographic properties of Ins(1,3,4)P3] and two InsP4 isomers [neither of which was Ins(1,3,4,5)P4] accumulated quickly in TSH-stimulated cells. ATP immediately provoked a large increase in intracellular calcium concentration ([Ca2+]i) in Indo 1-AM-loaded cells. TSH provoked a small and delayed [Ca2+]i elevation in only some experiments. We therefore confirm that activation of P2-purinergic receptors and alpha 1-adrenergic receptors provokes PIC activation, an accumulation of Ins(1,4,5)P3 and its metabolites and rapid [Ca2+]i mobilization in FRTL-5 cells. By contrast, TSH provokes no rapid PIC-catalysed PtdIns(4,5)P2 hydrolysis or immediate [Ca2+]i mobilization. These results fail to support the widespread view that the TSH receptor of FRTL-5 cells signals, in part, through PIC activation. Our results suggest that TSH activates another, still undefined, mechanism that causes accumulation of an InsP3 and two isomers of InsP4.

Adenosine Triphosphate↗

Hypertension in the syndrome of apparent mineralocorticoid excess due to mutation of the 11 beta-hydroxysteroid dehydrogenase type 2 gene.

BACKGROUND: 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) catalyses the interconversion of hormonally active cortisol to inactive cortisone and is vital for dictating specificity for the mineralocorticoid receptor. Thus, in patients with congenital deficiency of 11 beta-HSD (the syndrome of apparent mineralocorticoid excess, AME), cortisol and not aldosterone acts as a mineralocorticoid, resulting in hypertension and hypokalaemia with suppression of the renin-angiotensin-aldosterone axis. Two isoforms of human 11 beta-HSD have been described, but it is the NAD-dependent type 2 isoform (11 beta-HSD2), first characterised in placental tissue, that is expressed in the mineralocorticoid target tissues, kidney and colon. We have analysed the 11 beta-HSD2 gene as a candidate gene in explaining the molecular basis of AME. METHODS: By exon-specific PCR-amplification of the 11 beta-HSD2 gene in a consanguineous kindred with AME, we found a point mutation (C1228T) in two affected siblings, and also in placental DNA obtained from a stillbirth pregnancy. FINDINGS: The mutation in exon 5 of the 11 beta-HSD2 gene resulted in a premature stop site at codon 374 instead of a normal arginine (R374X), with the deletion of 32 aminoacids from the C-terminus of the 11 beta-HSD2 enzyme protein. Both parents, who are phenotypically normal, are heterozygote for the C1228T mutation in keeping with an autosomal recessive form of inheritance. NAD-dependent 11 beta-HSD activity was severely attenuated in the stillbirth placenta compared with control placental tissue, and no 11 beta-HSD immunostaining was observed in this placenta with antisera derived against a C-terminal 11 beta-HSD2 peptide sequence. INTERPRETATION: AME is due to a mutation in the 11 beta-HSD2 gene, and is an example of human hypertension arising from a single gene defect.

11-beta-Hydroxysteroid Dehydrogenases↗

Treatment options for acromegaly.

Treatment options for acromegaly include surgical removal of the adenoma, radiotherapy, or pharmacological reduction of growth hormone (GH) levels by dopamine agonists or somatostatin analogs. Whether such treatment can truly cure acromegaly is debatable. A problem with evaluating efficacy of treatment is the lack of consensus of what constitutes a cure. Despite modern neurosurgical techniques for resecting GH-secreting pituitary adenomas, more than 50% of patients may have persistent GH hypersecretion; radiotherapy may take years to produce an effect. There is thus interest in pharmacological relief of symptoms and reduction in GH secretion. We report on eight patients with a biochemical diagnosis of acromegaly (failure of suppression of GH levels to < 2.5 micrograms/L following a glucose tolerance test [GTT]). The use of Sandostatin-LAR (Sandoz Pharma Ltd, Basel, Switzerland) in doses of 20 to 30 mg intramuscularly at 4 week intervals produced consistent and therapeutic serum octreotide concentrations, suppressed GH secretion to 5 micrograms/L in all eight subjects, lowered insulin-like growth factor-1 (IGF-1) levels in all and normalized values in seven of eight, improved or led to disappearance of symptoms and signs, and was not associated with an increase in adverse events as compared with subcutaneous treatment.

Acromegaly↗

Relation between serum interleukin-6 and thyroid hormone concentrations in 270 hospital in-patients with non-thyroidal illness.

OBJECTIVES: Non-thyroidal illness (NTI) is frequently accompanied by alterations in circulating thyroid hormone concentrations, despite patients remaining clinically euthyroid. The mechanisms accounting for these changes in circulating thyroid hormone concentrations remain unknown. Much attention has focussed on the role of inflammatory cytokines which are known to be important mediators of disease. The aim of this study was to investigate the role of the cytokine interleukin-6 (IL-6) in alterations of thyroid hormone metabolism seen in NTI. DESIGN: Longitudinal study of hospital in-patients, correlating serum IL-6 concentrations with circulating thyroid hormone concentrations. PATIENTS: Two hundred and seventy in-patients recruited consecutively, excluding those with known or suspected thyroid disorder. The patients were divided into 5 subgroups reflecting the nature of their NTI and comprised 41 patients with liver disease, 99 with renal disease, 19 intensive care (ITU) patients, 22 with cardiac disease and 89 patients with general medical, or surgical conditions. MEASUREMENTS: Serum IL-6 concentrations were determined using a commercially obtained immunoassay (IL-6 Quantikine assay, R&D Systems, Abingdon, UK). Serum total T4 and total T3 were measured using chemiluminescent immunometric assays (Kodak Clinical Diagnostics Ltd, Amersham, UK) and serum TSH was measured using a third-generation chemiluminescent immunometric assay (Amerlite TSH 30, Kodak Clinical Diagnostics Ltd, Amersham, UK). RESULTS: Ninety-three patients studied (35%) had a serum T3 below the normal range (<1.0 nmol/l), 89 patients (33%) had a serum T4 below the normal range (<65 nmol/l) and in 58 patients (21%) both serum T3 and T4 were below the normal range. There was a significant negative correlation between serum total T3 and IL-6 (r = -0.219; P < 0.001) and total T4 and IL-6 (r = -0.32; P = 0.32), but not between TSH and IL-6 (r = -0.075; P = 0.22). The ITU patient subgroup had the highest IL-6 concentrations (229.3 +/- 48.1 ng/l, mean +/- standard error), whilst also having the lowest T3 (0.93 +/- 0.08 nmol/l), TSH (0.79 +/- 0.25 mU/l) and T4 concentrations (66.6 +/- 7.3 nmol/l). The subgroup of patients under general medical or surgical care had least disturbance of their T3 (low in 19%) and T4 (low in 8%) concentrations, whilst also having the lowest mean IL-6 concentration (39.0 +/- 5.3 ng/l). The renal patient subgroup, whilst including a high proportion of patients with low T3 (39%) and T4 (45%) concentration, demonstrated only modest elevation of IL-6 concentrations (mean 41.4 +/- 8.5 ng/l). CONCLUSIONS: Our data revealed a statistical relation between elevated serum IL-6 concentrations and alterations in circulating thyroid hormone concentrations seen in NTI; however, the findings in patients with renal disease suggest that circulating IL-6 is not the only factor responsible for alteration in thyroid hormone metabolism in NTI.

Euthyroid Sick Syndromes↗

Regulation of type I 5'-deiodinase by thyroid hormone and dexamethasone in rat liver and kidney cells.

Type I 5'-deiodinase (5'D-I) is crucial for the generation of circulating 3,5,3'-triiodothyronine (T3) and so is a major determinant of thyroid hormone action. Liver and kidney 5'D-I activity is reduced in nonthyroidal illness (NTI), but the exact cause of reduced 5'D-I activity remains unknown. Elevated circulating glucocorticoid hormone concentrations are one factor postulated to play a role. We have studied regulation of 5'D-I expression in cultured rat liver (phi 1) and kidney (NRK-52E) cells in response to treatment with T3 and the glucocorticoid dexamethasone. 5'D-I mRNA was measured by Northern hybridization and 5'D-I activity was measured in a sub-strate conversion assay. Expression of the sodium pump alpha 1-subunit (Na+/K(+)-ATPase alpha 1-subunit) mRNA was measured as an index of T3 and dexamethasone effects. In ø1 liver cells, T3 increased 5'D-I mRNA by 76 +/- 17% and 5'D-I activity by 101 +/- 30% (all results mean +/- SEM; n = 9). Dexamethasone increased 5'D-I mRNA by 55 +/- 16% and 5'D-I activity by 128 +/- 6%. In NRK-52E rat kidney cells, 5'D-I mRNA increased by 87 +/- 15% with T3 treatment and by 76 +/- 14% with dexamethasone. 5'D-I activity in NRK-52E cells was measurable only after stimulation by combined T3 and dexamethasone treatment. Na+/K(+)-ATPase alpha 1-subunit mRNA expression was stimulated following T3 and dexamethasone treatment in both cell lines. These results provide evidence for direct pretranslational regulation of 5'D-I by T3 and dexamethasone in both rat liver and kidney cells. Our findings do not support the hypothesis that glucocorticoids are directly responsible for inhibition of 5'D-I enzyme activity in NTI.

Animals↗

Cardiac hypertrophy as a result of long-term thyroxine therapy and thyrotoxicosis.

OBJECTIVES: To define the effects of long-term thyroxine treatment upon heart rate, blood pressure, left ventricular systolic function, and left ventricular size, as well as indices of autonomic function, and to compare findings with those in patients with thyrotoxicosis before and during treatment. DESIGN: Cross sectional study of patients prescribed thyroxine long term (n = 11), patients with thyrotoxicosis studied at presentation (n = 23), compared with controls (n = 25); longitudinal study of patients with thyrotoxicosis studied at presentation and serially after beginning antithyroid drug treatment (n = 23). METHODS: 24 h ambulatory monitoring of pulse and blood pressure, echocardiography, forearm plethysmography, and autonomic function tests. RESULTS: Long-term thyroxine treatment in doses that reduced serum thyrotrophin to below normal had no effect on blood pressure, heart rate, left ventricular systolic function or stroke volume index, but was associated with an 18.4% increase in left ventricular mass index (mean (SEM) 101.9 (3.09) g/m2 v controls 86.1 (4.61), P < 0.01). Thryoxine treatment, like thyrotoxicosis, had no effect on tests of autonomic function. Untreated thyrotoxicosis resulted in pronounced changes in systolic and diastolic blood pressure and an increase in heart rate during waking and sleep. Patients with thyrotoxicosis at presentation had an increase in left ventricular systolic function (ejection fraction 70.5 (1.66)% v 65.4 (1.79), P < 0.01; fractional shortening 40.4 (1.54)% v 35.6 (1.46), P < 0.01), increased stroke volume index (45.9 (2.4) ml/m2 v 36.6 (1.7), P < 0.001), and an increase in forearm blood flow, and decrease in vascular resistance. They had a similar degree of left ventricular hypertrophy to that associated with thyroxine treatment (99.3 (4.03) g/m2); all changes were corrected within 2 months by antithyroid drugs. CONCLUSIONS: The development of left ventricular hypertrophy in patients receiving thyroxine in the absence of significant changes in heart rate, blood pressure, and left ventricular systolic function is consistent with a direct trophic effect of thyroid hormone on the myocardium. The presence of left ventricular hypertrophy determines that further studies are essential to assess cardiovascular risk in patients taking thyroxine long term.

Adult↗