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Biomedical subjects

M C Sheppard

Publications and source records attributed to M C Sheppard.

At least 127 records · Page 7Linked to original sources
PubMed1993

Thyroxine prescription in the community: serum thyroid stimulating hormone level assays as an indicator of undertreatment or overtreatment.

Examination of thyroxine usage in a study in the United States of America revealed that many patients were prescribed thyroxine for non-thyroid indications, such as obesity and fatigue. Many of those receiving thyroxine had high or low serum thyroid stimulating hormone levels, indicating prescription of incorrect doses or lack of patient compliance with therapy. Long term thyroxine therapy may have effects upon the risk of osteoporosis. The aims of this study were to investigate indications for thyroxine prescription in the United Kingdom and to examine the frequency of abnormal serum thyroid stimulating hormone concentrations in those prescribed thyroxine for hypothyroidism. This was in order to determine the relevance of measurement of thyroid stimulating hormone level in monitoring thyroxine therapy. Subjects receiving thyroxine were identified from the computerized prescribing records of four general practices in the West Midlands. Of 18,944 patients registered, 146 (0.8%) were being prescribed thyroxine; 134 of these had primary hypothyroidism and the remainder had other thyroid or pituitary diseases prior to treatment. Of the 97 patients with primary hypothyroidism who agreed to have their thyroid stimulating hormone level measured, abnormal serum levels were found in 48%, high levels in 27% and low levels in 21%. There was a significant relationship between prescribed thyroxine dose and median serum thyroid stimulating hormone level: high hormone levels were found in 47% of those prescribed less than 100 micrograms thyroxine per day, while low levels were found in 24% of those prescribed 100 micrograms or more. Thus, thyroxine prescription was common in the four practices sampled, although indications for its use were appropriate.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Thyroid nodules in the population living around Chernobyl.

OBJECTIVE: To determine the baseline incidence, prevalence, and characteristics of thyroid nodules in the population living around the Chernobyl nuclear power plant and to compare the findings with unexposed populations. DESIGN: Prevalence study. Population samples from seven highly contaminated villages were compared with six nearby control villages of the same size and type. The data were obtained as part of the International Chernobyl Project conducted in 1990. SETTING: The study was conducted 4.5 years after the Chernobyl reactor accident that released large quantities of radionuclides, including radioiodine. PATIENTS OR OTHER PARTICIPANTS: Population samples of approximately 100 persons residing in both highly contaminated villages and control villages since the accident were compared. Individuals were selected on the basis of birth date as being 5, 10, 40, or 60 years old at the time of the study. All persons selected underwent a thyroid examination. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Two main outcome measures were used, both for thyroid nodularity: clinical palpation and high-resolution ultrasonography. RESULTS: There was no significant difference in thyroid nodularity between the study groups. Nodules were palpated in 0.7% of children and 2.9% of adults. Discrete nodules were found by ultrasonography in 0.5% of children and 14.9% of adults. Multinodular goiter was found in 3% of adults. Nodules were more common in females. CONCLUSIONS: Four and a half years after the Chernobyl accident, the incidence, prevalence, and characteristics of thyroid nodules were the same in population samples from both highly contaminated and control settlements and similar to results reported for unexposed populations in other countries.

Accidents↗
PubMed1992

Long-term thyroxine treatment and bone mineral density.

Studies of the effect of thyroxine replacement therapy on bone mineral density have given conflicting results; the reductions in bone mass reported by some have prompted recommendations that prescribed doses of thyroxine should be reduced. We have examined the effect of long-term thyroxine treatment in a large homogeneous group of patients; all had undergone thyroidectomy for differentiated thyroid cancer but had no history of other thyroid disorders. The 49 patients were matched with controls for age, sex, menopausal status, body mass index, smoking history, and calcium intake score; in all subjects bone mineral density at several femoral and vertebral sites was measured by dual-energy X-ray absorptiometry. Despite long-term thyroxine therapy (mean duration 7.9 [range 1-19] years) at doses (mean 191 [SD 50] micrograms/day) that resulted in higher serum thyroxine and lower serum thyrotropin concentrations than in the controls, the patients showed no evidence of lower bone mineral density than the controls at any site. Nor was bone mineral density correlated with dose, duration of therapy, or cumulative intake, or with tests of thyroid function. There was a decrease in bone density with age in both groups. We suggest that thyroxine alone does not have a significant effect on bone mineral density and hence on risk of osteoporotic fractures.

Absorptiometry, Photon↗
PubMed1992

Tissue localization of 11 beta-hydroxysteroid dehydrogenase and its relationship to the glucocorticoid receptor.

11 beta-Hydroxysteroid dehydrogenase (11 beta-HSD) dictates specificity for the mineralocorticoid receptor (MR) by converting the active steroid cortisol to cortisone in man (corticosterone to 11-dehydrocorticosterone in rodents), leaving aldosterone to occupy the MR. However cortisol is the principal circulating glucocorticoid in man and 11 beta-HSD, distributed in a tissue specific fashion, may represent a powerful mechanism in regulating exposure of active steroid to the glucocorticoid receptor (GR). A detailed localization study of 11 beta-HSD gene expression and activity in numerous rat tissues has been performed and compared with the presence of GR mRNA. 11 beta-HSD mRNA (1.4 kB) measured by hybridization to a cDNA derived from hepatic 11 beta-HSD, and enzyme activity, measured by percentage conversion of [3H]corticosterone to [3H]11-dehydrocorticosterone by tissue homogenate, was widespread, present in all tissues studied except spleen, brain cortex and heart. There was a close correlation between tissue 11 beta-HSD mRNA levels and activity (r = 0.91, P less than 0.001) suggesting pretranslational regulation of the enzyme at a tissue level. There was also close co-localization of GR mRNA (7 kB), measured by hybridization to a rat GR cRNA probe, and enzyme mRNA/activity in every tissue studied except heart and brain cortex in which GR mRNA was found. In the mineralocorticoid target tissues kidney and colon, additional 11 beta-HSD mRNA bands were seen (kidney 1.8 kB, colon 3.4 kB), suggesting the presence of multiple dehydrogenase species. 11 beta-HSD is widely distributed and suitably placed to modulate ligand occupancy of the GR. The possibility of multiple dehydrogenase species in mineralocorticoid target tissues is consistent with the hypothesis that the ubiquitous 'native' 1.4 kB hepatic enzyme regulates the GR, and these separate dehydrogenases regulate the MR.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1992

HLA class II gene polymorphism contributes little to Hashimoto's thyroiditis.

UNLABELLED: Previous studies of HLA and Hashimoto's thyroiditis have shown weak associations between the disease and various HLA-DR antigens. OBJECTIVE: To define better the contribution of HLA class II alleles to susceptibility to Hashimoto's thyroiditis. DESIGN AND MEASUREMENTS: Comparison of HLA-DRB, DQA and DQB restriction fragment length polymorphisms in patients with Hashimoto's thyroiditis and control subjects, and meta-analysis of this and other published studies. PATIENTS: Fifty Caucasian patients with Hashimoto's thyroiditis and 93 racially-matched control subjects. RESULTS: A 4.6 kb Taq 1 DQA restriction fragment length polymorphism occurred in 60% of patients compared with 35.5% of controls, Pc < 0.025. No other restriction fragment length polymorphism was significantly associated with the disease. Meta-analysis of several studies demonstrated weak, positive associations between the disease and DR3 and DR4. An association with DR5 was not significant. CONCLUSIONS: DR antigens are unlikely to determine disease susceptibility directly. These findings indicate that any contribution of HLA genes to inherited susceptibility to Hashimoto's thyroiditis is small and requires confirmation in family studies.

Disease Susceptibility↗
PubMed1992

Circulating lipids and minor abnormalities of thyroid function.

OBJECTIVE: We determined the effect of subclinical hyperthyroidism (defined as low circulating TSH with normal serum free T4) and subclinical hypothyroidism (raised serum TSH with normal free T4) on fasting levels of blood lipids. DESIGN: Prospective study of lipid concentrations in patients identified as having abnormal TSH. PATIENTS: Patients were identified in a population screening study of those over 60 years, with persistently low TSH with normal free T4 (n = 27) or high TSH but normal free T4 (n = 57). Patients were matched to controls with normal serum TSH by age, sex and body mass index. MEASUREMENTS: Serum TSH, free T4, free T3, total cholesterol, low density lipoprotein (LDL) cholesterol and high density lipoprotein (HDL) cholesterol. RESULTS: Serum free T4 measurements were significantly higher in those with subclinical hyperthyroidism than in their controls (P < 0.001) and lower in those with subclinical hypothyroidism than in matched controls (P < 0.001). Measurement of fasting lipids in patients and controls revealed a marked (12.2%) reduction in serum total cholesterol in subclinical hyperthyroidism (P < 0.01); no significant difference in fasting lipids between patients with subclinical hypothyroidism and controls was observed. CONCLUSIONS: Differences in free T4 between those with low or high TSH and controls with normal TSH suggest that abnormalities of TSH directly reflect thyroid hormone excess and deficiency. A reduction in cholesterol in those with subclinical hyperthyroidism suggests a direct influence of thyroid hormone excess on lipid metabolism in these patients.

Aged↗
PubMed1992

Severity of alcoholic liver disease and markers of thyroid and steroid status.

Alcoholic liver disease is associated with abnormalities in circulating levels of thyroid, adrenal and gonadal steroid hormones. The relative importance of ethanol consumption and severity of liver disease in the aetiology of these changes and their relationship to clinical abnormalities are unclear. We studied 31 subjects with alcohol-induced liver disease divided into three groups according to the severity of histological features: fatty change, hepatitis and cirrhosis. Circulating concentrations of thyroid, adrenal and gonadal steroid hormones, together with their major binding proteins, were measured in all subjects, and changes related to histology and tests of liver function, as well as clinical endocrine status. A reduction in circulating free tri-iodothyronine (fT3) was seen in subjects with alcoholic hepatitis and cirrhosis, in association with normal or reduced levels of thyrotrophin (TSH). The absence of abnormalities in subjects with fatty change despite similar ethanol intake to the other groups, and correlations between fT3 and liver function tests, suggest that changes in fT3 reflect the severity of underlying liver disease. Similarly, marked increases in circulating cortisol in the hepatitis and cirrhosis groups, and correlations between cortisol and liver function, suggest that changes largely reflect hepatic disease. The absence of clinical features of hypothyroidism or Cushing's syndrome in these groups, despite abnormalities of fT3 and cortisol, suggest an altered tissue sensitivity to hormone effects. In contrast, increases in circulating oestradiol and reductions in testosterone were found in all three groups in males. These findings suggest that both direct effects of ethanol and hepatic dysfunction determine changes in gonadal steroids in males.

Adrenal Cortex Hormones↗
PubMed1992

Basic fibroblast growth factor: an autocrine mitogen of rat thyroid follicular cells?

Basic fibroblast growth factor (FGF) is a mitogen for the rat thyroid cell line FRTL-5. A possible autocrine role for this growth factor has been investigated in rat thyroid follicular cells both in vitro and in vivo. We report here the synthesis and localisation of basic FGF and one of its high affinity receptors (flg) in FRTL-5 cells, shown by Northern hybridization analysis, Western blotting, and immunohistochemistry. Two major species of basic FGF mRNA of approximately 2.2 and 7.0 kilobases and one major species of flg mRNA of approximately 4.2 kilobases were identified in FRTL-5 cells. The basic FGF immunoreactivity observed histologically was attributed to a heparin-binding protein of approximately 20 kilodaltons mol wt. The physiological relevance of basic FGF to the thyroid is underlined by the demonstration of significant stores of immunoreactive protein, predominantly in the basement membrane of thyroid follicular cells, in paraffin sections of the normal rat thyroid, although basic FGF mRNA was not detected by in situ or Northern hybridization analysis. The mitogenic response of FRTL-5 cells to human recombinant basic FGF has been further characterized, and the factor shown to stimulate with an ED50 of 4 ng/ml. The mitogenic effects of exogenously supplied and endogenously produced basic FGF were shown to be potentiated by heparin. Examination of the mitogenic activity of both exogenous and endogenous basic FGF and its immunoneutralization in vitro suggests that locally produced basic FGF may be an important autocrine regulator of thyroid follicular cell growth.

Animals↗
PubMed1992

The significance of TSH values measured in a sensitive assay in the follow-up of hyperthyroid patients treated with radioiodine.

Use of sensitive assays for TSH in the follow-up of patients treated with radioiodine (131I) for thyrotoxicosis has led to questions regarding the significance of abnormal TSH values found in association with normal circulating thyroid hormone levels, especially TSH results below normal. We have investigated the relationship between serum TSH and the likelihood of maintenance of euthyroidism, as well as the relationship between serum TSH and free T4, in 389 subjects treated with 131I 2-35 years previously who had free T4 and free T3 values within the normal range and who were not receiving thyroxine or antithyroid therapy. In those with undetectable TSH (less than 0.05 mU/L), TSH remained undetectable in 54.5% at 1 yr but rose to detectable or normal values in the remainder. In those with low but measurable TSH (0.05-0.5 mU/L), results were similar at 1 yr in 47.5% and returned to normal in 45%. No patient with a TSH value below normal became hypothyroid (defined as a reduction in serum free T4). In those with normal TSH (0.5-5.0 mU/L) at time 0, TSH remained normal in 83%, fell in 4% and became elevated in 13%. The yr 1 incidence of hypothyroidism was 1%; one patient became thyrotoxic. In those with TSH values above normal (5.0-15.0 mU/L), TSH remained elevated in 90.6%; the incidence of hypothyroidism was 14.5% in yr 1. The small risk of development of hypothyroidism in those with subnormal or normal TSH indicates that biochemical testing is not essential for 1-2 yr in such patients; this contrasts with a need for repeat testing within a period not exceeding 1 yr in those with elevated TSH. The relationship between serum-free T4 and TSH suggests that TSH results outside the normal range reflect thyroid hormone excess or deficiency. Persistence of undetectable TSH values during follow-up and the observation of higher free T4 at time 0 in those whose TSH remained undetectable compared with those whose TSH rose suggest that undetectable TSH concentrations are of greater significance than low but detectable values.

Adult↗
PubMed1992

Effect of Mg2+ on Na(+)-dependent inositol transport. Role for Mg2+ in etiology of diabetic complications.

Diabetes mellitus is associated with a significant reduction in the serum concentration of Mg2+. Several studies have suggested that hypomagnesemia may be implicated in the etiology of diabetic complications; however, no mechanism has been proposed. This study demonstrates that Mg2+ is a positive effector of inositol transport and is capable of promoting a 2.5-fold increase in the affinity of the transporter for inositol. Analysis of the kinetics of inositol transport shows that, at physiological concentrations of inositol, the reductions in Mg2+ concentrations that occur in diabetic patients would result in a significant decline in the rate of inositol transport (1.5- to 2-fold). We suggest that hypomagnesemia may be linked to the development of diabetic complications via reduction in the rate of inositol transport and subsequent intracellular inositol depletion. This assertion allows hypomagnesemia and the polyol theory to be unified into one mechanistic model for the development of diabetic complications.

Biological Transport↗
PubMed1992

Thyroid hormone regulation of human pituitary alpha subunit gene expression.

The thyroid hormone T3 exerts an inhibitory effect upon pre-translational expression of the alpha subunit gene in the anterior pituitary. In the intact animal oestrogen alone is without effect upon alpha gene expression but oestrogen modulates the influence of T3 deficiency upon the alpha gene. T3 effects upon alpha transcription are mediated via sequences within 98 bp of the transcriptional start site of the gene and similar 5' flanking sequences of the alpha gene mediate both T3 regulation and oestrogen modulation of T3 inhibition. This oestrogen effect may be mediated directly via interaction of the oestrogen receptor with the alpha gene thyroid hormone response element to which the oestrogen receptor is able to bind.

Animals↗
PubMed1991

Changes in the kinetics of inositol transport during TPA-induced differentiation of HL60 cells towards monocytes.

When exposed to the phorbol ester TPA, HL60 cells undergo growth arrest and differentiate towards monocytes. During TPA-induced differentiation there was a 2.6-fold increase in the rate of inositol transport (Vmax), a 2.1-fold increase in intracellular inositol and a 1.5-fold increase in inositol lipid. An increase in the Vmax of inositol transport did not occur when the variant cell line HL60Ast3 was exposed to TPA, which has been shown in this cell line to induce growth arrest but not differentiation. This observation suggests that the change in inositol transport during HL60 monocyte differentiation is specifically associated with the process of cell differentiation as opposed to growth arrest.

Biological Transport↗
PubMed1991

Thyroid hormone and glucocorticoid regulation of receptor and target gene mRNAs in pituitary GH3 cells.

We have examined the effects of triiodothyronine (T3), in dose-response and time-course studies, on T3 receptor (T3R) alpha and beta and glucocorticoid receptor (GR) mRNAs in rate pituitary GH3 cells, in parallel with T3 actions on expression of the growth hormone (GH) target gene. Modulatory influences of dexamethasone (dex) on T3 action were studied by treatment with dex before and during T3 treatment. T3 treatment (1-100 nM) for 24 h reduced T3R alpha mRNA, while the presence of dex (1 microM) enhanced the T3 effect on T3R alpha mRNA and induced T3 inhibition of T3R beta mRNA. Stimulatory effects of T3 treatment on GH mRNA and release were seen in the face of inhibition of T3R mRNAs; these effects on GH were also enhanced by the presence of dex. T3 treatment for 24 h increased GR mRNA; this effect was inhibited by the presence of dex. We next examined the influence of dex on GR and T3R alpha and beta mRNAs, in parallel with effects of dex on the prolactin (PRL) target gene. Modulatory influences of T3 on dex action were studied by treatment of cells with T3 before and during dex treatment. Treatment with dex (0.1-10 microM) for 24 h reduced GR mRNA, an action enhanced by the presence of T3 (100 nM). Dex treatment resulted in inhibition of PRL mRNA and release despite parallel inhibition of GR mRNA by dex; these effects were enhanced by the presence of T3. In contrast to actions on GR, dex has no effect on T3R mRNAs. These effects of T3 and dex on receptor mRNAs suggest that glucocorticoid modulation of T3 action is not related to direct actions on T3R synthesis. In contrast, the mechanism of T3 modulation of glucocorticoid action may be due in part to alteration of GR mRNA expression. Effects of T3 and dex on target gene expression were observed in the presence of parallel reduction of their respective receptor mRNAs. This provides new evidence that interactions between these hormones are likely to be mediated by mechanisms other than regulation of receptor gene expression.

Animals↗