Search PubMed⌕ Search

Biomedical subjects

M C Sheppard

Publications and source records attributed to M C Sheppard.

At least 145 records · Page 8Linked to original sources
PubMed1991

Serum thyroglobulin measurements in thyroid cancer: evaluation of 'false' positive results.

OBJECTIVE: Serum thyroglobulin (Tg) should be undetectable in patients successfully treated for thyroid carcinoma. We have examined the course of disease in 19 patients with raised serum Tg (greater than 5 micrograms/l) on initial measurement but no other evidence of residual, recurrent or metastatic cancer. DESIGN: 416 patients from several centres were followed for periods between 1 and 9 years. Serum Tg was measured at 6-12-month intervals. PATIENTS: All had differentiated thyroid cancer, treated by partial or total thyroidectomy and/or 131I ablation, and were receiving suppressive thyroxine therapy. MEASUREMENT: Serum Tg was measured and clinical, X-ray and scan assessment made of presence or absence of residual, recurrent or metastatic cancer. RESULTS: Of 416 patients initially assessed, only 19 had Tg greater than 5 micrograms/l but no clinical or radiological evidence of disease. At follow-up, 11 patients had developed overt signs of malignancy; one had been treated with 131I with a subsequent fall in Tg; five had Tg between 5 and 20 micrograms/l with incompletely suppressed TSH levels; two subjects remained with slightly elevated Tg and undetectable TSH. CONCLUSION: Patients with elevated Tg require careful follow-up even in the apparent absence of disease. Moderate elevation of serum Tg may be due to inadequate thyroxine suppression therapy, assessed by detectable TSH values measured in a sensitive assay.

Biomarkers, Tumor↗
PubMed1991

Long-term follow-up of treatment of thyrotoxicosis by three different methods.

In view of continuing debate regarding the best definitive therapy for thyrotoxicosis, we examined the long-term outcome of radioiodine (131I) or surgical treatment of 1918 thyrotoxic patients divided into three groups: those given 131I at a dose calculated from thyroid size, 131I uptake and effective half-life to administer a fixed radioactivity dose to the thyroid; those treated with a dose of 131I (110, 185 or 370 MBq) chosen empirically; and those treated by partial thyroidectomy. A minimum 10-year follow-up was achieved for 1119 patients treated with a calculated 131I dose; a single dose resulted in control of disease in 90.5%. At 5 years, 18% were hypothyroid, the prevalence rising to 42% at 20 years. Of 504 patients treated with an empirical 131I dose and followed for at least 5 years, thyrotoxicosis was controlled by a single dose in 89.7%. The rate of hypothyroidism at 5 years (38.5%) was higher than that found in the calculated dose group. A minimum 10-year follow-up was achieved for 295 surgically treated patients; thyrotoxicosis was controlled in 89.2%. The prevalence of hypothyroidism (2% at 5 years, 27.5% at 20 years) was lower than that found after 131I, whether given by calculated or empirical dose. Each of the treatments employed resulted in an acceptable rate of cure of thyrotoxicosis. If maintenance of euthyroidism is the major objective, our findings suggest that surgery represents the treatment of choice. Furthermore, calculated dose 131I administration has advantages in terms of risk of hypothyroidism over empirical dose treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Prevalence and follow-up of abnormal thyrotrophin (TSH) concentrations in the elderly in the United Kingdom.

Increasing use of assays for TSH with improved sensitivity as a first-line test of thyroid function has raised questions regarding prevalence and clinical significance of abnormal results, especially values below normal. We have assessed the thyroid status of 1210 patients aged over 60 registered with a single general practice by measurement of serum TSH using a sensitive assay. High TSH values were more common in females (11.6%) than males (2.9%). TSH values below normal were present in 6.3% of females and 5.5% of males, with values below the limit of detection of the assay present in 1.5% of females and 1.4% of males. Anti-thyroid antibodies were found in 60% of those with high TSH but only 5.6% of those with subnormal TSH. Eighteen patients were hypothyroid (high TSH, low free thyroxine) and one thyrotoxic (low TSH, raised free thyroxine) at initial testing. Seventy-three patients with elevated TSH but normal free T4 were followed for 12 months; 13 (17.8%) developed low free T4 levels and commenced thyroxine, TSH returned to normal in four (5.5%) and 56 (76.7%) continued to have high TSH values. Sixty-six patients with TSH results below normal were followed. Of the 50 subjects with low but detectable TSH at initial testing, 38 (76%) returned to normal at 12 months; of those 16 with undetectable TSH followed, 14 (87.5%) remained low at 12 months. Only one subject (who had an undetectable TSH) developed thyrotoxicosis. In view of the marked prevalence of thyroid dysfunction in the elderly, we suggest that screening of all patients over 60 should be considered.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1991

Endocrinology.

Explore the source record for details and available documents.

Adult↗
PubMed1991

Localization of renal 11 beta-dehydrogenase by in situ hybridization: autocrine not paracrine protector of the mineralocorticoid receptor.

In the kidney, 11 beta-dehydrogenase (11 beta-DH) converts the active steroid cortisol to inactive cortisone (corticosterone to 11-dehydrocorticosterone in the rat). In man, congenital and acquired deficiency of 11 beta-dehydrogenase are rare causes of hypertension in which cortisol acts as a potent mineralocorticoid. Observations from these clinical studies indicate that 11 beta-DH conveys specificity for the mineralocorticoid receptor in distal tubules and collecting ducts. However, while some studies do indicate 11 beta-DH activity in rat distal tubules and collecting ducts, immunohistochemical studies localize 11 beta-DH only to proximal tubules. to resolve this dilemma, we have performed in situ hybridization localization of 11 beta-DH mRNA in rat kidney tissue using 35S-labeled sense and antisense cRNA probes to rat 11 beta-DH. In contrast to our immunohistochemical studies in which 11 beta-DH protein was localized predominantly to proximal tubules in the inner cortex, 11 beta-DH mRNA was expressed in tubules in both the inner and outer cortex, most probably proximal and distal tubules, and in collecting ducts extending across the corticomedullary junction to the papillary tip. Weak hybridization was also seen in glomeruli, but no hybridization to the sense 11 beta-DH cRNA or to sections pretreated with RNase-A was observed. We conclude that renal 11 beta-DH is suitably located to prevent access of glucocorticoid to the MR in an autocrine and not a paracrine fashion. 11 beta-DH in proximal tubules may protect the glucocorticoid receptor.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1991

Calcium/calmodulin regulation of the rat prolactin gene is conferred by the proximal enhancer region.

The effects of the calcium/calmodulin signaling system on expression of the rat PRL gene were studied in rat pituitary GH3 cells using two specific naphthalene sulfonamide calmodulin (CaM) antagonist drugs, W7 and a more potent and more highly specific iodo-derivative, 5-iodo-1-C8. PRL (but not GH) mRNA accumulation was markedly inhibited by W7, which in coincubations abolished the stimulation normally seen with TRH. Transient transfection assays showed that expression of the reporter gene chloramphenicol acetyl transferase (CAT) linked to 5'-flanking sequences from the PRL gene was inhibited by the calcium-channel blocker verapamil and by the two CaM antagonists. The calcium effects showed partial promoter specificity, in that transcription of PRL-CAT constructs was markedly inhibited by verapamil, but the Rous sarcoma virus-CAT construct also showed significant inhibition, whereas the pBL-CAT2 construct was unaffected. Three hundred ninety five base pairs were sufficient to confer the full inhibitory effect of calcium channel blockade or CaM antagonist seen with longer constructs. The data indicate that CaM is important for PRL gene transcription, and that the effects of CaM are exerted on DNA sequences within the proximal 395bp of prolactin 5'-flanking DNA.

Animals↗
PubMed1991

Regulation by thyroid status of c-myc, c-fos and H-ras mRNAs in the rat myocardium.

Effects of thyroid status on expression of a variety of myocardial genes, such as those encoding contractile proteins, have been reported, as well as interactions between thyroid hormones and developmental and haemodynamic regulation of contractile protein synthesis. In addition, it is clear that developmental and haemodynamic factors regulate expression of specific proto-oncogenes, including c-myc, c-fos and H-ras, in the myocardium but the effect of thyroid status on such proto-oncogene products, which are proposed to play a critical signal-transducing role in the heart, has been previously unexplored. In order to determine whether changes in thyroid status are associated with changes in expression of these putative intracellular signals, we examined the effect of hypothyroidism and tri-iodothyronine (T3) treatment on myocardial levels of c-myc, c-fos and H-ras mRNAs in the rat. The induction of hypothyroidism was associated with a marked increase in myocardial c-myc, c-fos and H-ras mRNAs, changes reversed by 72 h of T3 replacement. Administration of T3 to euthyroid rats had no significant effect on myocardial c-myc or c-fos mRNAs, but inhibition of H-ras mRNA by T3 was evident. These observations demonstrating influences of thyroid status on expression of specific proto-oncogenes suggest that thyroid hormones, as well as exerting direct effects on expression of functionally important myocardial genes, also interact with the cellular transduction pathways mediated by the products of the c-myc, c-fos and H-ras genes.

Animals↗
PubMed1991

Thyroid autocrine factors: regulation of secretion of insulin-like growth factor binding proteins from sheep thyroid cells by autocrine basic fibroblast growth factor.

The mRNA for basic fibroblast growth factor has been detected in primary cultures of sheep thyroid cells. RNA species of 2.0 kb, 3.3 kb and 7.2 kb have been identified. The effects of this autocrine factor on the production of insulin-like growth factor binding proteins (IGFBPs) have been examined. bFGF enhanced the secretion of IGFBP-2 and, like epidermal growth factor (EGF) and the tumour promoting phorbol ester (TPA), induced the appearance of IGFBP-3. We conclude that bFGF is synthesized by sheep thyroid cells and has autocrine potential since it can regulate the secretion of other thyroid autocrine factors which, in turn, may regulate thyroid growth and function.

Animals↗
PubMed1991

Assessment of a screening process to detect patients aged 60 years and over at high risk of hypothyroidism.

General practitioners are increasingly expected to screen elderly patients for common disorders, such as hypothyroidism, and the identification of at-risk patients by simple means would reduce the financial and other costs of such screening. A general practice based study of 1193 patients aged 60 years and over has been carried out to investigate the usefulness of the following factors in identifying those in whom biochemical testing for hypothyroidism would be indicated: personal history or family history of thyroid disease, symptoms of thyroid disease and body mass index. Of the 190 patients with either a personal or family history of thyroid disease, 28 (14.7%) had an elevated concentration of thyroid-stimulating hormone. Thus, 66 of the 94 patients (70.2%) with elevated concentrations of thyroid-stimulating hormone had no such thyroid history. Similarly, only nine (4.7%) of the patients with a personal or family history of thyroid disease required thyroxine replacement therapy. Thus, 22 of the 31 patients (71.0%) requiring such treatment had no such history. Discriminant analysis of the responses of women patients to questions concerning personal or family history of thyroid disease, the presence of symptoms of hypothyroidism, their age and body mass index identified only 51.3% of those with an elevated thyroid-stimulating hormone concentration and 77.2% of those with normal thyroid-stimulating hormone. Analysis of the responses of the men patients was even less discriminating.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1990

Thyroxine-binding prealbumin gene polymorphism: a population study.

The human thyroxine-binding prealbumin (TBPA) gene was examined for restriction fragment length polymorphism (RFLP) in normal subjects and a subject with euthyroid hyperthyroxinaemia, due to increased thyroxine binding by TBPA, using 16 restriction enzymes. Only Taq I and Msp I were shown to detect RFLPs. In a male of the normal population and one of his daughters, an additional Taq I site was found in the 3'-flanking region of the TBPA gene. The RFLP in a subject with euthyroid hyperthyroxinaemia was due to the deletion of a MspI site. All three subjects with RFLPs were heterozygous.

Adult↗
PubMed1990

Multiple DNA elements determine basal and thyroid hormone regulated expression of the human glycoprotein alpha subunit gene in pituitary cells.

Basal and thyroid hormone-regulated expression of constructs containing varying lengths of 5' flanking sequence of the human glycoprotein hormone alpha subunit gene ligated to the reporter gene encoding chloramphenicol acetyl transferase (CAT) were examined in transfected pituitary GH3 cells. CAT gene expression was quantified by measurement of CAT enzyme activity. In addition, an RNase protection assay was used to confirm changes in CAT mRNA levels and to verify regulation of transcription from the authentic alpha gene start site. The pattern of basal alpha promoter activity indicated the presence of inhibitory DNA elements between -98 and -172 and upstream of -846 relative to the transcriptional start site, as well as a stimulatory element between -346 and -846. Each of the transfected constructs exhibited tri-iodothyronine inhibition of alpha promoter activity, suggesting the presence of an inhibitory thyroid hormone response element within 98 bp of the alpha gene transcriptional start site.

Cell Line↗
PubMed1990

Regulation of alpha and thyrotrophin-beta subunit mRNA levels by androgens in the female rat.

Thyroid and steroid hormones act by similar mechanisms to influence gene expression in the anterior pituitary gland. The genes encoding the common alpha and TSH-beta glycoprotein subunits are known to be regulated by thyroid hormones; we report here the effects of androgen administration on levels of alpha and TSH-beta mRNA in pituitary cytoplasm in the euthyroid and hypothyroid female rat. Dihydrotestosterone (DHT) suppressed both alpha and TSH-beta mRNAs to levels lower than those found in untreated animals; a similar reduction was seen in hypothyroid animals treated with DHT. A biphasic response of TSH-beta mRNA was seen following administration of tri-iodothyronine (T3) to hypothyroid rats, with early stimulation followed by later inhibition; these changes were also evident after administration of T3 to androgen-treated animals, although mRNA levels were again suppressed. The effects of testosterone were similar to those of DHT. In contrast to the changes in mRNA levels, androgen administration did not lead to significant alterations in serum TSH concentrations or pituitary TSH content. These results indicate that, like thyroid hormones, androgens suppress both alpha and TSH-beta subunit mRNA levels in the female rat. Androgens, however, exert differential effects on TSH synthesis and release which contrast with those of thyroid hormones.

Analysis of Variance↗
PubMed1990

Basic fibroblast growth factor affects DNA synthesis and cell function and activates multiple signalling pathways in rat thyroid FRTL-5 and pituitary GH3 cells.

We have used a recombinant human basic fibroblast growth factor (basic FGF) to study its effects on cell proliferation, gene expression and accumulation of cyclic AMP (cAMP) and inositol phosphates in two well-characterized endocrine cell lines, FRTL-5 rat thyroid and GH3 rat pituitary cells. Basic FGF induced a dose-dependent increase in mitogenesis (assessed by measuring incorporation of [3H]thymidine) in FRTL-5 cells (40 ng basic FGF/ml increased mitogenesis above the control value by 2148 +/- 108% (mean +/- S.E.M.), but inhibited mitogenesis in GH3 cells at all doses (85 +/- 4% of control with 40 ng basic FGF/ml]. Thyroglobulin mRNA concentration was increased in FRTL-5 cells (126 +/- 6% of control with 40 ng basic FGF/ml) as was prolactin mRNA in GH3 cells (246 +/- 11% of control with 40 ng basic FGF/ml), but GH mRNA in GH3 cells was not significantly affected by any dose of basic FGF. Intracellular cAMP was reduced by basic FGF in both FRTL-5 and GH3 cells (40 ng bFGF/ml giving 80 +/- 5% of the control value in FRTL-5, and 67 +/- 15% of the control value in GH3 cells) despite increased levels when FRTL-5 cells were stimulated with 150 microU TSH/ml (5645 +/- 484% of control) or GH3 cells were stimulated by 10 mumol forskolin/l (3347 +/- 396% of control). In both FRTL-5 and GH3 cells, accumulation of [3H]inositol phosphates were increased by 40 ng basic FGF/ml (201 +/- 6 and 330 +/- 51% of control values respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Giant invasive prolactinoma: a case report and review of nine further cases.

Very large prolactinomas are rare and may be difficult to treat. We present the report of a patient with an exceptionally aggressive tumour which extended outside the skull and emerged within the internal jugular vein. Bromocriptine induced only transient suppression of serum prolactin. In vitro studies of tissue from this prolactinoma showed that although prolactin secretion was reduced by both bromocriptine and dopamine, neither agent affected cytoplasmic levels of prolactin mRNA, suggesting relative autonomy of prolactin synthesis. We reviewed the progress of nine other patients with very large prolactinomas and serum prolactin levels greater than 100,000 mU/l. In three cases, treatment with bromocriptine rapidly reduced tumour size and serum prolactin levels became normal, but in the other cases responses were slower and less marked. Substantial amounts of residual pituitary tumour were seen in all cases where serum prolactin remained above 1000 mU/l, but also in one case where serum prolactin returned to normal, showing that serum prolactin levels are not reliable indicators of tumour size. Two patients died: one developed a CSF leak, and one pneumococcal meningitis in the absence of recognized CSF leakage. This emphasizes the significant morbidity associated with very large prolactinomas. The ideal long-term treatment of these tumours remains uncertain, but bromocriptine therapy alone is often inadequate. Cases of apparent bromocriptine resistance may reflect abnormal regulation of prolactin gene expression.

Adult↗
PubMed1989

Thyroid hormone response elements in pituitary genes.

Thyroid hormones regulate the transcription of a number of genes in the anterior pituitary gland. A thyroid hormone response element in the regulatory region of the rat growth hormone gene has previously been shown to mediate the effects of thyroid hormones on growth hormone gene transcription. The 5' flanking regions of the thyrotrophin alpha and beta subunit and prolactin genes have now been examined for the presence of sequences similar to this response element. Southern blotting reveals that no such sequences are present in the regions of the thyrotrophin subunit and prolactin genes examined, suggesting that the thyroid response elements of these genes differ from that of the rat growth hormone gene.

Animals↗