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Biomedical subjects

F M Creagh

Publications and source records attributed to F M Creagh.

At least 19 recordsLinked to original sources
PubMed1994

The iodide perchlorate discharge test in women with previous post-partum thyroiditis: relationship to sonographic appearance and thyroid function.

BACKGROUND: Post-partum thyroid disease occurs in 50% of anti-thyroid peroxidase (TPO) antibody positive women (detected at 16 weeks' gestation) and is characterized by a transient episode of hyper, hypo or hyper-hypothyroidism. In approximately 20% of these women the hypothyroidism is permanent. However, the extent of long-term thyroid dysfunction, possibly mediated by immune attack, in those anti-TPO Ab + ve women who have had only transient or no thyroid dysfunction during the postpartum period is not clear. OBJECTIVE: We have therefore studied the frequency of iodide organification defects by iodide perchlorate discharge testing, and of thyroid morphological abnormalities by ultrasound scanning in euthyroid women following their episode of post-partum thyroiditis (PPT). DESIGN: The study group comprised 17 women with previous PPT (PPT + ve) and 12 women who had positive anti-TPO antibodies during pregnancy but who did not develop PPT (PPT - ve). Women were studied 15-47 months following their episode of PPT. RESULTS: Iodide perchlorate discharge tests were positive (more than 10% discharge) in 7 (41%) PPT + ve and 5 (42%) PPT-ve subjects (P = NS). Morphological abnormalities on thyroid ultrasound were detected in 7 of 14 (50%) PPT + ve and 7 of 9 (77%) PPT - ve subjects (P = NS). There was a strong association between abnormalities of iodide organification and morphology: of 11 subjects with positive iodide perchlorate discharge tests, 10 had abnormal (positive) ultrasound scans; of 12 subjects with negative iodide perchlorate discharge tests 8 had negative ultrasound scans (P = 0.013, Fisher's exact test). CONCLUSIONS: Long-term subtle defects of thyroid function and morphology are common in women with anti-TPO antibodies in pregnancy, whether or not they develop post-partum thyroiditis. The clinical significance of these findings is unclear but a continuing thyroid pathological process is suggested.

Adult↗
PubMed1991

Comparison of subcutaneous soluble human insulin and insulin analogues (AspB9, GluB27; AspB10; AspB28) on meal-related plasma glucose excursions in type I diabetic subjects.

OBJECTIVE: To compare postprandial glucose excursions and plasma free insulin-analogue levels after subcutaneous injection of three novel human insulin analogues (AspB10; AspB9, GluB27; and AspB28) with those after injection of soluble human insulin (Actrapid HM U-100). RESEARCH DESIGN AND METHODS: Six male subjects with insulin-dependent diabetes, at least 1 wk apart and after an overnight fast and basal insulin infusion, received 72 nmol (approximately 12 U) s.c. of soluble human insulin 30 min before, or 72 nmol of each of the three analogues immediately before, a standard 500-kcal meal. RESULTS: Mean basal glucoses were similar on the 4 study days. Compared to human insulin (6.3 +/- 0.8 mM), mean +/- SE peak incremental glucose rises were similar after analogues AspB10 (5.4 +/- 0.8 mM) and AspB9, GluB27 (5.4 +/- 0.7 mM) and significantly lower after analogue AspB28 (3.6 +/- 1.2 mM, P less than 0.02). Relative to soluble human insulin (100% +/- SE21), incremental areas under the glucose curve between 0 and 240 min were 79% +/- 34 (AspB10, NS), 70% +/- 29 (AspB9, GluB27, NS), and 43% +/- 23 (AspB28, P less than 0.02). Basal plasma free insulin levels were similar on the 4 study days. Plasma free insulin-analogue levels rose rapidly to peak 30 min after injection at 308 +/- 44 pM (AspB10); 1231 +/- 190 pM (AspB9, GluB27) and 414 +/- 42 pM (AspB28) and were significantly higher than corresponding (i.e., 30 min postmeal) plasma free insulin levels of 157 +/- 15 pM (P less than 0.02 in each case). CONCLUSIONS: Plasma profiles of the insulin analogues were more physiological than that of human insulin after subcutaneous injection. All three analogues given immediately before the meal are at least as effective as soluble human insulin given 30 min earlier. These analogues are promising potential candidates for short-acting insulins of the future.

Adult↗
PubMed1988

Immunoprecipitation of human adrenal microsomal antigen.

Human adrenal microsomes have been labelled with 125I and immunoprecipitated with sera from patients with Addison's disease. The immunoprecipitates were then analysed by SDS-PAGE and autoradiography. 13 of the 23 sera from the Addison patients studied contained antibodies which reacted with a 55 kDa adrenal microsomal protein. The same 13 sera were also positive for adrenal antibodies as judged by immunofluorescence. The 55 kDa protein was not immunoprecipitated from placenta or thyroid microsomes by Addison sera. Furthermore, patients with Graves' disease or rheumatoid arthritis did not immunoprecipitate the 55 kDa protein from adrenal microsomes. Our studies suggest therefore that Addison sera contain antibodies to a 55 kDa adrenal specific protein which may well be the antigen observed on immunofluorescence.

Addison Disease↗
PubMed1988

Non-mydriatic Polaroid photography in screening for diabetic retinopathy: evaluation in a clinical setting.

Because of fears that Polaroid colour prints produced with a non-mydriatic fundus camera may not detect important sight threatening lesions in diabetes a study was conducted comparing retinal images obtained on Polaroid prints taken in "field" conditions with those on 35 mm transparencies and fluorescein angiograms. Almost one in five (22/127) Polaroid prints could not be assessed owing to poor quality compared with 3 (2.4%) 35 mm transparencies and 2 (1.6%) fluorescein angiograms. The pick up rate of microaneurysms, haemorrhages, and hard and soft (cotton wool spots) exudates was equivalent for Polaroid prints and 35 mm transparencies of equivalent quality. In two cases with disc new vessels, however, these were not seen on the Polaroid prints. The widespread use of Polaroid colour prints obtained with a non-mydriatic camera without the necessary operative and interpretive skills further limits the usefulness of the technique.

Diabetic Retinopathy↗
PubMed1987

The TSH receptor: structure and interaction with autoantibodies in thyroid disease.

Studies of the TSH receptor using affinity labelling with photoactive derivatives of TSH and analysis by SDS-PAGE have shown that the receptor contains 2 subunits (A and B), linked by a disulphide bridge. Similar results are obtained with TSH receptors from human, porcine and guinea pig thyroid tissue and from guinea pig fat. Analysis of affinity labelled receptors under non-denaturing conditions suggest that subunits additional to the A and B subunits are not present. Hydrodynamic measurements indicate that the receptor A subunit has an approximately spherical structure (Stokes' radius 70 A) and when this interacts with TSH (an elongated structure with Stokes' radius 56A) a very elongated complex (Stokes' radius 104A) is formed. Isoelectric focusing studies of the TSH receptor A subunit, TSH and TSH receptor antibodies indicate that charge-charge interactions are of considerable importance in the binding of hormone and antibody to the receptor.

Animals↗
PubMed1986

Thyroid-stimulating immunoglobulins and thyroid function tests in two siblings with neonatal thyrotoxicosis.

Thyroid function and serum TSI levels in two siblings with neonatal thyrotoxicosis are described. The first infant was treated with exchange transfusion and potassium iodide. The second infant was treated with intrauterine propylthiouracil followed by potassium iodide. In contrast to the first infant, the second infant had no clinical sign of neonatal thyrotoxicosis. He also had lower TSI levels with a biological half-life of 5 days. Only one of three assays showed some TSI activity in breast milk.

Adult↗
PubMed1986

Characterization of TSH antagonist activity in the serum of patients with thyroid disease.

The ability of sera from patients with thyroid disease to block TSH stimulation of cyclic AMP release from isolated porcine thyroid cells has been assessed and the blocking activity characterized. TSH receptor binding activity was also measured. No blocking or receptor binding activity was detectable in patients with primary myxoedema (n = 23), Hashimoto's disease (n = 11), multinodular goitre (n = 6), or rheumatoid arthritis (n = 10). However, analysis of sera from 23 patients (out of an initial screen of 110 patients) with treated Graves' disease which did not stimulate cyclic AMP production in the bioassay showed that two of these sera contained powerful blocking and receptor binding activity. Both these patients had been treated with 131I. Analysis of the two sera by gel filtration on Sephadex G-200 indicated that blocking and TSH receptor binding activity were associated only with the IgG fraction. Digestion of the IgG with pepsin followed by reduction showed that both (Fab)2 and Fab fragments contained high levels of blocking and binding activity. Antibody divalency was not necessary therefore for TSH antagonist activity. However, our studies suggest that autoantibodies of this type with TSH antagonist activity do not occur frequently in patients from the Cardiff region with primary myxoedema, Hashimoto's or treated Graves' disease.

Biological Assay↗
PubMed1986

IgG thyrotrophin receptor antibody activity in Graves' disease; a study of TSH agonist and antagonist activities by isoelectric focusing.

The distribution of TSH receptor antibody activity in the 7S and 19S fractions of Graves' sera has been re-evaluated. Serum fractions were obtained by gel filtration from 12 Graves' sera and assayed for TSH receptor binding activity in a radioreceptor assay. Thyroid stimulating activity was determined in a cultured porcine thyroid cell bioassay. In apparent contrast to the findings of Baker et al. (1983) TSH receptor binding activity was confined to the 7S gel filtration fraction, containing IgG, and was not detected in the 19S fraction, containing IgM. Similarly thyroid stimulating activity was detected only in the 7S fraction. 7S fractions from seven Graves' sera were fractionated by isoelectric focusing and the fractions analysed for TSH receptor binding activity and TSH agonist and antagonist activities. Five of the IgGs showed TSH agonist activity and in all five, the peak thyroid stimulating activity (measured by stimulation of cyclic AMP release from isolated porcine thyroid cells) was in fractions with a pI of between 8.0 and 9.5. In four of these five IgGs, TSH receptor binding activity showed similar isoelectric distribution to the thyroid stimulating activities. High levels of TSH receptor binding activity without associated TSH agonist or antagonist activity were however observed in some isoelectric fractions of the fifth stimulating Graves' IgG studied. All the isoelectric fractions from the fifth IgG with thyroid stimulating activities contained TSH receptor binding activity. Two of the Graves' IgGs showed TSH antagonist activity and both the TSH receptor binding and TSH antagonist activities of these IgGs showed similar isoelectric distribution with the peak activities at a pI of around 9.0. Consequently, it was not possible to separate TSH agonist or TSH antagonist activities from TSH receptor binding activity in seven Graves' sera by isoelectric focusing although in one IgG several isoelectric fractions contained isolated receptor binding activity. These findings are in keeping with the hypothesis that the biological activities of Graves' IgGs are intimately related to their ability to bind to the TSH receptor.

Animals↗
PubMed1985

Interaction of autoantibodies to thyrotropin receptor with a hydrophilic subunit of the thyrotropin receptor.

Reduction of human thyroid membranes with dithiothreitol caused the release of a water-soluble glycoprotein which neutralized the thyrotropin (TSH) receptor-binding and thyroid-stimulating activities of Graves' serum. Analysis of the protein by gel filtration and sucrose density gradient centrifugation allowed estimates of 3.45 nm for the Stokes' radius, 3.6 S for the s20,w and 47 000 +/- 5000 (mean +/- S.D.; n = 4) for the Mr. The material released by dithiothreitol treatment could be crosslinked to 125I-labelled TSH coupled to N-hydroxysuccinimidyl 4-azidobenzoate (125I-HSAB-TSH), suggesting that it contained a component of the TSH receptor. Furthermore, analysis of the crosslinked material by sodium dodecyl sulphate/polyacrylamide-gel electrophoresis indicated that it contained the TSH receptor A subunit (Mr 50 000). Several factors suggested therefore that the glycoprotein released by dithiothreitol treatment of human thyroid membranes was the TSH receptor A subunit. In particular, (a) both preparations were hydrophilic and were released from membranes by reduction, (b) they had similar Mr values and (c) both preparations crosslinked to 125I-HSAB-TSH. Material similar to the TSH receptor A subunit was released from thyroid membranes by treatment with papain, probably as a result of cleavage of the receptor A subunit at a site close to the interchain disulphide bridge. A similar mechanism, involving thyroid proteinases, was probably involved in release of material with similar properties to the TSH receptor A subunit during freezing and thawing of human thyroid homogenates.

Autoantibodies↗
PubMed1985

Immunoprecipitation of TSH-TSH receptor complexes.

The ability of Graves' sera to interact with the TSH receptor crosslinked to a 125I-labelled photoactive derivative of TSH has been investigated. Crosslinked complexes were prepared using non-purified detergent solubilized human thyroid and guinea pig fat TSH receptors. Affinity purified porcine TSH receptor preparations wee also used. After crosslinking, the crosslinked TSH-TSH receptor complexes were separated from aggregates and free TSH on Sephacryl S-300, incubated with test sera followed by immunoprecipitation using anti-IgG or Protein A. Using non-purified human TSH receptors crosslinked to TSH, a mean +/- SD of 12.1 +/- 4.9% of the crosslinked complex was immunoprecipitated with Graves' sera (n = 7) compared with 10.3 +/- 2.6% with Hashimoto sera (n = 6; P greater than 0.14) and 3.8 +/- 1.0% with normal sera (n = 6; P less than 0.004). These values were markedly reduced when TSH receptor preparations free of other thyroid autoantigens (guinea pig fat TSH receptors) were used. Under these conditions immunoprecipitation with Graves' sera (n = 24) was 1.6 +/- 1.3% compared with 0.8 +/- 0.6% for Hashimoto sera (n = 13) and 0.8 +/- 0.4% for normal sera (n = 12; P less than 0.003). In addition complexes formed between TSH and affinity purified porcine TSH receptors gave low immunoprecipitation values for Graves' (1.44 +/- 0.73%; n = 20) and Hashimoto sera (1.7 +/- 0.94; n = 11) which were not significantly different (P greater than 0.4). Overall, therefore, the effects of Graves' and Hashimoto sera were similar and the amounts of material immunoprecipitated were markedly reduced when TSH receptor preparations containing reduced amounts of other autoantigens were used. Consequently the Graves' sera did not appear to interact specifically with crosslinked TSH-TSH receptor complexes. However the Graves' sera studied did contain TSH receptor antibodies which could inhibit the binding of labelled TSH to TSH receptors in the preparations used and our results suggest that the binding of TSH and these antibodies to the receptor is mutually exclusive. There is considerable evidence that serum from patients with Graves' disease contains antibodies to the TSH receptor (Rees Smith, 1981). Several studies have suggested that binding of the receptor antibody and TSH to the TSH receptor is mutually exclusive (Manley et al., 1977; Petersen et al., 1977; Rickards et al., 1981) but recently the formation of termolecular complexes consisting of detergent solubilized receptors, labelled TSH and Graves' IgG has been reported (Konishi et al., 1982; De Bruin et al., 1984).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1985

Thyroid stimulation by (Fab)2 and Fab fragments of TSH receptor antibody.

The TSH receptor binding and thyroid stimulating properties of (Fab)2 and Fab fragments of Graves' IgG have been investigated. (Fab)2 fragments were prepared by pepsin digestion of IgG and Fab fragments by reduction of (Fab)2 or papain digestion of IgG. (Fab)2 and Fab were effective in inhibiting TSH binding to its receptor with all five patients' sera studied and both preparations stimulated cyclic AMP release from isolated thyroid cells. However Fab fragments were less active thyroid stimulators than their parent (Fab)2 in all five cases. These studies indicate that antibody divalency is not essential for thyroid stimulation by TSH receptor antibodies.

Antibodies↗
PubMed1985

Retroperitoneal fibrosis with normal intravenous urogram.

A 58 year old male presented with a two week history of low back pain and malaise. The intravenous urogram (IVU) at presentation was normal but within three months he had developed renal failure with bilateral ureteric obstruction on repeat IVU. Primary retroperitoneal fibrosis was confirmed at operation. This case demonstrates that retroperitoneal fibrosis may progress rapidly to renal failure within a few months of the first symptoms. In addition, the IVU may be normal in the early stages of the illness.

Acute Kidney Injury↗
PubMed1985

Thyrotropin receptor antibodies.

The thyrotropin (TSH) receptor is an integral membrane protein which contains 2 subunits linked by a disulphide bridge. The A subunit (mol. wt. 50,000) is water soluble and forms the binding site for TSH, whereas the B subunit (mol. wt. 30,000) penetrates the lipid bilayer and probably forms the site for interaction with adenylate cyclase. Autoantibodies to the TSH receptor are found in the sera of patients with Graves' disease. The antibodies bind to the same region of the receptor's A subunit as TSH and usually act as TSH agonists, causing hyperthyroidism. Occasionally, TSH receptor autoantibodies are found which can act as TSH antagonists. Isoelectric focusing and binding studies indicate that these antibodies also bind to the same region of the receptor A subunit as TSH.

Animals↗
PubMed1983

Effect of timolol on clinical features and echocardiographic assessment of left ventricular function in hyperthyroidism.

The effect of timolol, a beta-adrenoceptor blocking drug on the clinical status, thyroid status and left ventricular function as measured by serial M-mode echocardiographic recordings was assessed in a double-blind randomised study in 18 hyperthyroid patients. A significant clinical improvement was documented after 2 weeks of timolol treatment compared with placebo. There was no evidence that timolol impaired peripheral monodeiodination of thyroxine (T4). There were significant increases in left ventricular fractional shortening (Fr. Sh.) and velocity of circumferential shortening (Vcf) as well as a significant decrease in the left ventricular systolic internal dimension (LVIDs) (all P less than 0.01) in the untreated thyrotoxic patients compared with a normal euthyroid control group. After timolol treatment (2/52) there were significant increases in LVIDs and LVIDd and a significant decrease in Vcf (all P less than 0.05). No further changes occurred after a further 2/52 treatment with carbimazole. The cardiac data suggest that both an augmented sympathetic drive and a direct effect of thyroid hormone on myocardial contractility are mediators of the haemodynamic changes in hyperthyroidism.

Adult↗