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Biomedical subjects

D B Ramsden

Publications and source records attributed to D B Ramsden.

At least 19 recordsLinked to original sources

Activation of bovine plasma benzylamine oxidase (BzAO) by 1-methyl-4-(2-methylphenyl)-1,2,3,6-tetrahydropyridine.

We have shown previously that certain analogues of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are potent inhibitors of human and bovine plasma benzylamine oxidase (BzAO: EC 1.4.3.6). Inhibition was competitive, reversible and allosteric. Under certain conditions competitive inhibitors of allosteric enzymes can act as allosteric activators. In the present work, 1-methyl-4-(2-methylphenyl)-1,2,3,6-tetrahydropyridine (2'-CH3MPTP) was found to activate bovine plasma BzAO at low substrate and 2'-CH3MPTP concentrations. At higher 2'-CH3MPTP concentrations, the activation was negated.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

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

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

Serum tetraiodothyroacetate (T4A) levels in normal healthy euthyroid individuals determined by gas chromatography-mass fragmentography (GC-MF).

A gas chromatography-mass fragmentography (GC-MF) assay for T4A in human serum is described. The assay involves a multistage extraction, followed by conversion of T4A to its dimethyl derivative prior to GC-MF. Using this assay, the concentration of T4A in 37 normal euthyroid subjects was, mean +/- S.D., 114.5 +/- 26.4 pmol/l, which is considerably lower than previous reports. Thyroxine binding prealbumin (TBPA) did not appear to be a major determinant of T4A concentration.

Chromatography, Gas

The role of thyronine in thyroid hormone metabolism.

Thryonine (T0) has been identified in human urine using gas chromatography-mass fragmentography (G.C.M.F.). In 22 normal individuals urinary T0 concentration was found to range between 8--25 nmol/24h. Assuming the mean normal thyroxine (T4) production rate to be approximately 100 nmol/24h, our findings indicate that less than 20% of this could be accounted for as urinary T0 excretion, thus supporting earlier findings that the peripheral metabolism of T4 is not limited solely to deiodination.

Chromatography, Gas

Effects of surgical stress and corticotrophin on the peripheral metabolism of thyroid hormones in rabbits.

The effect of surgical stress and ACTH injection on the peripheral monodeiodination of thyroxine (T4) was studied in the rabbit. These stimuli resulted in a switch from the peripheral formation of tri-iodothyronine (T3) to reverse T3 in normal rabbits and in rabbits whose thyroidal secretion was suppressed by administration of T4. This is analogous to the situation in man. These changes were not due to alterations in the serum binding capacity for thyroid hormones.

Adrenocorticotropic Hormone

The inter-relationship of thyroid hormones, vitamin A and their binding proteins following acute stress.

The effects of surgical stress on the metabolism of the retinol-binding-protein-thyroxine-binding-prealbumin complex were investigated. The immediate postsurgical period was characterized by a rapid decline in the serum concentration of retinol, retinol binding protein and triiodothyronine and an increase in the 24 h urinary excretion of retinol, retinol-binding-protein and thyroxine. Similar, but less pronounced, changes were seen in other subjects suffering acute myocardial infarction but were not observed in normal healthy euthyroid males or in pre-operative euthyroid patients. The preparation of specific anti-retinol binding protein anti-serum and the use of this in 'monorocket' immunoelectrophoresis are also described.

Antibodies

Concentration of thyroxine-binding globulin: value of direct assay.

The concentration of thyroxine-binding globulin (TBG) in the serum can now be measured by direct assays that are simple and inexpensive. Comparison of a direct measurement of TBG concentration with a widely used indirect method (Thyopac-3) showed that the indirect method was inaccurate when TBG concentrations were high. This will result in an increase in the derived free thyroxine index (FTI), so that euthyroid patients with a raised TBG concentration may be at risk of being labelled thyrotoxic. Correction of serum total thyroxine (T4) concentration according to the actual TBG concentration (T4:TBG ratio) provided a better correlation with thyroid state than FTI.

Adolescent

Metabolism of thyroid hormones by the isolated perfused rabbit kidney.

The metabolism of thyroxine and triiodothyronine in the isolated perfused rabbit kidney was monitored by specific radioimmunoassay for each hormone. The amount of thyroxine catabolised was proportional to the amount added initially and no saturation effects were observed over a wide range (3.9-82 nmol). After addition of thyroxine alone, triiodothyronine could be detected in the perfusion medium within 10 minutes but only much later in the urine. It was proposed that circulating thyroxine contributes indirectly to the level of urinary triiodothyronine.

Animals

A new theoretical description of the binding of thyroid hormones by serum proteins.

A theoretical model is proposed which describes the binding of thyroid hormones to serum proteins in terms of easily determined parameters, Not only free hormone concentration but also the distribution of hormone among various binding sites may be computed. The mathematical approach is capable of dealing with models of differing complexity of binding from simple 'one binding site per protein molecule' systems to those involving 'negative co-operativity'. The approach gives predictions of thyroid function parameters which are in good agreement with those observed in practice.

Binding Sites

Effect of a single dose of dexamethasone on serum concentrations of thyroid hormones.

In ten euthyroid subjects, in whom endogenous thyroid-stimulating hormone (T.S.H.) production was suppressed by oral thyroxine (T4), a single dose of dexamethasone resulted in reduced serum-3,3'5-triidothyronine (T3) concentration and raised serum-3,3',5'-triiodothyronine (reverse T3 or rT3) concentration after 24 h. These changes were not related to changes in free hormones or binding proteins. Adrenal glucocorticoids may have a pathophysiological role in modulating the peripheral metabolism of thyroid hormones in stress.

Adult