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Biomedical subjects

R Holder

Publications and source records attributed to R Holder.

At least 55 records · Page 3Linked to original sources
PubMed1995

Parathyroid hormone-related protein (PTHrP) in breast cancer and benign breast tissue.

Parathyroid hormone-related protein (PTHrP) 1-86 was quantified by immunoassay in extracts of 132 breast cancers, 27 samples of normal breast tissue and four fibroadenomas. PTHrP 1-86, was detected in 68% of primary tumours (range 40-302,000 fmol/g), 33% of normal breast tissues (range 100-1800 fmol/g), and all four fibroadenomas (range 110-11,600 fmol/g). PTHrP displayed molecular heterogeneity on gel filtration chromatography, and 1-86, 1-34 and 37-67 immunoreactivity eluted as 25-27 kDa together with a peak of 19-21 kDA containing only 37-67 activity. Tumour PTHrP 1-86 levels correlated inversely with age (P < 0.05) and were higher in premenopausal women (P = 0.05). The proportion of tumours containing PTHrP was higher in axillary node positive premenopausal women (P < 0.05). These data suggest that oestrogen may regulate expression of PTHrP in breast cancer and that production of PTHrP may be linked to development of axillary node metastases.

Adult↗
PubMed1995

Effect of estrogen replacement therapy upon bone mineral density in thyroxine-treated postmenopausal women with a past history of thyrotoxicosis.

We have shown that previous thyrotoxicosis and subsequent levothyroxine (L-T4) therapy are together associated with reduction in femoral and lumbar vertebral bone mineral density (BMD) in postmenopausal women. To determine whether estrogen replacement therapy exerts a beneficial effect upon bone loss in this situation, we performed a cross-sectional study comparing BMD measurements of the femur and lumbar spine in four groups of women (n = 15 in each group) matched for age and duration of menopause: (i) those with a previous history of thyrotoxicosis who were subsequently receiving both L-T4 and estrogen replacement therapy for at least 3 years (L-T4 + HRT group), (ii) previously thyrotoxic women matched to group (i) for L- dose and duration who had never used estrogen replacement (L-T4 alone group), (iii) those with no history of thyroid disease who had received estrogen replacement therapy for at least 3 years (HRT alone group), and (iv) those with no history of thyroid disease who had never received estrogen replacement therapy (control group). BMD measurements were higher at each site in the HRT alone group than in controls (6.0-13.6% increases in BMD, p < 0.05 for measurements at femoral neck, Ward's triangle, and trochanter) while measurements of BMD were lower at each site in the L-T4 alone group than in controls (3.3-6.1% reductions in BMD), although values did not reach statistical significance. Measurements at each site in the L-T4 + HRT group were higher than those from the L-T4 alone group (2.2-16.1% increases in BMD, p < 0.05 for measurements at lumbar spine), although lower than in the group receiving HRT alone (p < 0.05 for femoral neck and Ward's triangle) and similar to those in untreated controls. Our results indicate that estrogen replacement therapy abolishes reduction in femoral and vertebral BMD in postmenopausal women with previous thyrotoxicosis and subsequent L-T4 therapy. This potentially beneficial influence of estrogen replacement upon both BMD and fracture risk in postmenopausal women with a history of thyroid disease suggests that estrogen administration should be encouraged in this group.

Body Mass Index↗
PubMed1995

Diabetes care in South Asian and white European patients with type 2 diabetes.

Aspects of diabetes care in South Asian and white European patients with Type 2 diabetes attending a hospital review clinic were explored. Among the clinic population of 1710 patients, 258 (15%) were of South Asian origin. A significantly greater proportion (95% CI for difference in proportions 8-22%) of these patients was treated with oral hypoglycaemic drugs than in white Europeans, in whom there was a correspondingly greater proportion receiving insulin treatment. In a case-control study, where 154 patients in each racial group were stratified according to treatment regimen, significantly more South Asian patients (13/30 vs 6/30, p < 0.05) on insulin were treated with a once-daily regimen. Despite these observed differences in treatment of diabetes, glycaemic control was no worse in South Asian patients when compared to their white European counterparts. South Asian diabetic patients attending hospital diabetes clinics in the UK can experience similar levels of glycaemic control to white Europeans.

Asia↗
PubMed1995

Radioiodine therapy compared in patients with toxic nodular or Graves' hyperthyroidism.

In view of uncertainty regarding the most appropriate radioiodine dose for patients with hyperthyroidism due to toxic nodular disease or Graves' disease, we prospectively studied outcome in patients with these disorders given a single 5 mCi (185 MBq) dose of radioiodine. We studied 103 patients receiving their first radioiodine dose; 44 with toxic nodular hyperthyroidism and 59 with Graves' hyperthyroidism. Thyroid status (off anti-thyroid drug therapy) at 6 and 12 months after radioiodine was related to diagnosis, use of carbimazole before or after radioiodine, and physical and biochemical findings. At 6 months, persistent hyperthyroidism was less frequent in toxic nodular disease than in Graves' disease (34.1% vs. 55.9%, p < 0.05); hypothyroidism was also less frequent (11.4% vs. 27.1%, p < 0.05). Those with persistent hyperthyroidism at 6 months were given a second (10 mCi, 370 MBq) dose of radioiodine. At 12 months after the first dose, 80.6% of the group with toxic nodular hyperthyroidism were either euthyroid or hypothyroid, and 74.5% of those with Graves' disease were euthyroid or hypothyroid, the rate of hypothyroidism again being less in toxic nodular disease (19.4% vs. 58.8%, p < 0.05). Logistic regression and stepwise discriminant analysis demonstrated that 'cure' (euthyroidism or hypothyroidism) at 6 months was related to serum free T4 at presentation (p < 0.001) and administration of carbimazole before or after radioiodine (p < 0.001) (severe hyperthyroidism and carbimazole increasing the likelihood of persistent hyperthyroidism) but was not related to the diagnosis of toxic nodular or Graves' hyperthyroidism.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

ACTH precursors characterize the ectopic ACTH syndrome.

OBJECTIVE: ACTH is secreted by the pituitary following processing of larger molecular weight precursors, proopiomelanocortin and pro-ACTH. Ectopic ACTH syndrome refers to the secretion of ACTH by non-pituitary tumours, but the predominant circulating form of proopiomelanocortin-related peptides remains unclear. PATIENTS: Fifteen patients with ectopic ACTH syndrome were compared to 20 patients with pituitary-dependent Cushing's syndrome, 22 patients with small cell lung carcinoma but no evidence of Cushing's syndrome, and 25 controls. DESIGN AND MEASUREMENTS: Measurement of plasma ACTH and ACTH precursors using specific monoclonal-based immunoradiometric assays at 0900 h and, in five patients with ectopic ACTH syndrome, at 15-minute intervals for 6-24 hours. RESULTS: ACTH precursors were grossly elevated in patients with ectopic ACTH syndrome (median 2194, range 139-18000 pmol/l) compared to patients with Cushing's disease (median 33, 8-73 pmol/l, P < 0.001), patients with small cell lung carcinomas (38, 8-117 pmol/l, P < 0.001) and controls (26, 10-39 pmol/l, P < 0.001). ACTH levels were also elevated in ectopic ACTH syndrome (0900 h median 34, 11-152 pmol/l) compared to patients with Cushing's disease (0900 h median 8, 3-19 pmol/l), but not to the same degree as ACTH precursors. In contrast with Cushing's disease, ACTH was secreted in a non-pulsatile fashion. ACTH precursors but not ACTH itself correlated with plasma cortisol in patients with ectopic ACTH syndrome (r = 0.65, P < 0.05). Chromatographic analysis of plasma from a patient with ectopic ACTH syndrome confirmed ACTH precursors and not ACTH to be the predominant circulating form. With the cross-reactivity of proopiomelanocortin and pro-ACTH in the ACTH IRMA of < 1 and < 10% respectively, ACTH precursors could represent all the ACTH immunoreactivity in patients with ectopic ACTH syndrome. CONCLUSIONS: Ectopic 'ACTH' is characterized by aberrant processing of proopiomelanocortin and should be more accurately referred to as 'ectopic ACTH precursor syndrome'.

ACTH Syndrome, Ectopic↗
PubMed1994

Bone mineral density in thyroxine treated females with or without a previous history of thyrotoxicosis.

OBJECTIVE: The results of studies examining the influence of T4 therapy upon bone mineral density (BMD) are conflicting. This conflict may, in part, reflect inclusion of patients with varying thyroid disorders. We have therefore examined the influence of preceding thyroid history and T4 therapy on BMD. DESIGN: Case-control studies of patients on long-term T4 therapy who have or have not previously received radioiodine treatment for thyrotoxicosis, as well as previously thyrotoxic patients who have not required T4 replacement. PATIENTS: Twenty-seven premenopausal and 60 postmenopausal females with a past history of thyrotoxicosis and subsequent T4 treated hypothyroidism (group 1), 39 post-menopausal females with a past history of radioiodine treated thyrotoxicosis not receiving T4 (group 2) and 22 post-menopausal females with primary hypothyroidism on T4 (group 3). Female controls individually matched to patients by age and menopausal status. MEASUREMENTS: BMD measured by dual-energy X-ray absorptiometry. Serum biochemistry and tests of thyroid function. RESULTS: No significant differences were found in femoral or lumbar spine BMD measurements between premenopausal patients and controls in group 1 or between group 2 patients and controls. Measurements of BMD at all sites were lower in post-menopausal patients in groups 1 and 2 than in controls; when allowance was made for differences in BMD due to body mass index by analysis of variance, significant reductions in femoral trochanter BMD (3.9%, P < 0.05) and lumbar spine (5.6-8.5%, P < 0.01) BMD results were found in post-menopausal females in group 1 and reductions in femoral trochanter (3.9%, P < 0.01), Ward's triangle (5.6%, P < 0.05) and lumbar spine (8.5%, P < 0.01) BMD results in group 2. Separate analysis of BMD results of those with normal or reduced serum TSH did not affect outcome. BMD measurements were not significantly correlated with duration of T4 therapy, T4 dose, or serum free T4 or TSH in any patient group. CONCLUSIONS: Thyroxine therapy alone does not represent a significant risk factor for loss of bone mineral density but there is a risk of bone loss in post-menopausal (but not premenopausal) females with a previous history of thyrotoxicosis treated with radioiodine.

Absorptiometry, Photon↗
PubMed1994

Antioxidant status in controlled and uncontrolled hypertension and its relationship to endothelial damage.

Hypertension is associated with an increased risk of atherosclerosis. Free radical oxidative damage has been implicated in the atherogenic process. We measured levels of the antioxidants uric acid, thiols, vitamins C, A and E as well as the total antioxidant capacity in 21 normotensive controls, 22 patients whose hypertension was controlled on drugs and 30 patients with uncontrolled hypertension. Mean BPs in the groups were 125/76, 132/80 and 181/98 mmHg, respectively. When compared with controls, both hypertensive groups had significantly lower serum ascorbic acid (54 +/- 5 vs. 37 +/- 6 vs. 38 +/- 5 mumol/l, P < 0.05) and albumin-corrected thiol levels (9.91 +/- 0.18 vs. 8.69 +/- 0.20 vs. 8.92 +/- 0.19 mumol/g, P < 0.05). The levels of the other antioxidants did not differ significantly between the groups. Levels of von Willebrand factor, a marker of endothelial damage, were correlated with SBP but not with antioxidant status. We conclude that hypertensive subjects have lower levels of the antioxidants vitamin C and thiols and this may reflect greater oxidative consumption. The implications for atherogenesis and endothelial function and integrity in hypertension are discussed.

Adult↗
PubMed1993

Thyroxine replacement therapy and circulating lipid concentrations.

OBJECTIVE: Hypothyroidism is a common disorder and while the association of overt hypothyroidism with hypercholesterolaemia is clear, the effect upon lipids of the minor abnormalities of thyroid function often found in those receiving T4 replacement therapy is unclear. The aim of the present studies was to define in those with hypothyroidism the effect upon circulating lipids of subtle changes in thyroid status, indicated by serum TSH values below or above the normal range. DESIGN: (i) Prospective study of short-term T4 treatment of those with subclinical hypothyroidism. (ii) Cross-sectional study of long-term T4 treatment, comparing non-T4 treated controls and T4 treated patients with serum TSH values either below or within the normal range. PATIENTS: Short-term T4 therapy was examined in 11 post-menopausal females with subclinical hypothyroidism (high TSH, normal free T4) studied before therapy and 6 weeks after T4 at incremental doses (50, 100, 150 micrograms/day). Long-term T4 treatment for hypothyroidism was investigated in 105 females on therapy for at least 1 year compared with 105 controls matched for age and menopausal status. MEASUREMENTS: Fasting levels of total cholesterol, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol and HDL subfractions were determined in patients and controls. RESULTS: (i) T4 treatment of subjects with subclinical hypothyroidism resulted in reductions in total and LDL cholesterol with increasing T4 dose (P < 0.001). Comparison of lipid results pretreatment with those when TSH was restored to normal revealed no significant difference in lipids; in contrast, comparison of lipids in those with normal TSH compared with the same subjects when TSH was suppressed revealed reductions in total and LDL cholesterol. (ii) Long-term T4 treatment was associated with a reduction in total and LDL cholesterol measurements in those over 55 years receiving suppressive doses of T4 but no significant difference in lipids in those with normal serum TSH compared with non-T4 treated controls. CONCLUSION: Effects of T4 upon lipid measurements suggest that patients with subclinical hypothyroidism should receive replacement therapy. Doses of T4 which suppress TSH to below normal may have a more significant influence upon lipids than doses of T4 which restore TSH to the normal range.

Aged↗
PubMed1993

The hypothalamo-pituitary-adrenal axis across the normal menstrual cycle and in polycystic ovary syndrome.

OBJECTIVE: We explored the hypothesis that activation of the hypothalamo-pituitary-adrenal axis is involved in the pathogenesis of hyperandrogenism in the polycystic ovary syndrome. PATIENTS: Seven women with polycystic ovary syndrome (mean age 27.6 +/- 1.6 (SEM) years) (hirsutism, oligo/amenorrhoea and elevated serum testosterone and dehydroepiandrosterone sulphate) and nine normal female controls (mean age 24.6 +/- 1.5 years) were studied. To exclude anovulation as a confounding factor, four of these normal women were studied in both the follicular and luteal phase of the menstrual cycle. DESIGN AND MEASUREMENTS: Plasma ACTH and cortisol levels were measured at 15-minute intervals between 0600 h and 1800 h. ACTH and cortisol mean levels, pulse number and amplitude were calculated using established computer software, programmed to identify ACTH and cortisol peaks. RESULTS: With the exception of mean plasma levels of ACTH over the 12-hour period, which were reduced in the luteal phase of the menstrual cycle (1.8 +/- 0.3 pmol/l) compared to the follicular phase (2.3 +/- 0.2 pmol/l, P < 0.05), there were no differences in the pattern of ACTH or cortisol secretion across the normal cycle. In polycystic ovary syndrome, 12-hour ACTH pulse frequency was reduced (3.6 +/- 0.7) compared with controls (5.9 +/- 0.6, P < 0.05), but cortisol pulsatility and ACTH and cortisol mean levels were similar in both groups. CONCLUSION: The hyperandrogenism of polycystic ovary syndrome cannot be explained by enhanced ACTH secretion. Normal circulating cortisol levels, yet elevated dehydroepiandrosterone sulphate levels, suggests that polycystic ovary syndrome is yet another example of discrepant adrenal glucocorticoid and androgen secretion, and provides further evidence for a putative adrenal androgen stimulating factor.

Adrenocorticotropic Hormone↗
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

Acceptability of opportunistic screening for occult gastrointestinal blood loss.

OBJECTIVE: To test patient compliance for faecal occult blood testing in suburban and inner city general practice. DESIGN: Prospective opportunistic trial using the Haemoccult test kit. Tests were offered during routine surgery attendance. SETTING: Three group general practices in Birmingham. SUBJECTS: All patients aged 40 years or older on the start date who routinely attended surgery during two years. MAIN OUTCOME MEASURES: Numbers of patients approached for testing and the numbers refusing, accepting, and returning the test kits. RESULTS: Only 26.3% (1230/4677) of the potential target population had been screened within the two years, although 988 (39.3%) of the suburban practice target were screened. However, 55.7% (1230/2207) of patients actually offered a test returned completed kits, with only 6% (133) refusing the kit. 683 (61.6%) patients aged 50-69 returned kits, compared with 343 (54.3%) aged 70 or over and 204 (43.8%) aged 40-49. These differences were significant (p less than 0.001). Patients from the inner city practice were significantly less likely to be offered the test than those in suburban practice (242 (11.2%) v 988 (39.9%), p less than 0.001) and return the samples (242 (38.8%) v 988 (62.4%), p less than 0.001). Patients from the inner city practice were also more likely to refuse the test (78 (12.5%) v 55 (3.5%), p less than 0.001). CONCLUSIONS: Opportunistic testing for occult faecal blood in asymptomatic patients was reasonably acceptable to patients, especially those in a suburban practice. If the test is shown to reduce mortality from colorectal cancer then formal screening would probably achieve acceptable target rates, especially among patients aged 50-69, who represent the prime risk group.

Adult↗
PubMed1992

A reliable index for correct positioning of precision attachments into an existing overdenture.

Limited space over abutment teeth may make incorporation of a precision attachment system within an existing overdenture technique sensitive. A special diagnostic index can be made to depict the available space within the prosthesis over the abutment teeth. This index is critical to determine the feasibility of attachment incorporation, as well as the selection and correct positioning of an appropriate attachment system. A method to improve predictability for precision attachment incorporation into an existing overdenture is described.

Dental Abutments↗
PubMed1992

Hypothalamic abnormalities in patients with pituitary-dependent Cushing's syndrome.

OBJECTIVE: We aimed to investigate the pattern of 24-hour ACTH and cortisol secretion in pituitary-dependent Cushing's syndrome and to evaluate the pituitary and hypothalamic contributions to the disease. PATIENTS: Five women with Cushing's disease (mean age 35 +/- 5 (SEM) years) and five normal female controls (mean age 25 +/- 2 years) were studied. DESIGN AND MEASUREMENTS: Plasma ACTH and cortisol levels were measured every 15 minutes for 24 hours using established IRMA and RIA respectively. ACTH and cortisol mean and trough levels, pulse number and amplitude were calculated using established computer software, programmed to identify ACTH and cortisol peaks. RESULTS: Patients with Cushing's disease had a twofold increase in 24-hour mean cortisol levels and a threefold increase in 24-hour mean ACTH levels (Cushing's 5.9 +/- 1.0, controls 1.9 +/- 0.2 pmol/l, P less than 0.01). This was predominantly mediated by an increase in ACTH pulse amplitude. However, 24-hour ACTH pulse number was also increased (Cushing's 15.2 +/- 2.6, controls 10.6 +/- 1.7, P less than 0.05) due to an increase in pulse number between 1800 and 2400 h. ACTH trough levels were also higher in patients with Cushing's disease (Cushing's 5.3 +/- 1.3, controls 2.3 +/- 0.2 pmol/l, P less than 0.05). CONCLUSIONS: Twenty-four-hour mean plasma cortisol and ACTH levels are elevated two to three-fold in patients with Cushing's disease. The increase in ACTH pulse amplitude suggests a pituitary abnormality in patients with Cushing's disease. However, the increased ACTH pulse frequency together with elevated trough levels is interpreted as indicating coexisting hypothalamic stimulation (or loss of inhibition).

Adrenocorticotropic Hormone↗
PubMed1992

Pilot study to compare the bronchodilator and metabolic responses to terbutaline infusion in seven asthmatic subjects--are they correlated?

We compared the changes in peak expiratory flow rate (PEFR), plasma potassium and plasma glucose during and after an infusion of the beta 2-agonist, terbutaline, in seven asthmatic subjects. Our aim was to establish whether these metabolic parameters could be correlated with PEFR. The percentage changes in PEFR were significantly correlated with the percentage changes in glucose (r = 0.60, P less than 0.001) and potassium (r = -0.64, P less than 0.001). Values for glucose and potassium changes were also correlated significantly with each other (r = 0.86, P less than 0.001). This suggests that in asthmatic subjects on beta 2-agonist treatment, plasma potassium could be used as a surrogate marker for beta 2 activity at bronchi. It also implies that the most effective beta 2-agonist bronchodilators will produce the greatest fall in plasma potassium. Further studies with a larger number of patients are needed to confirm this.

Adult↗
PubMed1990

Patterns of ACTH and cortisol pulsatility over twenty-four hours in normal males and females.

Patterns of plasma ACTH and cortisol concentrations were studied in 10 healthy subjects (five male, five female in the early follicular phase, overall age range 21-32 years) by sampling through an indwelling cannula every 15 min for 24 h. The subjects were in hospital, ambulant, and taking normal meals. Plasma ACTH was measured by a two-site immunoradiometric assay with a detection limit of 3.9 ng/l (0.9 pmol/l). Pulses were identified by the method of Clayton et al. (1987) using stringent criteria to minimize false positive peaks. All subjects showed a circadian rhythm of ACTH, the acrophase occurring between 0615 and 0920 h in all but one subject and the mesor value was between 9.2 and 18.6 ng/l (2.0 and 4.1 pmol/l). There were significantly fewer pulses between 1800 and 2400 h compared with the other three 6-h periods. The pattern of ACTH differed between males and females in several respects: more pulses (18 vs 10), greater mean peak amplitude (16.8 vs 10.3 ng/l), greater area under the 24-h profile (350.9 vs 206.6 ng/l h) and higher mean level (14.7 vs 8.6 ng/l) in the males. In contrast, the cortisol pattern did not show statistically different sex differences. The sex differences suggest greater sensitivity to, or availability of, ACTH to the female adrenal cortex, or different set points in cortisol feedback.

Adrenocorticotropic Hormone↗
PubMed1989

Abnormalities of thyrotrophin (TSH) evening rise and pulsatile release in haemodialysis patients: evidence for hypothalamic-pituitary changes in chronic renal failure.

Using a sensitive enzyme amplified immunoassay for TSH, the evening rise and pulsatile release of TSH were studied in 10 men with chronic renal failure treated by haemodialysis. Compared to euthyroid male controls the evening rise of TSH was attenuated (median 0.066 vs 0.195 mU/l/h, P less than 0.01) and the rate of rise correlated with the TSH response to TRH (r = 0.93, P less than 0.001). All subjects showed TSH pulsatility in at least one method of data analysis but the less sensitive incremental method showed no significant difference in pulse frequency and amplitude between the two groups. However, with time series analysis, periodicity was shorter (median 45 vs 95 min, P = 0.013) and pulse amplitude smaller (median 0.06 vs 0.175 mU/l, P = 0.017) in renal patients. Pulse amplitude, but not periodicity, correlated with the TSH response to TRH (r = 0.68, P less than 0.05). In addition, serum total thyroxine, free thyroxine and free triiodothyronine concentrations were reduced, while serum prolactin and 17 beta-oestradiol concentrations were raised. These changes in TSH evening surge and pulsatile release may contribute to the reduction in thyroidal hormone concentrations seen in renal failure and emphasize the value of sensitive methods of hormone and pulse data analysis.

Adult↗