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Biomedical subjects

P M Clark

Publications and source records attributed to P M Clark.

At least 37 records · Page 2Linked to original sources
PubMed2000

Urinary GH and IGF-I excretion in nine year-old children: relation to sex, current size and size at birth.

OBJECTIVES: To study the relationship of 24-hour urinary growth hormone (GH) and IGF-I excretion in childhood to sex and body size. To test the hypothesis that small size at birth followed by postnatal catch-up growth is associated with elevated IGF-I production. DESIGN AND SUBJECTS: Follow-up study of a cohort of 183 healthy children born in Salisbury, UK. MEASUREMENTS: Weight and height, 24-h urinary growth hormone (uGH) and IGF-I (uIGF-I) excretion, and systolic and diastolic blood pressures. RESULTS: At 9 years of age, 24-h uIGF-I excretion, but not uGH excretion, was strongly related to current weight (P < 0.001) and height (P < 0. 001). Urinary GH and IGF-I excretion were positively correlated (r = 0.15, P = 0.05). Boys excreted more uIGF-I per unit uGH than girls (uIGF-I/uGH molar ratio 32.1 compared to 21.0; P for difference = 0. 002). There were no significant relationships of uGH, uIGF-I or uIGF-I/uGH molar ratio with birthweight, birthlength or head circumference at birth, nor with blood pressure at 9 years. 'Catch-up' growth, indicated by an increase in height SD scores between birth and 9 years, was associated with higher IGF-I excretion (P = 0.01) and occurred in children with taller parents (P < 0.001). CONCLUSIONS: Boys appear to be more sensitive to GH than girls, generating more uIGF-I in relation to uGH. Urinary IGF-I excretion at 9 years is related to both absolute height and to the degree of catch-up in height from birth. Our results suggest that IGF-I production is strongly influenced by genetic factors, but also by either the degree to which intrauterine growth falls short of genetic growth potential, or the process of postnatal catch-up growth that follows.

Anthropometry↗
PubMed2000

Effects of the new oral hypoglycaemic agent nateglinide on insulin secretion in Type 2 diabetes mellitus.

AIMS: The new non-sulphonylurea oral hypoglycaemic agent nateglinide has been shown to enhance insulin secretion in animals and in healthy human volunteers and thus offers a potential advance in the treatment of Type 2 diabetes mellitus. This study examined whether nateglinide can enhance insulin secretion, and particularly the first phase insulin response, in patients with Type 2 diabetes. METHODS: A double-blind, placebo-controlled trial, examining the effects of a single oral dose of 60 mg nateglinide, given 20 min prior to an intravenous glucose tolerance test (IGTT), on insulin secretion in 10 otherwise healthy Caucasian men with recently diagnosed Type 2 diabetes (duration since diagnosis 0-44 months). RESULTS: Insulin secretion (both overall and first phase) was significantly increased by nateglinide (P < 0.001), as were C-peptide (P < 0.001) and proinsulin (P < 0.001) secretion. Overall glucose concentrations following glucose challenge were lower after nateglinide than after placebo (P = 0.05). CONCLUSIONS: Nateglinide significantly increases insulin secretion in Type 2 diabetic patients, in particular restoring the first phase insulin response. Further study is necessary to determine the effects of chronic administration on insulin secretion and blood glucose concentration.

Adult↗
PubMed2000

Abnormal nephron development associated with a frameshift mutation in the transcription factor hepatocyte nuclear factor-1 beta.

BACKGROUND: The transcription factor hepatocyte nuclear factor (HNF)-1 beta functions as a homodimer or as a heterodimer with the structurally related protein HNF-1 alpha. Both are expressed sequentially in rat kidney development, with HNF-1 beta being detected from the earliest inductory phases. HNF-1 beta gene mutations are associated with a unique disorder characterized by maturity-onset diabetes of the young (MODY) and early-onset and progressive nondiabetic renal dysfunction, which may lead to chronic renal failure. METHODS: The HNF-1 beta gene was screened for mutations in six subjects with early-onset diabetes and a history of renal dysfunction in the subjects or their families. RESULTS: A novel frameshift mutation in exon 4 of the HNF-1 beta gene and a deletion of CCTCT at codons 328 to 329 were detected in one subject. She was diagnosed as diabetic at the age of 21 in her second pregnancy. Glucose tolerance rapidly deteriorated over 18 months as a result of beta-cell dysfunction. The HNF-1 beta mutation arose de novo on a paternal chromosome and cosegregated with renal abnormalities in her family. The proband had bilateral small cysts in normal-sized kidneys and a reduced creatinine clearance of 66 mL/min (NR 80-120). Her first pregnancy was terminated at 17 weeks following an ultrasound diagnosis of bilateral, nonfunctioning cystic kidneys. Her first-born child had a small multicystic, dysplastic right kidney and a dysplastic left kidney with a reduced creatinine clearance (40 mL/min per 1.73 m2). Histologic examination of the large (5.8 vs. 1.4 g), polycystic fetal kidneys showed no normal nephrogenesis. CONCLUSIONS: These studies indicate that HNF-1 beta plays a central role in normal kidney development and pancreatic beta-cell function, and suggest that one mechanism by which HNF-1 beta gene mutations may cause renal dysfunction are by their effects on nephron development.

Abortion, Induced↗
PubMed1999

Clinical and biochemical response following withdrawal of a long-acting, depot injection form of octreotide (Sandostatin-LAR).

OBJECTIVE: Monthly injections of Sandostatin-LAR have been shown to be an effective therapy for patients with acromegaly. Because of an ongoing need to assess a patients response to definitive therapy such as surgery and/or radiotherapy, we aimed to evaluate GH levels and acromegaly symptom scores in patients withdrawing from Sandostatin-LAR. DESIGN AND PATIENTS: 12 patients with acromegaly previously treated with Sandostatin-LAR, 20-40 mg intramuscularly every 28 (n = 9) or 42 (n = 3) days for 12-36 months were studied at monthly intervals for 4 months following the withdrawal of the drug. MEASUREMENTS: Hourly fasting serum GH measurements between 0800 h and 1200 h, serum IGF-1 and symptom scores were undertaken at 4, 8, 12 and 16 weeks following the last injection of Sandostatin-LAR. MRI/CT scans of the pituitary were undertaken at 16 weeks and compared to scans taken on Sandostatin-LAR within the previous 10 months. RESULTS: Serum GH rose progressively from 7.7 (1.5 to 14.6) (median (range)) mIU/l at 4 weeks to 9.9 (1.5-21.8), to 12.6 (4.9-31.9) (P < 0.05 vs 4 weeks) and to 13.1 (6.0-39.1) mIU/l (P < 0.002) at 8, 12 and 16 weeks, respectively, following cessation of Sandostatin-LAR. IGF-1 rose from 38.5 (12.6-73.8) nmol/l at 4 weeks to 62.4 (37.4-159) at 16 weeks (P < 0.002) and mean symptom score (comprising headache, sweating, arthralgia, paraesthesiae, tiredness) from 4.0 (0 to 10) (4 weeks) to 4.5 (0-9) (8 weeks) to 6.0 (2-10) (12 weeks) to 6.5 (4-12) (16 weeks, P < 0.05). Individual GH profiles indicated a rise in GH in 5/12 patients between weeks 4-8 and between weeks 8-12 in a further 5/12 patients. There were no changes in pituitary tumour size following discontinuation of Sandostatin-LAR. CONCLUSIONS: GH and symptom scores rise progressively following discontinuation of Sandostatin-LAR in acromegalic patients. However, GH and symptom scores remain suppressed in some patients for at least 8 weeks following cessation of Sandostatin-LAR. We suggest that a withdrawal period of 3 months from Sandostatin-LAR is required in order to perform a meaningful re-assessment of GH and clinical status.

Acromegaly↗
PubMed1999

Cortisol metabolism in human obesity: impaired cortisone-->cortisol conversion in subjects with central adiposity.

For a given body mass index (BMI), mortality is higher in patients with central compared to generalized obesity. Glucocorticoids play an important role in determining body fat distribution, but circulating cortisol concentrations are reported to be normal in obese patients. Our recent studies show enhanced conversion of inactive cortisone (E) to active cortisol (F) through the expression of 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) in cultured omental adipose stromal cells; the autocrine production of F may be a crucial factor in the pathogenesis of central obesity. We have now analyzed F metabolism in subjects with BMIs between 20-25 kg/m2 (group A), 25-30 kg/m2 (group B), and more than 30 kg/m2 (group C; n 12 in each group; six males and six premenopausal females; aged 23-44 yr). Glucose/insulin were measured using a 75-g oral glucose tolerance test, and each subject had total body and regional fat (scapular, waist, hip, and thigh) quantified using dual energy x-ray absorptiometry. Urinary total F metabolites (measured by gas chromatography/mass spectrometry) were increased in subjects with obesity [group A, 11,176 +/- 1,530 microg/24 h (mean +/- SE); group C, 13,661 +/- 1,444], although not significantly so (P = 0.08). There was a significant reduction in the urinary tetrahydrocortisol (THF) +/- 5alpha-THF/tetrahydrocortisone (THE) and the cortol/cortolone ratio in obesity (group A vs. C, 1.06 +/- 0.08 vs. 0.84 +/- 0.04 and 0.41 +/- 0.03 vs. 0.34 +/- 0.03, respectively; both P < 0.05). Urinary free F (UFF) excretion was similar in all three groups, as was the UFF/urinary free E (UFE) ratio. The 0900 h circulating F, E, and ACTH pre- and postovernight 1-mg dexamethasone suppression values were similar in all three groups, but a reduction in the generation of serum F from dexamethasone-suppressed values after oral cortisone acetate (25 mg) was evident in both obese groups [e.g. 546 +/- 37 nmol/L in group A vs. 412 +/- 40 in group B (P < 0.05) and 388 +/- 38 in group C (P < 0.01) 180 min post-E]. Insulin resistance was present in groups B and C, but regression analysis revealed no relationship between F metabolites or the THF +/- 5alpha-THF/THE ratio and insulin action (homeostasis model assessment analysis and insulin values in the oral glucose tolerance test). There was, however, a highly significant relationship between the THF +/- 5alpha-THF/THE ratio and BMI (t = -3.44; P < 0.01) and total body fat (t = -2.27; P < 0.05). Stepwise regression analyses indicated an inverse relationship between THF+/-5alpha-THF/THE and scapular and waist fat (t = -2.25; P = 0.03) and a direct relationship with hip and thigh fat (t = 2.42; P = 0.02) in both sexes. The fall in the THF + 5alpha-THF/THE ratio but unchanged UFF/UFE ratio together with impaired F concentrations after oral E indicates inhibition of 11betaHSD1 in subjects with obesity. This results in an increased MCR for F, explaining the increased F secretion rate in obesity in the face of normal circulating F concentrations. 11BetaHSD1 activity is highly related to body fat distribution, with android or central obesity, but not gynoid obesity, associated with reduced activity in both sexes. This reduction in 11betaHSD1 activity raises new questions as to the primary role of 11betaHSD1 in the pathogenesis of insulin resistance and central obesity.

Adipose Tissue↗
PubMed1998

Programming of the hypothalamo-pituitary-adrenal axis and the fetal origins of adult disease hypothesis.

UNLABELLED: There is now a large body of evidence to support the hypothesis that events in fetal life permanently alter the structure or function of an individual, programming later adult disease. Reduced birth weight is associated with higher blood pressure in childhood and adult life, and thinness at birth with glucose intolerance and non-insulin dependent diabetes mellitus. Programming of the hypothalamo-pituitary-adrenal (HPA) axis is an attractive hypothesis linking fetal experience and later disease, as an excess of glucocorticoids may be associated with hypertension and glucose intolerance. Moreover, animal data support this hypothesis. Exposing fetal rats to glucocorticoid reduces birth weight and leads to raised blood pressure, as well as to alterations in the HPA axis. Data on the long-term effects of exposure to glucocorticoids in human subjects are limited. Recently, however, reduced size at birth was found to be associated with higher fasting 9 a.m. plasma cortisol concentrations in adults. Raised plasma cortisol concentrations were, in turn, associated with higher blood pressure, and inversely related to measures of glucose tolerance. CONCLUSION: Programming of the HPA axis by events in fetal life may be one of the mechanisms linking reduced size at birth with raised blood pressure and glucose intolerance in later life. Studies of the effects of antenatal and neonatal dexamethasone administration on later blood pressure and glucose tolerance may be warranted.

Animals↗
PubMed1998

Weight gain in pregnancy, triceps skinfold thickness, and blood pressure in offspring.

OBJECTIVE: To determine whether women who are poorly nourished in early pregnancy, as determined by triceps skinfold thickness, or who have poor pregnancy weight gain have offspring with higher blood pressure (BP). METHODS: We evaluated 296 11-year-old children born to women who had taken part in a study of nutrition in pregnancy. Women had been weighed at 18 and 28 weeks' gestation and had had their triceps skinfold thickness measured at 18 weeks. In our follow-up study, their children were weighed and had their BP recorded. Blood pressure was adjusted for weight, gender, ethnic group, cuff size, and time of measurement. RESULTS: The children's mean (standard deviation [SD]) systolic BP was 106 (12) mmHg and their mean (SD) diastolic BP was 62 (7) mmHg. Maternal triceps skinfold thickness at 18 weeks' gestation and maternal pregnancy weight gain between 18 and 28 weeks' gestation were weakly inversely related to the children's BP. However, among women with triceps skinfold thickness at 18 weeks below the group median (15 mm), reduced pregnancy weight gain was associated with significantly higher BP in the offspring; systolic pressure increased by 11.3 mmHg (95% confidence interval [CI] 2.2, 20.4) and diastolic pressure by 10.1 mmHg (95% CI 3.2, 17.1) for each kilogram-per-week decrease in pregnancy weight gain. CONCLUSION: In women who were poorly nourished in early pregnancy, reduced pregnancy weight gain was associated with higher BP in the 11-year-old offspring. We suggest that fetal adaptations to poor maternal nutrition lead to elevated BP in childhood but adequate maternal weight gain during pregnancy may protect against this.

Adaptation, Physiological↗
PubMed1998

Defining the normal cortisol response to the short Synacthen test: implications for the investigation of hypothalamic-pituitary disorders.

OBJECTIVE: To define the normal cortisol response to the Short Synacthen Test using four different cortisol immunoassays and to assess the implications for the investigation of hypothalamic-pituitary disorders. DESIGN AND PATIENTS: The cortisol response to 250 micrograms im ACTH1-24 (Synacthen, Ciba Geigy) in 100 healthy volunteers using four different cortisol immunoassays has been measured. In 44 newly diagnosed and untreated patients with pituitary disease, basal and 30 minute post-ACTH cortisol results were also determined using the four immunoassays. RESULTS: The distribution of cortisol results at all time points and for all methods were non-Gaussian and significant differences in the absolute values of the 5th-95th percentiles were found between methods (P < 0.01). At 30 min post-Synacthen in normals the 5th percentile of the cortisol response ranged from 510 to 626 nmol/l with the different methods. Similarly the relationship between assay results differed at different time points. No effect of age on the cortisol response was found but for stimulated cortisol values and the incremental responses females showed significantly higher responses than males (P < 0.05) for most methods. Although there was a significant positive linear correlation (P < 0.001) between stimulated and basal cortisol values for all methods, no significant relationship was found between the incremental response and basal cortisol values. In the pituitary disease patients basal and 30 minute post-ACTH cortisol results were significantly lower (P < 0.05 and < 0.001) than the control group using the same cortisol assay. When the results were compared to the 5th percentile of the gender and assay specific control group 33.3% of male and 17.4% of female patients failed the Synacthen test at 30 min. CONCLUSIONS: The definition of the 'normal' response to Synacthen should be both gender and method related at all time points. The data suggest that up to one-third of untreated patients with pituitary disease may have subtle defects in the hypothalamic-pituitary-adrenal axis.

Adult↗
PubMed1998

Circulating thyroid hormone concentrations and placental thyroid hormone receptor expression in normal human pregnancy and pregnancy complicated by intrauterine growth restriction (IUGR).

Thyroid hormones are critical to growth and development of the human fetus. Abnormal placental development, a major cause of intrauterine growth restriction (IUGR), is associated with a high perinatal mortality and morbidity. Thyroid status has been postulated to play a role in the pathogenesis of such morbidity. In the present study, we have investigated fetal thyroid function and placental expression of thyroid hormone receptor (TR) alpha and beta variants during normal human pregnancy and in pregnancy associated with IUGR. Measurement of free thyroid hormones and TSH concentrations revealed significant rises in free T4 and free T3 between the second and third trimesters of normal pregnancy. Serum concentrations of free T4 and free T3 were lower in fetuses affected by IUGR, although serum TSH levels were not significantly different. Immunocytochemistry demonstrated the presence of TR alpha1, alpha2, and beta1 proteins within the nuclei of trophoblast and stromal placental cells. Immunostaining for these TR variants increased with increasing gestation in normal placenta. Comparison of IUGR placental samples with normal samples revealed greater immunostaining for TR alpha1, alpha2, and beta1 variants in IUGR. Examination of pretranslational expression of TR alpha1, alpha2, beta1, and beta2 variants by semiquantitative RT-PCR revealed increasing expression of TR alpha1, alpha2, and beta2 messenger RNAs with increasing gestation in normal pregnancy, which "mirrored" post-translational expression. However, and in contrast, there were no significant differences in expression of TR messenger RNAs in normal and IUGR placenta. The present findings of reduction in serum free thyroid hormones and increased expression of TR alpha and beta proteins in association with IUGR highlight the potential importance of thyroid status in influencing long-term fetal outcome in this condition.

Blotting, Western↗
PubMed1998

Otitis media with effusion and size at birth.

To investigate whether recurrent or persistent otitis media with effusion (OME) was associated with particular patterns of fetal growth, we conducted a case control study of 129 children admitted for insertion of grommets and 150 controls. The risk of OME was not statistically significantly related to gestational age or individual measures of size at birth, but the ratio of head circumference to total length and the ponderal index at birth were statistically significantly lower in children with OME, both before and after adjustment for the potentially confounding effects of sex, age at current operation, and maternal gravidity. Mothers of cases were 2.2 times more likely than those of controls to have had one or more previous pregnancies that had not ended in a live birth (95% CI 1.3-3.8). We conclude that fetal growth, reflected by proportions at birth, may affect later risk of recurrent and persistent OME.

Anthropometry↗
PubMed1998

Cancer-related fatigue: clinical practice issues.

The purpose of this paper is to review current nursing literature and practice in cancer-related fatigue and to provide a suggested plan of treatment. Cancer-related fatigue is one of the most common and challenging symptom-management problems. The successful treatment of fatigue depends on the clinician's understanding of the symptom's continuum within the cancer experience, its etiologies, assessment strategies, and research-based interventions. Clinical outcomes are measured by the patient's ability to balance energy expenditure and restoration. By applying this knowledge to clinical practice, oncology nurses can have a profound impact on the patient's quality of life.

Energy Metabolism↗
PubMed1997

Fetal undernutrition and disease in later life.

Recent findings suggest that coronary heart disease and stroke, and the associated conditions, hypertension and non-insulin dependent diabetes, originate through impaired growth and development during fetal life and infancy. These diseases may be consequences of 'programming', whereby a stimulus or insult at a critical, sensitive period of early life results in long-term changes in physiology or metabolism. Animal studies provide many examples of programming, which occurs because the systems and organs of the body mature during periods of rapid growth in fetal life and infancy. There are critical windows of time during which maturation must be achieved; and failure of maturation is largely irrecoverable.

Animals↗