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Biomedical subjects

P Hindmarsh

Publications and source records attributed to P Hindmarsh.

At least 19 recordsLinked to original sources
PubMed2003

Neonates with symptomatic hyperinsulinemic hypoglycemia generate inappropriately low serum cortisol counterregulatory hormonal responses.

Serum cortisol plays an important role in counterregulation to hypoglycemia. It antagonizes the peripheral effects of insulin and also directly influences glucose metabolism. Classically serum cortisol concentrations rise in response to hypoglycemia, but the response in neonates with hyperinsulinemic hypoglycemia is unclear. To investigate the serum cortisol responses in neonates with hyperinsulinemic hypoglycemia, 13 neonates (34-40 wk gestation; male/female ratio, 7/6) with hyperinsulinemic hypoglycemia underwent diagnostic fasts. The serum cortisol concentration was measured before the commencement of the fast and at the time of hyperinsulinemic hypoglycemia. The hypoglycemia was then treated with iv glucose (1 ml/kg bolus of 10% dextrose), and serum cortisol concentrations were measured at 10-min intervals for a total of 50 min. Six of the 13 neonates had plasma ACTH concentrations measured at the time of hypoglycemia and then received a 62.5- microg i.v. bolus injection of Synacthen. The mean (+/-SEM) serum cortisol concentration 15 min before the hypoglycemic episode was 156 +/- 24 nmol/liter, and that at the time of hypoglycemia was 182 +/- 28 nmol/liter. Mean cortisol concentrations at 10, 20, 30, 40, and 50 min for the first seven neonates who were not given Synacthen at the time of hypoglycemia were 213 +/- 44, 223 +/- 48, 209 +/- 49, 228 +/- 46, and 252 +/- 30 nmol/liter, respectively. The six neonates who received an i.v. bolus dose of Synacthen had significantly greater (P < 0.01) serum cortisol concentrations at the same time points, 208 +/- 39, 219 +/- 46, 378 +/- 139, 664 +/- 57, 905 +/- 121, 1048 +/- 247, and 1192 +/- 105 nmol/liter, respectively. Plasma ACTH levels were inappropriately low in all six neonates at the time of hypoglycemia (mean plasma ACTH concentration, 13.2 pg/ml). Neonates with hyperinsulinemic hypoglycemia fail to generate an adequate serum cortisol counterregulatory hormonal response. This appears to be related to the lack of drive from the hypothalamic-pituitary axis, with inappropriately low plasma ACTH concentrations at the time of hypoglycemia. The normal serum cortisol response to an i.v. bolus injection of Synacthen suggests that this is a centrally mediated phenomenon and does not imply that these patients have adrenal insufficiency.

Adrenocorticotropic Hormone↗
PubMed2003

Spontaneous hypoglycemia in childhood is accompanied by paradoxically low serum growth hormone and appropriate cortisol counterregulatory hormonal responses.

Hypoglycemia is a potent stimulus for GH and cortisol secretion. The insulin tolerance test (ITT) is the gold standard for assessing GH and cortisol responses from the hypothalamic-pituitary-adrenal axis. The serum GH and cortisol responses to spontaneous hypoglycemia in 22 children were compared with those of 16 children undergoing an ITT for diagnostic purposes. The mean serum GH and cortisol concentrations 1 h before spontaneous hypoglycemia were 6.9 +/- 1.1 mU/liter and 424 +/- 51 nmol/liter, respectively, and at the time of spontaneous hypoglycemia they were 6.7 +/- 1.3 mU/liter and 601 +/- 66 nmol/liter, respectively. The mean serum GH and cortisol values at +10, +20, +30, +40, and +50 min from the time of hypoglycemia were 5.4 +/- 1.0, 4.7 +/- 0.7, 4.6 +/- 1.0, 5.4 +/- 1.4, and 5.5 +/- 1.3 mU/liter and 633 +/- 69, 645 +/- 71, 668 +/- 70, 680 +/- 72, and 662 +/- 77 nmol/liter, respectively. There was no significant difference between any of these means for GH secretion. In contrast, in the ITT the mean serum GH concentration before hypoglycemia was 5.1 +/- 1.3 mU/liter, and at the time of hypoglycemia it was 29.2 +/- 7.30 mU/liter. The difference between these means was highly significant (P < 0.01, by t test). There was no significant difference between the cortisol response to spontaneous hypoglycemia and that to the ITT. Physiological changes in the serum nonesterified fatty acid concentration had no significant effect on serum GH secretion. In conclusion, the mechanism(s) of the serum GH response to spontaneous hypoglycemia is different from that due to the ITT. A low GH level detected at the time of spontaneous hypoglycemia does not necessarily imply GH deficiency or GH as a cause of the hypoglycemia.

Blood Glucose↗
PubMed2002

Evaluating the effects of asthma therapy on childhood growth: principles of study design.

Inhaled corticosteroids have been established as the most effective treatment for childhood asthma. However, concerns persist regarding their potential effects on growth and, most importantly, final height. To assess their effects on growth, inhaled corticosteroids can be compared with placebo (type 1 study), nonsteroidal anti-asthma therapy (type 2 study), another inhaled corticosteroid (type 3 study) or "real-life" anti-asthma therapy (type 4 study). Owing to the difficulties in obtaining final height data, several different surrogate measures have often been used: short-term lower leg growth, longer-term statural height growth velocity, childhood height and predicted final height. This paper discusses the choice of end point, key trial design issues (including selection and number of subjects in the active and control populations) duration of assessments and methods for measuring height and data analysis, in the context of the different study types. Specific study design recommendations have been developed after consideration of these factors, and these principles will be used to guide the interpretation of previously published growth studies.

Anti-Asthmatic Agents↗
PubMed2002

Evaluating the effects of asthma therapy on childhood growth: what can be learnt from the published literature?

The difficulties of assessing the effects of asthma therapy on childhood growth were explored in the first part of this review. In this part of the review growth studies with inhaled corticosteroids were selected that included a control group, measured height by stadiometry and were of > or = 1 yr duration. The studies were classified as type 1 (placebo control), type 2 (nonsteroidal therapy control), type 3 (comparator inhaled corticosteroid control) or type 4 ("real-life" studies with dose adjustment). The design attributes of these studies were then compared with the recommendations described in the first part of this review. Of the 18 studies identified, 17 were susceptible to one or more important confounding factors. Nevertheless, the outcomes of all 18 studies were mostly consistent. At recommended doses, beclomethasone dipropionate and budesonide demonstrated a small degree of growth suppression over 1-2 yrs (study types 1 and 2), but there was little evidence of such an effect with fluticasone propionate. Studies comparing different inhaled corticosteroids at recommended doses indicated more rapid growth with fluticasone propionate than with beclomethasone dipropionate or budesonide. However, none of the inhaled corticosteroids appeared to affect final height. In conclusion, the results from the majority of published growth studies with inhaled corticosteroids must be interpreted with a degree of caution owing to their potential susceptibility to important confounding factors. Further well-designed studies are needed to establish whether different inhaled corticosteroids have different effects on growth in the long term.

Anti-Asthmatic Agents↗
PubMed2002

Does birth weight predict adult serum cortisol concentrations? Twenty-four-hour profiles in the United kingdom 1920-1930 Hertfordshire Birth Cohort.

Low birth weight and weight in infancy are associated with adult insulin resistance and type 2 diabetes. A proposed mechanism is programming of the hypothalamic-pituitary-adrenal axis by intrauterine undernutrition, leading to persistently elevated cortisol concentrations. We examined 24-h serum cortisol profiles (samples every 20 min) in 83 healthy elderly men and women whose birth weight and infant weight were recorded. Variables derived from these profiles included trough, peak, and area under the curve concentrations; the time of onset, rate of rise, duration, and peak of the early morning cortisol rise; postprandial secretion; and regularity of secretion (approximate entropy). None of these parameters was related to birth weight, weight at 1 yr, or change in weight SD score between birth and 1 yr. Consistent with other studies, 0730-0900 h cortisol concentrations were higher in men and women of lower birth weight, although this was not statistically significant (P = 0.08). Our findings do not support the hypothesis that reduced intrauterine and infant growth are associated with continuously raised cortisol concentrations in old age. Programmed effects on the hypothalamic-pituitary-adrenal axis may influence reactivity rather than resting secretion.

Aged↗
PubMed2001

Gaining consent to freeze spermatozoa from adolescents with cancer: legal, ethical and practical aspects.

Sperm banking for early adolescent cancer patients requires delicate, sensitive handling and, in the UK, consideration is required of statutory elements. No information at present exists about how adolescents with cancer are normally treated or counselled for sperm banking. Here we highlight the type of issues in relation to fertility preservation faced by clinicians and those faced by adolescents at a sperm storage laboratory. We explore the very real difficulties of bringing together these medical fields of assisted reproduction, oncology and the various pieces of legislation and focus specifically on gaining consent. Attention is paid to counselling and communication to help the patient reach an effective and informed decision to store spermatozoa. The role of parents in contributing towards communication and support, together with the legal constraints in decision making, is acknowledged. How absolute and fully 'informed' consent should be will always remain a contentious issue amongst the various specialists and disciplines. In relation to sperm storage, as a minimum the patients should understand the process that they are undertaking so that it is undertaken freely and without pressure. The practical approach to gaining consent that we are using seems a logical and practical method to help early adolescent patients to store spermatozoa.

Adolescent↗
PubMed2001

Base-pair substitutions in avian sarcoma virus U5 and U3 long terminal repeat sequences alter the process of DNA integration in vitro.

We have described a reconstituted avian sarcoma virus (ASV) concerted DNA integration system with specially designed mini-donor DNA containing a supF transcription unit, a supercoiled plasmid acceptor, purified bacterially expressed ASV integrase (IN), and human high-mobility-group protein I(Y). Integration in this system is dependent upon the mini-donor DNA having IN recognition sequences at both ends and upon both ends of the same donor integrating into the acceptor DNA. The integrated DNA product exhibits all of the features associated with integration of viral DNA in vivo (P. Hindmarsh et al., J. Virol., 73:2994-3003, 1999). Individual integrants are isolated from bacteria containing drug-resistant markers with amber mutations. This system was used to evaluate the importance of sequences in the terminal U5 and U3 long terminal repeats at positions 5 and/or 6, adjacent to the conserved CA dinucleotide. Base-pair substitutions introduced at these positions in U5 result in significant reductions in recovered integrants from bacteria, due to increases in one-ended insertion events. Among the recovered integrants from reactions with mutated U5 but not U3 IN recognition sequences were products that contain large deletions in the acceptor DNA. Base-pair substitutions at positions 5 and 6 in U3 mostly reduce the efficiency of integration of the modified donor. Together, these results indicate that sequences directly 5' to the conserved CA dinucleotide are very important for the process of concerted DNA integration. Furthermore, IN interacts with U3 and U5 termini differently, and aberrant end-processing events leading to nonconcerted DNA integration are more common in U5 than in U3.

Avian Sarcoma Viruses↗
PubMed2001

Management of hyponatraemia in patients with acute cerebral insults.

Hyponatraemia is a common finding in patients with acute cerebral insults. The main differential diagnosis is between syndrome of inappropriate ADH secretion and cerebral salt wasting. Our aim is to review the topic of hyponatraemia in patients with acute cerebral insults and suggest a clinical approach to diagnosis and management.

Acute Disease↗
PubMed2000

Evidence for digenic inheritance in some cases of Antley-Bixler syndrome?

The Antley-Bixler syndrome has been thought to be caused by an autosomal recessive gene. However, patients with this phenotype have been reported with a new dominant mutation at the FGFR2 locus as well as in the offspring of mothers taking the antifungal agent fluconazole during early pregnancy. In addition to the craniosynostosis and joint ankylosis which are the clinical hallmarks of the condition, many patients, especially females, have genital abnormalities. We now report abnormalities of steroid biogenesis in seven of 16 patients with an Antley-Bixler phenotype. Additionally, we identify FGFR2 mutations in seven of these 16 patients, including one patient with abnormal steroidogenesis. These findings, suggesting that some cases of Antley-Bixler syndrome are the outcome of two distinct genetic events, allow a hypothesis to be formulated under which we may explain all the differing and seemingly contradictory circumstances in which the Antley-Bixler phenotype has been recognised.

Abnormalities, Drug-Induced↗
PubMed1999

HMG protein family members stimulate human immunodeficiency virus type 1 and avian sarcoma virus concerted DNA integration in vitro.

We have reconstituted concerted human immunodeficiency virus type 1 (HIV-1) integration in vitro with specially designed mini-donor HIV-1 DNA, a supercoiled plasmid acceptor, purified bacterium-derived HIV-1 integrase (IN), and host HMG protein family members. This system is comparable to one previously described for avian sarcoma virus (ASV) (A. Aiyar et al., J. Virol. 70:3571-3580, 1996) that was stimulated by the presence of HMG-1. Sequence analyses of individual HIV-1 integrants showed loss of 2 bp from the ends of the donor DNA and almost exclusive 5-bp duplications of the acceptor DNA at the site of integration. All of the integrants sequenced were inserted into different sites in the acceptor. These are the features associated with integration of viral DNA in vivo. We have used the ASV and HIV-1 reconstituted systems to compare the mechanism of concerted DNA integration and examine the role of different HMG proteins in the reaction. Of the three HMG proteins examined, HMG-1, HMG-2, and HMG-I(Y), the products formed in the presence of HMG-I(Y) for both systems most closely match those observed in vivo. Further analysis of HMG-I(Y) mutants demonstrates that the stimulation of integration requires an HMG-I(Y) domain involved in DNA binding. While complexes containing HMG-I(Y), ASV IN, and donor DNA can be detected in gel shift experiments, coprecipitation experiments failed to demonstrate stable interactions between HMG-I(Y) and ASV IN or between HMG-I(Y) and HIV-1 IN.

Animals↗
PubMed1999

Retroviral DNA integration.

DNA integration is a unique enzymatic process shared by all retroviruses and retrotransposons. During integration, double-stranded linear viral DNA is inserted into the host genome in a process catalyzed by the virus-encoded integrase (IN). The mechanism involves a series of nucleophilic attacks, the first of which removes the terminal 2 bases from the 3' ends of the long terminal repeats and of the second which inserts the viral DNA into the host genome. IN specifically recognizes the DNA sequences at the termini of the viral DNA, juxtaposing both ends in an enzyme complex that inserts the viral DNA into a single site in a concerted manner. Small duplications of the host DNA, characteristic of the viral IN, are found at the sites of insertion. At least two host proteins, HMG-I(Y) and BAF, have been shown to increase the efficiency of the integration reaction.

Avian Sarcoma Viruses↗
PubMed1999

Profiles of endogenous circulating cortisol and bone mineral density in healthy elderly men.

Exogenous glucocorticoids are known to increase the risk of osteoporosis. However, the contribution made by endogenous circulating cortisol concentrations to adult skeletal status remains unknown. We examined this issue in a sample of 34 healthy men, aged 61-72 yr. Venous blood samples were obtained under standard conditions every 20 min over a 24-h period. Measurements were made of serum cortisol and cortisol-binding globulin. Bone mineral density was measured at the lumbar spine and proximal femur using dual energy x-ray absorptiometry. Measurements were made at baseline and 4 yr later. There was a weak negative association between integrated cortisol concentration and lumbar spine bone density (r = -0.37; P < 0.05); similar relationships (P < 0.05) existed at three of five proximal femoral sites. There were also statistically significant positive associations between the trough cortisol concentration and bone loss rate at the lumbar spine (r = 0.38; P < 0.05), femoral neck (r = 0.47; P < 0.001), and the trochanteric region (r = 0.41; P = 0.02) over the 4-yr follow-up period. The cross-sectional relationships between cortisol concentration and bone density were removed by adjustment for body mass index, but the influence on bone loss rate remained significant after adjusting for adiposity, cigarette smoking, alcohol consumption, dietary calcium intake, physical activity, and serum testosterone and estradiol levels. These observations suggest that the endogenous cortisol profile of healthy elderly men is a determinant of their bone mineral density and their rate of involutional bone loss.

Aged↗