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Biomedical subjects

C G Brook

Publications and source records attributed to C G Brook.

At least 37 records · Page 2Linked to original sources
PubMed1999

Thyrotoxicosis in children: thirty years' experience.

Optimal treatment for thyrotoxicosis remains controversial in adults, but more so in paediatric practice. We have conducted a retrospective review of the records of 76 paediatric patients seen between 1965 and 1995 to determine management practice and outcome of therapeutic interventions. Seventeen are currently on antithyroid drug (ATD) treatment, while four have had their care transferred. Of the remaining 55, 21 (38%) achieved long-term remission with ATD alone following a mean treatment duration of 3.3 y (range 0.5-7 y). Block-replacement (high dose of ATD with thyroxine replacement) was more convenient than the titration regimen (3.4+/-0.3 visits to hospital per year versus 6.1+/-0.4, p<0.001). Surgery (subtotal/total thyroidectomy) was carried out in 27 patients, of whom 24 subsequently became hypothyroid and were treated with thyroxine. I131 was used successfully in six patients, two following surgery. ATD should remain the first-line therapy; a block-replacement regimen is more convenient. Surgery in a specialized centre carries a low risk. Caution should still be exercised in the use of I131 in young children.

Adolescent↗
PubMed1999

Peak and trough growth hormone (GH) concentrations influence growth and serum insulin like growth factor-1 (IGF-1) concentrations in short children.

OBJECTIVE: Growth hormone (GH) is secreted in a pulsatile fashion promoting growth and a number of diverse metabolic actions. The precise components of the pulsatile signal involved in growth regulation are unclear. DESIGN: A retrospective analysis of 24 h serum GH concentration profiles to evaluate the relative contribution of peak and trough serum GH concentrations to growth regulation, GH response to insulin induced hypoglycaemia (ITT) and serum insulin like growth factor-1 (IGF-1) concentration. PATIENTS: Fifty short prepubertal children (age 5.2-11.9 years). MEASUREMENT: Analysis of the hormone profile by a concentration distribution method that determines the concentration at or below which the serum GH concentrations in the 24 hour profile spend a percentage of the total time. The method generates an estimate of the observed concentrations (OC) below which 95% and 5% of the values in the time series lie: OC 95 (peaks) and OC5 (troughs). RESULTS: Twenty six of the children were growing at a normal rate for short children with a height velocity standard deviation score (HVSDS) between +0.4 and -0.8 whereas twenty four were growing more slowly (HVSDS between -0.9 to -3.9). The former group had a mean peak GH response to ITT of 27.3 (11.1) mU/l whereas the latter had a mean value of 8.7 (6.5) mU/l. There was no relationship between (peak and trough GH concentration) and the age of the individual or body mass index. Peak GH levels were positively related to HVSDS and serum IGF-1 values (r = 0.44; P = 0.002 and r = 0.53; P = 0.002, respectively). GH trough levels were inversely related to these measurements (r = -0.29; P = 0.05; and r = -0.46; P = 0.002, respectively). Further analysis showed that individuals with the slowest growth rates and lowest IGF-1 concentrations had the lowest peak and highest trough GH concentrations (ANOVA F = 6.0; P = 0.002). Similarly, the peak GH response to ITT was lowest in those individuals with high troughs and low peaks (ANOVA F = 9.99; P < 0.001). CONCLUSIONS: These results suggest that the peak values of a GH concentration profile influence growth rate and the IGF-1 axis whereas elevated trough values have the greatest influence on growth rate and IGF-1 values when GH peaks are low.

Analysis of Variance↗
PubMed1999

Leptin concentrations in maternal serum and cord blood: relationship to maternal anthropometry and fetal growth.

OBJECTIVE: To determine 1. the relationship between maternal serum leptin concentrations and maternal anthropometry and 2. the relationship between cord serum leptin concentrations at birth and neonatal anthropometry. DESIGN: Prospective cohort study of fetal growth in low-risk pregnancies. SETTING: University teaching hospital. SAMPLE: Thirty-nine women and their babies taking part in a fetal growth study. METHODS: Blood was taken from the women between 10-20 weeks of gestation and from the umbilical cord of their babies at delivery. Serum leptin was measured by radio-immunoassay. Maternal anthropometric measurements were recorded at booking. Neonatal anthropometric measurements were recorded within 48 hours after delivery. Linear regression analysis was used to explore the relationship between serum leptin concentrations and anthropometric measures and multiple regression analysis then applied to determine which variables remained independently associated with leptin. RESULTS: The median (range) leptin concentration in maternal serum was 11.8 ng/mL (1.7-39.7) and in cord blood was 4.2 ng/mL (0.6-21.4). Maternal leptin levels correlated with maternal weight, body mass index, midarm circumference and skinfold thickness, but not with birthweight, placental weight or maternal height. Body mass index and midarm circumference remained significant after multiple regression analysis. Cord leptin levels correlated with birthweight, birthlength, placental weight and skinfold thickness but not with ponderal index. Birthweight and subscapular skinfold thickness remained significant after multiple regression analysis. Cord leptin concentrations did not correlate with maternal leptin concentrations. CONCLUSIONS: We suggest that there are very strong associations between maternal leptin and maternal adiposity in pregnancy, and between cord leptin at delivery and birthweight, as well as other anthropometric markers of fetal growth.

Adult↗
PubMed1999

Evidence for an association between birth weight and blood pressure.

Evidence is presented to support the concept that there is an association between birth weight and blood pressure in humans. This relationship probably reflects an interaction between the genetic make-up of the individual and the environment. On average, a decrease in birth weight is associated with a rise in blood pressure in adult life.

Adult↗
PubMed1999

Growth hormone therapy in hypochondroplasia.

Patients with hypochondroplasia present with variable phenotypes. Children with severe short stature and disproportion of the body segments usually have the mutation Asn540Lys. They respond to growth hormone (GH) therapy with an increase in spinal length and, coupled with a surgical leg-lengthening procedure, it is possible for some patients to achieve adult heights within the normal range. Some children who present with proportionate short stature and hypochondroplasia fail to increase their growth rate at puberty, although the growth spurt can be restored by GH therapy. Others, with an identical presentation, seem to grow normally during puberty. At present, there is no way of predicting who will undergo a normal pubertal growth spurt. We therefore monitor all patients during childhood and give GH treatment only to those patients who fail to develop a growth spurt at puberty. Severe cases may occasionally need treatment before puberty if their growth velocity is compromised, but these will probably also be candidates for a surgical leg-lengthening procedure.

Achondroplasia↗
PubMed1999

Androgen secreting adrenocortical tumours.

BACKGROUND: Androgen secreting adrenocortical tumours are rare in children and the determination of their malignant potential can be difficult. OBJECTIVES: To assess the presentation, histology, and clinical behaviour of these tumours. SETTING: Two tertiary referral centres. STUDY DESIGN: Retrospective analysis of children diagnosed with an androgen secreting adrenocortical tumour between 1976 and 1996. PATIENTS: Twenty three girls and seven boys aged 0-14 years. RESULTS: Pubic hair was observed in all children, clitoromegaly or growth of the phallus in 23 children, acceleration of linear growth in 22 children, and advanced bone age (> 1.5 years) in 18 children. Hypersecretion of androgens was detected by assessment of serum androgen concentrations alone in four patients and by 24 hour urine steroid excretion profiles in 22 patients. All 16 tumours measuring < 5 cm in diameter were benign. Of the tumours measuring 5-9 cm, three were malignant and seven were benign, whereas all four tumours > 10 cm were malignant. Histological slides were available for reassessment in 25 children. Although mitoses and necrosis were more characteristic of tumours with malignant behaviour, no exclusive histological features of malignancy were seen. CONCLUSION: Histological criteria for malignancy are not reliable, whereas tumour size is important in assessing malignant potential.

Adolescent↗
PubMed1999

Tests of adrenal insufficiency.

AIM: In suspected adrenal insufficiency, the ideal test for assessing the hypothalamo-pituitary-adrenal axis is controversial. Therefore, three tests were compared in patients presenting with symptoms suggestive of adrenal insufficiency. METHOD: Responses to the standard short Synacthen test (SSST), the low dose Synacthen test (LDST), and the 08:00 hour serum cortisol concentration were measured in 32 patients. A normal response to the synacthen test was defined as a peak serum cortisol of >/= 500 nmol/l and/or incremental concentration of >/= 200 nmol/l. The sensitivity and specificity of the 08:00 hour serum cortisol concentration compared with other tests was calculated. RESULTS: Three patients had neither an adequate peak nor increment after the SSST and LDST. All had a serum 08:00 hour cortisol concentration of < 200 nmol/l. Eight patients had abnormal responses by both criteria to the LDST but had normal responses to the SSST. Three reported amelioration of their symptoms on hydrocortisone replacement. Twenty one patients had a normal response to both tests (of these, 14 achieved adequate peak and increment after both tests and seven did not have an adequate peak after the LDST but had a normal increment). The lowest 08:00 hour serum cortisol concentration above which patients achieved normal responses to both the LDST and SSST was 500 nmol/l. At this cut off value (compared with the LDST), the serum 08:00 hour cortisol concentration had a sensitivity of 100% but specificity was only 33%. CONCLUSION: The LDST revealed mild degrees of adrenal insufficiency not detected by the SSST. The value of a single 08:00 hour serum cortisol concentration is limited.

Adolescent↗
PubMed1999

Failure of IGF-I and IGFBP-3 to diagnose growth hormone insufficiency.

BACKGROUND: Growth hormone insufficiency (GHI) is diagnosed conventionally by short stature and slow growth, and is confirmed by diminished peak GH response to a provocation test. Insulin-like growth factor I (IGF-I) and IGF binding protein 3 (IGFBP-3) have previously been considered individually OBJECTIVE: To test the hypothesis that the combined analysis of IGF-I and IGFBP-3 could act as a surrogate marker for the diagnosis of GHI. DESIGN: Reference ranges for IGF-I and IGFBP-3 were calculated using 521 normal individuals. A retrospective analysis was performed on 318 children referred for investigation of short stature. RESULTS: No significant difference was found between either the IGF-I or IGFBP-3 standard deviation scores (SDSs) in children with and without GHI. If the requirement were for both tests to be positive (< -2 SDS) for a diagnosis of GHI, then 99% of children without GHI would be correctly identified; however, the sensitivity of the test was only 15%. CONCLUSIONS: Neither IGF-I nor IGFBP-3 alone is a marker for GHI. In addition, they cannot be used as an effective screening test in combination.

Adolescent↗
PubMed1999

Mechanism of puberty.

The hypothalamo-pituitary-gonadal axis in children is fully functional in fetal life and immediately after birth. The reason why it declines with advancing years of childhood is not clear but gonadotropin pulsatility is at a nadir at 6 years of age. From that time pulsatile gonadotropin starts to reappear but, again, the reason why this happens is completely unknown. All of the events of puberty can be ascribed to pulsatile gonadotropin-releasing hormone stimulation causing pulsatile gonadotropin stimulation of sex steroids. The sex steroids explain the development of the pubertal characteristics; the fact that girls have an earlier growth spurt than boys is explained by the differential effect of oestradiol and testosterone on hypothalamic control of pituitary growth hormone secretion.

Female↗
PubMed1999

Treatment of late puberty.

The induction of puberty is physically and emotionally disturbing. For that reason, low doses of medication need to be introduced and increased slowly, regardless of the age at which treatment is started. In boys with growth delay, the growth spurt may be induced earlier in the sequence of pubertal developmental by using oxandrolone, but puberty itself is induced by slowly increasing doses of testosterone. For girls with ovarian failure, oestradiol should be introduced from the age of 8 or 9 years, but doses should be very cautiously increased in order to allow time for cosmetic development of breasts and growth of the uterus.

Adolescent↗
PubMed1999

Compliance with growth hormone treatment - is it a problem?

Treatments fail for a number of reasons. These include the failure of medicines at a molecular level, failure to achieve the correct diagnosis and therefore use of the correct medication, problems surrounding the doctor-patient relationship, and failure of the service to meet patients' expectations. Compliance is characteristically viewed as the major cause of treatment failures but implicit in the use of the term compliance is the reliance on an imbalance of power where the patient follows what is ordered. Such an approach is likely to lead to failure. A better model is concerned with promoting the full participation of the patient to generate a therapeutic alliance. Despite the need for parental administration and a daily therapeutic regimen there appears to be little evidence to suggest that concordance is a major problem in growth hormone therapy. This is probably because treatment administration relies on the presence of a carer and there are tangible effects. However, concordance is likely to be an issue where there is mismatch between the patient's expectations and those of the doctor. Such a situation may arise when the therapeutic margin is narrow or the therapeutic effect minimal. To resolve this situation, adequate pre-intervention discussion is essential, which should include a clear statement of short- and long-term treatment targets and the likelihood of these being achieved or not. Carefully constructed health care plans are the key and should include educational programmes, home support and regular reinforcement. When concordance problems are suspected, careful consideration needs to be given as to whether the diagnosis is correct, is the treatment really effective and appropriate and does the patient really want the treatment.

Drug Monitoring↗
PubMed1999

Treatment of achondroplasia with growth hormone: six years of experience.

We describe the effects of recombinant hGH (r-hGH) therapy for up to 6 y on stature and body proportions of 35 children with achondroplasia (Ach). Consecutive height (Ht) measurements were plotted on disease-specific Ach growth curves, but age and sex SD scores (SDS) of Ht, sitting Ht, subischial leg length, and Ht velocity were made with respect to Tanner normal standards. r-hGH was administered by daily subcutaneous injections at a median (range) dose of 30 (15.8-40) U/m2 per week [0.06 (0.04-0.08) mg.kg(-1).24 h(-1)]. Patients were treated for 3 (1-6) y from age 2.25 (1.2-9.3) y. Before treatment, Ht SDS was -4.6 (-6.5 to -3.24). Treatment caused a significant increase in Ht SDS year to year until y 4 (ANOVA F = 46.94; p < 0.01) that was subsequently sustained with no significant further change (y 5 and 6 versus y 4, p > 0.05). When the response to r-hGH was also expressed as a change in Ht velocity, there was a significant increase in the first year of therapy that was maintained over subsequent treatment years (ANOVA = 4.28, p = 0.001). Age was the most important variable accounting for the first-year response in Ht SDS (r2 = 0.41, p < 0.001), and dose of r-hGH did not influence this. Increments in sitting Ht SDS were greater than subischial leg length SDS (F = 26.25, p < 0.001; F = 9.04, p < 0.001, respectively). r-hGH treatment improved the Ht position of Ach children relative to their normal and Ach peers without obvious side effects. A young age at initiation of therapy prevented the characteristic Ht deficit from accumulating. The greater increase in spinal Ht accentuated the existing disproportion. The addition of later surgical leg lengthening could offer the possibility of proportionate adult stature just within the normal range.

Achondroplasia↗
PubMed1999

A sexually dimorphic pattern of growth hormone secretion in the elderly.

In rodents, the sexually dimorphic pattern of pulsatile GH secretion is an important determinant of growth, liver enzyme function and insulin-like growth factor I (IGF-I) expression. Whether this difference is present in humans at different ages is unclear. We studied GH secretory patterns in the elderly by constructing 24-h serum GH profiles in 45 male and 38 female (age, 59.4-73.0 yr) volunteers and related patterns to IGF-I, IGF-binding protein-3 (IGFBP-3), and GH-binding protein levels; body mass index; and waist/hip ratio. Serum GH concentrations were measured in samples drawn at 20-min intervals and analyzed using a sensitive chemiluminescent assay (Nichols Institute Diagnostics: sensitivity, 0.036 mU/L). The 24-h serum GH profiles were analyzed using a concentration distribution method to determine GH peak and trough levels, spectral analysis, and assessment of serial irregularity by approximate entropy (ApEn). There was a highly significant difference in mean 24-h serum GH concentrations in females compared to males (males, 0.88 mU/L; females, 1.31 mU/L; P = 0.009) as a result of significantly higher trough GH levels (males, 0.04 mU/L; females, 0.16 mU/L; P < 0.001). Peak values were not significantly different. Serum IGF-I levels were significantly higher in males (males, 162.4 ng/mL; females, 87.8 ng/ mL; P < 0.001). Peak GH values were related to serum IGF-I levels (males: r = 0.39; P = 0.009; females: r = 0.5; P = 0.002), whereas trough GH levels were not. IGFBP-3 levels were similar and related to GH peaks only in males (r = 0.32; P = 0.03). GH was secreted with a dominant periodicity of 200 min in males and 280 min in females (P < 0.025). The proportion of time taken up by regular oscillatory activity was less in females (females, 11.1%; males, 14.7%; P = 0.01). GH secretion assessed by ApEn was more disordered in females (males, 0.60; females, 0.81; P < 0.001), and increasing disorder was associated with lower IGF-I levels. Body mass index was negatively related to GH in both sexes. In males, trough values were the major determinant (r = -0.31; P = 0.04), whereas in females, the peak value was the major determinant (r = 0.35; P = 0.04). Trough GH levels were inversely related in both sexes to waist/hip ratio (males: r = -0.40; P = 0.006; females: r = -0.44; P = 0.006) and to increasing secretory disorder (ApEn; r = -0.46; P < 0.001). These data demonstrate a sexually dimorphic pattern of GH secretion in the elderly.

Aged↗
PubMed1998

Collagen metabolism and growth in prepubertal children with asthma treated with inhaled steroids.

OBJECTIVE: To investigate growth and markers of collagen and bone metabolism in prepubertal children with asthma. STUDY DESIGN: We measured growth velocity over 12 months and markers of collagen types I and III synthesis (PINP, PICP, PIIINP), collagen type I degradation (ICTP), and bone metabolism (bone-specific alkaline phosphatase and osteocalcin) on one occasion in 56 prepubertal children with stable asthma, 39 of whom were treated with inhaled budesonide or beclomethasone. Collagen data were compared with normal control values. RESULTS: Children treated with inhaled steroids had reduced collagen synthesis (PINP, PIIINP) compared with control subjects (p = 0.038, p = 0.045), although PICP was increased (p = 0.05). Carboxyterminal telopeptide of type I collagen was reduced in patients treated with inhaled steroids (p < 0.0005) compared with nonsteroid-treated patients. Serum osteocalcin but not bone-specific alkaline phosphatase was significantly reduced in children treated with inhaled steroids (p < 0.02). Significant correlation was observed between PIIINP and ICTP and growth velocity. CONCLUSION: Collagen turnover is reduced in children with asthma receiving long-term inhaled steroid treatment. Markers of collagen synthesis provide a more accurate reflection of growth disturbance than osteocalcin and bone-specific alkaline phosphatase.

Administration, Inhalation↗
PubMed1998

Mortality in patients with congenital adrenal hyperplasia: a cohort study.

OBJECTIVE: To determine mortality in patients with congenital adrenal hyperplasia (CAH) compared with that in the general population. DESIGN: We identified 333 children with CAH, treated at several pediatric endocrinology departments in the United Kingdom since 1964, and monitored their mortality to mid 1996. Standardized mortality ratios were calculated, comparing mortality in the cohort with that in the general population, adjusted for sex, age, and calendar period. RESULTS: All-cause mortality in the cohort was 3 times that expected. Mortality was significantly increased at ages 1 to 4 years (standardized mortality ratio = 18.3) but not at older ages and was significantly increased in patients of Indian-subcontinent ethnicity (standardized mortality ratio = 20.4), particularly in girls. From case notes and death certificates, it appears that most deaths were caused by adrenal crisis, often after infection. CONCLUSIONS: Although survival of patients with CAH has greatly improved since steroid therapy has been used, this disease can still have fatal consequences. The high mortality rate in Indian ethnic girls may well reflect lack of parental acceptance and understanding of the disease, as well as of the action required when their child becomes acutely ill. Better communication with and education of parents of children with CAH, especially those from immigrant ethnic minorities, is important.

Adolescent↗
PubMed1998

Genotype and phenotype in hypochondroplasia.

Mutations in the tyrosine kinase domain of fibroblast growth factor receptor gene (FGFR3) have been described in some cases of hypochondroplasia (Hch). We screened 65 children with Hch diagnosed by clinical and radiologic criteria for 2 previously described mutations, C1620A and C1620C in FGFR3; 28 (43%) of 65 patients were heterozygous for the C1620A transversion resulting in lysine to asparagine substitution at codon 540 in the tyrosine kinase domain of FGFR3. The height, sitting height, and subischial leg length of these children and of 18 children with achondroplasia were analyzed at presentation, and SD scores were calculated. For comparison of growth data the patients were divided into three groups: group 1, achondroplasia defined by radiology and the presence of the G1138A mutation in the transmembrane domain of FGFR3; group 2, Hch with C1620A mutation; and group 3, Hch with no mutation identified so far. Height, sitting height, and subischial leg length SD scores were analyzed as group mean data by analysis of variance with the Student Neuman-Keuls test after testing for multiple contrasts were performed. All three groups were significantly compromised in height, although the children with achondroplasia were much shorter with significant reduction in subischial leg length. The same pattern was evident in group 2, with additional shortening of the back, the third group was proportionately short. Children with the common C1620A mutation met all of the criteria for the diagnosis of Hch with a severe phenotype that resembled achondroplasia and disproportionate short stature in early childhood. However, a substantial number of patients with proportionate short stature presented at an older age with the same radiologic characteristics and failure of the puberty growth spurt. The genetic basis of this milder phenotype not yet known.

Achondroplasia↗
PubMed1998

Gonadotrophin pulsatility in girls with the Turner syndrome: modulation by exogenous sex steroids.

OBJECTIVES: The endocrine manifestation of puberty, nocturnal pulsatile secretion of gonadotrophins precedes the physical manifestations by 2 years. Whether gonadal steroids and inhibin have a role to play in the regulation of pulsatile gonadotrophin release is unclear. The agonadal model, girls with Turner's syndrome (TS), has been used to determine the role of the hypothalamic pulse generator in the ontogeny of gonadotrophin secretion in man. We evaluated the ontogeny of gonadotrophin secretion in TS girls with respect to amplitude and frequency and compared these results to those obtained in a group of normal girls. The effects of treatment with ethinyloestradiol (EE2) or oxandrolone (OX) on parameters of gonadotrophin secretion were also evaluated. PATIENTS: We studied 32 girls with TS, aged 4.3-12.4 years. All were prepubertal at the start of the study and longterm follow up revealed that none entered spontaneous puberty. The pulse amplitude and frequency was evaluated and compared to the results obtained in 23 normal girls, aged 4.9-12.8 years who acted as controls. MEASUREMENTS: Samples were taken at 20 minute intervals for 24 h for the measurement of serum concentrations of luteinising (LH) and follicle stimulating (FSH) hormones. The girls were than randomized to receive EE2 or OX and were then re-admitted 6 months into the course of the treatment for a repeat 24 h serum profile of LH and FSH levels. RESULTS: The girls with TS showed a clearly defined dominant pulse periodicity of 180 min and that in the normal cohort was 160-220 min. The girls with TS had an increased oscillatory activity between 120 and 260 min compared to the normal. Mean 24 h serum gonadotrophin concentration in TS girls was always higher than in the normal cohort. The inflection points of the fitted polynomial regression equation relating sex hormone concentration with age was similar for the two groups. EE2 lead to a significant change in pulse periodicity in TS girls but OX had no significant effect on the pulse periodicity. CONCLUSION: These results demonstrate that girls with Turner syndrome have gonadotrophin pulse periodicity in the prepubertal years similar to those of normal girls. The oscillatory activity was much greater in girls with Turner syndrome at all ages in the prepubertal years, suggesting a role for the ovary in modulating gonadotrophin secretion in the prepubertal years. Our data confirm that in girls with Turner syndrome the normal pattern of gonadotrophin secretion evolving with time is preserved.

Anabolic Agents↗