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Biomedical subjects

C J Kelnar

Publications and source records attributed to C J Kelnar.

At least 19 recordsLinked to original sources
PubMed2001

Child and parental mental ability and glycaemic control in children with Type 1 diabetes.

AIMS: Many psycho-social factors can affect the glycaemic control of children with Type 1 diabetes, but the influence of the intelligence of the child and their parents has not been reported. METHODS: Seventy-eight children and adolescents with Type 1 diabetes and their mothers performed standardized tests to assess psychometric intelligence. The children were aged (median (range)) 12.0 (5-17) years with duration of diabetes 5.0 (1.0-13.0) years and required an insulin dose of (mean +/- SD) 1.0 +/- 0.3 U/kg per day. The children completed the Wide Range Achievement Test 3 reading test (WRAT3) and Raven's Standard Progressive Matrices (RSPM). A mean annual HbA1c was calculated for each subject (8.6 +/- 1.4%). The mothers performed the National Adult Reading Test (NART) and provided details of the occupation of the main wage-earner in the family from which social class (SC) was derived. RESULTS: The HbA1c of the child correlated with their age (r = 0.26, P = 0.02), SC (Kendall's rank correlation, tau = 0.17, P = 0.03) and with the NART error score of their mother (r = 0.28, P = 0.01), but no correlation was observed with the child's WRAT3 or RSPM score. Stepwise regression revealed that age and NART error score were the strongest independent determinants of glycaemic control (total adjusted r2 = 0.117). CONCLUSIONS: Parental intelligence appears to have a significant influence on the glycaemic control of a child with Type 1 diabetes, accounting for 7.6% of the reliable variance in HbA1c.

Adolescent↗
PubMed2001

Hypothalamic-pituitary-ovarian dysfunction after prepubertal chemotherapy and cranial irradiation for acute leukaemia.

BACKGROUND: We assessed adult hypothalamic-pituitary-ovarian function following treatment with chemotherapy and cranial irradiation for childhood acute lymphoblastic leukaemia. METHODS: The patients (n = 12) had median age at diagnosis of 4.7 years, and at assessment of 20.8 years. They collected a daily urine sample over two to five consecutive menstrual cycles (total of 41 cycles) for analysis of LH and steroid excretion. Blood sampling and ovarian ultrasound examination was performed in the early follicular phase. Sixteen healthy women with regular menstrual cycles were recruited as controls. RESULTS: Urinary LH excretion was significantly lower in patients throughout the cycle, particularly during the LH surge (P < 0.0001). The length of the luteal phase was significantly shorter in patients than in normal controls (12.2 +/- 0.3 versus 13.6 +/- 0.4 days, P = 0.01) with a high prevalence of short (< or =11 days) luteal phases (15/39 cycles). Luteal phase pregnanediol excretion was slightly but not significantly lower. Follicular and luteal phase excretion of oestrone was lower in patients than in controls (P = 0.01). Early follicular phase plasma oestradiol was also lower in the patient group (P = 0.032) although LH, FSH, inhibin A and B concentrations were similar. CONCLUSIONS: These data indicate that treatment for childhood leukaemia results in subtle ovulatory disorder in some patients, probably related to cranial irradiation. Follow-up of these women is required to detect any effect on reproductive potential.

Acute Disease↗
PubMed2001

Short stature in Noonan syndrome: response to growth hormone therapy.

BACKGROUND: Growth hormone (GH) has been used to promote growth in both the short and long term in a number of dysmorphic syndromes, including Turner syndrome. As this condition shares many clinical features with Noonan syndrome, it would seem logical to treat the latter group with GH. AIMS: To assess the short and long term response to GH therapy in patients with Noonan syndrome. METHODS: Analysis of patients with Noonan syndrome in the Pharmacia & Upjohn International Growth Study (this post-marketing database contains data on the majority of patients currently treated with GH in the UK). A questionnaire was also sent to participating clinicians. RESULTS: Data on 66 patients (54 males) were available for study. At the start of GH therapy children were short, compared with both normal and Noonan children. During the first year of GH therapy height velocity increased from a mean of 4.9 to 7.2 cm per year. For patients treated long term with GH, mean height SDS increased from -2.9 pretreatment to -2.6 after one year and -2.3 after five years. Of the 10 patients at near final height, only one had a height above the 3rd centile for normal adults and above the mean for untreated Noonan patients. The mean increment in final height was 3.1 cm (range -1.1 to 6.5 cm). CONCLUSIONS: GH therapy in patients with Noonan syndrome will improve height velocity in the short term. Longer-term therapy results in a waning of effect; initial indications are that final height is not improved substantially in most patients.

Adolescent↗
PubMed2001

Growth hormone therapy and growth in children with Noonan's syndrome: results of 3 years' follow-up.

Growth data from the first 3 yr of a multicenter study examining the efficacy and safety of recombinant human GH [rhGH; 4 IU (1.3 mg)/m(2).day, sc] in children with Noonan's syndrome (NS) are reported for 23 subjects. Sixteen male and seven female patients (age, 9.3 +/- 2.6 yr at onset of GH therapy, mean +/- SD; range, 4.8-13.7) were each assessed at 1, 2, and 3 yr after starting treatment. Comparisons were made with a group of eight subjects (six males and two females, age, 9.0 +/- 4.1 yr; range, 4.1-14.8) with NS, not treated with rhGH, measured over the same period. All treated subjects underwent annual cardiac assessment. Height SD score increased from -2.7 +/- 0.4 at the start of GH therapy to -1.9 +/- 0.9 3 yr later (P < 0.001, two-tailed t test). This corresponded to an increase in height from 116.1 +/- 13.2 to 137.3 +/- 14.0 cm. Height velocity increased from 4.4 +/- 1.7 cm/yr in the year before treatment to 8.4 +/- 1.7 (P < 0.001), 6.2 +/- 1.7 (P < 0.001), and 5.8 +/- 1.8 (P = 0.01, two-tailed t test compared with baseline) during the first, second, and third years of GH treatment, respectively. Height acceleration was not significant during the second or third years when pubertal subjects were excluded. The comparison group showed an increase in height from 116.0 +/- 19.8 to 131.9 +/- 21.1 cm over the 3 yr (height SD score, -2.7 +/- 0.6 to -2.4 +/- 0.7, P = 0.3). None of the 23 children developed hypertrophic cardiomyopathy during GH treatment. The increase in growth rate in NS resulting from 1 yr of GH therapy seems to be maintained during the second year, although height velocity shows a less significant increase over pretherapy values. Possible abnormal anabolic effects of rhGH on myocardial thickness were not confirmed, and no treated patient developed features of hypertrophic cardiomyopathy.

Adolescent↗
PubMed2001

Idiopathic short stature.

Idiopathic short stature (ISS) is a term used to describe the status of children with short stature that cannot be attributed to a specific cause. Many children diagnosed as having ISS have partial GH insensitivity, which can result from disturbances at various points of the GH-IGF-I axis. Several clinical studies on spontaneous growth in ISS showed that adult height was almost in the range of target height. GH treatment led to adult height not significantly higher than the pretreatment predicted adult height in most reports. No metabolic side effects have been observed, even when the dose was higher than in GH deficiency. Manipulation of puberty with gonadotrophin releasing hormone analogues reported by a few authors in a small number of children has shown conflicting results. Long-term psychological benefits of GH therapy for short normal children have not been demonstrated to date.

Adolescent↗
PubMed2001

Isolated growth hormone deficiency in children and adolescents.

Although it is difficult to reach international agreement on the definition of growth hormone deficiency (GHD) in children and adolescents, great efforts to do so have been made during the last two decades. A somewhat limited definition of GHD is: a combination of auxological, clinical, biochemical and metabolic abnormalities caused by lack or insufficiency of GH secretion that results in a decrease in the production of GH-dependent hormones and growth factors. Its aetiology is very complex. Therefore, specific studies must be performed during different periods of childhood (neonatal, prepubertal and pubertal periods). Auxological parameters, particularly growth velocity (GV), are still considered the best clinical measures for analysing human growth. The spectacular advances in our understanding of molecular biology during the past twenty years have allowed, and will continue to allow, a more and more precise diagnosis of the molecular anomalies of human growth. This will, in turn, allow changes caused by genetic lesions to be more efficiently distinguished from those due to nutritional, organic, tumoural, psychological or traumatic causes. Our knowledge of the molecular bases of undergrowth due to a deficiency in GH has developed as a result of the localisation and characterisation of human genes which code for proteins implicated in the hormonal regulation of growth. These genes include pituitary GH (GH1), pituitary transcription factor 1 (Pit-1), the prophet of Pit-1 (PROP-1), the pituitary transcription factor LHX3, the transcription factor HESX1 and the GH-releasing hormone receptor (GHRHr). In addition, magnetic resonance imaging is the best available imaging method for the evaluation of size and structure of the pituitary and the parasellar region.

Adolescent↗
PubMed2001

Comparison of androgen receptor and oestrogen receptor beta immunoexpression in the testes of the common marmoset (Callithrix jacchus) from birth to adulthood: low androgen receptor immunoexpression in Sertoli cells during the neonatal increase in testosterone concentrations.

The aims of this study were: (i) to investigate the cellular immunoexpression of androgen receptor and oestrogen receptor beta in the testes of the common marmoset (Callithrix jacchus) during neonatal life compared with their expression at later ages; (ii) to establish whether neonatal marmoset Sertoli cells are targets for androgens or oestrogens or both; and (iii) to investigate the relationship between neonatal plasma testosterone concentrations and androgen receptor immunoexpression by abolishing the neonatal testosterone surge with a potent GnRH antagonist. Androgen receptor and oestrogen receptor beta immunoexpression were evaluated in neonatal animals aged 1-4 days, 4 weeks and 6 weeks, and compared with immunoexpression in animals aged 18-22 weeks (early infancy), 35 weeks (late infancy), 58-62 weeks (late pubertal) and > 100 weeks (adult). Immunoexpression of androgen receptor in the reproductive tract was also evaluated at each age. Sertoli cell immunoexpression of androgen receptor was weak or absent in neonatal animals, but increased substantially in infant animals, reaching adult levels by the end of infancy. In contrast, immunoexpression of androgen receptor during the neonatal period was strong in testicular interstitial cells and very strong in epithelial cell nuclei throughout the reproductive tract, and did not change greatly with age in these cells or tissues. Similarly, immunoexpression of oestrogen receptor beta was prominent in many Sertoli cells and in the germ cells of neonatal animals, and was relatively constant throughout life. Weak immunoexpression of androgen receptor in neonatal Sertoli cells was associated with high plasma testosterone concentrations (2.7-5.5 ng ml(-1)), whereas strong Sertoli cell immunoexpression was associated with baseline (approximately 0.12 ng ml(-1)) testosterone concentrations in infant animals and with > 10 ng ml(-1) in late pubertal and adult animals. Immunoexpression of androgen receptor and oestrogen receptor beta was also evaluated in co-twin males aged 4 and 35 weeks, after treatment from birth to 4 weeks or from week 25 to week 35, respectively, with either vehicle or with GnRH antagonist at a dose known to suppress the neonatal testosterone surge completely. Only GnRH antagonist treatment during weeks 25-35 reduced androgen receptor immunoexpression, whereas immunoexpression of oestrogen receptor beta was unaffected by treatment during either period. On the basis of these findings it is suggested that: (i) neonatal marmoset Sertoli cells may be targets primarily for oestrogens rather than androgens; (ii) androgen receptor expression in the testes of neonatal and infant marmosets is not regulated in a straightforward way by testosterone; and (iii) high neonatal concentrations of plasma testosterone are not absolutely necessary for expression of androgen receptor in marmoset testes at this time.

Aging↗
PubMed2000

Growth hormone therapy in noonan syndrome.

Noonan syndrome (NS) is an autosomal dominant disorder that can be difficult to diagnose. Growth retardation is a consistent feature, however, and although children are not typically growth hormone (GH) deficient, a minority may have suboptimal GH levels. An ongoing multicentre study examining the safety and efficacy of GH therapy in NS showed increases in height standard deviation scores (SDS; p < 0. 0001) and height velocity (p < 0.0001) after 12 months of GH at pharmacological doses. There was no increase in mean maximal cardiac left ventricular wall thickness during the 12-month treatment period. Long-term follow-up data covering 3 years of GH therapy showed sustained increases in height SDS and height velocity compared with baseline (p < 0.02). Further large and appropriately controlled studies of high-quality design are essential to further our understanding of NS and to establish the long-term safety and efficacy of GH.

Adolescent↗
PubMed2000

Bone turnover and growth during and after continuing chemotherapy in children with acute lymphoblastic leukemia.

Children treated for acute lymphoblastic leukemia may develop reduced bone mineral density during treatment, but there is little information on the mechanisms involved. In a prospective, longitudinal study on 15 children with ALL, we undertook serial measurements of markers of bone and collagen turnover, insulin-like growth factor (IGF)-I and its binding proteins (IGFBPs)-3 and -2 during the second year of continuing chemotherapy. In eight patients we also measured lower leg length by knemometry. Height SD scores, lower leg length velocity, IGF-I, and markers of bone collagen turnover did not differ significantly from healthy children. However, bone alkaline phosphatase, a marker of the differentiated osteoblast, was lower (mean SD score, -0.64; p < 0.0001), whereas procollagen type III N-terminal propeptide (P3NP, a marker of soft tissue collagen turnover; mean SD score, +0.93, p < 0.05), IGFBP-3 (mean SD score, +0.76; p < 0.01), and IGFBP-2 (mean SD score, +1.24, p = 0.01) were all higher than in healthy children. IGFBP-3 decreased during episodes of afebrile neutropenia (p < 0.05). Within 3 mo after completion of treatment, bone ALP increased in all eight patients, but collagen markers showed little change. IGFBP-2 returned to normal posttreatment, but P3NP and IGFBP-3 remained significantly elevated compared with healthy children (mean SD scores, +1.51 and +1.36, respectively; p < 0.01). We conclude that continuing chemotherapy was associated with normal growth and bone collagen turnover but enhanced soft tissue collagen turnover. Bone bone alkaline phosphatase was low throughout treatment, which suggests impaired osteoblast differentiation resulting from a direct effect of chemotherapy on bone. Although the effect was reversible, the long-term implications for bone health in survivors remain uncertain.

Adolescent↗
PubMed2000

The boom that never was: results of a 10 year audit of paediatric growth hormone prescribing in Scotland.

OBJECTIVE: To investigate trends in paediatric growth hormone (GH) prescribing in Scotland. DESIGN: Annual audit of paediatric GH patients, analysed by geographical distribution, diagnosis, age and duration of treatment, dosage, sex ratio and prescribing body. SUBJECTS AND SETTING: Paediatric patients receiving GH who attended the four tertiary referral centres in Scotland: Glasgow, Edinburgh, Dundee and Aberdeen, from 1990-1999. RESULTS: The annual total number of paediatric GH recipients ranged from 296-393. The maximum was recorded in 1994, with a progressive decline thereafter. The latest total (296, 1999) represents a 19% decrease since 1990. There is a marked disparity between these figures and projections published by the Scottish Office Clinical Research and Audit Group (CRAG) in 1990 of 500 patients in 1995 and 600 by 2000. CRAG postulated that GH would prove efficacious in a wider range of conditions, that the number of survivors of childhood cancer would increase and that GH therapy would continue following clinical trials. While there has been a relative increase in oncology survivors during the 10-year period, the overall decline in numbers is largely attributable to familial short stature patients in whom there has been a five fold decrease, following completion of clinical trials of GH. The number of children classified "idiopathic growth hormone deficient" has also decreased, as the overlap between this condition and normal variant short stature is increasingly recognised. CONCLUSION: This expensive drug is being used relatively conservatively in Scotland, in the light of research experience. While a small degree of ad hoc usage is inevitable, we strongly support participation in national trials wherever possible. The adoption of an open approach with the Scottish Office regarding GH usage has proved beneficial in alleviating fear of escalating costs and preventing prescribing problems in a country in which 98% of GH is prescribed by general practitioners.

Adolescent↗
PubMed1999

Effects of a third intensification block of chemotherapy on bone and collagen turnover, insulin-like growth factor I, its binding proteins and short-term growth in children with acute lymphoblastic leukaemia.

Children with acute lymphoblastic leukaemia (ALL) have reduced bone turnover caused by the disease itself and early intensive chemotherapy, but the effects of later chemotherapy using different drug combinations are uncertain. We report here a longitudinal study on 9 children with ALL randomised to receive an additional third intensification block of chemotherapy, compared with 9 children receiving continuing chemotherapy over the same period. During third intensification, bone alkaline phosphatase, procollagen type I C-terminal propeptide, the carboxyterminal propeptide of type I collagen, procollagen type III N-terminal propeptide and lower leg length all decreased in response to dexamethasone, then returned to (but not beyond) baseline levels after dexamethasone was stopped and other drugs started. These changes were unrelated to circulating insulin-like growth factor (IGF)-I, IGF binding protein (IGFBP)-3 or IGFBP-2. In all children, bone alkaline phosphatase remained below the population mean throughout. We conclude that dexamethasone decreased bone and soft tissue turnover, probably through direct effects on target tissues. The postdexamethasone phase of third intensification and continuing chemotherapy had no major deleterious effect on collagen turnover, but there was evidence of continuing suboptimal bone mineralisation.

Adolescent↗
PubMed1999

Ovarian and uterine characteristics after total body irradiation in childhood and adolescence: response to sex steroid replacement.

OBJECTIVE: To study the effect of total body irradiation (14.4 Gray) in childhood and adolescence on ovarian and uterine characteristics, and to investigate the response to physiological sex steroid serum concentrations. DESIGN: All long term post-pubertal female survivors of total body irradiation who had been treated in paediatric centres in Scotland were identified. Their ovarian and uterine characteristics were studied. SETTING: Recruitment was from follow up oncology clinics. SAMPLE: Nine women were identified, eight of whom were assessed and five progressed to detailed investigation. A control population of 12 women treated for acute leukaemia, but not treated with total body irradiation, and five healthy women with no history of childhood malignancy were recruited as controls. METHODS: Ovarian function was determined by measurement of serum gonadotrophins and sex steroids. Uterine response to physiological sex steroid replacement was investigated in women with ovarian failure, and to endogenous sex steroid production in women with ovarian function by ultrasound scan. The physiological sex steroid replacement was achieved with transdermal oestradiol patches and self administered vaginal progesterone pessaries. MAIN OUTCOME MEASURES: Determination of ovarian function and uterine response to physiological sex steroid serum concentrations. RESULTS: Six of eight women treated with total body irradiation had ovarian failure; preservation of function was seen in two girls treated pre-pubertally who had biochemical evidence of incipient ovarian failure. Four women with ovarian failure had reduced uterine volume, undetectable blood supply and absent endometrium at baseline assessment; after three months of physiological sex steroid replacement treatment uterine blood supply and endometrial response were not significantly different from controls; uterine volume improved but remained significantly smaller than controls and correlated with age at total body irradiation. CONCLUSIONS: Ovarian failure after total body irradiation is common and risk relates to age at treatment. Physiological sex steroid replacement improved uterine measures and these women may benefit from assisted reproductive technology.

Adolescent↗
PubMed1999

A decade of growth hormone treatment in girls with Turner syndrome in the UK. UK KIGS Executive Group.

Fifteen per cent of children treated with growth hormone (GH) are receiving treatment for Turner syndrome, but few results are available on final height in the UK. In this study, data were obtained from the UK KIGS database for 485 girls with Turner syndrome who were treated from 1986, allowing an audit of practice and outcome over 10 years. Over the decade, the mean age of starting growth hormone treatment fell from 10.4 to 8.5 years and the starting dose increased from 0.55 to 0.95 IU/kg/week. The frequency of injections increased from three to six or seven/week. Some girls received suboptimal doses, which also differed depending on whether they were based on weight or surface area. To assess what height gain might be expected at final height, all 52 girls who were prepubertal at the start of treatment, which continued for four years or more, and who had reached final height or had a growth velocity < 2 cm/year were selected. Their mean gain in final height was 5.2 cm and the GH dose was 0.78 IU/kg/week over 5.8 years. Final height gain correlated significantly with duration of treatment, total dose received, and first year response, which itself related to starting dose. This audit shows a changing pattern of treatment over the past decade, which in many instances has been inadequate. When treatment starts before puberty and continues through to final height, with a dose of 30 IU/m2/week in six or seven injections, a mean increase in final height of 5 cm or more would be expected.

Adolescent↗
PubMed1999

Should we treat children with idiopathic short stature?

The use of growth hormone (GH) to treat short children who are clearly GH-deficient is now well accepted. However, GH treatment of short children who have no currently recognizable abnormalities in their GH-insulin-like growth factor I axis remains controversial. Whether such children with so-called idiopathic short stature (ISS) should be treated with GH was the subject of an international workshop held in St.-Paul-de-Vence, France, in April 1999. This article summarizes the issues discussed at the workshop, including the definition of ISS, ethical and health-economic aspects of treatment, results from clinical trials and surveillance studies, and the use of prediction models in aiding treatment decisions.

Body Height↗
PubMed1999

Bone and collagen markers in preterm infants: relationship with growth and bone mineral content over the first 10 weeks of life.

In a longitudinal study of 25 preterm infants, we have examined the relationship of bone-specific alkaline phosphatase (ALP), C-terminal propeptide of type I collagen (PICP), N-terminal propeptide of type III procollagen (P3NP), C-terminal telopeptide of type I collagen, urinary pyridinoline (Pyd) and deoxypyridinoline (Dpd), with rates of gain in weight, length, and lower leg length and with bone mineral content (BMC), all measured at weekly intervals over the first 10 wk of life. Concentrations of all collagen markers were 10-fold higher than in older children. Each marker showed a distinctive pattern of postnatal change, with early increases in PICP and P3NP and decreases in ICTP reflecting postnatal growth. Once markers had reached a plateau during weeks 4-10, P3NP was positively correlated, whereas Pyd and Dpd were negatively correlated with rate of weight gain (r = +0.44, -0.46, and -0.40, respectively, p < 0.05). P3NP was also positively correlated with overall linear growth (r = +0.44, p < 0.05). PICP was strongly correlated with mean BMC (r = +0.63,p < 0.01) and with total BMC attained by the end of the study period (r = +0.81, p < 0.001). Bone ALP was positively correlated with the rate of bone mineral accretion (r = +0.55, p = 0.01). We conclude that the marker of soft-tissue collagen formation, P3NP, is a good marker for overall ponderal and linear growth in preterm infants, whereas the markers of collagen breakdown, Pyd and Dpd, have inverse relationships with weight gain. The osteoblast markers, PICP and bone ALP, seem to be good surrogate markers for bone mineralization in preterm infants. Markers may provide information on whole-body turnover of bone and collagen that is complementary to traditional physical measures of growth and bone mineralization.

Alkaline Phosphatase↗
PubMed1998

Hypoglycaemic symptoms reported by children with type 1 diabetes mellitus and by their parents.

To compare the hypoglycaemic symptoms reported by children with Type 1 diabetes and signs observed by and symptoms reported to their parents, 101 pairs, consisting of a child with diabetes and one of their parents, were asked to report the frequency with which they experienced, or witnessed, each of 31 symptoms during hypoglycaemia. The hypoglycaemic symptoms reported by the children and the reported symptoms and signs observed by their parents were classified, using multivariate statistical analyses, and compared. Close agreement was observed between the children and their respective parents' scores for frequencies of most symptoms/signs, as demonstrated by Spearman's rank correlations (median tau s = 0.25, p < 0.02). Principal Components Analysis of the symptoms/signs observed by the parents showed three factors: autonomic, neuroglycopenic, and behavioural disturbance. Analysis of the symptoms experienced by the children also identified three factors: behavioural disturbance, malaise and a third factor consisting of a combination of autonomic and neuroglycopenic symptoms. The parents could differentiate three separate groups of reported hypoglycaemic symptoms and signs (autonomic, neuroglycopenic, and behavioural disturbance) in their children. The children reported a similar group of behavioural symptoms but did not discriminate between autonomic and neuroglycopenic symptoms. These findings have important implications for the education of parents and children with Type 1 diabetes regarding the symptoms and signs of hypoglycaemia.

Adolescent↗