Dynamics of continental accretion.

Subduction zones become congested when they try to consume buoyant, exotic crust. The accretionary mountain belts (orogens) that form at these convergent plate margins have been the principal sites of lateral continental growth through Earth's history. Modern examples of accretionary margins are the North American Cordilleras and southwest Pacific subduction zones. The geologic record contains abundant accretionary orogens, such as the Tasmanides, along the eastern margin of the supercontinent Gondwana, and the Altaïdes, which formed on the southern margin of Laurasia. In modern and ancient examples of long-lived accretionary orogens, the overriding plate is subjected to episodes of crustal extension and back-arc basin development, often related to subduction rollback and transient episodes of orogenesis and crustal shortening, coincident with accretion of exotic crust. Here we present three-dimensional dynamic models that show how accretionary margins evolve from the initial collision, through a period of plate margin instability, to re-establishment of a stable convergent margin. The models illustrate how significant curvature of the orogenic system develops, as well as the mechanism for tectonic escape of the back-arc region. The complexity of the morphology and the evolution of the system are caused by lateral rollback of a tightly arcuate trench migrating parallel to the plate boundary and orthogonally to the convergence direction. We find geological and geophysical evidence for this process in the Tasmanides of eastern Australia, and infer that this is a recurrent and global phenomenon.

Torque removal force for osseointegrated implants--two experimental studies.

OBJECTIVE: To introduce a rabbit-based model for testing the torque removal force (TRF) of implants and to compare the TRF of a series of titanium implants. METHODS: Two experiments were performed at the University of the Witwatersrand. In the first, a Swedish- (SSM-N) or a South African-manufactured (SSM-S) implant was implanted into the tibiae of 12 rabbits and the TRF measured at 1, 3 and 6 months. In the second experiment, the TRF of 4 South African-manufactured titanium implants in the tibia or femur of 32 rabbits were compared at 3 and 6 weeks. The implants were: 1 threaded machined (SSM-S), and 3 surface-enhanced--1 threaded (SLA), 1 threaded tapered (MTT) and 1 pitted (RI). RESULTS: In experiment 1, TRF increased significantly with time (p<0.05) but there was no significant difference between TRF for the South African and Swedish machined-surface implant types. In experiment 2, the TRF of the MTT implant was significantly greater (p<0.0001) than the other 3 types, which did not differ significantly from each other. Time had no significant effect. CONCLUSION: In an internationally used rabbit-based model, South African and Swedish machined-surface titanium implants were equivalent; surface-enhanced implants produced higher TRF, and a tapered implant showed the highest TRF.

Increasing body weight predicts the earlier onset of insulin-dependant diabetes in childhood: testing the 'accelerator hypothesis' (2).

AIMS AND METHODS: It has recently been hypothesized that weight gain in childhood accelerates the onset of Type 1 diabetes, as well as increasing its risk, and that Type 1 diabetes and Type 2 diabetes may be one and the same disorder of insulin resistance. An explanation is needed for the rising incidence of childhood diabetes and, to test the Accelerator Hypothesis, we examined the anthropometric measurements recorded from birth in 168 young people presenting with Type 1 diabetes between 1980 and 2002. Pre-onset as well as peri- and post-onset measurements of height and weight were available, and waist circumference was recorded at various intervals after onset. RESULTS: The mean birth weight of the children and their height, weight and body mass index (BMI) at diagnosis lay close to the population mean. However, pre-onset and post-onset BMI were both well above the population mean, were closely correlated with each other (r = 0.79, P < 0.001) and (inversely) with age at onset (r = -0.30, P < 0.001). A significant correlation was also found between BMI standard deviation scores (sds) and year of diagnosis (r = 0.27, P < 0.001) and, importantly, waist circumference sds in the children with Type 1 diabetes was found to be substantially greater than average for the population [boys: +0.96 (sd 1.04), girls: +1.30 (sd 0.89)]. CONCLUSIONS: The data suggest that children with Type 1 diabetes have become progressively heavier at diagnosis over the past 20 years, and that the heavier child develops it earlier. Waist circumference, a proxy for visceral fat mass and insulin resistance, is substantially greater in children with Type 1 diabetes. Weight centile crossing appears to be an important environmental accelerator which may contribute to or account for the striking increase in both Type 1 diabetes and Type 2 diabetes in childhood. A reduction of body weight and improved lifestyle might reverse this trend in both types of diabetes.

Clinical features, diagnosis, treatment and molecular studies in paediatric Cushing's syndrome due to primary nodular adrenocortical hyperplasia.

BACKGROUND: Primary nodular adrenocortical hyperplasia (PNAH) is a well recognized, but infrequently studied cause of paediatric Cushing's syndrome (CS). OBJECTIVE: To assess presentation, diagnosis, radiological imaging, treatment and molecular analysis of patients with childhood-onset CS due to PNAH. PATIENTS: Four males and two females (median age 12.9 years, range 10.9-16.9 years) were studied. RESULTS: All had growth failure (mean height SDS -1.2; range -2.5-0.0), weight gain [mean body mass index (BMI) SDS 3.5; range 2.5-4.6] and clinical virilization, while five had hypertension [mean systolic blood pressure (SBP) 130 mmHg, diastolic blood pressure (DBP) 83 mmHg]. One patient had generalized lentigines, one had a tibial chondromyxomatous cyst and two had facial freckling. One patient had a family history of primary nodular adrenocortical disease. The diagnosis of CS was based on elevation of sleeping midnight serum cortisol and urinary free cortisol excretion, and impaired suppression of cortisol on both low- and high-dose dexamethasone suppression tests (DST). All patients had undetectable plasma ACTH with absent responses of both plasma ACTH and serum cortisol to an intravenous (i.v.) corticotrophin-releasing hormone (CRH) test. Computed tomography or magnetic resonance imaging showed normal or small adrenals, with nodules in two patients. All patients underwent bilateral adrenalectomy, performed by open (n = 2) or laparoscopic surgery (n = 4) at a mean of 0.4 years (range 0.2-0.8 years) from diagnosis. Hypercortisolaemia was treated preoperatively by metyrapone alone 0.50-0.75 g/day (n = 4), metyrapone 0.75-1.50 g/day + o'p'DDD/mitotane 1-2 g/day (n = 1), or ketoconazole (n = 1). Adrenal histology showed nodular cortical hyperplasia with shrinkage of intervening cortical tissue and pigmentation, present in four patients. Molecular analysis of the type 1-alpha regulatory subunit of protein kinase A (PRKAR1A) gene revealed a novel germline mutation in one patient. Postadrenalectomy, three patients, had catch-up growth with height velocities increasing from 3.0, 3.9 and 2.5-8.9, 8.3 and 9.0 cm/years, respectively. All six are well at a follow-up (mean 4.0 years; range 0.5-10.8 years). CONCLUSIONS: PNAH was associated with cushingoid features, virilization and hypertension with a lack of cortisol suppression on high DST, undetectable plasma ACTH and absent cortisol and ACTH responses to CRH. Adrenals were normal or small on imaging. PRKAR1A gene analysis may be helpful in the assessment of these patients.

An assessment of pancreatic endocrine function and insulin sensitivity in patients with transient neonatal diabetes in remission.

AIMS: To examine derived indices of beta cell function, peripheral insulin sensitivity, and the pancreatic response to intravenous glucose loading in children with a previous history of transient neonatal diabetes currently in remission, repeated after a period of two or more years. METHODS: The standard intravenous glucose tolerance test (IVGTT) was used to measure the first phase insulin response (FPIR) cumulatively at one and three minutes. In addition, fasting insulin and glucose values were used to estimate insulinogenic indices (beta cell function) and QUICKI (insulin sensitivity). PATIENTS: Six patients with known previous transient neonatal diabetes currently in remission with no exogenous insulin requirement were tested. Control data from 15 children of a similar age were available for derived fasting indices of beta cell functional capacity and insulin sensitivity. RESULTS: One child had a subnormal insulin secretory response to intravenous glucose that remained abnormal two and four years later. The other children had relatively normal or entirely normal responses over two years. Measures of beta cell function and insulin sensitivity in the fasting state showed comparable results to those obtained from normal controls. CONCLUSIONS: Most children with transient neonatal diabetes in remission have no evidence of beta cell dysfunction or insulin resistance in the fasting state, although they might have been expected to show subtle defects given the tendency to relapse in adolescence. Measures of insulin response to intravenous glucose loading are often normal but suggest future recurrence if profoundly abnormal.

Congenital hypothyroidism and apparent athyreosis with compound heterozygosity or compensated hypothyroidism with probable hemizygosity for inactivating mutations of the TSH receptor.

OBJECTIVE: We wished to ascertain whether mutations in the TSH receptor (TSHR) gene were present in two siblings with congenital hypothyroidism with no parental consanguinity. DESIGN: The pituitary-thyroid axis and thyroid gland morphology were investigated in both affected siblings and their parents. The TSHR gene was analysed in each subject. MEASUREMENTS: Basal thyroid function together with circulating thyroglobulin levels were measured in each subject. In addition, a TRH stimulation test was undertaken in each parent. All family members underwent thyroid ultrasonography. The TSHR gene was amplified from genomic DNA using the polymerase chain reaction and receptor mutations were identified by sequence analysis. RESULTS: Two siblings were diagnosed with severe congenital hypothyroidism (total T4 19-21 nmol/l, TSH 160-230 mU/l on neonatal screening). Although radioiodine scanning showed no tracer uptake and ultrasound imaging in both individuals failed to demonstrate thyroid tissue, suggesting complete athyreosis, circulating thyroglobulin levels were measurable. The thyroid status of the parents was discordant: in the father, baseline thyroid function (FT4 13 pmol/l, TSH 4 mU/l), the peak TSH level after TRH stimulation (30 mU/l) were normal and he exhibited an appropriate rise in circulating thyroid hormones in response to the elevated TSH; in contrast, in the mother, baseline thyroid function was abnormal (FT4 10 pmol/l, TSH 15 mU/l), the TSH response to TRH was exaggerated (110 mU/l), with no subsequent rise in circulating thyroid hormones. An eutopic, slightly hypoplastic thyroid gland was visualized on ultrasonography in the mother and her thyroid antibody status was negative. Both children were compound heterozygotes for missense (alanine to threonine at codon 553, A553T) and premature stop (tryptophan at codon 546, W546X) mutations in the fourth transmembrane domain of the TSH receptor. The mother and father were heterozygous for W546X and A553T mutations, respectively. Each mutation is known to abolish the function or cellular surface expression of the TSH receptor. CONCLUSIONS: Inactivating mutations in the TSH receptor can be associated with severe TSH resistance presenting as congenital hypothyroidism with apparent athyreosis. Our observations also suggest that heterozygosity for an inactivating TSHR mutation may be associated with compensated hypothyroidism and thyroid hypoplasia.

Personality functioning: the influence of stature.

BACKGROUND: The Wessex Growth Study has monitored the psychological development of a large cohort of short normal and average height control participants since school entry. AIMS: To examine the effect of stature on their personality functioning now that they are aged 18-20 years. METHODS: This report contains data from 48 short normal and 66 control participants. Mean height SD score at recruitment was: short normals -2.62 SD, controls -0.22 SD. Final height SD score was: short normals -1.86, controls 0.07. The Adolescent to Adult Personality Functioning Assessment (ADAPFA) measures functioning in six domains: education and employment, love relationships, friendships, coping, social contacts, and negotiations. RESULTS: No significant effect of recruitment height or final height was found on total ADAPFA score or on any of the domain scores. Socioeconomic status significantly affected total score, employment and education, and coping domain scores. Gender had a significant effect on total score, love relationships, coping, and social contacts domain scores. Salient aspects of daily living for this sample were identified from the interviews (prevalence%): consuming alcohol (94%), further education (63%), love relationships (55%), current drug use (29%), experience of violence (28%), parenthood (11%), and unemployment (9%). Stature was not significantly related to behaviour in any of these areas. CONCLUSIONS: Despite previously reported links between short stature and poorer psychosocial adaptation, no evidence was found that stature per se significantly affected the functioning of the participants in these areas as young adults.

Diabetes care in childhood and adolescence.

The presentation of diabetes in young people has changed significantly over recent years. Not only has there been a rising incidence of Type 1 diabetes, especially in young children, but also there is an increasing recognition of Type 2 diabetes. Young people are also increasingly being diagnosed with genetic defects of B-cell function and with diabetes in association with cystic fibrosis and other chronic diseases. There have also been significant changes in the pattern of paediatric diabetes care. This is increasingly being provided by a specialized paediatric multidisciplinary team in each health district working to agreed national standards. Despite improvements, diabetes control is still suboptimal with a high incidence of complications being reported in young adults. The challenge over the next few years is the provision of a uniform, equitable and first class paediatric service throughout the UK together with the introduction of new approaches to care, aiming to improve individual diabetic control and reduce long-term complications. Increased collaboration with adult colleagues is needed to enable the transition of care in adolescence to a service that young adults perceive to meet their needs, encourage their attendance and improve their diabetes control and quality of life. A national paediatric diabetes register together with regular audit will encourage these objectives.

Type 2 diabetes in obese white children.

We report four white adolescents aged 13 to 15 years (three females, one male) from the south and west region of England who presented with type 2 diabetes mellitus associated with significant obesity (body mass index more than +3SDS) in the past two years. Although these are the first reported obese, white cases from the UK to present with diabetes, we believe this clinical scenario will become more prevalent given the epidemic of childhood obesity in this country.

Longitudinal study of urinary albumin excretion in young diabetic patients--Wessex Diabetic Nephropathy Project.

AIMS: This study was established to follow changes in albumin/creatinine ratio (ACR) and to determine the prevalence and degree of progression of microalbuminuria (MA) or of clinical proteinuria (CP) in children with Type 1 diabetes. The study has investigated subjects for up to 12 years in establishing the correlation between MA and gender, age, duration of diabetes and glycated haemoglobin (HbA1c). The study has defined clinical cut-offs for MA in daytime clinic urine samples in young diabetic subjects. METHODS: Three hundred and sixty-one patients were involved in the study, with 221 (61.2%) having over six sets of data. Urine samples were collected at routine annual clinic visits and analysed without prior freezing for ACR. Blood samples were taken for HbA1c measurement. Data including sex, age and duration of diabetes were recorded. RESULTS: A random clinic ACR of < 4.5 mg/mmol (males) and 5.2 mg/mmol (females) creatinine was used as the 'clinical cut-off' to define the presence of MA. The presence of MA was independent of HbA1c and duration of diabetes but appeared be associated with the adolescent years (> 10 years). There was little evidence of progression from normoalbuminuria to MA, or from MA to CP. Of patients aged 10-18 years, 30.9% of males and 40.4% of females had one or more episodes of MA. CONCLUSIONS: Persistent MA and random episodes of MA or CP may be associated with the adolescent years but not with duration of diabetes. Further study will reveal if the substantial increases in ACR sometimes seen during adolescence are predictive of diabetic nephropathy. Clinical cut-offs of < 4.5 and < 5.2 mg/mmol creatinine for males and females, respectively, are suggested for the interpretation of changes in ACR in random urine samples in young people with Type 1 diabetes.

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.

Hormones and handedness.

BACKGROUND: The Wessex Growth Study has monitored the growth and psychological development of short normal (SN) and average height control subjects since they entered school in 1985/1986. During psychometric testing, we found that 25% SN compared to 9% control subjects wrote with their left hand. The short group also attained significantly lower scores on measures of IQ and attainment and displayed less internalisation of control. Laterality, however, is thought to be influenced by the intrauterine environment and has been associated with pubertal delay. At recruitment, short children had a relatively low birth weight, delayed bone age and were more likely than controls to be short for family. OBJECTIVES: To determine if birth conditions were associated with lateral preference and whether laterality could account for the differences found during the psychometric assessment or predict pubertal timing of SN children. METHODS: Subjects were classified as right- (RH) or left-handed (LH) according to the writing hand and the data were investigated examining the effect of handedness and stature. RESULTS: RH and LH SN children were no more likely to suffer birth complications than those of average height. Psychometric testing did not reveal any significant differences between RH and LH SN children and their patterns of growth appeared to be similar. However, both RH and LH SN children scored less well on tests of cognitive ability and analyses of covariance revealed significant gender/handedness effects for both the timing of puberty and final height. CONCLUSIONS: The increase in left-handedness among SN children did not appear to be related to adverse birth conditions, but it may be that the hormones responsible for growth and development also play some part in brain laterality and cognitive development.

A multicentre trial of recombinant growth hormone and low dose oestrogen in Turner syndrome: near final height analysis.

BACKGROUND: Turner syndrome accounts for 15-20% of childhood usage of growth hormone (GH) in the UK but final height benefit remains uncertain. The most effective strategy for oestrogen replacement is also unclear. METHODS: Fifty eight girls who, at start of treatment, were of mean age 9.1 years and projected final height 142.2 cm were randomised to receive in year 1, either low dose ethinyloestradiol 50-75 ng/kg/day, GH 28 IU/m(2) surface area/week as a daily injection, or a combination of ethinyloestradiol and GH. After the first year, the ethinyloestradiol treated girls received combination treatment. After two years, girls aged over 12 years were given escalating ethinyloestradiol to promote pubertal development. RESULTS: Near final height was available for 49 girls at age 16.5 years, 146.8 cm, representing a gain of 4.6 cm, range -7.9 to +11.7 cm. Twelve of the 49 girls gaining 7.5 cm or more were less than 13 years at the start and had received GH for at least four years. Height gain was correlated with greater initial height deficit. Fifteen girls (31%) reached 150 cm or more compared to a predicted 10%. Early supplementation with ethinyloestradiol provided no final height advantage. CONCLUSIONS: Final height gain was modest at 4.6 cm. Younger, shorter girls gained greatest height advantage from GH. Low dosage ethinyloestradiol before planned induction of puberty was not beneficial.

Pancreatic exocrine insufficiency and type 1 diabetes mellitus.

Studies in adults suggest that some patients with type 1 diabetes mellitus have pancreatic exocrine insufficiency (PEI). The primary aim of this study was to explore the association between pancreatic exocrine function and type 1 diabetes in young people under 17 years. The secondary aim was to evaluate the relationship between PEI in patients with diabetes, their clinical symptoms and blood glucose control. The importance of providing a highly trained multidisciplinary support network are also discussed.

An assessment of paediatric diabetes care in three centres in Russia and in Southampton, UK. The Paediatric Teams in Moscow, Tula, Tambov, Southampton.

AIMS: Young people in Russia with diabetes have an increased morbidity and a 10-fold increase in mortality compared with many European countries. This joint international study was set up to compare of care and outcomes against published guidelines in three Russian centres and one UK centre. METHODS: An assessment of the diabetic care of 368 children, based on the principles of the St Vincent Declaration, was undertaken in each centre. Data on prevalence, management, control and complications were collected in young people with diabetes < 16 years of age in each of the four centres over a 4-week period. RESULTS: The prevalence of diabetes was greater in Southampton (1:702 vs. 1:1378). At diagnosis Russian children had a higher incidence of ketoacidosis (69 vs. 29%) and stayed in hospital longer (30 vs. 3 days). In management Russian children received more injections per day (5 vs. 2). There was no significant difference in insulin dose for those under 10 years between countries (Southampton 0.69 U/kg vs. Russian 0.73 U/kg, P=NS). Older Russian children did not increase their insulin dosage, while children over 10 years in Southampton received significantly more insulin than the Russian children (Southampton 1.0 U/kg vs. Russian 0.77 U/kg, P< or =0.001). Twenty-nine per cent of the Russian children reported that they had insufficient insulin and 14% had to buy extra. HbA1c was higher in the Russian children (9.8% vs. 8.3%), increasing significantly with age. The Russian children showed a height deficit which correlated with HbA1c and diabetes duration. The Southampton children were heavier and with a higher body-mass index and their HbA1c did not rise similarly as in Russia. Severe hypoglycaemia was more common in the Southampton children (32 vs. 12%). Retinopathy was reported in 12% of the Russian children (Southampton 0%) and systolic blood pressure > 95th centile in 21% (Southampton 8%). CONCLUSIONS: This study demonstrates a significant difference in diabetic control and complications between the two countries which could be partially explained by a decreased availability and prescribing of insulin and blood glucose monitoring in Russia. Southampton has an education and management policy based on ambulatory care resulting in reduced hospital stay.

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.

Pubertal growth of the short normal girl.

OBJECTIVES: To determine the timing, magnitude and duration of the pubertal spurt for short normal and average height girls, to compare these with Tanner's standard and to investigate predictors of pubertal growth. METHODS: The growth of 46 short normal and 55 control girls, identified at school entry, was monitored throughout puberty. Height and weight were measured at 6-month intervals from which body mass index (BMI) was derived. Annual velocities were calculated and used to estimate the age and magnitude of peak height velocity (PHV). Age of menarche was recorded to the nearest month. Parents provided information on the child's medical and social history. RESULTS: The mean age at PHV, the magnitude of PHV and age at menarche were similar for both groups and close to Tanner's 50th centile values. Pre-pubertal BMI predicted age at menarche for short and control girls, accounting for 17% of the variance. There was a tendency for early maturing girls of average stature to have greater PHV. However, this relationship was not observed in short girls, nor did any other variable, genetic or environmental, predict the timing or magnitude of their pubertal spurt. CONCLUSIONS: Delayed puberty in short normal girls is unlikely and their growth during puberty is comparable to girls of average height. The pubertal variables measured remain close to Tanner's original standards for both groups, suggesting the lack of a secular trend towards earlier puberty in girls. The onset of menstruation is influenced by pre-pubertal BMI. However, the clinician should be aware that short normal girls have normal pubertal growth and that no genetic or environmental variable can predict the timing or magnitude of their growth spurt.