A will and a way to fund medicines for rare diseases: the story of human growth hormone replacement for adults with growth hormone deficiency.

Growth hormone (GH) replacement therapy was recently recommended by the Pharmaceutical Benefits Advisory Committee (PBAC) for listing on the Pharmaceutical Benefits Scheme for adults with severe GH deficiency and impaired quality of life. This approval was significant for two reasons. First, the application was initiated and coordinated by a health professional working group, who prepared a 'public interest' submission to PBAC. Second, it resulted in a recommendation to subsidise therapy for a rare disease after two prior rejections on the basis of uncertainty about efficacy and cost effectiveness. There are important lessons to learn about the power of professional groups to drive health policy and attain funding for rare diseases.

Impaired bone and muscle development in young people treated with antiepileptic drugs.

OBJECTIVE: Antiepileptic drugs (AEDs) are associated with reduced bone density, balance impairment, and increased fracture risk in adults. However, pediatric data are limited. Therefore, we aimed to examine bone, muscle, and balance outcomes in young patients taking AEDs. METHODS: We undertook a case-control study utilizing an AED exposure-discordant matched-pair approach. Subjects were aged 5-18 years with at least 12 months of AED exposure. Pairs were twins, nontwin siblings and first cousins, sex- and age-matched (to within 2 years), allowing for greater power than with unrelated control subjects. Dual energy x-ray absorptiometry (DXA), peripheral quantitative computed tomography (pQCT), and muscle force/balance were tested, with questionnaires were administered for bone health and epilepsy details. RESULTS: Twenty-three pairs were recruited, (median age 12.9 years [subjects] and 13.5 years [controls])-7 twin, 14 sibling, and 2 cousin pairs. Those taking AEDs had an increased prevalence of fractures (15 fractures in 8 subjects, compared with 4 fractures in 3 controls, p < 0.01). Trabecular volumetric bone mineral density (vBMD) measured by pQCT at the 4% site (tibia) was reduced by 14% (p = 0.03) in subjects. Subjects exerted a decreased maximum force compared to body weight (Fmax total/g) at the tibia. There were no differences seen in either bone mineral parameters measured by DXA or balance measures. SIGNIFICANCE: Young people taking AEDs reported more fractures and had reductions in tibial vBMD and lower limb muscle force compared to their matched controls. These findings suggest that further exploration of bone health issues of young patients on AED therapy is required. Longitudinal studies are required to confirm these changes in the muscle-bone unit and to further explore the clinical outcomes.

Intravenous glucagon in a deliberate insulin overdose in an adolescent with type 1 diabetes mellitus.

Massive insulin overdose may be associated with unpredictable and prolonged hypoglycemia. Concerns surrounding the potential provocation of insulin release from beta cells have previously prevented the use of intravenous glucagon as an adjunct to infusion of dextrose in this situation. We describe the case of a 15-yr-old boy with type 1 diabetes mellitus (T1DM) who presented with profound hypoglycemia following an overdose of an unknown quantity of premixed insulin. Owing to an increasing dextrose requirement and a dependence on hourly intramuscular glucagon injections, a continuous intravenous infusion of glucagon was commenced which successfully avoided the requirement for central venous access or concentrated dextrose infusion. Nausea was managed with anti-emetics. Intramuscular and subcutaneous glucagon is effective in the management of refractory and severe hypoglycemia in youth with both T1DM and hyperinsulinism. Concerns regarding the precipitation of rebound hypoglycemia with the use of intravenous glucagon do not relate to those with T1DM. This treatment option may be a useful adjunct in the management of insulin overdose in youth with T1DM and may avoid the requirement for invasive central venous access placement.

Comparison of weight- vs body surface area-based growth hormone dosing for children: implications for response.

OBJECTIVE: To compare weight (per kg)- vs body surface area (BSA, per m(2) )-based growth hormone (GH) dosing formats in children and to derive a useful conversion formula between the two formats. PATIENTS AND DESIGN: Growth hormone doses (>33,000) from 1874 children were obtained from the national Australian database (OZGROW) and used to derive conversion formulae and to confirm the accuracy of a conversion formula based on a weight-only BSA estimate. A further 27,000 doses were used to test the accuracy of all formulae. The best conversion formula was used to compare weight- and surface area-based GH dosing, which included an analysis of first year response (∆SDS height or growth velocity, GV). MEASUREMENTS: Growth hormone doses in mg/m(2) /wk and mg/kg/wk, dose estimates, residuals, first year ∆SDS, first year GV. RESULTS: The formula, [Formula: see text] based on a weight-only BSA estimate, provides accurate dose conversion (mean residual, 0·005 mg/kg/week). A constant mg/m(2) /week dose expressed in terms of mg/kg/week declines quickly with increasing body weight to approximately 15 kg after which the decline continues although less dramatically. For Australian patients, despite an increase in mean per m(2) dose with increased starting weight/age, the per kg dose decreased. This was associated with a greater decline in first year GV than estimated if a per kg dose had been maintained. CONCLUSIONS: Growth hormone doses can be accurately converted between formats. Surface area-based GH dosing is likely to result in a reduced height response as children become heavier when compared with weight-based GH dosing.

Where should we measure waist circumference in clinically overweight and obese youth?

AIMS: Waist circumference (WC) measurement is a useful tool in the assessment of overweight/obese individuals, but standard measures may miss an apron of 'overhanging' fat (termed 'panniculus'). The objective of this study was to assess whether, in clinically overweight/obese youth, 'pannicular' WC better correlates with fat mass than a standard WC measurement. METHODS: Standard and pannicular WC, alongside body composition (BC) measures, were collected from 181 consultations on 127 overweight and obese children/adolescents (52% male; mean (standard deviation) age 12.5 (3.4) years). Correlation coefficients describe associations between WC and measures of BC, and between ΔWC and ΔBC, while linear regression models assessed which of the WC measures explained more of the variability in BC and ΔBC over time. RESULTS: Standard and pannicular WC were highly correlated (r = 0.95). Correlation coefficients with measures of BC were generally greater for pannicular than standard WC, with greatest correlations seen for whole body (r = 0.94 vs. 0.85, respectively) and truncal (r = 0.86 vs. 0.77) fat mass. Furthermore, pannicular and Δpannicular WC explained more variability in truncal fat and Δtruncal fat than the standard measure of WC. CONCLUSIONS: These data show that pannicular, rather than standard, WC measurements better correlate with absolute measures of fat mass, and their change over time, in clinically overweight/obese youth.

Comparison of Centers for Disease Control and Prevention and World Health Organization references/standards for height in contemporary Australian children: analyses of the Raine Study and Australian National Children's Nutrition and Physical Activity cohorts.

AIM: (i) To compare the Centers for Disease Control and Prevention (CDC) reference and World Health Organization (WHO) standard/reference for height, particularly with respect to short stature and eligibility for growth hormone (GH) treatment by applying them to contemporary Australian children; (ii) To examine the implications for identifying short stature and eligibility for GH treatment. METHODS: Children from the longitudinal Raine Study were serially measured for height from 1991 to 2005 (2-15-year-old girls (660) and boys (702) from Western Australia). In the cross-sectional Australian National Children's Nutrition and Physical Activity survey (2-16-year-old boys (2415) and girls (2379) from all states), height was measured in 2007. Heights were converted to standard deviation scores (SDSs) based on CDC and WHO. RESULTS: Means and standard deviations of height-SDS varied between CDC and WHO definitions and with age and gender within each definition. However, both identified similar frequencies of short stature (<1st centile for GH eligibility), although these were very significantly less than the anticipated 1% (0.1-0.7%) of the Australian cohorts. Mean heights in the Australian cohorts were greater than both the WHO and CDC means. CONCLUSIONS: Neither CDC nor WHO height standardisations accurately reflect the contemporary Australian child population. Australian children are taller than the CDC or WHO height means, and significantly less than 1% of Australian children are defined as being short using either CDC or WHO. This study suggests there may be a case for an Australian-specific standard/reference for height.

Response to growth hormone treatment in Prader-Willi syndrome: auxological criteria versus genetic diagnosis.

AIM: The Australian Prader-Willi Syndrome (PWS) database was established to monitor the efficacy and safety of growth hormone (GH) treatment in PWS. This study aims to compare response to GH based on eligibility criteria. METHODS: Comparative study: 72 children received GH on the basis of short stature or evidence of GH deficiency (pre-2009: PWS-SS) and 94 on a genetic diagnosis (post-2009: PWS-Dx). We report on mandatory patient data for GH prescription: median and standard deviation score (SDS) for height and body mass index (BMI), waist/height ratio, bone age/chronological age ratio and adverse events. Comparisons were made using non-parametric tests. RESULTS: At baseline, the PWS-SS cohort was shorter (height SDS: -2.6 vs. -1.1, P < 0.001), had a lower BMI (0.6 vs. 1.5 SDS, P < 0.05) and greater bone age delay (bone age/chronological age: 0.7 vs. 0.9, P < 0.05) than the PWS-Dx cohort. PWS-SS parents were shorter (mid-parental height SDS: -0.13 vs. 0.28, P < 0.005). Mean change in height over 2 years was 0.9 SDS and in BMI using PWS reference standards -0.3 SDSPWS (n = 106) (year 2, height SDS: PWS-SS = -1.7, PWS-Dx = 0.1; BMI SDSPWS : PWS-SS = -1.0, PWS-Dx = -0.6). The waist/height ratio reduced (PWS-Dx: 0.60 vs. 0.56, P < 0.05) and bone age delay was unchanged over this period. No serious adverse events were reported. CONCLUSIONS: The PWS-SS cohort represents a subgroup of the wider PWS-Dx population; however both cohorts improved height SDS with normalisation of height in the PWS-Dx cohort and lowering of BMI relative to PWS standards supporting the efficacy of treatment under the current Australian GH programme.

Growth hormone regimens in Australia: analysis of the first 3 years of treatment for idiopathic growth hormone deficiency and idiopathic short stature.

OBJECTIVE: To investigate response to growth hormone (GH) in the first, second and third years of treatment for all idiopathic GH-deficient (GHD) and idiopathic short stature (ISS) patients in Australia. CONTEXT: Eligibility for subsidized GH treatment in Australia is determined on auxological criteria for the indication of Short Stature and Slow Growth (SSSG), which includes ISS (SSSG-ISS). The biochemical GHD (BGHD, peak GH < 10 mU/l) and SSSG indications are treated similarly: starting dose of 4·5 mg/m(2)/week with provision for incremental dosing. Some ISS patients were specifically diagnosed with familial short stature (SSSG-FSS). DESIGN: Responses for each year of treatment for BGHD, SSSG-ISS and SSSG-FSS cohorts were compared in relation to influencing variables and with international benchmarks. The effect of incremental dosing was assessed. PATIENTS: Australian BGHD, SSSG-ISS and SSSG-FSS patients who had completed 1, 2, or 3 years of treatment and were currently receiving GH. MEASUREMENTS: Growth hormone dose, change in height-standard deviation score (ΔSDS) and growth velocity (GV). RESULTS: First-year response was 2-3 times greater than that in subsequent years: ΔSDS(1st year) = 0·92, 0·50 and 0·46 for BGHD, SSSG-ISS and SSSG-FSS, respectively. Responses were similar to international reports and inversely related to age at commencement of GH. First-year GV-for-age for BGHD patients was similar to international standards for idiopathic GHD. However, girls had an inferior response to boys when treatment commenced at <6 years of age. First-year GV-for-age for SSSG-ISS/FSS patients was less than ISS standards. Dose increments attenuated the first- to second-year decline in response to BGHD but marginally improved the responses for SSSG-ISS/FSS. CONCLUSIONS: The Australian auxology-based GH programme produces comparable responses to international programmes. A lower starting dose is offset by the initiation of treatment at younger ages. Incremental dosing does not appear optimal. A first-year dose of 6·4-6·9 mg/m(2)/week for GHD and 8·9 mg/m(2)/week for ISS with early commencement of GH treatment may be most efficacious.

Effects of fluctuating glucose levels on neuronal cells in vitro.

There is increasing evidence for glucose fluctuation playing a role in the damaging effects of diabetes on various organs, including the brain. We aimed to study the effects of glycaemic variation (GV) upon mitochondrial activity using an in vitro human neuronal model. The metabolic disturbance of GV in neuronal cells, was mimicked via exposure of neuroblastoma cells SH-SY5Y to constant glucose or fluctuating (i.e. 6 h cycles) for 24 and 48 h. Mitochondrial dehydrogenase activity was determined via MTT assay. Cell mitochondrial activity (MTT) was moderately decreased in constant high glucose, but markedly decreased following 24 and 48 h of cyclical glucose fluctuations. Glucose transport determined via 2-deoxy-D-[1-(14)C] glucose uptake was regulated in an exaggerated manner in response to glucose variance, accompanied by modest changes in GLUT 1 mRNA abundance. Osmotic components of these glucose effects were investigated in the presence of the osmotic-mimics mannitol and L: -glucose. Both treatments showed that fluctuating osmolality did not result in a significant change in mitochondrial activity and had no effects on (14)Cglucose uptake, suggesting that adverse effects on mitochondrial function were specifically related to metabolically active glucose fluctuations. Apoptosis gene expression showed that both intrinsic and extrinsic apoptotic pathways were modulated by glucose variance, with two major response clusters corresponding to (i) glucose stress-modulated genes, (ii) glucose mediated osmotic stress-modulated genes. Gene clustering analysis by STRING showed that most of the glucose stress-modulated genes were components of the intrinsic/mitochondrial apoptotic pathway including Bcl-2, Caspases and apoptosis executors. On the other hand the glucose mediated osmotic stress-modulated genes were mostly within the extrinsic apoptotic pathway, including TNF receptor and their ligands and adaptors/activators/initiators of apoptosis. Fluctuating glucose levels have a greater adverse effect on neuronal cell energy regulation mechanisms than either sustained high or low glucose levels.

An in vitro paradigm for diabetic cerebral oedema and its therapy: a critical role for taurine and water channels.

The pathophysiology of cerebral oedema (CE) in diabetic ketoacidosis (DKA) remains enigmatic. We investigated the role of the idiogenic osmol taurine and aquaporin channels in an in vitro model, the SH-SY5Y neuroblastoma cell line, by sequentially mimicking DKA-like hyperglycemia/hypertonicity and hypotonic fluid therapy. Exposure to DKA-like hyperosmolarity led to shrinkage, while hypotonic fluid exposure led to cell swelling and impaired viability. Low sodium compensated in part for elevated glucose, pointing to a critical role for overall osmolality. Taurine, was synthesized and retained intracellularly during DKA-like hypertonicity, and released during hypotonicity, in part mitigating neuronal swelling. Metabolic labeling showed that the rate of taurine release was inadequate to fully prevent neuronal swelling during hypotonic fluid therapy following DKA-like hypertonicity. Under these conditions, Aquaporin4 & 9 channels were respectively down and up-regulated. Our study provides further novel insights into molecular mechanisms contributing to CE in DKA and its therapy.

Overgrowth syndromes.

PURPOSE OF REVIEW: Human growth ensues from a complex interplay of physiological factors, in the wider setting of varying genetic traits and environmental influences. Intensive research in these divergent areas, and particularly in the field of genetics, continues to clarify the molecular basis of disorders which result in overgrowth, and it is therefore timely to provide a review of these findings. RECENT FINDINGS: This article provides an overview of the factors which regulate growth, followed by a discussion of the more commonly encountered overgrowth syndromes and their genetic basis as it is understood at the current time. There is also an added focus on recently discovered genetic associations in some conditions, such as Weaver, Perlman and Proteus syndromes. SUMMARY: New discoveries continue to be made regarding the genetic basis for many overgrowth syndromes and the development of a much needed molecular classification system for overgrowth may become possible as the interlinking functions of these genes on growth are unravelled. As there exists a wide spectrum of syndromes, disorders resulting in overgrowth can represent a diagnostic and therapeutic challenge, from those causing prenatal overgrowth with a poor prognosis to less severe genetic aberrations which are identified in later childhood or adult life.

Growth hormone treatment for Turner syndrome in Australia reveals that younger age and increased dose interact to improve response.

OBJECTIVE: To investigate response to growth hormone (GH) in the first, second and third years of treatment in the total clinical cohort of Turner syndrome (TS) patients in Australia. CONTEXT: Short stature is the most common clinical manifestation of TS. GH treatment improves growth. DESIGN: Response was measured for each year of treatment. Stepwise multiple regression analyses were used to identify factors that significantly influenced response. PATIENTS: Prepubertal TS patients who completed 1 year (n=176), 2 years (n=148), or 3 years (n=117) of treatment and were currently receiving GH. MEASUREMENTS: Change in TS specific Height Standard Deviation Score (ΔTSZ) was the main response variable used. Major influencing variables considered included dose, starting age and height, BMI, bone age delay, karyotype, parental height, and interactions between dose and starting age or height. RESULTS: Response was greatest in first year and declined thereafter (median ΔTSZ: 1st year= +0·705, 2nd year= +0·439, 3rd year= +0·377) despite the median dose increasing [1st year= 5·5 mg/m(2) /week (0·23 mg/kg/week), 2nd year= 6·4(0·24), 3rd year= 7·2(0·26)]. An Age*Dose interaction was identified influencing first, second year, and total ΔTSZ. The ΔTSZ over 3 years was significantly influenced by first-year dose. Dose increments only attenuated the general decline in response. An acceptable first-year response (ΔTSZ>1·01) was achieved by only 17·6% of patients. CONCLUSIONS: Growth response is greatest and most influenced by dose in the first year. Dose in first year is a major factor contributing to total response. A starting Age*Dose interaction effect was observed such that young girls on a high dose respond disproportionately better. Optimal GH treatment of short stature in TS thus requires early initiation with the highest safe dose in the first year.

Looking back in time: conducting a cohort study of the long-term effects of treatment of adolescent tall girls with synthetic hormones.

OBJECTIVE: Public health research is an endeavour that often involves multiple relationships, far-reaching collaborations, divergent expectations and various outcomes. Using the Tall Girls Study as a case study, this paper will present and discuss a number of methodological, ethical and legal challenges that have implications for other public health research. APPROACH: The Tall Girls Study was the first study to examine the long-term health and psychosocial effects of oestrogen treatment for tall stature. RESULTS: In undertaking this study the research team overcame many hurdles: in maintaining collaboration with treating clinicians and with the women they had treated as girls - groups with opposing points of view and different expectations; using private practice medical records to trace women who had been patients up to forty years earlier; and exploring potential legal issues arising from the collection of data related to treatment. CONCLUSION: While faced with complex challenges, the Tall Girls Study demonstrated that forward planning, ongoing dialogue between all stakeholders, transparency of processes, and the strict adherence to group-developed protocols were keys to maintaining rigour while undertaking pragmatic research. IMPLICATIONS: Public health research often occurs within political and social contexts that need to be considered in the planning and conduct of studies. The quality and acceptability of research findings is enhanced when stakeholders are engaged in all aspects of the research process.

IGFBP-2 at the interface of growth and metabolism--implications for childhood obesity.

The growth hormone/insulin-like growth factor-I (IGF-I) axis is at the centre of normal human childhood growth. Six well characterised binding proteins (IGFBP-1 to IGFBP-6) act as general carriers of IGF-I, but they also modulate IGF-I bioavailability and activity in a tissue-specific, and developmentally appropriate, manner. Recent findings also point to several binding proteins possessing specific 'lGF-independent' actions and, in particular, there is now substantial evidence linking IGFBP-2 with nutritional status and insulin sensitivity. IGFBP-2 concentrations are reduced in obesity, and further reductions are seen in those with Type 2 diabetes. As IGFBP-2 is the major IGFBP expressed in infancy, and is also the predominant IGFBP produced from adipocytes, it is ideally positioned to act as a keystone between nutrition, growth and metabolism. Childhood obesity is associated with an increased risk of long-term morbidity and mortality, but the factors that determine which obese children will develop these long-term complications are not fully understood. IGFBP-2 may be integrally involved in the molecular processes that govern the development of obesity and subsequent weight-related disease. Within this manuscript, we explore the associations between IGFBP-2 and obesity with a particular emphasis on how an increased understanding of the role of IGFBP-2 in metabolism may lead to improvements in the prevention and treatment of childhood obesity.

Neuropsychological profiles of young people with type 1 diabetes 12 yr after disease onset.

BACKGROUND: Lowered neuropsychological performance is evident in youth with type 1 diabetes, although evidence for associations with specific illness variables is inconsistent. This study examined the neuropsychological profiles of a cohort of youth with type 1 diabetes studied prospectively from diagnosis 12 yr previously. METHODS: A total of 106 youth with type 1 diabetes and 75 healthy controls participated. There were no significant group differences on Full-scale IQ assessed on study entry 12 yr previously, current socioeconomic status, gender distribution, or age. Neuropsychological tests assessed eight cognitive domains: verbal abilities, perceptual reasoning, new learning, working memory, non-verbal processing speed, mental efficiency, divided attention, and sustained attention. Episodes of serious hypoglycemia and HbA(1c) levels were recorded from diagnosis. RESULTS: Youth with type 1 diabetes performed more poorly than controls on working memory (p < .05). Early onset diabetes was related to poorer sustained (p < .001) and divided attention (p = .001), new learning, and mental efficiency (both p < .05). Hypoglycemia was found to adversely effect verbal abilities, working memory, and non-verbal processing speed (all p < .05). Poorer working memory was associated with hyperglycemia (p < .05). Youth with any combination of two or three illness risk factors (i.e., early onset diabetes, hypo-, hyperglycemia), performed more poorly than controls and youth with no or one risk on verbal abilities, working memory, and mental efficiency. CONCLUSIONS: This study documents poorer neuropsychological performance and its association with illness risk factors in youth with type 1 diabetes. Findings suggest that early disease onset and hypoglycemia impact on the developing central nervous system, with hyperglycemia playing a lesser role.

An observational study of type 2 diabetes within a large Australian tertiary hospital pediatric diabetes service.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is emerging as a significant clinical problem within the pediatric population. OBJECTIVE: The objective of this study was to identify patients with T2DM in a large tertiary hospital diabetes service and examine aspects relating to clinical course and management. METHODS: An initial audit of our diabetes service (over 6 yr) was followed by a 2-yr period of prospective case ascertainment to identify patients with T2DM. Comprehensive data collection was then undertaken in these individuals. RESULTS: Within our service (n = 1574), 33 young people with T2DM were identified. Significant levels of co-morbidity were evident - dyslipidaemia (56%), microalbuminuria (45%), hypertension (30%) and abnormal retinal findings (25%). Hypertension was more likely in those with greater initial and follow-up body mass index (BMI) [mean (SD) BMI: 36.3 (5.0) vs. 28.0 (6.3) kg/m(2) , p = 0.001, and 36.8 (5.3) vs. 28.5 (7.8) kg/m(2) , p = 0.007, respectively] and BMI standard deviation score (SDS) [mean (SD) BMI SDS: 2.34 (0.30) vs. 1.72 (0.66), p = 0.001, and 2.26 (0.31) vs. 1.38 (0.87), p < 0.001, respectively], whereas abnormal retinal findings were seen in those with higher HbA1c values at last appointment [geometric mean (range) 10.9 (8.4-13.6) vs. 7.4 (5.6-12.5)%, p = 0.01) and those with greater increases in HbA1c over time (+4.1 (3.1) vs. +0.2 (1.9)%, p = 0.009). Of the 33,9 (27%) were lost to follow-up. CONCLUSIONS: At present, T2DM in youth remains a low burden on our services. Patients with this diagnosis, however, have significant problems that present a major challenge to the development of effective management strategies.

New directions in childhood obesity research: how a comprehensive biorepository will allow better prediction of outcomes.

BACKGROUND: Childhood obesity is associated with the early development of diseases such as type 2 diabetes and cardiovascular disease. Unfortunately, to date, traditional methods of research have failed to identify effective prevention and treatment strategies, and large numbers of children and adolescents continue to be at high risk of developing weight-related disease. AIM: To establish a unique 'biorepository' of data and biological samples from overweight and obese children, in order to investigate the complex 'gene × environment' interactions that govern disease risk. METHODS: The 'Childhood Overweight BioRepository of Australia' collects baseline environmental, clinical and anthropometric data, alongside storage of blood samples for genetic, metabolic and hormonal profiles. Opportunities for longitudinal data collection have also been incorporated into the study design. National and international harmonization of data and sample collection will achieve required statistical power. RESULTS: Ethical approval in the parent site has been obtained and early data indicate a high response rate among eligible participants (71%) with a high level of compliance for comprehensive data collection (range 56% to 97% for individual study components). Multi-site ethical approval is now underway. CONCLUSIONS: In time, it is anticipated that this comprehensive approach to data collection will allow early identification of individuals most susceptible to disease, as well as facilitating refinement of prevention and treatment programs.

Type 1 diabetes--still the commonest form of diabetes in children.

Obesity is rife within the community, and associated conditions such as type 2 diabetes and cardiovascular disease threaten the future health of our children. While type 2 diabetes has been the focus of much media attention, type 1 diabetes mellitus remains the commonest form of newly diagnosed diabetes in childhood. This case study acts to remind practitioners that all young people (even those with established obesity) who present with symptoms, and/or biochemical derangements compatible with diabetes, should be managed acutely in order to avoid a delayed diagnosis of type 1 diabetes.

Epidermal homeostasis: the role of the growth hormone and insulin-like growth factor systems.

GH and IGF-I and -II were first identified by their endocrine activity. Specifically, IGF-I was found to mediate the linear growth-promoting actions of GH. It is now evident that these two growth factor systems also exert widespread activity throughout the body and that their actions are not always interconnected. The literature highlights the importance of the GH and IGF systems in normal skin homeostasis, including dermal/epidermal cross-talk. GH activity, sometimes mediated via IGF-I, is primarily evident in the dermis, particularly affecting collagen synthesis. In contrast, IGF action is an important feature of the dermal and epidermal compartments, predominantly enhancing cell proliferation, survival, and migration. The locally expressed IGF binding proteins play significant and complex roles, primarily via modulation of IGF actions. Disturbances in GH and IGF signaling pathways are implicated in the pathophysiology of several skin perturbations, particularly those exhibiting epidermal hyperplasia (e.g., psoriasis, carcinomas). Additionally, many studies emphasize the potential use of both growth factors in the treatment of skin wounds; for example, burn patients. This overview concerns the role and mechanisms of action of the GH and IGF systems in skin and maintenance of epidermal integrity in both health and disease.

Oestrogen treatment for tall stature in girls: estimating the effect on height and the error in height prediction.

OBJECTIVE: To determine the effect of oestrogen treatment on attenuating the growth of tall girls after adjusting for error in height prediction. DESIGN: Retrospective cohort study. PATIENTS: Tall girls assessed by Australian paediatric endocrinologists between 1959 and 1993. A total of 279 girls received oestrogen treatment (diethylstilboestrol or ethinyl oestradiol) and 367 girls were assessed but not treated. MEASUREMENTS: Estimated mature height (EMH) was calculated using radiographic assessment of bone age in adolescence. Final adult height was self-reported at follow-up. To control for error in the EMH predictions and their different distributions by treatment status, pairs of treated and untreated girls, matched on EMH within 1 cm, were selected for analysis. Covariate adjusted estimates of treatment effect (final height - EMH) were calculated. RESULTS In the sample of 108 matched pairs, the mean difference between the final height and EMH was -1.4 cm (SE 0.29) in the treated group and 1.1 cm (SE 0.23) in the untreated group, giving an unadjusted treatment effect of -2.5 cm (95% CI -3.2 to 1.8). A regression model based on 107 pairs of treated and untreated girls contained a significant interaction between bone age at treatment initiation and treatment, which estimated an approximately 1 cm per year decrease in treatment effect. The treatment effect was greatest in those commencing treatment at an early bone age and was significant if initiated before a bone age of 15 years. CONCLUSIONS: On average, oestrogen treatment resulted in an adult height that was less than predicted. Although treatment was more effective in the least mature girls, the mean height difference was relatively modest for most treated girls.