The search for a unifying diagnosis involving neurological, endocrine and immune dysfunction: a case report of a novel presentation of DAVID syndrome.

BACKGROUND: We report a novel presentation of deficit in anterior pituitary function with variable immune deficiency (DAVID) syndrome in a healthy young girl presenting in Addisonian crisis with raised intracranial pressure. Nearly all cases of DAVID syndrome described in the literature have presented with recurrent infections and variable immunodeficiency. Pseudotumour cerebri has not been reported in DAVID syndrome to date. CASE PRESENTATION: A four-year-old girl represented to hospital with vomiting, confusion and diplopia after ten days of tiredness, neck and abdominal pain, and headache. Her cranial nerve examination demonstrated a right abducens nerve palsy and papilloedema, and she was found to have ketotic hypoglycaemia and hypocortisolaemia secondary to adrenocorticotrophic hormone (ACTH) deficiency. Her neuroimaging was consistent with pseudotumour cerebri, and her lumbar puncture opening pressure confirmed raised intracranial pressure (30-40 cmH2O). Cerebrospinal fluid analysis was normal. The patient's symptoms improved with hydrocortisone replacement and acetazolamide, but the raised intracranial pressure recurred after acetazolamide was discontinued. She was subsequently found to have panhypogammaglobulinaemia, and DAVID syndrome was diagnosed. Genetic testing demonstrated a truncating mutation in the NFKB2 gene c.2557C > T, p.(Arg853*). CONCLUSIONS: This case demonstrates pseudotumour cerebri as a novel neurological presentation of DAVID syndrome, highlights the rare association between adrenal insufficiency and intracranial hypertension, and shows the challenges in diagnosing isolated ACTH deficiency. We emphasise that cortisol should be checked in pre-pubertal children with pseudotumour cerebri and a diagnosis of DAVID syndrome considered in those presenting with low cortisol and neurological symptoms.

A brief self-compassion intervention for adolescents with type 1 diabetes and disordered eating: a feasibility study.

AIM: To examine the feasibility and acceptability of a brief self-compassion intervention for adolescents with type 1 diabetes and disordered eating behaviour. METHODS: Twenty-seven adolescents with type 1 diabetes were recruited and randomized to receive the brief (two 2.5-h sessions) self-compassion intervention, either in the intervention group (n=11) or in a waitlist control group (n=8). The intervention was adapted from the standardized eight-session 'Making Friends with Yourself' programme, and sessions were delivered 1 week apart. Acceptability was assessed through qualitative questionnaires and feasibility was assessed based on session attendance and recruitment metrics. Possible changes to disordered eating behaviour, self-care behaviours, diabetes-related distress, self-compassion, stress and glycaemic control were also assessed. RESULTS: Nineteen participants completed the study, and they reported an increased sense of common humanity (acknowledging that we are not alone), mindfulness, and coping resources. In terms of feasibility, recruitment took longer than expected (8 months) and not all participants were able to attend both sessions (nine could only attend one of the two sessions). CONCLUSIONS: While self-compassion is a strong conceptual fit for the issues of type 1 diabetes and disordered eating behaviour in adolescence, and the intervention content appears acceptable, feasibility issues were such that brief self-compassion programmes will probably need to be adapted into digital interventions for future research. (Trial registration number: ANZCTR 12619000541101).

A pilot randomized controlled trial of a gratitude intervention for adolescents with Type 1 diabetes.

AIM: Cost-effective psychosocial interventions that can feasibly be implemented into busy clinical settings are needed to improve psychological and physical health outcomes in adolescents with Type 1 diabetes. We examined the efficacy of a gratitude journalling intervention to improve psychological well-being and glycaemic control in adolescents aged 10-16 years with Type 1 diabetes. METHODS: Eighty adolescents were randomized to the 8-week gratitude intervention (N = 40) or standard care (N = 40). Self-reported measures of stress, quality of life, self-care, depression and gratitude were assessed at baseline and 8 weeks after baseline. Glycaemic control (HbA1c ) was assessed at baseline and 12 weeks after baseline. A per-protocol analysis was conducted with the adolescents who completed all questionnaires (N = 60). Analysis of covariance (ANCOVA) was used to examine differences between treatment arms at follow-up adjusting for baseline scores. RESULTS: There was no evidence of any between-group differences in the psychological or behavioural measures at follow-up (all P-values > 0.05). Glycaemic control slightly increased in the control group while remaining stable in the gratitude group, with a between-group difference of 6.1 mmol/mol [95% confidence interval (CI) -2.6 to 14.7; 0.6%, 95% CI -0.2 to 1.3] at 12 weeks after baseline. After adjusting for baseline HbA1c , this between-group difference was significant (P = 0.048). CONCLUSIONS: This is the first randomized trial of a gratitude journalling intervention for adolescents with Type 1 diabetes. Gratitude journalling interventions represent a clinically usable approach. If and how it helps to stabilise glycaemic control in adolescents with Type 1 diabetes remains to be confirmed in future research.

Effects of antenatal exercise in overweight and obese pregnant women on maternal and perinatal outcomes: a randomised controlled trial.

OBJECTIVE: To assess whether antenatal exercise in overweight/obese women would improve maternal and perinatal outcomes. DESIGN: Two-arm parallel randomised controlled trial. SETTING: Home-based intervention in Auckland, New Zealand. POPULATION AND SAMPLE: Pregnant women with body mass index ≥25 kg/m(2) . METHODS: Participants were randomised to a 16-week moderate-intensity stationary cycling programme from 20 weeks of gestation, or to a control group with no exercise intervention. MAIN OUTCOME MEASURES: Primary outcome was offspring birthweight. Perinatal and maternal outcomes were assessed, with the latter including weight gain, aerobic fitness, quality of life, pregnancy outcomes, and postnatal body composition. Exercise compliance was recorded with heart rate monitors. RESULTS: Seventy-five participants were randomised in the study (intervention 38, control 37). Offspring birthweight (adjusted mean difference 104 g; P = 0.35) and perinatal outcomes were similar between groups. Aerobic fitness improved in the intervention group compared with controls (48.0-second improvement in test time to target heart rate; P = 0.019). There was no difference in weight gain, quality of life, pregnancy outcomes or postnatal maternal body composition between groups. However, compliance with exercise protocol was poor, with an average of 33% of exercise sessions completed. Sensitivity analyses showed that greater compliance was associated with improved fitness (increased test time (P = 0.002), greater VO2 peak (P = 0.015), and lower resting heart rate (P = 0.014)), reduced postnatal adiposity (reduced fat mass (P = 0.007) and body mass index (P = 0.035)) and better physical quality of life (P = 0.034). CONCLUSIONS: Maternal non-weight-bearing moderate-intensity exercise in pregnancy improved fitness but did not affect birthweight or clinical outcomes. TWEETABLE ABSTRACT: Moderate-intensity exercise in overweight/obese pregnant women improved fitness but had no clinical effects.

Shorter mothers have shorter pregnancies.

We assessed whether maternal height was associated with gestational age in a cohort of 294 children born at term. Increasing maternal height was associated with longer pregnancy duration (p = 0.002). Stratified analyses showed that the main effect on pregnancy length appears to occur among shorter mothers (<165 cm tall), whose pregnancies were ∼0.6 and ∼0.7 weeks shorter than pregnancies of mothers 165-170 cm (p = 0.0009) and >170 cm (p = 0.0002) tall, respectively. Further, children of shorter mothers were more likely to be born early term than those of average height (p = 0.021) and taller (p = 0.0003) mothers. Maternal stature is likely to be a contributing factor influencing long-term outcomes in the offspring via its effect on pregnancy length.

The phenotype of an IVF child is associated with peri-conception measures of follicular characteristics and embryo quality.

STUDY QUESTION: Are childhood measures of phenotype associated with peri-conception parental, IVF treatment and/or embryonic characteristics of IVF children? SUMMARY ANSWER: Birthweight, childhood body mass index (BMI) and height of pre-pubertal IVF children were strongly associated with peri-conception factors, including follicular and embryonic characteristics. WHAT IS KNOWN ALREADY: A growing number of studies have identified a range of phenotypic differences between IVF and naturally conceived pre-pubertal children; for example, birthweights are lower following a fresh compared with a thawed embryo transfer. STUDY DESIGN, SIZE, DURATION: This retrospective cohort study included IVF children (n = 96) born at term (>37 weeks) after a singleton pregnancy from the transfer of either fresh or thawed embryos in New Zealand. Between March 2004 and November 2008, these children were subjected to clinical assessment before puberty. PARTICIPANTS/MATERIALS, SETTING, METHODS: Clinical assessment provided anthropometric measures of children aged 3.5-11 years old. Peri-conception factors (n = 36) derived retrospectively from parental, treatment, laboratory and embryonic variables (n = 69) were analysed using multiple stepwise regression with respect to standard deviation scores (SDSs) of the birthweight, mid-parental corrected BMI and height of the IVF children. Data from children conceived from fresh (n = 60) or thawed (n = 36) embryos, that met inclusion criteria and had high-quality data with >90% completeness, were analysed. MAIN RESULTS AND THE ROLE OF CHANCE: Embryo treatment at transfer was identified as a predictor of birthweight with thawed embryos resulting in heavier birthweights than fresh embryos [P = 0.02, 95% confidence interval (CI) fresh minus thawed: -1.047 to -0.006]. Birthweight SDS was positively associated with mid-parental corrected BMI SDS (P = 0.003, slope 0.339 ± 0.100). Four factors were related (P < 0.05) to mid-parental corrected height SDS. In particular, child height was inversely associated with the diameter of lead follicles at oocyte retrieval (P < 0.0001, slope -0.144 ± 0.040) and with the quality score of embryos at transfer (P = 0.0008, slope -0.425 ± 0.157), and directly associated with the number of follicles retrieved (P = 0.05, slope 1.011 ± 0.497). Child height was also positively associated with the transfer of a fresh as opposed to thawed embryo (P < 0.001, 95% CI 0.275-0.750). LIMITATIONS, REASONS FOR CAUTION: More than one embryo was transferred in most cycles so mean development and quality data were used. The large number of variables measured was on a relatively small sample size. Large cohorts from multiple clinics using a variety of treatment protocols and embryology methods are needed to confirm the associations identified and ultimately to test these factors as possible predictors of phenotype. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study to directly associate peri-conception measures of IVF treatment with a pre-pubertal child's phenotype. Demonstration that peri-conception measures relate to a pre-pubertal child's phenotype extends the range of factors that may influence growth and development. These findings, if corroborated by larger studies, would provide invaluable information for practitioners, who may want to consider the impact of ovarian stimulation protocols as well as the quality of the embryo transferred on a child's growth and development, in addition to their impact on pregnancy rate. STUDY FUNDING/COMPETING INTERESTS: This work was supported by grants from the National Research Centre of Growth and Development New Zealand (grant 3682065) and the Australasian Paediatric Endocrine Group (APEG; grant 3621994), as well as a fellowship from Fertility Associates New Zealand awarded to M.P.G. In terms of competing interest, J.C.P is a shareholder of Fertility Associates. M.P.G. currently holds the position of Merck Serono Lecturer in Reproductive Biology. W.S.C. and P.L.H. have also received grants and non-financial support from Novo Nordisk, as well as personal fees from Pfizer that are unrelated to the current study. The other authors have no conflict of interest to declare.

Effect of reduced total blood volume on left ventricular volumes and kinetics in type 2 diabetes.

AIM: Although impaired left ventricular (LV) diastolic function is commonly observed in patients with type 2 diabetes, it remains unclear whether the impairment is caused by altered LV relaxation or changes in LV preload. The purpose of this study was to examine the influence of LV function and LV loading conditions on stroke volume in men with type 2 diabetes. METHODS: Cardiac magnetic resonance imaging scans were performed in eight men with type 2 diabetes and 11 non-diabetic men matched for age, weight and physical activity level. Total blood volume was determined with the Evans blue dye dilution technique. RESULTS: End-diastolic volume (EDV), the ratio of peak early to late mitral inflow velocity (E/A) and stroke volume were lower in men with type 2 diabetes than in non-diabetic individuals. Peak filling rate and peak ejection rate were not different between diabetic and non-diabetic individuals; however, men with type 2 diabetes had proportionally longer systolic duration than non-diabetic individuals. Heart rate was higher and total blood volume was lower in men with type 2 diabetes. The lower total blood volume was correlated with a lower EDV in men with type 2 diabetes. CONCLUSIONS: Men with type 2 diabetes have an altered cardiac cycle and lower end-diastolic and stroke volume. A lower total blood volume and higher heart rate in men with type 2 diabetes suggest that changes in LV preload, independent of changes in LV relaxation or contractility, influence LV diastolic filling and stroke volume in this population.

Ethnicity and social deprivation independently influence metabolic control in children with type 1 diabetes.

AIMS/HYPOTHESIS: This study was performed to evaluate the influence of ethnicity and socioeconomic status (SES) on metabolic control in a population-based cohort of children with type 1 diabetes mellitus, and to evaluate whether any relationship between ethnicity and HbA(1c) is mediated by SES. METHODS: We performed a retrospective review of all patients under age 16 years with type 1 diabetes (n = 555) from 1995 to 2005 in the greater Auckland region, New Zealand. Diabetes care variables and HbA(1c) values were collected prospectively, during clinic visits. RESULTS: The mean population HbA(1c) was 8.3 +/- 1.3%. Maori and Pacific patients had poorer metabolic control than their European counterparts (9.1% and 9.3% vs 8.1%, p < 0.001) and higher rates of moderate to severe hypoglycaemia (31.1 and 24.8 vs 14.9 events/100 patient-years, p = 0.03). In multiple linear regression analysis, both ethnicity and SES were independently associated with HbA(1c) (p < 0.001). Other factors associated with higher HbA(1c) level were longer duration of diabetes, higher insulin dose, lower BMI z score and less frequent blood glucose monitoring (p < 0.001). CONCLUSIONS/INTERPRETATION: Both ethnicity and SES independently influenced metabolic control in a large, unselected population of children with type 1 diabetes. Irrespective of SES, Maori and Pacific youth with type 1 diabetes were at greater risk of both moderate to severe hypoglycaemia and long-term complications associated with poor metabolic control.

An angled insertion technique using 6-mm needles markedly reduces the risk of intramuscular injections in children and adolescents.

AIMS: The aims of this study were (i) to establish which children with Type 1 diabetes are at risk of intramuscular or intradermal insulin injections and (ii) to determine a needle length and technique that reliably administers insulin into subcutaneous fat. METHODS: Seventy-two healthy diabetic children (age 6.3-14.3 years, body mass index standard deviation score 1.0 +/- 1.4) were recruited for study 1 and 37 of this cohort participated in study 2. In study 1, 200 microl air was injected into the abdomen and anterior thigh by a pinched skin-fold technique using either a perpendicular insertion of NovoFine(R) 31G 6-mm or an angled insertion of NovoFine(R) 30G 8-mm needles. In study 2, subjects received injections into abdomen and anterior thigh via angled 6-mm needles with either an unpinched or pinched technique. The site of air injection was visualized by ultrasound scan and measurements taken of subcutaneous fat thickness. RESULTS: In study 1, intramuscular injections were detected in 32% of subjects, and in a further 22% air was visualized at the muscle fascia. In study 2, intramuscular injections occurred in 3% of subjects and a further 11% had muscle fascia air detected. No intramuscular injections occurred in subjects injecting with a 6-mm needle and an angled pinched skin-fold technique. Pinching abdomen and thigh skin folds increased the subcutaneous fat thickness by 192 +/- 16% and 22 +/- 6%, respectively. In very lean subjects, pinching thighs actually reduced subcutaneous fat thickness. CONCLUSIONS: While intramuscular injections were observed frequently using standard injection protocols, an angled 6-mm needle technique reliably injects into the subcutaneous fat.

Combination therapy with acipimox enhances the effect of growth hormone treatment on linear body growth in the normal and small-for-gestational-age rat.

Growth hormone (GH) therapy is often associated with adverse side effects, including impaired insulin sensitivity. GH treatment of children with idiopathic short stature does not lead to an optimized final adult height. It has been demonstrated that FFA reduction induced by pharmacological antilipolysis can stimulate GH secretion per se in both normal subjects and those with GH deficiency. However, to date, no investigation has been undertaken to establish efficacy of combination treatment with GH and FFA regulators on linear body growth. Using a model of maternal undernutrition in the rat to induce growth-restricted offspring, we investigated the hypothesis that combination treatment with GH and FFA regulators can enhance linear body growth above that of GH alone. At postnatal day 28, male offspring of normally nourished mothers (controls) and offspring born with low birth weight [small for gestational age (SGA)] were treated with saline, GH, or GH (5 mg.kg(-1).day(-1)) in combination with acipimox (GH + acipimox, 20 mg.kg(-1).day(-1)) or fenofibrate (GH + fenofibrate, 30 mg.kg(-1).day(-1)) for 40 days. GH plus acipimox treatment significantly enhanced linear body growth in the control and SGA animals above that of GH, as quantified by tibial and total body length. Treatment with GH significantly increased fasting plasma insulin, insulin-to-glucose ratio, and plasma volumes in control and SGA animals but was not significantly different between saline and GH-plus-acipimox-treated animals. GH-induced lipolysis was blocked by GH plus acipimox treatment in both control and SGA animals, concomitant with a significant reduction in fasting plasma FFA and insulin concentrations. This is the first study to show that GH plus acipimox combination therapy, via pharmacological blocking of lipolysis during GH exposure, can significantly enhance the efficacy of GH in linear growth promotion and ameliorate unwanted metabolic side effects.

Prematurity--another example of perinatal metabolic programming?

Low birth weight is associated with both later adult diseases such as type 2 diabetes mellitus and a number of metabolic abnormalities, the foremost of which is insulin resistance. Indeed the link between an adverse perinatal environment, manifested by low birth weight, and adult life pathology may be an early, permanent reduction in insulin sensitivity. A reduction in insulin sensitivity has been demonstrated in small for gestational age (SGA), term subjects from childhood through to adulthood. Less is known about children born premature into an adverse neonatal environment. We present data demonstrating that premature infants also have metabolic abnormalities similar to those observed in term, SGA children and that these occur irrespective of whether they are SGA or appropriate for gestational age (AGA).

Insulin sensitivity in people born pre-term, with low or very low birth weight and small for gestational age.

Evidence has accumulated that small for gestational age (SGA) children have long-term adult health consequences including obesity, Type 2 diabetes mellitus, hypertension, coronary artery disease and stroke. This increased risk of later adult disease is likely a consequence of an early, persistent reduction in insulin sensitivity. The SGA children and adults studied were predominantly at term gestation, and it appears that prematurity also leads to insulin resistance with possibly similar health consequences for later life. Both term SGA and premature children have an abnormal early environment: one in utero and one post-natally. Parallels are made among those born SGA at term or premature to show the potential importance of maternal factors, the intrauterine milieu, including nutrient supply and intake in fetal and early newborn life. It is possible that manipulation of these factors during early neonatal life in premature babies could lead to normalisation of insulin sensitivity. To confirm this hypothesis, further studies are needed to better understand the pathophysiological mechanisms leading to reduced insulin sensitivity and confirm that prematurity is linked with similar long-term health consequences as being born SGA.

Evaluation of the buserelin stimulation test in diagnosing gonadotropin deficiency in males with delayed puberty.

OBJECTIVE: To assess the efficacy of the gonadotropin-releasing hormone (GnRH) agonist buserelin in a stimulated gonadotropin test for the investigation of delayed puberty in males. STUDY DESIGN: Prepubertal males (n = 31; age range, 10.3 to 17.2 years) were studied; buserelin (100 microg) was administered subcutaneously, with blood sampling at 0 and 4 hours for serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH). At follow-up (mean, 4.2 years), 8/31 (26%) failed to progress into puberty, constituting hypogonadotropic hypogonadism (HH), but 23/31 (74%) had testicular enlargement (> or =8 mL) consistent with a normal hypothalamic-pituitary-gonadal (HPG) axis. RESULTS: Stimulated serum LH response to buserelin was lower in males with HH (mean +/- standard error under the mean for HH, 1.4 +/- 0.5 U/L, compared with a normal HPG axis of 17.4 +/- 2.0 U/L; P < .0001). Stimulated serum FSH response was nondiscriminatory (HH, 7.7 +/- 2.2 U/L; normal HPG axis, 11.5 +/- 1.6 U/L; P = .27). All males with HH had a stimulated serum LH level <5 U/L, whereas only 1/23 with a normal HPG axis had a stimulated serum LH below this level. Using this value as the criterion for diagnosing HH, the buserelin stimulation test yielded a sensitivity of 100%, specificity of 96%, and positive predictive value of 89%. CONCLUSIONS: The buserelin stimulation test is a highly specific and sensitive GnRH agonist test for the investigation of males with delayed puberty.

Neonatal leptin treatment reverses developmental programming.

An adverse prenatal environment may induce long-term metabolic consequences, in particular obesity and insulin resistance. Although the mechanisms are unclear, this programming has generally been considered an irreversible change in developmental trajectory. Adult offspring of rats subjected to undernutrition during pregnancy develop obesity, hyperinsulinemia, and hyperleptinemia, especially in the presence of a high-fat diet. Reduced locomotor activity and hyperphagia contribute to the increased fat mass. Using this model of maternal undernutrition, we investigated the effects of neonatal leptin treatment on the metabolic phenotype of adult female offspring. Leptin treatment (rec-rat leptin, 2.5 microg/g.d, sc) from postnatal d 3-13 resulted in a transient slowing of neonatal weight gain, particularly in programmed offspring, and normalized caloric intake, locomotor activity, body weight, fat mass, and fasting plasma glucose, insulin, and leptin concentrations in programmed offspring in adult life in contrast to saline-treated offspring of undernourished mothers who developed all these features on a high-fat diet. Neonatal leptin had no demonstrable effects on the adult offspring of normally fed mothers. This study suggests that developmental metabolic programming is potentially reversible by an intervention late in the phase of developmental plasticity. The complete normalization of the programmed phenotype by neonatal leptin treatment implies that leptin has effects that reverse the prenatal adaptations resulting from relative fetal undernutrition.

Reduced insulin sensitivity and the presence of cardiovascular risk factors in short prepubertal children born small for gestational age (SGA).

BACKGROUND: Epidemiological studies have shown that the metabolic syndrome, a combination of type 2 diabetes mellitus, hypertension, dyslipidaemia and a high body mass index (BMI), occurs more frequently among adults who were born with a low birth weight. Because insulin is thought to play a key role in the pathogenesis of this syndrome we investigated insulin sensitivity and risk factors for cardiovascular disease in short prepubertal children born small for gestational age (SGA). PATIENTS AND METHODS: Frequently sampled intravenous glucose tolerance tests (FSIGT) were performed in 28 short prepubertal children born SGA. Short stature was defined as a height < -2SD. SGA was defined as a birth length and/or a birth weight for gestational age < -2SD. Twelve short children born appropriate for gestational age (AGA) were used as controls for the FSIGT's results only. AGA was defined as a birth weight and/or birth length for gestational age > -2SD. In short SGA children, blood pressure (BP), fasting levels of serum free fatty acids (FFA), triglycerides (TG), total cholesterol (TC), high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) were measured and compared to reference values. RESULTS: Mean insulin sensitivity (Si) level in short SGA children was significantly reduced to 38% of the mean Si level measured in short AGA controls (P = 0.004). Mean acute insulin response (AIR) was significantly higher in SGA children compared to short AGA controls (P < 0.001). Differences in Si and AIR between the two groups remained significant after adjusting for age and BMI (P < 0.001 and P = 0.003, respectively). The mean (SD) systolic BP SDS was 1.3 (1,1), being significantly higher than zero. Mean fasting serum levels of FFA, TC, TG, HDL and LDL were all within the normal range. However, 6 of the 28 SGA children had serum FFA levels above the normal range. Cardiovascular risk factors could statistically be represented in two clusters. Both clusters played a significant role in the development of insulin insensitivity (1/Si). CONCLUSION: Although the metabolic syndrome has been described in adulthood, our study showed that risk factors for the development of type 2 diabetes mellitus and cardiovascular disease are already present during childhood in short prepubertal children born SGA, suggesting a pretype 2 diabetes mellitus phenotype.

The metabolic consequences of prematurity.

An association between low birth weight, commonly a reflection of an adverse in utero environment, and the subsequent development of diseases such as type 2 diabetes and hypertension in later life is now generally accepted - as is an association between an adverse perinatal environment and a permanent reduction in insulin sensitivity. This and other metabolic abnormalities have been demonstrated from childhood through to adulthood in subjects who were born full-term but small for gestational age (SGA). Less is known about children born prematurely into an adverse neonatal environment. We present data demonstrating that premature infants also have metabolic abnormalities similar to those observed in full-term, SGA children, and that these occur irrespective of whether the premature infants are SGA or appropriate for gestational age (AGA).

The changing presentation of children with newly diagnosed type 1 diabetes mellitus.

Although it is known that the incidence of type 1 diabetes mellitus (DM) in childhood is progressively increasing, it is less clear whether the presentation of newly diagnosed DM is changing. The aim of this study was to establish whether any biochemical or clinical presentation parameters have altered over time. A retrospective study was performed comparing newly diagnosed children with DM in two 24 month time intervals, 8 yrs apart (1988-89 and 1995-96). Fifty-seven children were diagnosed with type 1 DM in 1988-89 and 70 children in 1995-96. At presentation, children born in the later cohort had a higher pH (p < 0.001) and lower serum glucose (p < 0.05). Although the frequency of diabetic ketoacidosis (DKA) was higher in the 1988/89 cohort (63% vs. 42% in 1995/96) the absolute number of children with DKA in each time interval was similar (33 subjects in 1988-89 vs. 30 subjects in 1995/96). Islet cell antibody (ICA) levels were very different between the two cohorts; higher antibody levels were found in the 1988/89 group (p < 0.01). DKA was also associated with higher ICA titres (p < 0.05). Hospital admission stay decreased from 6.5 DS to 3.4 DS over the 8-year period (p < 0.0001). At our institution, the presentation of children with type 1 DM is changing with many more children diagnosed before developing DKA. We speculate that a new environmental factor(s) may be responsible for the absolute increase in patients presenting without DKA, while older etiologies (both genetic and environmental) are responsible for the steady, unchanging number of patients with a more severe presentation. Greater awareness of diabetes in children is not the factor contributing to earlier diagnosis before DKA develops.

Fetal origins of hyperphagia, obesity, and hypertension and postnatal amplification by hypercaloric nutrition.

Environmental factors and diet are generally believed to be accelerators of obesity and hypertension, but they are not the underlying cause. Our animal model of obesity and hypertension is based on the observation that impaired fetal growth has long-term clinical consequences that are induced by fetal programming. Using fetal undernutrition throughout pregnancy, we investigated whether the effects of fetal programming on adult obesity and hypertension are mediated by changes in insulin and leptin action and whether increased appetite may be a behavioral trigger of adult disease. Virgin Wistar rats were time mated and randomly assigned to receive food either ad libitum (AD group) or at 30% of ad libitum intake, or undernutrition (UN group). Offspring from UN mothers were significantly smaller at birth than AD offspring. At weaning, offspring were assigned to one of two diets [a control diet or a hypercaloric (30% fat) diet]. Food intake in offspring from UN mothers was significantly elevated at an early postnatal age. It increased further with advancing age and was amplified by hypercaloric nutrition. UN offspring also showed elevated systolic blood pressure and markedly increased fasting plasma insulin and leptin concentrations. This study is the first to demonstrate that profound adult hyperphagia is a consequence of fetal programming and a key contributing factor in adult pathophysiology. We hypothesize that hyperinsulinism and hyperleptinemia play a key role in the etiology of hyperphagia, obesity, and hypertension as a consequence of altered fetal development.

A1 adenosine receptors potently regulate heart rate in mammalian embryos.

A1 adenosine receptors (A1ARs) have been recently shown to be expressed in rodent embryonic hearts at very early stages of development. To determine the functional significance of fetal cardiac A1AR expression during embryogenesis, murine fetal heart preparations were studied between postconceptual days 9 and 12. Dose-response curves generated using a variety of adenosine agonists revealed that A1AR activation potently regulated fetal heart rates. The A1AR agonist, N6-cyclopentyladenosine, inhibited heart rates in a dose-dependent manner (half-maximal effective concentration = 3.6 x 10(-8) M) and stopped fetal cardiac contractions in 63% of preparations. In contrast, A2a and A2b receptor activation did not alter heart rates, and activation of A3 receptors produced modest declines in heart rates. Endogenous adenosine also acted tonically to suppress fetal heart rates, as demonstrated by the A1AR antagonist 1,3-dipropyl-8-cyclopentylxanthine, increasing heart rates, whereas the adenosine reuptake blocker dipyridamole lowered fetal heart rates. Pertussis toxin treatment blocked A1AR action, showing that A1AR action was G protein mediated. Using drugs that alter cAMP levels and ion channel action, we were able to show that A1AR action involves events mediated by cAMP, ATP-dependent K, L-type calcium, sodium, and chloride channels, and the pacemaker current. These data show that adenosine and A1ARs potently regulate mammalian heart rates via multiple effector systems at very early stages of prenatal development.

Insulin resistance in short children with intrauterine growth retardation.

Epidemiological studies have demonstrated an association between intrauterine growth retardation and an increased risk of adult diseases that include essential hypertension, noninsulin-dependent diabetes mellitus, and ischemic heart disease. A common feature of these diseases is insulin resistance. To investigate whether abnormal insulin sensitivity was a characteristic of subjects with intrauterine growth retardation (IUGR), we compared two groups of short prepubertal children: a group with IUGR (birth weight less than the tenth percentile; n = 15) and a normal birth weight group (n = 12). Subjects underwent a modified frequently sampled iv glucose tolerance test that permitted calculation of the acute insulin response, insulin sensitivity index, and glucose effectiveness. A marked difference in the insulin sensitivity index was noted between groups, with the IUGR group being less insulin sensitive [6.9 vs. 16.9 10(-4)min-1.(microU/mL); P = 0.0048]. The acute insulin response was also significantly different between groups, with IUGR subjects having higher insulin levels (445 vs. 174 microU/mL; P = 0.005). There was no difference in glucose effectiveness between groups. Short prepubertal IUGR children have a specific impairment in insulin sensitivity compared to their normal birth weight peers. In short IUGR children, impaired insulin sensitivity is a potential marker for the early identification and intervention in the development of late adult-onset noninsulin-dependent diabetes mellitus.