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Adverse childhood experiences (ACEs) have consistently been associated with adult psychopathology and are commonly reported among military populations, with women more likely to report many types of ACEs than men. Limited research has examined the role of gender in the association between ACEs and mental health in military populations. The current study assessed the significance of gender differences in ACEs and mental health and explored the associations among these variables in a sample of Canadian Armed Forces recruits/officer cadets. Analyses with cross-sectional Recruit Health Questionnaire (RHQ) data from 50,603 recruits/officer cadets indicated that women were more likely to report witnessing domestic violence, experiencing sexual abuse, and living with someone with mental health problems or alcohol misuse, odds ratios (ORs) = 1.22-4.35, ps.001. Women were more likely to screen positive for depression, adjusted (aORs) = 1.25-1.49, p.001-p = .002, and anxiety, aORs = 2.00-2.33, ps.001, before basic military training. ACEs were associated with screening positive for probable mental health conditions, aORs = 1.54-6.13, p.001-p = .017. A significant interaction suggested the association between childhood sexual abuse and depression was stronger for men, aOR = 2.49, p.001, than women, aOR = 1.63, p = .002, as was the association between childhood sexual abuse and posttraumatic stress disorder, men: aOR = 6.06, p.001, women: aOR = 3.36, p.001. These results underscore the importance of considering gender and childhood trauma in mental health interventions with military personnel.

Recent studies showing an association between adverse childhood experiences and the development of alexithymia in military personnel have generated interest regarding the role of alexithymia in the pathway linking childhood trauma exposure to mental health disorders. Accordingly, the current study was conducted to (a) examine the associations among adverse childhood experiences, alexithymia, and symptoms of depression and posttraumatic stress disorder (PTSD) among recently deployed Canadian military personnel and (b) assess the mediating role of alexithymia in these associations. Data collected from 2,927 members of the Canadian Armed Forces at baseline and after their return from an overseas deployment were subjected to a prospective path analysis. The results of the path analysis, R2 = .35, pointed to a significant direct effect of childhood adversity on postdeployment mental health symptoms. Contrary to our expectations, the results also pointed to a negative indirect effect of childhood neglect, suggesting that childhood neglect contributed to lower levels of postdeployment depression and PTSD symptoms through the dimension of alexithymia related to difficulty in describing feelings. These patterns of associations, for the most part, persisted even when accounting for combat exposure during recent deployments, R2 = .42. The present results are discussed in light of study limitations and methodological considerations, and policy and clinical implications are noted.

Aims To determine the efficacy and patient perception of various transfer procedures from paediatric to adult diabetes services. Methods Comparison between four districts in the Oxford Region employing different transfer methods, by retrospective study of case records and interviews of patients recently transferred from paediatric diabetes clinics. The main outcome measures were age at transfer, clinic attendance rates, HbA1c measurements and questionnaire responses. Results Two hundred and twenty-nine subjects (57% males) > 18 years old in 1998 and diagnosed with Type 1 diabetes

We have investigated the relation between nocturnal insulin requirements and nocturnal growth hormone (GH) release in 26 diabetic adolescents at various puberty stages and have examined the effect of nocturnal GH suppression on pre-breakfast insulin requirement. In all the studies, euglycaemia was maintained overnight using a computer-calculated variable-rate insulin infusion, and 15-min blood samples were collected for GH assay. During initial clamp studies, insulin infusion rates were greater from 0500-0800 h (15.22 +/- 0.95 mU/kg/h, mean +/- SEM) than from 0100-0400 h (12.42 +/- 0.84 mU/kg/h, P less than 0.001). The increase in insulin infusion rate correlated with mean overnight GH concentration (r = 0.68, P less than 0.001), and was maximal at puberty stage 3 in both sexes. In seven of the subjects, a second identical clamp was performed following administration of 100 mg oral pirenzepine. During these studies, mean overnight GH levels were reduced by 11-85%, from 17.6 +/- 1.6 to 7.5 +/- 2.2 mU/l; P less than 0.01. Insulin requirements were not significantly different between the periods 0100-0400 and 0500-0800 h during these studies, and the reduction in pre-breakfast (0500-0800 h) insulin requirement when compared with the baseline studies correlated with the fall in GH secretion (rs = 0.82, P less than 0.01). The dawn increase in insulin requirement in adolescents with IDDM is related to the overnight GH secretion during puberty, and pre-breakfast insulin requirement can be reduced by suppressing nocturnal GH release.

Following a standard mixed meal, plasma concentrations of growth hormone releasing hormone (GHRH), somatostatin (SMS) and growth hormone (GH) were measured every 30 min for 300 min in six young adults with type I insulin-dependent diabetes mellitus (IDDM) and five normal controls. Mean blood glucose concentrations were higher and mean free insulin levels lower in the diabetics compared with controls both in fasting specimens and at all times following the mixed meal. Basal concentrations (mean +/- SEM) of GHRH were similar in diabetic (12.7 +/- 1.8 pg/ml) and control subjects (11.8 +/- 1.1 pg/ml). Following ingestion of the mixed meal, a rise in GHRH was observed in the control subjects maximal between 30 and 240 min (P less than 0.025) but the response was blunted in the diabetics. Mean GHRH concentrations were greater in the controls than in the diabetic subjects at all stages during the test, the maximum difference being noted at 120 mins (P less than 0.04). Basal SMS concentrations and those observed after the mixed meal were similar in diabetic and control subjects. These results indicate that glucose and insulin may play a role in the regulation of GHRH release following a mixed meal but circulating levels of GHRH and SMS are unlikely to be relevant to the abnormal regulation of GH in IDDM.

To determine the extent to which spontaneous plasma GH concentrations are abnormal in adolescents with insulin-dependent diabetes mellitus we performed 12-h overnight plasma GH profiles in 21 diabetic adolescents (11 males and 10 females; aged 9.8-16.5 yr; median, 13.6 yr) and 34 healthy adolescent controls (17 males and 17 females; aged 9.1-20.9 yr; median, 13.1 yr). Data were analyzed using the pulse detection program Pulsar and time series analysis, and are presented with respect to age and puberty stage. Mean and maximum GH concentrations, sum of the peak amplitudes, and mean calculated baseline concentrations in the normal children were higher during puberty; highest levels were seen in girls at puberty stages 2-3, and in boys at stages 4-5. A similar pattern was observed in the diabetic adolescents, but all measures of pulse height and mean calculated baseline concentrations were significantly greater than those in the normal subjects (multivariate analysis, P less than 0.001). Pulse frequency did not change during puberty in the normal or diabetic subjects, and the dominant pulse periodicity in both groups was about 180 min. We conclude that the predominant change in GH release during puberty is in pulse amplitude, and that this is increased in diabetes, whereas pulse frequency remains constant in both normal and diabetic adolescents.

Aims Carbohydrate (CHO) quantification is used to adjust pre-meal insulin in intensive insulin regimens. However, the precision in CHO quantification required to maintain postprandial glycaemic control is unknown. We determined the effect of a ±10-g variation in CHO amount, with an individually calculated insulin dose for 60 g CHO, on postprandial glycaemic control. Methods Thirty-one children and adolescents (age range 9.5–16.8 years), 17 using continuous subcutaneous insulin infusion (CSII) and 14 using multiple daily injections (MDI), participated. Each subject consumed test lunches of equal macronutrient content, differing only in carbohydrate quantity (50, 60, 70 g CHO), in random order on three consecutive days. For each participant, the insulin dose was the same for each meal, based on their usual insulin : CHO ratio for 60 g CHO. Activity was standardized. Continuous glucose monitoring was used. Results The CSII and MDI subjects demonstrated no difference in postprandial blood glucose levels (BGLs) for comparable carbohydrate loads (P > 0.05). The 10-g variations in CHO quantity resulted in no differences in BGLs or area under the glucose curves for 2.5 h (P > 0.05). Hypoglycaemic episodes were not significantly different (P = 0.32). The 70-g meal produced higher glucose excursions after 2.5 h, with a maximum difference of 1.9 mmol/l at 3 h (P = 0.01), but the BGLs remained within international postprandial targets. Conclusions In patients using intensive insulin therapy, an individually calculated insulin dose for 60 g of carbohydrate maintains postprandial BGLs for meals containing between 50 and 70 g of carbohydrate. A single mealtime insulin dose will cover a range in carbohydrate amounts without deterioration in postprandial control.

Objective: Type 1 diabetes mellitus (T1DM) is a chronic condition whose management affects the whole family, and siblings of children with chronic conditions have been shown to be at higher risk of emotional and behavioural problems. The aims of this study were to investigate sibling adjustment to T1DM using a cross-sectional questionnaire survey design. Methods: Forty-one families (48% of those eligible) were recruited from a children’s diabetes clinic. From each family, one parent and one sibling of the child with T1DM participated. Parents completed questionnaires measuring sibling adjustment and measures of major life events, social support and parenting stress. Demographic and disease information was obtained from medical records. Siblings completed questionnaires assessing cognitive appraisals and coping strategies. A semi-structured interview was also administered to siblings. Results: Siblings were found to be better adjusted than normative data (p

BACKGROUNDCerebral oedema is a major cause of morbidity and mortality in children with insulin dependent diabetes.AIMSTo determine the risk and outcome of cerebral oedema complicating diabetic ketoacidosis (DKA).METHODSAll cases of cerebral oedema in England, Scotland, and Wales were reported through the British Paediatric Surveillance Unit between October 1995 and September 1998. All episodes of DKA were reported by 225 paediatricians identified as involved in the care of children with diabetes through a separate reporting system between March 1996 and February 1998. Further information about presentation, management, and outcome was requested about the cases of cerebral oedema. The risk of cerebral oedema was investigated in relation to age, sex, seasonality, and whether diabetes was newly or previously diagnosed.RESULTSA total of 34 cases of cerebral oedema and 2940 episodes of DKA were identified. The calculated risk of developing cerebral oedema was 6.8 per 1000 episodes of DKA. This was higher in new (11.9 per 1000 episodes) as opposed to established (3.8 per 1000) diabetes. There was no sex or age difference. Cerebral oedema was associated with a significant mortality (24%) and morbidity (35% of survivors).CONCLUSIONSThis first large population based study of cerebral oedema complicating DKA has produced risk estimates which are more reliable and less susceptible to bias than those from previous studies. Our study indicates that cerebral oedema remains an important complication of DKA during childhood and is associated with significant morbidity and mortality. Little is known of the aetiology of cerebral oedema in this condition and we are currently undertaking a case control study to address this issue.

Objective— To determine the relative effects of growth hormone and insulin on ketogenesis during puberty. Research Design and Methods— We studied overnight changes in plasma ketones—3-hydroxybutyrate and acetoacetate—in 35 normal and 26 IDDM adolescents at different stages of puberty. The diabetic adolescents either were on their normal insulin regimen or were studied during an overnight euglycemic clamp with or without suppression of endogenous growth hormone release. Results— Total ketone body and 3-hydroxybutyrate concentrations in the normal adolescents rose significantly from 2000 (29 ± 5 μM), reaching a peak at 0200 (103 ± 16 μM, P < 0.001 vs. 2000). After a brief fall, a further rise occurred before breakfast. Fasting 3-hydroxybutyrate concentrations showed a negative correlation with fasting insulin levels (r = −0.46, P = 0.005) and decreased with advancing puberty, while insulin concentrations increased. In the diabetic patients on their usual insulin regimen, free insulin levels waned overnight, and an exaggerated rise in ketones was observed before breakfast. During the euglycemic clamp studies, ketone levels were higher than normal throughout the night. Mean overnight growth hormone and free insulin levels also were higher than in the normal control subjects. The addition of the anticholinergic drug pirenzepine reduced growth hormone secretion and obliterated the early-night peak of 3-hydroxybutyrate. Conclusions— We conclude that the early-night peak of ketone concentrations is related to growth hormone release, whereas the fasting levels are largely determined by insulin concentration. Inadequate insulin delivery in the presence of the high growth hormone concentrations characteristic of diabetic adolescents could lead to rapid decompensation and ketoacidosis.

Diabet. Med. 27, 348–353 (2010) Abstract Aims Carbohydrate (CHO) counting allows children with Type 1 diabetes to adjust mealtime insulin dose to carbohydrate intake. Little is known about the ability of children to count CHO and whether a particular method for assessing CHO quantity is better than others. We investigated how accurately children and their caregivers estimate carbohydrate, and whether counting in gram increments improves accuracy compared with CHO portions or exchanges. Methods One hundred and two children and adolescents (age range 8.3–18.1 years) on intensive insulin therapy and 110 caregivers independently estimated the CHO content of 17 standardized meals (containing 8–90 g CHO), using whichever method of carbohydrate quantification they had been taught (gram increments, 10-g portions or 15-g exchanges). Results Seventy-three per cent (n = 2530) of all estimates were within 10–15 g of actual CHO content. There was no relationship between the mean percentage error and method of carbohydrate counting or glycated haemoglobin (HbA1c) (P > 0.05). Mean gram error and meal size were negatively correlated (r = −0.70, P

Diabetes control is poor in children in the UK compared with most European countries; only 17% of children achieve HbA1c levels below the target value of 7.5%.1 Historically, we have tended to use insulin regimens requiring twice-daily injections (before breakfast and before the evening meal), meaning that children did not generally require an insulin injection or blood glucose check during the school day. However, the majority of large centres in this country and most in Europe are now using multiple injection therapy (MIT) and continuous subcutaneous insulin infusions (insulin pumps) which are more physiological and have the potential of improving glycaemic control when used intensively. Both require much greater input throughout the day as insulin is required at every meal-time, and, in order to improve control further, the dose of insulin must be related to the carbohydrate content of the meal and to the prevailing blood glucose level. Diabetes management during the day has thus become far more complex. Parents have learned the new skills well, particularly when these regimens are started from diagnosis, but there are often huge obstacles to setting appropriate support in place in schools. For children over the age of about 10–11 years, who are largely able to carry out their own injections reliably, schools will still have minimal input in most cases. The greater problem comes when doctors and parents wish to use these regimens in children who are too young to perform their own injections and blood glucose testing, even under supervision. So how should we move forward? Do children have the right to help in school or should we adjust the daily regimens so that insulin injections are not required at school? The landmark Diabetes Control and Complications Trial showed beyond doubt that intensive insulin regimens (and this trial was carried out …

Aims To determine the prevalence of abnormal lipid levels in a large group of children and adolescents with Type 1 diabetes and to examine the changes longitudinally. In addition, to study the relationships of any lipid abnormalities to glycaemic control, age and duration of diabetes. Methods Non-fasting blood samples were taken annually from all the patients in the Oxford Children's diabetes clinic and total cholesterol (TC), high-density lipoprotein (HDL) cholesterol, triglycerides (TG) and glycated haemoglobin (HbA1c) measured over a period of 8 years. Low-density lipoprotein (LDL) cholesterol and non-HDL were calculated from these values and compared. Tests performed less than 4 months after diagnosis were excluded. Results A total of 229 children had complete data from more than 1 year and 798 sets of data were examined. TC was lower in males and increased with duration of diabetes and with increasing HbA1c. HDL cholesterol fell with increasing age, but independently increased with duration, and was not related to HbA1c. LDL cholesterol and non-HDL cholesterol were highly correlated (r = 0.9). Both were lower in males and increased with duration of diabetes. Non-HDL cholesterol increased with HbA1c. A total of 23.7% had HDL cholesterol 5.2 mmol/l. Thirty-eight per cent had LDL cholesterol > 2.6 mmol/l and 10.8% > 3.4 mmol/l, the thresholds for lifestyle and drug intervention respectively. Conclusions Abnormalities in plasma lipid levels are common in this age group and the prevalence increases with poor glycaemic control and with duration of diabetes. Around 10% of adolescents would fit criteria for lipid-lowering medication in adults, but further study is needed to examine the risks and benefits in this age group.

This study investigated the prevalence of mothers' anxiety, depression, and posttraumatic stress disorder (PTSD) symptoms triggered by their child's type 1 diabetes and identified individual diabetes-related traumatic stressors. Sixty mothers of children who had been diagnosed with diabetes within the past 5 years were interviewed using the Structured Clinical Interview (SCID) DSM-IV-PTSD module, and completed the Posttraumatic Stress Diagnostic Scale (PDS) and the Hospital Anxiety and Depression Scale (HADS). Fifteen percent of participants met criteria for partial and 10% for full PTSD. Fifty-five percent of participants identified hearing about their child's diagnosis as the traumatic stressor. Forty percent of participants reported moderate to severe symptoms of state-anxiety and 17% moderate to severe symptoms of depression. This study highlights the significant emotional impact this diagnosis in children can have on mothers, and identifies a population with clinical needs.

Aims To determine whether higher than average albumin excretion during early puberty identifies subjects who will subsequently develop microalbuminuria (MA) and clinical proteinuria. Methods Longitudinal data from the Oxford Regional Prospective Study of Childhood Diabetes (ORPS; n = 554, median duration of follow-up 10 years; range 3.0–16.7) with assessment of albumin/creatinine ratios in three early morning urine samples collected annually. An albumin excretion phenotype was derived from longitudinal data, for each individual, defining deviation from the mean of regression models, including covariates gender, age, duration of diabetes and age at assessment. Tracking of the phenotypes was confirmed in a second independent cohort from Perth, Australia. Results The albumin excretion phenotype showed reasonable correlation between age 11–15 years and age 16–18 years in both cohorts, indicative of good ‘tracking’. In the ORPS cohort, tertiles of the albumin excretion phenotype at aged 11–15 years were predictive of subsequent risk for the development of MA. All of the subjects developing clinical proteinuria had an albumin excretion phenotype in the upper tertile or an HbA1c > 9% at aged 11–15 years. Conclusions Identification of adolescents at risk of diabetic nephropathy using an albumin excretion phenotype is feasible. When combined with elevated HbA1c, it may identify subjects for trial of early intervention with angiotensin-converting enzyme inhibitors/angiotensin-II receptor antagonists and statins to improve long-term prognosis in these subjects where sustained improvement in glycaemic control may be difficult to achieve.

BACKGROUND: A single family has been described in which obesity results from a mutation in the leptin-receptor gene (LEPR), but the prevalence of such mutations in severe, early-onset obesity has not been systematically examined. METHODS: We sequenced LEPR in 300 subjects with hyperphagia and severe early-onset obesity, including 90 probands from consanguineous families, and investigated the extent to which mutations cosegregated with obesity and affected receptor function. We evaluated metabolic, endocrine, and immune function in probands and affected relatives. RESULTS: Of the 300 subjects, 8 (3%) had nonsense or missense LEPR mutations -- 7 were homozygotes, and 1 was a compound heterozygote. All missense mutations resulted in impaired receptor signaling. Affected subjects were characterized by hyperphagia, severe obesity, alterations in immune function, and delayed puberty due to hypogonadotropic hypogonadism. Serum leptin levels were within the range predicted by the elevated fat mass in these subjects. Their clinical features were less severe than those of subjects with congenital leptin deficiency. CONCLUSIONS: The prevalence of pathogenic LEPR mutations in a cohort of subjects with severe, early-onset obesity was 3%. Circulating levels of leptin were not disproportionately elevated, suggesting that serum leptin cannot be used as a marker for leptin-receptor deficiency. Congenital leptin-receptor deficiency should be considered in the differential diagnosis in any child with hyperphagia and severe obesity in the absence of developmental delay or dysmorphism

Objective: To ascertain whether initial depression of conscious level in children with diabetic ketoacidosis (DKA) is related to hyperosmolality, acidosis or other factors. Objective: Methods: In 225 episodes of DKA without evidence of cerebral edema, we examined the relationship between conscious level and initial biochemical variables. We contrasted these findings with those in 42 children who later developed cerebral oedema. Results: On admission, 42/225 (19%) had mild (pH 7.26–7.35); 96 (44%) moderate (pH 7.11–7.25); and 80 (37%) severe DKA (pH ≤ 7.10). Conscious level: alert and oriented (group 1, n = 123), drowsy but oriented when woken (group 2, n = 62), semiconscious or confused/agitated (group 3, n = 9), comatose (group 4, n = 4). Glasgow Coma Score (GCS) was available in 65. pH varied significantly with conscious level; group 1, 7.20 ± 0.11(mean ± SD); group 2, 7.10 ± 0.16; group 3, 6.96 ± 0.11; group 4, 6.88 ± 0.09 (anova, p

Aims/hypothesis Cerebral oedema complicating diabetic ketoacidosis (DKA) remains the major cause of morbidity and mortality in children with type 1 diabetes, but its aetiology remains unknown. Our objective was to determine the impact of baseline biochemical factors and of treatment-related variables on risk of the development of cerebral oedema in children with DKA. Materials and methods This was a national UK case– control study. Through the British Paediatric Surveillance Unit we identified 43 cases of cerebral oedema. Through a parallel reporting system, we also identified 2,940 episodes of DKA and selected 169 control subjects on the basis of comparable age, sex, numbers of new or known cases of diabetes and date of admission. Baseline biochemical data and treatment-related variables were extracted from the clinical notes of cases and control subjects. Results Allowing for differences in age, sex and new or known diabetes, cases were more acidotic at diagnosis of DKA (odds ratio [OR] for events in the least acidotic compared with the most acidotic tertile=0.02 [95% CI: 0.002–0.15], p

Meckel's diverticula (MD) with areas of gastric heterotopia (metaplasia) are more likely to become symptomatic than those that contain mucosa of purely an intestinal type. Helicobacter pylori has been associated with the pathogenesis of various diseases. The aim of the study was to evaluate whether H. pylori could be identified within metaplastic gastric mucosa in MD. A retrospective evaluation of the histopathological features and the clinical presentation of patients with MD was undertaken. The study group included 32 cases (20 paediatric and 12 adults). The commonest modes of presentation were acute pain (25%), obstruction (19%), bleeding (12.5%) and hernias (9%). On histological examination, heterotopic gastric mucosa was noted to be present in 12 cases. Of these, 3 specimens were noted to have H. pylori organisms present using a specific immunostaining technique. Two patients had concurrent gastric biopsies; one stained positively for H. pylori but the second (1 mm biopsy) was rapid urease-test positive only. In conclusion, the study provides strong evidence that H. pylori may colonise heterotopic gastric mucosa in a minority of MD. H. pylori is apparently not involved in the pathogenesis of most cases of complicated MD. Nonetheless, all 3 patients who had evidence of H. pylori were symptomatic.

Aims/hypothesis. We measured insulin clearance rates in children and young adults with Type I (insulin-dependent) diabetes mellitus to establish their relation with insulin sensitivity and with factors such as growth hormone secretion and body mass index.¶Methods. We studied 46 subjects [mean (range) age 14.4 (9.8–24.6) years), body mass index 21.1 (15.8–29.6)Kgm2] using an overnight (1800–0800 hours) variable rate insulin infusion euglycaemic clamp protocol (5 mmol/l). Plasma free insulin concentrations during steady-state euglycaemia were used as an index of insulin sensitivity and insulin clearance determined as a ratio of insulin infusion rate to plasma free insulin.¶Results. During steady-state euglycaemia (0500–0730 hours), insulin sensitivity [mean (SEM) plasma insulin 0.020 (0.002) mU/l] and insulin clearance rates [19.1 (1.8) ml · kg–1· min] varied with age non-linearly and in a reciprocal fashion to each other (cubic regression F = 4.09, p = 0.01; F = 3.55, p = 0.02, respectively). Insulin sensitivity was negatively related to BMI (r = –0.37, p = 0.011) and mean overnight growth hormone concentrations (r = –0.40, p = 0.007). Insulin clearance was only related to growth hormone concentrations (r = –0.37, p = 0.014). These relations were still evident after stepwise multiple regression analysis (potential determinants: C peptide, sex, age, puberty stage, HbA1 c, duration of diabetes): insulin sensitivity r = 0.55, p < 0.001; insulin clearance r = 0.37, p < 0.02.¶Conclusions/interpretation. Insulin clearance rates vary with age in young subjects with Type I diabetes and are highest during mid-adolescence when insulin sensitivity is at its lowest. Both insulin sensitivity and insulin clearance are related to circulating growth hormone concentrations. [Diabetologia (2000) 43: 61–68]

BACKGROUND Mortality rates in children with insulin dependent diabetes (IDDM) in the UK are unknown and the causes of death not well documented. AIM To determine the mortality rate and causes of death in children with IDDM. METHODS The Office of National Statistics (England and Wales) and the General Register Office (Scotland) notified all deaths under 20 years of age from 1990 to 1996 with diabetes on the certificate. Further details were provided by coroners, pathologists, and clinicians. RESULTS 116 deaths were notified and 83 were caused by diabetes. The standardised mortality ratio was 2.3 (95% confidence interval (CI), 1.9 to 2.9), being highest in the age group 1–4 years, at 9.2 (95% CI, 5.4 to 14.7). Of the 83 diabetic deaths, hyperglycaemia/diabetic ketoacidosis (DKA) was implicated in 69 and hypoglycaemia in 7. Cerebral oedema was the most common cause of death in young children (25 of 36 diabetes related deaths in children under 12 years of age). 34 young people (10–19 years; 24 male) were either found dead at home (n = 26) or moribund on arrival at hospital (n = 8). In 24 of these, it appeared that DKA was the cause of death, in four hypoglycaemia was likely. Nine of these were found “dead in bed”. CONCLUSIONS Children with IDDM have a higher mortality than the general population. Cerebral oedema accounts for most hospital deaths in young children. There are a large number of young men dying at home from neglected IDDM. Early diagnosis of IDDM in children and closer supervision of young people might prevent some of these deaths. Key messages Children and young people with insulin dependent diabetes still have an increased mortality compared with the general population Diabetic ketoacidosis is the leading cause of death, particularly if it is complicated by cerebral oedema Hypoglycaemia is a rare cause of death even in those dying unexpectedly at home

Seventy-two diabetic (38 males) and 86 normal (41 males) children provided timed overnight urine collections. Fourteen of the diabetic and 33 of the normal children had concurrent overnight plasma insulin profiles. Urinary insulin clearance in the diabetic subjects was compared with excretion of albumin, growth hormone, retinol-binding protein, and N-acetyl-beta-D-glucosaminidase. In the normal subjects, urinary insulin excretion correlated with mean overnight plasma levels in the boys (r = 0.82, p < 0.001) but not in the girls (r = 0.32), and varied with puberty stage in the boys. Insulin clearance was greater in boys than girls during puberty, and fell in both sexes with advancing puberty. Insulin excretion was greater in diabetic than normal children in both sexes at all puberty stages. Insulin clearance was also greater in diabetic than normal subjects (1.05 +/- 0.1 ml min-1 1.73 m-2 vs 0.48 +/- 0.05 ml min-1 1.73 m-2, p < 0.001). Insulin excretion as a percentage of the filtered load was also greater in diabetic than normal subjects (1.9 +/- 0.27% vs 0.85 +/- 0.09%, p < 0.01). In the diabetic children, there was a correlation between urinary insulin and growth hormone excretion (r = 0.52, p < 0.02), and retinol-binding protein in those (n = 10) with higher retinol binding protein excretion (r = 0.76, p = 0.01). The value of urinary insulin excretion as a measure of free plasma insulin levels in normal and diabetic children may be limited by sex differences in renal insulin clearance, and by proximal renal tubular dysfunction in children with diabetes.

Summary. objective The aim was to investigate the relationship between the nocturnal pulsatile secretory patterns of immunoreactive and bioactive luteinizing hormone In normal children at various stages of puberty. design Blood samples were taken at 15-minute Intervals from 2000 hours to 0800 hours. Pubertal stage was assessed by the method of Tanner (1962). patients Thirty-four healthy siblings (17 males, 17 females) of diabetic children were recruited (median age 13.1, range 9.1–20.9 years). They were of normal height, non-obese, and covered the range of puberty. measurements Follicle stimulating and luteinizing hormone levels were measured by radioimmunoassay in all 34 subjects; bioactive LH (B-LH) was assayed In a sub-group of 13 subjects selected to encompass the range of normal puberty. Oestradiol (girls) and testosterone (boys) were also measured at hourly intervals. results Immunoreactive luteinizing and follicle stimulating hormone concentrations showed a progressive rise during puberty in both sexes. FSH concentrations were significantly higher in females than in males at all stages of puberty. Overnight mean bioactive lutelnizing hormone concentrations were higher than immunoreactive luteinlzing hormone levels in all the girls studied (n= 7). Although the number of bioactive luteinizing hormone pulses (31) was greater than Immunoreactive pulses (27), the profiles were generally very similar. In the early pubertal girls an increase In the bloactive:immunoreactive ratio was observed during the middle of the night with the onset of pulsatility. Oestrogen was detected in the girls in breast stage 4–5 but not in two of the early pubertal girls, despite pulses of immunoreactive and bioactive luteinizing hormone. The boys had higher mean bloactive than immunoreactive luteinizing hormone levels and overall bloactive and immunoreactive luteinizing hormone and testosterone concentrations Increased with puberty stage. Concordance between bioactive and immunoreactive hormone pulses was good although more immunoreactive pulses (16) were seen than bioactive pulses (14). As in the girls, an Increase in the bioactlve:lmmunoreactive ratio was observed In the middle of the night with the onset of pulsatility at genital stage 2 but, in contrast to the oestrogen data In the girls, testosterone secretion always followed lutelnizing hormone pulsatility overnight. conclusion We conclude that mean overnight immunoreactive luteinizing and follicle stimulating hormone concentrations increase during puberty in both sexes. Bioactive luteinizing hormone levels are two to three times higher than Immunoreactive luteinizing hormone in both sexes, but there Is very little discordance between Immunoreactive and bioactive luteinizing hormone pulse-Silty. The bioactive:immunoreactive ratio increases with the occurrence of pulsatility overnight In early pubertal children. The relationship between these changes in bioactive and immunoreactive luteinizing hormone and sex steroids is clearest in boys where the nocturnal testosterone rise always follows pulsatile LH secretion.

The excretion of urinary growth hormone was measured by a highly sensitive direct immunoradiometric assay in a cross-sectional study during puberty in 70 children with Type 1 (insulin-dependent) diabetes mellitus and 94 normal children. In normal children (n = 24) and diabetic children (n = 17) overnight urinary growth hormone excretion correlated significantly with the mean overnight plasma concentration (r = 0.70, p less than 0.001, and r = 0.70, p less than 0.001), indicating that urinary GH excretion reflects the circulating endogenous GH level. Overnight urinary growth hormone excretion increased during puberty. In normal and in diabetic children there was a peak in boys at genital stage 4 (both p less than 0.01), and in girls at breast stage 2 (both p less than 0.02). The diabetic children excreted more urinary growth hormone than the normal children at every pubertal stage. Excretion of albumin, retinol binding protein and N-acetyl-beta-D-glucosaminidase was measured in urine from 38 diabetic children. Urinary growth hormone correlated weakly with urinary albumin (r = 0.49, p less than 0.01), retinol binding protein (r = 0.42, p less than 0.01), and N-acetyl-beta-D-glucosaminidase (r = 0.43, p less than 0.01). Urinary GH excretion was not related to blood glucose control (HbA1) in boys (n = 31) or girls (n = 39). The measurement of urinary growth hormone provides an assessment of endogenous growth hormone during puberty in normal and diabetic children. However, caution must be exercised in interpreting urinary growth hormone data from diabetic patients with increased excretion of albumin and retinol binding protein.

Auxological and endocrine data from 6 children (3 male, 3 female) aged 8.5-12.8 years with Noonan's syndrome and the results of treatment with human biosynthetic growth hormone (hGH) are presented. All the children were short (Ht SDS -3.5 to -2.3) and height velocity SDS ranged between -1.76 and +0.03. The maximum plasma growth hormone (GH) response to standard provocation tests ranged from 17 to 52 mU/l, yet, plasma insulin-like growth factor I (IGF-I) concentrations were low or low normal. Overnight GH secretory profiles were normal in all but 2 children who had disordered pulsatility with high trough concentrations. In 5 children who have completed one year of hGH therapy mean height velocity increased from 4.8 to 7.4 cm/year and the height velocity SDS ranged from +0.2 to +3.75. This improvement was associated with an increase in plasma IGF-I in three subjects. These results suggest that a defect of the GH/IGF-I axis may be present in some children with Noonan's syndrome and hGH therapy may have a role in the management of the short stature in these children.

Circulating levels of the low molecular weight insulin-like growth factor binding protein-1 (IGFBP-1) are insulin dependent and vary markedly throughout the day. IGFBP-1 levels are abnormally high in diabetes but the relationship between this and the metabolic status of the patient has not been defined. We have therefore measured fasting IGFBP-1 levels at 0800 h in 32 diabetic adolescents. IGFBP-1 was measured in 19 of these patients after a normal night and in 27 after a night of euglycaemia, maintained with a glucose clamp. In 13 patients both studies were performed and could be compared. Puberty-matched control data were obtained from 69 normal children. In normal prepubertal children IGFBP-1 levels were high; lower levels were found with advancing pubertal development. This fall in IGFBP-1 correlated with pubertal stage (r= 0.68, p less than 0.001) and with fasting insulin levels (r = 0.60, p less than 0.001) which rose with pubertal advancement. In the diabetic children IGFBP-1 levels also correlated inversely with the 0800 h free insulin level but there was no clear relationship with pubertal development. However, when measured after overnight euglycaemia IGFBP-1 levels correlated inversely with pubertal development (r = 0.67, p less than 0.001) as in the normal children. In the patients studied on two comparable occasions the IGFBP-1 level measured after a normal night relative to that measured under standardized euglycaemic conditions was found to correlate closely with the glycosylated haemoglobin level (r = 0.71, p less than 0.005).

A simple, unbiased insulin-varying glucose clamp program is described. The aim of the program was to utilize a continuously updated array of data to predict insulin requirements for normoglycaemia. In assessing Type 1 diabetes the quantity of insulin required for maintenance of basal euglycaemia can be more clinically informative than other clamp methods. We present a method which uses an iterative computer program to predict changes in insulin infusion rate required for glucose clamping. After initial parameter estimation, the program uses no fixed algorithm but makes predictions according to previous blood glucose responses to infusion rates. The program has flexible data entry, graphic display, and running statistics including mean infusion data, mean glucose levels, and their respective standard deviations. Data for 26 consecutive overnight clamp studies have been analysed. The median coefficient of variation of glucose values at the end of the clamp was 4.1% (range 1.4-12.0%). The mean bias during the last 2 h was 0.20 +/- 0.24 mmol l-1. Cross-correlation showed that insulin had its maximal effect on the rate of decline of glucose after 15 min, and the nadir of glucose occurred 45 min after a change in insulin infusion rate.

Ffty cases of malignant pleural mesothelioma (47 men and 3 women) have been diagnosed during the period 1966-76 in Barrow-in-Furness, all of them histologically proved and accepted by the Pneumoconiosis Panel. At the time of writing only three survive. There was a history of industrial exposure to asbestos in all 47 men, who had worked in various trades in the shipyard, as had one of the women. One of the women was married to a shipyard plumber, who may have brought home asbestos dust on his clothes. Only one patient, a housewife, aged 28 at diagnosis, had no known asbestos contact. The asbestos content of the lungs has been measured in the last 20 cases, in 18 of whom it was found to be substantially greater than the accepted levels for the general population. In a small number studied by electron microscopy, the predominant fibre was crocidolite. A positive histological diagnosis was achieved in 39 subjects during life in the expectation of securing industrial compensation, but, in spite of this, less than half of the dependants are currently receiving payments. Metastases, though never clinically apparent, were frequent at necropsy.

Summary Two patients with paraseptal (peri-acinar) emphysema are described. Bilateral spontaneous pneumothorax occurred in one patient and rapid enlargement of a bulla in the other, in each case causing severe acute dyspnœa: neither had complained of dyspnœa before. The radiographic features were the combination of hair-line ring and polygonal shadows with avascular areas distributed under the pleura, characteristic of the condition. Pulmonary function studies showed remarkably little airway obstruction and the lungs were evenly ventilated: the minor degree of impairment was consistent with a cushioning effect of the peripheral bull˦. One of the patients died after operation, enabling detailed pathological studies of this unusual condition to be made.

Objective To evaluate an approach to measure β-cell function by frequent testing of C-peptide concentrations in dried blood spots (DBSs). Patients Thirty-two children, aged 7 to 17 years, with a recent diagnosis of type 1 diabetes. Design Mixed-meal tolerance test (MMTT) within 6 and again at 12 months after diagnosis, with paired venous and DBS C-peptide sampling at 0 and 90 minutes. Weekly DBS C-peptide before and after standardized breakfasts collected at home. Results DBS and plasma C-peptide levels (n = 115) correlated strongly (r = 0·91; P < 0.001). The Bland-Altman plot indicated good agreement. The median number of home-collected DBS cards per participant was 24 over a median of 6.9 months. Repeated DBS C-peptide levels varied considerably within and between subjects. Adjustment for corresponding home glucose measurements reduced the variance, permitting accurate description of changes over time. The correlation of the C-peptide slope over time (assessed by repeated home DBS) vs area under the curve during the two MMTTs was r = 0.73 (P < 0.001). Mixed models showed that a 1-month increase in diabetes duration was associated with 17-pmol/L decline in fasting DBS C-peptide, whereas increases of 1 mmol/L in glucose, 1 year older age at diagnosis, and 100 pmol/L higher baseline plasma C-peptide were associated with 18, 17, and 61 pmol/L higher fasting DBS C-peptide levels, respectively. In addition, glucose responsiveness decreased with longer diabetes duration. Conclusion Our approach permitted frequent assessment of C-peptide, making it feasible to monitor β-cell function at home. Evaluation of changes in the slope of C-peptide through this method may permit short-term evaluation of promising interventions., Frequent C-peptide measurements in subjects with newly diagnosed type 1 diabetes through the use of dried blood spots at home provide a convenient and reliable method for monitoring β-cell function.

SUMMARY GH release is abnormally regulated in insulin-dependent diabetes (IDDM), and paradoxical stimulation of GH release after TRH has been reported. However, overnight GH pulsatility is increased in IDDM, and it may be difficult to distinguish TRH-stimulated release from spontaneous secretory episodes. To resolve this question, we carried out two overnight GH profiles followed by either TRH or saline control tests in six adolescents with IDDM; ages 11.4–14.7 years, duration IDDM 2.4–6.7 years. A rise in GH was seen in four of six following TRH, but with no consistent pattern. A rise was also seen in four of six following saline. Peak GH levels were similar after TRH and saline (19.3 ± 4.4 vs 25.8 ± 5.5 mU/l; mean ± SEM). Mean blood glucose was no different during TRH and saline tests (9.5 ± 1.6 vs 7.5 ± 0.6 mmol/l). The two subjects who had an early GH peak after TRH were those in whom GH levels had already begun to rise, suggesting the coincident occurrence of a spontaneous GH pulse. The timing of the next GH pulse could be predicted equally well after TRH and saline from the overnight secretory profile using autocorrelation. Paradoxical GH stimulation after TRH is not seen in adolescents with IDDM, but apparent responses may be due to timing coincident with the increased spontaneous pulsatility.

One hundred and three patients with small cell lung carcinoma were stratified according to stage of disease (47 limited disease, 56 extensive disease) and then randomised to receive etoposide 300 mg/m2 alone for two days or a combination (VAC) of vincristine 1 mg/m2, doxorubicin (Adriamycin) 50 mg/m2, and cyclophosphamide 1000 mg/m2. The drugs were given at three week intervals. Patients were assessed after three cycles of treatment and continued with the same regimen if in complete remission and with the alternative regimen if in partial remission; they were withdrawn if the disease had progressed. Twenty four patients (23%) achieved complete remission and this occurred more often when patients were receiving VAC (19 of 82) than etoposide (5 of 75). There was no difference, however, in overall survival between those initially treated with etoposide and those having combination chemotherapy, whether for limited disease (both 8 months) or extensive disease (7 and 5.5 months). Toxicity was less with etoposide. Survival was disappointing, especially with limited disease, even in patients who showed a complete response to treatment.

The measurement of GH in urine may have many clinical applications, particularly in childhood. We have used a highly sensitive direct immunoradiometric assay to examine urinary GH excretion in children during puberty. Fifty-five healthy schoolchildren collected timed overnight urine samples. A further 36 children (15 normal, six of short stature and 15 diabetic) collected urine samples during a total of 50 overnight plasma GH secretory profiles (15-min sampling). Overnight urinary GH excretion increased during puberty, with a peak at breast stage 2 in girls, and genital stage 4 in boys, before declining at stage 5. There was a positive correlation (r = 0.57, p = 0.003) with height velocity in girls, but not in boys. At each puberty stage except 2, the diabetics excreted more urinary GH than the normal children. There was a highly significant correlation (r = 0.79, p less than 0.001) between mean overnight plasma GH concentrations and urinary GH excretion, suggesting that the latter accurately reflects physiological GH secretion.