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LAY SUMMARYThis study compared the baseline physical and mental health of officer candidates attending military college and officer training programs (i.e., non-direct-entry officer or non-DEO stream) with those of officers entering through a direct stream (direct-entry officer or DEO stream). Overall, DEO candidates had better health than non-DEO candidates. Female DEO and non-DEO candidates also reported more physical activity than male DEO and non-DEO candidates, and female non-DEO candidates had more symptoms of mental illness than male non-DEO candidates. A better understanding of these groups may lead to opportunities to customize health screening and supports depending on officer entry stream and sex; however, more research is needed to inform policy.

Physics-based electrochemical battery models derived from porous electrode theory are a very powerful tool for understanding lithium-ion batteries, as well as for improving their design and management. Different model fidelity, and thus model complexity, is needed for different applications. For example, in battery design we can afford longer computational times and the use of powerful computers, while for real-time battery control (e.g. in electric vehicles) we need to perform very fast calculations using simple devices. For this reason, simplified models that retain most of the features at a lower computational cost are widely used. Even though in the literature we often find these simplified models posed independently, leading to inconsistencies between models, they can actually be derived from more complicated models using a unified and systematic framework. In this review, we showcase this reductive framework, starting from a high-fidelity microscale model and reducing it all the way down to the Single Particle Model (SPM), deriving in the process other common models, such as the Doyle-Fuller-Newman (DFN) model. We also provide a critical discussion on the advantages and shortcomings of each of the models, which can aid model selection for a particular application. Finally, we provide an overview of possible extensions to the models, with a special focus on thermal models. Any of these extensions could be incorporated into the microscale model and the reductive framework re-applied to lead to a new generation of simplified, multi-physics models., 50 pages, 9 figures

Introduction: Transition to civilian life may not only be highly challenging for service members, but also for their spouses, especially following a medical release. Often, the families of ill or injured service members must confront unexpected responsibilities related to caring for the member, while having to adjust to civilian life. This study was conducted to examine military to civilian transition challenges and engagement in caregiving among spouses of newly released Canadian Armed Forces (CAF) Veterans and their associations with spousal well-being. Methods: The Canadian Armed Forces Transition and Well-Being Survey (CAFTWS) was administered to spouses of CAF Veterans released in 2016 ( N = 595). The survey assessed spouses’ experiences with a range of military to civilian transition challenges and engagement in caregiving, as well as various indicators of their well-being (e.g., daily stress and psychological distress). Regression analyses were conducted to assess the associations of transition challenges and caregiving with well-being. Results: Results revealed that challenges related to finding educational opportunities and health care providers, and loss of military identity, as well as more frequent engagement in caregiving, were significantly associated with elevated levels of daily stress and psychological distress among spouses of Veterans. Discussion: This study is among the first to examine transition experiences, caregiving and well-being in a representative sample of Veterans’ spouses. Findings outline key challenges experienced and underline important predictors of well-being. Recommendations on services that could help facilitate or improve the experiences of families during the transition process are discussed.

Aim To assess cholesterol screening of children with Type 1 diabetes by diabetes professionals using a survey of current practice, given that National Institute of Health and Care Excellence guidelines on childhood Type 1 diabetes do not recommend cholesterol screening, yet the National Paediatric Diabetes Audit has an annual cholesterol measure (> 12 years) as a key outcome indicator. Methods An online survey was sent to 280 members of the Association of Children's Diabetes Clinicians to assess cholesterol screening practice in children. Results A total of 87 diabetes professionals (31%) responded. The results showed that 94% of respondents measured cholesterol, 33% did this annually on all children, and 7% measured fasting cholesterol. A total of 63% used no guidelines to decide treatment or further investigation. The definition of ‘high’ cholesterol varied from > 4.5 to > 8 mmol/l, with 40% giving no response or specific level. Only 14% of clinicians had started statin therapy in their diabetes clinic in the previous 5 years. Conclusion Whilst the majority of diabetes professionals measured cholesterol in children with Type 1 diabetes, there was marked variability in sampling, in children screened and in action taken if levels were considered abnormal. It is debatable whether cholesterol measures should be undertaken, certainly more than once, and whether cholesterol level should feature as a key outcome in the national audit in future., What's new? Annual measurement of cholesterol in children aged > 12 years with Type 1 diabetes is one of the seven core care processes outlined in the National Paediatric Diabetes Audit (NPDA).The National Institute for Health and Care Excellence (NICE) guidelines (NG18) for management of children and young people with diabetes 2015, do not include cholesterol screening for children with Type 1 diabetes.There is much variation in cholesterol measurement, evaluation and treatment among clinicians looking after children with Type 1 diabetes.We suggest further evidence is needed on the utility of cholesterol screening in the paediatric population, and consistency is needed between NICE guidance and NPDA standards.

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.

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.

Type 1 diabetes in childhood is one of the commoner long term conditions of childhood. It is treated by specialist teams in secondary care using increasingly intensive insulin regimens, but the onset is generally diagnosed by primary care physicians, sometimes later than is ideal. #### Case scenario A 7 year old boy with acute abdominal pain and vomiting is brought to see his general practitioner by his mother. He was being bullied at school, and because his mother attributed his recent onset of bed wetting to stress she did not mention this symptom to the GP. The GP considers appendicitis a possibility but first decides to rule out a urinary tract infection. A urine dipstick test is positive for glucose and ketones. She refers the child at once to the paediatric team for immediate management of his diabetic ketoacidosis. #### How common is it? About 30% of children with newly diagnosed diabetes have had at least one related medical visit before the diagnosis, suggesting that medical practitioners are missing the diagnosis.5 Drinking a lot and …

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.

aDivision of Endocrinology, Children’s Hospital Boston, MA, USA; bSchool of Women’s and Children’s Health, University of New South Wales, Sydney, Australia; cUniversity of Toronto, The Hospital for Sick Children, Toronto, Canada; dDepartment of Paediatrics, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK; eDepartment of Paediatrics, John Radcliffe Hospital, Oxford, UK; fEndocrinology Service Department of Paediatric Medicine, KK Children’s Hospital, Singapore; gDivision of Endocrinology, Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL, USA; hDepartment of Pediatric Endocrinology, Children’s Hospital, University of Pittsburgh, PA, USA; iDepartment of Pediatrics, Uddevalla Hospital, Uddevalla, Sweden

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

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

Aims The long duration of action of soluble insulin given in the evening could contribute to the high prevalence of nocturnal hypoglycaemia seen in young children with Type 1 diabetes mellitus (T1DM). We examined whether replacing soluble insulin with insulin lispro reduced this risk in children on a three times daily insulin regimen. Methods Open crossover study comparing insulin lispro vs. soluble insulin in 23 (16 boys) prepubertal children (age 7–11 years) with T1DM on three injections/day; long-acting isophane insulin remained identical. At the end of each 4-month treatment arm, an overnight 15-min venous sampled blood glucose profile was performed. Results Despite similar blood glucose levels pre-evening meal (lispro vs. soluble: mean ± se 6.5 ± 1.0 vs. 7.1 ± 1.1 mmol/l, P = 0.5), post-meal (18.00–22.00 h) blood glucose levels were lower on insulin lispro (area under curve 138 ± 12 vs. 170 ± 13 mmol min−1 l−1, P = 0.03). In contrast, in the early night (22.00–04.00 h) the prevalence of low blood glucose levels (

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

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.

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.

A study of the prognostic value of serum fibrin/fibrinogen degradation products (FDP) in 137 consecutive patients with acute myocardial infarction showed a positive correlation between high FDP levels and poor prognosis. Both the frequency of complications and the mortality were related to increased levels of FDP, the highest of which were found between the fourth and eighth days after infarction.

The effects of short exposures to low intensities of red, far-red, blue and white light, applied separately and in certain combinations, have been studied with respect to plastid development in dark-grown beans. 'Rapid' effects, occurring within a few hours of illumination, were the transformation and loss of the prolamellar bodies together with changes of the thylakoid area per plastid. All light treatments except blue, effectively transformed the prolamellar body and all the light treatments induced falls in prolamellar body volume. Red light, or illumination treatments containing red light, gave a 'rapid' stimulation to thylakoid development while blue and far-red given alone were inhibitory. 'Slow' effects on plastid development appeared to be primarily controlled by phytochrome, in addition to which there was some indication that low intensity treatments with blue light partially reversed the phytochrome effects. These 'slow' effects were on plastid expansion, plastid division and the formation of the internal membranes of the plastids.

The development of increased activities of ribulosediphosphate carboxylase (EC 4.1.1.39) and of phosphoribulokinase (EC 2.7.1.19) in greening bean leaves was completely inhibited by D-threo chloramphenicol but unaffected by L-threo chloramphenicol. This indicates that these enzymes are synthesized by the ribosomes of the developing plastids. A different mechanism appears to be responsible for the development of activity of NADP-dependent triosephosphate dehydrogenase (EC 1.2.1.13) where the D-threo isomer gave 45% inhibition and the L-threo isomer gave 18% inhibition. Thus both specific (D-threo isomer) and unspecific (both isomers) inhibition occurred. It is suggested that the development of NADP-dependent triosephosphate dehydrogenase activity may result from the allosteric activation, in the plastids, of the NAD-dependent enzyme (Muller et al., 1969) which has been synthesized by cytoplasmic ribosomes. Neither isomer inhibited the development of five other enzymes of the photosynthetic carbon cycle namely ribosephosphate isomerase (EC 5.3.1.6), phosphoglycerate kinase (EC 2.7.2.3), triosephosphate isomerase (EC 5.3.1.1), tructosediphosphate aldolase (EC 4.1.2.13) and transketolase (EC 2.2.1.1), but there was a significant stimulation of the activity of transketolase by D-threo chloramphenicol.

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.

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.

GH release is abnormally regulated in insulin-dependent diabetes (IDDM). Paradoxical stimulation of GH after TRH and an association with retinopathy has been reported in young adults. However, overnight secretion of GH is also increased in IDDM, and it may be difficult to distinguish spontaneous release from that seen after TRH. To resolve this question we carried out TRH and saline control studies following overnight GH profiles in 6 adolescents with IDDM. 4 boys and 2 girls (age 11.4-14.7 y; pubertal stage 2-4: duration IDDM 2.4-6.7 y; HbA1C 8.4-11.5%) had 2 GH profiles (15 min aliquots by continuous sampling from 20.00-08.00 hrs) 4-6 wks apart. At 08.10 hrs TRH (200 mcg) or saline (1ml 0.9%) were given IV. Samples were taken at -10, 0, 10, 20, 30, 10, 60 and 90 min Tor GH. A rise in GH was seen in 4 of 6 following TRH, but with no consistent pattern, the peak occurring at any time between 10 and 90 min. A rise was also seen in 5 of 6 following saline. Mean blood glucose was identical during TRH and saline tests (9.5 ± 1.6 vs 7.5 ± 0.6 mmol/l, x ± SEM, p = 0.35). Peak GH levels were similar (19.3 ± 4.4 vs 25.8 ± 5.5 mU/l) after TRH and saline (p = 0.4), as were mean GH and areas under GH curve. The timing of the GH peak after both TRH and saline could be predicted from the overnight secretory profile. Paradoxical GH rise following TRH is not seen in adolescents with IDDM. Previous reports of GH release after TRH may have been due to timing coincident with a normal GH pulse.

Recent evidence that the non-GH dependent IGF-BP is not only a carrier protein but also has an active role in the growth process is enhanced by observations of a marked circadian rhythm. We have measured RIA levels of this IGF-BP over 12 or 24 hours in 11 poorly controlled diabetic adolescents & 7 normals (4 adolescents & 3 adults). In 5 diabetics, overnight profiles were also obtained with euglycaemia maintained by an insulin clamp. In normal adults IGF-BP was undetectable except for a nocturnal peak of 30-40ng/mL. In 2 diabetics receiving long-acting insulin in the evening, levels of 10-20ng/mL in the day and 100-120ng/mL at night were found. In 3 diabetics receiving long-acting insulin in the morning levels reached 410-460ng/mL at night concomitant with elevated plasma glucose, with which a close correlation was found. Maintenance of euglycaemia overnight failed to suppress the IGF-BP peak although this occurred earlier than on the unclamped night. However in one subject who became hypoglycaemic the nocturnal peak was considerably blunted. These findings show for the first time that in young diabetics whilst markedly elevated non-GH dependent IGF-BP levels are found the nyctohemeral rhythm is maintained irrespective of metabolic control. Levels are consistent with insulin being a major regulator of this IGF-BP in the circulation.