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OBJECTIVE: To ascertain whether initial depression of conscious level in children with diabetic ketoacidosis (DKA) is related to hyperosmolality, acidosis or other factors. 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

Objective: To determine hypoglycemia prevalence in prepubertal children on thrice (TID) and twice (BID) daily insulin regimens, using the Medtronic Minimed Continuous Glucose Monitoring System.Research Design and Methods: Twenty-eight children aged <12 years (median 9.8, range 6.9-11.8) wore the sensor for three consecutive days and nights. Hypoglycemia was defined as glucose <60 mg/dl for >15 min. Data are expressed as the percentage of time period spent hypoglycemic.Results: Hypoglycemia prevalence was 10.1% (mean 2.6 h. subject(-1) x day(-1)). Hypoglycemia was more common at night compared with daytime (18.81 vs. 4.4%, P < 0.001); 78 and 43% of subjects showed hypoglycemia on at least one night and two or more nights, respectively. Nocturnal episodes were prolonged (median 3.3 h) and asymptomatic (91% of episodes). Prevalence was greater between 0400 and 0730 h than between 2200 and 0400 h (25.5 vs. 15.4%, P < 0.001). On a TID compared with a BID regimen, nocturnal hypoglycemia prevalence was reduced, particularly between 0400-0730 h (22.9 vs. 27.4%, P = 0.005), whereas hypoglycemia the following morning (0730-1200 h) was greater (7.8 vs. 2.8%, P < 0.001). Nocturnal hypoglycemia risk was associated with decreasing age (by a factor of 0.6 for a year less in age), increased insulin dose (by 1.6 for an increase of 0.1 units. kg(-1) x day(-1)), insulin regimen (by 0.2 on a BID compared with a TID regimen), and increased weight standard deviation score (SDS) (by 2.7 for a one SDS rise).Conclusions: Use of standard insulin regimens results in high prevalence and large intraindividual variation in hypoglycemia, particularly at night. Independent risk factors for nocturnal hypoglycemia were younger age, greater daily insulin dose, insulin regimen, and increasing weight. [ABSTRACT FROM AUTHOR]

Objective: To compare blood glucose control and incidence of nocturnal hypoglycemia in adolescents with type 1 diabetes on multiple injection regimens managed with either an insulin analog combination or NPH insulin plus regular human insulin.Research Design and Methods: In a randomized cross-over study, 28 adolescents with type 1 diabetes on multiple injection therapy received either insulin glargine prebedtime plus lispro preprandially (LIS/GLAR) or NPH insulin prebedtime plus regular human insulin preprandially (R/NPH). During each 16-week treatment arm, subjects completed home blood glucose profiles, and at the end of each treatment arm, they were admitted for an overnight metabolic profile. A total of 25 subjects completed the study.Results: Compared with R/NPH therapy, LIS/GLAR was associated with lower mean blood glucose levels (LIS/GLAR versus R/NPH): fasting (8.0 vs. 9.2 mmol/l, P < 0.0001), 2 h postbreakfast (8.1 vs. 10.7 mmol/l, P < 0.0005), prelunch (8.9 vs. 10.1 mmol/l, P < 0.01), and 2 h postlunch (8.0 vs. 9.5 mmol/l, P < 0.002). However, there was no difference in mean blood glucose levels before or after the evening meal. Incidence of nocturnal hypoglycemia on overnight profiles was 43% lower on LIS/GLAR compared with R/NPH therapy; however, there was no difference in rates of self-reported symptomatic hypoglycemia. Total insulin dose required to achieve target blood glucose control was lower on LIS/GLAR (1.16 IU/kg) compared with R/NPH therapy (1.26 IU/kg, P < 0.005), but there was no significant difference in HbA(1c) levels (LIS/GLAR versus R/NPH: 8.7 vs. 9.1%, P = 0.13).Conclusions: Combination therapy with insulin glargine plus lispro reduced the incidence of nocturnal hypoglycemia and was at least as effective as R/NPH insulin therapy in maintaining glycemic control in adolescents on multiple injection regimens. [ABSTRACT FROM AUTHOR]

OBJECTIVE--Regular insulin given with the evening meal could contribute to the risk of nocturnal hypoglycemia in adolescents with type 1 diabetes using a multiple injection regimen. To test this hypothesis, we compared glucodynamics and free insulin levels on two separate study nights. RESEARCH DESIGN AND METHODS--A total of 14 adolescents were recruited. On both nights, identical doses of regular insulin or insulin lispro were administered 30 min or 10 min, respectively, before the evening meal, using a double-blind randomized crossover study design. Doses of NPH insulin and carbohydrate content of the evening meal and snack were kept identical. Blood samples were taken every 15 min for blood glucose and every 60 min for free insulin and ketones. RESULTS--After insulin lispro administration, glucose levels were significantly lower between the evening meal and the bedtime snack (analysis of variance [ANOVA] P = 0.02), and four hypoglycemic episodes were recorded. This corresponded to a higher (458 +/- 48 vs. 305 +/- 33 pmol/l, P = 0.02), earlier (64 +/- 4.6 vs. 103 +/- 12 min, P = 0.01), and shorter-lasting (245 +/- 21 vs. 365 +=/- 39 min, P = 0.01) insulin peak in contrast to regular insulin. After the bedtime snack, glucose levels increased dramatically during the lispro night and stayed higher, up to 0300 in the morning (ANOVA P = 0.01), corresponding to lower mean insulin levels (146 +/- 20 vs. 184 +/- 27 pmol/l, P = 0.04). No differences were seen in glucose and insulin levels between 0300 and 0800. Four episodes of nocturnal hypoglycemia were documented after the bedtime snack during the regular insulin night, in contrast to one episode after insulin lispro. No differences in ketone levels were observed. CONCLUSIONS--The replacement of regular insulin with insulin lispro may reduce the risk of late hypoglycemia, but redistribution of the evening carbohydrate may be needed to ensure good metabolic control and prevent early postprandial hypoglycemia. [ABSTRACT FROM AUTHOR]

We describe a method for the synthesis of visual speech movements using a hybrid unit selection/model-based approach. Speech lip movements are captured using a 3D stereo face capture system and split up into phonetic units. A dynamic parameterisation of this data is constructed which maintains the relationship between lip shapes and velocities; within this parameterisation a model of how lips move is built and is used in the animation of visual speech movements from speech audio input. The mapping from audio parameters to lip movements is disambiguated by selecting only the most similar stored phonetic units to the target utterance during synthesis. By combining properties of model-based synthesis (e.g., HMMs, neural nets) with unit selection we improve the quality of our speech synthesis.

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. [ABSTRACT FROM AUTHOR]

Aims: To assess staffing levels of healthcare professionals involved in the care of children and young people with diabetes in the UK., Methods: A web-based questionnaire was distributed to lead consultant paediatricians from all paediatric diabetes services in the UK between October and December 2014. Data on staffing levels and other aspects of diabetes services were collected and differences between the four nations of the UK and across the 10 English diabetes networks were explored., Results: Some 175 services (93%) caring for 29 711 children and young people aged ≤ 24 years with diabetes participated in the survey. Northern Ireland and Wales had the lowest ratio of total staff to patient population. Nursing caseloads per one whole-time equivalent (WTE) nurse ranged from 71 patients in England to 110 patients in Northern Ireland with only 52% of the UK services meeting the Royal College of Nursing recommended nurse-to-patient ratio of > 1 : 70. Scotland and Northern Ireland had the highest ratio of consultants and fully trained doctors per 1000 patients (3.5 WTE). Overall, 17% of consultants had a Certificate of Completion of Training in Endocrinology and Diabetes. Some 44% of dietitians were able to adjust insulin dose. Only 43% of services provided 24-h access to advice from the diabetes team and 82% of services had access to a psychologist. Staffing levels adjusted for volume were not directly related to glycaemic performance of services in England and Wales., Conclusions: Wide variations in staffing levels existed across the four nations of the UK and important gaps were present in key areas., (© 2017 Diabetes UK.)

Aims: To assess the management of diabetic ketoacidosis in young people, which differs in the UK between paediatric and adult services, and to evaluate outcomes and extent to which national guidelines are used., Methods: A standardized questionnaire was sent to all paediatric and adult diabetes services in England, requesting details of all diabetic ketoacidosis admissions in young people aged > 14 years in paediatric services ('paediatric' patients), and in young adults up to the age of 22 years in adult services ('adult' patients)., Results: A total of 64 adult patients aged ≤ 22 years (mean age 19.2 years) were reported, of whom seven were aged between 10 and 16 years. A total of 71 paediatric patients were reported [mean (range) age 14.9 (11-18) years]. We found that 85% of paediatric and 69% of adult patients were treated according to national guidelines, 99% of paediatric and 89% of adult patients were treated with 0.9% saline and fixed-rate insulin infusions and 16% of adult patients received an insulin bolus. Insulin treatment was initiated later in paediatric patients than in adult patients (100 vs 39 min; P < 0.001). In 23% of adult patients and 8.8% of paediatric patients, potassium levels were < 3.5 mmol/l (P < 0.005). The lowest mean potassium levels were 3.8 mmol/l in paediatric and 3.5 mmol/l in adult patients (P < 0.005). Hypoglycaemia occurred in 42.3% of paediatric and 36% of adult patients. Time to resolution was similar in paediatric and adult patients (16.0 vs 18.2 h), as was duration of hospital stay (2.35 vs 2.53 days)., Conclusions: Young people were treated according to national guidelines, but the quality of monitoring was variable in both paediatric and adult settings. The incidence of hypoglycaemia and hypokalaemia was unacceptably high., (© 2016 Diabetes UK.)

Objectives: The physiological requirements underlying soccer-specific exercise are incomplete and sex-based comparisons are sparse. The aim of this study was to determine the effects of a repeated-sprint protocol on the translational repressor 4E-BP1 and sprint performance in male and female soccer players., Design: Cross-over design involving eight female and seven male university soccer players., Methods: Participants performed four bouts of 6 × 30-m maximal sprints spread equally over 40 min. Heart rate, sprint time and sprint decrement were measured for each sprint and during the course of each bout. Venous blood samples and muscle biopsies from the vastus lateralis were taken at rest, at 15 min and 2h post-exercise., Results: While males maintained a faster mean sprint time for each bout (P < 0.05) females exhibited a greater decrement in sprint performance for each bout (P < 0.05), indicating a superior maintenance of sprint performance in males, with no sex differences for heart rate or lactate. Muscle analyses revealed sex differences in resting total (P < 0.05) and phosphorylated (P < 0.05) 4E-BP1 Thr37/46, and 15 min post-exercise the 4E-BP1 Thr37/46 ratio decreased below resting levels in males only (P < 0.05), indicative of a decreased translation initiation following repeated sprints., Conclusions: We show that females have a larger sprint decrement indicating that males have a superior ability to recover sprint performance. Sex differences in resting 4E-BP1 Thr37/46 suggest diversity in the training-induced phenotype of the muscle of males and females competing in equivalent levels of team-sport competition., (Copyright © 2014 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.)

Purpose: High-intensity short-duration interval training (HIT) stimulates functional and metabolic adaptation in skeletal muscle, but the influence of HIT on mitochondrial function remains poorly studied in humans. Mitochondrial metabolism as well as mitochondrial-associated protein expression were tested in untrained participants performing HIT over a 2-week period., Methods: Eight males performed a single-leg cycling protocol (12 × 1 min intervals at 120% peak power output, 90 s recovery, 4 days/week). Muscle biopsies (vastus lateralis) were taken pre- and post-HIT. Mitochondrial respiration in permeabilized fibers, citrate synthase (CS) activity and protein expression of peroxisome proliferator-activated receptor gamma coactivator (PGC-1α) and respiratory complex components were measured., Results: HIT training improved peak power and time to fatigue. Increases in absolute oxidative phosphorylation (OXPHOS) capacities and CS activity were observed, but not in the ratio of CCO to the electron transport system (CCO/ETS), the respiratory control ratios (RCR-1 and RCR-2) or mitochondrial-associated protein expression. Specific increases in OXPHOS flux were not apparent after normalization to CS, indicating that gross changes mainly resulted from increased mitochondrial mass., Conclusion: Over only 2 weeks HIT significantly increased mitochondrial function in skeletal muscle independently of detectable changes in mitochondrial-associated and mitogenic protein expression.

Previous studies have suggested that breath gases may be related to simultaneous blood glucose and blood ketone levels in adults with type 2 and type 1 diabetes. The aims of this study were to investigate these relationships in children and young people with type 1 diabetes in order to assess the efficacy of a simple breath test as a non-invasive means of diabetes management. Gases were collected in breath bags and measurements were compared with capillary blood glucose and ketone levels taken at the same time on a single visit to a routine hospital clinic in 113 subjects (59 male, age 7 years 11 months-18 years 3 months) with type 1 diabetes. The patients were well-controlled with relatively low concentrations of the blood ketone measured (β hydroxybutyrate, 0-0.4 mmol l(-1)). Breath acetone levels were found to increase with blood β hydroxybutyrate levels and a significant relationship was found between the two (Spearman's rank correlation ρ = 0.364, p < 10(-4)). A weak positive relationship was found between blood glucose and breath acetone (ρ = 0.16, p = 0.1), but led to the conclusion that single breath measurements of acetone do not provide a good measure of blood glucose levels in this cohort. This result suggests a potential to develop breath gas analysis to provide an alternative to blood testing for ketone measurement, for example to assist with the management of type 1 diabetes.

Cerebral edema during diabetic ketoacidosis (DKA) is a rare complication but it can be devastating, with significant mortality and long-term morbidity. Certain risk factors have been teased out with some large case-control studies, but more research needs to be done to make management guidelines safer. This article will discuss how DKA might be prevented from occurring in the first instance, known risk factors for cerebral edema, fluid and insulin management, the importance of careful monitoring during DKA treatment, and the importance of recognizing and acting on the earliest symptoms to prevent long-term harm., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Diabetic ketoacidosis (DKA) is the leading cause of mortality in childhood diabetes, and at diagnosis might represent delayed presentation. The extent and reasons for delays are unclear, but identifying and targeting factors associated with DKA could reduce this incidence., Objective: To compare the patient pathway before diagnosis of type 1 diabetes mellitus (T1DM) in children presenting with DKA and non-acidotic hyperglycaemia., Design, Setting and Patients: Over a 3-month period, children newly diagnosed with T1DM were identified on admission to UK hospitals. Parents and medical teams completed a questionnaire about events before diagnosis., Results: Data were available for 261 children (54% male), median age 10.3y (range 0.8-16.6 y). 25% presented with DKA, but more commonly in children <2y (80% vs 23%, p<0.001). Fewer children with DKA reported polyuria (76% vs 86%) or polydipsia (86% vs 94%) (both p<0.05), but more reported fatigue (74% vs 52%) and weight loss (75% vs 54%) (both p<0.01). 24% of children had multiple healthcare professional (HCP) contacts, and these children had lower pH on admission. 46% of children with a delayed presentation to secondary care had non-urgent investigations. 64% of parents had considered a diagnosis of diabetes, and these children were less likely to present with DKA (13% vs 47%, p<0.001)., Conclusions: Multiple HCP contacts increased risk of presentation in DKA, whereas, parental awareness of diabetes was protective. Improved public and health professional education targeting non-classical symptoms, awareness of diabetes in under 2 y, and point-of-care testing could reduce DKA at diagnosis of diabetes.

Concurrent resistance and aerobic exercise (CE) is recommended to ageing populations, though is postulated to induce diminished acute molecular responses. Given that contraction-induced cytokine mRNA expression reportedly mediates remunerative postexercise molecular responses, it is necessary to determine whether cytokine mRNA expression may be diminished after CE. Eight middle-aged men (age, 53.3 ±1.8 years; body mass index, 29.4 ± 1.4 kg·m(-2)) randomly completed (balanced for completion order) 8 × 8 leg extensions at 70% maximal strength (RE), 40 min of cycling at 55% of peak aerobic workload (AE), or (workload-matched) 50% RE and 50% AE (CE). Muscle (vastus lateralis) was obtained pre-exercise, and at 1 h and 4 h postexercise, and analyzed for changes of glycogen concentration, tumor necrosis factor (TNF)α, TNF receptor-1 and -2 (TNF-R1 and TNF-R2, respectively), interleukin (IL)-6, IL-6R, IL-1β, and IL-1 receptor-antagonist (IL-1ra). All exercise modes upregulated cytokine mRNA expression at 1 h postexercise comparably (TNFα, TNF-R1, TNF-R2, IL-1β, IL-6) (p < 0.05). Expression remained elevated at 4 h after RE and AE (p < 0.05), though returned to pre-exercise levels after CE (p > 0.05). Moreover, AE and RE upregulated IL-1β and IL-1ra expression, whereas CE upregulated IL-1β expression only (p < 0.05). Only AE reduced muscle glycogen concentration (p < 0.05), whilst upregulating receptor expression the greatest; though, IL-6R expression remained unchanged after all modes (p > 0.05). In conclusion, in middle-aged men, all modes induced commensurate cytokine mRNA expression at 1 h postexercise; however, only CE resulted in ameliorated expression at 4 h postexercise. Whether the RE or AE components of CE are independently or cumulatively sufficient to upregulate cytokine responses, or whether they collectively inhibit cytokine mRNA expression, remains to be determined.

Understanding transcriptional regulation of pancreatic development is required to advance current efforts in developing beta cell replacement therapies for patients with diabetes. Current knowledge of key transcriptional regulators has predominantly come from mouse studies, with rare, naturally occurring mutations establishing their relevance in man. This study used a combination of homozygosity analysis and Sanger sequencing in 37 consanguineous patients with permanent neonatal diabetes to search for homozygous mutations in 29 transcription factor genes important for murine pancreatic development. We identified homozygous mutations in 7 different genes in 11 unrelated patients and show that NKX2-2 and MNX1 are etiological genes for neonatal diabetes, thus confirming their key role in development of the human pancreas. The similar phenotype of the patients with recessive mutations and mice with inactivation of a transcription factor gene support there being common steps critical for pancreatic development and validate the use of rodent models for beta cell development., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

The effect of duration-matched concurrent exercise training (CET) (50% resistance (RET) and 50% endurance (EET) training) on physiological training outcomes in untrained middle-aged men remains to be elucidated. Forty-seven men (age, 48.1 ± 6.8 years; body mass index, 30.4 ± 4.1 kg·m(-2)) were randomized into 12-weeks of EET (40-60 min of cycling), RET (10 exercises; 3-4 sets × 8-10 repetitions), CET (50% serial completion of RET and EET), or control condition. The following were determined: intervention-based changes in fitness and strength; abdominal visceral adipose tissue (VAT), total body fat (TB-FM) and fat-free (TB-FFM) mass; plasma cytokines (C-reactive protein (CRP), tumor necrosis factor-α (TNFα) interleukin-6 (IL-6)); muscle protein content of p110α and glucose transporter 4 (GLUT4); mRNA expression of GLUT4, peroxisome proliferator-activated receptor-γ coactivator-1α-β, cytochrome c oxidase, hexokinase II, citrate synthase; oral glucose tolerance; and estimated insulin sensitivity. CET promoted commensurate improvements of aerobic capacity and muscular strength and reduced VAT and TB-FM equivalently to EET and RET (p < 0.05), yet only RET increased TB-FFM (p < 0.05). Although TNFα and IL-6 were reduced after all training interventions (p < 0.05), CRP remained unchanged (p > 0.05). EET reduced area under the curve for glucose, insulin, and C-peptide, whilst CET and RET respectively reduced insulin and C-peptide, and C-peptide only (p < 0.05). Notwithstanding increased insulin sensitivity index after all training interventions (p < 0.05), no change presented for GLUT4 or p110α total protein, or chronic mRNA expression of the studied mitochondrial genes (p > 0.05). In middle-aged men, 12 weeks of duration-matched CET promoted commensurate changes in fitness and strength, abdominal VAT, plasma cytokines and insulin sensitivity, and an equidistant glucose tolerance response to EET and RET; despite no change of measured muscle mechanisms associative to insulin action, glucose transport, and mitochondrial function.

Aim: Hospital inpatient care for children with diabetes is frequently mentioned by parents as unsatisfactory. The aim of this study was to examine the reasons for inpatient admission of children with diabetes and to understand patient and carer experience in order to improve services., Methods: Questionnaires were given to medical teams, parents and children during admissions of children with diabetes under 16 years of age in three regions of England., Results: There were 401 admissions over 6 months from 3247 patients: 334 (83%) emergency admissions and 59 (15%) elective; the reason is unknown in eight (2%). One hundred and forty-three (36%) were emergency admissions with diabetic ketoacidosis/hyperglycaemia. Clinical teams reported adverse events around insulin administration in 25, hypoglycaemia (sometimes recurrent) in 120 and food provision in 14 admissions. Others included seven incidents around elective surgery. Diabetes clinical teams were not always informed about admissions and only 33% were informed within 2 h. Parents and children reported fewer problems: 62% were involved in care most of the time and 87% were able to give insulin. Most negative comments were about poor staff management of out-of-range blood glucose levels, knowledge of insulin pumps and care of children waiting in the emergency department., Conclusions: There were a large number of admissions and the majority were emergencies. Parents generally felt that they receive good care, although with some lack of knowledge amongst the ward staff. There were an unacceptable number of adverse incidents reported. We recommend that education of ward staff in diabetes is carried out regularly with reference to the standards of care., (© 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.)

We determined myofibrillar and mitochondrial protein fractional synthesis rates (FSR), intramuscular signaling protein phosphorylation, and mRNA expression responses after isolated bouts of resistance exercise (RE), aerobic exercise (AE), or in combination [termed concurrent exercise (CE)] in sedentary middle-aged men. Eight subjects (age = 53.3 ± 1.8 yr; body mass index = 29.4 ± 1.4 kg·m(2)) randomly completed 8 × 8 leg extension repetitions at 70% of one repetition-maximum, 40 min of cycling at 55% peak aerobic power output (AE), or (consecutively) 50% of the RE and AE trials (CE). Biopsies were obtained (during a primed, constant infusion of l-[ring-(13)C(6)]phenylalanine) while fasted, and at 1 and 4 h following postexercise ingestion of 20 g of protein. All trials increased mitochondrial FSR above fasted rates (RE = 1.3-fold; AE = 1.5; CE = 1.4; P < 0.05), although only CE (2.2) and RE (1.8) increased myofibrillar FSR (P < 0.05). At 1 h postexercise, phosphorylation of Akt on Ser(473) (CE = 7.7; RE = 4.6) and Thr(308) (CE = 4.4; RE = 2.9), and PRAS40 on Thr(246) (CE = 3.8; AE = 2.5) increased (P < 0.05), with CE greater than AE for Akt Ser(473)-Thr(308) and greater than RE for PRAS40 (P < 0.05). Despite increased phosphorylation of Akt-PRAS40, phosphorylation of mammalian target of rapamycin (Ser(2448)) remained unchanged (P > 0.05), while rpS6 (Ser(235/236)) increased only in RE (10.4) (P < 0.05). CE and AE both resulted in increased peroxisome proliferator receptor-γ coactivator 1-α (PGC1α) expression at 1 h (CE = 2.9; AE = 2.8; P < 0.05) and 4 h (CE = 2.6; AE = 2.4) and PGC1β expression at 4 h (CE = 2.1; AE = 2.6; P < 0.05). These data suggest that CE-induced acute stimulation of myofibrillar and mitochondrial FSR, protein signaling, and mRNA expression are equivalent to either isolate mode (RE or AE). These results occurred without an interference effect on muscle protein subfractional synthesis rates, protein signaling, or mRNA expression.

The aim of this study was to examine the effects of wearing different grades of graduated compression stockings (GCS) on 10-km running performance. After an initial familiarization run, 9 male and 3 female competitive runners (VO₂max 68.7 ± 5.8 ml·kg⁻¹·min⁻¹) completed 4 10-km time trials on an outdoor 400-m track wearing either control (0 mm Hg; Con), low (12-15 mm Hg; Low), medium (18-21 mm Hg; Med), or high (23-32 mm Hg; Hi) GCS in a randomized counterbalanced order. Leg power was assessed pre and postrun via countermovement jump using a jump mat. Blood-lactate concentration was assessed pre and postrun, whereas heart rate was monitored continuously during exercise. Perceptual scales were used to assess the comfort, tightness, and any pain associated with wearing GCS. There were no significant differences in performance time between trials (p = 0.99). The change in pre to postexercise jump performance was lower in Low and Med than in Con (p < 0.05). Mean heart rate (p = 0.99) and blood lactate (p = 1.00) were not different between trials. Participants rated Con and Low as more comfortable than Med and Hi (p < 0.01), Med and Hi were rated as tighter than Low (p < 0.01), all GCS were rated as tighter than Con (p < 0.01), and Hi was associated with the most pain (p < 0.01). In conclusion, GCS worn by competitive runners during 10-km time trials did not affect performance time; however Low and Med GCS resulted in greater maintenance of leg power after endurance exercise. Athletes rated low-grade GCS as most comfortable garments to wear during exercise.

Introduction: There is some evidence of long-term tracking of HbA(1c) levels within diabetes centres, but little evidence of individual tracking., Methods: HbA(1c) levels of children in the clinic over a period of 15 years were retrieved from the clinical chemistry laboratory information system. We measured the correlation of HbA(1c) between years (Spearman and Pearson rank correlation), as well as the relationship of HbA(1c) with age and the change over time in the clinic., Results: Data were collected from 362 children and young people [158 female (44%)], aged 0-18 years (median 10.4 years), with 0-13.6 years of follow-up (median 4.7 years). Mean HbA(1c) levels fell from 9.3 ± 1.5% (78 ± 16 mmol/mol) in 2001 to 8.1 ± 1.3% (65 ± 14 mmol/mol) in 2009 in those at least 6 months after diagnosis (P<0.0001). HbA(1c) levels gradually rise with increasing age. HbA(1c) levels from year to year are significantly correlated. This is better for adjacent than subsequent years, but there is a significant correlation up to 9 years from diagnosis. Only 4 of 49 children with a 6-month HbA(1c) level of 9% (75 mmol/mol) or more had a long-term (2-5 years) median HbA(1c) <8% (64 mmol/mol)., Conclusions: HbA(1c) levels track in individuals within an improvement in overall clinic levels, suggesting that, if optimal control can be achieved in the first 6 months, it can persist for up to 9 years., (© 2010 The Authors. Diabetic Medicine © 2010 Diabetes UK.)

Aim: To assess the provision of UK paediatric and adolescent diabetes services and examine changes in service delivery since 2002., Method: Questionnaires were sent to the lead paediatric consultant from all paediatric and adolescent diabetes services (n=205). Questions were based on National Institute for Health and Clinical Excellence and Scottish Intercollegiate Guidelines recommendations for diabetes care in childhood. Results were analysed using parametric and non-parametric tests., Results: 129 Services (63%) returned questionnaires involving 220 clinics. Staffing has improved and 98% of consultants have a special interest in diabetes (89%, 2002). In 88% of services, the diabetes specialist nurse worked solely in paediatric diabetes (53%, 2002). Only 21% of clinics have a psychological professional integrated within the diabetes team (20%, 2002). Over 94% of services offered support with intensive insulin regimens causing problems at school for 36% of services. Almost all services offer annual microvascular screening (98-100%) but transitional care was variable; only 76% of services have specific local protocols for transition and 21% organise transfer by letter only., Conclusion: Paediatric and adolescent diabetes services are rising to the challenge of providing high-quality care despite rising prevalence and increasingly complex insulin regimes. Services have improved in a number of key areas but serious deficiencies remain.

This study examined the effect of wearing different grades of graduated compression stockings (GCS) on physiological and perceptual measures during and following treadmill running in competitive runners. Nine males and one female performed three 40-min treadmill runs (80 +/- 5% maximal oxygen uptake) wearing either control (0 mmHg; CON), low (12-15 mmHg; LO-GCS), or high (23-32 mmHg; HI-GCS) grade GCS in a double-blind counterbalanced order. Oxygen uptake, heart rate and blood lactate were measured. Perceptual scales were used pre- and post-run to assess comfort, tightness and any pain associated with wearing GCS. Changes in muscle function, soreness and damage were determined pre-run, immediately after running and 24 and 48 h post-run by measuring creatine kinase and myoglobin, counter-movement jump height, perceived soreness diagrams, and pressure sensitivity. There were no significant differences between trials for oxygen uptake, heart rate or blood lactate during exercise. HI-GCS was perceived as tighter (P < 0.05) and more pain-inducing (P < 0.05) than the other interventions; CON and LO-GCS were rated more comfortable than HI-GCS (P < 0.05). Creatine kinase (P < 0.05), myoglobin (P < 0.05) and jump height (P < 0.05) were higher and pressure sensitivity was more pronounced (P < 0.05) immediately after running but not after 24 and 48 h. Only four participants reported muscle soreness during recovery from running and there were no differences in muscle function between trials. In conclusion, healthy runners wearing GCS did not experience any physiological benefits during or following treadmill running. However, athletes felt more comfortable wearing low-grade GCS whilst running.

Minimising carbohydrate (CHO) status in the peri-training period may accelerate the training adaptations normally observed. The aim of this study was to compare adaptations to endurance training undertaken in the acutely CHO fed and overnight-fasted states. Eight female and six male untrained, healthy participants: aged 26.6+/-5.8 years (mean+/-SD); height 174.7+/-7.6 cm; weight 75.3+/-11.4 kg; VO(2max) 3.48+/-0.67 l/min; were randomly divided into two training groups and undertook four weeks of five days per week endurance cycle ergometer training in either the overnight-fasted (FAST) or acutely fed (FED) state. FAST training had no effect on RER or plasma glucose, lactate and FFA concentrations during subsequent submaximal exercise. Training-induced changes in Vastus lateralis citrate synthase (CS) and 3-hydroxy-CoA dehydrogenase (HAD) activities were not different between training groups (P=0.655 and 0.549, respectively), but when the effect of gender was considered, men responded better to FAST and women responded better to FED. The FAST group showed a significantly greater training-induced increase in VO(2max) and resting muscle glycogen concentration than FED (P=0.014 and P=0.047 respectively), but there was no gender interaction. In conclusion, these results suggest that (a) meal ingestion prior to daily exercise can modify some of the exercise training-induced adaptations normally seen with endurance training compared to when daily exercise is undertaken in the overnight-fasted state; and (b) the extent of these adaptations in skeletal muscle differ slightly between men and women., (Copyright 2010 Sports Medicine Australia. All rights reserved.)

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 (HbA(1c)) (P > 0.05). Mean gram error and meal size were negatively correlated (r = -0.70, P < 0.0001). The longer children had been CHO counting the greater the mean percentage error (r = 0.173, P = 0.014). Core foods in non-standard quantities were most frequently inaccurately estimated, while individually labelled foods were most often accurately estimated., Conclusions: Children with Type 1 diabetes and their caregivers can estimate the carbohydrate content of meals with reasonable accuracy. Teaching CHO counting in gram increments did not improve accuracy compared with CHO portions or exchanges. Large meals tended to be underestimated and snacks overestimated. Repeated age-appropriate education appears necessary to maintain accuracy in carbohydrate estimations.

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 < 0.01). Factors associated with poorer sibling adjustment were higher sibling age at diagnosis, higher levels of parenting stress, more difficult sibling temperament, poorer adjustment of the child with T1DM, higher levels of parental distress and more negative sibling perceptions of diabetes and its impact on the family. Results suggest that sibling perceptions of diabetes and parental distress are important predictors of sibling adjustment to T1DM., Conclusions: The findings from this study emphasize the relationships between the adjustment of the sibling and that of the child with T1DM and their parents. Many parents worry about how the siblings may cope with the diabetes, but the results of this study are generally reassuring.

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 HbA(1c) > 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 HbA(1c), 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.

This article reviews the management of diabetic ketoacidosis (DKA) in adults with a focus on the three basic principles of treatment: intravenous fluid therapy, intravenous insulin administration and potassium replacement. The recommendations are modelled on the national guidance for the management of DKA in children. We highlight the importance of being alert to signs of life-threatening complications of the condition such as cerebral oedema and adult respiratory distress syndrome (ARDS). We also discuss the use of near-patient testing of capillary beta-hydroxybutyrate (b-OHB) using a ketone meter as an aid to managing and preventing DKA.

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<0.001). In addition, cases had higher potassium and urea levels at baseline. Calculated osmolality and baseline glucose were not significantly different. After allowing for severity of acidosis, insulin administration in the first hour (OR 12.7 [1.41-114.5], p=0.02) and volume of fluid administered over the first 4 h (OR 6.55 [1.38-30.97], p=0.01) were associated with risk. Low baseline plasma sodium and an elevated p(a)CO(2) also contributed to risk in the final regression model. Bicarbonate administration was not associated with increased risk of an event when corrected for acidosis., Conclusions/interpretation: In this case-control study of DKA, baseline acidosis and abnormalities of sodium, potassium and urea concentrations were important predictors of risk of cerebral oedema. Additional risk factors identified were early administration of insulin and high volumes of fluid. These observations should be taken into account when designing treatment protocols.

Background: Previous surveys of children's diabetes service provision in the UK have shown gradual improvements but continuing deficiencies., Aim: To determine whether further improvements in services have occurred., Methods: A questionnaire was mailed to all paediatricians in the UK identified as providing care for children and adolescents with diabetes. Responses were compared with results of three previous surveys, and with recommendations in the Diabetes NSF and the NICE type 1 diabetes guidelines., Results: Replies were received from 187 consultant paediatricians in 169 centres looking after children; 89% expressed a special interest in diabetes, 98% saw children in a designated diabetic clinic, and 95% clinics now have more than 40 patients. In 98% of the clinics there was a specialist nurse (82% now children's trained), but 61% clinics had a nurse:patient ratio <1:100; 39% of clinics did not have a paediatric dietician and in 78% there was no access to psychology/psychiatry services in clinics. Glycated haemoglobin was measured routinely at clinics in 86%, annual screening for retinopathy performed in 80%, and microalbuminuria in 83%. All centres now have local protocols for ketoacidosis, but not for children undergoing surgery (90%) or severe hypoglycaemia (74%). Mean clinic HbA1c levels were significantly lower in the clinics run by specialists (8.9%) than generalists (9.4%). There have been incremental improvements over the last 14 years since the surveys began, but only two clinics met all the 10 previously published recommendations on standards of care., Conclusions: The survey shows continuing improvements in organisational structure of services for children with diabetes but serious deficiencies remain. Publication and dissemination of the results of the previous surveys may have been associated with these improvements and similar recurrent service review may be applicable to services for other chronic childhood conditions.

Aims/hypothesis: It has been postulated that hypoglycaemia-related cardiac dysrhythmia and, in particular, prolonged cardiac repolarisation, may contribute to increased mortality rates in children and adolescents with type 1 diabetes., Methods: We examined the prevalence of prolonged QT interval on ECG during spontaneous hypoglycaemia in 44 type 1 diabetic subjects (aged 7-18 years), and explored the relationships between serial overnight measurements of QT interval corrected for heart rate (QTc) and serum glucose, potassium and epinephrine levels. Each subject underwent two overnight profiles; blood was sampled every 15 min for glucose measurements and hourly for potassium and epinephrine. Serial ECGs recorded half-hourly between 23.00 and 07.00 hours were available on 74 nights: 29 with spontaneous hypoglycaemia (defined as blood glucose <3.5 mmol/l) and 45 without hypoglycaemia., Results: Mean overnight QTc was longer in females than in males (412 vs 400 ms, p=0.02), but was not related to age, diabetes duration or HbA(1)c. Prolonged QTc (>440 ms) occurred on 20 out of 74 (27%) nights, with no significant differences between male and female subjects, and was more prevalent on nights with hypoglycaemia (13/29, 44%) than on nights without (7/45, 15%, p=0.0008). Potassium levels were lower on nights when hypoglycaemia occurred (minimum potassium 3.4 vs 3.7 mmol/l, p=0.0003) and were inversely correlated with maximum QTc (r=-0.40, p=0.03). In contrast, epinephrine levels were not higher on nights with hypoglycaemia and were not related to QTc., Conclusions/interpretation: In young type 1 diabetic subjects, prolonged QTc occurred frequently with spontaneous overnight hypoglycaemia and may be related to insulin-induced hypokalaemia.

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 (< 3.5 mmol/l) was lower on lispro (8% of blood glucose levels) than on soluble insulin (13%, P = 0.01). In the early morning (04.00-07.00 h) mean blood glucose and prevalence of low levels were no different between the two treatment groups, and fasting (07.00 h) blood glucose levels were similar (6.1 +/- 0.8 vs. 6.3 +/- 0.9 mmol/l, P = 0.8). At the end of each treatment arm there were no differences in HbA1c (lispro vs. soluble 8.6% vs. 8.4%, P = 0.3), or in insulin doses (mean, range 0.97, 0.68-1.26 vs. 0.96, 0.53-1.22 U/kg per day, P = 0.2)., Conclusions: The shorter duration of action of insulin lispro given before the evening meal may reduce the prevalence of early nocturnal hypoglycaemia without compromising HbA1c in young children with T1DM.

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 < 16 years of age between 1985 and 1995, identified from the regional diabetes register. The notes audit was completed for 222 (97%) and 164 (72%) were interviewed by a single research nurse. Mean age at transfer was 17.9 years (range 13.3-22.4 years). Few young people were lost to follow-up at the point of transfer. There was a high rate of clinic attendance (at least 6 monthly) 2 years pretransfer (94%), but this declined to 57% 2 years post-transfer (P < 0.0005). There was large interdistrict variation in clinic attendance 2 years post-transfer (29% to 71%); higher rates were seen in districts where young people had the opportunity to meet the adult diabetes consultant prior to transfer. The importance of this opportunity was confirmed by questionnaire responses on interview., Conclusions: Adolescence is a vulnerable period for patients with diabetes. This regional survey demonstrated a marked decline in clinic attendance around the time of transition from paediatric to adult services. The reasons are complex, but mode of transfer may be an important factor.

Neurological deterioration during an episode of diabetic ketoacidosis is usually assumed to be caused by cerebral oedema. We present a case of cerebral venous sinus thrombosis presenting in a similar manner, also associated with severe iron deficiency anaemia. Computed tomography scanning provided the correct diagnosis and allowed institution of anticoagulation with improvement in neurological outcome. Neuroimaging should always be performed in suspected cerebral oedema associated with diabetic ketoacidosis in order to exclude other pathologies.

Background: Cerebral oedema is a major cause of morbidity and mortality in children with insulin dependent diabetes., Aims: To determine the risk and outcome of cerebral oedema complicating diabetic ketoacidosis (DKA)., Methods: All 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., Results: A 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)., Conclusions: This 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.

Cerebral oedema remains the leading cause of death and morbidity in children with Type 1 diabetes mellitus. Around seven per thousand episodes of diabetic ketoacidosis (DKA) are complicated by cerebral oedema, and one-quarter of those children will die from it. The cause or causes of cerebral oedema are still very poorly understood, but lawyers are already keen to implicate various aspects of the management of DKA. There have been many theories as to the pathophysiology of cerebral oedema, and possible contributing factors may be excessive rate of rehydration, falling plasma osmolality (particularly that due to a reduction in plasma sodium concentration), hypoxia and insulin dosage. There is some supportive evidence for all of these factors in some cases, but there have been no sizeable case-control studies, in part because of the rarity of the condition. Furthermore, cerebral oedema can still occur even when the management of DKA follows current 'best practice' guidelines. As the mechanisms of cell volume regulation within the brain are increasingly understood, different questions may provide greater insights. For example, what is it about children that makes them so much more susceptible to cerebral oedema than adults? And why does one child treated in a certain way develop cerebral oedema whereas another does not? The anxiety over causing cerebral oedema has driven most of the changes in the management of DKA over recent decades, yet there is no evidence that the incidence has reduced. Until the causes are understood, we cannot be dogmatic about treatment recommendations., (Copyright 2000 John Wiley & Sons, Ltd.)