Target setting in intensive insulin management is associated with metabolic control: the Hvidoere childhood diabetes study group centre differences study 2005.

OBJECTIVE: To evaluate glycaemic targets set by diabetes teams, their perception by adolescents and parents, and their influence on metabolic control. METHODS: Clinical data and questionnaires were completed by adolescents, parents/carers and diabetes teams in 21 international centres. HbA1c was measured centrally. RESULTS: A total of 2062 adolescents completed questionnaires (age 14.4 +/- 2.3 yr; diabetes duration 6.1 +/- 3.5 yr). Mean HbA 1c = 8.2 +/- 1.4% with significant differences between centres (F = 12.3; p < 0.001) range from 7.4 to 9.1%. There was a significant correlation between parent (r = 0.20) and adolescent (r = 0.21) reports of their perceived ideal HbA1c and their actual HbA1c result (p < 0.001), and a stronger association between parents' (r = 0.39) and adolescents' (r = 0.4) reports of the HbA1c they would be happy with and their actual HbA1c result. There were significant differences between centres on parent and adolescent reports of ideal and happy with HbA1c (8.1 < F > 17.4;p < 0.001). A lower target HbA1c and greater consistency between members of teams within centres were associated with lower centre HbA1c (F = 16.0; df = 15; p < 0.001). CONCLUSIONS: Clear and consistent setting of glycaemic targets by diabetes teams is strongly associated with HbA1c outcome in adolescents. Target setting appears to play a significant role in explaining the differences in metabolic outcomes between centres.

Are family factors universally related to metabolic outcomes in adolescents with Type 1 diabetes?

AIMS: To assess the importance of family factors in determining metabolic outcomes in adolescents with Type 1 diabetes in 19 countries. METHODS: Adolescents with Type 1 diabetes aged 11-18 years, from 21 paediatric diabetes care centres, in 19 countries, and their parents were invited to participate. Questionnaires were administered recording demographic data, details of insulin regimens, severe hypoglycaemic events and number of episodes of diabetic ketoacidosis. Adolescents completed the parental involvement scale from the Diabetes Quality of Life for Youth--Short Form (DQOLY-SF) and the Diabetes Family Responsibility Questionnaire (DFRQ). Parents completed the DFRQ and a Parental Burden of Diabetes score. Glycated haemoglobin (HbA(1c)) was analysed centrally on capillary blood. RESULTS: A total of 2062 adolescents completed a questionnaire, with 2036 providing a blood sample; 1994 parents also completed a questionnaire. Family demographic factors that were associated with metabolic outcomes included: parents living together (t = 4.1; P < 0.001), paternal employment status (F = 7.2; d.f. = 3; P < 0.001), parents perceived to be over-involved in diabetes care (r = 0.11; P < 0.001) and adolescent-parent disagreement on responsibility for diabetes care practices (F = 8.46; d.f. = 2; P < 0.001). Although these factors differed between centres, they did not account for centre differences in metabolic outcomes, but were stronger predictors of metabolic control than age, gender or insulin treatment regimen. CONCLUSIONS: Family factors, particularly dynamic and communication factors such as parental over-involvement and adolescent-parent concordance on responsibility for diabetes care appear be important determinants of metabolic outcomes in adolescents with diabetes. However, family dynamic factors do not account for the substantial differences in metabolic outcomes between centres.

Persistent differences among centers over 3 years in glycemic control and hypoglycemia in a study of 3,805 children and adolescents with type 1 diabetes from the Hvidøre Study Group.

OBJECTIVE: Twenty-one international pediatric diabetes centers from 17 countries investigated the effect of simple feedback about the grand mean HbA(1c) level of all centers and the average value of each center on changes in metabolic control, rate of severe hypoglycemia, and insulin therapy over a 3-year period. RESEARCH DESIGN AND METHODS: Clinical data collection and determination of HbA(1c) levels were conducted at a central location in 1995 (n = 2,780, age 0-18 years) and 1998 (n = 2,101, age 11-18 years). RESULTS: Striking differences in average HbA(1c) concentrations were found among centers; these differences remained after adjustment for the significant confounders of sex, age, and diabetes duration. They were apparent even in patients with short diabetes duration and remained stable 3 years later (mean adjusted HbA(1c) level: 8.62 +/- 0.03 vs. 8.67 +/- 0.04 [1995 vs. 1998, respectively]). Three centers had improved significantly, four centers had deteriorated significantly in their overall adjusted HbA(1c) levels, and 14 centers had not changed in glycemic control. During the observation period, there were increases in the adjusted insulin dose by 0.076 U/kg, the adjusted number of injections by 0.23 injections per day, and the adjusted BMI by 0.95 kg/m(2). The 1995 versus 1998 difference in glycemic control for the seven centers could not be explained by prevailing insulin regimens or rates of hypoglycemia. CONCLUSIONS: This study reveals significant outcome differences among large international pediatric diabetes centers. Feedback and comparison of HbA(1c) levels led to an intensification of insulin therapy in most centers, but improved glycemic control in only a few.

Good metabolic control is associated with better quality of life in 2,101 adolescents with type 1 diabetes.

OBJECTIVE: It is unclear whether the demands of good metabolic control or the consequences of poor control have a greater influence on quality of life (QOL) for adolescents with diabetes. This study aimed to assess these relations in a large international cohort of adolescents with diabetes and their families. RESEARCH DESIGN AND METHODS: The study involved 2,101 adolescents, aged 10-18 years, from 21 centers in 17 countries in Europe, Japan, and North America. Clinical and demographic data were collected from March through August 1998. HbA(1c) was analyzed centrally (normal range 4.4-6.3%; mean 5.4%). Adolescent QOL was assessed by a previously developed Diabetes Quality of Life (DQOL) questionnaire for adolescents, measuring the impact of diabetes, worries about diabetes, satisfaction with life, and health perception. Parents and health professionals assessed family burden using newly constructed questionnaires. RESULTS: Mean HbA(1c) was 8.7% (range 4.8-17.4). Lower HbA(1c) was associated with lower impact (P < 0.0001), fewer worries (P < 0.05), greater satisfaction (P < 0.0001), and better health perception (P < 0.0001) for adolescents. Girls showed increased worries (P < 0.01), less satisfaction, and poorer health perception (P < 0.01) earlier than boys. Parent and health professional perceptions of burden decreased with age of adolescent (P < 0.0001). Patients from ethnic minorities had poorer scores for impact (P < 0.0001), worries (P < 0.05), and health perception (P < 0.01). There was no correlation between adolescent and parent or between adolescent and professional scores. CONCLUSIONS: In a multiple regression model, lower HbA(1c) was significantly associated with better adolescent-rated QOL on all four subscales and with lower perceived family burden as assessed by parents and health professionals.

Endothelial cell damage in piglet coronary artery after intravenous administration of E. coli endotoxin. A scanning and transmission electron-microscopic study.

E. Coli endotoxin was administered to 6 piglets from a litter of 10. Three days after the endotoxin stimulus 3 piglets showed definitive morphological evidence of endothelial damage to their left coronary artery. The proximal parts of the coronary artery were severely damaged. In scanning electron microscopy, the changes varied from disappearance of the microvilli to complete exfoliation of the endothelial cells. In cases of severe endothelial cell damage transmission electron microscopy revealed severe changes or even signs of cell death in the inner medial smooth muscle cells. Only of the piglets died prematurely. We are sufficiently encouraged to continue testing the theory that repeated endothelial cell damage initiates stenosing lesions in the coronary arteries.

Effect of repeated endotoxin treatment and hypercholesterolemia on preatherosclerotic lesions in weaned pigs. Part II. Lipid and glycosaminoglycan analysis of intima and inner media.

We compared the effects of mild hypercholesterolemia and repeated endotoxin infusions on the biochemical composition of aortic intima and inner media of 24 piglets divided into 4 groups 5 days after weaning: controls on normal diet (group I); normal diet and endotoxin (group II); fat-supplemented diet (group III); and fat-supplemented diet and endotoxin (group IV). It was found that mild hypercholesterolemia increased the concentration of arterial esterified cholesterol and the relative amount of the fraction containing chondroitin sulphates A and C in total glycosaminoglycans. Endotoxin infusions partly prevented the increase of serum cholesterol caused by the fat-supplemented diet but had no independent effect on the arterial biochemical composition; nor did they affect the biochemical changes caused by hypercholesterolemia. When the results of all groups were combined, chondroitin sulphates A and C showed a significant positive correlation with the concentration of arterial esterified cholesterol and the percentage of linoleic acid in arterial cholesteryl esters. Serum total cholesterol did not correlate with arterial cholesterol fractions, but the ratio of high density lipoprotein-cholesterol to total serum cholesterol showed a negative association with arterial esterified cholesterol. The present findings indicate that (1) mild hypercholesterolemia is atherogenic in young piglets, and (2) changes in arterial glycosaminoglycan composition might be one of the earliest biochemical alterations in atherogenesis.

Effect of repeated endotoxin treatment and hypercholesterolemia on preatherosclerotic lesions in weaned pigs. Part 1. Scanning and transmission electron microscopic study.

Endothelial cell damage is considered to be the primary event in atherogenesis. In this study we compared the effects of mild hypercholesterolemia and repeated E. coli endotoxin infusions on the endothelial cells of the coronary arteries of the pig. We divided 24 pigs into 4 groups: I: controls on normal diet; II: normal diet and endotoxin treatment; III: fat-supplemented diet; IV: fat-supplemented diet and endotoxin treatment. The animals on a fat-supplemented diet showed the most frequent and most severe endothelial cell damage. The damage was less when this diet was combined with endotoxin treatment. Endotoxin reduced the serum total cholesterol level (P less than 0.01). The cholesterol level correlated very significantly (P less than 0.001) with endothelial damage of the coronary arteries. Mild hypercholesterolemia (s-cholesterol 5.68 mmol/l, controls 2.28 mmol/l) was thus associated with toxic effects in the endothelial cells. The E. coli endotoxin infusions did not have any cumulative effect on the lesions.

Clarithromycin vs. amoxicillin suspensions in the treatment of pediatric patients with acute otitis media.

Clarithromycin is a new macrolide antibiotic that is active in vitro against a variety of organisms that are responsible for acute otitis media in children. The parent compound is metabolized to microbiologically active 14-hydroxy clarithromycin, which is especially active against Haemophilus influenzae. The safety and efficacy of clarithromycin and amoxicillin suspensions were compared in the treatment of acute otitis media in children 1 to 12 years of age inclusive. This was a Phase III, single blind (investigator-blind), randomized, multicenter clinical trial. Clarithromycin oral suspension was given in a dose of 7.5 mg/kg (maximum, 500 mg) twice daily, and amoxicillin suspension in a dose of 20 mg/kg (maximum, 750 mg) was given twice daily for 7 to 10 days in a 1:1 ratio. Clinical evaluations were performed pretreatment, within 48 hours posttreatment and 10 to 14 days posttreatment. Myringotomy was performed in every child to obtain a microbiologic sample pretreatment and at subsequent visits as clinically indicated. A total of 79 children were enrolled, 39 in the clarithromycin and 40 in the amoxicillin treatment group. Thirty-two children were excluded from the efficacy analysis for various reasons. Clinical success (cure and improvement) rates at 0 to 4 days posttreatment were 93% for clarithromycin and 90% for amoxicillin (P > 0.999). Altogether 17 children (10 receiving clarithromycin, 7 receiving amoxicillin) experienced some adverse event, with gastrointestinal disorders being the most common complaint. No clinically significant differences in laboratory tests were found between the groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Associations of serum lipids with metabolic control and diet in young subjects with insulin-dependent diabetes mellitus in Finland.

Association of serum lipids with metabolic control and diet were studied in 72 young subjects with insulin-dependent diabetes mellitus (IDDM). Data on food consumption were collected by the 48-h recall method. Glycosylated haemoglobin (Hb) A1 was used as a measure of metabolic control. There were no differences between males and females in the mean values for serum total cholesterol (TC, 4.5 and 4.9 mmol/l, respectively), low density lipoprotein cholesterol (LDL-C, 2.7 and 3.0 mmol/l), high density lipoprotein cholesterol (HDL-C, 1.3 and 1.4 mmol/l), or serum triglycerides (TG, 1.1 and 1.0 mmol/l). Diabetic subjects who were in better metabolic control (HbA1 < 10.5%), when compared with those in poorer control (HbA1 > or = 10.5%) had lower TC and TG values and a higher HDL-C/TC ratio. HbA1 level and intake of saturated fatty acids were positively associated with serum TC and LDL-C values and explained 14% and 15% of the variation in TC and LDL-C, respectively. HbA1 level and insulin dose per kg of body weight were positively associated with serum TG values and explained 30% of the variation in TG. Serum TC and LDL-C levels of young subjects with IDDM could be lowered by improving their metabolic control and decreasing their saturated fatty acid intake.

Morphotypes of the subgingival microflora in diabetic adolescents in Finland.

The morphotypes of the subgingival microflora from 85 12 to 18-year-old Finnish adolescents with insulin-dependent diabetes mellitus (IDDM) were studied in Gram- and Rhodes-stained smears. A comparison was made with subgingival plaque samples from paired age- and sex-matched healthy controls. Significant differences were found in the distribution of the morphotypes. The microflora in the IDDM patient group contained significantly lower proportions of Gram-positive and Gram-negative cocci and total Gram-positive bacteria and higher proportions of Gram-negative rods, fusiforms, and total Gram-negative bacteria. In the Rhodes-stained samples, the patients had more straight and curved rods and less fusiforms than the controls. The proportions of spirochetes and flagellated bacteria were almost identical in both groups. The clinical periodontal status of the subjects had been reported in a separate study. In spite of similar Plaque Index scores, the patients had more gingivitis than the controls. This finding may be explained by the distribution of morphotypes: more Gram-negative rods and total Gram-negative bacteria (periodontally more pathogenic forms) in the diabetic patients.

Care in diabetic emergencies.

A review is presented on the care of three diabetic emergencies: diabetic ketoacidosis (DKA), hypoglycemias and sick days. A treatment scheme, based on low-dose insulin regime and i.v. insulin administration is presented. Plenty of emphasis is laid on fluid and electrolyte therapy. It is stressed that the primary goal in the treatment of DKA is not to reduce blood glucose, but to correct the fluid and electrolyte deficit and by administering insulin to correct the metabolic acidosis and change catabolism into anabolism. The use of bicarbonate in severe DKA is discouraged, and the risk of cerebral edema as a complication of the treatment is stressed. A diabetic child being treated for DKA needs particularly love and care. The three categories of hyperglycemias, mild, moderate, and severe, are briefly reviewed. In severe hypoglycemia (hypoglycemic shock) the treatment is either i.m. glucagon or i.v. glucose. In acute illnesses the use of extra doses of regular insulin is emphasized, in order to prevent DKA.

Establishing glycaemic control with continuous subcutaneous insulin infusion in children and adolescents with type 1 diabetes: experience of the PedPump Study in 17 countries.

AIMS/HYPOTHESIS: To assess the use of paediatric continuous subcutaneous infusion (CSII) under real-life conditions by analysing data recorded for up to 90 days and relating them to outcome. METHODS: Pump programming data from patients aged 0-18 years treated with CSII in 30 centres from 16 European countries and Israel were recorded during routine clinical visits. HbA(1c) was measured centrally. RESULTS: A total of 1,041 patients (age: 11.8 +/- 4.2 years; diabetes duration: 6.0 +/- 3.6 years; average CSII duration: 2.0 +/- 1.3 years; HbA(1c): 8.0 +/- 1.3% [means +/- SD]) participated. Glycaemic control was better in preschool (n = 142; 7.5 +/- 0.9%) and pre-adolescent (6-11 years, n = 321; 7.7 +/- 1.0%) children than in adolescent patients (12-18 years, n = 578; 8.3 +/- 1.4%). There was a significant negative correlation between HbA(1c) and daily bolus number, but not between HbA(1c) and total daily insulin dose. The use of <6.7 daily boluses was a significant predictor of an HbA(1c) level >7.5%. The incidence of severe hypoglycaemia and ketoacidosis was 6.63 and 6.26 events per 100 patient-years, respectively. CONCLUSIONS/INTERPRETATION: This large paediatric survey of CSII shows that glycaemic targets can be frequently achieved, particularly in young children, and the incidence of acute complications is low. Adequate substitution of basal and prandial insulin is associated with a better HbA(1c).

Transfilter evidence for a zone of polarizing activity participating in limb morphogenesis.

Barriers were inserted into stage-20 HH chick embryo wing buds to separate the zone of polarizing activity from the anterior two-thirds of the wing bud with its overlying apical ectodermal ridge. Half of the barrier length projected out of the wing bud at insertion. Sham-operated wing buds developed only occasionally into wings with cartilage deletions. After insertion of an impermeable membrane (Cellophane), the typical wing skeleton contained only a humerus and a radius. In order to differentiate between diffusion, cell contact and cell penetration, Nuclepore filters with pore sizes of 0.05 micrometer 1.0 micrometer and 8.0 micrometer, respectively, were inserted. The typical wing skeleton after Nucleopore filter insertion was one with post-axial deletions. None, however, developed with complete distal deletions as after Cellophane. Deletions in the wing skeletons after Nuclepore insertion were the least with 1.0 micrometer filters and the most with 8.0 micrometer filters. Elevation of the apical ectodermal ridge was noted until 18 h after the insertions. In none of the groups did the ridge flatten. The results suggest that the zone of polarizing activity does have a role in normal limb morphogenesis. The mechanism by which its morphogen spreads is diffusion rather than being mediated via cell contacts.

Lack of correlation between mesenchymal cell death and morphogenesis after different extents of apical ectodermal ridge/rim ectoderm removal in the chick embryo wing bud.

The removal of the apical ectodermal ridge (A.E.R.) subsequently causes distal deletion defects in the limb. There have been contradictory reports as to the appearance of cell death in the mesenchyme after A.E.R. removal, as well as to its morphogenetic significance. In our study the A.E.R./ rim ectoderm removal was varied to test whether different degrees of cell death would correlate with different degrees of distal deletions. From the right wing bud of stage 19 and 20 (HH) embryos the rim ectoderm was removed in four ways: all of the rim, the anterior third, the middle third (most of the A.E.R.), or its posterior third. The removal of all or of the anterior third caused a definite band of subwound mesenchymal cell death to appear. There was little or no cell death after removal of the middle or posterior thirds. Removal of the anterior third caused no distal deletion defects, and only a few were noted after removal of the posterior third. The proximo-distal level of the distal deletions, however, was the same after removal of all of the rim or only its middle third. As there was no difference in the degree of distal deletions after the removal of all or of the middle third of the rim but a definite difference in the mesenchymal cell death patterns we conclude that cell death is not part of the mechanisms of the distal deletion defect. Our findings also suggest that cell death does not play a role in the A.E.R.-mesenchyme reciprocal interaction that controls limb proximo-distal morphogenesis.

Caries and saliva in 12-18-year-old diabetics and controls.

Eighty-five 12-18-yr-old adolescents suffering from insulin-dependent diabetes mellitus (IDDM) and their healthy age- and sex-matched controls were investigated with respect to dental caries, salivary flow rate, pH and buffering capacity of saliva, counts for lactobacilli and mutans streptococci, and salivary glucose content. The diabetics had their disease well controlled according to the HbA1 levels. The results showed no statistically significant difference between diabetics and controls in DMF and DMFS indexes and the number of initial caries lesions. Mean number of initial caries lesions was 3.2 in diabetics, 2.3 in controls. Mean stimulated salivary flow rate was 1.2 ml/min in the patients, 1.4 ml/min in the controls. The pH and buffering capacity values were 7.3 and 4.8 in the patients, 7.4 and 5.1 in the controls, respectively. High counts of mutans streptococci (> 10(6) CFU/ml) and lactobacilli (> 10(5) CFU/ml) were observed more often, but not significantly so, among the patients than in the controls. The mean concentration of glucose in saliva was 10.3 micrograms/ml in the patients, 9.7 1 microgram/ml in the controls. Thus, if the patients' IDDM is well controlled, their salivary and caries data does not differ from that of healthy controls.

Periodontal status of Finnish adolescents with insulin-dependent diabetes mellitus.

The periodontal status of 85 12-18 year-old Finnish adolescents with insulin-dependent diabetes mellitus (IDDM) and their paired, age- and sex-matched healthy controls was assessed clinically and radiographically. The clinical examination consisted of plaque index, gingival index (GI), retentive calculus index, WHO community periodontal index of treatment needs, number of pockets greater than or equal to 4 mm and number of surfaces bleeding after probing. Alveolar bone loss was measured interproximally from the first molars in bite-wing radiographs (all subjects) and from the first incisors in periapical X-rays (patients only). The results show that in spite of similar plaque scores, the patients had higher GI scores and more surfaces bleeding after probing. No differences were found in the number of greater than or equal to 4 mm pockets or radiographical bone loss in the first molars.

Ketoacidosis at the diagnosis of type 1 (insulin dependent) diabetes mellitus is related to poor residual beta cell function. Childhood Diabetes in Finland Study Group.

The determinants of the degree of metabolic decompensation at the diagnosis of type 1 (insulin dependent) diabetes mellitus (IDDM) and the possible role of diabetic ketoacidosis in the preservation and recovery of residual beta cell function were examined in 745 Finnish children and adolescents. Children younger than 2 years or older than 10 years of age were found to be more susceptible to diabetic ketoacidosis than children between 2 and 10 years of age (< 2 years: 53.3%; 2-10 years: 16.9%; > 10 years: 33.3%). Children from families with poor parental educational level had ketoacidosis more often than those from families with high parental educational level (24.4% v 16.9%). A serum C peptide concentration of 0.10 nmol/l or more was associated with a favourable metabolic situation. Low serum C peptide concentrations, high requirement of exogenous insulin, low prevalence of remission, and high glycated haemoglobin concentrations were observed during the follow up in the group of probands having diabetic ketoacidosis at the diagnosis of IDDM. Thus diabetic ketoacidosis at diagnosis is related to a decreased capacity for beta cell recovery after the clinical manifestation of IDDM in children.

Randomised prospective study of short-term and long-term initial stay in hospital by children with diabetes mellitus.

To assess how an isolated change in the pattern of care influences outcome of care and hospital use, a randomised prospective 2-year study was done in which 31 of 61 consecutive children with newly diagnosed insulin-dependent diabetes mellitus (IDDM) were admitted to hospital at disease onset for about a week and compared with the other 30 children who were admitted for about 4 weeks. Insulin treatment and education about diabetes were similar in the two groups. Duration of initial stay in hospital had no effect on metabolic control during the 2 years but time since diagnosis was significant with respect to effect on haemoglobin A1 (p = 0.001), haemoglobin A1c (p = 0.004), and insulin dose (p less than 0.001). At 2 years, 45% of the children in the short-term group and 29% in the long-term group were C-peptide positive (p = NS); C-peptide positivity correlated with age. A change in the pattern of care of children with IDDM, led to a pronounced decrease in hospital use by this patient group. Irrespective of the length of initial stay in hospital, equally good metabolic control was obtained in both groups for 2 years.

Predictive validity of preadolescent type A determinants for type A dimensions in young adulthood--a 6-year follow-up.

This study examined the predictive validity of preadolescent Type A determinants for Type A dimensions in young adulthood (n = 375). Predictive variables, i.e. hyperactivity, aggression, social maladjustment and self-esteem were measured when the subjects were aged 12. Type A dimensions, i.e. hard-driving, competitiveness plus aggression and impatience were measured in the same subjects when they were aged 18. "Impatience" was predicted by means of preadolescent hyperactivity, and "competitiveness-aggression" by social maladjustment. "Hard-driving", which was most strongly related to CHD risk factor levels in young adulthood, was anteceded by the subject's feeling that he or she could not cope with life. This supports the hypothesis that Type A behaviour is a coping mechanism: a person tries to cope with stress by increasing his or her level of achievement.