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.

Insulin detemir compared with NPH insulin in children and adolescents with Type 1 diabetes.

AIMS: This study compared the effect of insulin detemir on glycaemic control (HbA(1c), fasting plasma glucose and variability thereof) with that of Neutral Protamine Hagedorn human isophane (NPH) insulin, both combined with insulin aspart, in children with Type 1 diabetes mellitus, and compared the safety of these treatments. METHODS: In this 26-week, open-label, randomized (2 : 1), parallel-group study, 347 (140 prepubertal and 207 pubertal) children with Type 1 diabetes, aged 6-17 years, received insulin detemir (n = 232) or NPH insulin (n = 115) once or twice daily, according to the prestudy regimen, plus premeal insulin aspart. RESULTS: The mean HbA(1c) decreased by approximately 0.8% with both treatments. After 26 weeks, the mean difference in HbA(1c) was 0.1% (95% confidence interval -0.1, 0.3) (insulin detemir 8.0%, NPH insulin 7.9%). Within-subject variation in self-measured fasting plasma glucose was significantly lower with insulin detemir than with NPH insulin (SD 3.3 vs. 4.3, P < 0.001), as was mean fasting plasma glucose (8.4 vs. 9.6 mmol/l, P = 0.022). The risk of nocturnal hypoglycaemia (22.00-07.00 h) was 26% lower with insulin detemir (P = 0.041) and the risk of 24-h hypoglycaemia was similar with the two treatments (P = 0.351). The mean body mass index (BMI) Z-score was lower with insulin detemir (P < 0.001). CONCLUSIONS: Basal-bolus treatment with insulin detemir or NPH insulin and premeal insulin aspart in children and adolescents with Type 1 diabetes mellitus improved HbA(1c) to a similar degree. The lower and more predictable fasting plasma glucose, lower risk of nocturnal hypoglycaemia and lower BMI observed with insulin detemir are clinically significant advantages compared with NPH insulin.

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.

Distribution of NADPH-diaphorase reactivity and effects of nitric oxide on feeding and locomotory circuitry in the pteropod mollusc, Clione limacina.

The action of nitric oxide (NO) and the distribution of putative nitric oxide synthase-containing cells in the pelagic pteropod mollusc Clione limacina were studied using nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) histochemistry and conventional microelectrode techniques in the isolated central nervous system and in semi-intact preparations. The majority of NADPH-d-reactive neuronal somata were restricted to the cerebral ganglia. The labeled cells were small in diameter (20-30 microm) and were located in the medial areas of the ganglia. A pair of symmetrical neurons was found in the peripheral "olfactory organ." NADPH-d-reactive non-neuronal cells were detected in the periphery and were mainly associated with secretorylike cells and organs of the renopericardial system. The NO donor, diethylamine NO complex sodium salt (10-100 microM), activated neurons from both feeding and locomotory circuits. The cGMP analog, 8-Br-cGMP, mimicked the effects of NO on neurons. We suggest that NO is an endogenous neuromodulator involved in the control of some aspects of feeding and locomotor behavior of Clione.

Insulin management and metabolic control of type 1 diabetes mellitus in childhood and adolescence in 18 countries. Hvidøre Study Group on Childhood Diabetes.

Insulin regimens and metabolic control in children and adolescents with Type 1 diabetes mellitus were evaluated in a cross-sectional, non-population-based investigation, involving 22 paediatric departments, from 18 countries in Europe, Japan, and North America. Blood samples and information were collected from 2873 children from March to August 1995. HbA1c was determined once and analysed centrally (normal range 4.4-6.3%, mean 5.4%). Year of birth, sex, duration of diabetes, height, body weight, number of daily insulin injections, types and doses of insulin were recorded. Average HbA1c in children under 11 years was 8.3 +/- 1.3% (mean +/- SD) compared with 8.9 +/- 1.8% in those aged 12-18 years. The average insulin dose per kg body weight was almost constant (0.65 U kg(-1) 24 h(-1)) in children aged 2-9 years for both sexes, but there was a sharp increase during the pubertal years, particularly in girls. The increase in BMI of children with diabetes was much faster during adolescence compared to healthy children, especially in females. Sixty per cent of the children (n = 1707) used two daily insulin injections while 37% (n = 1071) used three or more. Of those on two or three injections daily, 37% used pre-mixed insulins, either alone or in combination with short- and intermediate-acting insulin. Pre-adolescent children on pre-mixed insulin showed similar HbA1c levels to those on a combination of short- and long-acting insulins, whereas in adolescents significantly better HbA1c values were achieved with individual combinations. Very young children were treated with a higher proportion of long-acting insulin. Among adolescent boys, lower HbA1c was related to use of more short-acting insulin. This association was not found in girls. We conclude that numerous insulin injection regimens are currently used in paediatric diabetes centres around the world, with an increasing tendency towards intensive diabetes management, particularly in older adolescents. Nevertheless, the goal of near normoglycaemia is achieved in only a few.

Paternal uniparental disomy for chromosome 6 causes transient neonatal diabetes.

We report an infant with intrauterine growth retardation and transient neonatal diabetes who has paternal uniparental disomy for chromosome 6. The infant was not dysmorphic and had no congenital anomalies. To our knowledge, this is the third case of paternal uniparental disomy occurring in an infant with transient neonatal diabetes, thus confirming the association.

Startle phase of escape swimming is controlled by pedal motoneurons in the pteropod mollusk Clione limacina.

Escape swimming in the pteropod mollusk Clione limacina includes an initial startle response in which one or two powerful wing beats propel the animal up to 18 body lengths per second, followed by a variable period of fast swimming with a maximal speed of 6 body lengths per second. The initial startle response is the focus of this report. Two pairs of large pedal neurons (50-60 microns) initiate wing contractions that are several times stronger than those produced during slow or fast swimming. These "startle" neurons are silent, with very low resting potentials and high activation thresholds. Each startle neuron has widespread innervation fields in the ipsilateral wing, with one pair of neurons innervating the dorsal musculature and producing dorsal flexion of the wing (d-phase) and the other innervating the ventral musculature and producing a ventral flexion of the wing (v-phase). Startle neurons are motoneurons, because they produce junctional potentials or spike-like responses in both slow-twitch and fast-twitch muscle cells with 1:1 ratios of spikes to excitatory postsynaptic potentials. Muscle activation persists in high-divalent saline, suggesting monosynaptic connections. The musculature innervated by startle neurons is the same used during normal slow and fast swimming. However, startle neuron activity is independent of normal swimming activity: startle neurons do not influence the activity of swim pattern generator interneurons or motoneurons, nor do swim neurons alter the activity of startle neurons. The startle response shows significant response depression with repetitive mechanical stimulation of the tail or wings. A major focus for this depression is at the neuromuscular junction. In reduced preparations, repetitive direct stimulation of a startle neuron does not result in a significant decrease in spike number or frequency, but does produce a decrease in force generation (decrease to 20% of original value after 5 stimuli delivered at 3-s intervals). Inputs that activate the wing retraction reflex as well as swim inhibition inhibit startle neurons. The inhibition appears to originate in the retraction interneurons, because direct connections from retraction sensory cells or retraction motoneurons are not found. Mechanical stimulation of a wing or the tail, which usually initiates startle response in intact animals, produces spikes or large EPSPs in startle neurons. The startle neurons appear to be likely candidates for direct control of the swim musculature during the startle phase of escape swimming in Clione.

What is core? Guidelines for the core curriculum in paediatrics.

A key point that the UK General Medical Council addressed in its recommendations on the undergraduate medical education was the concept of 'core curriculum' (General Medical Council 1993). Although enthusiastic for the idea of reducing factual overload, many medical teachers found themselves facing the task of how to define what a core curriculum is, what should be included and why. Predictably, our initial response is to include common and important topics, but how common is common, and how does one determine the relative importance of topics? We do not claim to have unravelled all the ambiguities surrounding the subject nor to have resolved all the controversies that are inevitably encountered. We hope, however, to describe some of the principles that governed our approach and put forward some guidelines, that may contribute to the debate.

Localisation of the multidrug resistance-associated protein, MRP, in resistant large-cell lung tumour cells.

The drug transport protein, P-glycoprotein, confers multidrug resistance (MDR) by expelling drugs across the cell surface. The structurally similar multidrug resistance-associated protein, or MRP, is also involved with drug efflux. In MDR variants of the human lung tumour cell line COR-L23 that overexpress MRP, there are also changes in intracellular drug distribution. To ascertain whether MRP could be involved in either process, experiments were performed to identify where MRP was located in these cells. Following separation of membranes by sucrose gradient centrifugation, MRP was found predominantly in the lighter membrane fractions containing plasma membrane enzyme activity. Immunofluorescent staining with a monoclonal antibody raised against MRP confirmed that MRP is present at the cell surface of these MDR lung tumour cells.

Comparisons of P-glycoprotein expression in isolated rat brain microvessels and in primary cultures of endothelial cells derived from microvasculature of rat brain, epididymal fat pad and from aorta.

In vivo expression of P-glycoprotein in isolated rat brain microvessels is compared with that in vitro in primary cultures of brain endothelial cells. More P-glycoprotein is detected by Western immunoblotting in microvessels than in cultured endothelium. RT-PCR with isoform-specific primers and immunoblotting with a mdr1b-specific antibody reveals only mdr1a in vivo but both mdr1a and mdr1b in vitro. Thus mdr1a decreases whereas mdr1b increases during culture. P-Glycoprotein activity is evident in vitro, with resistance modulators, e.g. verapamil, producing increases in intracellular [3H]vincristine accumulation. Endothelial cells cultured from epididymal fat pad microvasculature and aorta contain little or no P-glycoprotein. Here, resistance modulators are less effective.

The role of the i.v. specialist in health care reform.

IV nurses must have a better understanding of health care reform to understand why hospitals are decreasing nursing positions in general and why administrators always seem to cut i.v. nursing positions first. It is also important to learn strategies that i.v. teams can adopt to demonstrate their contribution to quality patient care so they are less likely to be eliminated.

Investigation of the molecular basis of the genetic deficiency of UDP-glucuronosyltransferase in Crigler-Najjar syndrome.

Liver biopsy samples were obtained from eight Crigler-Najjar patients. Bilirubin UDPGT activity, assayed by a microassay with HPLC analysis, was not detectable in type I livers, and low levels (9-26% of controls) of monoglucuronide conjugates only were observed in type II livers. 1-Naphthol UDPGT activity was normal in most patients, where membrane integrity was maintained by correct sample procurement and preparation. Our data on type II livers suggest that a defect in UDPGA transport is an unlikely cause of the hyperbilirubinaemia, but reduced affinity for UDPGA was observed in one sample. Analysis of four patient liver samples by immunoblot analysis revealed the heterogeneous nature of this inherited disease within the patient population, and one sample where 1-naphthol UDPGT activity was considerably reduced appeared to correlate with the non-detection of a phenol UDPGT protein. Progress towards a molecular genetic diagnosis of Crigler-Najjar syndromes is discussed.

Rapid diagnosis of community-acquired bacterial pneumonia.

Rapid identification of pathogens in patients with bacterial pneumonia is important for optimal antimicrobial therapy. Coagglutination was compared with counterimmunoelectrophoresis (CIE) for sensitivity and specificity in the detection of Streptococcus pneumoniae, Hemophilus influenzae, Klebsiella pneumoniae, and Pseudomonas aeruginosa antigens in sputum specimens of 101 patients with community-acquired pneumonia. Coagglutination detected the appropriate bacterial antigen in 16 of 17 (94%) definite etiology patients and CIE detected 11 (64%). In 17 probable etiology patients, bacterial antigens were detected by coagglutination in 15 (88%) and by CIE in 7 (41%). Only 1 pathogen was falsely identified in the 19 culture-negative control patients, indicating a high degree of specificity for both tests. Coagglutination was more sensitive than CIE (p less than 0.05) or sputum stained with Gram's stain (p less than 0.05) in correctly identifying the putative pathogen in sputum. Our results strongly suggest that coagglutination is a useful diagnostic technique for establishing a rapid etiologic diagnosis in community-acquired pneumonia.

Pulmonary function measurements in patients with thermal injury and smoke inhalation.

We performed serial pulmonary function measurements in 28 patients with thermal injury in order to investigate the pulmonary effects of smoke inhalation, small and large surface burns, and the combination of burn and inhalation. Patients were studied at postinjury time intervals of 9.0 +/- 0.6 (M +/- SEM), 22.0 +/- 1.6, 37.3 +/- 2.2, 58.4 +/- 2.5 hours; 11.5 +/- 0.6 days; 1.1 +/- 0.1 and 5.0 +/- 0.5 months. Spirometry was found to be as useful as more sophisticated measurements in the examination of both burn and smoke inhalation groups. Smoke inhalation caused severe airway obstruction 9 h after exposure. Patients with surface burn resuscitated with 4 ml of Ringer's lactate/per cent surface area burn/kilogram developed a significant restrictive defect over the first 58 h, despite normal pulmonary capillary wedge pressures. The restrictive defect in these patients correlated with the size of surface and chest burn, degree of fluid retention, and reduction in colloid osmotic pressure. Surface burn and smoke inhalation caused the greatest deterioration in pulmonary function. These defects gradually resolved during the period of observation.

Arterial blood-gas interpretations in the respiratory intensive-care unit.

The role of the nurse in the respiratory intensive-care unit requires increased sophistication as our knowledge of the patient becomes more complex. This expanded role should include a thorough understanding of disturbances in acid-base balance, the relationship of PaCO2 to ventilation, the difference in acute and chronic respiratory problems, and the causes and treatment of hypoxemia. The ability to analyze and evaluate blood-gas determinations is simply one more important tool the nurse may utilize in the care and treatment of the critically ill patient.