Clinical Correlates of a Nonplexiform Vasculopathy in Patients With a Diagnosis of Idiopathic Pulmonary Arterial Hypertension.

BACKGROUND: The clinical phenotype of idiopathic pulmonary arterial hypertension (IPAH) patients has changed. Whether subgroups of patients with IPAH have different vascular phenotypes is a subject of debate. RESEARCH QUESTION: What are the histologic patterns and their clinical correlates in patients with a diagnosis of IPAH or hereditary pulmonary arterial hypertension (PAH)? STUDY DESIGN AND METHODS: In this this cross-sectional registry study, lung histologic examination of 50 patients with IPAH was assessed qualitatively by two experienced pathologists. In addition, quantitative analysis by means of histopathologic morphometry using immunohistochemistry was performed. Histopathologic characteristics were correlated with clinical and hemodynamic parameters. RESULTS: In this cohort of 50 patients with IPAH, a plexiform vasculopathy was observed in 26 of 50 patients (52%), whereas 24 of 50 patients (48%) showed a nonplexiform vasculopathy. The nonplexiform vasculopathy was characterized by prominent pulmonary microvascular (arterioles and venules) remodeling and vascular rarefaction. Although hemodynamic parameters were comparable in plexiform vs nonplexiform vasculopathy, patients with nonplexiform vasculopathy were older, more often were male, had a stronger history of cigarette smoking, and lower diffusing capacity of the lungs for carbon monoxide (Dlco) at diagnosis. No mutations in established PAH genes were found in the nonplexiform group. INTERPRETATION: This study revealed different vascular phenotypes within the current spectrum of patients with a diagnosis of IPAH, separated by clinical characteristics (age, sex, history of cigarette smoking, and Dlco at diagnosis). Potential differences in underlying pathobiological mechanisms between patients with plexiform and nonplexiform microvascular disease should be taken into account in future research strategies unravelling the pathophysiologic features of pulmonary hypertension and developing biology-targeted treatment approaches.

The incidence of brain metastases among patients with metastatic breast cancer: a systematic review and meta-analysis.

BACKGROUND: Patients with metastatic breast cancer (MBC) are living longer, but the development of brain metastases often limits their survival. We conducted a systematic review and meta-analysis to determine the incidence of brain metastases in this patient population. METHODS: Articles published from January 2000 to January 2020 were compiled from four databases using search terms related to breast cancer, brain metastasis, and incidence. The overall and per patient-year incidence of brain metastases were extracted from studies including patients with human epidermal growth factor receptor-2 positive (HER2+), triple negative, and hormone receptor (HR)+/hormone receptor negative (HER2-) MBC; pooled overall estimates for incidence were calculated using random effects models. RESULTS: 937 articles were compiled, and 25 were included in the meta-analysis. Incidence of brain metastases in patients with HER2+ MBC, triple negative MBC, and HR+/HER2- MBC was reported in 17, 6, and 4 studies, respectively. The pooled cumulative incidence of brain metastases was 31% for the HER2+ subgroup (median follow-up: 30.7 months, IQR: 24.0-34.0), 32% for the triple negative subgroup (median follow-up: 32.8 months, IQR: 18.5-40.6), and 15% among patients with HR+/HER2- MBC (median follow-up: 33.0 months, IQR: 31.9-36.2). The corresponding incidences per patient-year were 0.13 (95% CI: 0.10-0.16) for the HER2+ subgroup, 0.13 (95%CI: 0.09-0.20) for the triple negative subgroup, and only 0.05 (95%CI: 0.03-0.08) for patients with HR+/HER2- MBC. CONCLUSION: There is a high incidence of brain metastases among patients with HER2+ and triple negative MBC. The utility of a brain metastases screening program warrants investigation in these populations.

Abnormal locomotor muscle recruitment activity is present in horses with shivering and Purkinje cell distal axonopathy.

BACKGROUND: Cerebellar Purkinje cell axonal degeneration has been identified in horses with shivering but its relationship with abnormal hindlimb movement has not been elucidated. OBJECTIVES: To characterise surface electromyographic (sEMG) hindlimb muscle activity in horses with shivering, correlate with clinical scores and examine horses for Purkinje axonal degeneration. STUDY DESIGN: Descriptive controlled clinical study. METHODS: The hindlimb of seven shivering and six control draught horses were clinically scored. Biceps femoris (BF), vastus lateralis (VL), tensor fasciae latae and extensor digitorum longus were recorded via sEMG during forward/backward walking and trotting. Integrated (iEMG) and peak EMG activity were compared between groups and correlated with clinical locomotor exam scores. Sections of the deep cerebellar nuclei (DCN) of six of the seven shivering horses were examined with calbindin immunohistochemistry. RESULTS: In control horses, backward walking resembled forward walking (right hindlimb peak EMG: backward: 47.5 ± 21.9%, forward: 36.9 ± 15.7%) but displayed significantly higher amplitudes during trotting (76.1 ± 3.4%). However, in shivering horses, backward walking was significantly different from forward (backward: 88.5 ± 21.5%, forward: 49.2 ± 8.9%), and resembled activity during trotting (81.4 ± 4.8%). Specific to backward walking, mean sEMG amplitude fell outside two standard deviations of mean control sEMG for ≥25% of the stride in the BF for all seven and the VL for six of the seven shivering horses. Locomotor exam scores were correlated with peak EMG (r = 0.87) and iEMG (r = 0.87). Calbindin-positive spheroids were present in Purkinje axons in DCN of all shivering horses examined. MAIN LIMITATIONS: The neuropathological examination focused specifically on the DCN and, therefore, we cannot fully exclude additional lesions that may have influenced abnormal sEMG findings in shivering horses. CONCLUSION: Shivering is characterised by abnormally elevated muscle recruitment particularly in BF and VL muscles during backward walking and associated with selective Purkinje cell distal axonal degeneration.

Resonant Rydberg Dressing of Alkaline-Earth Atoms via Electromagnetically Induced Transparency.

We develop an approach to generate finite-range atomic interactions via optical Rydberg-state excitation and study the underlying excitation dynamics in theory and experiment. In contrast to previous work, the proposed scheme is based on resonant optical driving and the establishment of a dark state under conditions of electromagnetically induced transparency (EIT). Analyzing the driven dissipative dynamics of the atomic gas, we show that the interplay between coherent light coupling, radiative decay, and strong Rydberg-Rydberg atom interactions leads to the emergence of sizable effective interactions while providing remarkably long coherence times. The latter are studied experimentally in a cold gas of strontium atoms for which the proposed scheme is most efficient. Our measured atom loss is in agreement with the theoretical prediction based on binary effective interactions between the driven atoms.

Body fat measurement in adolescent girls with type 1 diabetes: a comparison of skinfold equations against dual-energy X-ray absorptiometry.

AIM: Skinfold measurement is an inexpensive and widely used technique for assessing the percentage of body fat (%BF). This study assessed the accuracy of prediction equations for %BF based on skinfold measurements compared to dual-energy X-ray absorptiometry (DXA) in girls with type 1 diabetes and healthy age-matched controls. METHODS: We included 49 healthy girls and 44 girls with diabetes aged 12-19 years old, comparing the predicted %BF based on skinfold measurements and the %BF values obtained by a Lunar DPX-L scanner. The agreement between the methods was assessed using an Bland-Altman plot. RESULTS: The skinfold measurements were significantly higher in girls with diabetes (p = 0.003) despite a nonsignificant difference in total %BF (p = 0.1). A significant association between bias and %BF was found for all tested equations in the Bland-Altman plots. Regression analysis showed that the association between skinfold measurements and %BF measured by DXA differed significantly (p = 0.039) between the girls with diabetes and the healthy controls. CONCLUSION: The accuracy of skinfold thickness equations for assessment of %BF in adolescent girls with diabetes is poor in comparison with DXA measurements as criterion. Our findings highlight the need for the development of new prediction equations for girls with type 1 diabetes.

Increase in physical activity is associated with lower HbA1c levels in children and adolescents with type 1 diabetes: results from a cross-sectional study based on the Swedish pediatric diabetes quality registry (SWEDIABKIDS).

AIMS: To evaluate the associations between physical activity (PA) and metabolic control, measured by glycated hemoglobin (HbA1c), in a large group of children and adolescents with type 1 diabetes. METHODS: Cross-sectional analysis of data from 4655 patients, comparing HbA1c values with levels of physical activity. The data for the children and adolescents were obtained from the Swedish pediatric diabetes quality registry, SWEDIABKIDS. The patients were 7-18 years of age, had type 1 diabetes and were not in remission. Patients were grouped into five groups by frequency of PA. RESULTS: Mean HbA1c level was higher in the least physically active groups (PA0: 8.8% ± 1.5 (72 ± 16 mmol/mol)) than in the most physically active groups (PA4: 7.7% ± 1.0 (60 ± 11 mmol/mol)) (p<0.001). An inverse dose-response association was found between PA and HbA1c (ß: -0.30, 95% CI: -0.34 to -0.26, p<0.001). This association was found in both sexes and all age groups, apart from girls aged 7-10 years. Multiple regression analysis revealed that the relationship remained significant (ß: -0.21, 95% CI: -0.25 to -0.18, p<0.001) when adjusted for possible confounding factors. CONCLUSIONS: Physical activity seems to influence HbA1c levels in children and adolescents with type 1 diabetes. In clinical practice these patients should be recommended daily physical activity as a part of their treatment.

Impaired metabolic control and socio-demographic status in immigrant children at onset of Type 1 diabetes.

AIM: The aim of the present study was to compare clinical and socio-demographic conditions at the onset of Type 1 diabetes in children born to immigrant families and children born to Swedish families, and to assess whether those conditions had an impact on metabolic status. METHODS AND DESIGN: This was an observational nationwide population-based matched cohort study on prospectively recorded registry data of all children with diabetes in Sweden and their families during 2000-2010. Out of a total of 13 415 children from the Swedish Childhood Diabetes Registry (SWEDIABKIDS), 879 children born to immigrant parents were collected. To these we added 2627 children with Swedish-born parents, matched for gender, age and year of onset of Type 1 diabetes. RESULTS: The proportion of low capillary pH (< 7.30) at onset was higher in the immigrant cohort [25.8% vs. 16.4% in the Swedish cohort (P < 0.001)]. HbA1c was also higher [95 mmol/mol (10.8%) vs. 88 mmol/mol (10.2%), respectively (P < 0.001)]. In a logistic regression model with low pH as the dependent variable, we were unable to reveal any significant association to socio-demographic factors, but the odds ratio for HbA1c was 0.983 (95% CI 0.976-0.991) and for plasma glucose was 0.953 (95% CI 0.933-0.973). CONCLUSION: Children born to immigrant parents have lower capillary pH and higher HbA1c at diabetes onset. Immigrant families harbour lower socio-demographic living conditions, but this fact does not seem to influence the inferior metabolic condition at diabetes onset.

Assembly of Ebola virus matrix protein VP40 is regulated by latch-like properties of N and C terminal tails.

The matrix protein VP40 coordinates numerous functions in the viral life cycle of the Ebola virus. These range from the regulation of viral transcription to morphogenesis, packaging and budding of mature virions. Similar to the matrix proteins of other nonsegmented, negative-strand RNA viruses, VP40 proceeds through intermediate states of assembly (e.g. octamers) but it remains unclear how these intermediates are coordinated with the various stages of the life cycle. In this study, we investigate the molecular basis of synchronization as governed by VP40. Hydrogen/deuterium exchange mass spectrometry was used to follow induced structural and conformational changes in VP40. Together with computational modeling, we demonstrate that both extreme N and C terminal tail regions stabilize the monomeric state through a direct association. The tails appear to function as a latch, released upon a specific molecular trigger such as RNA ligation. We propose that triggered release of the tails permits the coordination of late-stage events in the viral life cycle, at the inner membrane of the host cell. Specifically, N-tail release exposes the L-domain motifs PTAP/PPEY to the transport and budding complexes, whereas triggered C-tail release could improve association with the site of budding.

Increased fat mass and cardiac septal hypertrophy in newborn infants of mothers with well-controlled diabetes during pregnancy.

BACKGROUND: Improved glycaemic control during pregnancy in mothers with type 1 diabetes (T1DM) and gestational diabetes (GDM) has resulted in a marked reduction of perinatal mortality and morbidity, but the prevalence of macrosomia is usually high. OBJECTIVE: We used non-invasive anthropometric methods to estimate the body composition and the thickness of the interventricular heart septum in 18 infants of mothers with well-controlled T1DM, 10 infants of mothers with GDM and 28 infants of healthy control mothers matched for gestational age and mode of delivery. METHODS: Skinfold measurements were obtained with a Harpenden calliper within 48 h after delivery. Echocardiography was also performed to measure the thickness of the interventricular septum. Cord blood was sampled for assays of C-peptide, leptin and IGF-I. RESULTS: The rates of macrosomia (gestational age-adjusted birth weight >2 standard deviation score, SDS) were 56 and 30% in infants of mothers with T1DM and GDM, respectively, compared to 10% in control infants. The body fat content was 40% (0.2 kg) higher and the interventricular heart septum thickness was increased by 20% in both groups of infants of diabetic mothers. We found no associations between maternal levels of HbA1c during pregnancy and body composition or interventricular heart septum thickness. Cord levels of C-peptide and leptin were significantly higher in infants of T1DM mothers than in control infants. Cord leptin level was associated with birth weight SDS and percent body fat in infants of T1DM mothers. IGF-I was associated with percent body fat in infants of GDM mothers and control mothers. A multiple-regression analysis showed that 50% of the variation in body weight SDS could be determined, with IGF-I, leptin and C-peptide as independent variables. CONCLUSION: Both fat mass and cardiac septal thickness are increased in newborn infants of women with T1DM and GDM in spite of efforts to achieve good glycaemic control during pregnancy.

Extended evaluation of the safety and efficacy of GAD treatment of children and adolescents with recent-onset type 1 diabetes: a randomised controlled trial.

AIMS/HYPOTHESIS: The aim of this study was to investigate the safety and efficacy of alum formulated glutamic acid decarboxylase GAD(65) (GAD-alum) treatment of children and adolescents with type 1 diabetes after 4 years of follow-up. METHODS: Seventy children and adolescents aged 10-18 years with recent onset type 1 diabetes participated in a phase II, double-blind, randomised placebo-controlled clinical trial. Patients identified as possible participants attended one of eight clinics in Sweden to receive information about the study and for an eligibility check, including a medical history. Participants were randomised to one of the two treatment groups and received either a subcutaneous injection of 20 µg of GAD-alum or placebo at baseline and 1 month later. The study was blinded to participants and investigators until month 30. The study was unblinded at 15 months to the sponsor and statistician in order to evaluate the data. At follow-up after 30 months there was a significant preservation of residual insulin secretion, as measured by C-peptide, in the group receiving GAD-alum compared with placebo. This was particularly evident in patients with <6 months disease duration at baseline. There were no treatment-related serious adverse events. We have now followed these patients for 4 years. Overall, 59 patients, 29 who had been treated with GAD-alum and 30 who had received placebo, gave their informed consent. RESULTS: One patient in each treatment group experienced an episode of keto-acidosis between months 30 and 48. There were no treatment-related adverse events. The primary efficacy endpoint was the change in fasting C-peptide concentration from baseline to 15 months after the prime injection for all participants per protocol set. In the GAD-alum group fasting C-peptide was 0.332 ± 0.032 nmol/l at day 1 and 0.215 ± 0.031 nmol/l at month 15. The corresponding figures for the placebo group were 0.354 ± 0.039 and 0.184 ± 0.033 nmol/l, respectively. The decline in fasting C-peptide levels between day 1 and month 1, was smaller in the GAD-alum group than the placebo group. The difference between the treatment groups was not statistically significant. In those patients who were treated within 6 months of diabetes diagnosis, fasting C-peptide had decreased significantly less in the GAD-alum group than in the placebo-treated group after 4 years. CONCLUSION/INTERPRETATION: Four years after treatment with GAD-alum, children and adolescents with recent-onset type 1 diabetes continue to show no adverse events and possibly to show clinically relevant preservation of C-peptide. TRIAL REGISTRATION: ClinicalTrials.gov NCT00435981 FUNDING: The study was funded by The Swedish Research Council K2008-55X-20652-01-3, Barndiabetesfonden (The Swedish Child Diabetes Foundation), the Research Council of Southeast Sweden, and an unrestricted grant from Diamyd Medical AB.

Effects of fat supplementation on postprandial GIP, GLP-1, ghrelin and IGFBP-1 levels: a pilot study on adolescents with type 1 diabetes.

AIMS: To compare the responses of GIP, GLP-1, ghrelin and IGFBP-1 between meals with different fat and energy content in adolescents with type 1 diabetes (T1DM) and to relate them to gastric emptying and glycaemia. METHODS: On different days and in a random order, 7 adolescents with T1DM ingested a high- and low-fat meal (fat content: 38 and 2 g, energy content: 640 and 320 kcal, respectively). At normoglycaemia, the same prandial insulin dose was given at both meals and to all subjects. Postprandial blood samples were taken repeatedly over 4 hours. Gastric emptying was estimated by the paracetamol absorption method. RESULTS: The area under the curve (AUC) for GIP(0-240 min) and for GLP-1(0-120 min) was larger, but smaller for relative ghrelin(0-240 min), after the high-fat meal (p = 0.002, 0.030 and 0.043, respectively). IGFBP-1 decreased significantly, but not differently, after the meals. Larger GLP-1 secretion correlated with slower gastric emptying (p = 0.029) and higher fasting ghrelin levels correlated with lower postprandial glycaemia (p = 0.007). CONCLUSION: In adolescents with T1DM, the postprandial responses of GIP, GLP-1 and ghrelin, but not that of IGFBP-1, depend more on meal size than on insulin.

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.

Increased prevalence of burnout symptoms in parents of chronically ill children.

AIM: To examine the prevalence of burnout symptoms in the context of parenting a chronically ill child. METHODS: A total of 252 parents of children with Type 1 Diabetes Mellitus and 38 parents of children with Inflammatory Bowel Diseases participated in a population-based study. A control group consisted of 124 randomly selected parents of healthy children. We used self-report questionnaires to assess symptoms of burnout. RESULTS: The main finding was that significantly more parents of children with chronic diseases (36%) scored for clinical burnout, compared with parents of healthy children (20%). Burnout symptoms were most prominent among mothers of children with diabetes, although fathers of children with diabetes and mothers and fathers of children with inflammatory bowel diseases also reported higher levels of various burnout symptoms. CONCLUSION: Burnout may be a useful model for understanding long-term parental responses and should be acknowledged among the different types of psychological consequences of the multi-faceted experience of parenting a child with chronic illness. Gender seems to influence the risk of burnout symptoms. Continued research about other background factors, and how the parents' situation changes over time are warranted. In the clinic, we need to draw attention to the group of parents who may suffer from burnout.

Associations between physical activity, sedentary behavior, and glycemic control in a large cohort of adolescents with type 1 diabetes: the Hvidoere Study Group on Childhood Diabetes.

BACKGROUND: The Hvidoere Study Group on Childhood Diabetes has demonstrated persistent differences in metabolic outcomes between pediatric diabetes centers. These differences cannot be accounted for by differences in demographic, medical, or treatment variables. Therefore, we sought to explore whether differences in physical activity or sedentary behavior could explain the variation in metabolic outcomes between centers. METHODS: An observational cross-sectional international study in 21 centers, with demographic and clinical data obtained by questionnaire from participants. Hemoglobin A1c (HbA1c) levels were assayed in one central laboratory. All individuals with diabetes aged 11-18 yr (49.4% female), with duration of diabetes of at least 1 yr, were invited to participate. Individuals completed a self-reported measure of quality of life (Diabetes Quality of Life - Short Form [DQOL-SF]), with well-being and leisure time activity assessed using measures developed by Health Behaviour in School Children WHO Project. RESULTS: Older participants (p < 0.001) and females (p < 0.001) reported less physical activity. Physical activity was associated with positive health perception (p < 0.001) but not with glycemic control, body mass index, frequency of hypoglycemia, or diabetic ketoacidosis. The more time spent on the computer (r = 0.06; p < 0.05) and less time spent doing school homework (r = -0.09; p < 0.001) were associated with higher HbA1c. Between centers, there were significant differences in reported physical activity (p < 0.001) and sedentary behavior (p < 0.001), but these differences did not account for center differences in metabolic control. CONCLUSIONS: Physical activity is strongly associated with psychological well-being but has weak associations with metabolic control. Leisure time activity is associated with individual differences in HbA1c but not with intercenter differences.

Temporal trends of HLA genotype frequencies of type 1 diabetes patients in Sweden from 1986 to 2005 suggest altered risk.

The aim of this study was to compare the frequency of human leukocyte antigen (HLA) genotypes in 1-18-year-old patients with type 1 diabetes newly diagnosed in 1986-1987 (n = 430), 1996-2000 (n = 342) and in 2003-2005 (n = 171). We tested the hypothesis that the HLA DQ genotype distribution changes over time. Swedish type 1 diabetes patients and controls were typed for HLA using polymerase chain reaction amplification and allele specific probes for DQ A1* and B1* alleles. The most common type 1 diabetes HLA DQA1*-B1*genotype 0501-0201/0301-0302 was 36% (153/430) in 1986-1987 and 37% (127/342) in 1996-2000, but decreased to 19% (33/171) in 2003-2005 (P \ 0.0001). The 0501-0201/0501-0201 genotype increased from 1% in 1986-1987 to 7% in 1996-2000 (P = 0.0047) and to 5% in 2003-2005 (P > 0.05). This study in 1-18-year-old Swedish type 1 diabetes patients supports the notion that there is a temporal change in HLA risk.

Continuous Subcutaneous Glucose Monitoring System in diabetic mothers during labour and postnatal glucose adaptation of their infants.

AIMS: To assess a new technique for continuous monitoring of glucose concentration during labour in diabetic mothers. A second objective was to study maternal glucose levels in relation to postnatal glucose adaptation and the need for intravenous (IV) glucose treatment in the newborn infant. METHODS: Fifteen pregnant women with insulin-treated diabetes mellitus participated in this prospective pilot study. To measure their glucose control during labour we used the Continuous Subcutaneous Glucose Monitoring System (CGMS; Medtronic, Minneapolis, MN, USA) to calculate the mean glucose concentration and the area under the curve (AUC) in the last 120 min before delivery. All infants of these women were transferred to the neonatal care unit for early oral feeding and blood glucose measurements up to 14 h after delivery. Infants received IV glucose if blood glucose values were repeatedly < 2.2 mmol/l. RESULTS: All women coped well with the CGMS monitoring. AUC 0-120 min before delivery, mean glucose concentration 0-120 min before delivery and cord plasma insulin level were all significantly associated with the need for IV glucose in the newborn children. CONCLUSIONS: In this study we found an association between maternal glucose concentrations during labour and postnatal glucose adaptation and need for IV glucose treatment in the infants. Online monitoring of glucose levels during delivery might help us to achieve maternal normoglycaemia and further reduce the risk of postnatal hypoglycaemia in the offspring.

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.

Effects of fat supplementation on glycaemic response and gastric emptying in adolescents with Type 1 diabetes.

AIMS: To compare the glycaemic response to meals with different fat content in adolescents with Type 1 diabetes mellitus (T1DM) and to investigate associations with gastric emptying. METHODS: In this randomized, cross-over study, paired results were obtained from seven adolescents with T1DM who ingested on different days two meals with the same carbohydrate and protein content, but different fat and energy content (2 and 38 g fat, 320 and 640 kcal, respectively). Paracetamol was mixed into the meals and gastric emptying was estimated by the paracetamol absorption method. All subjects were normoglycaemic and given 7 IU insulin aspart at commencement of ingestion. Postprandial blood samples were taken during 4 h. RESULTS: The areas under the curves for plasma glucose and serum paracetamol concentrations were larger after the low-fat than after the high-fat meal during the first 2 h (P = 0.047 and P = 0.041, respectively). The difference between meals in time-to-peak in glucose and paracetamol concentrations did not reach statistical significance (high-fat vs. low-fat meal: 210 min (120-240) vs. 120 min (50-240), P = 0.080 and 120 min (75-180) vs. 60 min (60-120), P = 0.051, respectively). Changes in glucose concentrations correlated with simultaneous changes in paracetamol concentrations (P < 0.001). CONCLUSIONS: For the first time, we have shown that the initial glycaemic response is reduced after a meal with higher compared with a meal with lower fat content in adolescents with T1DM given a rapid-acting insulin analogue preprandially. The type and dose of preprandial insulin may need adjustment to the fat content of the meal to reach postprandial normoglycaemia.

IA-2 autoantibodies in incident type I diabetes patients are associated with a polyadenylation signal polymorphism in GIMAP5.

In a large case-control study of Swedish incident type I diabetes patients and controls, 0-34 years of age, we tested the hypothesis that the GIMAP5 gene, a key genetic factor for lymphopenia in spontaneous BioBreeding rat diabetes, is associated with type I diabetes; with islet autoantibodies in incident type I diabetes patients or with age at clinical onset in incident type I diabetes patients. Initial scans of allelic association were followed by more detailed logistic regression modeling that adjusted for known type I diabetes risk factors and potential confounding variables. The single nucleotide polymorphism (SNP) rs6598, located in a polyadenylation signal of GIMAP5, was associated with the presence of significant levels of IA-2 autoantibodies in the type I diabetes patients. Patients with the minor allele A of rs6598 had an increased prevalence of IA-2 autoantibody levels compared to patients without the minor allele (OR=2.2; Bonferroni-corrected P=0.003), after adjusting for age at clinical onset (P=8.0 x 10(-13)) and the numbers of HLA-DQ A1*0501-B1*0201 haplotypes (P=2.4 x 10(-5)) and DQ A1*0301-B1*0302 haplotypes (P=0.002). GIMAP5 polymorphism was not associated with type I diabetes or with GAD65 or insulin autoantibodies, ICA, or age at clinical onset in patients. These data suggest that the GIMAP5 gene is associated with islet autoimmunity in type I diabetes and add to recent findings implicating the same SNP in another autoimmune disease.

SUMO4 M55V polymorphism affects susceptibility to type I diabetes in HLA DR3- and DR4-positive Swedish patients.

SUMO4 M55V, located in IDDM5, has been a focus for debate because of its association to type I diabetes (TIDM) in Asians but not in Caucasians. The current study aims to test the significance of M55V association to TIDM in a large cohort of Swedish Caucasians, and to test whether M55V is associated in those carrying human leukocyte antigen (HLA) class II molecules. A total of 673 TIDM patients and 535 age- and sex-matched healthy controls were included in the study. PCR-RFLP was performed to identify the genotype and allele variations. Our data suggest that SUMO4 M55V is not associated with susceptibility to TIDM by itself. When we stratified our patients and controls based on heterozygosity for HLA-DR3/DR4 and SUMO4 genotypes, we found that presence of SUMO4 GG increased further the relative risk conferred by HLA-DR3/DR4 to TIDM, whereas SUMO4 AA decreased the risk. From the current study, we conclude that SUMO4 M55V is associated with TIDM in association with high-risk HLA-DR3 and DR4, but not by itself.