Safety and pharmacokinetics of daclizumab in pediatric renal transplant recipients

Abstract:  This study examined the safety and pharmacokinetics/pharmacodynamics of daclizumab in combination with mycophenolate mofetil (or azathioprine), corticosteroids, and cyclosporine or tacrolimus, in 61 pediatric renal allograft recipients in three age groups: less than or equal to five yr (n = 18), 6–12 yr (n = 18), and 13–17 yr (n = 25). The dosing regimen was daclizumab 1.0 mg/kg before transplantation, followed by four biweekly doses. The pharmacokinetics of daclizumab were described using NONMEM software. Median (range) estimated trough daclizumab levels achieved on day 56 (before dose 5) were 3.88 μg/mL (2.48–8.78), 4.54 μg/mL (1.79–18.7), and 4.94 μg/mL (0.05–10.6) in the less than or equal to five yr (n = 15), 6–12 yr (n = 17), and 13–17 yr (n = 22) age groups, respectively. Steady-state median (range) daclizumab exposures were 2040 mg · h/mL (1585–3778), 2757 mg · h/mL (1873–3494) and 3297 mg · h/mL (1705–6453), respectively. Saturation of the IL-2R occurred rapidly and was maintained for greater than or equal to three months after transplantation. Daclizumab was generally well-tolerated with no acute allergic or anaphylactic reactions, deaths or malignancies during the study. The proportion of patients who developed acute rejection at six and 12 months was 8.5% and 16.7%, respectively. This study shows that adding daclizumab at 1 mg/kg to standard immunosuppressive therapy provides safe and effective IL-2R blockade.     

Single photon emission tomography (SPECT) study of regional cerebral blood flow in normoalbuminuric children and adolescents with type 1 diabetes

Abstract: Cerebral damage in diabetes can be related to chronic hyperglycemia and recurrent severe hypoglycemia as well as due to the associated vasculopathy. The pattern of regional cerebral blood flow using cerebral single photon emission tomography (SPECT) was evaluated in normoalbuminuric type 1 diabetic children and adolescents and its relation to the metabolic control and cognitive functions. Thirty-one type 1 diabetics aged 10–18 yr (mean 14.7 ± 3.4) were included, 16 males and 15 females, divided into four groups: group I (n = 8) with history of recurrent severe hypoglycemia (≥ 3); group II (n = 8) with history of severe diabetic ketoacidosis (≥ 3); group III (n = 7) with recurrent minor hypoglycemia (≥ 3/week); and group IV (n = 8) with controlled diabetes. The control group (V) comprised seven healthy children, aged 10–18 yr (mean 14.2 ± 3.1). SPECT was done using technetium-99m hexamethyl propylene amine oxime. There was significant brain hypoperfusion in diabetics compared with controls, mainly in the basal ganglia (p < 0.01) and frontal regions (p < 0.01), with less changes in parietal and temporal regions. These changes were not related to the age, sex, diabetes duration, mean blood glucose or HbA1C. Basal ganglia hypoperfusion was significant in groups I (p < 0.01) and II (p < 0.01) compared with controlled diabetics. There was no correlation between cerebral SPECT changes and cognitive scores in type 1 diabetics.
Conclusion: Subclinical alterations in cerebral blood flow (hypoperfusion) are present in children and adolescents with type 1 diabetes mainly affecting the basal ganglia and frontal regions, usually not associated with measurable alterations of the cognitive functions     

Improved glycemic control and lower frequency of severe hypoglycemia with insulin detemir; long-term experience in 105 children and adolescents with type 1 diabetes

Objective:  To assess the effect of the insulin analog detemir on glycemic control and severe hypoglycemia in children and adolescents with type 1 diabetes.
Research design and methods:  A retrospective chart analysis was performed in 105 patients with type 1 diabetes after switching to insulin detemir between 2004 and 2007. In children below 12 yr of age (n = 53), evening neutral protomin hagedorn (NPH) insulin was replaced by insulin detemir if therapeutic goals were not reached and blood glucose levels were unpredictable or hardly controllable. In adolescents above 12 yr of age (n = 52), insulin detemir was started when changing to intensified insulin therapy.
Results:  In children below 12 yr of age, hemoglobin A1c (HbA1c) at start was 8.3 ± 0.8% and after 12 months of treatment with insulin detemir significantly lowered (7.6 ± 0.6%, p < 0.001). In the age-group above 12 yr of age at the start of the study, the improvement of HbA1c after 12 months of treatment was less pronounced (8.0 ± 1.2 vs. 7.6 ± 1.0%) but still significant (p < 0.01). The risk for severe hypoglycemia was significantly decreased compared with patients attending the outpatient clinic between 1995 and 2003 (4.8/100 patient years vs. 7.6/100 patient years, p = 0.003). From the beginning to the end of the follow-up period, body mass index dropped significantly in children below 12 yr of age but no effect was observed in adolescents.
Conclusions:  Use of insulin detemir allows a safe nocturnal glycemic control in children and adolescents with type 1 diabetes and is associated with significantly improved HbA1c levels and fewer severe hypoglycemic events. This makes insulin detemir a most valuable new tool for the treatment of children and adolescents with type 1 diabetes.     

A randomized prospective study of insulin pump vs. insulin injection therapy in very young children with type 1 diabetes: 12-month glycemic, BMI, and neurocognitive outcomes

Objective:  To compare glycemic control, body mass index (BMI), neurocognitive function, and parenting stress for preschool-aged diabetic children randomized to treatment either with continuous subcutaneous insulin infusion (CSII) or with intensive insulin injection therapy (IIT).
Methods:  Children <5 yr of age diagnosed with type 1 diabetes mellitus for at least 12 months were randomized to either CSII (n = 21) or IIT (n = 21) for 6 months. After 6 months, the IIT group began CSII therapy and the CSII group continued on pumps. Hemoglobin A1c (HbA1c) and BMI percent were collected at baseline, 3, 6, 9, and 12 months. Neurocognitive assessments (Developmental Test of Visual–Motor Integration and Stanford–Binet Intelligence Scale: Fourth Edition) were administered to children, and parenting and child behavior assessments (Parenting Stress Index and Child Behavior Checklist) were completed by parents and at baseline, 6, and 12 months.
Results:  Thirty-five children completed the study. Mean HbA1c decreased significantly over the study period (8.9% ± 0.6 vs. 8.5% ± 0.7, p = 0.006). Initiation of CSII resulted in an HbA1c decrease of 0.4% after 3 months (p = 0.002); however, in the CSII first group, the HbA1c at 12 months was not significantly different from study start (8.8% ± 0.6 vs. 8.5% ± 0.6; p = 0.4). There were no significant changes in BMI%, neurocognitive, parenting, and child behavior measures between groups.
Conclusion:  Initiation of CSII vs. continuing IIT does not significantly influence HbA1c, BMI, neurocognitive, or parenting stress parameters in a research study setting.     

Revisited impact of recipient age on the outcome of living donor liver transplantation for biliary atresia in the recent "transplantation era" in Japan

Abstract:  To re-evaluate the impact of recipient age on the outcome of LDLT for BA in an era in which LDLT is the established treatment for BA in Japan. Thirty-one patients with BA who underwent LDLT were divided into four groups regarding the age at LDLT: infants <1 yr old (group A; n = 14); young children 1 to 6 yr old (group B; n = 8); school children 6 to 15 yr old (group B; n = 5); and adults ≥15 yr old (group D; n = 4). Pre-, peri-, and postoperative factors were compared among the four groups. There was no significant difference in number of the previous laparotomy among the groups. Cholestasis was the dominant indication in group A. PELD score in group B was lower than that in the other groups, and blood loss in group B was significantly less than in groups A and D. Ratio of the graft weight to the recipient's body weight (GRWR) in group A was significantly higher than in other groups. Duration of operation in group D was lower than in groups A and B, but there was no significant difference in the length of postoperative hospital stay and graft survival. Although the case volume was not big, the age of the recipient did not have any significant impact on the outcome of LDLT in our series.     

The technical pitfalls of duct-to-duct biliary reconstruction in pediatric living-donor left-lobe liver transplantation: the impact of stent placement

Abstract:  The feasibility of D-D biliary reconstruction in pediatric LDLT using a left-lobe graft is still controversial. The medical records of 19 pediatric patients (age: four months to 16 yr) were reviewed. The biliary reconstruction was performed in an end-to-end fashion using absorbable sutures. An external biliary tube was placed into the bile duct through the anastomotic site (n = 10) and not through the anastomotic site (n = 4). An external tube was not used in five patients. The median follow-up was 4.7 yr. Nine patients had 11 biliary complications (leakage, n = 2; stricture, n = 7; stricture with leakage, n = 2). Due to biliary complications, conversion to an R-Y was required in five patients, and four patients required radiological or endoscopic management. The patients younger than one yr of age required conversion to R-Y within one wk after LDLT. The analysis of factors related to biliary complications revealed that the use of a trans-anastomotic biliary tube was the only significant factor to avoid biliary complications. In conclusion, D-D biliary reconstruction in LDLT using a left-lobe graft is feasible in selected cases, though it remains challenging. The use of a trans-anastomotic biliary tube is important to avoid biliary complications.     

Dermatological side effects and complications of continuous subcutaneous insulin infusion in preschool-age and school-age children

Objective:  The objective of this study was to evaluate whether very young children develop more dermatological complications during insulin pump treatment compared with school children.
Study design:  Cross-sectional study in 78 consecutive children using insulin pump treatment >4 months.
Results:  Children in group A [n = 40, 28 males (M) and 12 females (F)] were 2.3 ± 1.3 yr (±SD) and those in group B (n = 38, 13 M and 25 F) were 11.0 ± 2.9 yr old at the start of continuous subcutaneous insulin infusion (CSII). The mean duration of CSII was similar in both groups (23.6 ± 16.5 months in group A and 21.8 ± 16.1 in group B). The most common dermatological complications were scars <3 mm (50% in group A vs. 71% in group B, p < 0.05) and lipohypertrophic areas at the insertion sites (45% in group vs. 47% in group B). Local abscesses and blisters were rare findings in both groups (7.5–12%), none leading to interruption or stop of CSII.
Conclusions:  Dermatological side effects during CSII are not more frequent or severe in very young diabetic children compared with diabetic children in school age.     

Liver transplantation for fulminant hepatic failure in infancy: A single center experience

Abstract:  FHF is characterized by a high percentage of unknown causes leading to acute liver failure and furthermore by an increased morbidity and mortality prior to and post-Ltx. In different transplant centers, the reasons leading to FHF differ significantly as well as outcome. We report our single center experience with 30 pediatric patients receiving a liver transplant for FHF, out of a total of 83 children presenting with FHF. The time to transfer patients to the transplant center after the diagnosis of FHF was long, with a median of 14 days (Ltx group) and 12 days (controls), respectively. In nearly half of the patients (n = 14) in the Ltx group, we were not able to establish an exact diagnosis prior to Ltx: 50% suffered from encephalopathy, and 13 patients were treated in the intensive care unit prior to transplant. Because of the availability of different surgical techniques, all children received a timely transplant [split (n = 18), living donor (n = 9), whole organ (n = 2), and reduced liver (n = 1)]. Patient survival was 93.4%, and graft survival was 83.4% for at least one yr follow-up. Severe complications following Ltx included three cases with aplastic anemia and one child suffering from systemic mitochondrial depletion syndrome. The survival of patients treated medically was 83%. We conclude that a strong focus should be made on early referral to a specialized center and on improvement of diagnostic tools to timely detect the underlying reason for FHF. Results following Ltx for FHF are good.     

Health-related quality of life in intensively treated young patients with type 1 diabetes

Abstract:  This study aimed to analyse the impact of the disease and treatment on health-related quality of life (HRQOL) in intensively treated young patients with diabetes. Our main hypothesis was that metabolic control, gender, age and socio-economic status predict HRQOL. All children and adolescents (n = 400, 191 girls) and parents in a geographic population of two paediatric clinics in Sweden [mean age 13.2 yr, ±SD 3.9, range 2.6–19.6; mean duration of diabetes 5.1 yr, ±SD 3.8, range 0.3–17.6; yr mean haemoglobin A1c (HbA1c) 7.1%, ±SD 1.2, range 4.0–10.7] received the DISABKIDS questionnaire, a validated combined chronic generic and condition-specific HRQOL measure for children, and the EuroQol-5D questionnaire. Parents as proxy perceived HRQOL lower than their children. Adolescents with separated parents reported lower generic HRQOL (GeHRQOL) and diabetes-specific HRQOL (DiHRQOL) than those with parents living together (p = 0.027 and p = 0.043, respectively). Adolescent girls reported lower GeHRQOL (p = 0.041) and DiHRQOL (p = 0.001) than boys did. Parents of girls <8 yr of age reported lower DiHRQOL (p = 0.047) than did parents of boys <8 yr. In addition, a difference was found in HRQOL between centres. Intensive insulin therapy did not seem to lower HRQOL. If anything, along with better metabolic control, it increased HRQOL. A correlation between DiHRQOL and HbA1c was found in adolescents (r = −0.16, p = 0.046) and boys aged 8–12 yr (r = −0.28, p = 0.045). We conclude that the diabetes team can influence the HRQOL of the patients as there was a centre difference and because HRQOL is influenced by glycaemic control and insulin regimen. Girls seem to need extra support.     

Basal insulin and total daily insulin dose in children with type 1 diabetes using insulin pumps

Objective:  To assess the contribution of basal insulin to the total daily dose (CBITDD) and to identify the determinant factors in children with type 1 diabetes mellitus.
Study design:  Cross-sectional study in which the basal insulin requirement was established based on a memory read-out of insulin delivery from pumps. Factors such as glycated haemoglobin A1c (HbA1c), fasting C-peptide, standard deviation score of body mass index (sdsBMI) and demographic data were determined during routine hospital visits. Study group included a total of 90 well-controlled diabetic children with the mean HbA1c 6.6 ± 0.7 (5.2–7.9), age 10.4 ± 4.4 yr (1.1–17.9 yr), diabetes duration 3.0 ± 2.6 yr (0.3–10.9 yr) and sdsBMI 0.08 (−2.27 to 1.79), excluding patients with ketoacidosis or infectious diseases.
Results:  Correlations between CBITDD and age (r = 0.39 and p < 0.005) and diabetes duration (r = 0.61 and p < 0.0001) and an inverse correlation with C-peptide (r = −0.41 and p = 0.0001) were found. C-peptide-positive patients had a significantly lower percentage of basal insulin compared with C-peptide-negative patients (20.6 ± 11 vs. 31.6 ± 11.0%, respectively; p = 0.0004); yet, no significant difference in total insulin daily dose (0.65 ± 0.3 vs. 0.78 ± 0.2 U/kg/d, respectively) was observed.
Conclusions:  The percentage of basal insulin in diabetic children is below 50% and in well-controlled diabetic children is related to the fasting C-peptide level, age of patient and diabetes duration but not to HbA1c and sdsBMI.     

Evaluation of sensorimotor polyneuropathy in children and adolescents with type I diabetes: associations with microalbuminuria and retinopathy

Abstract: To investigate diabetic polyneuropathy, we measured peroneal motor conduction velocity, sural sensory nerve conduction velocity and vibratory sense threshold (biothesiometry) in 28 children and adolescents with insulin-dependent diabetes (type 1), and in 28 age- and sex-matched, normal controls. Age varied from 8 to 19 yr (mean ± SD = 13.04 ± 2.61); age at the onset of diabetes from 9 months to 12 yr (4.53 ± 2.42 yr); and the duration of diabetes from 5 to 16 yr (8.48 ± 2.98). Eight patients (28%) fulfilled the minimal criteria for the diagnosis of polyneuropathy. Four of these patients showed symptoms while three had clinical signs of neuropathy. Eight patients had abnormal, sural sensory nerve conduction velocities. The presence of polyneuropathy did not correlate with the duration of diabetes or degree of metabolic control of diabetes. The prevalence of microvascular complications (microalbuminuria and retinopathy) was 32%. The presence of microvascular complications did not correlate with metabolic control but did with the duration of diabetes. The relationship between polyneuropathy and microvascular complications was 34%.     

Development of autoantibodies to islet antigens during childhood: implications for preclinical type 1 diabetes screening

Abstract: Objective:  Serum islet antibodies signify increased risk for type 1 diabetes (T1D). Knowledge of the relationship between age and seroconversion would guide screening for at-risk individuals. We aimed to determine the effectiveness of islet antibody screening in early childhood, in particular the proportion of negative children who subsequently seroconverted.
Methods:  We identified 554 children with a first-degree relative with T1D who had tested negative for islet cell antibodies (ICA) and insulin autoantibodies (IAA) when first screened at a mean age of 7.2 yr. Of 423 who were eligible, 350 consented to re-testing for ICA and IAA and antibodies to glutamic acid decarboxylase (GADAb) and tyrosine phosphatase-like insulinoma antigen IA-2 (IA2Ab) at a mean age of 11.1 yr. GADAb and IA2Ab were measured in 239 of the initial stored samples.
Results:  Of the 350 children who tested negative at first screening, 12 (3.4%) subsequently seroconverted, becoming positive for ICA (n = 4), IAA (n = 7), GADAb (n = 6) or IA2Ab (n = 2). Of 239 initially negative for ICA and IAA, 8/239 (3.3%) now tested positive for GADAb (n = 7) or IA2Ab (n = 1). Four of these children were positive for GADAb in both tests; the one child initially positive for IA2Ab only was positive for all four antibodies 4.6 yr later and developed diabetes.
Conclusion:  Screening for ICA and IAA failed to identify 2–3% of genetically at-risk children who subsequently developed islet antibodies. Testing for GADAb and IA2Ab would not have avoided this. Maximizing the sensitivity of detecting risk for T1D requires repeat screening for islet antibodies throughout childhood.     

Lower levels of plasmacytoid dendritic cells in peripheral blood are associated with a diagnosis of asthma 6 yr after severe respiratory syncytial virus bronchiolitis

Plasmacytoid dendritic cells (pDC) play a crucial role in antiviral immunity and promoting Th1 polarization, possibly protecting against development of allergic disease. Examination of the relationship between peripheral blood plasmacytoid DC levels and manifestations of asthma and atopy early in life. We have isolated peripheral blood mononuclear cells (PBMC) from 73 children (mean age ± SD: 6.6 ± 0.5 yr old) participating in the RSV Bronchiolitis in Early Life (RBEL) study. Flow cytometry was performed on PBMC detecting DC surface-markers: Blood Dendritic Cell Antigens (BDCA) 1, 3, and 2 which identify myeloid type 1, type 2, and plasmacytoid cells, respectively. Total serum IgE, peripheral eosinophil count, and allergy skin tests were documented. About 45% (n = 33) of study participants had physician-diagnosed asthma by 6 yr of age. These children had significantly lower quantities (mean ± SD) of plasmacytoid DC than their non-asthmatic counterparts (1020 ± 921 vs. 1952 ± 1170 cells per 10⁶ PBMC, p = 0.003). We found significantly lower numbers of myeloid dendritic cells in children with asthma (3836 ± 2472 cells per 10⁶ PBMC) compared with those without asthma (4768 ± 2224 cells per 10⁶ PBMC, p = 0.02); however, this divergence was not significant after adjusting for covariates of age, gender, race, skin test reactivity, smoke exposure, and daycare attendance. We did not identify any direct association between DC levels and markers of atopy: skin test reactivity, peripheral eosinophilia, and IgE level. Children who are diagnosed with asthma after severe RSV bronchiolitis appear to have a relative deficiency of plasmacytoid DC in peripheral blood.     

Survival among children with portal vein thrombosis and end-stage liver disease

Al-Holou S, Mathur AK, Ranney D, Kubus J, Englesbe MJ. Survival among children with portal vein thrombosis and end-stage liver disease.
Pediatr Transplantation 2010: 14: 132–137. © 2009 John Wiley & Sons A/S.
Abstract:  Occlusive PVT concurrent with chronic liver disease is a common clinical entity among pediatric patients referred for transplantation. The natural history of PVT is unknown. Our aim was to determine, using a retrospective cohort design, if children under 13 yr with chronic liver disease and concomitant PVT have an increased mortality risk prior to and after transplantation. A total of 203 patients were included in the study. Nearly 10% of the population had PVT (n = 19); 63.2% of PVT patients (5.9% of total cohort) underwent liver transplantation (n = 12). PVT patients tended to be younger than non-PVT patients at evaluation (1.94 ± 3.51 vs. 3.79 ± 4.11, p = 0.059). Clinical and demographic factors were similar between the two groups. Regarding survival, four PVT patients died, of which two had undergone transplantation. Kaplan–Meier analyses indicated that PVT and non-PVT patients had similar survival from the time of evaluation, on the waiting list, and after transplant. Although limited by sample size, our study suggests that a diagnosis of PVT does not increase the mortality risk for children waiting for a liver transplant. Further study is needed to discern variations in mortality risk that may occur in the pediatric chronic liver disease population with PVT.     

Association of mast cells and liver allograft rejection

Abstract:  MCs are important effector cells in a broad range of immune responses. Their role in liver allograft rejection is not clear. Twenty-one liver transplant recipients (mean age ± s.d.; 10.2 ± 4.1 yr) who experienced a rejection episode are included in this study. Biopsy specimens from normal livers (allograft biopsy with normal histopathology n = 5 and naïve livers n = 6), transplanted livers with CR (n = 5), and transplanted livers with ACR (n = 26) were studied. The total number of PT in each biopsy specimen was documented, and the number of PT that contained MCs was expressed as a percentage of the total number of PT. MCs, percentage of PT containing MCs and the average number of MCs/PT was significantly higher in rejection specimens than in control biopsy samples. All parameters were significantly higher in CR group than AR groups. Increasing grades of rejection was also associated with progressively more MCs and MC/PT ( r  = 0.68 p = 0.000; r  = 0.58 p = 0.002). Only serum bilirubin level was related to the MCs in AR group. Only MC/PT was detected as an independent predictor of graft survival (p = 0.011, RR 2.87 95% CI 1.3–6.5). Despite the fact that the role of MCs in liver allograft rejection is still unknown; they exist in inflammatory infiltrates during pediatric liver allograft rejection. MC-rich portal infiltrates may distinguish chronic liver rejection from other inflammatory states such as AR, hepatitis and biliary obstruction.     

Long-term follow-up of portal hypertension after liver transplantation in children

Abstract:  We aimed to describe the long-term changes in the imaging and clinical features of PHALT in children. A retrospective review was undertaken of consecutive children undergoing their first liver transplant between 1993 and 2003. Details of clinical progress and ultrasound imaging were recorded at one-yr post-transplantation and at last follow-up. Data were extracted on 83 children (median age at transplant 1.7 yr, range one month to 17.5 yr, 44 girls) who underwent 89 transplants. Four of these children died at a mean 5.6 yr (range 3.8–6.9 yr) after transplantation. Of the survivors, follow-up at one yr (n = 83) and at last follow-up (n = 71, median 4.3 yr post-transplant) revealed imaging evidence of splenomegaly in 46% and 44%, ascites in 6% and 4%, and portal systemic collaterals in 12% and 14%, respectively. Gastrointestinal hemorrhage associated with portal hypertension had occurred in no children at one yr and in four (6%) at latest follow-up. Features of portal hypertension on ultrasound scan are common in children before liver transplantation. An important minority of children will suffer clinically significant complications of PHALT during long-term follow-up, caused by both vascular and parenchymal disease.     

Insulin autoantibodies are of less value compared with islet antibodies in the clinical diagnosis of autoimmune type 1 diabetes in children older than 3 yr of age

Abstract: Background:  Insulin autoantibodies (IAA), antibodies against endogenous insulin, may be detected in type 1 diabetic children before the start of insulin treatment.
Objective:  To relate IAA to islet antibodies (i.e., islet cell antibodies [ICA], and antibodies against two ICA-related islet antigens, glutamic acid decarboxylase 65 [GADA] and protein tyrosine phosphatase IA-2 [IA-2 A]) at diagnosis, and to endogenous β-cell function at follow-up after diagnosis in diabetic children.
Subjects:  We investigated 74 children, aged 1–15 yr, at the diagnosis of diabetes and 1–10 yr later. Insulin treatment may induce antibody development against exogenous insulin. Patients with insulin treatment ≥ 1 wk (n = 5) were therefore excluded from the final analysis.
Methods: Radioligand-binding assays based on human recombinant antigen were used to measure IAA, GADA, and IA-2 A. ICA were determined with indirect immunofluorescence.
Results:  IAA were detected at a significantly lower frequency (43%; p ≤ 0.001) than ICA (86%), GADA (72%), and IA-2 A (80%). In agreement, IAA measurements only marginally increased the frequency of positive autoimmune markers at diagnosis of diabetes (from 97 to 99% positive for at least one autoantibody). Preserved β-cell function (detectable fasting p-C-peptide levels) was found in only nine patients, who were older (13 ± 3 vs. 7 ± 6 yr, p = 0.002) and had fewer of the antibodies (IAA, GADA, IA-2 A, ICA) in high titer (> median) compared with 60 patients with undetectable p-C-peptide levels.
Conclusions:  Insulin autoantibodies are of less clinical value compared with islet antibodies in the diagnosis of autoimmune type 1 diabetes in children.     

Follow-up of children with rhinitis and cough associated with milk allergy

Young children sensitized with foods may develop early respiratory symptoms including nasal symptoms and cough, but not clinical manifestations in the skin or gastrointestinal tract. The long-term outcome of these patients is largely unknown. We studied 36 children sensitized with cow's milk and three different age-matched control groups. The patients were followed from 12 to 18 months of age for at least 5 yr with repeat skin testing and oral food challenge. After 2½ yr, 63.9% (n = 23) of those in the mild allergy group lost sensitivity to foods; after 5 yr, the number was 86.1% (n = 31). However, during the study period of 5 yr, 69.4% (n = 25) simultaneously developed a sensitivity to common indoor airborne allergens. A similar trend was found only in the egg allergy control group. A positive family history and a history of parental smoking significantly increased the relative risk (RR) of sustaining nasal allergy symptoms (RR = 3.33 and 1.79, respectively). We concluded that allergy march from food sensitivity to sensitivity to airborne allergens may occur in a subset of children before 4 yr of age. Genetics and environmental factors might independently contribute to the continuation of these respiratory symptoms.     

Effects of prior hypoglycemia and hyperglycemia on cognition in children with type 1 diabetes mellitus

Objective:  Despite the general consensus that youth with type 1 diabetes mellitus (T1DM) can experience modest cognitive impairment, debate continues over the role of severe hypoglycemia (Hypo) and/or hyperglycemia (Hyper) in producing such impairment. Our aim was to determine how Hypo and Hyper experienced during brain development predict patterns of subsequent cognitive performance in youth with T1DM.
Methods:  We tested youth aged 5–16 yr (T1DM, n = 117; non-diabetic sibling controls, n = 58) on cognitive tasks (verbal and spatial intelligence, verbal and spatial memory, and processing speed). T1DM participants were categorized as having experienced 0, 1–2, or 3 or more (3+) Hypo episodes, as having their first Hypo episode before or after 5 yr of age and as having early (before age 5) or late (after age 5) diabetes onset. Hyper exposure was estimated with median hemoglobin A1c, adjusted for diabetes duration for each subject.
Results:  The group with T1DM had lower estimated verbal intelligence than sibling controls. Within the T1DM group, verbal intelligence was reduced with increased exposure to Hyper, not to Hypo. In contrast, spatial intelligence and delayed recall were reduced only with repeated Hypo, particularly when Hypo episodes occurred before the age of 5 yr. Age of onset did not explain these results.
Conclusions:  Hypo and Hyper have qualitatively different effects on cognitive function in T1DM that depend in part on the timing of exposure during development, independent of onset age. This information extends the known benefits of avoiding both Hypo and chronic Hyper during childhood to include preservation of specific cognitive skills.     

Obesity dynamics and cardiovascular risk factor stability in obese adolescents

Aim:  Cross-sectional studies showed worsening of cardiovascular risk factors with increasing severity of childhood obesity. The aim of this study was to investigate the impact of obesity dynamics on cardiovascular risk factors and on the stability of the diagnosis of metabolic syndrome (MS) in obese youth.
Methods and results:  A longitudinal assessment of components of the MS using two definitions was performed in 186 obese adolescents (106 females/80 males, age 13.1 ± 2.5 yr). Components of the MS were assessed at baseline and after 19 ± 7 months. We stratified the cohort into three categories based on the 25th and 75th percentile of body mass index (BMI) z-score change: category 1 reduced BMI z-score by 0.09 or more, category 2 had a BMI z-score change of between −0.09 and 0.12, and category 3 increased BMI z-score by >0.12. Subjects who reduced their BMI z-score significantly decreased their fasting and 2-h glucose levels and triglyceride levels and increased their high density lipoprotein cholesterol in comparison to subjects who increased their BMI z-score. BMI z-score changes negatively correlated with changes in insulin sensitivity (r = −0.36, p < 0.001). Among those with no MS at baseline (n = 119), 10 (8%), most of whom significantly increased their BMI z-score, developed MS. Of 67 who had MS at baseline, 33 (50%), most of whom decreased their BMI z-score, lost the diagnosis.
Conclusions:  Obesity dynamics, tightly linked to changes in insulin sensitivity, have an impact on each individual component of the MS and on the stability of the diagnosis of MS in obese youth.