Prevalence of refractoriness when testing growth hormone levels in children.

OBJECTIVE: Late night spontaneous growth hormone (GH) pulses may influence the pituitary GH response to provocation tests. We evaluated GH response during arginine-insulin-tolerance test (AITT) after a GH peak during a short spontaneous nocturnal profile (SSNP) in children with short stature or low growth velocity. DESIGN: Using SSNP and subsequent AITT, we examined 257 children 4-18 years old (138 (53.7%) males) recruited from three hospitals. Medical records were reviewed retrospectively. Refractory children were defined as a GH peak ≥7 µg/L during SSNP but no GH peak ≥7 µg/L during AITT. RESULTS: In total, 201/257 children had a GH peak ≥7 µg/L at SSNP and/or AITT. Of these, 21.9% were refractory. The proportion of males (p = 0.033) and body mass index (BMI) standard deviation score (SDS) (p = 0.037) were higher in the refractory group than in children with a GH peak ≥7 µg/L during AITT. The median period between last GH peak ≥7 µg/L during SSNP and GHmax at AITT was 210 (30-390) minutes. The GHmax at AITT occurred 30 min earlier for children without a peak ≥7 µg/L during the SSNP (p = 0.004). The number of refractoriness differed somewhat between the hospitals (p = 0.025). CONCLUSIONS: Many children with short stature were refractory at testing; among them we found few clinical characteristics. Refractoriness might be influenced by some differences in procedure, but needs to be considered when evaluating GH response in children.

An Increased Diagnostic Sensitivity of Truncated GAD65 Autoantibodies in Type 1 Diabetes May Be Related to HLA-DQ8.

N-terminally truncated (96-585) GAD65 (tGAD65) autoantibodies may better delineate type 1 diabetes than full-length GAD65 (fGAD65) autoantibodies. We aimed to compare the diagnostic sensitivity and specificity between fGAD65 and tGAD65 autoantibodies for type 1 diabetes in relation to HLA-DQ. Sera from children and adolescents with newly diagnosed type 1 diabetes (n = 654) and healthy control subjects (n = 605) were analyzed in radiobinding assays for fGAD65 (fGADA), tGAD65 (tGADA), and commercial 125I-GAD65 (RSRGADA) autoantibodies. The diagnostic sensitivity and specificity in the receiver operating characteristic curve did not differ between fGADA and tGADA. At the optimal cutoff, the diagnostic sensitivity for fGADA was lower than tGADA at similar diagnostic specificities. In 619 patients, 64% were positive for RSRGADA compared with 68% for fGADA and 74% for tGADA. Using non-DQ2/non-DQ8 patients as reference, the risk of being diagnosed with fGADA and tGADA was increased in patients with DQ2/2 and DQ2/8. Notably, logistic regression analysis suggested that DQ8/8 patients had an increased risk to be diagnosed with tGADA (P = 0.003) compared with fGADA (P = 0.09). tGADA had a higher diagnostic sensitivity for type 1 diabetes than both fGADA and RSRGADA. As DQ8/8 patients represent 10-11% of patients with newly diagnosed type 1 diabetes <18 years of age, tGADA analysis should prove useful for disease classification.

Safety of inhaled budesonide: clinical manifestations of systemic corticosteroid-related adverse effects.

Inhaled corticosteroid (ICS) therapy is central to the long-term management of asthma and is extensively used in the management of chronic obstructive pulmonary disease (COPD). While administration via inhalation limits systemic exposure compared with oral or injected corticosteroids and, therefore, the risk of systemic corticosteroid-related adverse effects, concerns over the long-term safety of ICS persist. The assessment of the long-term effects of ICS therapy requires considerable research effort over years or even decades. Surrogate markers/predictors for clinical endpoints such as adrenal crisis, reduced final height and fractures have been identified for use in relatively short-term studies. However, the predictive value of such markers remains questionable.Inhaled budesonide has been available since the early 1980s and there is a considerable evidence base investigating the safety of this agent. To assess the long-term safety of inhaled budesonide therapy in terms of the actual incidence of the clinical endpoints adrenal crisis/insufficiency, reduced final height, fractures and pregnancy complications, we undertook a review of the scientific literature. The external databases BIOSIS, Cochrane Central Register of Controlled Trials, Current Contents, EMBASE, International Pharmaceutical Abstracts and MEDLINE were searched, in addition to AstraZeneca's internal product literature database Planet, up to 29 February 2008. Only original articles of epidemiological studies, national surveys, clinical trials and case reports concerning inhaled budesonide were included.Eight surveys of adrenal crisis were found. The only survey with specified criteria for diagnosis involved 2912 paediatricians and endocrinologists and revealed 33 patients with adrenal crisis associated with ICS therapy; only one patient used budesonide (in co-treatment with fluticasone propionate). In addition, 14 case reports of adrenal crisis in budesonide-treated patients were found. In only two of these, budesonide was used at recommended doses and in the absence of interacting medication.Three retrospective studies and one prospective study assessing final height were found. None of them showed any reduced final height in patients receiving inhaled budesonide during childhood or adolescence.Seventeen epidemiological studies investigating the risk of fractures were found. When adjusting for confounding factors, they did not provide any unequivocal data for an increased fracture risk with budesonide. Four prospective placebo-controlled clinical trials of 2-6 years duration with inhaled budesonide in patients with asthma or COPD were found. None of the studies identified any association between inhaled budesonide and increased risk for fractures.Four studies using data from the Swedish birth and health registries showed there was no increased risk for congenital malformations, cardiovascular defects, decreased gestational age, birth weight or birth length among infants born to women using inhaled budesonide during pregnancy compared with the general population. This was confirmed by five observational studies in Australia, Canada, Hungary, Japan and the US. Similarly, one randomized clinical trial comparing pregnancy outcomes among asthma patients receiving inhaled budesonide or placebo did not demonstrate any difference in outcome of pregnancy.In summary, based on 25 years of experience with different doses and in different populations, inhaled budesonide therapy only in very rare cases appears to be associated with an increased risk of adrenal crisis, reduction in final height, increases in the number of fractures or complications during pregnancy.

Maternal enterovirus infection during pregnancy as a risk factor in offspring diagnosed with type 1 diabetes between 15 and 30 years of age.

Maternal enterovirus infections during pregnancy may increase the risk of offspring developing type 1 diabetes during childhood. The aim of this study was to investigate whether gestational enterovirus infections increase the offspring's risk of type 1 diabetes later in life. Serum samples from 30 mothers without diabetes whose offspring developed type 1 diabetes between 15 and 25 years of age were analyzed for enterovirus-specific immunoglobulin M (IgM) antibodies and enterovirus genome (RNA), and compared to a control group. Among the index mothers, 9/30 (30%) were enterovirus IgM-positive, and none was positive for enterovirus RNA. In the control group, 14/90 (16%) were enterovirus IgM-positive, and 4/90 (4%) were positive for enterovirus RNA (n.s.). Boys of enterovirus IgM-positive mothers had approximately 5 times greater risk of developing diabetes (OR 4.63; 95% CI 1.22-17.6), as compared to boys of IgM-negative mothers (P < .025). These results suggest that gestational enterovirus infections may be related to the risk of offspring developing type 1 diabetes in adolescence and young adulthood.

A novel missense mutation in GALNT3 causing hyperostosis-hyperphosphataemia syndrome.

OBJECTIVE: Hyperostosis-hyperphosphataemia syndrome (HHS) is a rare hereditary disorder characterized by hyperphosphataemia, inappropriately normal or elevated 1,25-dihydroxyvitamin D(3) and localized painful cortical hyperostosis. HHS was shown to be caused by inactivating mutations in GALNT3, encoding UDP-N-acetyl-alpha-D-galactosamine: polypeptide N-acetylgalactosaminyltransferase 3 (GalNAc-transferase; GALNT3). Herein, we sought to identify the genetic cause of hyperphosphataemia and tibial hyperostosis in a 19-year-old girl of Colombian origin. METHODS: Genomic DNA was extracted and sequencing analysis of the GALNT3 and fibroblast growth factor 23 (FGF23) genes performed. Serum levels of intact and C-terminal FGF23 were measured using two different ELISA methods. RESULTS: Mutational analysis identified a novel homozygous missense mutation in exon 6 of GALNT3 (1584 G>A), leading to an amino acid shift from Arg to His at residue 438 (R438H). The mutation was not found in over 200 control alleles or in any single nucleotide polymorphism databases. The R438 residue is highly conserved throughout species and in all known GalNAc-transferase family members. Modelling predicted the substitution deleterious for protein structure. Importantly, the phosphaturic factor FGF23 was differentially processed, as reflected by low intact (15 pg/ml) but high C-terminal (839 RU/ml) serum FGF23 levels. CONCLUSIONS: We report on the first missense mutation in GALNT3 giving rise to HHS, since previous GALNT3 mutations in HHS caused aberrant splicing or premature truncation of the protein. The R438H substitution likely abrogates GALNT3 activity, in turn causing enhanced FGF23 degradation and subsequent hyperostosis/hyperphosphataemia.

Number of islet autoantibodies present in newly diagnosed type 1 diabetes children born to non-diabetic mothers is affected by islet autoantibodies present at birth.

OBJECTIVE: Cord blood islet autoantibodies in children born to mothers with type 1 diabetes may be associated with a reduced risk of islet autoimmunity and diabetes. The aim of this study was to investigate in children with type 1 diabetes but born to non-diabetic mothers whether islet autoantibodies at birth affected their presence at diagnosis. PATIENTS AND METHODS: Serum samples at birth and at diagnosis were available from 141 children who developed type 1 diabetes between 1 and 19 yr of age (median 9.0 yr; male/female ratio 83/58). The samples were tested for autoantibodies against glutamic acid decarboxylase, insulinoma-associated antigen 2, and insulin as well as for islet cell antibodies. The human leukocyte antigen genotype was also determined. RESULTS: The frequency of islet autoantibodies in the umbilical cord blood was 11% compared with 91% at diagnosis. Children with fewer islet autoantibodies at diagnosis were more likely to have had autoantibodies at birth (p = 0.02). Autoantibodies present in cord blood at birth were observed in 25% (3/12) of children with no islet autoantibodies at diagnosis, in 17% (7/42) of children with one or two antibodies at diagnosis, and in only 5% (4/86) of children with more than two antibodies, demonstrating an inverse relationship between autoantibodies at birth and at diagnosis (test for trend, p < 0.001). CONCLUSIONS: Our preliminary data suggest that exposure to cord blood islet autoantibodies may influence the presence of islet autoantibodies at the time of diagnosis of type 1 diabetes and explain why some type 1 diabetes children are islet autoantibody negative at clinical diagnosis.

Exposure of infants to budesonide through breast milk of asthmatic mothers.

BACKGROUND: Maintenance treatment with inhaled corticosteroids is often required for asthmatic nursing women. Data on the transfer of inhaled corticosteroids from plasma to breast milk and the subsequent exposure of the breast-feeding infant has been unavailable. OBJECTIVE: We sought to assess budesonide concentrations in milk and plasma of asthmatic nursing women receiving maintenance treatment with the Pulmicort Turbuhaler and estimate the exposure of their breast-fed infants. METHODS: Milk and plasma samples were collected up to 8 hours after dosing from 8 mothers receiving budesonide maintenance treatment (200 or 400 microg twice daily). Pharmacokinetic parameters were calculated from budesonide milk and plasma concentrations. Infant exposure was estimated based on average milk budesonide concentrations. A single blood sample was obtained from 5 infants close to expected infant maximum concentration. RESULTS: Budesonide concentrations in milk reflected those in maternal plasma, supporting passive diffusion of budesonide between plasma and milk, and was always lower than that in plasma. The mean milk/plasma ratio was 0.46. The estimated daily infant dose was 0.3% of the daily maternal dose for both dose levels, and the average plasma concentration in infants was estimated to be 1/600th of the concentrations observed in maternal plasma, assuming complete infant oral bioavailability. Budesonide concentrations in infant plasma samples were all less than the limit of quantification. CONCLUSION: Maintenance treatment with inhaled budesonide (200 or 400 microg twice daily) in asthmatic nursing women results in negligible systemic exposure to budesonide in breast-fed infants. CLINICAL IMPLICATIONS: These data support continued use of inhaled budesonide during breast-feeding.

Safety and tolerability of inhaled budesonide in children in the Steroid Treatment As Regular Therapy in early asthma (START) trial.

The safety and tolerability of asthma medications are still a concern to many asthma patients receiving long-term treatment. Therefore, more safety data from long-term, controlled trials are needed. The aim of this study was to evaluate the safety and tolerability of long-term treatment with once-daily budesonide in children aged 5-10 yrs with mild persistent asthma of recent onset in the inhaled Steroid Treatment As Regular Therapy in early asthma (START) study. Children aged 5-10 yrs with early asthma were randomized to double-blind treatment with budesonide 200 microg or placebo once daily via Turbuhaler in addition to usual asthma therapy, for 3 yrs. Adverse events were recorded from both spontaneous reports and responses to standard questions, and asthma-related events and asthma control were recorded between visits and subsequently graded by the blinded investigators. Of the study population of 1981 children (1004 budesonide and 977 usual care), 81% (812 of 1004) in the budesonide group and 82% (797 of 977) in the usual care group experienced a total of 6414 events listed by preferred term (3209 budesonide plus usual care and 3205 placebo plus usual care). The most commonly reported events included respiratory infection, pharyngitis, rhinitis, viral infection and bronchitis, and there were no clinically relevant differences in incidence between treatments. There were no reports of tuberculosis or aspergillosis, and no evidence of increased risk of systemic or ocular adverse events with budesonide relative to placebo. There were 106 serious adverse events in the budesonide group and 128 with usual care. The most frequent, aggravated asthma, was more common with usual care than with budesonide. There were no deaths among children participating in START. In conclusion, the addition of once-daily inhaled budesonide 200 microg via Turbuhaler to usual care is safe and well tolerated in children with recent-onset mild persistent asthma.

Levothyroxine treatment reduces thyroid size in children and adolescents with chronic autoimmune thyroiditis.

CONTEXT: The use of levothyroxine to reduce thyroid size in pediatric patients with goiter due to chronic autoimmune thyroiditis (AIT) remains controversial. In overtly hypothyroid patients, reductions in thyroid volume have been reported, whereas the effect in subclinically hypothyroid and euthyroid patients is less clear. OBJECTIVE: The objective of the study was to evaluate the effect of levothyroxine treatment on thyroid size (determined with thyroid ultrasonography) in children and adolescents with AIT. DESIGN AND SETTING: This study included patients with AIT treated at a university hospital outpatient clinic between 1987 and 2004. PATIENTS: Ninety children with AIT (73 girls and 17 boys, aged 6.1-17.7 yr) were included in the study. INTERVENTION: Intervention was treatment with levothyroxine for a median 2.8 yr (range 0.5-10.2). MAIN OUTCOME MEASURE: Change in thyroid volume sd score (SDS) during the study period was measured. RESULTS: Median thyroid volume SDS was reduced in patients euthyroid (-0.4 SDS, P < 0.001), subclinically hypothyroid (-1.4 SDS, P < 0.001), and overtly hypothyroid (-1.8 SDS, P < 0.002) at diagnosis of AIT. Both hypothyroid and euthyroid patients with goiter (thyroid volume > 2.0 SDS) at baseline reduced their median thyroid volume SDS (-1.6 and -0.9, respectively, P < 0.001). Hypothyroid patients without goiter also reduced median thyroid volume SDS (-1.2, P < 0.004), whereas no change was noticed in euthyroid children without goiter. CONCLUSIONS: Levothyroxine treatment is effective in reducing thyroid volume in pediatric patients and is suggested in treatment of goiter caused by AIT, especially in cases of hypothyroid, but also in euthyroid children.

Thyroid autoantibodies in cord blood sera from children and adolescents with autoimmune thyroiditis.

Autoimmune thyroid disease is common among women of childbearing age. Thyroid autoantibodies are predominantly of the immunoglobulin G (IgG)-type and pass the placental barrier from mother to child. Recent studies have suggested a pathogenetic role for transplacentally transmitted autoantibodies in the development of autoimmune disease. The aim of the present study was to investigate if children and adolescents with autoimmune thyroiditis (AIT) have been exposed to thyroid autoantibodies already in utero. Cord blood sera taken at delivery from 34 newborns who had developed AIT during childhood and adolescence, and sera from 31 of their mothers, were analyzed for the presence of autoantibodies against thyroid peroxidase (TPOAb) and thyroglobulin (TgAb), and compared to 233 randomly selected control children and their mothers. The prevalence of TPOAb in cord blood sera was elevated among the children and adolescents with AIT compared to controls (38% versus 14%; odds ratio [OR] 4.12, p < 0.001). An increased prevalence of TPOAb was also found among their mothers (29% versus 15%; OR 2.17, p < 0.048). No significant difference in the prevalence of TgAb was found either between children with AIT and the control children (18% versus 9%; OR 2.16, p < 0.15), or between their mothers and the control mothers (23% versus 12%; OR 2.17, p < 0.16). Most of the TPOAb-positive children had TPOAb-positive mothers, indicating the maternal origin of their TPOAb. In conclusion, a large proportion of children who later developed AIT had already been exposed to transplacentally transmitted TPOAb in utero. Whether these autoantibodies have any pathogenetic role in the development of AIT in offspring or if they simply mirror the inheritance of AIT, remains to be investigated.

Long-term safety of once-daily budesonide in patients with early-onset mild persistent asthma: results of the Inhaled Steroid Treatment as Regular Therapy in Early Asthma (START) study.

BACKGROUND: The Inhaled Steroid Treatment as Regular Therapy in Early Asthma (START) study is a worldwide, randomized, prospective study to investigate early intervention with inhaled corticosteroids in recent-onset mild persistent asthma. OBJECTIVE: To evaluate the safety and tolerability of long-term treatment with once-daily budesonide therapy in patients with mild persistent asthma. METHODS: Patients aged 5 to 66 years with mild persistent asthma for fewer than 2 years and no previous regular corticosteroid treatment received budesonide or placebo once daily for 3 years, in addition to their usual asthma therapy. The daily budesonide dose was 200 microg for children younger than 11 years and 400 microg for those 11 years or older. RESULTS: Overall, 7,221 patients were included in the safety analysis, and a total of 21,520 adverse events were reported (10,850 in the budesonide group and 10,670 in the placebo group). The most commonly reported events included respiratory infections, rhinitis, pharyngitis, bronchitis, viral infections, and sinusitis. The number of deaths and serious adverse events were similar for children and adults in both treatment groups. Fewer asthma-related serious adverse events were reported with budesonide (162) compared with placebo (276). Oral candidiasis was reported more frequently with budesonide (1.2%) than with placebo (0.5%); the frequencies of other adverse effects previously reported to be associated with inhaled corticosteroids (psychiatric disorders, skin disorders, and allergic reactions) were similar. CONCLUSIONS: Three-year treatment with budesonide once daily (200 or 400 microg) is safe and well tolerated in children and adults with newly detected mild persistent asthma.

Parent responses to participation in genetic screening for diabetes risk.

Screening for type 1 diabetes (T1DM) risk in newborns has little negative emotional impact on mothers. In this study, the impact on the mother and the father was evaluated both in the general population and in families with diabetes. All parents with a newborn in Skane, Sweden, were invited to a screening for T1DM risk in their children (the Diabetes Prediction in Skane (DiPiS)). Blood was obtained at delivery from the mother and the child. When the child was 2 months old, parents gave written consent and filled out questionnaires, but were not informed about the genetic risk. Of the 10 538 invited families, 6831 (64.8%) consented and 806 (7.7%) declined participation. Five questions addressing both parents were filled out by 6676 (63.4%) mothers and 6099 (57.8%) fathers. In 146/6676 (2.2%) families, one family member had diabetes (D-families). Participation in DiPiS did not affect most parents and the majority was satisfied with the information. The majority of parents (28.9%) were reassured and only 1.1% (140/12,670) reported increased worries because of participation, compared to 2.8% of the mothers in D-families. Parents in D-families more often ascribed diabetes risk to their child as well as the risk being higher. Mothers and fathers differed in their answers on four of the five study questions, with mothers being more satisfied with the information, reporting more knowledge of diabetes, estimating lower risk of their child to get diabetes, but reporting more worries of possible future chronic disease in the child. Parents with lower education, being born abroad, or being younger who reported worries of chronic disease in the child were also reassured by participation in the study. These results confirm that screening for T1DM risk in newborns does not create worries in most parents, but stress that fathers differ from mothers in opinions and reactions, that parents' reactions are affected by diabetes in the family, and that demographic factors might be important for the parents' reports.

Genetic and perinatal factors as risk for childhood type 1 diabetes.

The mechanisms by which gestational infections, blood incompatibility, birth weight, mother's age and other prenatal or neonatal events increase the risk for type 1 diabetes are not understood. Studies so far have been retrospective, and there is a lack of population-based prospective studies. The possibility of identifying children at type 1 diabetes risk among first-degree relatives has resulted in prospective studies aimed at identifying postnatal events associated with the appearance of autoantibody markers for type 1 diabetes and a possible later onset of diabetes. However, the majority (85%) of new onset type 1 diabetes children do not have a first-degree relative with the disease. Population-based studies are therefore designed to prospectively analyse pregnant mothers and their offspring. One such study is DiPiS (Diabetes Prediction in Skåne), which is examining a total of about 10,000 pregnancies expected every year in the Skåne (Scania) region of Sweden that has 1.1 million inhabitants. Blood samples from all mothers in this region are obtained during pregnancy and at the time of delivery. Cord blood is analysed for HLA high-risk alleles and for autoantibodies against the 65 kD isoform of glutamic acid decarboxylase (GADA), the protein tyrosine phosphatase-related IA-2 antigen (IA-2A) and insulin (IAA) as a measure of prenatal autoimmune exposure. Identifying high-risk children by genetic, autoimmune and gestational risk factors followed by prospective analyses will make it possible to test the hypothesis that gestational events may trigger beta cell autoimmunity as a prerequisite for childhood type 1 diabetes.

Interpretation of normative thyroid volumes in children and adolescents: is there a need for a multivariate model?

The use of thyroid ultrasonography for determination of thyroid volume requires reliable reference criteria. The current World Health Organization/International Council for the Control of Iodine Deficiency Disorders (WHO/ICCIDD) reference has been questioned since iodine-sufficient children have been found throughout the world with distinctly smaller thyroid volumes. A difference in part explained by a systematic bias when generating the WHO/ICCIDD reference data. The objective with this study was to evaluate normative thyroid volumes in our region and, if possible, develop a multivariate model for their interpretation. Thyroid ultrasonography was performed and anthropometrical measurements were taken in 561 children and adolescents. The best predictor for thyroid volume in both girls and boys was body surface area (BSA), followed by age, weight, and height. References for normative thyroid volumes were calculated for each of the predictors. When these references were compared with other references throughout the world, the age-specific references were in good accord, but distinct differences were found between our BSA-specific references and other references based on a majority of children younger than ours. Using multivariate analyses, BSA and age were found to significantly influence thyroid volume, independently of each other. Multiple regression models by gender using BSA and age as predictors for thyroid volume were constructed. Using these models the difference between the BSA-specific references could be markedly reduced. To interpret thyroid volume accurately we propose the use of a multivariate model using age and BSA as predictors of thyroid volume.

Intrauterine exposure to maternal enterovirus infection as a risk factor for development of autoimmune thyroiditis during childhood and adolescence.

Maternal intrauterine enterovirus infection during pregnancy increases the risk for the offspring to develop type 1 diabetes mellitus. Type 1 diabetes mellitus and autoimmune thyroiditits (AIT) are closely linked. A common pathogenetic factor is possible. The objective of this study was to investigate a possible association between maternal enterovirus infection during pregnancy and the development of AIT in the offspring. Sera taken at delivery from 31 mothers whose children subsequently developed AIT was analyzed for immunoglobulin (Ig)A, IgG, and IgM antibodies against enterovirus, and compared to a control group comprising 233 randomly selected maternal sera. Of the mothers whose children developed AIT, 5 of 31 (16%) were enterovirus IgM-positive, compared to 17 of 233 (7%) in the control group (p = 0.16). The age at diagnosis of AIT was significantly lower in the group of children with IgM-positive mothers compared to children with IgM-negative mothers (p < 0.05). In addition, 3 children (60%) in the IgM-positive group were overtly hypothyroid at diagnosis of AIT, compared to no child (0%) in the IgM-negative group (p < 0.01). No significant differences were found in IgA and IgG antibody titers between the mothers whose children developed AIT and the control group. Although this study did not have enough power to reveal intrauterine exposure to maternal enterovirus infection during pregnancy as a risk factor for development of AIT during childhood and adolescence, it suggested an association with earlier onset of clinical disease in children to enterovirus IgM-seropositive mothers.

Islet autoantibodies in cord blood from patients who developed type 1 diabetes mellitus at 15-30 years of age.

Islet cell autoantibodies are early markers for type 1 diabetes. The aim of this study was to determine whether islet autoantibodies were present at birth in young adults who developed type 1 diabetes at 15-30 years of age. Cord blood sera from 30 patients who developed type 1 diabetes between 15 and 25 years of age and sera from 320 randomly selected control children were tested for islet cell antibodies (ICA) by indirect immunofluorescence and autoantibodies against the 65 kD isoform of glutamic acid decarboxylase (GADA), islet cell antigen-2 (IA-2A) and insulin (IAA) by radiobinding assays. The young adults who developed type 1 diabetes did not differ from controls in the cord blood prevalence of any of the four islet autoantibodies. This is in contrast to our previous findings that children who developed type 1 diabetes below 15 years of age had an increased prevalence of cord blood islet autoantibodies. Our present data suggest that, in contrast to children, pre- and perinatal risk factors are less likely to be involved in the development of type 1 diabetes in young adults.

Islet cell autoantibodies in cord blood from children with blood group incompatibility or hyperbilirubinemia.

Blood group incompatibility is a risk factor for type 1 diabetes. Our aim was to test the hypothesis that islet cell autoantibodies, as markers for beta cell autoimmunity, are increased in cord blood from newborns with a diagnosis of blood group incompatibility. Using the diagnosis register of the Malmö University Hospital we obtained cord blood from 151 children with ABO immunization, 311 children with hyperbilirubinemia and a control group of 320 other children born during the same time period. The cord blood samples were analyzed for islet cell antibodies (ICA) by indirect immunofluorescence and autoantibodies against the Islet Cell Antigen-2 (IA-2Ab) and the 65 kDa isoform of glutamic acid decarboxylase (GAD65Ab) by standard radioligand binding assays. The prevalence of ICA was increased compared to controls (0.6%) not only in children with ABO immunization (4.0%, p = 0.02), but also in newborn children with hyperbilirubinemia (4.2%, p = 0.003). The prevalence of IA2Ab, but not of GAD65Ab, was increased in children with ABO immunization (3.3%) compared to the hyperbilirubinemia group without incompatibility (0.6%, p = 0.04), or the controls (0.3%, p = 0.02). Our findings that hyperbilirubinemia is associated with an increased prevalence of ICA, and blood group incompatibility with both ICA and IA-2, suggests that intra-uterine factors may be associated with islet cell autoimmunity.

Enterovirus infection during pregnancy is not a risk factor for celiac disease in the offspring.

BACKGROUND: There is a strong genetic influence on the susceptibility to celiac disease but it is also evident that environmental factors play a role in the development of the disease. Diverging studies about adenovirus infection as a possible triggering factor in the pathogenesis have been reported. Our study was undertaken to determine whether enterovirus infection during pregnancy is a risk factor for the development of celiac disease later in childhood. METHODS: Cord blood from 76 mothers whose children developed celiac disease before 15 years of age were analyzed for IgA, IgG, and IgM antibodies for enteroviruses and Ig-A endomysium antibodies. The control group comprised cord blood from 327 mothers with children without known celiac disease. RESULTS: There were no significant differences in antibody titers for enterovirus between the two groups. IgA-endomysium antibodies were elevated in 3 of the 76 mothers, whereas none had known celiac disease. CONCLUSION: This study does not show that enterovirus infection during pregnancy is associated with the development of celiac disease in childhood. Of the mothers whose children developed celiac disease, 4% had Ig-A endomysium antibodies, which may reflect a silent celiac disease.

Transglucosidation of methyl and ethyl D-glucopyranosides by alcoholysis.

The transglucosidations of methyl 4-O-methyl-alpha- and -beta-D-glucopyranoside in ethanolic camphor-10-sulfonic acid, and of ethyl 4-O-methyl-alpha- and -beta-D-glucopyranoside in methanolic camphor-10-sulfonic acid, have been studied. Samples were removed at intervals and the proportions of the glucosides determined by GC of their acetates. The results show that the anomer with the inverted configuration predominates in the initially formed product (approximately 59-70%). This indicates that all the studied reactions proceed via the same mechanism, involving exocyclic C-O cleavage and formation of a glucopyranosylium ion, but that the eliminated alcohol exerts some steric hindrance, which favors the approach of the other alcohol from the opposite side.