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.

Respiratory infection recurrence and passive smoking in early atherosclerosis in children and adolescents with type 1 diabetes.

BACKGROUND: Optimal glucose control in juvenile type 1 diabetes mellitus is necessary but not sufficient to reduce the burden of cardiovascular events in later life. This emphasizes the importance of searching for other possible risk factors associated with diabetes. We investigated whether recurrent episodes of acute respiratory infections and exposure to tobacco smoke could influence vascular phenotypes for early atherosclerosis in children and adolescents with type 1 diabetes. MATERIALS AND METHODS: Common carotid artery elasticity and intima-media thickness along with circulating markers of lipid, inflammatory and glycaemic profiles were investigated in up to 98 children and adolescents with type 1 diabetes. The number of clinically manifest acute respiratory tract infections (RTI) during the past year, and the degree of exposure to environmental tobacco smoke (ETS), were assessed by separate questionnaires. RESULTS: Carotid artery compliance (CAC) was decreased in patients with high (>or= 4/year; n = 22) recurrence of RTI compared to the remaining patients (n = 40; P < 0.05). In a multivariate analysis, the number of RTI during the past year and HbA(1C) were independently associated with decreased CAC (P < 0.05 for both). The inverse relationship between RTI recurrence and CAC was strengthened by frequent exposure to ETS. CONCLUSIONS: High recurrence of respiratory infections in young type 1 diabetics is associated with increased stiffening of the carotid artery particularly in those often exposed to tobacco smoke.

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.

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.

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 beta-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 > or = 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 < or = 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 beta-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.

Parents' reactions and recommendations after diagnosis and hearing aid fitting.

This study was designed to explore parent reactions to the early stages of audiologic assessment and intervention. A total of 213 parents whose children were under the age of 6 years returned a mail survey. Respondents from 45 states participated. Parents were asked to (1) report the approximate age of diagnosis and hearing aid fitting; (2) comment on reasons for any delays encountered from diagnosis to fitting; and (3) respond to questions concerning their reactions to the initial fitting of amplification. The median age of identification was earlier than some previous investigations; however, substantial delays occurred between diagnosis and hearing aid fitting. Reasons for delay included the need for further audiologic evaluation, problems obtaining return appointments, illness of the child, and difficulties obtaining adequate earmolds. Parent reactions to hearing aids, once fitted, included concerns about appearance and questions about maintenance and use, but attitudes regarding hearing aids and their perceived benefits improved over time.

Early urinary changes in Tamm-Horsfall protein and epidermal growth factor in diabetic children.

Both glomerular and tubular markers have been used to follow diabetic nephropathy. However, neither albumin nor proximal tubular markers have proven useful in prepubertal diabetes. Hence we studied two markers derived from the distal tubular cells, Tamm-Horsfall protein (THP) and epidermal growth factor (EGF). The urinary excretion of THP and EGF was examined in samples obtained during the first 20 days and 1 year after diagnosis of diabetes in children aged 4-15 years. Fourteen children without and 18 with ketonuria were examined, and 17 age-matched healthy children participated as controls. The excretion rate of EGF was increased at diagnosis, while that of THP was not. After 20 days of treatment the excretion of EGF had normalized, while the excretion of THP was decreased. Similar results were obtained after 1 year. In conclusion, in spite of good metabolic control a reduced excretion of THP persisted for at least 1 year after the diagnosis of diabetes. Whether the finding of reduced excretion of THP has any biological significance awaits further study.

Islet cell antibody frequency differs from that of glutamic acid decarboxylase antibodies/IA2 antibodies after diagnosis of diabetes.

The combination of glutamic acid decarboxylase (GAD) 65 antibodies (GADA) and protein tyrosine phosphatase-like protein IA2 antibodies (IA2-ab), measured by radioligand binding assays, has been suggested to replace islet cell antibodies (ICA), measured by indirect immunofluorescence, as a marker for autoimmune type I diabetes. The aim of this study was to compare the frequency of ICA and GADA and/or IA2-ab not only at, but also after the diagnosis of diabetes. ICA, GADA and IA2-ab were therefore assessed at and up to 11 y after the diagnosis of diabetes in 86 children (1-15-y-old). At diagnosis, ICA were found in 74 (86%) and GADA and/or IA2-ab in 79 (92%) of the diabetic children. Hence, there was no major difference in frequency between ICA and GADA and/or IA2-ab at diagnosis of diabetes. At follow-up, however, ICA were less frequent than GADA and/or IA2-ab; 1-3 y after diagnosis ICA were found in 12 (44%) and GADA and/or IA2-ab in 24 (89%) of 27 children (p=0.001); 4-6 y after diagnosis ICA were found in 7 (24%) and GADA and/or IA2-ab in 27 (93%) of 29 children (p < 0.0001); 7-11 y after diagnosis ICA were found in 4 (13%) and GADA and/or IA2-ab in 21 (70%) of 30 children (p < 0.0001). We conclude that the frequency of ICA does not always correspond to that of GADA and/or IA2-ab. Many years after diagnosis of diabetes, measurements of GADA and IA2-ab, but not ICA, detect autoimmunity in high frequency.

Psychological reactions at the onset of insulin-dependent diabetes mellitus in children and later adjustment and metabolic control.

The initial psychological reactions at the onset of insulin-dependent diabetes mellitus (IDDM) in a population-based sample of 76 children were studied with staff observations and a self-report questionnaire for children 12 years of age and more. Younger children reacted with more anger and less distress than the older children. High initial self-reported distress was associated with poorer subjective psychological IDDM adjustment at a follow-up 10 months later for the older children. The children's initial reactions as well as later adjustment were intimately associated with maternal initial reactions in the total group. The metabolic control, estimated as the mean level of the major fraction of glycosylated haemoglobin (Hb AIc) during the first 2 years, was poorer in the adolescent group. Initial anxiety over injections and protest but low general distress in mothers and children were associated with better metabolic control.

Relations between age, metabolic control, disease adjustment and psychological aspects in insulin-dependent diabetes mellitus.

The relations between age, metabolic control, disease adjustment, and psychological factors in boys and girls with recently diagnosed insulin-dependent diabetes mellitus (IDDM) were studied. Older girls had significant higher postremission glycosylated haemoglobin A (Hb AIc) levels (p = 0.008). Girls with more hospitalizations had a lower developmental level (p = 0.05), and had significantly more problems in the behavioural rating (p = 0.05). Boys with more hospitalizations had a more external locus of control (p = 0.01), more difficulties with disease adjustment, more emotional problems, and were also clinically assessed as having more behavioural problems. Boys showing more difficulties in psychological adjustment to the disease also had higher postremission Hb AIc levels (p = 0.02). Although Swedish children with IDDM of short disease duration do not differ from healthy children in important psychological aspects, older girls and a small group of problematic younger boys are at risk of developing metabolic imbalance after a short disease duration.

Psychological stress and the onset of IDDM in children.

OBJECTIVE: The purpose of the study was to determine whether psychosocial stress during different life periods could be a risk factor in the etiology/pathogenesis of insulin-dependent diabetes mellitus (IDDM) in children. RESEARCH DESIGN AND METHODS: In a population-based sample of 67 case patients 0-14 years of age and 61 matched healthy control subjects, life events during the entire lifespan before the onset of IDDM were recorded as well as measures of child behavior before onset, social support, and family function. RESULTS: Negative life events occurring during the first 2 years of life, life events with difficult adaptation, child behavioral deviances, and a more chaotic family function were more common in the case group. A stepwise logistic regression indicated that negative life events in the first 2 years increased the risk of IDDM and that premorbid child behavior as well as dysfunctional hierarchical family pattern affect the risk. CONCLUSIONS: Stress early in life may increase the risk for IDDM, presumably by affecting the autoimmune process. To confirm these results, it is necessary to make a truly prospective study.

Family therapy in poorly controlled juvenile IDDM: effects on diabetic control, self-evaluation and behavioural symptoms.

Diabetic control, behavioural symptoms and self-evaluation were assessed in 25 children with IDDM who were in poor metabolic control (P group), before and subsequent to one of two treatment conditions: family therapy and conventional treatment (C). In addition, data were collected from 12 patients in optimal control (O group). Prior to treatment the patients in poor control were rated higher than those in the O group for symptoms indicating somatization and internalization of conflict and showed a gloomier self-image. The O group patients had fewer behavioural symptoms and a more positive self-image than non-diabetic reference groups. Diabetic control improved after family therapy only. Furthermore, the family therapy group improved on a combined measure of behavioural symptoms and one aspect of self-evaluation (relations to parents and family). The results suggest that IDDM may either interfere with or foster the child's development towards autonomy, depending on family interaction patterns which affect the child's behaviour and self-esteem. Family therapy is a treatment option which can mediate improved diabetic control by changing family relationships to allow for a better balance between parental and self-care of the child with poorly controlled IDDM.

Cooperation between parents in caring for diabetic children: relations to metabolic control and parents' field-dependence-independence.

Aspects of parental interaction were assessed in 20 families with diabetic, insulin-dependent children, using hour-long video-taped interviews, the children being in optimal (O, n = 10) or poor (P, n = 10) metabolic control and showing optimal or poor psychological adaptation. In comparison with the O-group parents, the P-group parents were less appreciative of one another, were less congruent in their attitudes to diabetes care, and appeared not to respect their childrens' independence and integrity; the mothers were discontented with the support given them by their husbands; the children assumed less responsibility for managing their diabetes and seemed less confident during the interview. The results are interpreted in light of an earlier finding that the P-group fathers are more field-dependent (FD) than their wives while the opposite is true for the O-group fathers. With reference to evidence from the cognitive style literature, we suggest that the relatively FD P-group fathers have difficulties in acting as autonomous sources of support to their wives resulting in marital discord and a delayed transition from maternal to self care in their children.

Affinity chromatographic identification and quantitation of blood group A-active oligosaccharides in human milk and feces of breast-fed infants.

The finding of large quantities of blood group A-active oligosaccharides in the feces of a blood group A breast-fed infant motivated a search for the origin of these compounds. Using an affinity chromatographic technique, the nature of A-active oligosaccharides in human milk is demonstrated. The amounts of A-active tetrasaccharide (A-tetra) and the Lewis b-active lacto-N-difucohexaose I (LND-I) varied between 19-375 mg/L for A-tetra and 14-710 mg/L for LND-I. Using the same technique, the amounts of A-tetra and LND-I in milk samples from five women of different blood groups were compared with those in the feces of their breast-fed infants. The A-tetra was present only in feces from infants of blood group A or AB mothers and the amount per 24 h corresponded roughly to that in a I-L portion of milk. One of the milk samples was also analyzed for the presence of larger A-active oligosaccharides (A-pentasaccharide, A-hexasaccharide, and A-heptasaccharide). Their amounts were much less as compared to the amounts present in feces. These results indicate that milk is a possible source for the smallest A-tetrasaccharide found in the feces of breast-fed infants, while the larger A-active oligosaccharides might be the result of an intestinal metabolic modification.

Sialylated oligosaccharides in human milk and feces of preterm, full-term, and weaning infants.

The amount of free and glycosidically bound sialic acid was quantitated in the oligosaccharide fraction of breast milk from nine women in the 2nd-3rd week of lactation. These amounts showed a certain individual variation but the amount of bound sialic acid was higher than the free sialic acid in each sample. A similar study on the feces from preterm and full-term breast-fed infants revealed that the amount of free sialic acid increased while the bound sialic acid decreased during maturation, which could possibly be a result of increasing activity of an intestinal sialidase in the newborn child. The fecal oligosaccharide patterns in one blood group A secretor breast-fed infant were studied every 2 months during weaning until the age of 1 year. It was seen that the fecal oligosaccharide pattern disappears, along with the blood group A-active compounds, with a corresponding decrease in the amount of breast milk in the diet.

Diabetic children and their parents: personality correlates of metabolic control.

Test measures of field-dependence-independence and impulsiveness-control were obtained from two groups of diabetic children and their parents, the children being in optimal (O, n = 12) or poor (P. n = 27) metabolic control and, according to the judgment of clinicians, showing optimal or poor psychological adaptation. Children of the O-group scored lower in impulsiveness and higher in realistic functioning than those of the P-group. Differences which parallelled these were found between the two groups of fathers. The P-group fathers were decidedly more field-dependent than their wives, while the opposite was found for the O-group. Group differences of the kind obtained were seen as possible determinants of disturbed family interaction or emotional stress in the child in the P-group and of autonomy and self-reliance in the child in the O-group. It is concluded that the role of fathers of diabetic children has been underestimated.

Effect of selenium supplementation on the distribution of selenium among plasma proteins of a patient with maple syrup urine disease.

Selenium (Se) status was studied in a patient with classical maple syrup urine disease (MSUD) receiving Se supplement. The basal plasma Se concentration was 0.06 mumol/l increasing to 2.1 mumol/l after 40 days of supplementation. When the plasma Se distribution was analysed by gel filtration, a major peak was seen close to the high molecular weight proteins with a second peak in the albumin region. When the Se dose was decreased in a stepwise manner from 50 micrograms/day to 25 micrograms/day and then to 17 micrograms/day plasma Se decreased, but the proportion of plasma Se in the two protein peaks did not change. In a healthy girl not supplemented with Se, the proportion of plasma Se in the albumin region was somewhat lower. In the MSUD patient glutathione peroxidase activity was initially low, and increased ten-fold during Se supplementation. The study indicates that the Se requirement for plasma glutathione peroxidase activity was fulfilled at the lowest dose of Se used and that Se is incorporated into several plasma proteins after supplementation.

Oligosaccharides from feces of preterm infants fed on breast milk.

Nine neutral and five acidic oligosaccharides were isolated from feces of a preterm (30th postmenstrual week) blood group A nonsecretor infant fed on pooled breast milk. Structural analyses were carried out using sugar and methylation analyses, fast atom bombardment mass spectrometry, and 1H NMR. The acidic oligosaccharides are well-known components of human milk. The neutral oligosaccharides are characteristic of nonsecretor milk. Surprisingly, no secretor gene-dependent oligosaccharides were present in the feces. Another preterm (27th postmenstrual week) blood group A, secretor infant fed on pooled breast milk showed the same fecal oligosaccharide pattern as above during the first week after birth, despite being a secretor individual. Also notable was the absence of blood group A-active oligosaccharides in this sample. Another sample of feces collected 8 weeks later from the latter infant contained the expected blood group A-active oligosaccharides. Furthermore, free sialic acid was present at the cost of the sialyl oligosaccharides seen earlier. Thus, infants born prematurely do not show the same degree of development of oligosaccharide metabolism as their more mature counterparts.