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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.

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, 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.

Objective: Hereditary autoinflammatory syndromes are characterized by recurrent episodes of fever and inflammation. Seven subtypes have been described, caused by mutations in four different genes. Apart from a common phenotype of lifelong recurrent inflammatory attacks, all subtypes have distinct features and specific therapeutic options, which emphasizes the need for a specific diagnosis in each case. Our aim was to examine whether genetic screening would allow classification of previously unclassified patients, and whether individual patients suffering from an autoinflammatory syndrome carry additional mutations in one of the other autoinflammatory genes., Methods: We included 60 patients with an unclassified autoinflammatory syndrome, 87 patients diagnosed with either hyper-IgD syndrome, familial Mediterranean fever (FMF) or tumour necrosis factor (TNF)-receptor-associated periodic syndrome and 50 healthy controls. Deoxyribonucleic acid samples were screened for the most prevalent mutations in the MEFV, TNFRSF1A, MVK and CIAS1 genes., Results: We found only one possible diagnosis of FMF in the 60 previously unclassified patients. Two low-penetrance mutations were found in equal numbers in the groups of patients and controls., Conclusions: Screening of highly prevalent mutations in known genes involved in these disorders does not yield additional relevant information. Differential diagnosis of hereditary autoinflammatory syndromes can be made by thorough clinical examination followed by targeted genetic analysis of the one or two most likely syndromes. High-prevalence low-penetrant mutations from autoinflammatory genes do not occur more frequently in patients with hereditary autoinflammatory syndromes compared with the general population.

Objectives: The protein calprotectin is mainly derived from neutrophils. Increased fecal excretion of calprotectin has been reported in inflammatory bowel disease. The recommended cut-off level in adults (<50 microg/g feces) seems to be applicable in children aged 4 to 17 years. The aim of this study was to evaluate the use of fecal calprotectin to detect colorectal inflammation in children with gastrointestinal symptoms., Methods: We obtained stool samples on thirty-six children with gastrointestinal symptoms and suspected inflammation of the colon before they underwent colonoscopy. The samples were examined with an improved fecal calprotectin enzyme-linked immunosorbent assay method (Calprest, Eurospital). The results were correlated with the histopathologic findings in the colon., Results: In children with colorectal inflammation (n = 22) the median fecal calprotectin concentration was 349 microg/g (range, 15.4-1860 microg/g). The most common diagnosis in this group was inflammatory bowel disease. Median fecal calprotectin was 16.5 microg/g (range, 5.0-65 microg/g) in children with no inflammation (n = 14). When <50 microg/g was used as upper reference limit the fecal calprotectin test had a sensitivity of 95%, specificity 93%, positive predictive value 95% and negative predictive value 93% to detect colorectal inflammation., Conclusions: The improved fecal calprotectin enzyme-linked immunosorbent assay is a simple test with potential use in children. Increased fecal calprotectin strongly predicted the presence of colorectal inflammation in children with gastrointestinal symptoms. Fecal calprotectin can be used to select patients who should undergo diagnostic colonoscopy for investigation of colorectal inflammation, including inflammatory bowel disease.

Background: Treatment of coeliac disease (CD) requires lifelong adherence to a strict gluten free diet (GFD) which hitherto has consisted of a diet free of wheat, rye, barley, and oats. Recent studies, mainly in adults, have shown that oats are non-toxic to CD patients. In children, only open studies comprising a small number of patients have been performed., Aim: To determine if children with CD tolerate oats in their GFD., Patients and Methods: In this double blind multicentre study involving eight paediatric clinics, 116 children with newly diagnosed CD were randomised to one of two groups: one group was given a standard GFD (GFD-std) and one group was given a GFD with additional wheat free oat products (GFD-oats). The study period was one year. Small bowel biopsy was performed at the beginning and end of the study. Serum IgA antigliadin, antiendomysium, and antitissue transglutaminase antibodies were monitored at 0, 3, 6, and 12 months., Results: Ninety three patients completed the study. Median (range) daily oat intake in the GFD-oats group (n = 42) was 15 (5-40) g at the six month control and 15 (0-43) g at the end of the study. All patients were in clinical remission after the study period. The GFD-oats and GFD-std groups did not differ significantly at the end of the study regarding coeliac serology markers or small bowel mucosal architecture, including numbers of intraepithelial lymphocytes. Significantly more children in the youngest age group withdrew., Conclusions: This is the first randomised double blind study showing that the addition of moderate amounts of oats to a GFD does not prevent clinical or small bowel mucosal healing, or humoral immunological downregulation in coeliac children. This is in accordance with the findings of studies in adult coeliacs and indicates that oats, added to the otherwise GFD, can be accepted and tolerated by the majority of children with CD.

Dietary fat is an important source of nutrition. Here we identify eight mutations in SARA2 that are associated with three severe disorders of fat malabsorption. The Sar1 family of proteins initiates the intracellular transport of proteins in COPII (coat protein)-coated vesicles. Our data suggest that chylomicrons, which vastly exceed the size of typical COPII vesicles, are selectively recruited by the COPII machinery for transport through the secretory pathways of the cell.

We report on the reversal of protein-losing enteropathy (PLE) after heart transplantation (HTx) in a 10-yr-old boy with Fontan circulation, previously treated unsuccessfully with heparin for several months. The protein loss continued immediately after the Tx. During the following month, however, a gradual decrease in protein loss was observed, which correlated with a decrease in the inferior vena cava (IVC) pressure. The patient is doing well with a normal serum albumin level and a normal IVC pressure, 2 yr after Tx.

1. Primary Raynaud's phenomenon (PRP) is characterized by increased vasoconstrictor tone that develops during exposure to cold. The symptoms are most pronounced during the winter months with low outdoor temperature. The L-arginine-nitric oxide (NO)-cyclic GMP (cGMP) pathway plays an important role in counteracting vasospasm. The aim of the present study was to investigate if the venous cGMP response to whole-body cooling in women with PRP varied with the season of the year. 2. The study was performed as an open parallel-group comparison between women with PRP and healthy female controls during the winter months of February 1994 and 1995 and in the summer month of August 1994. Blood samples were drawn just before and 40 min after whole-body cooling. 3. There were no significant changes in venous cGMP after whole-body cooling in women with PRP during the winter months of February 1994 and 1995. Cold exposure in the summer month of August resulted, however, in a significant increase in venous cGMP (P < 0.01). In contrast, the healthy women responded with a significant increase in venous cGMP on all three test occasions: February 1994 (P < 0.05), August 1994 (P < 0.05) and February 1995 (P < 0.01), 4. A seasonal variation in venous cGMP response to whole-body cooling was observed only in women with PRP. Healthy women responded to cold exposure with an increase in venous cGMP during summer and winter, whereas females with PRP showed an increase only during summer. Results from the present study might indicate seasonal variation in the regulation of constitutive nitric oxide synthetase in women with PRP, which may contribute to new therapeutic approaches.

Primary Raynaud's phenomenon (PRP) is characterized by cold- or stress-induced transient attacks of impaired skin circulation in fingers and/or toes. PRP displays seasonal variation with less severe symptoms in the summer. The aetiology has not been clarified. The aims of the present study were (a) to assess the influence of cold exposure on the plasma levels of the nitric oxide (NO) metabolite, nitrate, in patients with PRP and in healthy control subjects; and (b) to investigate whether there is a seasonal variation in these plasma levels. In a group of women with PRP and matched control subjects, venous blood was sampled before and at the end of a 40-min period of whole-body cooling. The study was performed with the same protocol on two occasions; once in the winter and once in the summer. A seasonal variation was detected with higher plasma levels of nitrate in the winter than in the summer, both in PRP and in control subjects. However, the plasma level of nitrate was not changed in response to cold exposure on any occasion, either in the patient or in the control group. Our study indicates that NO formation is up-regulated in response to cold weather in both study groups. However, NO formation does not seem to be increased in response to whole-body cooling, either in PRP patients or in healthy subjects. Further investigations are required to reveal whether the observed seasonal variation in NO formation is a universal phenomenon in man.

Objective: To investigate influence of whole-body cooling on cyclic GMP (cGMP) in women with Raynaud's phenomenon and in healthy women., Design: The study was performed as an open, parallel-group comparison between women with Raynaud's phenomenon and healthy women during the winter month of February., Setting: The municipality of Västerås (Sweden)., Participants: The Raynaud group comprised 24 female patients. The control group consisted of 21 healthy females., Main Outcome Measure: The venous levels of cGMP were measured on three different occasions: just before and after 40 min of whole-body cooling and after 20 min rest at room temperature (21 degrees C)., Results: Venous cGMP increased significantly in the control group after cold exposure (mean difference 0.43 pmol mL-1; 95% CI, 0.018-0.848; t = 2.18; df = 20; P = 0.02) and remained at a high level after 20 min rest (mean difference 0.58 pmol mL-1; 95% CI, 0.063-1.108; t = 2.34; df = 20; P = 0.015). In contrast, the levels of venous cGMP in the Raynaud group did not change significantly. The difference in increase between the two groups was significant (P < 0.02). The diastolic blood pressure in the Raynaud group increased after 40 min of whole-body cooling and was still significantly increased (P < 0.001) after 20 min rest at room temperature (21 degrees C)., Conclusion: These results indicate that women suffering from Raynaud's phenomenon lack the physiological response of cGMP to cold exposure, which may explain their increased vasospastic response.

We describe two siblings with fat malabsorption and jejunal chylomicron retention. Plasma lipoproteins were studied in the patients and their first-degree relatives. The patients were a 14-year-old girl and her 8-year-old brother. Compared to healthy controls, they both had low fasting plasma concentrations of plasma total, HDL, and LDL cholesterol, as well as of apolipoproteins A-I and B. No increase in plasma lipoprotein levels or detectable apo B-48 was observed following an oral fat load. Histological studies of jejunal biopsy specimens obtained during fasting and 1 h postprandially showed severe steatosis, and an apparent block of chylomicron secretion from the endoplasmic reticulum into the Golgi apparatus was observed by electron microscopy. Liver biopsy specimens showed moderate steatosis and ultrastructural changes similar to those in the enterocytes. One healthy sister had a normal plasma lipoprotein pattern, and showed increased plasma triglyceride levels as well as the presence of apo B-48 following an oral fat load. Both parents had normal plasma total cholesterol levels, but clearly reduced fasting concentrations of HDL cholesterol and apo A-I. At least in this family, determination of plasma apo A-I levels might thus prove useful in the identification of heterozygotes.

The motilin agonist erythromycin was used successfully in four infants receiving prolonged parenteral nutrition for severe intestinal dysmotility after gastrointestinal surgery. In a further child with a neuropathic intestinal pseudo-obstruction erythromycin induced a striking small intestinal manometric response, but was without effect in a child with an intestinal myopathy.

The effects of two different vasodilating agents (MgSO4 infusion and the calcium antagonist nifedipine) on circulating levels of calcitonin gene-related peptide (CGRP) were studied in 12 women with pronounced primary Raynaud's phenomenon (PRP) and in 12 healthy females. There were no significant differences with regard to basal levels of circulating CGRP between women with PRP and the control group; median 15.5 (range 10-48) vs. 14 (range 10-69) pmol l-1, respectively. However, treatment with MgSO4 infusion significantly decreased circulating CGRP in women with PRP only from median 15.5 (range 10-48) to 10 (range 10-110) pmol l-1) (P < 0.05). On the other hand 14 days of treatment with nifedipine did not affect circulating CGRP in either of the investigated groups. Erythrocyte magnesium (ery-Mg) levels increased significantly after MgSO4 infusion in women with PRP (2.43 +/- 0.13 vs. 2.52 +/- 0.15 mmol l-1, P < 0.05) but not in the controls (2.51 +/- 0.24 vs. 2.57 +/- 0.28 mmol l-1, ns). In conclusion, the decrease of circulating CGRP after MgSO4 infusion in women with PRP provides further evidence that magnesium plays a significant role in the pathophysiology of PRP.

The effect of a short-term magnesium sulfate (MgSO4) infusion on venous plasma concentration of noradrenaline (NA) and neuropeptide-Y-like immunoreactivity (NPY-LI) was investigated in 12 women with primary Raynaud's phenomenon (PRP) and in 12 healthy matched controls. The Raynaud's patients did not demonstrate any significant changes in mean basal plasma NA concentration (0.29 +/- 0.15 vs 0.37 +/- 0.09 ng/mL, ns) after MgSO4 infusion. However, in the controls there was more than twice the amount of circulating noradrenaline (cNA) (0.21 +/- 0.14 vs 0.54 +/- 0.22 ng/mL, P < 0.001) after MgSO4 infusion, compared with the preinfusion value. Measurements during the cold pressor test prior to the MgSO4 infusion showed a significant increase of cNA in both the PRP group and the control group (from 0.29 +/- 0.15 to 0.33 +/- 0.16 ng/mL, P < 0.05, and from 0.21 +/- 0.14 to 0.29 +/- 0.16 ng/mL, P < 0.005, respectively). After MgSO4 infusion the levels of cNA during the cold pressor test increased significantly only in the PRP group (from 0.37 +/- 0.09 to 0.41 +/- 0.11 ng/mL, P < 0.05). Circulating NPY-LI concentrations increased significantly during MgSO4 infusion in the Raynaud's patients as well as in the controls from 105 +/- 21 to 127 +/- 23 pmol/L, P < 0.05, and from 107 +/- 17 to 132 +/- 27 pmol/L, P < 0.01, respectively. There were no detectable changes during the cold pressor tests in either group.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of a standardized cold pressor test on circulating noradrenaline and neuropeptide-Y-like immunoreactivity was investigated in 12 women with primary Raynaud's phenomenon and 12 healthy female controls before and after 2 weeks of treatment with the calcium antagonist, nifedipine. Measurement before treatment showed significant increase during the cold pressor test on circulating noradrenaline in both the primary Raynaud's phenomenon group and in the control group (from 0.29 +/- 0.15 ng/ml to 0.33 +/- 0.16 ng/ml, p < 0.05, and from 0.21 +/- 0.14 ng/ml to 0.29 +/- 0.16 ng/ml, p < 0.005, respectively). However, treatment with nifedipine resulted in significantly increased levels of circulating noradrenaline during the cold pressor test only in the control group (from 0.43 +/- 0.21 ng/ml to 0.50 +/- 0.20 ng/ml, p < 0.01). Plasma concentrations of neuropeptide-Y-like immunoreactivity were unchanged by the standardized cold pressor test, whether performed before or during nifedipine treatment in both groups. Nifedipine treatment per se significantly increased circulating noradrenaline in both the primary Raynaud's phenomenon patient group and in the control group (from 0.29 +/- 0.15 to 0.49 +/- 0.13 and 0.21 +/- 0.14 to 0.43 +/- 0.21 ng/ml, respectively, p < 0.001). Similarly, the circulating neuropeptide-Y-like immunoreactivity significantly increased in both the primary Raynaud's phenomenon group and in the control group (from 105 +/- 21 to 137 +/- 19 pmol/l and 107 +/- 17 to 147 +/- 13 pmol/l, respectively, p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

A group of 47 children with coeliac disease, born between 1973 and 1978 in the Swedish county of Västmanland, participated in a controlled questionnaire study. Health, self-esteem, knowledge of the disease and dietary compliance were investigated. The children with coeliac disease were otherwise just as healthy as the control children. Growth and self-esteem were normal. Good knowledge of coeliac disease and dietary treatment was found in 87% of children and dietary compliance was 81%. Girls and younger children (12-14 years) were more compliant than boys and older children (15-17 years). Compliance correlated positively to knowledge.

A boy with complete triploidy and extensive external and internal congenital malformations who survived for almost seven months is presented. He was born after 31 weeks of gestation, was utterly small for gestational age and the delivery was induced because of intrauterine asphyxia. The infant had typical features of the complete triploidy syndrome. He did not develop mentally or motorically even to a normal neonatal level. Banding analysis of chromosomes and HLA-antigen typing of the patient and his parents suggested that the abnormal cell division had occurred during the oogenesis. The boy suffered a fatal Pneumocystis carinii infection, suggesting defective cellular immunity. In the vast majority of previously reported cases of complete triploidy the infant has died either before birth or within the first postnatal hours and except for four patients, all reported patients have died before the age of 2 months. Our patient illustrates the fact that with modern neonatal intensive care, infants with severe malformation syndromes can survive for longer periods than previously, but in the case of patients with the complete triploidy syndrome without developing mentally at all. The ethical problem of artificially prolonged survival in severely handicapped children is discussed.

Plasma concentrations of 6-mercaptopurine (6-MP) were determined by gas chromatography-mass spectrometry. Ten children (nine with acute lymphatic leukemia) were studied on 2 consecutive days after oral intake of 6-MP. On one day the drug was administered in the fasting state and on the other (in random order) together with breakfast. The peak plasma concentrations of 6-MP after the dose intake with breakfast in percent of that in the fasting state (meal in % of fasting for each individual) varied between 33 and 181% (mean 111), and the area under the plasma concentration-time curve varied between 47 and 186% (mean 103). Thus, there were considerable variations among patients, but, for the group as a whole, there were no statistically significant differences between the two experimental conditions. This study cannot therefore form the basis for a recommendation as to whether 6-MP should be administered on an empty stomach or together with food.

Plasma and erythrocyte concentrations of 6-mercaptopurine (6-MP) were determined by gas chromatography-mass spectrometry. Eleven children (9 with acute lymphatic leukemia) were studied after oral intake of 6-MP doses ranging between 31 and 128 mg/m2 body surface area. The concentrations of 6-MP in plasma were found to vary considerably between patients even after dose normalization to 75 mg/m2. After dose normalization the mean peak plasma concentration was 0.68 microM (range 0.12-1.38) and the area under the plasma concentration-time curve (AUC) was 1.37 microM.h (range 0.12-3.04). The mean time taken to reach the peak concentration was 1.3 h (range 1-2), and the half-life of elimination was 1.8 h (range 0.6-2.5). No patient had detectable 6-MP concentrations 12 h after dose intake. The concentrations of 6-MP tended to be higher in erythrocytes than in plasma. The mean peak concentration in erythrocytes was 131% and the AUC 145% of that found in plasma. The mean half-life of elimination from erythrocytes was 2.0 h (range 0.7-2.8). These data indicate that 6-MP can pass through all membranes rapidly to reach intracellular concentrations equal to or even higher than in plasma. In summary, marked interindividual differences in pharmacokinetics were found, probably due to highly variable bioavailability of oral 6-MP. Further studies are needed to determine whether measurements of plasma concentrations of 6-MP can be used to optimize maintenance treatment of childhood leukemia.