Trait-environment interactions of saproxylic beetles as a guide to biodiversity conservation strategies.

Conservation of biodiversity requires in-depth knowledge of trait-environment interactions to understand the influence the environment has on species assemblages. Saproxylic beetles exhibit a wide range of traits and functions in the forest ecosystems. Understanding their responses to surrounding environment thus improves our capacity to identify habitats that should be restored or protected. We investigated potential interactions between ecological traits in saproxylic beetles (feeding guilds and habitat preferences) and environmental variables (deadwood, type and age of surrounding forest). We sampled beetles from 78 plots containing newly created high stumps of Scots pine and Silver birch in boreal forest landscapes in Sweden for three consecutive years. Using a model based approach, our aim was to explore potential interactions between ecological traits and the surrounding environment at close and distant scale (20 m and 500 m radius). We found that broadleaf-preferring beetle species are positively associated with the local broadleaf-originated deadwood and broadleaf-rich forests in the surrounding landscapes. Conifer-preferring species are positively associated with the local amount of coniferous deadwood and young and old forests in the surrounding landscape. Fungivorous and predatory beetles are positively associated with old forests in the surrounding landscapes. Our results indicate that both local amounts of deadwood and types of forests in the landscape are important in shaping saproxylic beetle communities. We particularly highlight the need to increase deadwood amounts of various qualities in the landscape, exempt older forests from production and to increase broadleaf-rich habitats in order to meet different beetle species' habitat requirements. Trait responses among saproxylic beetles provide insights into the significance of broadleaf forest and dead wood as essential attributes in boreal forest restoration, which helps conservation planning and management in forest landscapes.

Translocation of deadwood in ecological compensation: A novel way to compensate for habitat loss.

Restoration of degraded habitat is frequently used in ecological compensation. However, ecological restoration suffers from innate problems of long delivery times of features shown to be good proxies for biodiversity, e.g., large dead trees. We tested a possible way to circumvent this problem; the translocation of hard-to-come deadwood substrates from an impact area to a compensation area. Following translocation, deadwood density in the compensation area was locally equivalent to the impact area, around 20 m3 ha-1, a threshold for supporting high biodiversity of rare and red-listed species. However, deadwood composition differed between the impact and compensation area, showing a need to include more deadwood types, e.g., late decomposition deadwood, in the translocation scheme. To guide future compensation efforts, the cost for translocation at different spatial scales was calculated. We conclude that translocation of deadwood could provide a cost-efficient new tool for ecological compensation/restoration but that the method needs refinement.

RhoG deficiency abrogates cytotoxicity of human lymphocytes and causes hemophagocytic lymphohistiocytosis.

Exocytosis of cytotoxic granules (CG) by lymphocytes is required for the elimination of infected and malignant cells. Impairments in this process underly a group of diseases with dramatic hyperferritinemic inflammation termed hemophagocytic lymphohistiocytosis (HLH). Although genetic and functional studies of HLH have identified proteins controlling distinct steps of CG exocytosis, the molecular mechanisms that spatiotemporally coordinate CG release remain partially elusive. We studied a patient exhibiting characteristic clinical features of HLH associated with markedly impaired cytotoxic T lymphocyte (CTL) and natural killer (NK) cell exocytosis functions, who beared biallelic deleterious mutations in the gene encoding the small GTPase RhoG. Experimental ablation of RHOG in a model cell line and primary CTLs from healthy individuals uncovered a hitherto unappreciated role of RhoG in retaining CGs in the vicinity of the plasma membrane (PM), a fundamental prerequisite for CG exocytotic release. We discovered that RhoG engages in a protein-protein interaction with Munc13-4, an exocytosis protein essential for CG fusion with the PM. We show that this interaction is critical for docking of Munc13-4+ CGs to the PM and subsequent membrane fusion and release of CG content. Thus, our study illuminates RhoG as a novel essential regulator of human lymphocyte cytotoxicity and provides the molecular pathomechanism behind the identified here and previously unreported genetically determined form of HLH.

Medulloblastoma, macrocephaly, and a pathogenic germline PTEN variant: Cause or coincidence?

BACKGROUND: Medulloblastomas (MBs) are a heterogeneous group of childhood brain tumors with four consensus subgroups, namely MBSHH , MBWNT , MBGroup 3 , and MBGroup 4 , representing the second most common type of pediatric brain cancer after high-grade gliomas. They suffer from a high prevalence of genetic predisposition with up to 20% of MBSHH caused by germline mutations in only six genes. However, the spectrum of germline mutations in MBSHH remains incomplete. METHODS: Comprehensive Next-Generation Sequencing panels of both tumor and patient blood samples were performed as molecular genetic characterization. The panels cover genes that are known to predispose to cancer. RESULTS: Here, we report on a patient with a pathogenic germline PTEN variant resulting in an early stop codon p.(Glu7Argfs*4) (ClinVar ID: 480383). The patient developed macrocephaly and MBSHH , but reached remission with current treatment protocols. CONCLUSIONS: We propose that pathogenic PTEN variants may predispose to medulloblastoma, and show that remission was reached with current treatment protocols. The PTEN gene should be included in the genetic testing provided to patients who develop medulloblastoma at an early age. We recommend brain magnetic resonance imaging upon an unexpected acceleration of growth of head circumference for pediatric patients harboring pathogenic germline PTEN variants.

Longitudinal Pattern of First-Phase Insulin Response Is Associated With Genetic Variants Outside the Class II HLA Region in Children With Multiple Autoantibodies.

A declining first-phase insulin response (FPIR) is associated with positivity for multiple islet autoantibodies, irrespective of class II HLA DR-DQ genotype. We examined the associations of FPIR with genetic variants outside the HLA DR-DQ region in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study in children with and without multiple autoantibodies. Association between FPIR and class I alleles A*24 and B*39 and eight single nucleotide polymorphisms outside the HLA region were analyzed in 438 children who had one or more FPIR results available after seroconversion. Hierarchical linear mixed models were used to analyze repeated measurements of FPIR. In children with multiple autoantibodies, the change in FPIR over time was significantly different between those with various PTPN2 (rs45450798), FUT2 (rs601338), CTSH (rs3825932), and IKZF4 (rs1701704) genotypes in at least one of the models. In general, children carrying susceptibility alleles for type 1 diabetes experienced a more rapid decline in insulin secretion compared with children without susceptibility alleles. The presence of the class I HLA A*24 allele was also associated with a steeper decline of FPIR over time in children with multiple autoantibodies. Certain genetic variants outside the class II HLA region may have a significant impact on the longitudinal pattern of FPIR.

Class II HLA Genotype Association With First-Phase Insulin Response Is Explained by Islet Autoantibodies.

Context: A declining first-phase insulin response (FPIR) is characteristic of the disease process leading to clinical type 1 diabetes. It is not known whether reduced FPIR depends on class II human leukocyte antigen (HLA) genotype, islet autoimmunity, or both. Objective: To dissect the role of class II HLA DR-DQ genotypes and biochemical islet autoantibodies in the compromised FPIR. Design, Setting, Participants: A total of 438 children with defined HLA DR-DQ genotype in the prospective Finnish Type 1 Diabetes Prediction and Prevention Study were analyzed for FPIR in a total of 1149 intravenous glucose tolerance tests and were categorized by their HLA DR-DQ genotype and the number of biochemical islet autoantibodies at the time of the first FPIR. Age-adjusted hierarchical linear mixed models were used to analyze repeated measurements of FPIR. Main Outcome Measure: The associations between class II HLA DR-DQ genotype, islet autoantibody status, and FPIR. Results: A strong association between the degree of risk conferred by HLA DR-DQ genotype and positivity for islet autoantibodies existed (P < 0.0001). FPIR was inversely associated with the number of biochemical autoantibodies (P < 0.0001) irrespective of HLA DR-DQ risk group. FPIR decreased over time in children with multiple autoantibodies and increased in children with no biochemical autoantibodies (P < 0.0001 and P = 0.0013, respectively). Conclusions: The class II HLA DR-DQ genotype association with FPIR was secondary to the association between HLA and islet autoimmunity. Declining FPIR was associated with positivity for multiple islet autoantibodies irrespective of class II HLA DR-DQ genotype.

Ketoacidosis at diagnosis of type 1 diabetes: Effect of prospective studies with newborn genetic screening and follow up of risk children.

We studied the frequency of diabetic ketoacidosis (DKA) in children at diagnosis of type 1 diabetes (T1D) in a region where newborn infants have since 1995 been recruited for genetic screening for human leukocyte antigen (HLA)-conferred disease susceptibility and prospective follow up. The aim was to study whether participation in newborn screening and follow up affected the frequency of DKA, and to follow the time trends in DKA frequency. We first included children born in Oulu University Hospital since 1995 when the prospective studies have been ongoing and diagnosed with T1D <15 years by 2015 (study cohort 1, n = 517). Secondly, we included all children diagnosed with T1D <15 years in this center during 2002-2014 (study cohort 2, n = 579). Children who had an increased genetic risk for T1D and participated in prospective follow up had low frequency of DKA at diagnosis (5.0%). DKA was present in 22.7% of patients not screened for genetic risk, 26.7% of those who were screened but had not an increased risk and 23.4% of children with increased genetic risk but who were not followed up. In study cohort 2 the overall frequency of DKA was 18.5% (13.0% in children <5 years, 14.0% in children 5-10 years and 28.6% in children ≥10 years at diagnosis; P<.001). In children <2 years the frequency of DKA was 17.1%. Participation in prospective follow-up studies reduces the frequency of DKA in children at diagnosis of T1D, but genetic screening alone does not decrease DKA risk.

Dysregulation of glucose metabolism in preclinical type 1 diabetes.

Long-term prospective studies have provided valuable information about preclinical type 1 diabetes (T1D). Children who have seroconverted to positive for islet autoantibodies have also, in follow-up, had metabolic tests to understand the timing and development of abnormal glucose tolerance and declining insulin secretion before the clinical diagnosis of T1D. First phase insulin response (FPIR) in the intravenous glucose tolerance test (IVGTT) is lower in the progressors positive for multiple islet autoantibodies in all age groups and as early as 4-6 years before the diagnosis when compared with the non-progressors positive for only islet cell antibodies (ICA). An accelerated decline in FPIR is seen in the progressors during the last 1.5 years before the diagnosis. These results indicate that the progressors may have an early intrinsic defect in beta cell development or function. In the oral glucose tolerance test (OGTT) the peak C-peptide response is delayed in the progressors at least 2 years before diagnosis. Glucose levels and HbA1c are increasing about 2 years before clinical diagnosis. An increase in HbA1c and detection of abnormal glucose tolerance in OGTT are useful in the prediction of the timing of clinical onset of T1D. Continuous glucose monitoring (CGM) may be useful in the prediction of T1D as an early indicator of increased glycemic variability but more data from larger series are needed for confirmation. Children followed in the prospective studies are diagnosed earlier and have a decreased frequency of ketoacidosis at the diagnosis of T1D when compared with age-matched cases from the population.

Insulin secretion and sensitivity in the prediction of type 1 diabetes in children with advanced ß-cell autoimmunity.

OBJECTIVE: Reduced early insulin response has been shown to predict type 1 diabetes (T1D) in first-degree relatives of diabetic patients, while its role, as well as that of insulin resistance, has remained poorly defined in young children representing the general population. The predictive values of these markers and their relation to other risk factors of T1D were assessed in children with advanced ß-cell autoimmunity, i.e. persistent positivity for two or more autoantibodies. DESIGN AND METHODS: Intravenous glucose tolerance tests (IVGTTs) were carried out in 218 children with HLA-DQB1-conferred disease susceptibility and advanced ß-cell autoimmunity. Baseline, metabolic and growth data were compared between children progressing to diabetes and those remaining unaffected. Hazard ratios for the disease predictors and the progression rate of T1D were assessed. RESULTS: Children developing T1D were younger at seroconversion, progressed more rapidly to advanced ß-cell autoimmunity and had lower first-phase insulin response (FPIR) and homeostasis model assessment index for insulin resistance (HOMA-IR) than those remaining non-diabetic. The levels of HOMA-IR/FPIR, islet cell antibodies, insulin autoantibodies (IAA) and islet antigen 2 antibodies (IA-2A) were higher in progressors. BMI SDS, FPIR, age at IVGTT and levels of IAA and IA-2A were predictive markers for T1D. CONCLUSIONS: Young age, higher BMI SDS, reduced FPIR and higher levels of IAA and IA-2A predicted T1D in young children with HLA-DQB1-conferred disease susceptibility and advanced ß-cell autoimmunity. Disease risk estimates were successfully stratified by the assessment of metabolic status and BMI. The role of insulin resistance as an accelerator of the disease process was minor.

Family history of diabetes and distribution of class II HLA genotypes in children with newly diagnosed type 1 diabetes: effect on diabetic ketoacidosis.

OBJECTIVE: Our purpose was to assess whether family history of diabetes or the HLA-DR-DQ genotype of the index case was associated with the frequency of diabetic ketoacidosis (DKA) at diagnosis of childhood type 1 diabetes. PATIENTS AND METHODS: The study cohort comprised 1518 children aged <15 years and diagnosed with type 1 diabetes in Finland in 2002-2005. Family history of type 1 and type 2 diabetes among first-degree relatives (FDRs) and grandparents was assessed at diagnosis. HLA-DR-DQ genotypes were analysed using time-resolved fluorometry. RESULTS: In total, 12.6 and 1.7% of children had at least one FDR affected with type 1 or type 2 diabetes, respectively, and 6.6 and 34.8% had at least one grandparent with type 1 or type 2 diabetes. DKA (pH <7.30) occurred less frequently in children having a type 1 diabetes affected FDR (7.4 vs 20.5%, P<0.001). Type 2 diabetes among the parents or grandparents had no such effect. Lower risk HLA genotypes were observed to predispose to DKA (P<0.024). In a logistic regression analysis, the risk of DKA was independently associated with the absence of a family member affected by type 1 diabetes, the presence of a low-risk HLA genotype and older age at diagnosis (odds ratio 3.23, 1.45 and 1.07 respectively). CONCLUSION: The presence of type 1 diabetes in an FDR is associated with an decreased risk of DKA at diagnosis. The rate of DKA seems to be higher in children with lower HLA-conferred risk for type 1 diabetes.

Age-related differences in the frequency of ketoacidosis at diagnosis of type 1 diabetes in children and adolescents.

OBJECTIVE: We studied the prevalence of diabetic ketoacidosis (DKA) at diagnosis of type 1 diabetes in children in Finland. RESEARCH DESIGN AND METHODS: From 2002 to 2005, data on virtually all children <15 years of age diagnosed with type 1 diabetes (n = 1,656) in Finland were collected. RESULTS: DKA was present in 19.4% of the case subjects, and 4.3% had severe DKA. In children aged 0-4, 5-9, and 10-14 years, DKA was present in 16.5, 14.8, and 26.4%, respectively (P < 0.001). Severe DKA occurred in 3.7, 3.1, and 5.9%, respectively (P = 0.048). DKA was present in 30.1% and severe DKA in 7.8% of children aged <2 years. CONCLUSION: The overall frequency of DKA in children is low in Finland at diagnosis of type 1 diabetes. However, both children <2 years of age and adolescents aged 10-14 years are at increased risk of DKA.

Predictive characteristics of diabetes-associated autoantibodies among children with HLA-conferred disease susceptibility in the general population.

OBJECTIVE: As data on the predictive characteristics of diabetes-associated autoantibodies for type 1 diabetes in the general population are scarce, we assessed the predictive performance of islet cell autoantibodies (ICAs) in combination with autoantibodies against insulin (IAAs), autoantibodies against GAD, and/or islet antigen 2 for type 1 diabetes in children with HLA-defined disease predisposition recruited from the general population. RESEARCH DESIGN AND METHODS: We observed 7,410 children from birth (median 9.2 years) for beta-cell autoimmunity and diabetes. If a child developed ICA positivity or diabetes, the three other antibodies were measured in all samples available from that individual. Persistent autoantibody positivity was defined as continued positivity in at least two sequential samples including the last available sample. RESULTS: Pre-diabetic ICA positivity was observed in 1,173 subjects (15.8%), 155 of whom developed type 1 diabetes. With ICA screening, 86% of 180 progressors (median age at diagnosis 5.0 years) were identified. Positivity for four antibodies was associated with the highest disease sensitivity (54.4%) and negative predictive values (98.3%) and the lowest negative likelihood ratio (0.5). The combination of persistent ICA and IAA positivity resulted in the highest positive predictive value (91.7%), positive likelihood ratio (441.8), cumulative disease risk (100%), and specificity (100%). Young age at seroconversion, high ICA level, multipositivity, and persistent positivity for IAA were significant risk markers for type 1 diabetes. CONCLUSIONS: Within the general population, the combination of HLA and autoantibody screening resulted in disease risks that are likely to be as high as those reported among autoantibody-positive siblings of children with type 1 diabetes.

Role of insulin autoantibody affinity as a predictive marker for type 1 diabetes in young children with HLA-conferred disease susceptibility.

BACKGROUND: Insulin autoantibodies (IAA) are early markers of prediabetic autoimmunity. As transient and fluctuating IAA positivity are common among young children, distinguishing non-progressive IAA from destruction-related IAA is essential when preventive measures are considered. We tested whether children progressing rapidly to type 1 diabetes (progressors) are characterized by a higher prediabetic IAA affinity than IAA-positive children remaining unaffected or progressing more slowly to diabetes (non-progressors), and whether IAA affinity increases towards diagnosis. METHODS: Finnish children with HLA-conferred diabetes susceptibility were observed from birth for diabetes-associated autoantibodies and progression to overt type 1 diabetes. IAA levels and affinities of the first IAA-positive prediabetic samples and samples obtained closest to the diagnosis in 64 progressors were compared with corresponding values in 64 matched IAA-positive non-progressors. RESULTS: The median age at diagnosis was 3.9 years in progressors and the median follow-up time 7.6 years among unaffected subjects. In the first samples the median IAA affinity was 1.4 x 10(10) L/mol in both groups (p = 0.33), while at the second sampling it was 1.1 x 10(10) L/mol in progressors and 1.2 x 10(10) L/mol in unaffected subjects (p = 0.46). No changes in affinity levels were observed (p = 0.33 and p = 0.84, respectively). IAA titers increased towards diagnosis among progressors (from a median of 13.6 to 20.1 relative units; p = 0.02). CONCLUSIONS: Among young IAA-positive children with HLA-conferred disease susceptibility IAA affinity failed to distinguish rapid progressors from slowly or non-progressing subjects. In relation to IAA affinity, no maturation of the humoral immune response was observed over time from seroconversion to diagnosis.

Dysregulation of lipid and amino acid metabolism precedes islet autoimmunity in children who later progress to type 1 diabetes.

The risk determinants of type 1 diabetes, initiators of autoimmune response, mechanisms regulating progress toward beta cell failure, and factors determining time of presentation of clinical diabetes are poorly understood. We investigated changes in the serum metabolome prospectively in children who later progressed to type 1 diabetes. Serum metabolite profiles were compared between sample series drawn from 56 children who progressed to type 1 diabetes and 73 controls who remained nondiabetic and permanently autoantibody negative. Individuals who developed diabetes had reduced serum levels of succinic acid and phosphatidylcholine (PC) at birth, reduced levels of triglycerides and antioxidant ether phospholipids throughout the follow up, and increased levels of proinflammatory lysoPCs several months before seroconversion to autoantibody positivity. The lipid changes were not attributable to HLA-associated genetic risk. The appearance of insulin and glutamic acid decarboxylase autoantibodies was preceded by diminished ketoleucine and elevated glutamic acid. The metabolic profile was partially normalized after the seroconversion. Autoimmunity may thus be a relatively late response to the early metabolic disturbances. Recognition of these preautoimmune alterations may aid in studies of disease pathogenesis and may open a time window for novel type 1 diabetes prevention strategies.

Nasal insulin to prevent type 1 diabetes in children with HLA genotypes and autoantibodies conferring increased risk of disease: a double-blind, randomised controlled trial.

BACKGROUND: In mouse models of diabetes, prophylactic administration of insulin reduced incidence of the disease. We investigated whether administration of nasal insulin decreased the incidence of type 1 diabetes, in children with HLA genotypes and autoantibodies increasing the risk of the disease. METHODS: At three university hospitals in Turku, Oulu, and Tampere (Finland), we analysed cord blood samples of 116 720 consecutively born infants, and 3430 of their siblings, for the HLA-DQB1 susceptibility alleles for type 1 diabetes. 17 397 infants and 1613 siblings had increased genetic risk, of whom 11 225 and 1574, respectively, consented to screening of diabetes-associated autoantibodies at every 3-12 months. In a double-blind trial, we randomly assigned 224 infants and 40 siblings positive for two or more autoantibodies, in consecutive samples, to receive short-acting human insulin (1 unit/kg; n=115 and n=22) or placebo (n=109 and n=18) once a day intranasally. We used a restricted randomisation, stratified by site, with permuted blocks of size two. Primary endpoint was diagnosis of diabetes. Analysis was by intention to treat. The study was terminated early because insulin had no beneficial effect. This study is registered with ClinicalTrials.gov, number NCT00223613. FINDINGS: Median duration of the intervention was 1.8 years (range 0-9.7). Diabetes was diagnosed in 49 index children randomised to receive insulin, and in 47 randomised to placebo (hazard ratio [HR] 1.14; 95% CI 0.73-1.77). 42 and 38 of these children, respectively, continued treatment until diagnosis, with yearly rates of diabetes onset of 16.8% (95% CI 11.7-21.9) and 15.3% (10.5-20.2). Seven siblings were diagnosed with diabetes in the insulin group, versus six in the placebo group (HR 1.93; 0.56-6.77). In all randomised children, diabetes was diagnosed in 56 in the insulin group, and 53 in the placebo group (HR 0.98; 0.67-1.43, p=0.91). INTERPRETATION: In children with HLA-conferred susceptibility to diabetes, administration of nasal insulin, started soon after detection of autoantibodies, could not be shown to prevent or delay type 1 diabetes.

Fate of five celiac disease-associated antibodies during normal diet in genetically at-risk children observed from birth in a natural history study.

OBJECTIVES: To explore the natural history of antibodies against tissue transglutaminase (TGA), endomysium (EMA), reticulin (ARA), and gliadin (AGA-IgG and AGA-IgA) in children carrying HLA-conferred risk for celiac disease (CD) and observed frequently from birth. METHODS: TGA was measured in serum samples obtained between years 2000 and 2003 from 1,320 children carrying genetic CD risk. If a sample was TGA positive, all five antibodies were analyzed in all banked and forthcoming samples from that child, and a duodenal biopsy was recommended. At the end of this observation, in August 2004, the age of the children was from 1 to 9.5 yr (mean 4.1 yr). RESULTS: Forty-nine children (3.7%) were TGA positive. In these children, AGA-IgG had emerged at the mean age (+/- SD, range) of 2.0 +/- 1.5, 0.5-6.6 yr, while TGA, EMA, and ARA all emerged concurrently somewhat later (TGA at 3.2 +/- 1.5, 1.0-7.0 yr, P < 0.001 when compared to AGA-IgG). Despite continuing gluten exposure, positive TGA, EMA, ARA, AGA-IgA, and AGA-IgG values were spontaneously lost in 49%, 45%, 43%, 41%, and 32% of the children, respectively. CD was diagnosed by biopsy in 20 of the 26 TGA-positive children who consented to a biopsy. CONCLUSIONS: Potential CD trigger(s) other than only gluten probably function before AGA-IgG emerges, i.e., > or =3 months earlier than the transglutaminase-associated antibodies appear. In a remarkable proportion of the children, antibodies disappear spontaneously suggesting that regulatory immune phenomena under favorable circumstances are able to extinguish incipient CD in genetically at-risk children even without exclusion of gluten from the diet.

Ketoacidosis at diagnosis of type 1 diabetes in children in northern Finland: temporal changes over 20 years.

OBJECTIVE: To study the frequency of diabetic ketoacidosis (DKA) over a 20-year period among children diagnosed with type 1 diabetes in northern Finland. RESEARCH DESIGN AND METHODS: The study population comprised 585 patients (328 boys) diagnosed with type 1 diabetes aged <15 years in the Department of Pediatrics, Oulu University Hospital, between 1 January 1982 and 31 December 2001. The data for clinical characteristics were collected retrospectively from the patients' case records. The earlier 10-year period (1982-1991) was compared with the later 10-year period (1992-2001). Two definitions for DKA were used: DKA(i) pH <7.30 or DKA(ii) pH <7.30 and/or bicarbonate <15 mmol/l. RESULTS: During the later 10-year period, children less often had DKA at diagnosis [DKA(i) 15.2 vs. 22.4%, P = 0.028, and DKA(ii) 18.9 vs. 29.5%, P = 0.003]. The proportion of young children aged <5 years at diagnosis increased over time, but the frequency of DKA also was lower in this age-group during 1992-2001 compared with the earlier 10-year period [DKA(i) 17.7 vs. 32.1%, P = 0.052, and DKA(ii) 20.3 vs. 42.6%, P = 0.005]. In children aged <2 years at diagnosis, the frequency of DKA remained high during 1992-2001 [DKA(i) 39.1% and DKA(ii) 47.8%]. CONCLUSIONS: The overall frequency of DKA in children with newly diagnosed type 1 diabetes decreased over a 20-year period in northern Finland. However, children aged <2 years are still at high risk for DKA at diagnosis.

Natural history of transglutaminase autoantibodies and mucosal changes in children carrying HLA-conferred celiac disease susceptibility.

OBJECTIVE: The natural history of the appearance and fate of transglutaminase autoantibodies (TGAs) and mucosal changes in children carrying HLA-conferred celiac disease (CD) risk remains obscure. The aim of this study was to investigate the sequence of events leading to overt CD by retrospective analysis of TGA values in serum samples collected frequently from genetically susceptible children since birth or early childhood. MATERIAL AND METHODS: A total of 1101 at-risk children were recruited in the study. A duodenal biopsy was recommended to all TGA-positive children and performed if parental consent was obtained. RESULTS: During up to 8 years of follow-up, 35 of the cohort children developed TGAs, the youngest at age 1.3 years. After age 1.3 years the annual TGA seroconversion rate was constantly around 1% at least until age 6 years. However, 18 of the 35 TGA-positive children (51%) lost TGAs, without any dietary manipulation. A further 7 children were IgA deficient; of these children, 2 developed IgG antigliadin antibodies (IgG-AGA). Only 13 of the 21 children (62%) who had duodenal biopsies had villous atrophy. The time that passed since emergence of TGAs failed to predict the biopsy findings. Only one of the children with TGAs and both of the IgA-deficient children with IgG-AGA had noticeable abdominal symptoms. CONCLUSIONS: TGAs appear in children at a constant rate after 1 year of age until at least the age of 6 years. Over half of the children loose TGA without gluten exclusion, challenging TGA positivity-based CD prevalence estimates. In symptom-free children, a requirement of two consecutive TGA-positive samples taken >or=3 months apart before performing a duodenal biopsy might diminish the number of unnecessary intestinal biopsies.