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Children at increased genetic risk for type 1 diabetes (T1D) after environmental exposures may develop pancreatic islet autoantibodies (IA) at a very young age. Metabolic profile changes over time may imply responses to exposures and signal development of the first IA. Our present research in The Environmental Determinants of Diabetes in the Young (TEDDY) study aimed to identify metabolome-wide signals preceding the first IA against GAD (GADA-first) or against insulin (IAA-first). We profiled metabolomes by mass spectrometry from children's plasma at 3-month intervals after birth until appearance of the first IA. A trajectory analysis discovered each first IA preceded by reduced amino acid proline and branched-chain amino acids (BCAAs), respectively. With independent time point analysis following birth, we discovered dehydroascorbic acid (DHAA) contributing to the risk of each first IA, and γ-aminobutyric acid (GABAs) associated with the first autoantibody against insulin (IAA-first). Methionine and alanine, compounds produced in BCAA metabolism and fatty acids, also preceded IA at different time points. Unsaturated triglycerides and phosphatidylethanolamines decreased in abundance before appearance of either autoantibody. Our findings suggest that IAA-first and GADA-first are heralded by different patterns of DHAA, GABA, multiple amino acids, and fatty acids, which may be important to primary prevention of T1D.

The restoration of forest structure and function is increasingly being used in boreal forests in order to halt the loss of biodiversity. Often ecological restoration is aimed at increasing the volume of dead and dying trees to enhance the biodiversity of deadwood-dependent organisms, but it may also increase population sizes of pest bark beetle species, even several years following restoration. Herein, we used a large-scale restoration experiment in Northern Sweden to assess the 5 years post-restoration effects of restorative gap cutting and prescribed burning on the populations of a set of economically harmful pest bark beetles (Ips typographus , Polygraphus poligraphus , Tomicus piniperda and Pityogenes chalcographus) and the most important predators of bark beetles, Thanasimus spp. In addition, we assessed the effects of forest stand characteristics at stand and landscape scale on the abundance of I. typographus. Five years post-restoration, gap-cut stands supported the highest abundances of P. poligraphus and contained the highest count of spruce trees newly attacked by bark beetles. By contrast, prescribed burning generally sustained the lowest abundances of pest bark beetles, especially I. typographus and P. poligraphus , and the highest abundance of their natural predators Thanasimus spp. The population abundance of I. typographus was also positively affected by the area of clear cuts within a 500 m radius from the stand. In conclusion, prescribed burning appears to be a safer method for ecological restoration than gap cutting in the long-term. According to our results, a risk of a local bark beetle outbreak still remains 5 years following the initiation of ecological restoration treatments on spruce-dominated mature gap-cut stands. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Effective fire suppression in combination with intensive forestry has caused a large number of dead wood-dependent (saproxylic) species to become threatened in Fennoscandia. In order to return the fire disturbance dynamics and to increase the amount of dead wood, restoration actions are urgently needed. We studied the effects of restoring young (under 30 years old) pine-dominated ( Pinus sylvestris L.) forest stands on saproxylic beetle assemblages in eastern Finland, focusing especially on rare, red-listed, and pyrophilous ( RRLP) species. Our experiment included a restoration treatment including two tree felling levels for fuel load (10 or 20 m3/ha) followed by burning, and an untreated control. We sampled beetles before restoration in 2005, during the year of restoration in 2006, and in two post-treatment years in 2007 and 2011. Both restoration treatments increased the number of saproxylic and RRLP species. The species richness increased most in the year of restoration in 2006 and this trend continued in the following year 2007, but no differences in species assemblages were detected between the two fuel load levels. By 2011, however, the species richness and abundance had declined back to the pre-treatment level. We suggest that restoration burning can also be directed to young forests where biodiversity values are initially low. On the basis of the observed decline in the species richness, we suggest that fire could be introduced in neighboring areas in approximately 5-year intervals to maintain populations of the most demanding pyrophilous species. [ABSTRACT FROM AUTHOR]

Because celiac disease (CD) is a common partner of type 1 diabetes (T1D), the two diseases may share pathways in pathogenesis. In T1D Prediction and Prevention Study (DIPP) we examined serum samples from over 2000 children with HLA-conferred genetic T1D and CD susceptibility, born between 11/1994 and 12/2002. The samples were collected at 3- to 12-month intervals and examined for antibodies to tissue transglutaminase (TGA). If positive, all previous and forthcoming samples were also examined for endomysium (EMA), reticulin (ARA) and gliadin antibodies (AGA-IgA,AGA-IgG). Eighty one (ca 4%) of the 2000 children were TGA-positive. AGA-IgG emerged first at age 2.2 ± 1.7; 0.5-7.5 years (mean ± SD; range). TGA, EMA and ARA emerged slightly later (TGA at 3.5±1.9; 1.0-9.0 years; p<0.001). Very few TGA-positive children had symptoms of CD; most were symptom-flee. Because a majority of serum samples was collected before this CD study began, the children were continuously exposed to gluten until TGA positivity was retrospectively discovered using biobanked serum samples. Despite continued gluten exposure TGA, EMA, ARA, AGA-IgA and AGA-IgG positivity disappeared spontaneously in 47%, 36%, 37, 43% and 29% of the children, respectively. CD was diagnosed in 42 of 53 TGA positive children whose parents consented to biopsy. In conclusion, potential non-gluten factor(s) regulating onset of CD autoimmunity probably function before AGA-IgG emerges. In a large proportion of children CD-associated antibodies disappear spontaneously suggesting that regulatory immune phenomena often extinguish incipient CD without exclusion of gluten from the diet. [ABSTRACT FROM AUTHOR]

The ongoing type I Diabetes Prediction and Prevention project (DIPP) aims at studying processes leading to type 1 diabetes (TID). The study starts with screening of newborn babies for HLA class II conferred risk for T1D. Those at risk are recruited to frequent follow-up, and autoantibodies against β-cell antigens (ICA, IAA, GADA, IA-2A) are measured at 3-month intervals until two years of age, and then half-yearly. Children who develop signs of β-cell autoimmunity are invited to a separate prevention trial comparing efficacy of daily nasal insulin administration to that of placebo. In Turku, 54 DIPP children followed since birth have progressed to T1D. They all had diabetes-related autoantibodies in at least one sample before reaching the diagnosis of T1D. 73% of the children had developed at least one autoantibody before the age of 2 years, and 88% before the age of 3 years. The first autoantibody was most often IAA either alone (22 children; 41%) or together with other antibodies (18 children; 33%). In 26% of children another type of antibody was the first to appear. Before development of T1D 93% of the children were positive for ICA, 94% for IAA, 76% for IA-2A and 80% for GADA. Time from seroconversion to multiple autoantibody positivity was only 0.4±0.8 years (mean±SD). Time from seroconversion to diabetes varied from 0.1 to 7.3 years (mean 2.8). The age at diabetes diagnosis varied from 0.8 to 10.3 years (mean 4.5). 33 children (61%) participated in the prevention trial. To conclude, our sample series reaching from birth to clinical T1D show that almost all children progressing to T1D are multiple autoantibody positive before the disease develops. In almost all cases seroconversion happens at an early age, years before the clinical disease, underlining the importance of life events during the first two to three years of life on development of T1D. [ABSTRACT FROM AUTHOR]

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.