Search

Aims/hypothesis The aim of this study was to prospectively investigate whether psychological stress during childhood may be a risk factor for manifest type 1 diabetes. Methods The All Babies In Southeast Sweden (ABIS) study invited all families with babies born between 1 October 1997 and 30 September 1999 in southeast Sweden to participate. Our study subsample includes 10,495 participants in at least one of the data collections at 2-3, 5-6, 8 and 10-13 years of age not yet diagnosed with type 1 diabetes at inclusion; 58 children were subsequently diagnosed. Age at diagnosis was obtained from the national register SweDiabKids in 2012. Family psychological stress was measured via questionnaires given to the parents assessing serious life events, parenting stress, parental worries and the parents social support. Results Childhood experience of a serious life event was associated with a higher risk of future diagnosis of type 1 diabetes (HR 3.0 [95% CI 1.6, 5.6], p = 0.001) after adjusting for heredity of type 1 diabetes and age at entry into the study. The result was still valid when controlling for heredity of type 2 diabetes, size for gestational age, the parents education level and whether the mother worked at least 50% of full time before the childs birth (HR 2.8 [95% CI 1.5, 5.4], p = 0.002), and also when childhood BMI was added to the model (HR 5.0 [95% CI 2.3, 10.7], p less than 0.001). Conclusions/interpretation This first prospective study concluded that experience of a serious life event in childhood may be a risk factor for manifest type 1 diabetes., Funding Agencies|Swedish Research Council [K2005-72X-11242-11A, K2008-69X-20826-01-4]; Swedish Child Diabetes Foundation (Barndiabetesfonden); JDRF Wallenberg Foundation [K 98-99D-12813-01A]; Medical Research Council of Southeast Sweden (FORSS); Swedish Council for Working Life and Social Research [FAS2004-1775]

The Diabetes Virus Detection study (DiViD) is the first to examine fresh pancreatic tissue at the diagnosis of type 1 diabetes for the presence of viruses. Minimal pancreatic tail resection was performed 3-9 weeks after onset of type 1 diabetes in 6 adult patients (age 24-35 years). The presence of enteroviral capsid protein 1 (VP1) and the expression of class I HLA were investigated by immunohistochemistry. Enterovirus RNA was analyzed from isolated pancreatic islets and from fresh frozen whole pancreatic tissue using PCR and sequencing. Non-diabetic organ donors served as controls. VP1 was detected in the islets of all type 1 diabetes patients (2 of 9 controls). Hyperexpression of class I HLA molecules was found in the islets of all patients (1 of 9 controls). Enterovirus specific RNA sequences were detected in 4 of 6 cases (0 of 6 controls). The results were confirmed in different laboratories. Only 1.7 % of the islets contained VP1 positive cells and the amount of enterovirus RNA was low. The results provides evidence for the presence of enterovirus in pancreatic islets of type 1 diabetic patients, being consistent with the possibility that a low grade enteroviral infection in the pancreatic islets contribute to disease progression in humans.

Introduction: Pharmacotherapy of type 1 diabetes (T1D) is mainly restricted to insulin treatment. Insulin analogues have replaced human insulin sometimes without reason. A broader approach is needed. less thanbrgreater than less thanbrgreater thanAreas covered: Insulin and insulin analogues, but also other available hormone therapies and drugs, based on literature in PubMed are included in this study. less thanbrgreater than less thanbrgreater thanExpert opinion: At diagnosis, T1D patients should, when resources allow, participate in clinical trials aiming at preservation of beta cell function, for example, with combination therapies involving auto-antigen/s. In very young children insulin pump is recommended, when enough resources for ALL patients; in older patients pump or multiple insulin therapy is recommended. Human insulin still has a place, with insulin analogues on special indications. Patients with pronounced insulin resistance might need Metformin, and Glitazones need more studies. Incretins, for example, GLP-1 may be of interest in patients with residual C-peptide. Amylin will probably be restricted to highly motivated patients. IGF-1 also requires more studies. C-peptide may be a hormone, probably part of future treatment. Glucosoxidase inhibitors might be considered in obese patients. Whether drugs increasing glucosuria will be of clinical value in T1D remains to be shown. In summary, insulin replacement is not enough for several patients. A broader pharmacotherapy is needed, at onset, and later when metabolic control needs improvement., Funding Agencies|Diamyd Medical

Objectives To investigate the risk of future diabetes mellitus type 1 (T1D) in children who suffered from infection at time of gluten introduction. Study design Population-based prospective study. Parents filled out a diary at home. We hereby obtained data on date of gluten introduction, breastfeeding duration, and infections in 9414 children born in the southeast of Sweden from October 1, 1997, through October 1, 1999 (the All Babies in Southeast Sweden cohort). The Cox proportional hazards model was used to investigate the risk of future T1D until February 1, 2012, among children with infection at time of gluten introduction. Results Forty-six children (0.5%) developed T1D and were compared with 9368 reference children from the general population. Some 10 of 46 children with later T1D had an infection at time of gluten introduction (22%) compared with 2520 reference children (27%, P = .43). Later T1D was not associated with age at end of breastfeeding, age at any infection, or age at gluten introduction. Breastfeeding at time of gluten introduction was not protective against future T1D (hazard ratio 1.2; 95% CI, 0.5-2.7). In our final model, when we adjusted for age at gluten introduction, age at infection, and breastfeeding duration, infection at time of gluten introduction did not influence the risk of future T1D (hazard ratio 0.8; 95% CI, 0.3-1.6). Conclusion Infection at time of gluten introduction is not a major risk factor for future T1D in nonselected children., Funding Agencies|Swedish Society of Medicine; Swedish Research Council; Sven Jerring Foundation; Orebro Society of Medicine; Karolinska Institutet; Clas Groschinsky Foundation; Juhlin Foundation; Majblomman Foundation; Swedish Celiac Society; Juvenile Diabetes Research Foundation; Wallenberg Foundation [K98-99D-12813-01A]; Swedish Medical Research Council (MRF Vetenskapsradet) [K99-72X-11242-05A]; Swedish Child Diabetes Foundation (Barndiabetesfonden); Swedish Diabetes Association; Soderberg Foundation; Novo Nordisk Foundation; Karolinska Institute Board of Postgraduate education; Orebro University Hospital

n/a

Background: The infant microbiota may play a pathogenic role in coeliac disease (CD). Antibiotic treatment in pregnancy is common and could significantly impact the infant microbiota. In this study, we aimed to investigate the association between antibiotic exposure during pregnancy and CD in offspring. Methods: Prospective questionnaire data on antibiotic exposure in pregnancy were available in 8729 children participating in the All Babies in Southeast Sweden (ABIS) cohort study, and of these 46 developed CD until December 2006. Cox regression estimated hazard ratios (HRs) for CD in the offspring among mothers exposed to antibiotics during pregnancy, with adjustment for parent-reported diary data on breastfeeding, age at gluten introduction and number of infections in the childs first year of life. Results: Of the 1836 children exposed to antibiotics during pregnancy, 12 (0.7%) children developed CD as compared with 34/6893 (0.5%) unexposed children (HR = 1.33; 95% Cl = 0.69-2.56). Risk estimates remained unchanged after adjustment for breastfeeding, age at gluten introduction and infection load in the childs first year of life (HR = 1.28; 95% Cl = 0.66-2.48). Conclusions: We found no statistically significant association between antibiotic exposure during pregnancy and CD in offspring. This lack of association may either be true or the result of limited statistical power.

We determined A/H1N1-hemagglutinin (HA) antibodies in relation to HLAD-Q genotypes and islet autoantibodies at clinical diagnosis in 1141 incident 0.7 to 18-year-old type 1 diabetes patients diagnosed April 2009-December 2010. Antibodies to S-35-methionine-labelled A/H1N1 hemagglutinin were determined in a radio-binding assay in patients diagnosed before (n = 325), during (n = 355) and after (n = 461) the October 2009-March 2010 Swedish A(H1N1) pdm09 vaccination campaign, along with HLA-DQ genotypes and autoantibodies against GAD, insulin, IA-2 and ZnT8 transporter. Before vaccination, 0.6% patients had A/H1N1-HA antibodies compared with 40% during and 27% after vaccination (P less than 0.0001). In children less than3 years of age, A/H1N1-HA antibodies were found only during vaccination. The frequency of A/H1N1-HA antibodies during vaccination decreased after vaccination among the 3 less than 6 (P = 0.006) and 13 less than 18 (P = 0.001), but not among the 6 less than 13-year-olds. HLA-DQ2/8 positive children less than3 years decreased from 54% (15/28) before and 68% (19/28) during, to 30% (9/30) after vaccination (P = 0.014). Regardless of age, DQ2/2; 2/X (n = 177) patients had lower frequency (P = 0.020) and levels (P = 0.042) of A/H1N1-HA antibodies compared with non-DQ2/2; 2/X (n = 964) patients. GADA frequency was 50% before, 60% during and 51% after vaccination (P = 0.009). ZnT8QA frequency increased from 30% before to 34% during and 41% after vaccination (P = 0.002). Our findings suggest that young (less than3 years) along with DQ2/2; 2/X patients were low responders to Pandemrix (R). As the proportion of DQ2/8 patients less than3 years of age decreased after vaccination and the frequencies of GADA and ZnT8QA were enhanced, it cannot be excluded that the vaccine affected clinical onset of type 1 diabetes.

Objective. The aim was to investigate the mucosal activation of a broad range of genes associated with the T-helper 17 cell (Th17) signaling pathway in children at different stages of celiac disease (CD), including children with increased risk for CD and children with untreated and gluten-free diet (GFD)-treated CD. Material and methods. Small intestinal biopsies were taken from children with untreated and GFD-treated CD, transglutaminase antibody (TGA)-positive children with potential CD, and reference children. Real-time polymerase chain reaction (PCR) arrays were used to study the gene expression pattern of Th17-related genes, and quantitative PCR was used to study the interleukin (IL)-17A expression. Results. The mucosal expression of CD8A was elevated at all stages of CD. Children with untreated CD had diminished levels of IL-17RE, IL-23R, RORc, STAT6, CCL22, NFATC2, IL-18, CD4, CD247, and matrix metalloproteinase (MMP)9 but had elevated levels of MMP3, IL-17, interferon-gamma (IFN-gamma) and CD8A, compared to references. The majority of the aforementioned genes, being differentially expressed in untreated CD, displayed similar expression in GFD-treated children and references. Children with untreated and GFD-treated CD had elevated expression of IFN-gamma but had reduced expression of CD247. Interestingly, children with potential CD displayed reduced FOXP3, IL-21, and IL-17A levels. Conclusion. Mucosal upregulation of Th17 immunity occurs at the late stage of disease and is downregulated with dietary treatment, thus indicating that IL-17 immunity is not a fundamental feature of CD as Th1 immunity, which is not fully downregulated by GFD.

There are an increasing number of medical research studies involving children, including many long-term birth cohort studies. Involving children raises many issues, and little is known about childrens own views. This study explored childrens views (N = 5,851) on participation in a long-term screening study for type 1 diabetes. The results show that children 10 to 13 years of age have in general a positive attitude to pediatric research and emphasized trust in researchers. The children stressed the importance to receive information and to be involved in decisions. The children also reported feeling concerned about blood sampling and disease risk. Researchers involved in long-term pediatric research need to address these issues to promote involvement and decrease worry., Funding Agencies|Swedish Research Council (VR); Swedish Diabetes Foundation (Diabetesfonden); Swedish Child Diabetes Foundation (Barndiabetesfonden)

Aims/Hypothesis: Islet amyloid polypeptide (IAPP) is a beta cell hormone secreted together with insulin upon glucose stimulation. IAPP participates in normal glucose regulation, but IAPP is also known for its ability to misfold and form islet amyloid. Amyloid fibrils form through smaller cell toxic intermediates and deposited amyloid disrupts normal islet architecture. Even though IAPP and amyloid formation are much discussed in type 2 diabetes, our aim was to study the significance of IAPP in type 1 diabetes. Results: Plasma IAPP levels in children and adolescents with newly diagnosed type 1 diabetes (n = 224) were analysed and concentrations exceeding 100 pmol/L (127.2 - 888.7 pmol/L) were found in 11% (25/224). The IAPP increase did not correlate with C-peptide levels. Conclusions/Interpretation: Plasma levels of IAPP and insulin deviate in a subpopulation of young with newly-diagnosed type 1 diabetes. The determined elevated levels of IAPP might increase the risk for IAPP misfolding and formation of cell toxic amyloid in beta cells. This finding add IAPP-aggregation to the list over putative pathological factors causing type 1 diabetes.

Background: The infant microbiota may play a pathogenic role in coeliac disease (CD). Antibiotic treatment in pregnancy is common and could significantly impact the infant microbiota. In this study, we aimed to investigate the association between antibiotic exposure during pregnancy and CD in offspring. Methods: Prospective questionnaire data on antibiotic exposure in pregnancy were available in 8729 children participating in the All Babies in Southeast Sweden (ABIS) cohort study, and of these 46 developed CD until December 2006. Cox regression estimated hazard ratios (HRs) for CD in the offspring among mothers exposed to antibiotics during pregnancy, with adjustment for parent-reported diary data on breastfeeding, age at gluten introduction and number of infections in the childs first year of life. Results: Of the 1836 children exposed to antibiotics during pregnancy, 12 (0.7%) children developed CD as compared with 34/6893 (0.5%) unexposed children (HR = 1.33; 95% Cl = 0.69-2.56). Risk estimates remained unchanged after adjustment for breastfeeding, age at gluten introduction and infection load in the childs first year of life (HR = 1.28; 95% Cl = 0.66-2.48). Conclusions: We found no statistically significant association between antibiotic exposure during pregnancy and CD in offspring. This lack of association may either be true or the result of limited statistical power.

BackgroundAfter the first investigational study on the use of extracorporeal photopheresis for the treatment of cutaneous T-cell lymphoma was published in 1983 with its subsequent recognition by the FDA for its refractory forms, the technology has shown significant promise in the treatment of other severe and refractory conditions in a multi-disciplinary setting. Among the major studied conditions are graft versus host disease after allogeneic bone marrow transplantation, systemic sclerosis, solid organ transplant rejection and inflammatory bowel disease. Materials and methodsIn order to provide recognized expert practical guidelines for the use of this technology for all indications the European Dermatology Forum (EDF) proceeded to address these questions in the hands of the recognized experts within and outside the field of dermatology. This was done using the recognized and approved guidelines of EDF for this task. Results and conclusionThese guidelines provide at present the most comprehensive available expert recommendations for the use of extracorporeal photopheresis based on the available published literature and expert consensus opinion.

Objective. The aim was to investigate the mucosal activation of a broad range of genes associated with the T-helper 17 cell (Th17) signaling pathway in children at different stages of celiac disease (CD), including children with increased risk for CD and children with untreated and gluten-free diet (GFD)-treated CD. Material and methods. Small intestinal biopsies were taken from children with untreated and GFD-treated CD, transglutaminase antibody (TGA)-positive children with potential CD, and reference children. Real-time polymerase chain reaction (PCR) arrays were used to study the gene expression pattern of Th17-related genes, and quantitative PCR was used to study the interleukin (IL)-17A expression. Results. The mucosal expression of CD8A was elevated at all stages of CD. Children with untreated CD had diminished levels of IL-17RE, IL-23R, RORc, STAT6, CCL22, NFATC2, IL-18, CD4, CD247, and matrix metalloproteinase (MMP)9 but had elevated levels of MMP3, IL-17, interferon-gamma (IFN-gamma) and CD8A, compared to references. The majority of the aforementioned genes, being differentially expressed in untreated CD, displayed similar expression in GFD-treated children and references. Children with untreated and GFD-treated CD had elevated expression of IFN-gamma but had reduced expression of CD247. Interestingly, children with potential CD displayed reduced FOXP3, IL-21, and IL-17A levels. Conclusion. Mucosal upregulation of Th17 immunity occurs at the late stage of disease and is downregulated with dietary treatment, thus indicating that IL-17 immunity is not a fundamental feature of CD as Th1 immunity, which is not fully downregulated by GFD.

There are an increasing number of medical research studies involving children, including many long-term birth cohort studies. Involving children raises many issues, and little is known about childrens own views. This study explored childrens views (N = 5,851) on participation in a long-term screening study for type 1 diabetes. The results show that children 10 to 13 years of age have in general a positive attitude to pediatric research and emphasized trust in researchers. The children stressed the importance to receive information and to be involved in decisions. The children also reported feeling concerned about blood sampling and disease risk. Researchers involved in long-term pediatric research need to address these issues to promote involvement and decrease worry., Funding Agencies|Swedish Research Council (VR); Swedish Diabetes Foundation (Diabetesfonden); Swedish Child Diabetes Foundation (Barndiabetesfonden)

Background: The infant microbiota may play a pathogenic role in coeliac disease (CD). Antibiotic treatment in pregnancy is common and could significantly impact the infant microbiota. In this study, we aimed to investigate the association between antibiotic exposure during pregnancy and CD in offspring. Methods: Prospective questionnaire data on antibiotic exposure in pregnancy were available in 8729 children participating in the All Babies in Southeast Sweden (ABIS) cohort study, and of these 46 developed CD until December 2006. Cox regression estimated hazard ratios (HRs) for CD in the offspring among mothers exposed to antibiotics during pregnancy, with adjustment for parent-reported diary data on breastfeeding, age at gluten introduction and number of infections in the childs first year of life. Results: Of the 1836 children exposed to antibiotics during pregnancy, 12 (0.7%) children developed CD as compared with 34/6893 (0.5%) unexposed children (HR = 1.33; 95% Cl = 0.69-2.56). Risk estimates remained unchanged after adjustment for breastfeeding, age at gluten introduction and infection load in the childs first year of life (HR = 1.28; 95% Cl = 0.66-2.48). Conclusions: We found no statistically significant association between antibiotic exposure during pregnancy and CD in offspring. This lack of association may either be true or the result of limited statistical power.

Aims/Hypothesis: Islet amyloid polypeptide (IAPP) is a beta cell hormone secreted together with insulin upon glucose stimulation. IAPP participates in normal glucose regulation, but IAPP is also known for its ability to misfold and form islet amyloid. Amyloid fibrils form through smaller cell toxic intermediates and deposited amyloid disrupts normal islet architecture. Even though IAPP and amyloid formation are much discussed in type 2 diabetes, our aim was to study the significance of IAPP in type 1 diabetes. Results: Plasma IAPP levels in children and adolescents with newly diagnosed type 1 diabetes (n = 224) were analysed and concentrations exceeding 100 pmol/L (127.2 - 888.7 pmol/L) were found in 11% (25/224). The IAPP increase did not correlate with C-peptide levels. Conclusions/Interpretation: Plasma levels of IAPP and insulin deviate in a subpopulation of young with newly-diagnosed type 1 diabetes. The determined elevated levels of IAPP might increase the risk for IAPP misfolding and formation of cell toxic amyloid in beta cells. This finding add IAPP-aggregation to the list over putative pathological factors causing type 1 diabetes.

BackgroundAfter the first investigational study on the use of extracorporeal photopheresis for the treatment of cutaneous T-cell lymphoma was published in 1983 with its subsequent recognition by the FDA for its refractory forms, the technology has shown significant promise in the treatment of other severe and refractory conditions in a multi-disciplinary setting. Among the major studied conditions are graft versus host disease after allogeneic bone marrow transplantation, systemic sclerosis, solid organ transplant rejection and inflammatory bowel disease. Materials and methodsIn order to provide recognized expert practical guidelines for the use of this technology for all indications the European Dermatology Forum (EDF) proceeded to address these questions in the hands of the recognized experts within and outside the field of dermatology. This was done using the recognized and approved guidelines of EDF for this task. Results and conclusionThese guidelines provide at present the most comprehensive available expert recommendations for the use of extracorporeal photopheresis based on the available published literature and expert consensus opinion.

BackgroundAfter the first investigational study on the use of extracorporeal photopheresis for the treatment of cutaneous T-cell lymphoma was published in 1983 with its subsequent recognition by the FDA for its refractory forms, the technology has shown significant promise in the treatment of other severe and refractory conditions in a multi-disciplinary setting. Among the major studied conditions are graft versus host disease after allogeneic bone marrow transplantation, systemic sclerosis, solid organ transplant rejection and inflammatory bowel disease. Materials and methodsIn order to provide recognized expert practical guidelines for the use of this technology for all indications the European Dermatology Forum (EDF) proceeded to address these questions in the hands of the recognized experts within and outside the field of dermatology. This was done using the recognized and approved guidelines of EDF for this task. Results and conclusionThese guidelines provide at present the most comprehensive available expert recommendations for the use of extracorporeal photopheresis based on the available published literature and expert consensus opinion.

There are an increasing number of medical research studies involving children, including many long-term birth cohort studies. Involving children raises many issues, and little is known about childrens own views. This study explored childrens views (N = 5,851) on participation in a long-term screening study for type 1 diabetes. The results show that children 10 to 13 years of age have in general a positive attitude to pediatric research and emphasized trust in researchers. The children stressed the importance to receive information and to be involved in decisions. The children also reported feeling concerned about blood sampling and disease risk. Researchers involved in long-term pediatric research need to address these issues to promote involvement and decrease worry., Funding Agencies|Swedish Research Council (VR); Swedish Diabetes Foundation (Diabetesfonden); Swedish Child Diabetes Foundation (Barndiabetesfonden)

Objective. The aim was to investigate the mucosal activation of a broad range of genes associated with the T-helper 17 cell (Th17) signaling pathway in children at different stages of celiac disease (CD), including children with increased risk for CD and children with untreated and gluten-free diet (GFD)-treated CD. Material and methods. Small intestinal biopsies were taken from children with untreated and GFD-treated CD, transglutaminase antibody (TGA)-positive children with potential CD, and reference children. Real-time polymerase chain reaction (PCR) arrays were used to study the gene expression pattern of Th17-related genes, and quantitative PCR was used to study the interleukin (IL)-17A expression. Results. The mucosal expression of CD8A was elevated at all stages of CD. Children with untreated CD had diminished levels of IL-17RE, IL-23R, RORc, STAT6, CCL22, NFATC2, IL-18, CD4, CD247, and matrix metalloproteinase (MMP)9 but had elevated levels of MMP3, IL-17, interferon-gamma (IFN-gamma) and CD8A, compared to references. The majority of the aforementioned genes, being differentially expressed in untreated CD, displayed similar expression in GFD-treated children and references. Children with untreated and GFD-treated CD had elevated expression of IFN-gamma but had reduced expression of CD247. Interestingly, children with potential CD displayed reduced FOXP3, IL-21, and IL-17A levels. Conclusion. Mucosal upregulation of Th17 immunity occurs at the late stage of disease and is downregulated with dietary treatment, thus indicating that IL-17 immunity is not a fundamental feature of CD as Th1 immunity, which is not fully downregulated by GFD.

Background: The infant microbiota may play a pathogenic role in coeliac disease (CD). Antibiotic treatment in pregnancy is common and could significantly impact the infant microbiota. In this study, we aimed to investigate the association between antibiotic exposure during pregnancy and CD in offspring. Methods: Prospective questionnaire data on antibiotic exposure in pregnancy were available in 8729 children participating in the All Babies in Southeast Sweden (ABIS) cohort study, and of these 46 developed CD until December 2006. Cox regression estimated hazard ratios (HRs) for CD in the offspring among mothers exposed to antibiotics during pregnancy, with adjustment for parent-reported diary data on breastfeeding, age at gluten introduction and number of infections in the childs first year of life. Results: Of the 1836 children exposed to antibiotics during pregnancy, 12 (0.7%) children developed CD as compared with 34/6893 (0.5%) unexposed children (HR = 1.33; 95% Cl = 0.69-2.56). Risk estimates remained unchanged after adjustment for breastfeeding, age at gluten introduction and infection load in the childs first year of life (HR = 1.28; 95% Cl = 0.66-2.48). Conclusions: We found no statistically significant association between antibiotic exposure during pregnancy and CD in offspring. This lack of association may either be true or the result of limited statistical power.

Aims/Hypothesis: Islet amyloid polypeptide (IAPP) is a beta cell hormone secreted together with insulin upon glucose stimulation. IAPP participates in normal glucose regulation, but IAPP is also known for its ability to misfold and form islet amyloid. Amyloid fibrils form through smaller cell toxic intermediates and deposited amyloid disrupts normal islet architecture. Even though IAPP and amyloid formation are much discussed in type 2 diabetes, our aim was to study the significance of IAPP in type 1 diabetes. Results: Plasma IAPP levels in children and adolescents with newly diagnosed type 1 diabetes (n = 224) were analysed and concentrations exceeding 100 pmol/L (127.2 - 888.7 pmol/L) were found in 11% (25/224). The IAPP increase did not correlate with C-peptide levels. Conclusions/Interpretation: Plasma levels of IAPP and insulin deviate in a subpopulation of young with newly-diagnosed type 1 diabetes. The determined elevated levels of IAPP might increase the risk for IAPP misfolding and formation of cell toxic amyloid in beta cells. This finding add IAPP-aggregation to the list over putative pathological factors causing type 1 diabetes.

n/a

Objectives To investigate the risk of future diabetes mellitus type 1 (T1D) in children who suffered from infection at time of gluten introduction. Study design Population-based prospective study. Parents filled out a diary at home. We hereby obtained data on date of gluten introduction, breastfeeding duration, and infections in 9414 children born in the southeast of Sweden from October 1, 1997, through October 1, 1999 (the All Babies in Southeast Sweden cohort). The Cox proportional hazards model was used to investigate the risk of future T1D until February 1, 2012, among children with infection at time of gluten introduction. Results Forty-six children (0.5%) developed T1D and were compared with 9368 reference children from the general population. Some 10 of 46 children with later T1D had an infection at time of gluten introduction (22%) compared with 2520 reference children (27%, P = .43). Later T1D was not associated with age at end of breastfeeding, age at any infection, or age at gluten introduction. Breastfeeding at time of gluten introduction was not protective against future T1D (hazard ratio 1.2; 95% CI, 0.5-2.7). In our final model, when we adjusted for age at gluten introduction, age at infection, and breastfeeding duration, infection at time of gluten introduction did not influence the risk of future T1D (hazard ratio 0.8; 95% CI, 0.3-1.6). Conclusion Infection at time of gluten introduction is not a major risk factor for future T1D in nonselected children., Funding Agencies|Swedish Society of Medicine; Swedish Research Council; Sven Jerring Foundation; Orebro Society of Medicine; Karolinska Institutet; Clas Groschinsky Foundation; Juhlin Foundation; Majblomman Foundation; Swedish Celiac Society; Juvenile Diabetes Research Foundation; Wallenberg Foundation [K98-99D-12813-01A]; Swedish Medical Research Council (MRF Vetenskapsradet) [K99-72X-11242-05A]; Swedish Child Diabetes Foundation (Barndiabetesfonden); Swedish Diabetes Association; Soderberg Foundation; Novo Nordisk Foundation; Karolinska Institute Board of Postgraduate education; Orebro University Hospital

We determined A/H1N1-hemagglutinin (HA) antibodies in relation to HLAD-Q genotypes and islet autoantibodies at clinical diagnosis in 1141 incident 0.7 to 18-year-old type 1 diabetes patients diagnosed April 2009-December 2010. Antibodies to S-35-methionine-labelled A/H1N1 hemagglutinin were determined in a radio-binding assay in patients diagnosed before (n = 325), during (n = 355) and after (n = 461) the October 2009-March 2010 Swedish A(H1N1) pdm09 vaccination campaign, along with HLA-DQ genotypes and autoantibodies against GAD, insulin, IA-2 and ZnT8 transporter. Before vaccination, 0.6% patients had A/H1N1-HA antibodies compared with 40% during and 27% after vaccination (P less than 0.0001). In children less than3 years of age, A/H1N1-HA antibodies were found only during vaccination. The frequency of A/H1N1-HA antibodies during vaccination decreased after vaccination among the 3 less than 6 (P = 0.006) and 13 less than 18 (P = 0.001), but not among the 6 less than 13-year-olds. HLA-DQ2/8 positive children less than3 years decreased from 54% (15/28) before and 68% (19/28) during, to 30% (9/30) after vaccination (P = 0.014). Regardless of age, DQ2/2; 2/X (n = 177) patients had lower frequency (P = 0.020) and levels (P = 0.042) of A/H1N1-HA antibodies compared with non-DQ2/2; 2/X (n = 964) patients. GADA frequency was 50% before, 60% during and 51% after vaccination (P = 0.009). ZnT8QA frequency increased from 30% before to 34% during and 41% after vaccination (P = 0.002). Our findings suggest that young (less than3 years) along with DQ2/2; 2/X patients were low responders to Pandemrix (R). As the proportion of DQ2/8 patients less than3 years of age decreased after vaccination and the frequencies of GADA and ZnT8QA were enhanced, it cannot be excluded that the vaccine affected clinical onset of type 1 diabetes.

Background: The infant microbiota may play a pathogenic role in coeliac disease (CD). Antibiotic treatment in pregnancy is common and could significantly impact the infant microbiota. In this study, we aimed to investigate the association between antibiotic exposure during pregnancy and CD in offspring. Methods: Prospective questionnaire data on antibiotic exposure in pregnancy were available in 8729 children participating in the All Babies in Southeast Sweden (ABIS) cohort study, and of these 46 developed CD until December 2006. Cox regression estimated hazard ratios (HRs) for CD in the offspring among mothers exposed to antibiotics during pregnancy, with adjustment for parent-reported diary data on breastfeeding, age at gluten introduction and number of infections in the childs first year of life. Results: Of the 1836 children exposed to antibiotics during pregnancy, 12 (0.7%) children developed CD as compared with 34/6893 (0.5%) unexposed children (HR = 1.33; 95% Cl = 0.69-2.56). Risk estimates remained unchanged after adjustment for breastfeeding, age at gluten introduction and infection load in the childs first year of life (HR = 1.28; 95% Cl = 0.66-2.48). Conclusions: We found no statistically significant association between antibiotic exposure during pregnancy and CD in offspring. This lack of association may either be true or the result of limited statistical power.

AimsC-peptide secretion is currently the only available clinical biomarker to measure residual -cell function in type 1 diabetes. However, the natural history of C-peptide decline after diagnosis can vary considerably dependent upon several variables. We investigated the shape of C-peptide decline over time from type 1 diabetes onset in relation to age at diagnosis, haemoglobin A1c (HbA1c) levels and insulin dose. MethodsWe analysed data from 3929 type 1 diabetes patients recruited from seven European centres representing all age groups at disease onset (childhood, adolescence and adulthood). The influence of the age at onset on -cell function was investigated in a longitudinal analysis at diagnosis and up to 5-years follow-up. ResultsFasting C-peptide (FCP) data at diagnosis were available in 3668 patients stratified according to age at diagnosis in four groups (less than5years, n=344; greater than5yearsless than10years, n=668; greater than10yearsless than18years, n=991; greater than18years, n=1655). FCP levels were positively correlated with age (pless than0.001); the subsequent decline in FCP over time was log-linear with a greater decline rate in younger age groups (pless than0.0001). ConclusionsThis study reveals a positive correlation between age at diagnosis of type 1 diabetes and FCP with a more rapid decline of -cell function in the very young patients. These data can inform the design of clinical trials using C-peptide values as an end-point for the effect of a given treatment.

AIMS: The aim of this study was to explore whether islet cell antibodies (ICA) could be identified in children with newly onset diabetes mellitus but negative for autoantibodies against glutamic acid decarboxylase (GADA), islet antigen-2 (IA-2A), insulin (IAA), or any of the three variants with arginine (R), tryptophan (W), or glutamine (Q) at position 325 of the zinc transporter 8 (ZnT8A). METHODS: A population-based analysis of autoantibodies was performed from 1 May 2005 to 2 September 2010 in Swedish children newly diagnosed with diabetes. ICA was analyzed with an enzyme-linked immunosorbent assay and if positive, reanalyzed in the classical ICA immunofluorescence assay, in 341 samples among 3545 children who had been tested negative for all of GADA, IA-2A, IAA, or ZnT8A (R, W, Q). RESULTS: An isolated positivity for ICA was identified in 5.0% (17/341) of the newly diagnosed children. The levels of ICA in positive subjects ranged from 3 to 183 JDF-U (median 30). This finding increased the diagnostic sensitivity of islet autoimmunity as 3204/3545 patients (90.4%) were islet autoantibody positive without the ICA analyses and 3221 patients (90.9%) were positive with the inclusion of ICA. CONCLUSIONS: The finding of an isolated positivity for ICA despite negativity for GADA, IA-2A, IAA, and ZnT8A (R, W, Q) suggests that still another yet unidentified autoantigen(s) may contribute to the ICA immunofluorescence. Hence, ICA is important to analyze in type 1 diabetes children and adolescents that would otherwise be islet autoantibody negative.

Psychological stress is a public health issue even in children and has been associated with a number of immunological diseases. The aim of this study was to examine the relationship between psychological stress and immune response in healthy children, with special focus on autoimmunity. In this study, psychological stress was based on a composite measure of stress in the family across the domains: 1) serious life events, 2) parenting stress, 3) lack of social support, and 4) parental worries. PBMCs, collected from 5-y-old high-stressed children (n = 26) and from 5-y-old children without high stress within the family (n = 52), from the All Babies In Southeast Sweden cohort, were stimulated with Ags (tetanus toxoid and b-lactoglobulin) and diabetes-related autoantigens (glutamic acid decarboxylase 65, insulin, heat shock protein 60, and tyrosine phosphatase). Immune markers (cytokines and chemokines), clinical parameters (C-peptide, proinsulin, glucose), and cortisol, as an indicator of stress, were analyzed. Children from families with high psychological stress showed a low spontaneous immune activity (IL-5, IL-10, IL-13, IL-17, CCL2, CCL3, and CXCL10; p less than 0.01) but an increased immune response to tetanus toxoid, b-lactoglobulin, and the autoantigens glutamic acid decarboxylase 65, heat shock protein 60, and tyrosine phosphatase (IL-5, IL-6, IL-10, IL-13, IL-17, IFN-g, TNF-A, CCL2, CCL3, and CXCL10; p less than 0.05). Children within the high-stress group showed high level of cortisol, but low level of C-peptide, compared with the control group (p less than 0.05). This supports the hypothesis that psychological stress may contribute to an imbalance in the immune response but also to a pathological effect on the insulin-producing b cells.Copyright © 2014 by The American Association of Immunologists., Funding text:This work was supported by the Swedish Research Council (Grant K2009-70X-21086-01-3), the Swedish Council for Working Life and Social Research (Grant 2008-0284), the Medical Research Council of Southeast Sweden, and the Swedish Child Diabetes Foundation.

We studied the effects of probiotic treatment on the innate immune system during infancy. The study included a subgroup of infants recruited to the pilot study testing the feasibility of probiotics intervention in infants with genetic risk of type 1 diabetes (T1D). A mixture of Lactobacillus rhamnosus GG (5 x 109 cfu), Lactobacillus rhamnosus LC705 (5 x 109 cfu), Bifidobacterium breve Bbi99 (2 x 108 cfu) and Propionibacterium freudenreichii ssp. Shermani JS (2 x 109 cfu) was given to the infants beginning one to three weeks after birth until the age of 6 months. Blood samples were drawn at the age of 6, 12 and 24 months for the analyses of beta-cell autoantibodies and the phenotype and stimulation response of monocytes with flow-cytometry, including surface markers on circulating CD14+ monocytes and expression of co-stimulatory markers on CD14+ monocytes as response to stimulation with lipoteichoic acid (LTA) and lipopolysaccharide (LPS). Also gene expression of toll-like receptor (TLR) signalling molecules was studied in the peripheral blood mononuclear cell (PBMC) population. In the children who received probiotics the number of circulating CD14+ monocytes expressing CD58 was reduced at the age of 6 months, and a tendency for a decreased induction of CCR5, CD80 and CD58 expressing monocytes as response to LTA was seen when compared to the children who received placebo. At the age of 12 months, the number of monocytes expressing CCR5 was decreased in the probiotic group, and a decreased spontaneous expression of TNFRSF1A and an increased spontaneous expression of TLR9 was observed in the PBMC from the children treated with probiotics. In the whole study group, the numbers of circulating monocytes expressing CD80 increased with age as well as the induction of CCR5, CD80 and CD58 on monocytes as response to stimulation. By the age of 24 months one child in both groups developed multiple autoantibodies. We demonstrated that probiotics modulated the activation stage an

n/a

Background Early psychosocial exposures are increasingly recognized as crucial for health throughout life. A possible mechanism could be physiologic dysregulation due to stress. Cortisol in hair is a new biomarker, assessing long-term HPA axis activity. The objective was to investigate whether prenatal adverse psychosocial circumstances influence infant cortisol levels in hair and health outcome in children prospectively until age 10. Methods True prospective cohort study in the general community with a questionnaire covering 11 psychosocial items in the family during pregnancy formed a composite scale of prenatal psychosocial vulnerability, and cumulative incidence of diseases through diagnoses until age 10 in n=1876 children. At age 1, cortisol levels in hair were measured using a competitive radioimmunoassay on a subsample of n=209. Results Children with added prenatal psychosocial exposures had higher infant cortisol levels in hair (B=0.40, p<0.0001, adjusted for gender and size for gestational age) in a cumulative manner and were more often (p≤0.05) affected by 12 of the 14 most common childhood diagnoses with a general pattern of rising ORs. Conclusions These findings support the model of physiologic dysregulation as a plausible mechanism in how the duration and number of early detrimental psychosocial exposures determine health outcome. It indicates that the multiplicity of adversities should be targeted in future interventions and could help to identify children who are at high risk of poor health. Furthermore, given the prolonged nature of exposure to a stressful social environment, the novel biomarker of cortisol in hair could be of major importance.

BackgroundAfter the first investigational study on the use of extracorporeal photopheresis for the treatment of cutaneous T-cell lymphoma was published in 1983 with its subsequent recognition by the FDA for its refractory forms, the technology has shown significant promise in the treatment of other severe and refractory conditions in a multi-disciplinary setting. Among the major studied conditions are graft versus host disease after allogeneic bone marrow transplantation, systemic sclerosis, solid organ transplant rejection and inflammatory bowel disease. Materials and methodsIn order to provide recognized expert practical guidelines for the use of this technology for all indications the European Dermatology Forum (EDF) proceeded to address these questions in the hands of the recognized experts within and outside the field of dermatology. This was done using the recognized and approved guidelines of EDF for this task. Results and conclusionThese guidelines provide at present the most comprehensive available expert recommendations for the use of extracorporeal photopheresis based on the available published literature and expert consensus opinion.

Objective. The aim was to investigate the mucosal activation of a broad range of genes associated with the T-helper 17 cell (Th17) signaling pathway in children at different stages of celiac disease (CD), including children with increased risk for CD and children with untreated and gluten-free diet (GFD)-treated CD. Material and methods. Small intestinal biopsies were taken from children with untreated and GFD-treated CD, transglutaminase antibody (TGA)-positive children with potential CD, and reference children. Real-time polymerase chain reaction (PCR) arrays were used to study the gene expression pattern of Th17-related genes, and quantitative PCR was used to study the interleukin (IL)-17A expression. Results. The mucosal expression of CD8A was elevated at all stages of CD. Children with untreated CD had diminished levels of IL-17RE, IL-23R, RORc, STAT6, CCL22, NFATC2, IL-18, CD4, CD247, and matrix metalloproteinase (MMP)9 but had elevated levels of MMP3, IL-17, interferon-gamma (IFN-gamma) and CD8A, compared to references. The majority of the aforementioned genes, being differentially expressed in untreated CD, displayed similar expression in GFD-treated children and references. Children with untreated and GFD-treated CD had elevated expression of IFN-gamma but had reduced expression of CD247. Interestingly, children with potential CD displayed reduced FOXP3, IL-21, and IL-17A levels. Conclusion. Mucosal upregulation of Th17 immunity occurs at the late stage of disease and is downregulated with dietary treatment, thus indicating that IL-17 immunity is not a fundamental feature of CD as Th1 immunity, which is not fully downregulated by GFD.

There are an increasing number of medical research studies involving children, including many long-term birth cohort studies. Involving children raises many issues, and little is known about childrens own views. This study explored childrens views (N = 5,851) on participation in a long-term screening study for type 1 diabetes. The results show that children 10 to 13 years of age have in general a positive attitude to pediatric research and emphasized trust in researchers. The children stressed the importance to receive information and to be involved in decisions. The children also reported feeling concerned about blood sampling and disease risk. Researchers involved in long-term pediatric research need to address these issues to promote involvement and decrease worry., Funding Agencies|Swedish Research Council (VR); Swedish Diabetes Foundation (Diabetesfonden); Swedish Child Diabetes Foundation (Barndiabetesfonden)

OBJECTIVES:: Both breastfeeding duration and age at gluten introduction have been implicated in the pathogenesis of celiac disease (CD). We hypothesized that parental CD affects the feeding pattern of the offspring, mediated by parental health awareness increasing adherence to infant feeding guidelines. METHODS:: Prospectively collected infant feeding data were obtained through the All Babies in Southeast Sweden (ABIS) study. Information regarding infant feeding was available in 9,414 children. Twenty-two mothers had a history of biopsy-verified CD before delivery of a child in the study, 9,392 mothers had no diagnosis of CD prior to birth and thus constituted the unexposed or control population. Cox regression was used to compare the risk of early weaning and gluten introduction according to parental CD status, and logistic regression to assess if mothers with CD were more likely to breastfeed their children at gluten introduction. RESULTS:: Some 63% of children were breastfeed for at least 9 months. We found no association between maternal CD and early weaning (adjusted hazard ratio (HR), 1.0; 95% confidence interval (CI), 0.6-1.7), nor between paternal CD and early weaning (HR 0.5; 95% CI, 0.1-1.9). Sixty percent of children were introduced to gluten in months 5-6. Maternal CD was not associated with age at gluten introduction (adjusted HR, 0.8; 95% CI, 0.6-1.3) There was no statistically significant association between maternal CD and breastfeeding at time of gluten introduction (OR, 1.4; 95% CI, 0.4-4.7). CONCLUSIONS:: Feeding patterns do not seem to vary between offspring to mothers with CD and those without.

AIMS/HYPOTHESIS: Our aim was to study the risk of renal disease in patients with type 1 diabetes (T1D) and coexisting coeliac disease (CD). METHODS: Individuals with T1D were defined as having a diagnosis of diabetes recorded at ≤30 years of age in the Swedish Patient Register between 1964 and 2009. Individuals with CD were identified through biopsy reports with villous atrophy (Marsh stage 3) from 28 pathology departments in Sweden between 1969 and 2008. We identified 954 patients with both T1D and CD. For each patient with T1D + CD, we selected five age- and sex-matched reference individuals with T1D only (n = 4,579). Cox regression was used to estimate the following risks: (1) chronic renal disease and (2) end-stage renal disease in patients with CD + T1D compared with T1D patients only. RESULTS: Forty-one (4.3%) patients with CD + T1D and 143 (3.1%) patients with T1D only developed chronic renal disease. This corresponded to an HR of 1.43 for chronic renal disease (95% CI 0.94, 2.17) in patients with CD + T1D compared with T1D only. In addition, for end-stage renal disease there was a positive (albeit statistically non-significant) HR of 2.54 (95% CI 0.45, 14.2). For chronic renal disease, the excess risk was more pronounced after >10 years of CD (HR 2.03, 95% CI 1.08, 3.79). Risk estimates were similar when we restricted our cohort to the following T1D patients: (1) those who had an inpatient diagnosis of T1D; (2) those who had never received oral glucose-lowering medication; and (3) those who had not received their first diabetes diagnosis during pregnancy. CONCLUSIONS/INTERPRETATION: Overall this study found no excess risk of chronic renal disease in patients with T1D and CD. However, in a subanalysis we noted a positive association between longstanding CD and chronic renal disease in T1D.

Background: Preterm birth, low birth weight, and infant catch-up growth seem associated with an increased risk of respiratory diseases in later life, but individual studies showed conflicting results. Objectives: We performed an individual participant data meta-analysis for 147,252 children of 31 birth cohort studies to determine the associations of birth and infant growth characteristics with the risks of preschool wheezing (1-4 years) and school-age asthma (5-10 years). Methods: First, we performed an adjusted 1-stage random-effect meta-analysis to assess the combined associations of gestational age, birth weight, and infant weight gain with childhood asthma. Second, we performed an adjusted 2-stage random-effect meta-analysis to assess the associations of preterm birth (gestational age less than 37 weeks) and low birth weight (less than 2500 g) with childhood asthma outcomes. Results: Younger gestational age at birth and higher infant weight gain were independently associated with higher risks of preschool wheezing and school-age asthma (P less than. 05). The inverse associations of birth weight with childhood asthma were explained by gestational age at birth. Compared with term-born children with normal infant weight gain, we observed the highest risks of school-age asthma in children born preterm with high infant weight gain (odds ratio [OR], 4.47; 95% CI, 2.58-7.76). Preterm birth was positively associated with an increased risk of preschool wheezing (pooled odds ratio [pOR], 1.34; 95% CI, 1.25-1.43) and school-age asthma (pOR, 1.40; 95% CI, 1.18-1.67) independent of birth weight. Weaker effect estimates were observed for the associations of low birth weight adjusted for gestational age at birth with preschool wheezing (pOR, 1.10; 95% CI, 1.00-1.21) and school-age asthma (pOR, 1.13; 95% CI, 1.01-1.27). Conclusion: Younger gestational age at birth and higher infant weight gain were associated with childhood asthma outcomes. The associations of lower birth weigh

In several diseases where the immune system plays an important role there has been a tremendous progress in treatment efficacy during the last decades. Based on necessary basic science these improvements are results of rapid, numerous and open-minded clinical trials where pieces of positive results step by step have been added into treatment schemes. Treatment of Type 1 diabetes has certainly improved but too slowly. It has been difficult to convince the scientific community of opinions which among non-professionals have been regarded as common sense such as the value of normal blood glucose and preservation of insulin secretion. Lack of motivation to participate in clinical trials has slowed down progress, as well as too narrow views on both pathogenesis of Type 1 diabetes and how studies should be designed to test therapeutic interventions. Studies in experimental animals can create and support hypothesis for human conditions but must not delay clinical trials too long. There is already evidence enough for intervention trials where immune suppression is combined with antigen treatment, beta cell protection, anti-inflammatory treatment, and efforts to stimulate beta cell regeneration. Regimens should be elaborated and first tried in those groups of patients where response can be expected to be best, and thereafter adjusted to increase efficacy step-wise, and in broader patient categories.

BACKGROUND: This study aimed to analyse data from two different studies (Phase II and Phase III) regarding the safety and efficacy of treatment with alum formulated glutamic acid decarboxylase GAD65 (GAD-alum), 30 months after administration to children and adolescents with Type 1 diabetes (T1D). METHODS: The Phase II trial was a double-blind, randomized placebo-controlled study, including 70 children and adolescents which were followed for 30 months. Participants received a subcutaneous injection of either 20 µg of GAD-alum or placebo at baseline and one month later. During a subsequent larger European Phase III trial including three treatment arms, participants received two or four subcutaneous injections of either 20 µg of GAD-alum and/or placebo at baseline, 1, 3 and 9 months. The Phase III trial was prematurely interrupted at 15 months, but of the 148 Swedish patients, a majority completed the 21 months follow-up and 45 patients completed the trial at 30 months. Both studies included GADA-positive patients with fasting C-peptide ≥0.10 nmol/l. We have now combined the results of these two trials. RESULTS: There were no treatment related adverse events. In patients treated with 2 GAD-alum doses, stimulated C-peptide AUC had decreased significantly less (9 m: p < 0.037; 15 m p < 0.032; 21 m p < 0.003 and 30 m p < 0.004) and a larger proportion of these patients were also able to achieve a peak stimulated C-peptide >0.2 nmol/l (p < 0.05), as compared to placebo. CONCLUSION: Treatment with two doses of GAD-alum in children and adolescents with recent-onset T1D shows no adverse events and preserves residual insulin secretion. This article is protected by copyright. All rights reserved.

Aims/Hypothesis: Islet amyloid polypeptide (IAPP) is a beta cell hormone secreted together with insulin upon glucose stimulation. IAPP participates in normal glucose regulation, but IAPP is also known for its ability to misfold and form islet amyloid. Amyloid fibrils form through smaller cell toxic intermediates and deposited amyloid disrupts normal islet architecture. Even though IAPP and amyloid formation are much discussed in type 2 diabetes, our aim was to study the significance of IAPP in type 1 diabetes. Results: Plasma IAPP levels in children and adolescents with newly diagnosed type 1 diabetes (n = 224) were analysed and concentrations exceeding 100 pmol/L (127.2 - 888.7 pmol/L) were found in 11% (25/224). The IAPP increase did not correlate with C-peptide levels. Conclusions/Interpretation: Plasma levels of IAPP and insulin deviate in a subpopulation of young with newly-diagnosed type 1 diabetes. The determined elevated levels of IAPP might increase the risk for IAPP misfolding and formation of cell toxic amyloid in beta cells. This finding add IAPP-aggregation to the list over putative pathological factors causing type 1 diabetes.

BackgroundAfter the first investigational study on the use of extracorporeal photopheresis for the treatment of cutaneous T-cell lymphoma was published in 1983 with its subsequent recognition by the FDA for its refractory forms, the technology has shown significant promise in the treatment of other severe and refractory conditions in a multi-disciplinary setting. Among the major studied conditions are graft versus host disease after allogeneic bone marrow transplantation, systemic sclerosis, solid organ transplant rejection and inflammatory bowel disease. Materials and methodsIn order to provide recognized expert practical guidelines for the use of this technology for all indications the European Dermatology Forum (EDF) proceeded to address these questions in the hands of the recognized experts within and outside the field of dermatology. This was done using the recognized and approved guidelines of EDF for this task. Results and conclusionThese guidelines provide at present the most comprehensive available expert recommendations for the use of extracorporeal photopheresis based on the available published literature and expert consensus opinion.

Objective. The aim was to investigate the mucosal activation of a broad range of genes associated with the T-helper 17 cell (Th17) signaling pathway in children at different stages of celiac disease (CD), including children with increased risk for CD and children with untreated and gluten-free diet (GFD)-treated CD. Material and methods. Small intestinal biopsies were taken from children with untreated and GFD-treated CD, transglutaminase antibody (TGA)-positive children with potential CD, and reference children. Real-time polymerase chain reaction (PCR) arrays were used to study the gene expression pattern of Th17-related genes, and quantitative PCR was used to study the interleukin (IL)-17A expression. Results. The mucosal expression of CD8A was elevated at all stages of CD. Children with untreated CD had diminished levels of IL-17RE, IL-23R, RORc, STAT6, CCL22, NFATC2, IL-18, CD4, CD247, and matrix metalloproteinase (MMP)9 but had elevated levels of MMP3, IL-17, interferon-gamma (IFN-gamma) and CD8A, compared to references. The majority of the aforementioned genes, being differentially expressed in untreated CD, displayed similar expression in GFD-treated children and references. Children with untreated and GFD-treated CD had elevated expression of IFN-gamma but had reduced expression of CD247. Interestingly, children with potential CD displayed reduced FOXP3, IL-21, and IL-17A levels. Conclusion. Mucosal upregulation of Th17 immunity occurs at the late stage of disease and is downregulated with dietary treatment, thus indicating that IL-17 immunity is not a fundamental feature of CD as Th1 immunity, which is not fully downregulated by GFD.

There are an increasing number of medical research studies involving children, including many long-term birth cohort studies. Involving children raises many issues, and little is known about childrens own views. This study explored childrens views (N = 5,851) on participation in a long-term screening study for type 1 diabetes. The results show that children 10 to 13 years of age have in general a positive attitude to pediatric research and emphasized trust in researchers. The children stressed the importance to receive information and to be involved in decisions. The children also reported feeling concerned about blood sampling and disease risk. Researchers involved in long-term pediatric research need to address these issues to promote involvement and decrease worry., Funding Agencies|Swedish Research Council (VR); Swedish Diabetes Foundation (Diabetesfonden); Swedish Child Diabetes Foundation (Barndiabetesfonden)

Background: The infant microbiota may play a pathogenic role in coeliac disease (CD). Antibiotic treatment in pregnancy is common and could significantly impact the infant microbiota. In this study, we aimed to investigate the association between antibiotic exposure during pregnancy and CD in offspring. Methods: Prospective questionnaire data on antibiotic exposure in pregnancy were available in 8729 children participating in the All Babies in Southeast Sweden (ABIS) cohort study, and of these 46 developed CD until December 2006. Cox regression estimated hazard ratios (HRs) for CD in the offspring among mothers exposed to antibiotics during pregnancy, with adjustment for parent-reported diary data on breastfeeding, age at gluten introduction and number of infections in the childs first year of life. Results: Of the 1836 children exposed to antibiotics during pregnancy, 12 (0.7%) children developed CD as compared with 34/6893 (0.5%) unexposed children (HR = 1.33; 95% Cl = 0.69-2.56). Risk estimates remained unchanged after adjustment for breastfeeding, age at gluten introduction and infection load in the childs first year of life (HR = 1.28; 95% Cl = 0.66-2.48). Conclusions: We found no statistically significant association between antibiotic exposure during pregnancy and CD in offspring. This lack of association may either be true or the result of limited statistical power.