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1.	Brekke, Hilde Kristin, 1972, et al. (författare) Breastfeeding and introduction of solid foods in Swedish infants: the All Babies in Southeast Sweden study. 2005 Ingår i: The British journal of nutrition. - 0007-1145 .- 1475-2662. ; 94:3, s. 377-82 Tidskriftsartikel (refereegranskat)abstract The aim of this report is to describe breastfeeding duration and introduction of foods in Swedish infants born 1997-9, in relation to current recommendations. A secondary aim is to examine breastfeeding duration and introduction of certain allergenic foods in allergy-risk families (for whom allergy-preventive advice has been issued). Out of 21,700 invited infants, screening questionnaires were completed for 16,070 infants after delivery. Parents to 11,081 infants completed a follow-up questionnaire regarding breastfeeding and introduction of foods and 9849 handed in detailed food diaries at 1 year of age. The percentages of infants who were exclusively breast-fed at 3, 6 and >or=9 months of age were 78.4, 10.1 and 3.9, respectively. The corresponding percentages for partial breastfeeding were 87.8, 68.9 and 43.6. Gluten-containing foods were introduced to 66% of infants between 4 and 6 months, as recommended at the time of the study, and one-quarter had stopped breastfeeding when gluten was introduced. More than 90% of parents introduced the first sample of solid food during months 4-6, as recommended. Fish and eggs had been introduced during the first year in 43% and 29%, respectively, of infants with atopic heredity. Exclusive breastfeeding duration and time of introduction of solid foods, including gluten, seemed to have been in line with Swedish recommendations at the time, although gluten was often introduced late, and not during ongoing breastfeeding as recommended. The adherence to allergy-preventive advice was less than optimal in infants with atopic heredity.
2.	Girdhar, Khyati, et al. (författare) Dynamics of the gut microbiome, IgA response, and plasma metabolome in the development of pediatric celiac disease 2023 Ingår i: Microbiome. - : BMC. - 2049-2618. ; 11:1 Tidskriftsartikel (refereegranskat)abstract Background Celiac disease (CD) is an autoimmune disorder triggered by gluten consumption. Almost all CD patients possess human leukocyte antigen (HLA) DQ2/DQ8 haplotypes; however, only a small subset of individuals carrying these alleles develop CD, indicating the role of environmental factors in CD pathogenesis. The main objective of this study was to determine the contributory role of gut microbiota and microbial metabolites in CD onset. To this end, we obtained fecal samples from a prospective cohort study (ABIS) at ages 2.5 and 5 years. Samples were collected from children who developed CD after the final sample collection (CD progressors) and healthy children matched by age, HLA genotype, breastfeeding duration, and gluten-exposure time (n=15-16). We first used 16S sequencing and immunoglobulin-A sequencing (IgA-seq) using fecal samples obtained from the same children (i) 16 controls and 15 CD progressors at age 2.5 and (ii) 13 controls and 9 CD progressors at age 5. We completed the cytokine profiling, and plasma metabolomics using plasma samples obtained at age 5 (n=7-9). We also determined the effects of one microbiota-derived metabolite, taurodeoxycholic acid (TDCA), on the small intestines and immune cell composition in vivo.Results CD progressors have a distinct gut microbiota composition, an increased IgA response, and unique IgA targets compared to healthy subjects. Notably, 26 plasma metabolites, five cytokines, and one chemokine were significantly altered in CD progressors at age 5. Among 26 metabolites, we identified a 2-fold increase in TDCA. TDCA treatment alone caused villous atrophy, increased CD4+ T cells, Natural Killer cells, and two important immunoregulatory proteins, Qa-1 and NKG2D expression on T cells while decreasing T-regulatory cells in intraepithelial lymphocytes (IELs) in C57BL/6J mice.Conclusions Pediatric CD progressors have a distinct gut microbiota composition, plasma metabolome, and cytokine profile before diagnosis. Furthermore, CD progressors have more IgA-coated bacteria and unique targets of IgA in their gut microbiota. TDCA feeding alone stimulates an inflammatory immune response in the small intestines of C57BJ/6 mice and causes villous atrophy, the hallmark of CD. Thus, a microbiota-derived metabolite, TDCA, enriched in CD progressors plasma, has the potential to drive inflammation in the small intestines and enhance CD pathogenesis.
3.	Huus, Karina, et al. (författare) Exclusive breastfeeding of Swedish children and its possible influence on the development of obesity : a prospective cohort study 2008 Ingår i: BMC Pediatrics. - London : BioMed Central. - 1471-2431. ; 8, s. 42- Tidskriftsartikel (refereegranskat)abstract Background Overweight and obesity are increasing among children all over the world. Socio-economic factors may influence the development of overweight and obesity in childhood, and it has been proposed that breastfeeding may protect against obesity. The aim of our study was to examine the relationship between exclusive breastfeeding and obesity when potential confounders, such as socioeconomic factors, are considered.Methods The data analyzed was from ABIS (All Babies in Southeast Sweden), a prospective cohort study. All parents with children born between October 1, 1997 and October 1, 1999 in Southeast Sweden (n = 21,700) were asked to participate. Parents were asked to answer periodic questionnaires from the time of the child's birth (n = 16,058) until he/she was five years of age (n = 7,356). Cutoffs for overweight and obesity were defined according to Cole et al, age and gender adjusted. Short-term exclusive breastfeeding was defined as < 4 months of exclusive breastfeeding. Multiple logistic regressions were used to identify variables that predict the child's BMI (Body Mass Index) at five years of age.Results At five years of age, 12.9% of the children in the study wereoverweight and 4.3% were obese. At the age of three months, 78.4% of the children were being breastfed exclusively. The median exclusive breastfeeding duration was four months. High maternal BMI > 30 (AOR = 1.07; CI = 1.05–1.09; P < 0.001), maternal smoking (AOR = 1.43; CI = 1.05–1.95; P = 0.023) and being a single parent (AOR = 2.10; CI = 1.43–3.09; P < 0.001) were associated with short-term exclusive breastfeeding (less than 4 months). Short-term exclusive breastfeeding was less common if one of the parents had a university degree (Mother: AOR = 0.74; CI = 0.61–0.90; P = 0.003 Father: AOR = 0.73; CI = 0.58–0.92; P = 0.008) or if the father was more than 37 years old (AOR = 0.74; CI = 0.55–0.99; P = 0.045). Short-term exclusive breastfeeding was associated with obesity in five-year-old children (simple logistic regression: OR = 1.44; CI = 1.00–2.07; P = 0.050), but when including other independent factors in the analysis, short-term exclusive breastfeeding did not attain statistical significance.Conclusion We cannot exclude the possibility that exclusive breastfeeding influences weight development, but it does not seem to protect against obesity at five years of age.
4.	Huus, Karina, 1968-, et al. (författare) Relationship of food frequencies as reported by parents to overweight and obesity at 5 years 2009 Ingår i: Acta Paediatrica. - : Wiley. - 0803-5253 .- 1651-2227. ; 98:1, s. 139-143 Tidskriftsartikel (refereegranskat)abstract AIM: To investigate if food frequencies are related to overweight/obesity in 5-year-old children.METHODS: During 1997-1999, 21 700 infants were invited to participate in ABIS (All Babies in Southeast Sweden), a prospective, cohort study. Participants were followed from birth (n = 16 058) to 5 years (n = 7356). Food frequencies reported by parents at 2.5 and 5 years were studied in the relation to overweight/obesity at 5 years using multiple logistic regressions. A p-value < 0.01 was considered statistically significant.RESULTS: At 2.5 years frequencies of intake of cheese were positively associated with overweight/obesity at 5 years while porridge, fried potatoes/french fries and cream/crème fraiche showed a negative association. When adjusting for known risk factors, porridge and fried potatoes/french fries remained negatively associated with overweight/obesity. At 5 years, chocolate and lemonade were positively associated with overweight/obesity whereas cream/crème fraiche, pastries and candy were negatively associated. Candy remained negatively associated to overweight/obesity after adjustment for potential confounders.CONCLUSION: Food frequencies do not offer any simple explanation for overweight/obesity. Porridge at 2.5 years may protect against overweight/obesity at 5 years, while lemonade may contribute to overweight. Our finding that fried potatoes/french fries may protect against overweight/obesity is unexpected and must be interpreted with caution. These findings should be confirmed by prospective studies using objective recordings.
5.	Huus, Karina, et al. (författare) Risk factors in childhood obesity : findings from the All Babies In Southeast Sweden (ABIS) cohort 2007 Ingår i: Acta Paediatrica. - : Wiley. - 0803-5253 .- 1651-2227. ; 96:9, s. 1321-1325 Tidskriftsartikel (refereegranskat)abstract Aim: Our objective was to investigate whether overweight at a very young age predicts overweight at 5 years and to identify risk factors for overweight/obesity at 5 years, thereby making it easier for Child Health Services to focus their prevention strategies on risk groups.Methods: We analysed data from the ABIS study (All Babies In Southeast Sweden), a prospective cohort study. Parents answered questionnaires between childbirth (n = 16,058) and 5 years (n = 7356).Results: High body mass index (BMI; >95th percentile) at 1 year (adjusted odds ratio [AOR]= 6.57; 95% CI = 4.63–9.33; p < 0.001) and age-adjusted BMI > 25 at 2.5 years (AOR = 14.24; 95% CI = 10.52–19.29; p < 0.001) were associated with increased risk of obesity (age-adjusted BMI > 30) at 5 years. Heredity for type 2 diabetes (p = 0.022), high parental BMI and the child's own BMI at birth and at 1 year predicted higher BMI of the child at 5 years (p < 0.001). High parental education was inversely associated with child overweight (p = 0.054 respective p < 0.005).Conclusion: Obesity at age 1 and at 2.5 years predicts obesity at 5 years. Obese parents, especially in families with heredity for type 2 diabetes and low education, should be targeted in early obesity prevention strategies by the Child Health Service.
6.	Huus, Karina, 1968- (författare) Weight gain in children : possible relation to the development of diabetes 2009 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract Background: The prevalence of overweight and obesity among children has increased the last decades and is now defined as a global epidemic disease by the World Health Organization. Also the incidence of type 1 diabetes has increased and there are some hypothesises that argue there is a connection between overweight/obesity and type 1 diabetes.Aim: The general aim of this thesis was to study factors contributing to the development of overweight and obesity among children and to study possible relations to the development of diabetes.Method: All Babies in Southeast Sweden, ABIS, is a prospective cohort study. The study includes all babies who were born in southeast Sweden between Oct 1st 1997 until Oct1st 1999 and the design was to follow them up to school age in ABIS I and to follow them until 14 years in ABIS II, of the eligible 74 % entered the study. The families have answered questionnaires and biological samples were taken mainly from the children at the different time points: birth, 1 year, 2.5 years, 5 years and 8-9 years. In this thesis studies have been made including the whole cohort, but some studies have also been made involving only a part of the children.Results: The prevalence of overweight and obesity among children in the ABIS study was 12.9% overweight and 2.5 % obese at 5 years of age. One risk factor which appeared to have a great impact on the development of overweight and obesity at 5 years of age was the child’s own BMI at an early age and also the heredity for overweight/ obesity and the heredity for type 2 diabetes. If the father had a university degree, the child was less likely to be obese at 5 years of age. Other factors, such as the parents´ age, if the child had any siblings, and if the child lived with a single parent, did not show any significant correlation to the child’s BMI at 5 years of age.Early nutrition has been studied and no correlation could be found between breastfeeding less than 4 months and the development of overweight/obesity at 5 years of age. The parents answered questions about how frequent the child ate different food at 2.5 years and at 5 years. Intake of sweet lemonade was the only single food which was correlated to a higher BMI in 5 years old children. Porridge seemed to be protective against overweight/ obesity. In one of the studies the physical activity was measured by a step counter. The fewer steps the children were taking, the higher BMI and waist circumference they had. Low physical activity was also associated with a higher C-peptide value and decreased insulin sensitivity. Children who spent more time in front of TV/video had a higher fasting blood glucose value.Conclusions: A strong factor for the development of overweight and obesity among children is the child’s own BMI at an early age and also its heredity for overweight/ obesity and the heredity for type 2 diabetes. Early nutrition did not show any obvious correlations with overweight and obesity at 5 year old children. Low physical activity was associated with higher fasting C-peptide value and decreased insulin sensitivity. Low physical activity may cause β-cell stress which might contribute to an autoimmune process in individuals genetically predisposed to autoimmunity and, thereby, to the increasing incidence of Type 1 diabetes in children.
7.	Ludvigsson, Jonas, et al. (författare) Exclusive breastfeeding and risk of atopic dermatitis in some 8300 infants 2005 Ingår i: Pediatric Allergy and Immunology. - : Wiley. - 0905-6157 .- 1399-3038. ; 16:3, s. 201-208 Tidskriftsartikel (refereegranskat)abstract Earlier studies on breastfeeding and atopy in infants have yielded contradictory results. We examined the relationship between exclusive breastfeeding and atopic dermatitis (AD) in a cohort of infants born between 1 October 1997 and 1 October 1999 in south-east Sweden. We evaluated the risk of AD 'at least once' or 'at least three times' during the first year of life in relation to duration of exclusive breastfeeding: < 4 months (short exclusive breastfeeding, SEBF) vs. ≥4 months. All data were obtained through questionnaires. Of 8346 infants with breastfeeding data, 1943 (23.3%) had suffered from AD during the first year of life. Duration of exclusive breastfeeding was not associated with lower risk of AD (p = 0.868). SEBF did not influence the risk of any AD (OR = 1.03, 95% CI OR = 0.91-1.17, p = 0.614) or AD at least three times (OR = 0.97, 95% CI OR = 0.81-1.16, p = 0.755) during the first year of life. Adjustment for confounders did not change these point estimates. Neither was there any link between SEBF and risk of AD among infants with a family history of atopy [adjusted odds ratio (AOR) = 1.16, 95% CI AOR = 0.90-1.48, p = 0.254]. Furred pets at home were linked to a lower risk of AD both among infants with a family history of atopy (AOR = 0.76, 95% CI AOR = 0.60-0.96, p = 0.021) and among infants with no such history (AOR = 0.79, 95% CI AOR = 0.69-0.90, p < 0.001). Infants with no family history of atopy were less prone to develop AD if parents smoked (AOR = 0.76, 95% CI AOR = 0.61-0.95, p = 0.016). This study indicates that exclusive breastfeeding does not influence the risk of AD during the first year of life, while presence of furred pets at home seems to be negatively associated with AD. Copyright © 2005 Blackwell Munksgaard.
8.	Ludvigsson, Jonas F., et al. (författare) Celiac disease and risk of subsequent type 1 diabetes : a general population cohort study of children and adolescents 2006 Ingår i: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 29:11, s. 2483-2488 Tidskriftsartikel (refereegranskat)abstract OBJECTIVE:Earlier studies suggest that children with type 1 diabetes are more likely to have a subsequent diagnosis of celiac disease. However, research is sparse on the risk of subsequent type 1 diabetes in individuals with celiac disease. We sought to determine the risk of subsequent type 1 diabetes diagnosed before the age of 20 years in children and adolescents with celiac disease in a national, general population-based cohort.RESEARCH DESIGN AND METHODS:We identified 9,243 children with a diagnosis of celiac disease in the Swedish national inpatient register between 1964 and 2003. We then identified five reference individuals matched at time of diagnosis for age, calendar year, sex, and county (n = 45,680). Only individuals with >1 year of follow-up after study entry (diagnosis of celiac disease) were included in the analyses.RESULTS:Celiac disease was associated with a statistically significantly increased risk of subsequent type 1 diabetes before age 20 years (hazard ratio 2.4 [95% CI 1.9-3.0], P < 0.001). This risk increase was seen regardless of whether celiac disease was first diagnosed between 0 and 2 (2.2 [1.7-2.9], P < 0.001) or 3 and 20 (3.4 [1.9-6.1], P < 0.001) years of age. Individuals with prior celiac disease were also at increased risk of ketoacidosis or diabetic coma before the age of 20 years (2.3 [1.4-3.9], P = 0.001).CONCLUSIONS:Children with celiac disease are at increased risk of subsequent type 1 diabetes. This risk increase is low considering that 95% of individuals with celiac disease are HLA-DQ2 positive.
9.	Ludvigsson, Jonas F., et al. (författare) Coeliac disease and risk of renal disease : a general population cohort study 2006 Ingår i: Nephrology, Dialysis and Transplantation. - : Oxford University Press (OUP). - 0931-0509 .- 1460-2385. ; 21:7, s. 1809-1815 Tidskriftsartikel (refereegranskat)abstract BACKGROUND:Coeliac disease (CD) may be a risk factor for renal disease.METHODS:We investigated the risk of any form of glomerulonephritis (GN) (acute, chronic and non-specified), chronic glomerulonephritis (CGN) and renal replacement therapy including dialysis treatment and kidney transplantation (KT) in patients with CD in a general population-based cohort study. We used Cox regression to assess the risk of renal disease in 14,336 patients who had received a diagnosis of CD (1964-2003) and 69,875 reference individuals matched for age, calendar year, sex and county. Patients were identified using the Swedish Hospital Discharge Registry. Follow-up began 1 year after study entry.RESULTS:CD was associated with an increased risk of any form of GN (hazard ratio (HR) = 1.64; 95% confidence intervals (CI) = 1.01-2.66; P = 0.046; 89 events), CGN (HR = 2.65; 95% CI = 1.34-5.24; P = 0.005; 39 events), dialysis (HR = 3.48; 95% CI = 2.26-5.37; P < 0.001; 102 positive events) and KT (HR = 3.15; 95% CI = 1.29-7.71; P = 0.012; 22 events).CONCLUSION:We suggest that immune characteristics associated with CD increase the risk of chronic renal disease. Individuals with CD may also be at a moderately increased risk of any form of GN.
10.	Ludvigsson, Jonas F., et al. (författare) Coeliac disease in the father affects the newborn 2001 Ingår i: Gut. - : BMJ. - 0017-5749 .- 1468-3288. ; 49:2, s. 169-175 Tidskriftsartikel (refereegranskat)abstract BACKGROUND AND AIMS Untreated coeliac disease in the mother is associated with lower birth weight. We examined the risk of adverse neonatal outcome when the infant's mother, father, or other relative suffered from known coeliac disease.METHODS Mothers answered a questionnaire a few days after the birth of their infant. Of a total of 10597 single birth infants from Southeast Sweden, 53 infants had a mother with coeliac disease (father 27, sibling 70, other close relative 442). Adjusted odds ratios and adjusted differences for neonatal outcome were calculated.RESULTS Infants whose father suffered from coeliac disease had a lower birth weight (95% adjusted confidence interval (CI) −459, −72 g), more often belonged to the low birth weight (LBW) category (LBW ⩽2499 g) (95% CI adjusted odds ratio (AOR) 1.48–17.18), and had a shorter pregnancy duration (95% adjusted CI −1.53, −0.08 weeks) than non-coeliac controls. They also weighed less than infants whose father suffered from other autoimmune diseases (95% CI −549, −93 g). Infants whose mother suffered from coeliac disease had a lower birth weight (95% adjusted CI −370, −74 g) and more often belonged to the LBW category (95% CI AOR 2.60–15.08) than non-coeliac controls. These infants were more often in the LBW category than infants whose mother suffered from non-diabetic autoimmune diseases (95% CI AOR 1.24–9.65). Coeliac disease in other relatives was not associated with any adverse effect on neonatal outcome.CONCLUSIONS This study suggests that even treated coeliac disease, in either of the parents, has a negative effect on pregnancy, resulting in lower birth weight and perhaps shorter duration of pregnancy.
11.	Ludvigsson, Jonas F., et al. (författare) Effect of HLA DQ2, dietary exposure and coeliac disease on the development of antibody response to gliadin in children 2006 Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 41:8, s. 919-928 Tidskriftsartikel (refereegranskat)abstract OBJECTIVE: To study the effect of HLA DQ2, dietary history and development of coeliac disease (CD) on the induction of antibody response to wheat gliadin and cow's milk, beta-lactoglobulin between 1 and 2.5 years of age in children who developed CD and in healthy children. MATERIAL AND METHODS: Infants participating in a birth cohort study (the ABIS study) in Sweden were studied. Thirty-nine children developed CD (=cases), confirmed through biopsy, during follow-up until 2.5-5 years of age. A total of 181 healthy control children were matched for duration of exclusive breast-feeding, birth-weight, gender, maternal smoking and season of birth. IgG and IgA antigliadin and anti-beta-lactoglobulin antibodies were measured using enzyme immunoassay (EIA). The effects of HLA-risk genotypes, DQ2 and DQ8, on CD were also considered. RESULTS: Children who developed CD had higher IgG and IgA antigliadin and anti-beta-lactoglobulin antibody levels at 1 year of age than controls (all comparisons: p<0.001). Similar differences were seen between cases with as yet undiagnosed CD by 1 year of age and controls, and also when cases were compared with HLA-matched controls. Higher levels of IgG and IgA antibodies to beta-lactoglobulin (p=0.003; p=0.001), but not to gliadin, were found in treated cases versus controls at 2.5 years of age. HLA-DQ2-positive healthy children had lower levels of IgG and IgA antigliadin antibodies than HLA-DQ2 negative controls at 1 year of age (p=0.004; p=0.012). CONCLUSIONS: Enhanced humoral response emerging not only to gliadin, but also to other food antigens seems to be primarily associated with CD. Poor induction of antibody response to wheat gliadin in healthy children with the HLA-DQ2 risk molecule could at least partly explain the genetic predisposition to gluten intolerance and CD.
12.	Ludvigsson, Jonas F., et al. (författare) Milk consumption during pregnancy and infant birth weight Annan publikation (övrigt vetenskapligt/konstnärligt)abstract Objective To examine birth weight and risk of low birth weight (≤2 499g, LBW) in relation to milk intake.Design Questionnaire-based study.Setting Southeast SwedenPopulation Single birth infants within the ABIS project included during a two-year period (ABIS = All Babies In Southeast Sweden).Main outcome measures Birth weight and LBW.Results Low milk intake during pregnancy was associated with a decrease in infant birth weight (P<0,01l, Kruskal-Wallis) but did not correlate with LBW (P=0.434, Chi-2) (10 489 infants with complete data)When adjusting for confounders (regression analyses) low milk intake during pregnancy was associated with a decrease in infant birth weight (adjusted P for trend<0,001) and with an increased risk of LBW (adjusted P for trend= 0.028) (9 097 infants with complete data).Conclusion This study suggests that low milk intake in the pregnant mother is associated with lower birth weight of the newborn. Further research is needed to evaluate the relationship between low milk intake and the risk of LBW.
13.	Ludvigsson, Jonas F., 1943-, et al. (författare) Milk consumption during pregnancy and infant birthweight 2004 Ingår i: Acta Paediatrica. - 0803-5253 .- 1651-2227. ; 93:11, s. 1474-1478 Tidskriftsartikel (refereegranskat)abstract Aim: To examine the risk of low birthweight (>2500 g, LBW), intrauterine growth retardation (IUGR) and preterm birth (gestational age >37wk) in relation to milk intake.Methods: Observational study in southeast Sweden. Questionnaires were used to collect data on milk consumption during pregnancy and infant birthweight from mother-infant pairs during a 2-y period as part of the ABIS (All Babies in Southeast Sweden) study. Data on IUGR were obtained through the Swedish medical birth registry.Results: Adjusting for confounders, low milk intake during pregnancy was associated with an increased risk of IUGR (p= 0.019; n= 12880). LBW (p= 0.191) and preterm birth (p= 0.921) were not associated with milk intake during pregnancy.Conclusion: This study indicates that low milk intake in the pregnant mother may be associated with IUGR of the newborn. We cannot exclude the possibility that the correlation found between milk consumption and intrauterine growth may be due to undetected confounders. Hence, further research is needed to evaluate the relationship between low milk intake, birthweight and risk of IUGR.
14.	Ludvigsson, Jonas F., et al. (författare) Risk of pancreatitis in 14,000 individuals with celiac disease 2007 Ingår i: Clinical Gastroenterology and Hepatology. - : Elsevier BV. - 1542-3565 .- 1542-7714. ; 5:11, s. 1347-1353 Tidskriftsartikel (refereegranskat)abstract Background & Aims: The aim of this study was to examine the risk of pancreatitis in patients with celiac disease (CD) from a general population cohort. Methods: By using Swedish national registers, we identified 14,239 individuals with a diagnosis of CD (1964–2003) and 69,381 reference individuals matched for age, sex, calendar year, and county of residence at the time of diagnosis. Cox regression estimated the hazard ratios (HRs) for a subsequent diagnosis of pancreatitis. We restricted analyses to individuals with more than 1 year of follow-up and no diagnosis of pancreatitis before or within 1 year after study entry. Conditional logistic regression estimated the association of pancreatitis with subsequent CD. Results: CD was associated with an increased risk of subsequent pancreatitis of any type (HR, 3.3; 95% confidence interval [CI], 2.6–4.4; P < .001; on the basis of 95 positive events in individuals with CD vs 163 positive events in reference individuals) and chronic pancreatitis (HR, 19.8; 95% CI, 9.2–42.8; P < .001; on the basis of 37 and 13 positive events, respectively). Adjustment for socioeconomic index, diabetes mellitus, alcohol-related disorders, or gallstone disease had no notable effect on the risk estimates. The risk increase for pancreatitis was only found among individuals with CD diagnosed in adulthood. Pancreatitis of any type (odds ratio, 3.2; 95% CI, 2.5–4.3; P < .001) and chronic pancreatitis (odds ratio, 7.3; 95% CI, 4.0–13.5; P < .001) were associated with subsequent CD. Conclusions: This study suggests that individuals with CD are at increased risk of pancreatitis.
15.	Ludvigsson, Jonas F, et al. (författare) Tissue Transglutaminase Auto-antibodies in Cord Blood from Children to Become Celiacs 2001 Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 36:12, s. 1279-1283 Tidskriftsartikel (refereegranskat)abstract Background: Determination of tissue transglutaminase auto-antibodies (tTGAA) has been shown to be a sensitive and specific diagnostic tool for large-scale screening for celiac disease. The purpose of this study was to measure tissue tTGAA in cord blood in infants that later developed celiac disease to evaluate if this assay could serve as a predictive tool for later development of celiac disease.Methods: IgG tTGAA were analyzed in cord blood through immunoprecipitation from 51 future celiac patients and 102 age-matched controls. Cut-off level was set at 0.040.Results: No difference in tTGAA levels was found between cord blood from infants who later developed celiac disease and controls ( P = 0.746). 2/51 future celiac patients (3.9%) had levels above cut-off-value in cord blood, while 3/102 controls were positive (2.9%) ( P = 1.000). tTGAA levels were higher in the 1980s and at the beginning of the 1990s than they have been in recent years ( P = 0.003).Conclusions: Determination of tissue tTGAA in cord blood does not predict future celiac disease in children. tTGAA levels vary with time, which should be considered in retrospective studies analyzing tTGAA.
16.	Ludvigsson, Jonas F., et al. (författare) Tissue Transglutaminase autoantibodies in cord-blood from children of healthy mothers Annan publikation (övrigt vetenskapligt/konstnärligt)abstract Background/aims: Detemlination of tissue. transglutaminase autoantibodies (tTGAA) is a sensitive and specific diagnostic tool for large-scale screening for coeliac disease. Early diagnosis and treatment of coeliac disease eliminate gastrointestinal symptoms ru1d reduce the risk of secondmy complications. The purpose of this study was to correlate maternal and infant background factors and their association with tTGAA levels in cord-blood of the ABIS child cohort (ABIS= All Babies In Southeast Sweden).Methods: 2518 cord-blood samples were screened using immunoprecipitation for autoantibodies against tissue transglutaminase, GAD 65 (Glutamic Acid Decarboxylase) and IA-2 (Tyrosin phosphatase). Data on background factors were obtained from the mothers (questionnaire). Multiple comparisons in our analyses were handled by means of a modified Bonferroni adjustment; thus, P values ≤ 0.0019 (0.05/26) were considered to indicate statistical significance.Results: 10/2518 (0.40%) were positive for tTGAA (>0.040 Arbitrary Units (AU)). No cord-blood specimen from known coeliac mothers were positive for tTGAA. Neither absolute tTGAA nor positive tTGAA levels (>0.040AU) correlated with the independent variables in our model Seasonal variation in tTGAA levels (P=0.018) did not reach significance when adjusting for multiple comparisons.Conclusions: TTGAA levels do not seem to be influenced by the environmental or physical factors in our study, but the issue of seasonal variations in tTGAA levels should be further explored.
17.	Ludvigsson, Jonas, et al. (författare) Inflammatory bowel disease in mother or father and neonatal outcome 2002 Ingår i: Acta Paediatrica. - : Wiley. - 0803-5253 .- 1651-2227. ; 91:2, s. 145-151 Tidskriftsartikel (refereegranskat)abstract Even a minor decrease in birthweight predisposes to adult disease. Inflammatory bowel disease (IBD) in the mother is a risk factor for low birthweight and preterm infants. This study investigated the effect of IBD in the mother or father, adjusting for confounders, on the newborn infant, with the focus on birthweight and pregnancy duration. A total of 10 399 single-birth mother-infant pairs was prospectively enrolled within the ABIS project (All Babies In Southeast Sweden). Outcome measures included birth week, preterm birth (<37 wk), birthweight, low birthweight (<2500 g), birth length, caesarean section and neonatal hospital care. Ulcerative colitis (UC) in the mother was associated with lower birthweight in the infant (adjusted difference:—330 g, adjusted 95% confidence interval:—509 to—150 g, p < 0.001), and with even lower birthweight when the mother was treated with Mesalazine or steroids. No decrease in birthweight was seen in infants whose mother suffered from Crohn's disease (CD) (adjusted difference:—65 g, adjusted 95% confidence interval:—354 to 224 g, p > 0.05). Maternal UC or CD did not affect the pregnancy duration. The neonatal outcome of infants whose father suffered from UC and CD did not differ from the control group.Conclusion: UC in the mother affects the birthweight of the infant, which may predispose to future disease in the infant. Most women and men with UC and CD can, however, expect a healthy child with neither preterm birth nor low birthweight.
18.	Ludvigsson, Johnny, 1943-, et al. (författare) Parental smoking and risk of coeliac disease in offspring 2005 Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 40:3, s. 336-342 Tidskriftsartikel (refereegranskat)abstract Objective. In adults, smoking seems to give protection against coeliac disease (CD). But, only one study has thus far investigated the association between maternal smoking during pregnancy and risk of CD in offspring. However, that study did not adjust for duration of exclusive breastfeeding, or look at passive smoking after birth. Material and methods. The current study was part of a prospective cohort study of infants born between 1 October 1997 and 1 October 1999 (the ABIS study, All Babies in Southeast Sweden). Data on smoking and exclusive breastfeeding were obtained through questionnaires distributed at infant birth and at 1 year of age. Coeliac disease was confirmed through small-bowel biopsy. Subgroup analyses were carried out according to maternal body mass index. Results. Nine out of 53 (17%) children with CD as opposed to 1699 out of 15,344 (11.1%) non-coeliac children had mothers who had smoked during pregnancy (p = 0.172). Mothers who had smoked during pregnancy were hence not at increased risk of having a child with CD (OR = 1.64, 95% CI OR = 0.80-3.37). Adjusting for duration of exclusive breastfeeding and the sex of infants in some 9585 children with data on exclusive breastfeeding lowered the OR for CD in mothers who smoked (adjusted OR (AOR) = 0.89, 95% CI AOR = 0.27-2.93, p = 0.843). Parents who smoked during the child's first year of life were not at increased risk of having an offspring with CD (OR = 1.94, 95% CI AOR = 0.69-5.47, p = 0. 203). Conclusions. No association was found between CD and parental smoking habits during pregnancy or during the child's first year of life. However, further studies with larger numbers of coeliac children are needed.
19.	Ludvigsson, Johnny, et al. (författare) Screening for prediabetes in the general child population: maternal attitude to participation 2001 Ingår i: Pediatric Diabetes. - : Hindawi Limited. - 1399-543X. ; 2:4, s. 170-174 Tidskriftsartikel (refereegranskat)abstract Screening to predict serious diseases in the general population has been regarded as unethical as it is supposed to make people anxious. Therefore we have evaluated whether mothers become anxious when their babies participate in a project to predict diabetes in the general child population. Out of 21 700 newborn children, 16 300 (75%) entered the ABIS project (All Babies in South-east Sweden). The parents (usually the mothers) answered a questionnaire at the child's birth and then again after 1 yr. A total of 10 868 representative birth questionnaires had been analyzed. To the question, 'How do you feel when you know that your child is participating in this study?', only 2.5% of mothers of children with type 1 diabetes in the family answered 'more anxious/much more anxious', and even fewer (1.5%) of the mothers in the general population (p < 0.01). A total of 52.5% of the general population answered 'calmer/more reassured' (29.3% 'calmer' and 23.2% 'much calmer'), while 43.3% felt unaffected. Those 1.5% of mothers who reported becoming more anxious were more likely to be in an unstable social situation (unemployed, p < 0.001; born abroad, p < 0.001; low education, p < 0.001). At the 1-yr follow-up, 4948 unselected questionnaires had been analyzed. Only 1.2% of the mothers felt 'more anxious', while the overwhelming majority felt either unaffected (58.7%) or calmer (38.6%). At this follow-up, most of those who had felt 'more anxious' at birth did not feel that way any longer, and none of those with diabetes in the family. We conclude that large-scale screening studies for the prediction of diabetes in the general population can be performed without causing increased anxiety. A few parents, most often found in the group with known social problems, might need extra information and support.
20.	Ludvigsson, Jonas, 1969-, et al. (författare) Socio-economic determinants, maternal smoking and coffee consumption, and exclusive breastfeeding in 10 205 children 2005 Ingår i: Acta Paediatrica. - : Wiley. - 0803-5253 .- 1651-2227. ; 94:9, s. 1310-1319 Tidskriftsartikel (refereegranskat)abstract Aim: To examine socio-economic factors, smoking, coffee consumption and exclusive breastfeeding duration. Methods: This study was part of a prospective cohort study of children born between 1 October 1997 and 1 October 1999 (the All Babies in Southeast Sweden (ABIS) study). Eleven socio-economic characteristics (parental employment, civil status, whether parents were born in Sweden, parental education, residence at birth and during child's first year, crowded living), maternal smoking, coffee consumption, infant sex, siblings, parental age, and maternal alcohol consumption during pregnancy were analysed using logistic regression and Cox's proportional hazards method. All data were obtained through questionnaires distributed at infant birth and at 1 y of age. Exclusive breastfeeding duration <4 mo and actual breastfeeding duration were our main outcome measures. Results: Out of 10205 infants, 2206 (21.6%) were exclusively breastfed for less than 4 mo ("short exclusive breastfeeding", SEBF). Backward stepwise regression analysis identified the following risk factors for SEBF: maternal smoking (95% confidence interval for adjusted odds ratio, 95% CI AOR 2.00-2.82), low maternal education (95% CI AOR 1.45-2.19), maternal employment less than 3 mo during pregnancy (95% CI AOR 1.17-1.54), paternal age ≤29 y (95% CI AOR 1.14-1.47), maternal age ≤29 y (95% CI AOR 1.08-1.39) and low paternal education (95% CI AOR 1.08-1.48). The odds ratio for SEBF increased with the number of cigarettes smoked. Coffee consumption was not associated with duration of exclusive breastfeeding. Conclusion: This study indicates that socio-economic factors and smoking may be of importance to the risk of breastfeeding exclusively for less than 4 mo, while coffee consumption is not. © 2005 Taylor & Francis Group Ltd.
21.	Ludvigsson, Johnny, et al. (författare) Stressful life events, social support and confidence in the pregnant woman and risk of coeliac disease in the offspring 2003 Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 38:5, s. 516-521 Tidskriftsartikel (refereegranskat)abstract Background: Stressful life events just before conception or during pregnancy can affect fetal development and increase the risk of disease in the offspring. The purpose of our study was to examine stressful life events, maternal social support and confidence during pregnancy and the risk of coeliac disease in the offspring. Methods: Prospective cohort study of 16,286 children born between 1 October 1997 and 1 October 1999 in southeast Sweden. The study was part of the ABIS study (ABIS = All Babies In Southeast Sweden). Data on independent variables were obtained through questionnaires distributed at birth. The questionnaire included questions about parental disease, socio-economic factors, smoking, alcohol intake but also infections during pregnancy. Eight paediatric departments prospectively recorded all children with coeliac disease (confirmed through biopsy). Results: Exposure to stressful life events (OR = 0.48, 95% CI OR = 0.12-2.01, P = 0.318), lack of social support (OR = 3.17, 95% CI OR = 0.43-23.22, P = 0.257) and lack of confidence (OR = 0.04, 95% CI OR = 0.00-2.48 x 10(9), P = 0.794) in the pregnant woman were not linked to coeliac disease in the offspring. Conclusion: The study indicates that stressful life events, lack of social support and lack of confidence during pregnancy play no role in the development of coeliac disease in the offspring.
22.	Ludvigsson, Jonas, et al. (författare) Symptoms and signs have changed in Swedish children with coeliac disease. 2004 Ingår i: Journal of Pediatric Gastroenterology and Nutrition - JPGN. - 0277-2116 .- 1536-4801. ; 38, s. 181-186 Tidskriftsartikel (refereegranskat)
23.	Ludvigsson, Johnny, et al. (författare) Tissue transglutaminase autoantibodies in cord-blood from children of healthy mothers 2005 Ingår i: Journal of Clinical Gastroenterology. - : Lippincott Williams & Wilkins. - 0192-0790 .- 1539-2031. ; 39:1, s. 80-81 Tidskriftsartikel (refereegranskat)
24.	Marlid, Karl, et al. (författare) Antibiotic exposure in pregnancy and risk of coeliac disease in offspring : a cohort study 2014 Ingår i: BMC Gastroenterology. - London : BioMed Central. - 1471-230X. ; 14 Tidskriftsartikel (refereegranskat)abstract 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 child's 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 child's 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.
25.	Milletich, Patricia L., et al. (författare) Gut microbiome markers in subgroups of HLA class II genotyped infants signal future celiac disease in the general population : ABIS study 2022 Ingår i: Frontiers in Cellular and Infection Microbiology. - : Frontiers Media S.A.. - 2235-2988. ; 12 Tidskriftsartikel (refereegranskat)abstract Although gut microbiome dysbiosis has been illustrated in celiac disease (CD), there are disagreements about what constitutes these microbial signatures and the timeline by which they precede diagnosis is largely unknown. The study of high-genetic-risk patients or those already with CD limits our knowledge of dysbiosis that may occur early in life in a generalized population. To explore early gut microbial imbalances correlated with future celiac disease (fCD), we analyzed the stool of 1478 infants aged one year, 26 of whom later acquired CD, with a mean age of diagnosis of 10.96 +/- 5.6 years. With a novel iterative control-matching algorithm using the prospective general population cohort, All Babies In Southeast Sweden, we found nine core microbes with prevalence differences and seven differentially abundant bacteria between fCD infants and controls. The differences were validated using 100 separate, iterative permutations of matched controls, which suggests the bacterial signatures are significant in fCD even when accounting for the inherent variability in a general population. This work is the first to our knowledge to demonstrate that gut microbial differences in prevalence and abundance exist in infants aged one year up to 19 years before a diagnosis of CD in a general population.
26.	Mollazadegan, Kaziwe, et al. (författare) A Population-Based Study of the Risk of Diabetic Retinopathy in Patients With Type 1 Diabetes and Celiac Disease 2013 Ingår i: Diabetes Care. - Alexandria, USA : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 36:2, s. 316-321 Tidskriftsartikel (refereegranskat)abstract OBJECTIVE Celiac disease (CD) is associated with type 1 diabetes (T1D). In the current study, we examined whether CD affects the risk of diabetic retinopathy (DRP) in patients with T1D.RESEARCH DESIGN AND METHODS This was a population-based cohort study. Through the Swedish National Patient Register, we identified 41,566 patients diagnosed with diabetes in 1964–2009 and who were ≤30 years of age at diagnosis. CD was defined as having villous atrophy (Marsh stage 3) according to small intestinal biopsies performed between 1969 and 2008, with biopsy reports obtained from Sweden’s 28 pathology departments. During follow-up, 947 T1D patients had a diagnosis of CD. We used Cox regression analysis with CD as a time-dependent covariate to estimate adjusted hazard ratios (aHRs) for DRP in patients with T1D and CD and compared them with patients with T1D but no CD.RESULTS Duration of CD correlated with the risk of DRP. When results were stratified by time since CD diagnosis, individuals with T1D and CD were at a lower risk of DRP in the first 5 years after CD diagnosis (aHR 0.57 [95% CI 0.36–0.91]), followed by a neutral risk in years 5 to <10 (1.03 [0.68–1.57]). With longer follow-up, coexisting CD was a risk factor for DRP (10 to <15 years of follow-up, aHR 2.83 [95% CI 1.95–4.11]; ≥15 years of follow-up, 3.01 [1.43–6.32]).CONCLUSIONS Having a diagnosis of CD for >10 years is a risk factor for the development of DRP in T1D. Long-standing CD in patients with T1D merits intense monitoring of DRP.
27.	Mollazadegan, K, et al. (författare) Long-term coeliac disease influences risk of death in patients with type 1 diabetes 2013 Ingår i: Journal of Internal Medicine. - : Wiley-Blackwell. - 0954-6820 .- 1365-2796. ; 274:3, s. 273-280 Tidskriftsartikel (refereegranskat)abstract Aim. The aim of this study was to examine mortality in patients with both type 1 diabetes (T1D) and coeliac disease (CD). less thanbrgreater than less thanbrgreater thanMethods. Between 1969 and 2008, we identified individuals with CD through biopsy reports from all pathology departments (n = 28) in Sweden. T1D was defined as a diagnosis of diabetes recorded in the Swedish National Patient Register between 1964 and 2009 in individuals aged andlt;= 30 years. During follow-up, we identified 960 patients with both T1D and CD. For each individual with T1D and CD, we selected up to five subjects with T1D alone (i.e. no CD), matched for sex, age and calendar period of diagnosis, as the reference group (n = 4608). Using a stratified Cox regression analysis with CD as a time-dependent covariate, we estimated the risk of death in patients with both T1D and CD compared with those with T1D alone. less thanbrgreater than less thanbrgreater thanResults. Stratifying for time since CD diagnosis, CD was not a risk factor for death in patients with T1D during the first 5 years after CD diagnosis [hazard ratio (HR) 0.87, 95% confidence interval (CI) 0.43-1.73], but thereafter the HR for mortality increased as a function of follow-up time (5 to andlt;10 years, HR 1.44, 95% CI 0.74-2.79; 10 to andlt;15 years, HR 1.88, 95% CI 0.81-4.36). Having a CD diagnosis for andgt;= 15 years was associated with a 2.80-fold increased risk of death in individuals with T1D (95% CI 1.28-6.12). less thanbrgreater than less thanbrgreater thanConclusion. A diagnosis of CD for andgt;= 15 years increases the risk of death in patients with T1D.
28.	Mollazadegan, Kaziwe, et al. (författare) Risk of renal disease in patients with both type 1 diabetes and coeliac disease 2014 Ingår i: Diabetologia. - : Springer. - 0012-186X .- 1432-0428. ; 57:7, s. 1339-1345 Tidskriftsartikel (refereegranskat)abstract 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.
29.	Saduaskaite-Kühne, Vaiva, 1970-, et al. (författare) Inheritance of MHC class II genes in lithuanian families with type 1 diabetes 2003 Ingår i: IMMUNOLOGY OF DIABETES II: PATHOGENESIS FROM MOUSE TO MAN. - : New York Academy of Sciences. - 1573314609 ; 1005, s. 295-300 Konferensbidrag (refereegranskat)abstract Type 1 diabetes mellitus (DM) is caused by genetic and environmental factors. Twice as many fathers as mothers of children with type 1 DM have the disease. The reason for the differences remains unclear. We looked at the transmission rates of diabetes-related alleles from parents to children with diabetes. All children with newly diagnosed type 1 DM from August 1, 1996 to August 1, 2000, aged 0 to 15 years, in Lithuania were invited to participate. Blood samples for full genetic analysis were available from 125 families. HLA DQA1, DQB1, and DRB1 typing was done on DNA extracted from peripheral blood, by polymerase chain reaction amplification, manual dot-blotting onto nylon membranes, synthetic sequence-specific oligonucleotide probe 3′-end labeling with 32P-dCTP, and hybridization, followed by stringency washes, autoradiography, and allele calling. Frequency of diabetes risk-related alleles DQB10302, DQA10201, DR4, and DR3 was less prevalent among Lithuanian than among Swedish children with type 1 DM. Transmission rates of DR4-DQB10302-DQA10301 and DR3-DQB10201-DQA10501 haplotypes from parents were higher than expected: χ2 (TDT) 30.56, p < 0.0001, and χ2 (TDT) 11.26, p= 0.0008, respectively. DQB10302 and DR4 were significantly more frequently transmitted from both parents, but DR3 was transmitted more frequently only from mothers. Any of these alleles had similar frequencies among female and male offspring. We conclude that, besides DR4-DQB10302-DQA10301 and DR3-DQB10201-DQA1*0501, there are other inherited alleles that determine risk for type 1 DM among children in Lithuania. Fathers might transfer other alleles of disease susceptibility in higher frequency or mothers might provide a protective environment during pregnancy, which results in higher risk to offspring of fathers than mothers to develop diabetes.
30.	Welander, Adina, et al. (författare) Breastfeeding duration and gluten introduction among mother with celiac disaese 2014 Ingår i: Journal of Pediatric Gastroenterology and Nutrition - JPGN. - : Lippincott Williams & Wilkins. - 0277-2116 .- 1536-4801. ; 59:1, s. 89-92 Tidskriftsartikel (refereegranskat)abstract Objectives: Both breast-feeding 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 study. Information regarding infant feeding was available in 9414 children. Twenty-two mothers had a history of biopsy-verified CD before delivery of a child in the study, and 9392 mothers had no diagnosis of CD before 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 whether mothers with CD were more likely to breast-feed their children at gluten introduction.Results: Some 63% of children were breast-fed 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), or 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 and 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 breast-feeding at the time of gluten introduction (odds ratio 1.4, 95% CI 0.4–4.7).Conclusions: Feeding patterns do not seem to vary between offspring and mothers with CD and those without.
31.	Welander, Adina, et al. (författare) Infectious Disease and Risk of Later Celiac Disease in Childhood 2010 Ingår i: PEDIATRICS. - : American Academy of Pediatrics (AAP). - 0031-4005 .- 1098-4275. ; 125:3, s. E530-E536 Tidskriftsartikel (refereegranskat)abstract OBJECTIVE: The goal was to examine whether parent-reported infection at the time of gluten introduction increases the risk of future celiac disease (CD). METHODS: Through the population-based All Infants in Southeast Sweden study, parents recorded data on feeding and infectious disease prospectively. Complete data on gluten introduction and breastfeeding duration were available for 9408 children. Those children had 42 826 parent-reported episodes of infectious disease in the first year of life (including 4003 episodes of gastroenteritis). We identified 44 children with biopsy-verified CD diagnosed after 1 year of age, and we used Cox regression to estimate the risk of future CD for children with infection at gluten introduction. RESULTS: Eighteen children with CD (40.9%) had an infection at the time of gluten introduction, compared with 2510 reference individuals (26.8%; P = .035). Few children had gastroenteritis at the time of gluten introduction (1 child with CD [2.3%] vs 166 reference individuals [1.8%]; P = .546). With adjustment for age at gluten introduction and breastfeeding duration, we found no association between a future diagnosis of CD and either any infection (adjusted hazard ratio: 1.8 [95% confidence interval: 0.9-3.6]) or gastroenteritis (adjusted hazard ratio: 2.6 [95% confidence interval: 0.2-30.8]) at the time of gluten introduction. We found no associations between breastfeeding duration, age at gluten introduction, and future CD. CONCLUSION: These results indicate that parent-reported infection at the time of gluten introduction is not a major risk factor for CD.
32.	Welander, Adina, et al. (författare) Infectious Disease at Gluten Introduction and Risk of Childhood Diabetes Mellitus 2014 Ingår i: Journal of Pediatrics. - : Elsevier BV. - 0022-3476 .- 1097-6833. ; 165:2, s. 326-U160 Tidskriftsartikel (refereegranskat)abstract 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.
33.	Ahmadi, Shilan Seyed, et al. (författare) Risk factors for nephropathy in persons with type 1 diabetes: a population-based study 2022 Ingår i: Acta Diabetologica. - : Springer Science and Business Media LLC. - 0940-5429 .- 1432-5233. ; 59, s. 761-772 Tidskriftsartikel (refereegranskat)abstract Aims Albuminuria is strongly associated with risk of renal dysfunction, cardiovascular disease and mortality. However, clinical guidelines diverge, and evidence is sparse on what risk factor levels regarding blood pressure, blood lipids and BMI are needed to prevent albuminuria in adolescents and young adults with type 1 diabetes. Methods A total of 9347 children and adults with type 1 diabetes [mean age 15.3 years and mean diabetes duration 1.4 years at start of follow-up] from The Swedish National Diabetes Registry were followed from first registration until end of 2017. Levels for risk factors for a risk increase in nephropathy were evaluated, and the gradient of risk per 1 SD (standard deviation) was estimated to compare the impact of each risk factor. Results During the follow-up period, 8610 (92.1%) remained normoalbuminuric, 737 (7.9%) individuals developed micro- or macroalbuminuria at any time period of whom 132 (17.9% of 737) individuals developed macroalbuminuria. Blood pressure >= 140/80 mmHg was associated with increased risk of albuminuria (p <= 0.0001), as were triglycerides >= 1.0 mmol/L (p = 0.039), total cholesterol >= 5.0 mmol/L (p = 0.0003), HDL < 1.0 mmol/L (p = 0.013), LDL 3.5- < 4.0 mmol/L (p = 0.020), and BMI >= 30 kg/m(2) (p = 0.033). HbA1c was the strongest risk factor for any albuminuria estimated by the measure gradient of risk per 1 SD, followed by diastolic blood pressure, triglycerides, systolic blood pressure, cholesterol and LDL. In patients with HbA1c > 65 mmol/mol (> 8.1%), blood pressure > 140/70 mmHg was associated with increased risk of albuminuria. Conclusions Preventing renal complications in adolescents and young adults with type 1 diabetes need avoidance at relatively high levels of blood pressure, blood lipids and BMI, whereas very tight control is not associated with further risk reduction. For patients with long-term poor glycaemic control, stricter blood pressure control is advocated.
34.	Ahrens, Angelica P., et al. (författare) Infant microbes and metabolites point to childhood neurodevelopmental disorders 2024 Ingår i: Cell. - : Cell Press. - 0092-8674 .- 1097-4172. ; 187:8, s. 1853-1873.e15 Tidskriftsartikel (refereegranskat)abstract This study has followed a birth cohort for over 20 years to find factors associated with neurodevelopmental disorder (ND) diagnosis. Detailed, early-life longitudinal questionnaires captured infection and antibiotic events, stress, prenatal factors, family history, and more. Biomarkers including cord serum metabolome and lipidome, human leukocyte antigen (HLA) genotype, infant microbiota, and stool metabolome were assessed. Among the 16,440 Swedish children followed across time, 1,197 developed an ND. Significant associations emerged for future ND diagnosis in general and for specific ND subtypes, spanning intellectual disability, speech disorder, attention-deficit/hyperactivity disorder, and autism. This investigation revealed microbiome connections to future diagnosis as well as early emerging mood and gastrointestinal problems. The findings suggest links to immunodysregulation and metabolism, compounded by stress, early-life infection, and antibiotics. The convergence of infant biomarkers and risk factors in this prospective, longitudinal study on a large-scale population establishes a foundation for early-life prediction and intervention in neurodevelopment.
35.	Alstrand, N, et al. (författare) Symptomatic neuropathy in type 1 diabetes is preceded by subclinical electrophysiological abnormalities - a prospective study in DIABETOLOGIA, vol 53, issue , pp 2010 Ingår i: DIABETOLOGIA. - : Springer Science Business Media. Konferensbidrag (refereegranskat)abstract n/a
36.	Andersson, Cecilia K, et al. (författare) Islet cell antibodies (ICA) identify autoimmunity in children with new onset diabetes mellitus negative for other islet cell antibodies. 2014 Ingår i: Pediatric Diabetes. - : Hindawi Limited. - 1399-543X .- 1399-5448. ; 15:5, s. 336-344 Tidskriftsartikel (refereegranskat)abstract 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).
37.	Andersson, C, et al. (författare) Triple specificity of ZnT8 autoantibodies in relation to HLA and other islet autoantibodies in childhood and adolescent type 1 diabetes 2013 Ingår i: Pediatric Diabetes. - : Wiley-Blackwell. - 1399-543X .- 1399-5448. ; 14:2, s. 97-105 Tidskriftsartikel (refereegranskat)abstract Andersson C, Vaziri-Sani F, Delli AJ, Lindblad B, Carlsson A, Forsander G, Ludvigsson J, Marcus C, Samuelsson U, Ivarsson SA, Lernmark A, Elding Larsson H, the BDD Study group. Triple specificity of ZnT8 autoantibodies in relation to HLA and other islet autoantibodies in childhood and adolescent type 1 diabetes. Pediatric Diabetes 2013: 14: 97-105. Objective To establish the diagnostic sensitivity of and the relationships between autoantibodies to all three Zinc transporter 8 (Zinc transporter 8 autoantibody to either one, two, or all three amino acid variants at position 325, ZnT8A) variants to human leukocyte antigen (HLA)-DQ and to autoantibodies to glutamic acid decarboxylase (GADA), insulinoma-associated protein 2 (IA-2A), and insulin (IAA). Methods We analyzed 3165 patients with type 1 diabetes (T1D) in the Better Diabetes Diagnosis study for HLA-DQ genotypes and all six autoantibodies (ZnT8RA, arginine 325 Zinc transporter 8 autoantibody; ZnT8WA, tryptophan 325 Zinc transporter 8 autoantibody; ZnT8QA, glutamine 325 Zinc transporter 8 autoantibody; GADA, IA-2A, and IAA). Results ZnT8A was found in 65% of the patients and as many as 108 of 3165 (3.4%) had 13 ZnT8A alone. None had ZnT8QA alone. Together with GADA (56%), IA-2A (73%), and IAA (33%), 93% of the T1D patients were autoantibody positive. All three ZnT8A were less frequent in children below 2 yr of age (pandlt;0.0001). All three ZnT8A were associated with DQA1-B1X-0604 (DQ6.4) and DQA1-B103-0302 (DQ8). ZnT8WA and ZnT8QA were negatively associated with DQA1-B1*05-02 (DQ2). Conclusions Analysis of ZnT8A increased the diagnostic sensitivity of islet autoantibodies for T1D as only 7% remained islet autoantibody negative. The association between DQ6.4 and all three ZnT8A may be related to ZnT8 antigen presentation by the DQ6.4 heterodimer.
38.	Andersson White, Pär, et al. (författare) Household income and maternal education in early childhood and risk of overweight and obesity in late childhood : Findings from seven birth cohort studies in six high-income countries 2022 Ingår i: International Journal of Obesity. - : Springer Nature. - 0307-0565 .- 1476-5497. ; 46, s. 1703-1711 Tidskriftsartikel (refereegranskat)abstract Background/objectives This study analysed the relationship between early childhood socioeconomic status (SES) measured by maternal education and household income and the subsequent development of childhood overweight and obesity. Subjects/methods Data from seven population-representative prospective child cohorts in six high-income countries: United Kingdom, Australia, the Netherlands, Canada (one national cohort and one from the province of Quebec), USA, Sweden. Children were included at birth or within the first 2 years of life. Pooled estimates relate to a total of N = 26,565 included children. Overweight and obesity were defined using International Obesity Task Force (IOTF) cut-offs and measured in late childhood (8-11 years). Risk ratios (RRs) and pooled risk estimates were adjusted for potential confounders (maternal age, ethnicity, child sex). Slope Indexes of Inequality (SII) were estimated to quantify absolute inequality for maternal education and household income. Results Prevalence ranged from 15.0% overweight and 2.4% obese in the Swedish cohort to 37.6% overweight and 15.8% obese in the US cohort. Overall, across cohorts, social gradients were observed for risk of obesity for both low maternal education (pooled RR: 2.99, 95% CI: 2.07, 4.31) and low household income (pooled RR: 2.69, 95% CI: 1.68, 4.30); between-cohort heterogeneity ranged from negligible to moderate (p: 0.300 to < 0.001). The association between RRs of obesity by income was lowest in Sweden than in other cohorts. Conclusions There was a social gradient by maternal education on the risk of childhood obesity in all included cohorts. The SES associations measured by income were more heterogeneous and differed between Sweden versus the other national cohorts; these findings may be attributable to policy differences, including preschool policies, maternity leave, a ban on advertising to children, and universal free school meals.
39.	Andersson White, Pär, et al. (författare) Inequalities in cardiovascular risks among Swedish adolescents (ABIS): a prospective cohort study 2020 Ingår i: BMJ Open. - : BMJ PUBLISHING GROUP. - 2044-6055. ; 10:2 Tidskriftsartikel (refereegranskat)abstract Objectives To investigate if socioeconomic status (SES) is predictive of cardiovascular risk factors among Swedish adolescents. Identify the most important SES variable for the development of each cardiovascular risk factor. Investigate at what age SES inequality in overweight and obesity occurs. Design Longitudinal follow-up of a prospective birth cohort. Setting All Babies in Southeast Sweden (ABIS) study includes data from children born between October 1997 and October 1999 in five counties of south east Sweden. Participants A regional ABIS-study subsample from three major cities of the region n=298 adolescents aged 16-18 years, and prospective data from the whole ABIS cohort for overweight and obesity status at the ages 2, 5, 8 and 12 years (n=2998-7925). Outcome measures Blood pressure above the hypertension limit, overweight/obesity according to the International Obesity Task Force definition, low high-density lipoproteins (HDL) or borderline-high low-density lipoproteins according to National Cholesterol Education Program expert panel on cholesterol levels in children. Results For three out of four cardiovascular risk outcomes (elevated blood pressure, low HDL and overweight/obesity), there were increased risk in one or more of the low SES groups (p<0.05). The best predictor was parental occupational class (Swedish socioeconomic classification index) for elevated blood pressure (area under the receiver operating characteristic (ROC) curve 0.623), maternal educational level for overweight (area under the ROC curve 0.641) and blue-collar city of residence for low HDL (area under the ROC curve 0.641). SES-related differences in overweight/obesity were found at age 2, 5 and 12 and for obesity at age 2, 5, 8 and 12 years (all p<0.05). Conclusions Even in a welfare state like Sweden, SES inequalities in cardiovascular risks are evident already in childhood and adolescence. Intervention programmes to reduce cardiovascular risk based on social inequality should start early in life.
40.	Andersson White, Pär, et al. (författare) Low maternal education increases the risk of Type 1 Diabetes, but not other autoimmune diseases: a mediating role of childhood BMI and exposure to serious life events 2023 Ingår i: Scientific Reports. - : NATURE PORTFOLIO. - 2045-2322. ; 13:1 Tidskriftsartikel (refereegranskat)abstract The objective of this paper was to investigate if socioeconomic status (SES), measured by maternal education and household income, influenced the risk of developing autoimmune disease (Type 1 Diabetes, Celiac disease, Juvenile Idiopathic Arthritis, Crohns disease, Ulcerative colitis, and autoimmune thyroid disease), or age at diagnosis, and to analyse pathways between SES and autoimmune disease. We used data from the All Babies in Southeast Sweden (ABIS) study, a population-based prospective birth cohort, which included children born 1997-1999. Diagnoses of autoimmune disease was collected from the Swedish National Patient Register Dec 2020. In 16,365 individuals, low maternal education, but not household income, was associated with increased risk of Type 1 Diabetes; middle education RR 1.54, 95% CI 1.06, 2.23; P 0.02, low education RR 1.81, 95% CI 1.04, 3.18; P 0.04. Maternal education and household income was not associated with any other autoimmune disease and did not influence the age at diagnosis. Part of the increased risk of Type 1 Diabetes by lower maternal education was mediated by the indirect pathway of higher BMI and higher risk of Serious Life Events (SLE) at 5 years of age. The risk of developing Type 1 Diabetes associated to low maternal education might be reduced by decreasing BMI and SLE during childhood.
41.	Andersson White, Pär, 1983- (författare) Social Inequalities in Child Health : Type 1 Diabetes, Obesity, Cardiovascular Risk Factors and the Role of Self-control 2024 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract The Swedish Commission on Health Inequality defined health inequality as systematic differences in health between groups in society with different social positions. All avoidable socioeconomic health inequalities are unfair, and as stated by WHO's Commission on the Social Determinants of Health, we have a moral obligation to try to reduce them. "Putting these inequities right is a matter of social justice. Reducing health inequities is, for the Commission on Social Determinants of Health, an ethical imperative." This ethical imperative is especially apparent regarding the health of children and adolescents. Children’s right to the highest attainable standard of health is also enshrined in Article 24 of the Convention on the Rights of the Child. To reach the goal of a reduction of health inequalities, research is necessary to describe the social gradients of health. Research is also needed to better understand why these gradients occur. A better understanding and knowledge about health inequalities can lead to policies that reduce these inequalities and ensure children’s right to health.This thesis investigates social inequality in child health using data from a Swedish population-based prospective birth cohort, the All Babies in Southeast Sweden (ABIS) cohort. Social inequality in obesity in the ABIS cohort is also compared with other birth cohorts participating in the Elucidating Pathways to Child Health Inequality (EPOCH) collaboration which includes cohorts from six high-income countries; Sweden, the Netherlands, Canada (one national and one cohort from Quebec), UK, Australia, and USA.In Paper 1 we show that health inequalities in overweight and obesity are detectable already at two years of age and that these inequalities increase during childhood. In adolescents, low socioeconomic status increases the risk of becoming overweight and the risk of components of the metabolic syndrome, including high blood pressure and dyslipidemia (low high-density cholesterol).The level of inequality in obesity in the Swedish ABIS cohort was lower than in the other participating countries in the EPOCH collaboration (Paper 2). Inequality was lower in absolute and relative terms when SES was measured by household income. Inequality was also lower in absolute, but not relative, terms when SES was measured by maternal education. This finding indicates that some of the policies implemented in Sweden may attenuate social inequalities in obesity in children. Examples of such policies with evidence for reducing social inequality in obesity implemented in Sweden include universal preschools and free school meals.This thesis also investigates health inequalities in autoimmune disease (Paper 3). In this study, we found that low socioeconomic status increased the risk of Type 1 Diabetes but not the other autoimmune diseases investigated. Path analysis indicated that part of the increased risk in children with low SES of Type 1 Diabetes might be mediated by a higher body mass index and an elevated risk of serious life events.In the final paper, this thesis tests the hypothesis that differences in maternal and child self-control mediate social inequalities in obesity. Two measures of self-control were used; for mothers, the self-control variable was based on behaviors related to self-control (smoking during pregnancy, smoking during the child’s first year of life, breastfeeding duration, and participating in the ABIS study with biological samples). For the children, the self-control variable was based on questionnaire data on the impulsivity subscale of the Strengths and Difficulties Questionnaire (SDQ). The results showed that the two measures of self-control mediated 87.5 % of the increased risk of obesity at age 19 years in children with low maternal education and 93 % of the risk if maternal BMI was also included in the selfcontrol variable.In the discussion part of this thesis, the conclusions that can be deduced from understanding the mechanisms of social inequality in child health are discussed. A theory with a central role of self-control for health inequality predicts that social inequality will increase without interventions. In an environment with rising numbers of stimuli of the human reward system, stimuli that also have negative long-term consequences (socalled Limbic traps), child and adolescent health, in general, will decrease. Because of the mechanisms related to SES and self-control, children with low SES will be disproportionally affected. The result of this development will be increasing levels of social inequalities in child health.The discussion also includes implications for policies that may improve health and reduce inequalities. These policies should reduce the exposure of children and adolescents to harmful behaviors/limbic traps. Examples of policies that have this effect include universal preschools for all children, free healthy meals in preschools and schools, increased after-school activities for all children, and longer school days for adolescents with increased hours for physical activity, music, and art. Mobile phones and social media restrictions in schools and policies to reduce use at home should also be implemented. Finally, policies should be implemented to reduce residential and school segregation in the community.
42.	Antepohl, Wolfram, 1968-, et al. (författare) A follow-up of medical graduates of a problem-based learning curriculum 2003 Ingår i: Medical Education. - : Wiley. - 0308-0110 .- 1365-2923. ; 37:2, s. 155-162 Tidskriftsartikel (refereegranskat)abstract Introduction: There is little information available on the effects of problem-based undergraduate curricula on doctors and their performances after graduation. Therefore, we conducted a questionnaire study of all graduates of the new medical programme at the Faculty of Health Sciences, Link÷ping University. Methods: All 446 medical students who had graduated from the new programme were asked to fill in a questionnaire about selected activities during their studies and their careers after graduation. They were also asked to evaluate the quality of their undergraduate education retrospectively. Statistical analysis was performed using descriptive, multivariate and bivariate approaches. Results: A total of 77% of the graduates responded. They showed a high degree of overall contentment with their undergraduate education and felt well prepared for professional life during their preregistration period and specialist education (mean = 4.0 on a 6-point Likert scale ranging from 0 to 5). They felt especially well prepared in terms of skills for communication with patients, collaboration with other health professionals and development of critical thinking/scientific attitudes. The students' age at the beginning of their studies correlated positively with their contentment as graduates, especially in terms of preparation for patient communication and collaboration with other health professionals. No differences between students originally admitted via a local admission procedure and those admitted via a national procedure were detected concerning retrospective evaluation of undergraduate medical education. Conclusion: Graduates of the new curriculum showed a high degree of satisfaction with their undergraduate education and its preparation of them for medical practice. Specifically, they were very content with the particular emphases of the new curriculum.
43.	Arnqvist, Hans, et al. (författare) Early increase in HbA1c trajectory predicts development of severe microangiopathy in patients with type 1 diabetes: the VISS study 2024 Ingår i: BMJ Open Diabetes Research & Care. - : BMJ PUBLISHING GROUP. - 2052-4897. ; 12:3 Tidskriftsartikel (refereegranskat)abstract Introduction To study the HbA1c trajectory from the time of diagnosis to examine if patients at the greatest risk for severe microangiopathy can be identified early allowing clinicians to intervene as soon as possible to avoid complications. Research design and methods In a population-based observational study, 447 patients diagnosed with type 1 diabetes before 35 years of age, 1983-1987, were followed from diagnosis until 2019. Mean HbA1c was calculated each year for each patient. Severe diabetic microangiopathy was defined as proliferative diabetic retinopathy (PDR) or macroalbuminuria (nephropathy). Results After 32 years, 27% had developed PDR and 8% macroalbuminuria. Patients with weighted HbA1c (wHbA1c); <57 mmol/mol; <7.4% did not develop PDR or macroalbuminuria. The HbA1c trajectories for patients developing PDR and macroalbuminuria follow separate courses early on and stay separated for 32 years during the follow-up. Patients without severe complications show an initial dip, after which HbA1c slowly increases. HbA1c in patients with severe complications directly rises to a high level within a few years. Mean HbA1c calculated for the period 5-8 years after diabetes onset strongly predicts the development of severe complications. Females with childhood-onset diabetes exhibit a high peak in HbA1c during adolescence associated with higher wHbA1c and higher prevalence of PDR. Conclusions The HbA1c trajectory from diabetes onset shows that mean HbA1c for the period 5-8 years after diagnosis strongly predicts severe microangiopathy. Females with childhood-onset diabetes exhibit a high peak in HbA1c during adolescence associated with higher wHbA1c and a higher prevalence of PDR.
44.	Arnqvist, Hans, et al. (författare) Impact of HbA(1c) Followed 32 Years From Diagnosis of Type 1 Diabetes on Development of Severe Retinopathy and Nephropathy: The VISS Study 2022 Ingår i: Diabetes Care. - : AMER DIABETES ASSOC. - 0149-5992 .- 1935-5548. ; 45:11, s. 2675-2682 Tidskriftsartikel (refereegranskat)abstract OBJECTIVE To evaluate HbA(1c) followed from diagnosis, as a predictor of severe microvascular complications (i.e., proliferative diabetic retinopathy [PDR] and nephropathy [macroalbuminuria]). RESEARCH DESIGN AND METHODS In a population-based observational study, 447 patients diagnosed with type 1 diabetes before 35 years of age from 1983 to 1987 in southeast Sweden were followed from diagnosis until 2019. Long-term weighted mean HbA(1c) (wHbA(1c)) was calculated by integrating the area under all HbA(1c) values. Complications were analyzed in relation to wHbA(1c) categorized into five levels. RESULTS After 32 years, 9% had no retinopathy, 64% non-PDR, and 27% PDR, and 83% had no microalbuminuria, 9% microalbuminuria, and 8% macroalbuminuria. Patients with near-normal wHbA(1c) did not develop PDR or macroalbuminuria. The lowest wHbA(1c) values associated with development of PDR and nephropathy (macroalbuminuria) were 7.3% (56 mmol/mol) and 8.1% (65 mmol/mol), respectively. The prevalence of PDR and macroalbuminuria increased with increasing wHbA(1c), being 74% and 44% in the highest category, wHbA(1c) >9.5% (>80 mmol/mol). In comparison with the follow-up done after 20-24 years duration, the prevalence of PDR had increased from 14 to 27% and macroalbuminuria from 4 to 8%, and both appeared at lower wHbA(1c) values. CONCLUSIONS wHbA(1c) followed from diagnosis is a very strong biomarker for PDR and nephropathy, the prevalence of both still increasing 32 years after diagnosis. To avoid PDR and macroalbuminuria in patients with type 1 diabetes, an HbA(1c) <7.0% (53 mmol/mol) and as normal as possible should be recommended when achievable without severe hypoglycemia and with good quality of life.
45.	Asad, Samina, et al. (författare) HTR1A a Novel Type 1 Diabetes Susceptibility Gene on Chromosome 5p13-q13 2012 Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 7:5 Tidskriftsartikel (refereegranskat)abstract Background: We have previously performed a genome-wide linkage study in Scandinavian Type 1 diabetes (T1D) families. In the Swedish families, we detected suggestive linkage (LOD less than= 2.2) to the chromosome 5p13-q13 region. The aim of our study was to investigate the linked region in search for possible T1D susceptibility genes. Methodology/Principal Findings: Microsatellites were genotyped in the Scandinavian families to fine-map the previously linked region. Further, SNPs were genotyped in Swedish and Danish families as well as Swedish sporadic cases. In the Swedish families we detected genome-wide significant linkage to the 5-hydroxytryptamine receptor 1A (HTR1A) gene (LOD 3.98, pless than9.8x10(-6)). Markers tagging two separate genes; the ring finger protein 180 (RNF180) and HTR1A showed association to T1D in the Swedish and Danish families (pless than0.002, pless than0.001 respectively). The association was not confirmed in sporadic cases. Conditional analysis indicates that the primary association was to HTR1A. Quantitative PCR show that transcripts of both HTR1A and RNF180 are present in human islets of Langerhans. Moreover, immunohistochemical analysis confirmed the presence of the 5-HTR1A protein in isolated human islets of Langerhans as well as in sections of human pancreas. Conclusions: We have identified and confirmed the association of both HTR1A and RFN180, two genes in high linkage disequilibrium (LD) to T1D in two separate family materials. As both HTR1A and RFN180 were expressed at the mRNA level and HTR1A as protein in human islets of Langerhans, we suggest that HTR1A may affect T1D susceptibility by modulating the initial autoimmune attack or either islet regeneration, insulin release, or both.
46.	Axelsson, Stina, et al. (författare) Cellular and Humoral Immune responses in Type 1 Diabetic patients participating in a Phase III GAD-alum Intervention Trial 2013 Ingår i: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 36:11, s. 3418-3424 Tidskriftsartikel (refereegranskat)abstract OBJECTIVEGAD formulated in aluminum hydroxide (GAD-alum) has previously been shown to induce preservation of residual insulin secretion in recent-onset type 1 diabetes, but recent phase II and III GAD-alum trials failed to reach primary outcomes. The European phase III study was therefore closed after 15 months, and only a minority of patients completed the 30 months of follow-up.RESEARCH DESIGN AND METHODSThis study aimed to characterize cellular and humoral responses in the Swedish patients (n = 148) participating in the phase III trial, receiving four (4D) or two (2D) GAD-alum doses or placebo. Serum GAD(65) antibody (GADA) levels, GADA IgG1-4 subclass distribution, cytokine secretion, and proliferative responses in peripheral blood mononuclear cells (PBMCs) were analyzed.RESULTSThe GAD(65)-induced cytokine profile tended to switch toward a predominant Th2-associated profile over time both in the 2D and 4D group. The groups also displayed increased GADA levels and PBMC proliferation compared with placebo, whereas GADA IgG subclass distribution changed in 4D patients.CONCLUSIONSBoth 2D and 4D patients displayed GAD(65)-specifc cellular and humoral effects after GAD-alum treatment, but at different time points and magnitudes. No specific immune markers could be associated with treatment efficacy.
47.	Axelsson, Stina, et al. (författare) Cryopreserved peripheral blood mononuclear cells are suitable for the assessment of immunological markers in type 1 diabetic children 2008 Ingår i: Cryobiology. - : Elsevier BV. - 0011-2240 .- 1090-2392. ; 57:3, s. 201-208 Tidskriftsartikel (refereegranskat)abstract Cryopreserved peripheral blood mononuclear cells (PBMC) are commonly used when assessing immune responses in clinical trials, both for practical reasons and to minimize interassay variation, as samples are often collected and studied over time. This study investigated the effect of cryopreservation on cytokine and chemokine secretion, and on expression of regulatory T-cell associated markers, in samples from children with type 1 diabetes. PBMC were cultured before and after cryopreservation either with GAD(65) or PHA. Secretion of cytokines (IL-5, -6, -10, -12, -13 -17, IFN-gamma and TNF-alpha) and chemokines (IP-10, MCP-1, MIP-1 alpha, MIP-1 beta and RANTES) was analysed in cell supernatants using multiplex fluorochrome technique (Luminex). Expression of FOXP3 and TGF-beta mRNA was detected by multiplex real-time RT-PCR. Increased spontaneous secretion of IL-6, -10, -12, -13, IFN-gamma and MCP-1, and mRNA expression of FOXP3 and TGF-beta, was detected after cryopreservation. Stimulation with GAD65 induced higher levels of IL-6, IFN-gamma, TNF-alpha and MIP-1 alpha, whereas lower secretion was found for IL-10 and IL-13 in cryopreserved PBMC. Stimulation with PHA induced lower secretion of IP-10, MCPA and RANTES and FOXP3 mRNA expression after cryopreservation. Thus, cryopreserved PBMC were suitable to assess the immunological markers included in this study, even though their expression could differ from freshly handled cells.
48.	Axelsson, Stina, et al. (författare) Decreased GAD(65) -specific Th1/Tc1 phenotype in children with Type 1 diabetes treated with GAD-alum. 2012 Ingår i: Diabetic Medicine. - : Wiley-Blackwell. - 0742-3071 .- 1464-5491. ; 29:10, s. 1272-1278 Tidskriftsartikel (refereegranskat)abstract Aim The balance between T helper cell subsets is an important regulator of the immune system and is often examined after immune therapies. We aimed to study the immunomodulatory effect of glutamic acid decarboxylase (GAD) 65 formulated with aluminium hydroxide (GAD-alum) in children with Type 1 diabetes, focusing on chemokines and their receptors. Methods Blood samples were collected from 70 children with Type 1 diabetes included in a phase II clinical trial with GAD-alum. Expression of CC chemokine receptor 5 (CCR5) and CCR4 was analysed on CD4+ and CD8+ lymphocytes after in vitro stimulation with GAD(65) using flow cytometry, and secretion of the chemokines CCL2, CCL3 and CCL4 was detected in peripheral blood mononuclear cell supernatants with Luminex. Results Expression of Th1-associated CCR5 was down-regulated following antigen challenge, together with an increased CCR4/CCR5 ratio and CCL2 secretion in GAD-alum-treated patients, but not in the placebo group. Conclusion Our results suggest that GAD-alum treatment has induced a favourable immune modulation associated with decreased Th1/Tc1 phenotypes upon antigen re-challenge, which may be of importance for regulating GAD(65) immunity. © 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.
49.	Axelsson, Stina, et al. (författare) Early induction of GAD(65)-reactive Th2 response in type 1 diabetic children treated with alum-formulated GAD(65) 2010 Ingår i: Diabetes/Metabolism Research Reviews. - : John Wiley and Sons. - 1520-7552 .- 1520-7560. ; 26:7, s. 559-568 Tidskriftsartikel (refereegranskat)abstract Background We have previously shown that two injections of 20 mu g alum-formulated glutamic acid decarboxylase 65 (GAD(65)) (GAD-alum; Diamyd (R)) in children with recent-onset type 1 diabetes lead to preservation of residual insulin secretion. In vitro cytokine production at the 15 months follow-up indicated immunomodulation. In the present study, we took advantage of peripheral blood mononuclear cells, cryopreserved during early follow-ups, to investigate whether the immunomodulatory effect of GAD-alum was apparent earlier after treatment, preceding the changes previously reported at 15 months.Methods Peripheral blood mononuclear cells from 70 type 1 diabetic children, randomly assigned GAD-alum (n = 35) or placebo (n = 35), that had been frozen at baseline (n = 27) and after 1 (n = 58), 3 (n = 67) and 9 (n = 66) months, were stimulated in vitro with GAD(65), tyrosine phosphatase-like protein IA-2 peptide, insulin peptide, GAD-alum, alum formulation or phytohaemagglutinin. Interleukin (IL)-5, -6, -10, -12, -13, -17, tumour necrosis factor and interferon-gamma were measured in cell supernatants and serum samples using Luminex. Expression of FOXP3 and transforming growth factor-beta was determined by real-time reverse transcription polymerase chain reaction.Results Already 1 month after the first injection, GAD(65)-induced IL-5 and IL-13 together with FOXP3 were enhanced in GAD-alum-treated patients compared to those with placebo. The in vitro response at 3 and 9 months was characterized by a broader range of cytokines in the treated group. Notably, only the T-helper 2-associated cytokines IL-5 and IL-13 together with FOXP3 increased continuously over time.Conclusions Treatment with GAD-alum in type 1 diabetic children induced an early T-helper 2 immune enhanced response to GAD(65), followed by a wider spectrum of cytokines at 3 and 9 months. Copyright (C) 2010 John Wiley & Sons, Ltd.
50.	Axelsson, Stina, 1981- (författare) GAD65 An Immunomodulator in Type 1 Diabetes 2012 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract Type 1 diabetes (T1D) is caused by a deficiency of insulin as a result of an autoimmune destruction of the pancreatic ² -cells. A possibility to preserve remaining ² -cells in children with newly diagnosed T1D is of great importance since sustained ² -cell function is recognized to result in reduced end-organ complications. Glutamic acid decarboxylase 65 (GAD65) is one of the major antigens targeted by self-reactive T cells in T1D, and immunomodulation with GAD65 formulated in aluminum (GAD-alum) has been considered both in prevention and treatment of T1D. Results from a Phase II trial have shown clinical effect of subcutaneous injections with GAD-alum, this was unfortunately not fully confirmed in the following larger Phase III trial which therefore was closed after 15 months. The general aim of this thesis was to study the immunomodulatory effect of GAD-alum-treatment in children with T1D participating in the Phase II and Phase III trials. We hypothesized that treatment with GAD-alum contributes to the preservation of residual insulin secretion through deviation of the GAD65-specific immune response from a destructive to a protective process, accompanied by a shift from T helper (Th) 1 towards a predominant Th2 profile. In the Phase II trial, GAD-alum-treated patients responded with an early GAD65-specific Th2 skewed cytokine secretion, with highest IL-5 and IL-13 secretion in clinical responders. Also, the CCR4/CCR5 ratio indicating balance between Th2/Tc2 and Th1/Tc1 responses, increased in treated patients. The recall response to GAD65 was characterized by a wide range of cytokines, but the relative contribution of each cytokine suggests a shift towards a more pronounced Th2-associated profile over time. Induction of a CD4+ cell subset upon GAD65-stimulation 4 years after treatment, suggesting clonal expansion of the memory T-cell compartment upon antigen re-challenge, was seen in parallel to a persistent GAD65-specific cytokine response. Finally, even if the phase III trial failed to reach the primary endpoint at 15 months, a subgroup analysis showed that the treatment had an effect on preservation of residual insulin secretion, but the effect was not seen until after 30 months. Taken together, these results suggest that GAD-alum treatment might exert its effect through induction of an early Th2 skewed immune response which tends to deviate away from a destructive Th1/Tc1 response upon GAD65 re-challenge, and generation of GAD65-specific memory T cells that produce cytokines and exert effector responses which may be important for regulating GAD65 immunity. Continued research to better understand how immunomodulation with autoantigen modifies T-cell responses and also which patients are suitable for treatment, is crucial for optimizing future intervention trials using ² -cell antigens.

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