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  • 301.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    GAD-alum (Diamyd) - a new concept for preservation of residual insulin secretion2010In: EXPERT OPINION ON BIOLOGICAL THERAPY, ISSN 1471-2598, Vol. 10, no 5, p. 787-799Article in journal (Refereed)
    Abstract [en]

    Importance of the field: Type 1 diabetes is a common and very serious disease. There has been very active research going on for a long time aiming at preservation of the residual insulin secretion by some kind of intervention to stop the destructive autoimmune process. This review covers a new type of immune intervention using auto-antigen treatment. Areas covered in this review: Immune interventions in type 1 diabetes have been tried during the last 30 years, this review mentions some of them, but the main topic is the use of the auto-antigen glutamic acid decarboxylase ( GAD) to create tolerance to stop the autoimmune process. The clinical trials have been performed during the last 15 years and are all covered. What the reader will gain: This review will give the reader a picture of the research behind treatment with GAD as an immune intervention in type 1 diabetes. Take home message: The key finding so far is that treatment with Diamyd (R) has not only been shown to preserve residual beta cell function in type 1 diabetes, but this treatment may be the proof in humans of a new concept of treating and perhaps even preventing autoimmune diseases.

  • 302.
    Ludvigsson, Johnny
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Immune intervention at diagnosis - Should we treat children to preserve beta-cell function?2007In: Pediatric Diabetes, ISSN 1399-543X, E-ISSN 1399-5448, Vol. 8, no SUPPL. 6, p. 34-39Article in journal (Refereed)
    Abstract [en]

    Type 1 diabetes (T1D) is characterized by loss of beta-cell function. If beta-cell function can be preserved, it will lead to improved metabolic balance with improved quality of life and fewer acute and late complications, and if residual insulin secretion improves well enough, then that could lead to complete remission and even cure of the disease. Several efforts to save residual beta-cell function have been made for more than three decades without success. Proof of principle has been possible, and it seems clear that immune suppression or immune modulation, in fact, can stop the destructive process and thereby preserve beta-cell function. However, the effect seen in adult patients with T1D have been minimal or absent in diabetic children who seem to have another or at least more aggressive disease process. Furthermore, the immune interventions have had too serious and common adverse events in comparison to the scarce-positive effect. Recent more specific immune modulation with anti-CD3 monoclonal antibodies seems more encouraging with at least postponement of the C-peptide decline, but unfortunately still with common and quite threatening adverse effects. Even more promising are the autoantigen therapies, of which glutamic acid decarboxylase (GAD) vaccination has shown good results with impressive preservation of residual insulin secretion in 10- to 18-year-old type 1 diabetic patients with recent onset. In patients with short diabetes duration at intervention the effect was remarkable. Furthermore, these effects were achieved with no adverse events. Future studies will show whether the good effect seen so far can be confirmed. If so there is hope that GAD vaccination will cause remission and even cure and prevention of T1D will then no longer be just a dream. © 2007 The Authors Journal compilation.

  • 303.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Immune intervention in children with type 1 diabetes2010In: Current Diabetes Reports, ISSN 1534-4827, E-ISSN 1539-0829, Vol. 10, no 5, p. 370-379Article in journal (Refereed)
    Abstract [en]

    Not only T cells but also B cells play a role in the autoimmune process. Both monoclonal antiCD3 and antiCD20 antibodies seem efficacious. However, such treatments need to be refined to minimize adverse events. Use of autoantigens to create tolerance is a concept with great potential. GAD65 treatment has shown efficacy without adverse events thus far, and administration of the insulin B chain shows interesting immunologic effects. Other more or less speculative approaches to modulate the immune process need further studies with good design. Risks that are too serious cannot be motivated. In addition, as the beta cells may die even though the autoimmune process is stopped, protective measures may be valuable (eg, active insulin treatment, and perhaps interleukin-1 receptor antagonists to reduce the nonautoimmune inflammation). Combination of immune intervention, protection of the beta cells, and stimulation of regeneration may lead to a milder disease or even a cure in the future, and prevention is no longer unrealistic.

  • 304.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    In light of recent clinical trial results, what lies next for Type 1 diabetes vaccine research?2012In: Expert Review of Vaccines, ISSN 1476-0584, E-ISSN 1744-8395, Vol. 11, no 3, p. 263-265Article in journal (Other academic)
  • 305.
    Ludvigsson, Johnny
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Interns positive to currently used written tests2008In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 105, no 38, p. 2580-2581Article in journal (Refereed)
  • 306.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Is it time to challenge the established theories surrounding type 1 diabetes?2014In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 103, no 2, p. 120-123Article in journal (Refereed)
    Abstract [en]

    Type one diabetes (T1D) seems a well-defined disease, but its classification may be difficult. Evidence is weak that an autoimmune process with insulitis causes loss of the beta cells in all patients. Some scientists propose that it may be caused by a virus, increased hygiene or the early introduction of cows milk or gluten, while views about the nerve supply, vascular function and the beta cells own role tend to be disregarded. Immune interventions have had limited success. There are differences, but also similarities, between T1D and type 2 diabetes (T2D). ConclusionSeveral views on T1D have become so widely accepted that they may actually hamper progress into the true cause of this disease. Research on T1D needs to be carried out with an open mind, and clinicians might be wise to recommend a lifestyle that aims to decrease both the risk of T1D and T2D.

  • 307.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    »Läkare som uttalar sig offentligt får betänka sitt ansvar«: [Physicians who make public statements must consider their responsibility]2010In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 107, no 18, p. 1243-Article in journal (Refereed)
    Abstract [en]

    n/a

  • 308.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Novel therapies in the management of type I diabetes mellitus2012In: Panminerva Medica (Testo stampato), ISSN 0031-0808, E-ISSN 1827-1898, Vol. 54, no 4, p. 257-270Article in journal (Refereed)
    Abstract [en]

    Development of insulin pumps and glucose sensors together with sophisticated algoritms and connections leading to closed loop systems will probably soon improve and facilitate treatment for many patients with Type 1 diabetes (T1D). However, the burden for patients will not disappear completely, and such therapy will still require both competence and motivation of patients. Therefore the final goal should be either to cure the disease via replacement therapy (transplantions) or stop the destructive process, preserve residual insulin secretion or even improve via beta cell regeneration. This will give a milder disease, a more stable metabolism, simpler treatment and perhaps even cure. It is neither necessary nor even plausible that Type 1 diabetes has one single cause or pathogenesis. Infections may be one causal factor, and vaccinations will then turn the increasing incidence downwards. We will also soon know whether it is possible to prevent some cases of T1D by avoiding cows milk in the early nutrition. It is possible that probiotics can influence the gut flora so that the gut permeability is normlized and maturation of the immune system is improved which may also contribute to less incidence of Type 1 diabetes. However, for those who already have got the disease we need interventions to preserve exisiting beta cell function and facilitate regeneration of beta-cells. Broader immunosuppressive therapies have been disappointing. Phase III studies using monocloncal antiCD3 antibodies have recently failed, but one dose regimen showed promising effect in patients aged 8-20 years. Therefore furthers studies are needed. Autoantigen treatment is a promising concept, and has the great advantage of being easy, practical with no adverse events. Diapep277 has shown some positive results in adults with good C-peptide, and glutamic acid decarboxylase (GAD)-alum has given quite impressive results in children aged 10-20 years, even though the results from studies differ. It is time to start combination therapies where auto-antigen/s, alone or in combination, are used together with other agents such as Vitamin D and anti-inflammatory drugs. We need to learn how to treat subgroups of patients. Gradually a more individualized treatment may become successful.

  • 309.
    Ludvigsson, Johnny
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Prevention of adverse events in juvenile diabetes2004In: Minerva Pediatrica, ISSN 0026-4946, E-ISSN 1827-1715, Vol. 56, no 3, p. 277-290Article in journal (Refereed)
    Abstract [en]

    The most severe adverse event of juvenile diabetes is death. Still these days it happens that children with diabetes die from diabetes before having received any treatment at all, sometimes probably undiagnosed. We have to improve the awareness and knowledge, both in the general population and also among health care staff and physicians. Retarded growth and development was seen earlier, but is now rare. But long-term complications affecting primarily blood vessels and nerves are still a real threat and may develop already after a few years. Unless diabetes is well treated, the disease is as dangerous as ever before. We know that a good metabolic control prevents complications, but not how to reach such control in many patients. Severe hypoglycemia has been feared to limit our possibilities to reach good metabolic balance. However, near-normal HbA1c must not be accompanied by increasing incidence of severe hypoglycemia. Too many patients are never offered an insulin treatment as physiological as possible. Adequate use of basal and bolus insulin is a prerequisite. Continuous adjustments should be monitored on the basis of glucose profiles, but without effective education and psychosocial support the treatment tends to fail. Intense treatment of diabetes may become a heavy burden, an "adverse event" in itself, for the patient and the parents of a diabetic child. Psychosocial support is often needed. Realistic information already from the onset of the disease is important, together with optimism, encouragement and not only criticism. Short-term goals and realistic agreements may help the patient to accept the disease. Independence and capacity to manage the treatment successfully contribute to a good metabolic control and also improves quality of life. Children with diabetes cannot expect a "normal" life, but they should be able to expect a long, active, exciting and happy life.

  • 310.
    Ludvigsson, Johnny
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Primary prevention of type 1A diabetes: are we there yet?2007In: Pediatric Diabetes, ISSN 1399-543X, E-ISSN 1399-5448, Vol. 8, no 3, p. 115-116Article in journal (Other academic)
  • 311.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    The latest pharmacotherapy options for type 1 diabetes2014In: Expert Opinion on Pharmacotherapy, ISSN 1465-6566, E-ISSN 1744-7666, Vol. 15, no 1, p. 37-49Article, review/survey (Refereed)
    Abstract [en]

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

  • 312.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    The role of immunomodulation therapy in autoimmune diabetes2009In: Journal of Diabetes Science and Technology, E-ISSN 1932-2968, Vol. 3, no 2, p. 320-330Article, review/survey (Refereed)
    Abstract [en]

    Type 1 diabetes (T1DM) is characterized by loss of virtually all endogenous insulin secretion. If residual insulin secretion is preserved, this will lead to improved metabolic balance, less acute and late complications, improved quality of life, and, in case of pronounced improvement of residual insulin secretion, complete remission and even cure of the disease. Immune suppression or immune modulation have been demonstrated as a proof of principle to stop/decrease the destructive process and thereby preserve beta-cell function. Several methods to save residual beta-cell function have been tried for more than three decades with little or no evidence of efficacy. Positive effects have been seen mainly in adult patients but have been minimal or absent in children with diabetes. Furthermore, the safety of these immune interventions and/or their benefit to risk relationships have not been found to justify clinical use. More specific immune modulation with anti-CD3 monoclonal antibodies has resulted in more encouraging postponement of C-peptide decline, but with frequent and serious adverse effects. Still more promising are the autoantigen therapies, of which glutamic acid decarboxylase (GAD) vaccination has shown significant preservation of residual insulin secretion in 10-18-year-old type 1 diabetes patients with recent onset. Efficacy was most impressive in the subgroup of patients with diabetes of short duration (less than3 months). The treatment was simple, well tolerated, and showed no treatment-related adverse events. If these results can be confirmed, there is a realistic hope that GAD vaccination, perhaps in combination with vaccinations with other autoantigens and/or other therapies, will result in remission for some patients. The prospects of cure and prevention of T1DM will become less remote.

  • 313.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Therapy with GAD in diabetes2009In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 25, no 4, p. 307-315Article, review/survey (Refereed)
    Abstract [en]

    The enzyme glutamic acid decarboxylase (GAD) is of great importance for the neurotransmission in the central nervous system, and therefore of interest for treatment of pain and neurological disease. However, it is also released in pancreas although its role is not quite clear. GAD is a major auto-antigen in the process leading to type 1 diabetes with both a clear cell-mediated immune response to GAD and auto-antibodies to GAD (GADA), which call be used as a predictor of diabetes. Administration of the isoform GAD65 can prevent autoimmune destruction of pancreatic beta cells in non-obese diabetic (NOD) mice and the subsequent need for exogenous insulin replacement. In Phase I and II studies an alum-formulated vaccine (Diamyd) has shown to be safe, and in a dose-finding study in Latent Autoimmune Diabetes in Adults (LADA) patients 20-mu g was given subcutaneously one month apart indicating preservation of residual insulin secretion. A double-blind randomized Phase II trial in 70 patients (10-18 years old) with recent-onset type 1 diabetes showed significant preservation of residual insulin secretion and a GAD-specific immune response, both humoral and cell-mediated, but no treatment-related adverse events. With this promising background further studies are on their way, both intervention in newly diagnosed type 1 diabetic patients, and trials to prevent the disease.

  • 314.
    Ludvigsson, Johnny
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Varför blir diabetes bland barn allt vanligare?2005In: Incitament, ISSN 1103-503X, Vol. 7, p. 470-472Article in journal (Other (popular science, discussion, etc.))
  • 315.
    Ludvigsson, Johnny
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Why diabetes incidence inereases- A unifying theory2006In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1079, p. 374-382Article in journal (Refereed)
    Abstract [en]

    There is a wide spectrum within the diabetes syndrome. Type I diabetes may have a slow progression with good residual insulin secretion and without autoantibodies, while phenotypic type 2 diabetes may have autoantibodies. A single patient may have traits of both types of diabetes. Their incidence increases in parallel. The etiology is mainly unknown, but environmental factors play an important role in genetically predisposed individuals. The search for just one single cause of manifest diabetes may be confusing. Different mechanism may be important in different parts of the world. Furthermore, certain mechanisms may lead to islet inflammation while other/additional mechanisms may increase insulin demand and cause insulin deficiency with manifestation of clinical diabetes. Several hypothesis of etiology may fit different parts of the disease process. Thus, increased hygiene may contribute to an imbalance of the immune system, facilitating autoimmune reactions when virus infections, or proteins like cow's milk or gluten, provoke. Increased insulin demand because of rapid growth, or insulin resistance caused by stress, infections, puberty, etc., lead to beta cell stress, antigen presentation and may cause both an autoimmune reaction in genetically predisposed individuals, and insulin deficiency leading to manifest diabetes in individuals who have lost beta cell function. Vitamins may modulate the immune process, but we know too little to give vitamin substitution. However, we do know that low physical exercise, obesity, and stress, increases insulin demand resulting in insulin deficiency. Now we can therefore intervene to prevent the diabetic syndrome.

  • 316.
    Ludvigsson, Johnny
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Är HbA1c 40 mmol/mol tecken på god diabetesvård?: [Is HbA1c 40 mmol/mol a sign of good diabetes care?]2013In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 110, no 19-20, p. 928-929Article in journal (Other academic)
    Abstract [sv]

    För att motverka en överambitiös strävan bland en del patienter/patientföräldrar och diabetesteam att uppnå så lågt HbA1c som möjligt bör kvalitetsregister inte redovisa klinikers medel-/median-HbA utan i stället andelen patienter med för högt, och möjligen även för lågt, HbA1c.

  • 317.
    Ludvigsson, Johnny
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Bolli, GB
    Univ Perugia, Dept Internal Med, I-06126 Perugia, Italy Linkoping Univ, Div Pediat, Dept Hlth & Environm, S-58183 Linkoping, Sweden.
    Intensive insulin treatment in diabetic children2001In: Diabetes, Nutrition and Metabolism. Clinical and Experimental, ISSN 0394-3402, E-ISSN 1720-8343, Vol. 14, no 5, p. 292-304Article, review/survey (Refereed)
    Abstract [en]

    Intensification of insulin therapy which maintains long-term near-normoglycaemia (HbA(1c)<7.0%) strongly protects against onset and/or progression of diabetic microangiopathy in Type 1 diabetes mellitus of adults. Similar intensification of insulin therapy is needed in diabetic children as well, in order to prevent complications a few years after diabetes onset, ie very often in young age. Provided adequate psychosocial support and education are available, children should be treated with multiple daily injections of insulin or, when necessary, with continuous subcutaneous insulin infusion, along with blood glucose monitoring. Insulin regimens may differ from child to child and vary from day to day in the same child, depending on lifestyle and considering all the available insulin preparations. These include the short-acting insulin (both human regular and short-acting insulin analogues), the intermediate-acting insulin (NPH and Lente), as well as the new long-acting insulin analogue glargine. The latter seems a promising candidate to substitute of basal insulin. The concern that intensified insulin therapy increases the risk of hypoglycaemia, as indicated by the Diabetes Control and Complications Trial (DCCT), is no longer tenable. On the contrary, a physiological, flexible insulin regimen better than a fixed insulin regimen, usually the twice daily split-mixed regimen, protects against the risk of hypoglycaemia in relation to food ingestion, physical exercise and sleep. Thus, appropriate education should be delivered at diabetes onset to the child and parents in order to start the strategy of intensified insulin therapy as early as possible. (C) 2001, Editrice Kurtis.

  • 318.
    Ludvigsson, Johnny
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Carlsson, A
    University of Lund Hospital.
    Forsander, G
    Queen Silvia Childrens Hospital.
    Ivarsson, S
    University Hospital MAS.
    Kockume, I
    Karolinska Institute.
    Lernmark, A
    Lund University.
    Lindblad, B
    Queen Silvia Childrens Hospital.
    Marcus, C
    Karolinska University.
    Samuelsson, Ulf
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    C-peptide in the classification of diabetes in children and adolescents2012In: Pediatric Diabetes, ISSN 1399-543X, E-ISSN 1399-5448, Vol. 13, no 1, p. 45-50Article in journal (Refereed)
    Abstract [en]

    Aim: To report C-peptide results in newly diagnosed patients and the relation to clinical diagnosis of diabetes. less thanbrgreater than less thanbrgreater thanMethods: A nation-wide cohort, the Better Diabetes Diagnosis study was used to determine serum C-peptide at diagnosis in 2734 children and adolescents. Clinical data were collected at diagnosis and follow-up. C-peptide was determined in a validated and controlled time-resolved fluoroimmunoassay. less thanbrgreater than less thanbrgreater thanResults: The clinical classification of diabetes, before any information on human leukocyte antigen, islet autoantibodies, or C-peptide was received, was type 1 diabetes (T1D) in 93%, type 2 diabetes (T2D) in 1.9%, maturity onset diabetes of the young (MODY) in 0.8%, secondary diabetes (0.6%), while 3.3% could not be classified. In a random, non-fasting serum sample at diagnosis, 56% of the patients had a C-peptide value andgt; 0.2 nmol/L. Children classified as T2D had the highest mean C-peptide (1.83 + 1.23 nmol/L) followed by MODY (1.04 +/- 0.71 nmol/L) and T1D (0.28 +/- 0.25 nmol/L). Only 1/1037 children who had C-peptide andlt; 0.2 nmol/L at diagnosis was classified with a type of diabetes other than T1D. Predictive value of C-peptide andgt; 1.0 nmol/L for the classification of either T2D or MODY was 0.46 [confidence interval 0.37-0.58]. less thanbrgreater than less thanbrgreater thanConclusions: More than half of children with newly diagnosed diabetes have clinically important residual beta-cell function. As the clinical diagnosis is not always straightforward, a random C-peptide taken at diagnosis may help to classify diabetes. There is an obvious use for C-peptide determinations to evaluate beta-cell function in children with diabetes.

  • 319.
    Ludvigsson, Johnny
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Carlsson, Annelie
    University of Lund Hospital, Sweden .
    Deli, Ahmed
    Lund University, Sweden .
    Forsander, Gun
    Queen Silvia Childrens Hospital, Sweden .
    Ivarsson, Sten-A
    University Hospital MAS, Sweden .
    Kockum, Ingrid
    Karolinska Institute, Sweden .
    Lindblad, Bengt
    Queen Silvia Childrens Hospital, Sweden .
    Marcus, Claude
    Karolinska University Hospital, Sweden .
    Lernmark, Ake
    Lund University, Sweden .
    Samuelsson, Ulf
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Decline of C-peptide during the first year after diagnosis of Type 1 diabetes in children and adolescents2013In: Diabetes Research and Clinical Practice, ISSN 0168-8227, E-ISSN 1872-8227, Vol. 100, no 2, p. 203-209Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis: We studied the decline of C-peptide during the first year after diagnosis of Type 1 diabetes (T1D), and its relation to various factors. less thanbrgreater than less thanbrgreater thanMethods: 3824/4017 newly diagnosed patients (95%) were classified as T1D in a national study. In a non-selected subgroup of 1669 T1D patients we determined non-fasting C-peptide both at diagnosis and after 1 year, and analyzed decline in relation to clinical symptoms and signs, initial C-peptide and occurrence of auto-antibodies. less thanbrgreater than less thanbrgreater thanResults: Younger children lost more C-peptide (p andlt; 0.001) and the higher the C-peptide at diagnosis the larger the decline during the first year (p andlt; 0.0000). Patients with higher BMI had higher C-peptide at diagnosis but lost more (p andlt; 0.01), and those with lower HbA1c, without symptoms and signs at diagnosis, and with higher BMI, had higher C-peptide at diagnosis, but lost more during the first year (p andlt; 0.001). Finally, patients diagnosed during autumn had higher C-peptide at diagnosis, but lost more during the coming year (p andlt; 0.001). Occurrence of auto-antibodies did not correlate with C-peptide decline, except possibly for a more rapid loss in IAA-positive patients. less thanbrgreater than less thanbrgreater thanConclusions/interpretation: Even in a restricted geographical area and narrow age range (andlt; 18 years), the natural course of Type 1 diabetes is heterogeneous. This should be considered in clinical trials.

  • 320.
    Ludvigsson, Johnny
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Chéramy, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Axelsson, Stina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Pihl, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Åkerman, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Casas, Rosaura
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    GAD-treatment of children and adolescents with recent-onset Type 1 diabetes preserves residual insulin secretion after 30 months2014In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 30, no 5, p. 405-414Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: This study aimed to analyse data from two different studies (Phase II and Phase III) regarding the safety and efficacy of treatment with alum formulated glutamic acid decarboxylase GAD65 (GAD-alum), 30 months after administration to children and adolescents with Type 1 diabetes (T1D).

    METHODS: The Phase II trial was a double-blind, randomized placebo-controlled study, including 70 children and adolescents which were followed for 30 months. Participants received a subcutaneous injection of either 20 µg of GAD-alum or placebo at baseline and one month later. During a subsequent larger European Phase III trial including three treatment arms, participants received two or four subcutaneous injections of either 20 µg of GAD-alum and/or placebo at baseline, 1, 3 and 9 months. The Phase III trial was prematurely interrupted at 15 months, but of the 148 Swedish patients, a majority completed the 21 months follow-up and 45 patients completed the trial at 30 months. Both studies included GADA-positive patients with fasting C-peptide ≥0.10 nmol/l. We have now combined the results of these two trials.

    RESULTS: There were no treatment related adverse events. In patients treated with 2 GAD-alum doses, stimulated C-peptide AUC had decreased significantly less (9 m: p < 0.037; 15 m p < 0.032; 21 m p < 0.003 and 30 m p < 0.004) and a larger proportion of these patients were also able to achieve a peak stimulated C-peptide >0.2 nmol/l (p < 0.05), as compared to placebo.

    CONCLUSION: Treatment with two doses of GAD-alum in children and adolescents with recent-onset T1D shows no adverse events and preserves residual insulin secretion. This article is protected by copyright. All rights reserved.

  • 321.
    Ludvigsson, Johnny
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Endit Group, European Nicotinamide Diabetes Intervention Trial
    European Nicotinamide Diabetes Intervention Trial (ENDIT): a randomised controlled trial of intervention before the onset of type 1 diabetes.2004In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 363, p. 925-931Article in journal (Refereed)
  • 322.
    Ludvigsson, Johnny F
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Montgomery, S.M.
    Clinical Epidemiology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden, Clinical Research Centre, Örebro University Hospital, Linkoping, Sweden, Department of Primary Care and Social Medicine, Imperial College, London, United Kingdom.
    Ekbom, A.
    Clinical Epidemiology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden, Harvard School of Public Health, Boston, MA, United States.
    Risk of Pancreatitis in 14,000 Individuals With Celiac Disease2007In: Clinical Gastroenterology and Hepatology, ISSN 1542-3565, E-ISSN 1542-7714, Vol. 5, no 11Article in journal (Refereed)
    Abstract [en]

    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. © 2007 AGA Institute.

  • 323.
    Ludvigsson, Johnny
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Faresjö, Maria
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics .
    Hjorth, Maria
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics .
    Axelsson, Stina
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics .
    Chéramy, Mikael
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics .
    Pihl, Mikael
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics .
    Vaarala, Outi
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics .
    Forsander, Gun
    Ivarsson, Sten
    Johansson, Calle
    Lindh, Agne
    Nilsson, NO
    Åman, Jan
    Örtqvist, Eva
    Zerhouni, Peter
    Casas, Rosaura
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics .
    GAD treatment and insulin secretion in recent-onset type 1 diabetes2008In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 359, no 18, p. 1909-1920Article in journal (Refereed)
    Abstract [en]

    Background: The 65-kD isoform of glutamic acid decarboxylase (GAD) is a major autoantigen in patients with type 1 diabetes mellitus. This trial assessed the ability of alum-formulated GAD (GAD-alum) to reverse recent-onset type 1 diabetes in patients 10 to 18 years of age. Methods: We randomly assigned 70 patients with type 1 diabetes who had fasting C-peptide levels above 0.1 nmol per liter (0.3 ng per milliliter) and GAD autoantibodies, recruited within 18 months after receiving the diagnosis of diabetes, to receive subcutaneous injections of 20 μg of GAD-alum (35 patients) or placebo (alum alone, 35 patients) on study days 1 and 30. At day 1 and months 3, 9, 15, 21, and 30, patients underwent a mixed-meal tolerance test to stimulate residual insulin secretion (measured as the C-peptide level). The effect of GAD-alum on the immune system was also studied. Results: Insulin secretion gradually decreased in both study groups. The study treatment had no significant effect on change in fasting C-peptide level after 15 months (the primary end point). Fasting C-peptide levels declined from baseline levels significantly less over 30 months in the GAD-alum group than in the placebo group (-0.21 vs. -0.27 nmol per liter [-0.62 vs. -0.81 ng per milliliter], P = 0.045), as did stimulated secretion measured as the area under the curve (-0.72 vs. -1.02 nmol per liter per 2 hours [-2.20 vs. -3.08 ng per milliliter per 2 hours], P = 0.04). No protective effect was seen in patients treated 6 months or more after receiving the diagnosis. Adverse events appeared to be mild and similar in frequency between the two groups. The GAD-alum treatment induced a GAD-specific immune response. Conclusions: GAD-alum may contribute to the preservation of residual insulin secretion in patients with recent-onset type 1 diabetes, although it did not change the insulin requirement. (ClinicalTrials.gov number, NCT00435981.) Copyright © 2008 Massachusetts Medical Society. All rights reserved.

  • 324.
    Ludvigsson, Johnny
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Hanas, Ragnar
    Central Hospital, Uddevalla, Sweden.
    Continuous subcutaneous glucose monitoring improved metabolic control in pediatric patients with type 1 diabetes: A controlled crossover study2003In: Pediatrics, ISSN 0031-4005, E-ISSN 1098-4275, Vol. 111, no 5, p. 933-938Article in journal (Refereed)
    Abstract [en]

    Objective. To improve metabolic control and prevent complications, both acute and late, we need to adjust treatment on the basis of the blood glucose (BG) profile, as not even the most active BG self-monitoring gives sufficient information. Design. We have used Continuous Glucose Monitoring System (CGMS, Medtronic MiniMed, Northridge, CA) in a controlled crossover study including 27 diabetic patients aged 12.5 ± 3.3 (mean, standard deviation, range: 5-19) years. All patients were treated with intensive insulin therapy, 14 with multiple injections, and 13 with pumps. The patients were randomized into an open or blind study arm. Both arms wore the CGMS sensor for 3 days every 2 weeks. CGMS profiles were used in the open study arm to adjust insulin therapy at follow-up visits every 6 weeks. Both the patients and the diabetes team were masked to the CGMS profiles in the blinded arm, and insulin therapy adjustments were based solely on 7-point BG profiles performed by the patients. At 3 months the 2 study arms were crossed over. Results. Despite initial problems with a device new to both patients and the diabetes team, hemoglobin A1C decreased significantly in the open arm (from 7.70%-7.31%) but not in the blind arm (7.75%-7.65%). A total of 26/27 patients experienced daytime low subcutaneous glucose (<3.0 mmol/L, .8 episodes/day, duration 58 ± 29 minutes, 5.5% of total time), and 27/27 patients had at least 1 nocturnal episode of low subcutaneous glucose (.4 episodes/night, duration 132 ± 81 minutes, 10.1% of total time). Conclusions. Use of CGMS facilitated an improved treatment, and patients received new insight and increased motivation. In this study, we found CGMS to be a useful tool for education and improving metabolic control.

  • 325.
    Ludvigsson, Johnny
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Hjorth, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Chéramy, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Axelsson, Stina
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Pihl, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Forsander, G
    Queen Silvia Childrens Hospital.
    Nilsson, N-O
    Halmstad County Hospital.
    Samuelsson, B-O
    Boras Hospital.
    Wood, T
    Diamyd Therapeut.
    Aman, J
    Orebro University Hospital.
    Ortqvist, E
    Karolinska University Hospital.
    Casas, Rosaura
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Extended evaluation of the safety and efficacy of GAD treatment of children and adolescents with recent-onset type 1 diabetes: a randomised controlled trial2011In: DIABETOLOGIA, ISSN 0012-186X, Vol. 54, no 3, p. 634-640Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate the safety and efficacy of alum formulated glutamic acid decarboxylase GAD(65) (GAD-alum) treatment of children and adolescents with type 1 diabetes after 4 years of follow-up. Seventy children and adolescents aged 10-18 years with recent onset type 1 diabetes participated in a phase II, double-blind, randomised placebo-controlled clinical trial. Patients identified as possible participants attended one of eight clinics in Sweden to receive information about the study and for an eligibility check, including a medical history. Participants were randomised to one of the two treatment groups and received either a subcutaneous injection of 20 mu g of GAD-alum or placebo at baseline and 1 month later. The study was blinded to participants and investigators until month 30. The study was unblinded at 15 months to the sponsor and statistician in order to evaluate the data. At follow-up after 30 months there was a significant preservation of residual insulin secretion, as measured by C-peptide, in the group receiving GAD-alum compared with placebo. This was particularly evident in patients with andlt; 6 months disease duration at baseline. There were no treatment-related serious adverse events. We have now followed these patients for 4 years. Overall, 59 patients, 29 who had been treated with GAD-alum and 30 who had received placebo, gave their informed consent. One patient in each treatment group experienced an episode of keto-acidosis between months 30 and 48. There were no treatment-related adverse events. The primary efficacy endpoint was the change in fasting C-peptide concentration from baseline to 15 months after the prime injection for all participants per protocol set. In the GAD-alum group fasting C-peptide was 0.332 +/- 0.032 nmol/l at day 1 and 0.215 +/- 0.031 nmol/l at month 15. The corresponding figures for the placebo group were 0.354 +/- 0.039 and 0.184 +/- 0.033 nmol/l, respectively. The decline in fasting C-peptide levels between day 1 and month 1, was smaller in the GAD-alum group than the placebo group. The difference between the treatment groups was not statistically significant. In those patients who were treated within 6 months of diabetes diagnosis, fasting C-peptide had decreased significantly less in the GAD-alum group than in the placebo-treated group after 4 years. Four years after treatment with GAD-alum, children and adolescents with recent-onset type 1 diabetes continue to show no adverse events and possibly to show clinically relevant preservation of C-peptide. ClinicalTrials.gov NCT00435981 The study was funded by The Swedish Research Council K2008-55X-20652-01-3, Barndiabetesfonden (The Swedish Child Diabetes Foundation), the Research Council of Southeast Sweden, and an unrestricted grant from Diamyd Medical AB.

  • 326.
    Ludvigsson, Johnny
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Holmqvist, Britt-Marie
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Samuelsson, Ulf
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Does modern high standard life style cause type 1 diabetes in children?2013In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 29, no 2, p. 161-165Article in journal (Refereed)
    Abstract [en]

    Background Type 1 diabetes is a serious disease which, in spite of intensive treatment, causes serious complications and increased mortality. The incidence is increasing, but the aetiology is unknown. As part of modern lifestyle, increased hygiene has been suspected as one contributing cause but so far there is no evidence. Several large epidemiological studies, mainly restricted to children with increased genetic risk for type 1 diabetes, have so far given no clue. Methods All Babies in Southeast Sweden is unique in its design as it has followed an unselected group of children from birth 19971999 and onwards with regular follow-ups. This report is based on questionnaires from initially 16051 children of whom 80 have later on developed type 1 diabetes. The parents answered questionnaires at the birth of their child and then after 1, 23, 56 and 8years. A number of parameters possibly related to hygiene were analysed with several statistical methods, both with univariate and in regression models. Results Our study cannot identify any crucial environmental factor. This indicates that hygiene-related parameters traditionally regarded as part of modern life style do not play any important role for the aetiology of type 1 diabetes. Conclusions There is no reason to recommend a change of that part of our lifestyle. We find weak associations to previous gastrointestinal infections, which gives a hint that development of type 1 diabetes may be related to problems in the gut and maybe one should look closer into the microbes living in the gut.

  • 327.
    Ludvigsson, Johnny
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Huus, Karina
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Eklöv, Kristina
    Div of Pediatrics and Diabetes Research Centre, Department of Molecular and Clinical Medicine, Linköping University, Sweden.
    Klintström, Rebecka
    Div of Pediatrics and Diabetes Research Centre, Department of Molecular and Clinical Medicine, Linköping University, Sweden.
    Lahdenpera, Anne
    MSc, Div of Pediatrics and Diabetes Research Centre, Department of Molecular and Clinical Medicine, Link ¨ oping University, Sweden.
    Fasting plasma glucose levels in healthy preschool children: effects of weight and lifestyle2007In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 96, no 5, p. 706-709Article in journal (Refereed)
    Abstract [en]

    Aim: To investigate whether a modern lifestyle, with a high-energy intake and a low level of physical activity, influences fasting plasma glucose concentration in healthy children.

    Methods: As a part of the prospective study 'All Babies in Southeast Sweden', 127 children from six preschool units chose to participate. The children, 56% girls and 44% boys, were 5–7 years old. Parents answered a questionnaire about their children's heredity, and physical exercise and eating habits. In the morning, before the children ate breakfast, fasting plasma glucose levels and weight, height and waist circumference were measured.

    Results: Fasting plasma glucose levels varied between 3.7 and 6.1 mmol/L, with both mean and median values of 4.7 mmol/L. There was no association between fasting plasma glucose level and body mass index (BMI), eating habits or degree of physical exercise. BMI and waist circumference were significantly correlated (p < 0.01). Children who play outdoors most frequently had a significantly lower BMI (p < 0.05) and waist circumference (p < 0.01), whereas children who more often watch TV had a significantly higher BMI (p < 0.01).

    Conclusion: A modern lifestyle, with low levels of exercise and high-energy consumption, may explain the increasing weight and even obesity of otherwise healthy, preschool children, but does not influence their fasting plasma glucose levels.

  • 328.
    Ludvigsson, Johnny
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Krisky, David
    Diamyd Medical, Pittsburgh.
    Casas, Rosaura
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Battelino, Tadej
    University Medical Center–University Children's Hospital, Faculty of Medicine, Ljubljana, Slovenia .
    Castaño, Luis
    Hospital de Cruces–University of Basque Country, Barakaldo, Bizkaia, Spain .
    Greening, James
    Department of Paediatrics, Leicester Royal Infirmary, Leicester, UK.
    Kordonouri, Olga
    Diabetes Center for Children and Adolescents, Kinderkrankenhaus auf der Bult, Hannover, Germany .
    Otonkoski, Timo
    Children's Hospital, University of Helsinki, and Helsinki University Central Hospital, Helsinki, Finland.
    Pozzilli, Paolo
    University Campus Bio-Medico, Rome, Italy.
    Robert, Jean-Jacques
    Hôpital Necker–Enfants Malades, Université René Descartes Paris 5, Paris, France.
    Veeze, Henk J.
    Stichting Diabeter, Rotterdam, the Netherlands .
    Palmer, Jerry
    Department of Medicine, Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle, USA.
    Samuelsson, Ulf
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Elding Larsson, Helena
    Lunds universitet, Sweden.
    Åman, Jan
    Örebro universitet, Sweden.
    Kärdell, Gunilla
    Neiderud, Jan
    Helsingborgs lasarett, Sweden.
    Lundström, Göran
    Länssjukhuset Kalmar, Sweden.
    Albinsson, Eva
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Carlsson, Annelie
    Skånes universitetssjukhus, Lund, Sweden.
    Nordvall, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Norrköping.
    Fors, Hans
    Sahlgrenska akademin vid Göteborgs universitet, Sweden.
    Arvidsson, Carl-Göran
    Centrallasarettet, Västerås, Sweden.
    Edvardson, Stig
    Centrallasarettet, Växjö, Sweden.
    Hanås, Ragnar
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics. Linköping University, Faculty of Health Sciences.
    Larsson, Karin
    Rathsman, Björn
    Sachsska Barnsjukhuset, Stockholm, Sweden.
    Forsgren, Henrik
    Desaix, Helena
    Forsander, Gun
    Göteborg University, Sweden.
    Nilsson, Nils-Östen
    Lasarettet i Halmstad, Sweden.
    Åkesson, Carl-Göran
    Keskinen, Päivi
    University of Tampere, Finland .
    Veijola, Riitta
    Uleåborgs universitetssjukhus, Finland.
    Talvitie, Timo
    Raile, Klemens
    Charite, Berlin, Germany.
    Kapellen, Thomas
    University of Leipzig, Germany.
    Burger, Walter
    Neu, Andreas
    University Children's Hospital, Tuebingen, Germany.
    Engelsberger, Ilse
    Heidtmann, Bettina
    Catholic Children’s Hospital Wilhelmstift, Hamburg, Germany.
    Bechtold, Suzanne
    Leslie, David
    Blizard Institute, Queen Mary University of London, UK.
    Chiarelli, Francesco
    University of Chieti, Italy.
    Cicognani, Alesandro
    University of Bologna, Italy.
    Chiumello, Giuseppe
    Vita-Salute University, Milan, Italy.
    Cerutti, Franco
    University of Turin, Italy.
    Zuccotti, Gian Vincenzo
    University of Milan, Italy.
    Gomez Gila, Ana
    Rica, Itxaso
    Barrio, Raquel
    Clemente, Maria
    López Garcia, Maria José
    Rodriguez, Mercedes
    Gonzalez, Isabel
    Lopez, Juan Pedro
    Oyarzabal, Mirentxu
    Reeser, H M
    Nuboer, Roos
    Stouthart, Pauline
    Bratina, Natasa
    Bratanic, Nina
    de Kerdanet, Marc
    Weill, Jacques
    Ser, Nicole
    Barat, Pascal
    Bertrand, Anne Marie
    Carel, Jean-Claude
    Reynaud, Rachel
    Coutant, Regis
    Baron, Sabine
    GAD65 antigen therapy in recently diagnosed type 1 diabetes mellitus2012In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 366, no 5, p. 433-442Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The 65-kD isoform of glutamic acid decarboxylase (GAD65) is a major autoantigen in type 1 diabetes. We hypothesized that alum-formulated GAD65 (GAD-alum) can preserve beta-cell function in patients with recent-onset type 1 diabetes.

    METHODS: We studied 334 patients, 10 to 20 years of age, with type 1 diabetes, fasting C-peptide levels of more than 0.3 ng per milliliter (0.1 nmol per liter), and detectable serum GAD65 autoantibodies. Within 3 months after diagnosis, patients were randomly assigned to receive one of three study treatments: four doses of GAD-alum, two doses of GAD-alum followed by two doses of placebo, or four doses of placebo. The primary outcome was the change in the stimulated serum C-peptide level (after a mixed-meal tolerance test) between the baseline visit and the 15-month visit. Secondary outcomes included the glycated hemoglobin level, mean daily insulin dose, rate of hypoglycemia, and fasting and maximum stimulated C-peptide levels.

    RESULTS: The stimulated C-peptide level declined to a similar degree in all study groups, and the primary outcome at 15 months did not differ significantly between the combined active-drug groups and the placebo group (P=0.10). The use of GAD-alum as compared with placebo did not affect the insulin dose, glycated hemoglobin level, or hypoglycemia rate. Adverse events were infrequent and mild in the three groups, with no significant differences.

    CONCLUSIONS: Treatment with GAD-alum did not significantly reduce the loss of stimulated C peptide or improve clinical outcomes over a 15-month period.

  • 329.
    Ludvigsson, Johnny
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Ludvigsson, J F
    Barnklin Örebro.
    Stressful life events, social support and confidence in the pregnant woman and risk of coeliac disease in the offspring2003In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 38, no 5, p. 516-521Article in journal (Refereed)
    Abstract [en]

    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.

  • 330.
    Ludvigsson, Johnny
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Ludvigsson, Jonas
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics.
    Parental smoking and risk of coeliac disease in offspring2005In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 40, no 3, p. 336-342Article in journal (Refereed)
    Abstract [en]

    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.

  • 331.
    Ludvigsson, Johnny
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Ludvigsson, Mikael
    Sepa, Anneli
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Screening for prediabetes in the general child population: maternal attitude to participation2001In: Pediatric Diabetes, ISSN 1399-543X, Vol. 2, no 4, p. 170-174Article in journal (Refereed)
    Abstract [en]

    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.

  • 332.
    Ludvigsson, Johnny
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Nordfeldt, S
    Prevention of hypoglycaemia in diabetic children and adolescents2002In: Diabetes, Nutrition and Metabolism. Clinical and Experimental, ISSN 0394-3402, E-ISSN 1720-8343, Vol. 15, no 6, p. 395-399Article in journal (Refereed)
  • 333.
    Ludvigsson, Johnny
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    nämnden, för AT
    AT-skrivningar får gott omdöme av AT-läkarna2008In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 105, no 38, p. 2580-2581Article in journal (Other academic)
    Abstract [sv]

    [No abstract available]

  • 334.
    Ludvigsson, Johnny
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Samuelsson, Ulf
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Continuous insulin infusion (CSII) or modern type of multiple daily injections (MDI) in diabetic children and adolescents a critical review on a controversial issue2007In: Pediatric Endocrinology Reviews: diabetes, nutrition, metabolism, ISSN 1565-4753, Vol. 5, no 2, p. 666-678Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    There is a common opinion that CSII is superior to MDI. CSII offers the most physiological insulin substitution.

    METHOD:

    Review of recent publications (Cochrane criteria), on modern multiple daily injections (MDI) based on insulin analogues, modern self-control and education.

    RESULTS:

    There is a lack of randomised controlled studies comparing CSII with modern MDI in children and adolescents. In some studies CSII seems to give a slight decrease of HbA1c, a slightly better quality of life, perhaps less hypoglycemia. However, serious hypoglycemia, sometimes fatal, occurs, DKA seems to increase, weight gain and local infections at injection sites may occur and CSII is more expensive than MDI.

    CONCLUSION:

    CSII is a useful tool. It is reasonable to use it when there are appropriate indications. CSII does not solve all problems but has to be combined with other important parts of diabetes treatment.

  • 335.
    Ludvigsson, Johnny
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Skoglund, Camilla
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Chéramy, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Casas, Rosaura
    Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Linköping University, Faculty of Health Sciences.
    Hampe, C
    Department Med, Seattle.
    GAD(65) treatment induces high GADA but no changes in epitopes or adverse signs/symptoms in type 1 diabetic children2009In: in DIABETOLOGIA, vol 52., 2009, Vol. 52, p. S192-S192Conference paper (Refereed)
    Abstract [en]

    n/a

  • 336.
    Ludvigsson, Jonas
    et al.
    Barnkliniken Örebro.
    Ansved, Pär
    Barnkliniken, Kalmar .
    Fälth-Magnusson, Karin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Hammersjö, Jan-Åke
    Barnkliniken, Västervik .
    Johansson, Calle
    Barnkliniken, Jönköping .
    Edvardsson, Stig
    Barnkliniken, Växjö .
    Ljungkrantz, Magnus
    Barnkliniken, Karlskrona .
    Stenhammar, Lars
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Norrköping.
    Ludvigsson, Johnny
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Symptoms and signs have changed in Swedish children with coeliac disease.2004In: Journal of Pediatric Gastroenterology and Nutrition - JPGN, ISSN 0277-2116, E-ISSN 1536-4801, Vol. 38, p. 181-186Article in journal (Refereed)
  • 337.
    Ludvigsson, Jonas
    et al.
    Dept of Pediatrics, Örebro hospital.
    Eylert, Maike
    Clinical Epidemiology Unit, Dept of Medicine, KS, Stockholm.
    Ilonen, Jorma
    Dept of Virology, Turku, Finland.
    Ludvigsson, Johnny
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Vaarala, Outi
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Effect of HLA DQ2, dietary exposure and coeliac disease on the development of antibody response to gliadin in children2006In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 41, no 8, p. 919-928Article in journal (Refereed)
    Abstract [en]

    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. © 2006 Taylor & Francis.

  • 338.
    Ludvigsson, Jonas F.
    et al.
    Paediatric Department, Örebro Medical Centre Hospital, Sweden.
    Ludvigsson, Johnny
    Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Coeliac disease in the father affects the newborn2001In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 49, no 2, p. 169-175Article in journal (Refereed)
    Abstract [en]

    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.

  • 339.
    Ludvigsson, Jonas
    et al.
    Linköping University, Department of Molecular and Clinical Medicine. Linköping University, Faculty of Health Sciences.
    Ludvigsson, Johnny
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Paediatrics in Linköping.
    Socio-economic determinants, maternal smoking and coffee consumption, and exclusive breastfeeding in 10 205 children2005In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 94, no 9, p. 1310-1319Article in journal (Refereed)
    Abstract [en]

    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.

  • 340.
    Ludvigsson, Jonas
    et al.
    Dept of Pediatrics, University Hospital Örebro.
    Ludvigsson, Johnny
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Ekbom, Anders
    Montgomery, SM
    Celiac disease and risk of subsequent type 1 diabetes: A general population cohort study of children and adolescents2006In: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 29, no 11, p. 2483-2488Article in journal (Refereed)
    Abstract [en]

    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. © 2006 by the American Diabetes Association.

  • 341.
    Ludvigsson, Jonas
    et al.
    Kliniskt ForskningsCentrum, Universitetssjukhuset, Örebro.
    Montgomery, Scott
    Clinical Epidemiology Unit, Karolinska sjukhuset, Stockholm.
    Olén, Ola
    Avd för Pediatrik, Södersjukhuset, Stockholm.
    Ekbom, Anders
    Clinical Epidemiology Unit, Karolinska sjukhuset, Stockholm.
    Ludvigsson, Johnny
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Fored, Michael
    Clinical Epidemiology Unit, Karolinska sjukhuset, Stockholm.
    Coeliac disease and risk of renal disease - A general population cohort study2006In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 21, no 7, p. 1809-1815Article in journal (Refereed)
    Abstract [en]

    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. © 2006 Oxford University Press.

  • 342.
    Ludvigsson, Jonas
    et al.
    Barnkliniken Örebro.
    Mostrom, M
    Klinisk Epidemiologi Karolinska Institutet, Stockholm.
    Ludvigsson, Johnny
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Duchén, Karel
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Exclusive breastfeeding and risk of atopic dermatitis in some 8300 infants2005In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 16, no 3, p. 201-208Article in journal (Refereed)
    Abstract [en]

    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.

  • 343. Lundin, B
    et al.
    Croner, Stefan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Pediatrics . Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Munchausen syndrome by proxy - a literature review and Swedish case histories2001In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 98, no 19, p. 2302-+Article in journal (Refereed)
    Abstract [en]

    Munchausen syndrome by proxy (MSbP) is a potentially lethal form of child abuse. Mortality rates around 10 percent have been reported. A knowledge of the characteristics of MSbP is needed in order to reveal the diagnosis and to handle the management correctly. Swedish experience is in accordance with international reports.

  • 344.
    Lundin, Catarina
    et al.
    Lund University Hospital.
    Davidsson, Josef
    Lund University Hospital.
    Hjorth, Lars
    Lund University Hospital.
    Behrendtz, Mikael
    Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Johansson, Bertil
    Lund University Hospital.
    Tiling resolution array-based comparative genomic hybridisation analyses of acute lymphoblastic leukaemias in children with Down syndrome reveal recurrent gain of 8q and deletions of 7p and 9p2009In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 146, no 1, p. 113-115Article in journal (Other academic)
  • 345.
    Lundin, Catarina
    et al.
    Lund University, Sweden .
    Hjorth, Lars
    Lund University, Sweden .
    Behrendtz, Mikael
    Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Ehinger, Mats
    Lund University, Sweden .
    Biloglav, Andrea
    Lund University, Sweden .
    Johansson, Bertil
    Lund University, Sweden .
    Submicroscopic genomic imbalances in burkitt lymphomas/leukemias: Association with age and further evidence that 8q24/MYC translocations are not sufficient for leukemogenesis2013In: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 52, no 4, p. 370-377Article in journal (Refereed)
    Abstract [en]

    Chromosome banding analyses reveal secondary chromosome abnormalities in addition to the MYC translocations t(8;14)(q24;q32), t(8;22)(q24;q11), and t(2;8)(p11;q24) in 60%80% of Burkitt lymphomas/leukemias (BL). The high incidence of such aberrations indicates that additional changes are important, perhaps necessary, for malignant transformation, i.e., the 8q24/MYC rearrangements may not be sufficient. To investigate this possibility, we performed single nucleotide polymorphism (SNP) array analysis on 20 cases of 8q24/MYC-positive BL. Nineteen (95%) harbored genomic imbalances; the only case without such aberrations displayed secondary changes by chromosome banding analysis. Thus, all BL cases had abnormalities in addition to the 8q24 translocation. The adult cases harbored more changes (median 3; range 121) than did the childhood cases (median 1.5; range 05) (P = 0.034). Several recurrent aberrations were detected by SNP array analysis, in particular losses of 6q14.1-q22.33, 9p21.3, and 13q14.2-q14.3, gains of 1q23.3-q31.3, chromosome 7, 13q31.3, and partial uniparental isodisomies for 6p12.2-pter, 9p23-pter, and 17p11.2-pter. The molecular genetic consequences of these changes include deletions of the CDKN2A and TP53 genes, and gains/losses of several genes, such as MIR17HG and E2F2K, involved in the MYC pathway. Thus, deregulation of the MYC pathway, both directly through the 8q24/MYC translocation and indirectly through secondary genomic imbalances, may be essential not only for the initiation but also for the progression of BL.

  • 346.
    Lundin, Catarina
    et al.
    Lund University.
    Hjorth, Lars
    Skåne University Hospital.
    Behrendtz, Mikael
    Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Nordgren, Ann
    Karolinska Institute.
    Palmqvist, Lars
    Sahlgrens University Hospital.
    Klarskov Andersen, Mette
    Rigshospital, Copenhagen.
    Biloglav, Andrea
    Lund University.
    Forestier, Erik
    Umeå University.
    Paulsson, Kajsa
    Lund University.
    Johansson, Bertil
    Lund University.
    High frequency of BTG1 deletions in acute lymphoblastic leukemia in children with down syndrome2012In: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 51, no 2, p. 196-206Article in journal (Refereed)
    Abstract [en]

    Previous cytogenetic studies of myeloid and acute lymphoblastic leukemias in children with Down syndrome (ML-DS and DS-ALL) have revealed significant differences in abnormality patterns between such cases and acute leukemias in general. Also, certain molecular genetic aberrations characterize DS-related leukemias, such as GATA1 mutations in ML-DS and deregulation of the CRLF2 gene in DS-ALL. Whether microdeletions/microduplications also vary between DS and non-DS cases is presently unclear. To address this issue, we performed single nucleotide polymorphism array analyses of eight pediatric ML-DS and 17 B-cell precursor DS-ALL. In the ML-DS cases, a total of 29 imbalances (20 gains and nine losses) and two partial uniparental isodisomies (pUPDs) were detected. None of the 11 small (defined as less than10 Mb) imbalances were recurrent, nor were the pUPDs, whereas of the 18 large aberrations, three were recurrentdup(1q), +8 and +21. In contrast, several frequent changes were identified in the DS-ALL cases, which harbored 82 imbalances (30 gains and 52 losses) and four pUPDs. Of the 40 large changes, 28 were gains and 12 losses, with +X, dup(Xq), dup(1q), del(7p), dup(8q), del(9p), dup(9p), del(12p), dup(17q), and +21 being recurrent. Of the 40 microdeletions identified, several targeted specific genes, with the following being repeatedly deleted: BTG1 and CDKN2A/B (29% of cases), ETV6, IKZF1, PAX5 and SERP2 (18%), and BTLA, INPP4B, P2RY8, and RB1 (12%). Loss of the SERP2 and INPP4B genes, encoding the stress-associated endoplasmic reticulum protein family member 2 and the inositol polyphosphate 4-phosphatase-II, respectively, has previously never been implicated in leukemia. Although deletions of the other genes have been associated with ALL, the high frequency of BTG1 loss is a novel finding. Such deletions may characterize a clinical subgroup of DS-ALL, comprising mainly boys with a high median age. In conclusion, ML-DS and DS-ALL are genetically distinct, with mainly gains in ML-DS and deletions in DS-ALL. Furthermore, DS-ALL is characterized by several recurrent gene deletions, with BTG1 loss being particularly frequent.

  • 347.
    Lundström, Nils-Rune
    et al.
    Barnhjärtcentrum, Universitetssjukhuset, Lund.
    Björn, Åke
    Medevac, Universitetssjukhuset, Linköping.
    Jögi, Peeter
    Barnhjärtcentrum Universitetssjukhuset, Lund.
    Leijon, Ingemar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Bägesund, Mats
    Centrum för ortodonti/Pedodonti Folktandvården, Östergötland.
    Björkhem, Gudrun
    Barnhjärtcentrum Universitetssjukhuset, Lund.
    Nelson, Nina
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Svårt hjärtsjuka barn från Balkan opererades i Sverige: Redogörelse för 41 barn som behandlats via lyckad hjälpinsats2006In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 103, no 50-52, p. 4038-4041Article in journal (Refereed)
    Abstract [en]

    The Swedish Medical Program is a co-operation between Linköping University Hospital and the International Organisation for Migration (IOM) for medical support to Bosnia and Hercegovina and to Kosovo. Within this program 41 infants and children from Bosnia-Hercegovina and Kosovo with severe heart disease were transferred to Sweden during the period 1995 - 2003 for treatment, with good results. The program enabled pediatric cardiologists and surgeons from these countries to visit Sweden for shorter training periods and Swedish doctors to supervise local clinicians in these countries. With support from an Austrian team a limited number of children with heart malformations have been treated locally since 2002. It is the intention of the Swedish program to further support the establishment of pediatric heart surgery in Sarajevo.

  • 348.
    Mai, Xiao-Mei
    et al.
    Canada.
    Almqvist, Catarina
    Astrid Lindgrens barnsjukhus Stockholm.
    Nilsson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Wickman, Magnus
    Karolinska Institutet Stockholm.
    Birth anthropometric measures, body mass index and allergic diseases in a birth cohort study (BAMSE)2007In: Archives of Disease in Childhood, ISSN 0003-9888, E-ISSN 1468-2044, Vol. 92, no 10, p. 881-886Article in journal (Refereed)
    Abstract [en]

    Objective: We aimed to assess increased birth weight or birth length in relation to allergic diseases at 4 years of age, taking body mass index (BMI) at age 4 as a covariate in the adjustment. Methods: The parents of a large prospective birth cohort answered questionnaires on environmental factors and allergic symptoms when their children were 2 months and 1, 2 and 4 years old. Perinatal data on weight and length at birth were received from the child care health centres. The children were clinically examined at 4 years of age and height and weight recorded. Blood was drawn for analysis of specific IgE antibodies to common inhalant allergens. Risk associations between birth anthropometric measures and wheeze, allergic diseases or sensitisation were estimated in multivariate logistic regression analyses (n = 2869). Results: There were no clear overall associations between birth weight and allergic diseases at 4 years of age. Birth length ≥90th percentile was inversely associated with any wheeze at age 4 (adjusted OR 0.64, 95% Cl 0.44 to 0.92) but was significantly associated only with late-onset wheeze (adjusted OR 0.40, 95% Cl 0.21 to 0.77). No such associations were seen for persistent or transient wheeze, eczema, rhinitis or allergic sensitisation. Transient wheeze during the first 2 years of age tended to be associated with increased BMI at age 4. Conclusion: Increased birth weight was not associated with wheeze or allergic disease. Increased birth length may play a protective role in late-onset wheeze in early childhood.

  • 349.
    Mai, Xiaomei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics.
    Fagerås Böttcher, Malin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics.
    Bruhammar, M
    Allergicentrum US, Linköping.
    Nilsson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Zetterström, Olle
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Allergy Centre. Östergötlands Läns Landsting, Centre for Medicine, Allergy Centre UHL.
    Urinary inflammatory mediators and inhalation of hypertonic saline in children2005In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 60, no 1, p. 60-64Article in journal (Refereed)
    Abstract [en]

    Background: The inflammatory mechanisms of hypertonic saline-induced bronchoconstriction are not well understood. Methods: Seventeen asthmatics with (n = 11) and without bronchial hyperresponsiveness (BHR) (n = 6) and 18 randomly selected nonatopic nonasthmatic controls without BHR were evaluated by urine samples collected before and 1 h after hypertonic saline provocation test. Histamine, 11β-PGF2α, and LTE4 were analysed by enzyme immunoassay (EIA) and eosinophil protein X (EPX) by radioimmunoassay (RIA). Results: The levels of leukotriene E4 (LTE4) increased significantly after the challenge tests, both in the asthmatics (median: 354 pg/mg pre-challenge vs. 628 pg/mg post-challenge, P = 0.05) and in the controls (median: 294 pg/mg pre-challenge vs. 460 pg/mg post-challenge, P < 0.01). The levels of histamine also increased significantly in the latter (median: 299 μmol/mg pre-challenge vs. 569 μmol/mg post-challenge, P = 0.03). However, the levels of 11β-PGF2α and EPX did not change significantly after the challenge tests either in the asthmatics or in the controls. Conclusions: The inhalation of hypertonic saline increased urinary excretion of LTE4 both in the asthmatics and in the controls. The slight increase of leukotrienes was enough to induce airway obstruction in some of the asthmatics, because of the hyperresponsiveness in their airways.

  • 350.
    Mai, Xiaomei
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics.
    Fagerås Böttcher, Malin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics.
    Leijon, Ingemar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Pediatrics. Östergötlands Läns Landsting, Centre of Paediatrics and Gynecology and Obstetrics, Department of Paediatrics in Linköping.
    Leptin and asthma in overweight children at 12 years of age2004In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 15, no 6, p. 523-530Article in journal (Refereed)
    Abstract [en]

    Obesity is suggested as a risk factor for asthma, but the mechanisms are unclear. The relationship between obesity and asthma has not been considered in children born with very low-birth weight (VLBW). We hypothesized that overweight was a contributing factor for asthma in VLBW children, and that leptin and leptin-associated cytokines might play roles in overweight-related asthma. Seventy-four VLBW and 64 normal birth weight (NBW) children participated in a 12-yr follow up study assessing asthma and allergy. Twenty-seven (12 VLBW) of the 138 children were overweight according to the proposed international definition. The diagnosis of current asthma was made by a pediatrician. Serum levels of leptin and interferon (IFN)-γ were analyzed by enzyme-linked immunosorbent assay (ELISA). Leptin levels were considerably higher in the overweight than in the non-overweight children (median value: 18.1 vs. 2.8 ng/ml, p < 0.001). In the overweight children, current asthmatics had twice as high levels of leptin as children without current asthma (median value: 30.8 vs. 14.3 ng/ml, p = 0.14), but this was not the case in the non-overweight children. IFN-γ was more often detected in the overweight than in the non-overweight children (61% vs. 12%, p < 0.001), and there was a positive correlation between the levels of leptin and the levels of IFN-γ (Rho = 0.40, p < 0.001). In the VLBW group, the overweight children had a significantly increased risk for current asthma compared with the non-overweight children after adjustment for the neonatal risk factors [adjusted odds ratio (OR) 5.8, 95% confidence interval (CI): 1.2-27]. Thus, overweight was associated with asthma in the VLBW children. Our hypothesis remained that leptin might be involved in the pathogenesis of asthma in the overweight children, and IFN-γ might be a pathway in the process of leptin-induced inflammation.

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