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Background and purpose: The purpose was to examine the consequences of antiepileptic drug (AED) exposure during pregnancy on language abilities in children aged 5 and 8 years of mothers with epilepsy. Methods: The study population included children of mothers with and without epilepsy enrolled in the Norwegian Mother and Child Cohort Study 1999–2008. Mothers prospectively provided information on epilepsy diagnosis, AED use during pregnancy and the child's language abilities at age 5 and 8 years, in questionnaires with validated language screening tools. AED concentrations in gestation week 17–19 and in the umbilical cord were measured. Results: The study population included 346 AED‐exposed and 388 AED‐unexposed children of mothers with epilepsy, and 113 674 children of mothers without epilepsy. Mothers of 117 and 121 AED‐exposed children responded to the questionnaires at age 5 and 8 years, respectively. For AED‐exposed children, the adjusted odds ratio for language impairment was 1.6 [confidence interval (CI) 1.1–2.5, P = 0.03] at age 5 years and 2.0 (CI 1.4–3.0, P < 0.001) at age 8 years, compared to children of mothers without epilepsy. Children exposed to carbamazepine monotherapy had a significantly increased risk of language impairment compared to control children at age 8 years (adjusted odds ratio 3.8, CI 1.6–9.0, P = 0.002). Higher maternal valproate concentrations correlated with language impairment at age 5 years. Periconceptional folic acid supplement use protected against AED‐associated language impairment. Conclusion: Foetal AED exposure in utero is associated with an increased risk of language impairment in children aged 5 and 8 years of mothers with epilepsy. Periconceptional folic acid use had a protective effect on AED‐associated language impairment. [ABSTRACT FROM AUTHOR]

Background: Patients with hypoparathyroidism are at risk of both hypocalcemic and hypercalcemic crisis. Patients report that health professionals do not always respond adequately in an acute situation. The extent and handling of severe hypo- and hypercalcemia in hypoparathyroidism is unknown.Aims: To outline the need for a medical emergency card for primary hypoparathyroidism.Method: Postal survey amongst Norwegian and Swedish patients with chronic hypoparathyroidism of all causes. Altogether 455 invitations were sent (333 from Norway and 122 from Sweden).Results: Three hundred and thirty-six of 455 (74%) patients responded (253 from Norway and 83 from Sweden). The majority were women (79%), and the main cause was postsurgical hypoparathyroidism (66%). Overall 44% and 16% had been hospitalized at least once for hypo- or hypercalcemia, respectively. Eighty-seven per cent felt that an emergency card would be highly needed or useful. Amongst those hospitalized for hypocalcemia, 95% felt a card was needed compared to 90% amongst those hospitalized for hypercalcemia. Five per cent believed that a card would not be useful.Conclusions: The majority answered that an acute card is highly needed or useful. Hospitalization for acute hypocalcemia was more common (44%) than for acute hypercalcemia (16%). As a result of this survey, an emergency card will be distributed in three European countries to test its utility. [ABSTRACT FROM AUTHOR]

Summary: Turner syndrome (TS) is associated with an increased frequency of autoimmunity. Frequently observed autoimmune diseases in TS are also seen in the autoimmune polyendocrine syndrome type I (APS I), of which Addison disease is a key component. An overlapping antibody profile between TS and APS I could be considered. The aim of this work was to study women with TS regarding 21‐hydroxylase (21‐OH) antibodies and interferon omega (IFN‐ω) antibodies, a highly specific marker for APS I, to determine if there are immunological overlaps between TS and APS I. Blood samples from 141 TS were assayed for 21‐OH antibodies and IFN‐ω antibodies using in‐vitro‐transcribed and translated autoantigen. Indices with a cut‐off point of 57 and 200 for 21‐OH antibody and IFN‐ω antibody were used as reference. The median age of TS was 31·6 years (range = 11·2–62·2). Positive indices of 21‐OH antibodies were present in six TS (4%), with a mean of 144·8 (range = 60–535). None had apparent adrenal insufficiency. There was no age difference comparing 21‐OH antibody‐positive TS (median age = 33·9 years, range = 17·7–44·7) and 21‐OH antibody‐negative TS (median age = 31·6 years, range = 11·2–62·2) (P = 0·8). No TS was positive for IFN‐ω antibodies (mean = 42·4, range = –435–191). No overlapping autoimmune profile between TS and APS I was found. Autoimmunity against 21‐OH among TS patients was more prevalent than previously identified, suggesting an increased risk of adrenal failure in TS. However, whether adrenal impairment will develop remains unknown. [ABSTRACT FROM AUTHOR]

In common with several other autoimmune diseases, autoimmune Addison's disease (AAD) is thought to be caused by a combination of deleterious susceptibility polymorphisms in several genes, together with undefined environmental factors and stochastic events. To date, the strongest genomic association with AAD has been with alleles at the HLA locus, DR3-DQ2 and DR4. The contribution of other genetic variants has been inconsistent. We have studied the association of 16 single-nucleotide polymorphisms (SNPs) within the CD28-CTLA-4-ICOS genomic locus, in a cohort comprising 691 AAD patients of Norwegian and UK origin with matched controls. We have also performed a meta-analysis including 1002 patients from European countries. The G-allele of SNP rs231775 in CTLA-4 is associated with AAD in Norwegian patients (odds ratio (OR)=1.35 (confidence interval (CI) 1.10-1.66), P=0.004), but not in UK patients. The same allele is associated with AAD in the total European population (OR=1.37 (CI 1.13-1.66), P=0.002). A three-marker haplotype, comprising PROMOTER_1661, rs231726 and rs1896286 was found to be associated with AAD in the Norwegian cohort only (OR 2.43 (CI 1.68-3.51), P=0.00013). This study points to the CTLA-4 gene as a susceptibility locus for the development of AAD, and refines its mapping within the wider genomic locus. [ABSTRACT FROM AUTHOR]

Autoimmune Addison's disease ( AAD) is caused by selective destruction of the hormone-producing cells of the adrenal cortex. As yet, little is known about the potential role played by environmental factors in this process. Type I and/or type III interferons (IFNs) are signature responses to virus infections, and have also been implicated in the pathogenesis of autoimmune endocrine disorders such as type 1 diabetes and autoimmune thyroiditis. Transient development of AAD and exacerbation of established or subclinical disease, as well as the induction of autoantibodies associated with AAD, have been reported following therapeutic administration of type I IFNs. We therefore hypothesize that exposure to such IFNs could render the adrenal cortex susceptible to autoimmune attack in genetically predisposed individuals. In this study, we investigated possible immunopathological effects of type I and type III IFNs on adrenocortical cells in relation to AAD. Both types I and III IFNs exerted significant cytotoxicity on NCI- H295 R adrenocortical carcinoma cells and potentiated IFN-γ- and polyinosine-polycytidylic acid [poly ( I : C)]-induced chemokine secretion. Furthermore, we observed increased expression of human leucocyte antigen ( HLA) class I molecules and up-regulation of 21-hydroxylase, the primary antigenic target in AAD. We propose that these combined effects could serve to initiate or aggravate an ongoing autoimmune response against the adrenal cortex in AAD. [ABSTRACT FROM AUTHOR]

Primary adrenal insufficiency ( PAI), or Addison's disease, is a rare, potentially deadly, but treatable disease. Most cases of PAI are caused by autoimmune destruction of the adrenal cortex. Consequently, patients with PAI are at higher risk of developing other autoimmune diseases. The diagnosis of PAI is often delayed by many months, and most patients present with symptoms of acute adrenal insufficiency. Because PAI is rare, even medical specialists in this therapeutic area rarely manage more than a few patients. Currently, the procedures for diagnosis, treatment and follow-up of this rare disease vary greatly within Europe. The common autoimmune form of PAI is characterized by the presence of 21-hydroxylase autoantibodies; other causes should be sought if no autoantibodies are detected. Acute adrenal crisis is a life-threatening condition that requires immediate treatment. Standard replacement therapy consists of multiple daily doses of hydrocortisone or cortisone acetate combined with fludrocortisone. Annual follow-up by an endocrinologist is recommended with the focus on optimization of replacement therapy and detection of new autoimmune diseases. Patient education to enable self-adjustment of dosages of replacement therapy and crisis prevention is particularly important in this disease. The authors of this document have collaborated within an EU project (Euadrenal) to study the pathogenesis, describe the natural course and improve the treatment for Addison's disease. Based on a synthesis of this research, the available literature, and the views and experiences of the consortium's investigators and key experts, we now attempt to provide a European Expert Consensus Statement for diagnosis, treatment and follow-up. [ABSTRACT FROM AUTHOR]

Purpose: Almost all patients with autoimmune polyendocrine syndrome (APS)-I have high titer neutralizing autoantibodies to type I interferons (IFN), especially IFN-ω and IFN-α2, whatever their clinical features and onset-ages. About 90 % also have antibodies to interleukin (IL)-17A, IL-17F and/or IL-22; they correlate with the chronic mucocutaneous candidiasis (CMC) that affects ~90 % of patients. Our aim was to explore how early the manifestations and endocrine and cytokine autoantibodies appear in young APS-I patients. That may hold clues to very early events in the autoimmunization process in these patients. Methods: Clinical investigations and autoantibody measurements in 13 APS-I patients sampled before age 7 years, and 3 pre-symptomatic siblings with AIRE-mutations in both alleles. Results: Antibody titers were already high against IFN-α2 and IFN-ω at age 6 months in one sibling—8 months before onset of APS-I—and also against IL-22 at 7 months in another (still unaffected at age 5 years). In 12 of the 13 APS-I patients, antibody levels were high against IFN-ω and/or IL-22 when first tested, but only modestly positive against IFN-ω in one patient who had only hypo-parathyroidism. Endocrine organ-specific antibodies were present at age 6 months in one sibling, and as early as 36 and 48 months in two of the six informative subjects. Conclusion: This is the first study to collate the onset of clinical features, cytokine and endocrine autoantibodies in APS-I infants and siblings. The highly restricted early autoantibody responses and clinical features they show are not easily explained by mere loss of broad-specific self-tolerance inducing mechanisms, but hint at some more sharply focused early event(s) in autoimmunization. [ABSTRACT FROM AUTHOR]

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy ( APECED) is a recessive disorder resulting from mutations in the autoimmune regulator ( AIRE). The patients' autoantibodies recognize not only multiple organ-specific targets, but also many type I interferons ( IFNs) and most T helper type 17 ( Th17) cell-associated cytokines, whose biological actions they neutralize in vitro. These anti-cytokine autoantibodies are highly disease-specific: otherwise, they have been found only in patients with thymomas, tumours of thymic epithelial cells that fail to express AIRE. Moreover, autoantibodies against Th17 cell-associated cytokines correlate with chronic mucocutaneous candidiasis in both syndromes. Here, we demonstrate that the immunoglobulin ( Ig)Gs but not the IgAs in APECED sera are responsible for neutralizing IFN-ω, IFN-α2a, interleukin ( IL)-17 A and IL-22. Their dominant subclasses proved to be IgG1 and, surprisingly, IgG4 without IgE, possibly implicating regulatory T cell responses and/or epithelia in their initiation in these AIRE-deficiency states. The epitopes on IL-22 and IFN-α2a appeared mainly conformational. We also found mainly IgG1 neutralizing autoantibodies to IL-17 A in aged AIRE-deficient BALB/c mice - the first report of any target shared by these human and murine AIRE-deficiency states. We conclude that autoimmunization against cytokines in AIRE deficiency is not simply a mere side effect of chronic mucosal Candida infection, but appears to be related more closely to disease initiation. [ABSTRACT FROM AUTHOR]

Autoantibodies against interleukin (IL)-17A, IL-17F and IL-22 have recently been described in patients with autoimmune polyendocrine syndrome type I (APS I), and their presence is reported to be highly correlated with chronic mucocutaneous candidiasis (CMC). The aim of this study was to develop a robust high-throughput radioligand binding assays (RLBA) measuring IL-17F and IL-22 antibodies, to compare them with current enzyme-linked immunosorbent assays (ELISA) of IL-17F and IL-22 and, moreover, to correlate the presence of these antibodies with the presence of CMC. Interleukins are small molecules, which makes them difficult to express in vitro. To overcome this problem, they were fused as dimers, which proved to increase the efficiency of expression. A total of five RLBAs were developed based on IL-17F and IL-22 monomers and homo- or heterodimers. Analysing the presence of these autoantibodies in 25 Norwegian APS I patients revealed that the different RLBAs detected anti-IL-17F and anti-IL-22 with high specificity, using both homo- and heterodimers. The RLBAs based on dimer proteins are highly reproducible with low inter- and intravariation and have the advantages of high throughput and easy standardization compared to ELISA, thus proving excellent choices for the screening of IL-17F and IL-22 autoantibodies. [ABSTRACT FROM AUTHOR]

Autoimmune polyendocrine syndrome type 1 (APS1) is a rare monogenic autoimmune disorder caused by mutations in the autoimmune regulator (AIRE) gene. High-titre autoantibodies are a characteristic feature of APS1 and are often associated with particular disease manifestations. Pituitary deficits are reported in approximately 7% of APS1 patients, with immunoreactivity to pituitary tissue frequently described. Using APS1 patient serum to immunoscreen a pituitary cDNA expression library, testis specific, 10 (TSGA10) was isolated. Immunoreactivity against TSGA10 was detected in 5/99 (5.05%) patients with APS1, but also in 5/135 (3.70%) systemic lupus erythematosus (SLE) patients and 1/188 (0.53%) healthy controls. TSGA10 autoantibodies were not detected in the serum from patients with any other autoimmune disease. Autoantibodies against TSGA10 were detectable from a young age in 4/5 positive APS1 patients with autoantibody titres remaining relatively constant over time. Furthermore, real-time PCR confirmed TSGA10 mRNA to be most abundantly expressed in the testis and also showed moderate and low expression levels throughout the entire body. TSGA10 should be considered as an autoantigen in a subset of APS1 patients and also in a minority of SLE patients. No recognizable clinical phenotype could be found to correlate with positive autoantibody reactivity. [ABSTRACT FROM AUTHOR]

Autoimmune polyendocrine syndrome type I (APS I) is a recessive disorder caused by mutations in the autoimmune regulator ( AIRE) gene. AIRE is expressed in medullary epithelial cells where it activates transcription of organ-specific proteins in thymus, thereby regulating autoimmunity. Patients with APS I have, in addition to autoimmune manifestations in endocrine organs, also often ectodermal dystrophies and chronic mucocutaneous candidiasis. The aim of this study was to characterize immune cell subpopulations in patients with APS I and their close relatives. Extensive blood mononuclear cell immunophenotyping was carried out on 19 patients with APS I, 18 first grade relatives and corresponding sex- and age-matched healthy controls using flow cytometry. We found a significant relative reduction in T helper cells coexpressing CCR6 and CXCR3 in patients with APS I compared to controls (mean = 4.10% versus 5.94% respectively, P = 0.035). The pools of CD16+ monocytes and regulatory T cells (Tregs) were also lower in patients compared with healthy individuals (mean = 15.75% versus 26.78%, P = 0.028 and mean = 4.12% versus 6.73%, P = 0.029, respectively). This is the first report describing reduced numbers of CCR6+CXCR3+ T helper cells and CD16+ monocytes in patients with APS I We further confirm previous findings of reduced numbers of Tregs in these patients. [ABSTRACT FROM AUTHOR]

Autoimmune polyendocrine syndrome type I (APS-I) is a monogenic model disease of autoimmunity. Its hallmarks are chronic mucocutaneous candidosis, hypoparathyroidism and adrenal insufficiency, but many other autoimmune disease components occur less frequently. The first components usually appear in childhood, but may be delayed to adolescence or early adult life. There is enormous variation in presentation and phenotype, which makes the diagnosis difficult. Antibodies against interferon-ω and -α have recently been shown to be sensitive and relatively specific markers for APS-I, and mutational analysis of the autoimmune regulator gene gives the diagnosis in >95% of cases. The treatment and follow-up of patients is demanding and requires the collaboration of specialists of several fields. However, the literature is especially sparse regarding information on treatment and follow-up; hence, we present here a comprehensive overview on clinical characteristics, treatment and follow-up based on personal experience and published studies. [ABSTRACT FROM AUTHOR]

Aim: We previously demonstrated that a modified fatty acid, tetradecylthioacetic acid (TTA), improves transport and utilization of lipids and increases mitochondrial fatty acid oxidation in animal and cell studies. We conducted an exploratory study of safety and effects of this novel drug in patients with type 2 diabetes mellitus and investigated the mechanism of action in human cell lines. Methods: Sixteen male patients with type 2 diabetes mellitus received 1 g TTA daily for 28 days in an open-labelled study, with measurement of parameters of lipid metabolism, glucose metabolism and safety (ClinicalTrials.gov NCT00605787). The mechanism of action was further investigated in a human liver cell line (HepG2) and in cultured human skeletal muscle cells (myotubes). Results: Mean LDL cholesterol level declined from 4.2 to 3.7 mmol/l (p < 0.001), accompanied by increased levels of the HDL apolipoproteins A1 and A2, and a decline in LDL/HDL ratio from 4.00 to 3.66 (p = 0.008). Total fatty acid levels declined, especially the fraction of the polyunsaturated n-3 fatty acids docosahexaenoic acid (−13%, p = 0.002) and eicosapentaenoic acid (−10%, p = 0.07). Glucose metabolism was not altered and the drug was well tolerated. In cultured liver cells, TTA acted as a pan-PPAR agonist with predominant PPAR-α and PPAR-δ activation at low TTA concentrations. In myotubes, TTA and a PPAR-δ agonist, but not the PPAR-α or PPAR-γ agonists, increased the fatty acid oxidation. Conclusions: We demonstrate for the first time that TTA attenuates dyslipidaemia in patients with type 2 diabetes mellitus. These effects may occur through mechanisms involving PPAR-α and PPAR-δ activation, resulting in increased mitochondrial fatty acid oxidation. [ABSTRACT FROM AUTHOR]

Variants in the gene encoding NACHT leucine-rich-repeat protein 1 (NALP1), an important molecule in innate immunity, have recently been shown to confer risk for vitiligo and associated autoimmunity. We hypothesized that sequence variants in this gene may be involved in susceptibility to a wider spectrum of autoimmune diseases. Investigating large patient cohorts from six different autoimmune diseases, that is autoimmune Addison's disease (n=333), type 1 diabetes (n=1086), multiple sclerosis (n=502), rheumatoid arthritis (n=945), systemic lupus erythematosus (n=156) and juvenile idiopathic arthritis (n=505), against 3273 healthy controls, we analyzed four single nucleotide polymorphisms (SNPs) in NALP1. The major allele of the coding SNP rs12150220 revealed significant association with autoimmune Addison's disease compared with controls (OR=1.25, 95% CI: 1.06–1.49, P=0.007), and with type 1 diabetes (OR=1.15, 95% CI: 1.04–1.27, P=0.005). Trends toward the same associations were seen in rheumatoid arthritis, systemic lupus erythematosus and, although less obvious, multiple sclerosis. Patients with juvenile idiopathic arthritis did not show association with NALP1 gene variants. The results indicate that NALP1 and the innate immune system may be implicated in the pathogenesis of many autoimmune disorders, particularly organ-specific autoimmune diseases.Genes and Immunity (2009) 10, 120–124; doi:10.1038/gene.2008.85; published online 23 October 2008 [ABSTRACT FROM AUTHOR]

Autoimmune Addison's disease (AAD) is often associated with other components in autoimmune polyendocrine syndromes (APS). Whereas APS I is caused by mutations in the AIRE gene, the susceptibility genes for AAD and APS II are unclear. In the present study, we investigated whether polymorphisms or copy number variations in the AIRE gene were associated with AAD and APS II. First, nine SNPs in the AIRE gene were analyzed in 311 patients with AAD and APS II and 521 healthy controls, identifying no associated risk. Second, in a subgroup of 25 of these patients, AIRE sequencing revealed three novel polymorphisms. Finally, the AIRE copy number was determined by duplex quantitative PCR in 14 patients with APS I, 161 patients with AAD and APS II and in 39 healthy subjects. In two Scandinavian APS I patients previously reported to be homozygous for common AIRE mutations, we identified large deletions of the AIRE gene covering at least exon 2 to exon 8. We conclude that polymorphisms in the AIRE gene are not associated with AAD and APS II. We further suggest that DNA analysis of the parents of patients found to be homozygous for mutations in AIRE, always should be performed.Genes and Immunity (2008) 9, 130–136; doi:10.1038/sj.gene.6364457; published online 17 January 2008 [ABSTRACT FROM AUTHOR]

Polymorphisms in the low-affinity Fc γ receptors (Fc γR) modulate their capacity to bind IgG and the subsequent immune response. Different Fc γR polymorphisms have been reported to be associated with susceptibility and severity of various autoimmune diseases. We wanted to investigate associations between Fc γR polymorphisms and autoimmune primary adrenal failure (Addison's disease). We have genotyped 149 patients with Addison's disease and 89 healthy controls for common polymorphisms in the genes coding for Fc γRIIa, Fc γRIIIa and Fc γRIIIb using polymerase chain reaction. Patients with Addison's disease and controls showed no differences in genotype distributions of Fc γRIIa, Fc γRIIIa and Fc γRIIIb. The results indicate that different Fc γR polymorphisms do not have an impact on immune responses involved in the development of autoimmune Addison's disease. [ABSTRACT FROM AUTHOR]

Background– The triad of progressive external ophthalmoplegia, atypical retinal pigmentation and cardiac conduction defects characterizes Kearns-Sayre syndrome (KSS), which is most often caused by a single, large deletion of mitochondrial DNA. Endocrine disease appears to be more common in KSS than in other mitochondrial diseases. Materials, methods and results– A patient presenting with KSS developed Addison’s disease, hypothyroidism and glucose intolerance. Thyroid peroxidase antibodies and adrenal 21-hydroxylase antibodies were identified. She developed acute respiratory failure requiring invasive ventilatory support, but improved and currently requires only non-invasive, nocturnal BiPAP treatment. Discussion and conclusion– This case confirms the association of KSS and endocrine dysfunction. Our finding of autoantibodies to thyroid and adrenal glands distinguishes this patient from most other published cases and suggests a potential synergy between the two disease mechanisms. In addition, we demonstrate that respiratory failure can be a treatable event in this disease. [ABSTRACT FROM AUTHOR]

Autoantibodies against many proteins are common in sera from patients with various types of cancer. These antibodies are sometimes involved in the development of conditions associated with cancer, such as paraneoplastic neurologic disorders. We used a human brain cDNA expression library and serum from a paraneoplastic neurologic disorder patient to search for new autoantigens in the nervous system. Pyridoxal phosphatase was identified as a novel autoantigen. Expression studies showed that pyridoxal phosphatase was strongly expressed in various parts of the central nervous system. Sera contained antibodies against pyridoxal phosphatase in 22 of 243 (9.1%) patients with lung cancer and eight of 113 (7.1%) with other forms of cancer vs two of 88 (2.3%) healthy control subjects. In addition, 2-4% of patients with different autoimmune diseases had autoantibodies against pyridoxal phosphatase. None of the antipyridoxal phosphatase-positive patients were known to have a paraneoplastic neurologic disorder. Hence, autoantibodies against pyridoxal phosphatase correlate with cancer but not necessarily with the subset of patients with paraneoplastic neurological disorders although serum from such a patient was used to screen the cDNA library. This study showed that yet another enzyme involved in pyridoxal 5'-phosphate metabolism is an autoantigen. Thus, pyridoxal 5'-phosphate seems to be a common denominator for autoantigens involved in autoimmune diseases. [ABSTRACT FROM AUTHOR]

Background: Endoscopic ultrasonography (EUS) is generally accepted as a sensitive method for the detection of small pancreatic tumors. We report our experience with EUS for preoperative imaging of insulinomas. Methods: Nine patients with clinical and biochemical signs of insulinoma were examined by EUS using a 7.5/12 MHz radial-scanning ultrasound endoscope prior to surgery. EUS outcome was evaluated on the basis of surgery (open or laparoscopic) and examination of the resected specimens. Results: Two EUS-negative patients appeared, by reassessment of clinical and biochemical data, not to have an insulinoma and were not operated on. EUS correctly imaged and localized five of seven insulinomas that were surgically removed. One isoechoic tumor in the pancreatic head and one pedunculated tumor connected to the caudal side of the pancreatic body were missed by EUS. EUS could demonstrate the size and shape of the imaged tumors, as well as their relationship to adjacent structures, such as the pancreatic duct, bile duct, and large vessels. Conclusions: Our experience with seven insulinomas accords with previous reports claiming EUS to be the method of choice for preoperative imaging and localization of pancreatic islet cell tumors. [ABSTRACT FROM AUTHOR]