Differential insulitic profiles determine the extent of beta cell destruction and the age at onset of type 1 diabetes

Published onlineJOURNAL ARTICLEType 1 diabetes (T1D) results from a T-cell mediated destruction of pancreatic beta cells following the infiltration of leukocytes (including CD8+, CD4+ and CD20+ cells) into and around pancreatic islets ("insulitis"). Recently, we reported that two distinct patterns of insulitis occur in patients with recent-onset T1D from the UK and that these differ principally in the proportion of infiltrating CD20+ B-cells (designated "CD20Hi" and "CD20Lo" respectively). We have now extended this analysis to include patients from the nPOD (USA) and DiViD (Norway) cohorts and confirm that the two profiles of insulitis occur more widely. Moreover, we show that patients can be directly stratified according to their insulitic profile and that those receiving a diagnosis before the age of 7 years always display the CD20Hi profile. By contrast, individuals diagnosed beyond the age of 13 years are uniformly defined as CD20Lo. This implies that the two forms of insulitis are differentially aggressive and that patients with a CD20Hi profile lose their beta cells at a more rapid rate. In support of this, we also find that the proportion of residual insulin-containing islets (ICIs) increases in parallel with age at onset of T1D. Importantly, those diagnosed in, or beyond, their teenage years retain ∼40% ICIs at diagnosis, implying that a functional deficit rather than absolute beta cell loss may be causal for disease onset in these patients. We conclude that appropriate patient stratification will be critical for correct interpretation of the outcomes of intervention therapies targeted to islet-infiltrating immune cells in T1D

Influence of dietary administration of organic acids and increased feed structure on S. typhimurium infection in pigs

Several epidemiological investigations and reports from advisors practicing in swine herds have independent of each other pointed out commercial feed mixes compared to home mixed feed and dry feed compared to wet fermented feed to be the most important risk factors for increased Salmonella infection levels in Danish slaughter pigs (Dahl (1997), Stege (1997))

HLA class I upregulation and antiviral immune responses in Graves' disease

This is the final version. Available on open access from Oxford University Press via the DOI in this record. Data Availability: Restrictions apply to some or all the availability of data generated or analyzed during this study to preserve patient confidentiality. The corresponding author will on request detail the restrictions and any conditions under which access to some data may be provided.CONTEXT: The origin of Graves' disease (GD) remains elusive. However, evidence of an association between GD and viral infections is emerging. Human leukocyte antigen (HLA) class I presents viral antigens to circulating immune cells and plays a crucial role in the defense against viral infections. OBJECTIVE: To investigate HLA class I expression, enterovirus presence and the viral immune response proteins signal transducer and activation of transcription 1 (STAT1) and protein kinase R (PKR) in thyroid tissue from GD patients. DESIGN AND PATIENTS: We collected thyroid tissue from core needle biopsies or surgical specimens from 48 GD patients and 24 controls. Standard immunohistochemistry was used to detect HLA class I and enteroviral capsid protein 1 (VP1) on formalin-fixed and paraffin-embedded tissue. STAT1 and PKR were examined by combined immunofluorescence staining. MAIN OUTCOME MEASURES: HLA class I expression score. RESULTS: The HLA class I expression score, which takes both proportion and intensity of immunostaining into account, was significantly higher in GDs (3.1±3.3) than in controls (0.5±0.9) (p<0.001). Significantly more VP1 positive thyroid cells were found GD samples (50.1± 30.5%) than in controls (14.9±10.5%) (p<0.001). STAT1 and HLA class I was found within the same thyroid cells and PKR and VP1 were also colocalized within thyroid cells. CONCLUSION: HLA class I is upregulated in GD and enterovirus protein is prevalent in thyroid tissue. The colocalization of HLA class I with STAT1 and VP1 with PKR indicates an antiviral tissue response. These findings support the concept of a link between viral infections and GD.European Union FP7(FP7/2007-2013)South-Eastern Norway Regional Health Authority (Helse Sør-Øst)University of OsloDiabetes Research Foundatio

Immunological changes and increased expression of myxovirus resistance protein a in thyroid tissue of patients with recent onset and untreated Graves' disease

Background: Few studies have systematically examined the immune cells that infiltrate thyroid tissue at the time of the onset of Graves&#39; disease (GD). The role of viruses in the pathogenesis of autoimmune thyroid diseases is controversial. The present study analyzed inflammatory responses with respect to signs of virus infection. Methods: Thyroid tissue was obtained from 22 patients with newly diagnosed and untreated GD, 24 patients with chronic GD, and 24 controls. Inflammation was assessed by immunostaining for CD4+ and CD8+ T cells, plasma cells (CD138+), and plasmacytoid dendritic cells (PDCs). The production of interferon-inducible myxovirus resistance protein A (MxA) was analyzed as a sign of virus infection. Results: The degree of thyroid inflammation and fibrosis was significantly higher in both patient groups compared with that in controls. The number of CD4+ T cells and plasma cells (activated B cells) was significantly higher in both patient groups. CD8+ cells were only present in patients with chronic disease. MxA expression and the number of PDCs increased only in patients with newly diagnosed GD. There was a strong positive correlation between the number of PDCs and the number of MxA+ leucocytes. Conclusion: The increase in CD8+ T cells during the chronic stage of GD suggests that they may play a role in progression of the autoimmune process from early to chronic thyroiditis. Upregulation of MxA expression during the early stages of the disease, and the positive correlation between the number of PDCs and the number of MxA+ leucocytes, suggests that activated PDCs secrete type I IFNs at the lesion site, possibly in response to viral infection. &nbsp;</p

Detection of a low-grade enteroviral infection in the islets of Langerhans of living patients newly diagnosed with type 1 diabetes

Journal ArticleThis is an author-created, uncopyedited electronic version of an article accepted for publication in Diabetes. The American Diabetes Association (ADA), publisher of Diabetes, is not responsible for any errors or omissions in this version of the manuscript or any version derived from it by third parties. The definitive publisher-authenticated version is available in Diabetes, May 2015, vol. 64, no. 5 pp. 1682-1687 in print and online at http://diabetes.diabetesjournals.org/content/64/5/1682.abstractThe Diabetes Virus Detection study (DiViD) is the first to examine fresh pancreatic tissue at the diagnosis of type 1 diabetes for the presence of viruses. Minimal pancreatic tail resection was performed 3-9 weeks after onset of type 1 diabetes in six adult patients (age 24-35 years). The presence of enteroviral capsid protein 1 (VP1) and the expression of class I HLA were investigated by immunohistochemistry. Enterovirus RNA was analyzed from isolated pancreatic islets and from fresh-frozen whole pancreatic tissue using PCR and sequencing. Nondiabetic organ donors served as controls. VP1 was detected in the islets of all type 1 diabetic patients (two of nine controls). Hyperexpression of class I HLA molecules was found in the islets of all patients (one of nine controls). Enterovirus-specific RNA sequences were detected in four of six patients (zero of six controls). The results were confirmed in various laboratories. Only 1.7% of the islets contained VP1(+) cells, and the amount of enterovirus RNA was low. The results provide evidence for the presence of enterovirus in pancreatic islets of type 1 diabetic patients, which is consistent with the possibility that a low-grade enteroviral infection in the pancreatic islets contributes to disease progression in humans.Academy of FinlandSouth-Eastern Norway Regional HealthAuthorityNovo Nordisk FoundationPEVNET (Persistent Virus Infection in Diabetes Network) Study GroupEuropean Union’s Seventh Framework ProgrammeSwedish Medical Research CouncilDiabetes Wellness FoundationJDR

Parental rating of sleep in children with attention deficit/hyperactivity disorder

Objective: Sleep problems have often been associated with attention deficit/hyperactivity disorder (ADHD). Parents of those with ADHD and children with ADHD report sleep difficulties more frequently than healthy children and their parents. The primary objective of this paper is to describe sleep patterns and problems of 5 to 11-year-old children suffering from ADHD as described by parental reports and sleep questionnaires. Method: The study included 321 children aged 5–11 years (average age 8.4 years); 45 were diagnosed with ADHD, 64 had other psychiatric diagnoses, and 212 were healthy. One hundred and ninety-six of the test subjects were boys and 125 were girls. A semi-structured interview (Kiddie-SADS-PL) was used to DSM-IV diagnose ADHD and comorbidity in the clinical group. Sleep difficulties were rated using a structured sleep questionnaire (Children Sleep Behaviour Scale). Results: Children diagnosed with ADHD had a significantly increased occurrence of sleep problems. Difficulties relating to bedtime and unsettled sleep were significantly more frequent in the ADHD group than in the other groups. Children with ADHD showed prolonged sleep onset latency, but no difference was shown regarding numbers of awakenings per night and total sleep time per night. Comorbid oppositional defiant disorder appeared not to have an added effect on problematic behaviour around bedtime. Conclusion: Parents of children with ADHD report that their children do not sleep properly more often than other parents. The ADHD group report problems with bedtime resistance, problems with sleep onset latency, unsettled sleep and nightmares more often than the control groups. It may therefore be relevant for clinicians to initiate a closer examination of those cases reporting sleep difficulties

Loss of sucrase-isomaltase function increases acetate levels and improves metabolic health in Greenlandic cohorts

Background & Aims The sucrase-isomaltase (SI) c.273_274delAG loss-of-function variant is common in Arctic populations and causes congenital sucrase-isomaltase deficiency, which is an inability to break down and absorb sucrose and isomaltose. Children with this condition experience gastrointestinal symptoms when dietary sucrose is introduced. We aimed to describe the health of adults with sucrase-isomaltase deficiency. Methods The association between c.273_274delAG and phenotypes related to metabolic health was assessed in 2 cohorts of Greenlandic adults (n = 4922 and n = 1629). A sucrase-isomaltase knockout (Sis-KO) mouse model was used to further elucidate the findings. Results Homozygous carriers of the variant had a markedly healthier metabolic profile than the remaining population, including lower body mass index (β [standard error], –2.0 [0.5] kg/m2; P = 3.1 × 10–5), body weight (–4.8 [1.4] kg; P = 5.1 × 10–4), fat percentage (–3.3% [1.0%]; P = 3.7 × 10–4), fasting triglyceride (–0.27 [0.07] mmol/L; P = 2.3 × 10–6), and remnant cholesterol (–0.11 [0.03] mmol/L; P = 4.2 × 10–5). Further analyses suggested that this was likely mediated partly by higher circulating levels of acetate observed in homozygous carriers (β [standard error], 0.056 [0.002] mmol/L; P = 2.1 × 10–26), and partly by reduced sucrose uptake, but not lower caloric intake. These findings were verified in Sis-KO mice, which, compared with wild-type mice, were leaner on a sucrose-containing diet, despite similar caloric intake, had significantly higher plasma acetate levels in response to a sucrose gavage, and had lower plasma glucose level in response to a sucrose-tolerance test. Conclusions These results suggest that sucrase-isomaltase constitutes a promising drug target for improvement of metabolic health, and that the health benefits are mediated by reduced dietary sucrose uptake and possibly also by higher levels of circulating acetate