Effect of Hydrolyzed Infant Formula vs Conventional Formula on Risk of Type 1 Diabetes: The TRIGR Randomized Clinical Trial.

Importance: Early exposure to complex dietary proteins may increase the risk of type 1 diabetes in children with genetic disease susceptibility. There are no intact proteins in extensively hydrolyzed formulas. Objective: To test the hypothesis that weaning to an extensively hydrolyzed formula decreases the cumulative incidence of type 1 diabetes in young children. Design, Setting, and Participants: An international double-blind randomized clinical trial of 2159 infants with human leukocyte antigen-conferred disease susceptibility and a first-degree relative with type 1 diabetes recruited from May 2002 to January 2007 in 78 study centers in 15 countries; 1081 were randomized to be weaned to the extensively hydrolyzed casein formula and 1078 to a conventional formula. The follow-up of the participants ended on February 28, 2017. Interventions: The participants received either a casein hydrolysate or a conventional adapted cow's milk formula supplemented with 20% of the casein hydrolysate. The minimum duration of study formula exposure was 60 days by 6 to 8 months of age. Main Outcomes and Measures: Primary outcome was type 1 diabetes diagnosed according to World Health Organization criteria. Secondary outcomes included age at diabetes diagnosis and safety (adverse events). Results: Among 2159 newborn infants (1021 female [47.3%]) who were randomized, 1744 (80.8%) completed the trial. The participants were observed for a median of 11.5 years (quartile [Q] 1-Q3, 10.2-12.8). The absolute risk of type 1 diabetes was 8.4% among those randomized to the casein hydrolysate (n = 91) vs 7.6% among those randomized to the conventional formula (n = 82) (difference, 0.8% [95% CI, -1.6% to 3.2%]). The hazard ratio for type 1 diabetes adjusted for human leukocyte antigen risk group, duration of breastfeeding, duration of study formula consumption, sex, and region while treating study center as a random effect was 1.1 (95% CI, 0.8 to 1.5; P = .46). The median age at diagnosis of type 1 diabetes was similar in the 2 groups (6.0 years [Q1-Q3, 3.1-8.9] vs 5.8 years [Q1-Q3, 2.6-9.1]; difference, 0.2 years [95% CI, -0.9 to 1.2]). Upper respiratory infections were the most common adverse event reported (frequency, 0.48 events/year in the hydrolysate group and 0.50 events/year in the control group). Conclusions and Relevance: Among infants at risk for type 1 diabetes, weaning to a hydrolyzed formula compared with a conventional formula did not reduce the cumulative incidence of type 1 diabetes after median follow-up for 11.5 years. These findings do not support a need to revise the dietary recommendations for infants at risk for type 1 diabetes. Trial Registration: clinicaltrials.gov Identifier: NCT00179777.

Population-based incidence of diabetes in Australian youth aged 10-18 yr: increase in type 1 diabetes but not type 2 diabetes.

BACKGROUND: Global incidence of childhood type 2 diabetes has increased, with a greater rise amongst certain ethnic groups. OBJECTIVES: To examine the change in the incidence of type 1 and type 2 diabetes in Australian youth, aged 10-18 yr, in New South Wales, Australia. METHODS: Prospective population-based incidence study (2001-2008). Primary case ascertainment was from the Australasian Paediatric Endocrine Group Diabetes Register, secondary independent ascertainment from the National Diabetes Register. RESULTS: There were 202 incident cases of type 2 diabetes (96 boys, 48%). The mean age at diagnosis (±SD) was 14.6 ± 2.5 yr; 93% were overweight (International Obesity Taskforce Grade ≥1). Mean HbA1c was 8.8 ± 2.8%. Ethnicity was Caucasian 31%, Indigenous Australian 20%, Southeast Asian 11%, North African/Middle Eastern 9%, and NewZealander/Melanesian/Polynesian 8%. The mean annual incidence of type 2 diabetes was 3.0 per 100 000 per year (95% confidence interval (CI): 2.6-3.4) and did not change over time. The mean annual incidence of type 1 diabetes was 22.0 per 100 000 per year (95% CI: 20.8-23.1), and increased by 3.8% per year [incidence rate ratio IRR: 1.04, 95% CI: 1.02-1.06, p = 0.001]. Incidence was higher in Indigenous vs. non-Indigenous youth, IRR: 6.9 (95% CI: 4.7-10.2, p < 0.001). CONCLUSION: In 10-18 yr old youth, in Australia, the incidence of type 2 diabetes has remained steady during the last decade; however, the incidence of type 1 diabetes continues to rise. Most common diabetes in Australian youth is type 1 diabetes.

Hydrolyzed infant formula and early ß-cell autoimmunity: a randomized clinical trial.

IMPORTANCE: The disease process leading to clinical type 1 diabetes often starts during the first years of life. Early exposure to complex dietary proteins may increase the risk of ß-cell autoimmunity in children at genetic risk for type 1 diabetes. Extensively hydrolyzed formulas do not contain intact proteins. OBJECTIVE: To test the hypothesis that weaning to an extensively hydrolyzed formula decreases the cumulative incidence of diabetes-associated autoantibodies in young children. DESIGN, SETTING, AND PARTICIPANTS: A double-blind randomized clinical trial of 2159 infants with HLA-conferred disease susceptibility and a first-degree relative with type 1 diabetes recruited from May 2002 to January 2007 in 78 study centers in 15 countries; 1078 were randomized to be weaned to the extensively hydrolyzed casein formula and 1081 were randomized to be weaned to a conventional cows' milk-based formula. The participants were observed to April 16, 2013. INTERVENTIONS: The participants received either a casein hydrolysate or a conventional cows' milk formula supplemented with 20% of the casein hydrolysate. MAIN OUTCOMES: AND MEASURES: Primary outcome was positivity for at least 2 diabetes-associated autoantibodies out of 4 analyzed. Autoantibodies to insulin, glutamic acid decarboxylase, and the insulinoma-associated-2 (IA-2) molecule were analyzed using radiobinding assays and islet cell antibodies with immunofluorescence during a median observation period of 7.0 years (mean, 6.3 years). RESULTS: The absolute risk of positivity for 2 or more islet autoantibodies was 13.4% among those randomized to the casein hydrolysate formula (n = 139) vs 11.4% among those randomized to the conventional formula (n = 117). The unadjusted hazard ratio for positivity for 2 or more autoantibodies among those randomized to be weaned to the casein hydrolysate was 1.21 (95% CI, 0.94-1.54), compared with those randomized to the conventional formula, while the hazard ratio adjusted for HLA risk, duration of breastfeeding, vitamin D use, study formula duration and consumption, and region was 1.23 (95% CI, 0.96-1.58). There were no clinically significant differences in the rate of reported adverse events between the 2 groups. CONCLUSIONS AND RELEVANCE: Among infants at risk for type 1 diabetes, the use of a hydrolyzed formula, when compared with a conventional formula, did not reduce the incidence of diabetes-associated autoantibodies after 7 years. These findings do not support a benefit from hydrolyzed formula. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00179777.

A diabetes awareness campaign prevents diabetic ketoacidosis in children at their initial presentation with type 1 diabetes.

OBJECTIVE: To evaluate the effect of a diabetes awareness campaign on the incidence of diabetic ketoacidosis (DKA) at the first presentation of type 1 diabetes in children (0-18 yr). METHODS: This study was a controlled population intervention study with a 2-yr baseline period and a 2-yr intervention period. Data were collected on all children presenting with their initial diagnosis of type 1 diabetes [pH, bicarbonate, base excess, blood glucose level (BGL), urea, and creatinine] at Gosford, Newcastle, and Sydney (Sydney Children's Hospital and Royal North Shore Hospital). During the intervention period, diabetes education occurred in the intervention region (Gosford). Child care centers, schools, and doctor's offices were offered education and posters about the symptoms of type 1 diabetes. Doctor's offices were given glucose and ketone testing equipment. The control regions (Newcastle and Sydney) did not receive any educational intervention or test equipment. DKA was defined as pH < 7.3 or bicarbonate < 15 mmol/L. RESULTS: In Gosford, the proportion of children presenting in DKA decreased from 37.5% (15/40) during the 2-yr baseline period to 13.8% (4/29) during the 2-yr intervention (p < 0.03). There was no significant change in the control regions during the same time periods, 37.4% (46/123) and 38.6% (49/127), respectively. In Gosford, the average BGL at presentation was 27.5 mmol/L during the baseline and 21.2 mmol/L during the intervention (p < 0.01). CONCLUSION: During the diabetes awareness campaign, the rate of DKA at initial diagnosis of type 1 diabetes in children decreased by 64%.

Universal Subsidized Continuous Glucose Monitoring Funding for Young People With Type 1 Diabetes: Uptake and Outcomes Over 2 Years, a Population-Based Study.

OBJECTIVE: Continuous glucose monitoring (CGM) is increasingly used in type 1 diabetes management; however, funding models vary. This study determined the uptake rate and glycemic outcomes following a change in national health policy to introduce universal subsidized CGM funding for people with type 1 diabetes aged <21 years. RESEARCH DESIGN AND METHODS: Longitudinal data from 12 months before the subsidy until 24 months after were analyzed. Measures and outcomes included age, diabetes duration, HbA1c, episodes of diabetic ketoacidosis and severe hypoglycemia, insulin regimen, CGM uptake, and percentage CGM use. Two data sources were used: the Australasian Diabetes Database Network (ADDN) registry (a prospective diabetes database) and the National Diabetes Service Scheme (NDSS) registry that includes almost all individuals with type 1 diabetes nationally. RESULTS: CGM uptake increased from 5% presubsidy to 79% after 2 years. After CGM introduction, the odds ratio (OR) of achieving the HbA1c target of <7.0% improved at 12 months (OR 2.5, P < 0.001) and was maintained at 24 months (OR 2.3, P < 0.001). The OR for suboptimal glycemic control (HbA1c ≥9.0%) decreased to 0.34 (P < 0.001) at 24 months. Of CGM users, 65% used CGM >75% of time, and had a lower HbA1c at 24 months compared with those with usage <25% (7.8 ± 1.3% vs. 8.6 ± 1.8%, respectively, P < 0.001). Diabetic ketoacidosis was also reduced in this group (incidence rate ratio 0.49, 95% CI 0.33-0.74, P < 0.001). CONCLUSIONS: Following the national subsidy, CGM use was high and associated with sustained improvement in glycemic control. This information will inform economic analyses and future policy and serve as a model of evaluation diabetes technologies.

Autonomic nerve testing predicts the development of complications: a 12-year follow-up study.

OBJECTIVE: Cardiac autonomic nerve tests have predicted increased mortality in adults with diabetes, predominantly due to nephropathy, cardiac disease, and hypoglycemia. The significance of subclinical autonomic nerve test abnormalities has not been systematically studied in adolescents. We aimed to reassess an adolescent cohort, whose autonomic nervous system had been tested 12 years earlier by both pupillometry and cardiovascular tests. RESEARCH DESIGN AND METHODS: From 1990 to 1993, adolescents with type 1 diabetes (n = 335) were assessed for autonomic neuropathy (median age 14.7 years [interquartile range 13.0-16.8], duration of diabetes 6.3 years [4.0-9.6], and A1C 8.3% [7.5-9.4]). Between 2003 and 2005, contact was made with 59% of the original group. Individual assessment 12 years later included completion of a validated hypoglycemia unawareness questionnaire (n = 123) and urinary albumin-to-creatinine ratio (n = 99) and retinal (n = 102) screening, as well as analysis of reports from external doctors (n = 35). RESULTS: At baseline, there was no difference in age, duration of diabetes, or complications between those who participated in the follow-up phase (n = 137) and those who did not participate (n = 196). However, baseline A1C was lower in the follow-up participants (8.2 vs. 8.5% for participants vs. nonparticipants, respectively, P = 0.031). At 12 years of follow-up, 93% were aware and 7% were unaware that they had hypoglycemia; 32 (31%) had no retinopathy, but 10% required laser therapy, and 80 (81%) had no microalbuminuria. Small pupil size at baseline was independently associated with the development of microalbuminuria (odds ratio 4.36 [95% CI 1.32-14.42], P = 0.016) and retinopathy (4.83 [1.3-17.98], P = 0.019) but not with the development of hypoglycemia unawareness. There was no association with baseline cardiovascular tests and the development of complications 12 years later. CONCLUSIONS: In this study, we found an association between baseline pupillometry tests and the presence of microalbuminuria and retinopathy at 12 years of follow-up. This suggests that pupillometry abnormalities may be early indicators of patients who are at high risk of future microvascular disease.

Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes.

BACKGROUND: Patients with permanent neonatal diabetes usually present within the first three months of life and require insulin treatment. In most, the cause is unknown. Because ATP-sensitive potassium (K(ATP)) channels mediate glucose-stimulated insulin secretion from the pancreatic beta cells, we hypothesized that activating mutations in the gene encoding the Kir6.2 subunit of this channel (KCNJ11) cause neonatal diabetes. METHODS: We sequenced the KCNJ11 gene in 29 patients with permanent neonatal diabetes. The insulin secretory response to intravenous glucagon, glucose, and the sulfonylurea tolbutamide was assessed in patients who had mutations in the gene. RESULTS: Six novel, heterozygous missense mutations were identified in 10 of the 29 patients. In two patients the diabetes was familial, and in eight it arose from a spontaneous mutation. Their neonatal diabetes was characterized by ketoacidosis or marked hyperglycemia and was treated with insulin. Patients did not secrete insulin in response to glucose or glucagon but did secrete insulin in response to tolbutamide. Four of the patients also had severe developmental delay and muscle weakness; three of them also had epilepsy and mild dysmorphic features. When the most common mutation in Kir6.2 was coexpressed with sulfonylurea receptor 1 in Xenopus laevis oocytes, the ability of ATP to block mutant K(ATP) channels was greatly reduced. CONCLUSIONS: Heterozygous activating mutations in the gene encoding Kir6.2 cause permanent neonatal diabetes and may also be associated with developmental delay, muscle weakness, and epilepsy. Identification of the genetic cause of permanent neonatal diabetes may facilitate the treatment of this disease with sulfonylureas.

Prevalence of diabetes complications in adolescents with type 2 compared with type 1 diabetes.

OBJECTIVE: To compare the prevalence of diabetes complications and their risk factors in youth with type 1 versus type 2 diabetes. RESEARCH DESIGN AND METHODS: We performed a comparative clinic-based study of 1,433 patients with type 1 diabetes and 68 patients with type 2 diabetes aged <18 years from New South Wales, Australia. Retinopathy was assessed by seven-field stereoscopic retinal photography; albumin excretion rate from three consecutive, timed, overnight urine collections; peripheral neuropathy by thermal and vibration threshold; and autonomic neuropathy by pupillometry. HbA(1c) (A1C) and lipids were measured in all patients and C-peptide in patients with type 2 diabetes. RESULTS: In patients with type 1 versus type 2 diabetes, median (interquartile range) age was 15.7 years (13.9-17.0) and 15.3 years (13.6-16.4), respectively (P = 0.2), whereas median diabetes duration was 6.8 years (4.7-9.6) and 1.3 years (0.6-3.1), respectively (P < 0.0001). Retinopathy was significantly more common in patients with type 1 diabetes (20 vs. 4%, P = 0.04), while microalbuminuria and hypertension were significantly less common (6 and 16% in type 1 diabetes vs. 28 and 36% in type 2 diabetes). Rates of peripheral and autonomic neuropathy were similar (27 and 61% in type 1 diabetes vs. 21 and 57% in type 2 diabetes). In multivariate analyses, microalbuminuria was significantly associated with older age (odds ratio 1.3 [95% CI 1.2-1.5], P < 0.001) and systolic hypertension (3.63 [2.0-6.3], P < 0.001) in type 1 diabetes, while only higher A1C (1.7 [1.3-2.9], P = 0.002) was significant in patients with type 2 diabetes. CONCLUSIONS: Youth with type 2 diabetes have significantly higher rates of microalbuminuria and hypertension than their peers with type 1 diabetes, despite shorter diabetes duration and lower A1C. The results of this study support recommendations for early complications screening and aggressive targeting of glycemic control in patients with type 2 diabetes.

The case for biennial retinopathy screening in children and adolescents.

OBJECTIVE: Current guidelines recommend annual retinopathy screening 2 years after onset (for pubertal-onset type 1 diabetes) and after 5 years (or age 11, whichever is earlier) for prepubertal onset. Our aim was to describe the natural history of retinopathy and to explore optimal retinal screening intervals for children and adolescents (aged <20 years) screened according to these guidelines. RESEARCH DESIGN AND METHODS: More than 1,000 children and adolescents, followed longitudinally, were screened for retinopathy using seven-field stereoscopic fundus photography through dilated pupils. Of these, 668 had baseline and follow-up retinal screening. Using generalized estimating equations, we compared the risk of retinopathy with baselines at yearly intervals, in older and younger groups, in higher risk groups (diabetes duration >10 years or HbA(1c) >10% at any screening), and after stratification 10% recorded at any visit, retinopathy increased significantly after 2 years (P = 0.001) but not until 3 years in the group whose HbA(1c) was always 2 years later. Individuals with especially poor control, duration >10 years, or significant retinopathy should be screened more frequently.

Discordant trends in microvascular complications in adolescents with type 1 diabetes from 1990 to 2002.

OBJECTIVE: Since the Diabetes Control and Complications Trial, diabetes management goals have changed. The aims of the present study were to assess complication rates, including nerve abnormalities, in adolescents from 1990 to 2002 and to investigate associated risk factors. RESEARCH DESIGN AND METHODS: Cross-sectional analysis of complications was assessed in three study periods (1990-1994 [T1], 1995-1998 [T2], and 1999-2002 [T3]) in adolescents matched for age and diabetes duration (n = 878, median age 14.6 years, median duration 7.5 years). Retinopathy was assessed by seven-field stereoscopic fundal photography, albumin excretion rate (AER) from three consecutive timed overnight urine collections, peripheral nerve function by thermal and vibration thresholds, and autonomic nerve function by cardiovascular reflexes. RESULTS: Retinopathy declined significantly (T1, 49%; T2, 31%; and T3, 24%; P < 0.0001), early elevation of AER (> or = 7.5 microg/min) declined (38, 30, and 25%, respectively, P = 0.022), and microalbuminuria (AER > or = 20 microg/min) declined (7, 3, and 3%, respectively; P = 0.017, T1 vs. T2 and T3). Autonomic nerve abnormalities were unchanged (18, 21, and 18%, respectively; P = 0.60), but peripheral nerve abnormalities increased (12, 19, and 24%, respectively; P = 0.0017). More patients were treated with three or more injections per day (12, 46, and 67%, respectively; P < 0.0001) and insulin dose increased (1.08, 1.17, and 1.22 units x kg(-1) x day(-1), respectively; P < 0.0001), but median HbA(1c) (A1C) was unchanged (8.5, 8.5, and 8.4%, respectively). BMI and height SD score increased: BMI 0.46, 0.67, and 0.79, respectively (P < 0.0001), and height -0.09, 0.05, and 0.27, respectively (P < 0.0001). CONCLUSIONS: Retinopathy and microalbuminuria declined over time in this cohort, but the increased rate of peripheral nerve abnormalities is of concern. Despite intensified management (higher insulin dose and more injections), A1C has not changed and remains well above the recommended targets for adolescents.

Do all prepubertal years of diabetes duration contribute equally to diabetes complications?

OBJECTIVE: This study was designed to explore the timeline of protection against complications in prepubertal children with diabetes, in particular the effects of diabetes duration before age 5 years. RESEARCH DESIGN AND METHODS: In this study, 193 adolescents with prepubertal diabetes onset were followed longitudinally for retinopathy (early background and clinical) and microalbuminuria (albumin excretion rate >7.5 micro g/min and >20 micro g/min). Multiple logistic regression analysis was used to compare the effect of pre- and postpubertal diabetes duration on the risk of each complication in 90 subjects reassessed as young adults. For the entire cohort, Kaplan-Meier estimates were used to determine time free of each complication, and survival was compared in those diagnosed before and after age 5 years. Accelerated failure time modeling was used to estimate the effect of covariates, including diabetes duration before puberty, on the risk of complications. RESULTS: Prepubertal duration improved the prediction for retinopathy over postpubertal duration alone in the young adults. The survival-free period of retinopathy and microalbuminuria was significantly longer (2-4 years) for those diagnosed before age 5 years compared with those diagnosed after age 5 years. Time to onset of all complications increased progressively with longer diabetes duration before gonadarche. Higher HbA(1c) during adolescence had an independent effect on the risk of retinopathy and microalbuminuria. CONCLUSIONS: Prepubertal diabetes duration remains a significant predictor of retinopathy in young adults. The effect of time on the risk of retinopathy and microalbuminuria is nonuniform, with an increasing delay in the onset of complications in those with longer prepubertal duration. These findings are of major clinical importance when setting targets of glycemic control in young children who are at greatest risk of hypoglycemia.

The virus-induced HSPs regulate the apoptosis of operatus APCs that result in autoimmunity, not in homeostasis.

The viruses stand salient as environmental factors that trigger autoimmunity. The virus realizes its effects through induction of heat-shock proteins (HSPs) as well as by the viral IE-axis-mediated conversion of organ epithelial cells into virgin de novo professional antigen-presenting cells (APCs). The HSP is the accomplished operator in homeostasis by the logic of it being the regulator of apoptosis. By virtue of its regulation of apoptosis, the HSP is also involved in autoimmunity: (1) adornment of viral IE-axis-generated virgin de novo professional APCs with HSP-induced co-stimulatory molecules which transform these otherwise epithelial cells to competent antigen presenters, the operatus APCs, liable to apoptosis that becomes the initiator of organ damages; (2) molecular mimicry mechanism: epitopes on the HSP may be mistaken for viral peptides and be presented by operatus APCs to autoreactive TCRs resulting in the apoptosis of the operatus APCs; (3) regulation of MHC class II DR-mediated apoptosis of operatus APCS which can result in organ-specific autoimmune syndromes. We should remember, however, that Nature's intended purpose for apoptosis of the professional APCs is benevolence: as a principal regulator of immune homeostasis. But the apoptosis of our postulated operatus APCs can result in autoimmunity. The transformation of virgin de novo professional APCs to operatus APCs mirrors the maturation of DCs through their acquisition of HSP-induced costimulatory molecules. What happens to mature DCs as antigen presenters that end in homeostasis is replicated by what happens to operatus APCs that ends instead in autoimmunity.

The virus-induced HSPs regulate the apoptosis of operatus APCs that results in autoimmunity, not in homeostasis.

The viruses are salient in the roles of environmental factors that trigger autoimmunity. The virus realizes its effects by the power of its induction of heat shock proteins (HSPs) as well as by the viral IE-axis-mediated conversion of organ epithelial cells into virgin de novo professional antigen-presenting cells (APCs). The HSP is the accomplished operator in homeostasis by the logic of it being the regulator of apoptosis. That HSP which regulates and controls different points in the pathways of apoptosis is rationally propitious as both HSP and apoptosis are highly conserved in multicellular organisms. By virtue of its regulation of apoptosis, the HSP is also involved in human autoimmunity and this involvement is tripartite: (i) adornment of viral IE-axis-generated virgin de novo professional APCs with HSP-induced co-stimulatory molecules which transform these otherwise epithelial cells to achieve the status of fledged competent antigen-presenters, the operatus APCs, which are liable to apoptosis that becomes the initiator of organ damages that can culminate in the autoimmune syndrome(s); apoptosis is a routine fate that befalls all APCs following their antigen presentation; (ii) molecular mimicry mechanism: epitopes on the HSP may be mistaken for viral peptides and be presented by operatus APCs to autoreactive TCRs resulting in the apoptosis of the operatus APCs; and (iii) regulation of MHC class II-DR-mediated apoptosis of operatus APCs which can ultimately consequent in organ-specific autoimmune syndromes. We should remember, however, that Nature's intended purpose for the apoptosis of the professional APCs is benevolence: as a principal regulator of homeostasis. It is only from the apoptosis of our postulated operatus APCs that the apoptotic consequence can be deleterious, an autoimmune syndrome(s). The transformation of virgin de novo professional APCs to operatus APCs mirrors the maturation of DCs, through their acquisition of HSP-induced co-stimulatory molecules; and what happens to mature DCs as antigen-presenters that ends in homeostasis is replicated by what happens to operatus APCs that ends instead in autoimmune syndromes (Fig. 1).

The mosaic of environment involvement in autoimmunity: the abrogation of viral latency by stress, a non-infectious environmental agent, is an intrinsic prerequisite prelude before viruses can rank as infectious environmental agents that trigger autoimmune diseases.

An autoimmune disease (AD), organ-specific or systemic, results from an aberrant response in which the protective immune system normally schooled to recognize and destroy invading infectious agents (viruses, etc.) instead fails to distinguish self-antigens and proceeds to attack and destroy the host's organs. There can be familial aggregation in which a single AD may occur in members of a family, or a single family may be afflicted with multiple ADs. Finally, sometimes multiple ADs co-occur in a single individual: the kaleidoscope of autoimmunity. Autoimmunity is a multifactorial process in which genetic, hormonal, immunological and environmental factors act in concert to materialize the mosaic of autoimmunity phenomenon. A genetically primed individual may yet not develop an AD: the contribution by an environmental factor (non-infectious or infectious) is essential for completion of the act. Of the non-infectious factors, stress plays a determinative step in autoimmunity in that it abrogates viral latency and thereby ordains the viruses to qualify as infectious environmental factors that trigger ADs. This is note-worthy as viruses rank first as the most important environmental triggers of ADs. Furthermore, all these viruses experience going through latency. Hence the hypothesis: "The abrogation of viral latency by stress, a non-infectious environmental agent, is an intrinsic prerequisite prelude before viruses can rank as infectious environmental agents that trigger autoimmune diseases". There is collaboration here between non-infectious- and infectious-agent to achieve the cause of autoimmunity. We say viral latency and stress have a covenant: continued perpetration of autoimmunity is dependent on the intervention by stress to reactivate latent infections.

The viral enterprises in autoimmunity: conversion of target cells into de novo APCs is the presage to autoimmunity.

An autoimmune disease (AD) occurs in a situation where an individual's protective immune system attacks and destroys the individual's own tissues and organ(s), causing a recognizable syndrome(s). The viruses feature in the triggering of autoimmune diseases in genetically primed individuals through generating a viral group of regulatory immediate early proteins (IE). The IE indulges in promiscuous regulations of the viral replications as well as of host intracellular proteins. But there are consequences in the IE controlling host cell protein regulations, which we suggest as: the IE titration of the transactivator protein, autoimmune regulator (AIRE), which causes abolition of central tolerance; and the IE titration of the repressor protein, FOXP3, which results in the breach of peripheral tolerance. Titrations of AIRE and FOXP3 allow the escape of autoreactive T cells into the (peripheral) circulation where they can reach and zero in on self-tissues. The AD-predisposing MHC-II-DR-DQ haplotypes probably play a crucial role in the shaping of the T cell repertoire intrathymically for the survival of budding autoreactive T cell receptors (TCRs). Finally, we suggest there is IE titration of the repressors, the histone deacetylases (HDACs), in target organ cells which then consequentially express de novo MHC-II molecules and become de novo non-professional antigen-presenting cells (APCs), able to present viral peptides to cognate TCRs, thereby enrolling themselves for apoptotic death: a destiny of all APCs in immune responses, in general. Extensive apoptotic destruction of organ cells leads to an autoimmune syndrome(s).

Children with islet autoimmunity and enterovirus infection demonstrate a distinct cytokine profile.

Cytokines are upregulated in prediabetes, but their relationship with Enterovirus (EV) infection and development of islet autoimmunity is unknown. Cytokines (n = 65) were measured using Luminex xMAP technology in a nested case-control study of 67 children with a first-degree relative with type 1 diabetes: 27 with islet autoantibodies (Ab(+)) and 40 age-matched persistently autoantibody negative (Ab(-)) control subjects. Of 74 samples, 37 (50%) were EV-PCR(+) in plasma and/or stool (EV(+)) and the remainder were negative for EV and other viruses (EV(-)). Fifteen cytokines, chemokines, and growth factors were elevated (P ≤ 0.01) in Ab(+) versus Ab(-) children (interleukin [IL]-1ß, IL-5, IL-7, IL-12(p70), IL-16, IL-17, IL-20, IL-21, IL-28A, tumor necrosis factor-α, chemokine C-C motif ligand [CCL]13, CCL26, chemokine C-X-C motif ligand 5, granulocyte-macrophage colony-stimulating factor, and thrombopoietin); most have proinflammatory effects. In EV(+) versus EV(-) children, IL-10 was higher (P = 0.005), while IL-21 was lower (P = 0.008). Cytokine levels did not differ between Ab(+)EV(+) and Ab(+)EV(-) children. Heat maps demonstrated clustering of some proinflammatory cytokines in Ab(+) children, suggesting they are coordinately regulated. In conclusion, children with islet autoimmunity demonstrate higher levels of multiple cytokines, consistent with an active inflammatory process in the prediabetic state, which is unrelated to coincident EV infection. Apart from differences in IL-10 and IL-21, EV infection was not associated with a specific cytokine profile.

The Co-operative Specificity Theory: phenotypic protection from T1D by certain HLA Class II DRB1 and DQ alleles identifies the absence of co-operation between the respective DR and DQ molecules eventuating in no T1D-predisposition.

It is well established that both DR and DQ genes are involved in type 1 diabetes (T1D) -susceptibility. But how the DR and DQ molecules contrive to effect collectively the same function of T1D predisposition remains unexplained. We advance the Co-operative Specificity Theory which attempts to project the relationship by which this occurs. The Co-operative Specificity Theory says that what is involved and being observed is a phenomenon of specific reciprocal recognition between corresponding DR- and DQ-molecules in a haplotype, resulting in a co-operation that realizes effects: this specificity varies in degrees. It is a situation of co-operative participation restricted to a specific DR- and its corresponding specific DQ-molecules that results in susceptibility. Thus susceptibility may not result when a corresponding specific DR or DQ allele is substituted by a non-specific allele in the haplotype. It thus ensues that phenotypic protection identifies the absence of this specific co-operation between the respective DR and DQ molecules giving rise to no predisposition.

Case report: consumptive hypothyroidism consequent to multiple infantile hepatic haemangiomas.

A 10-month-old infant with multiple infantile hepatic hemangiomas and developmental delay is reported. He was found to be profoundly hypothyroid. Evaluation and management issues are discussed. This case emphasizes the importance of screening for hypothyroidism in patients with hemangiomas and the potential therapeutic benefit of prednisolone therapy in this condition.

Type 2 diabetes in Indigenous and non-Indigenous children and adolescents in New South Wales.

OBJECTIVE: To determine the incidence of type 2 diabetes mellitus (T2DM) in 2001-2006 in young people < 19 years and the characteristics of T2DM in the Indigenous group. DESIGN AND SETTING: Prospective population-based incidence study, New South Wales. PARTICIPANTS: Primary ascertainment was from the Australasian Paediatric Endocrine Group NSW Diabetes Register, with secondary ascertainment from the National Diabetes Register (Australian Institute of Health and Welfare). MAIN OUTCOME MEASURES: Incidence of T2DM in young people in NSW; incidence of T1DM and T2DM in Indigenous young people; characteristics at diagnosis. RESULTS: There were 128 incident cases of T2DM (62 boys, 66 girls) in the study period. The median age at diagnosis was 14.5 years (interquartile range, 13.0-16.4), and 90% were overweight or obese (body mass index > 85th percentile for age). Mean annual incidence was 2.5/100,000 person-years (95% CI, 2.1-3.0) in 10-18-year-olds. Of the ethnic groups represented, white Australian comprised 29%, Indigenous 22%, Asian 22%, North African/Middle Eastern 12% and Maori/Polynesian/Melanesian 10%. The incidence of T2DM was significantly higher in the Indigenous than the non-Indigenous group (incidence rate ratio, 6.1; 95% CI, 3.9-9.7; P<0.001), but incidence rates of T1DM were similar (15.5 v 21.4/100,000, respectively). CONCLUSIONS: T2DM accounts for 11% of incident cases of diabetes in 10-18-year-olds, and the majority are overweight or obese. The high rate among Indigenous Australian children supports screening for T2DM in this population.