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Expanding behavioral and neurobiological evidence affirms benefits of shared (especially parent-child) reading on cognitive development during early childhood. However, the majority of this evidence involves factors under caregiver control, the influence of those intrinsic to the child, such as interest or engagement in reading, largely indirect or unclear. The cerebellum is increasingly recognized as playing a \"smoothing\" role in higher-level cognitive processing and learning, via feedback loops with language, limbic and association cortices. We utilized functional MRI to explore the relationship between child engagement during a mother-child reading observation and neural activation and connectivity during a story listening task, in a sample of 4-year old girls. Children exhibiting greater interest and engagement in the narrative showed increased activation in right-sided cerebellar association areas during the task, and greater functional connectivity between this activation cluster and language and executive function areas. Our findings suggest a potential cerebellar \"boost\" mechanism responsive to child engagement level that may contribute to emergent literacy development during early childhood, and synergy between caregiver and child factors during story sharing.

The American Academy of Pediatrics recommends limits on digital media use (“screen time”), citing cognitive-behavioral risks. Media use in early childhood is ubiquitous, though few imaging-based studies have been conducted to quantify impacts on brain development. Cortical morphology changes dynamically from infancy through adulthood and is associated with cognitive-behavioral abilities. The current study involved 52 children who completed MRI and cognitive testing at a single visit. The MRI protocol included a high-resolution T1-weighted anatomical scan. The child’s parent completed the ScreenQ composite measure of media use. MRI measures included cortical thickness (CT) and sulcal depth (SD) across the cerebrum. ScreenQ was applied as a predictor of CT and SD first in whole-brain regression analyses and then for regions of interest (ROIs) identified in a prior study of screen time involving adolescents, controlling for sex, age and maternal education. Higher ScreenQ scores were correlated with lower CT in right-lateralized occipital, parietal, temporal and fusiform areas, and also lower SD in right-lateralized inferior temporal/fusiform areas, with substantially greater statistical significance in ROI-based analyses. These areas support primary visual and higher-order processing and align with prior findings in adolescents. While differences in visual areas likely reflect maturation, those in higher-order areas may suggest under-development, though further studies are needed.

Insulin sparks autoimmunity Autoimmune reactions, in which the body's white blood cells harm its own tissues, cause many diseases including diabetes, multiple sclerosis and arthritis. It is not known why immune cells target certain organs, and in particular for childhood diabetes, why only insulin-producing cells are killed. Nakayama et al . now report that this may be because insulin itself is a primary autoantigen for autoimmune diabetes. In NOD mice, the standard animal model for diabetes, when the part of the insulin molecule that gives rise to autoantibodies is altered, autoimmune diabetes disappears. This also suggests that deletional immune therapy could be a practical proposition. The possible clinical relevance of this work is confirmed by a separate study by Kent et al . of human patients with type 1 diabetes. T lymphocytes found in the draining lymph nodes around the pancreas specifically recognize part of the insulin protein. This has implications for antigen specific therapies and islet-cell transplantation in diabetes. A fundamental question about the pathogenesis of spontaneous autoimmune diabetes is whether there are primary autoantigens. For type 1 diabetes it is clear that multiple islet molecules are the target of autoimmunity in man and animal models 1 , 2 . It is not clear whether any of the target molecules are essential for the destruction of islet beta cells. Here we show that the proinsulin/insulin molecules have a sequence that is a primary target of the autoimmunity that causes diabetes of the non-obese diabetic (NOD) mouse. We created insulin 1 and insulin 2 gene knockouts combined with a mutated proinsulin transgene (in which residue 16 on the B chain was changed to alanine) in NOD mice. This mutation abrogated the T-cell stimulation of a series of the major insulin autoreactive NOD T-cell clones 3 . Female mice with only the altered insulin did not develop insulin autoantibodies, insulitis or autoimmune diabetes, in contrast with mice containing at least one copy of the native insulin gene. We suggest that proinsulin is a primary autoantigen of the NOD mouse, and speculate that organ-restricted autoimmune disorders with marked major histocompatibility complex (MHC) restriction of disease are likely to have specific primary autoantigens.

Type 1 diabetes (T1D) results from progressive loss of pancreatic islet mass through autoimmunity targeted at a diverse, yet limited, series of molecules that are expressed in the pancreatic β cell. Identification of these molecular targets provides insight into the pathogenic process, diagnostic assays, and potential therapeutic agents. Autoantigen candidates were identified from microarray expression profiling of human and rodent pancreas and islet cells and screened with radioimmunoprecipitation assays using new-onset T1D and prediabetic sera. A high-ranking candidate, the zinc transporter ZnT8 (Slc30A8), was targeted by autoantibodies in 60-80% of new-onset T1D compared with <2% of controls and <3% type 2 diabetic and in up to 30% of patients with other autoimmune disorders with a T1D association. ZnT8 antibodies (ZnTA) were found in 26% of T1D subjects classified as autoantibody-negative on the basis of existing markers [glutamate decarboxylase (GADA), protein tyrosine phosphatase IA2 (IA2A), antibodies to insulin (IAA), and islet cytoplasmic autoantibodies (ICA)]. Individuals followed from birth to T1D showed ZnT8A as early as 2 years of age and increasing levels and prevalence persisting to disease onset. ZnT8A generally emerged later than GADA and IAA in prediabetes, although not in a strict order. The combined measurement of ZnT8A, GADA, IA2A, and IAA raised autoimmunity detection rates to 98% at disease onset, a level that approaches that needed to detect prediabetes in a general pediatric population. The combination of bioinformatics and molecular engineering used here will potentially generate other diabetes autoimmunity markers and is also broadly applicable to other autoimmune disorders.

The SLC30A8 gene encodes the islet-specific transporter ZnT-8, which is hypothesized to provide zinc for insulin-crystal formation. A polymorphic variant in SLC30A8 is associated with altered susceptibility to type 2 diabetes. Several groups have examined the effect of global Slc30a8 gene deletion but the results have been highly variable, perhaps due to the mixed 129SvEv/C57BL/6J genetic background of the mice studied. We therefore sought to remove the conflicting effect of 129SvEv-specific modifier genes. The impact of Slc30a8 deletion was examined in the context of the pure C57BL/6J genetic background. Male C57BL/6J Slc30a8 knockout (KO) mice had normal fasting insulin levels and no change in glucose-stimulated insulin secretion (GSIS) from isolated islets in marked contrast to the ∼50% and ∼35% decrease, respectively, in both parameters observed in male mixed genetic background Slc30a8 KO mice. This observation suggests that 129SvEv-specific modifier genes modulate the impact of Slc30a8 deletion. In contrast, female C57BL/6J Slc30a8 KO mice had reduced (∼20%) fasting insulin levels, though this was not associated with a change in fasting blood glucose (FBG), or GSIS from isolated islets. This observation indicates that gender also modulates the impact of Slc30a8 deletion, though the physiological explanation as to why impaired insulin secretion is not accompanied by elevated FBG is unclear. Neither male nor female C57BL/6J Slc30a8 KO mice showed impaired glucose tolerance. Our data suggest that, despite a marked reduction in islet zinc content, the absence of ZnT-8 does not have a substantial impact on mouse physiology.

Background The American Academy of Pediatrics (AAP) recommends shared reading beginning as soon as possible after birth to promote healthy development. Shared reading quality can strongly influence outcomes, especially in children from low-SES households. Dialogic reading is a method developed to enhance verbal interactivity and engagement through book sharing, advocated by the AAP and clinic-based programs such as Reach Out and Read. There is no brief, validated, caregiver report measure of dialogic reading or shared reading quality currently available. Methods This cross-sectional study involved 49 healthy mother-child dyads (mean child age 4.5 yrs., SD  = 0.6 yrs.) from 2 separate MRI-based studies. The DialogPR was administered by trained research coordinators following MRI, along with the READ subscale of the validated StimQ-P measure of home cognitive environment. The DialogPR consists of eight items developed in consultation with experts in early literacy, based on the PEER/CROWD dialogic reading conceptual model. Estimated reading level is 6th grade. Descriptive statistics were computed at both the item and scale levels. Modern theory Rasch methods were used to analyze all eight DialogPR items along with preliminary estimates of reliability and validity. Results Our combined sample involved 15 boys and 34 girls, and was diverse in terms of age, household income, and maternal education. DialogPR administration time was less than 2 min, with no problems reported. The DialogPR demonstrated strong internal consistency and reliability (Cronbach’s alpha = 0.82), and criterion-related validity with the StimQ-P READ (Spearman’s rho coefficient = 0.53). Rasch analysis revealed strong psychometric properties in terms of reliability, variability in item difficulty, and inter-item and item-measure correlations. Conclusions Preliminary evidence suggests that the DialogPR may be an efficient means to assess shared reading quality and dialogic reading via caregiver report for clinical and research purposes, warranting further investigation.

Background Approximately 210 million people are estimated to have chronic obstructive pulmonary disease [COPD] worldwide. The burden of disease is known to be high, though less is known about those of a younger age. The aim of this study was to investigate the wider personal, economic and societal burden of COPD on a cross country working-age cohort. Methods A cross-country [Brazil, China, Germany, Turkey, US, UK] cross-sectional survey methodology was utilised to answer the research questions. 2426 participants aged 45-67 recruited via a number of recruitment methods specific to each country completed the full survey. Inclusion criteria were a recalled physician diagnosis of COPD, a smoking history of > 10 pack years and the use of COPD medications in the previous 3 months prior to questioning. The survey included items from the validated Work Productivity and Activity Impairment [WPAI] scale and the EuroQoL 5 Dimension [EQ-5D] scale. Disease severity was measured using the 5-point MRC [Medical Research Council] dyspnoea scale as a surrogate measure. Results 64% had either moderate [n = 1012] or severe [n = 521] COPD, although this varied by country. 75% of the cohort reported at least one comorbid condition. Quality of life declined with severity of illness [mild, mean EQ-5D score = 0.84; moderate 0.58; severe 0.41]. The annual cost of healthcare utilisation [excluding treatment costs and diagnostic tests] per individual was estimated to be $2,364 [£1,500]. For those remaining in active employment [n: 677]: lost time from work cost the individual an average of $880 [£556] per annum and lifetime losses of $7,365 [£4,661] amounting to $596,000 [£377,000] for the cohort. 447 [~40%] of the working population had retired prematurely because of COPD incurring individual estimated lifetime income losses of $316,000 [£200,000] or a combined total of $141 m [£89.6 m]. As the mean age of retirees was 58.3 and average time since retirement was 4 years, this suggests the average age of retirement is around 54. This would mean a high societal and economic impact in all study countries, particularly where typical state retirement ages are higher, for example in Brazil, Germany and the UK [65] and the US [65,66,67], compared to Turkey [58 for women, 60 for men] and China [60]. Conclusions Although generalisation across a broader COPD population is limited due to the varied participant recruitment methods, these data nevertheless suggest that COPD has significant personal, economic and societal burden on working age people. Further efforts to improve COPD diagnosis and management are required.

Zinc transporter 8 (ZnT8) is a recently identified major autoantigen in type 1 diabetes, and autoantibodies to ZnT8 (ZnT8A) are new markers for disease prediction and diagnosis. Here we report the results of the first international proficiency evaluation of ZnT8A assays by the Diabetes Antibody Standardization Program (DASP). After a pilot workshop in 2007, an expanded ZnT8A workshop was held in 2009, with 26 participating laboratories from 13 countries submitting results of 63 different assays. ZnT8A levels were measured in coded sera from 50 patients with newly diagnosed type 1 diabetes and 100 blood donor controls. Results were analyzed comparing area under the ROC curve (ROC-AUC), sensitivity adjusted to 95% specificity (AS95), concordance of sample ZnT8A positive or negative designation, and autoantibody levels. ZnT8A radio binding assays (RBAs) based on combined immunoprecipitation of the 2 most frequent ZnT8 COOH-terminal domain polymorphic variants showed a median ROC-AUC of 0.848 [interquartile range (IQR) 0.796-0.878] and a median AS95 of 70% (IQR 60%-72%). These RBAs were more sensitive than assays using as antigen either 1 ZnT8 variant only or chimeric constructs joining NH(2)- and COOH-terminal domains, assays based on immunoprecipitation and bioluminescent detection, or assays based on immunofluorescent staining of cells transfected with full-length antigen. The DASP workshop identified immunoprecipitation-based ZnT8A assays and antigen constructs that achieved both a high degree of sensitivity and specificity and were suitable for more widespread clinical application.

Elevated fasting blood glucose (FBG) is associated with increased risk for the development of type 2 diabetes and cardiovascular-associated mortality. Genome-wide association studies (GWAS) have linked polymorphisms in G6PC2 with variations in FBG and body fat, although not insulin sensitivity or glucose tolerance. G6PC2 encodes an islet-specific, endoplasmic reticulum–resident glucose-6-phosphatase catalytic subunit. A combination of in situ perfused pancreas, in vitro isolated islet, and in vivo analyses were used to explore the function of G6pc2 in mice. G6pc2 deletion had little effect on insulin sensitivity and glucose tolerance, whereas body fat was reduced in female G6pc2 knockout (KO) mice on both a chow and high-fat diet, observations that are all consistent with human GWAS data. G6pc2 deletion resulted in a leftward shift in the dose-response curve for glucose-stimulated insulin secretion (GSIS). As a consequence, under fasting conditions in which plasma insulin levels were identical, blood glucose levels were reduced in G6pc2 KO mice, again consistent with human GWAS data. Glucose-6-phosphatase activity was reduced, whereas basal cytoplasmic calcium levels were elevated in islets isolated from G6pc2 KO mice. These data suggest that G6pc2 represents a novel, negative regulator of basal GSIS that acts by hydrolyzing glucose-6-phosphate, thereby reducing glycolytic flux.

A Common Nonsynonymous Single Nucleotide Polymorphism in the SLC30A8 Gene Determines ZnT8 Autoantibody Specificity in Type 1 Diabetes Janet M. Wenzlau 1 , Yu Liu 2 , Liping Yu 1 , Ong Moua 1 , Kimberly T. Fowler 1 , Sampathkumar Rangasamy 1 , Jay Walters 1 , George S. Eisenbarth 1 , Howard W. Davidson 1 and John C. Hutton 1 1 Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado 2 Department of Endocrinology, Nanjing Medical University, First Affiliated Hospital, Nanjing, China Corresponding author: John C. Hutton, john.hutton{at}uchsc.edu Abstract OBJECTIVE— Zinc transporter eight ( SLC30A8 ) is a major target of autoimmunity in human type 1A diabetes and is implicated in type 2 diabetes in genome-wide association studies. The type 2 diabetes nonsynonymous single nucleotide polymorphism (SNP) affecting aa 325 lies within the region of highest ZnT8 autoantibody (ZnT8A) binding, prompting an investigation of its relationship to type 1 diabetes. RESEARCH DESIGN AND METHODS— ZnT8A radioimmunoprecipitation assays were performed in 421 new-onset type 1 diabetic Caucasians using COOH-terminal constructs incorporating the known human aa 325 variants (Trp, Arg, and Gln). Genotypes were determined by PCR-based SNP analysis. RESULTS— Sera from 224 subjects (53%) were reactive to Arg 325 probes, from 185 (44%) to Trp 325 probes, and from 142 (34%) to Gln 325 probes. Sixty subjects reacted only with Arg 325 constructs, 31 with Trp 325 only, and 1 with Gln 325 only. The restriction to either Arg 325 or Trp 325 corresponded with inheritance of the respective C- or T-alleles. A strong gene dosage effect was also evident because both Arg- and Trp-restricted ZnT8As were less prevalent in heterozygous than homozygous individuals. The SLC30A8 SNP allele frequency (75% C and 25% T) varied little with age of type 1 diabetes onset or the presence of other autoantibodies. CONCLUSIONS— The finding that diabetes autoimmunity can be defined by a single polymorphic residue has not previously been documented. It argues against ZnT8 autoimmunity arising from molecular mimicry and suggests a mechanistic link between the two major forms of diabetes. It has implications for antigen-based therapeutic interventions because the response to ZnT8 administration could be protective or immunogenic depending on an individual's genotype. Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 30 June 2008. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted June 24, 2008. Received February 2, 2008. DIABETES