Early-Onset, Coexisting Autoimmunity and Decreased HLA-Mediated Susceptibility Are the Characteristics of Diabetes in Down Syndrome

OBJECTIVE: Down syndrome (DS) is associated with an increased risk of diabetes, particularly in young children. HLA-mediated risk is however decreased in children with DS and diabetes (DSD). We hypothesized that early-onset diabetes in children with DS is etiologically different from autoimmune diabetes. RESEARCH DESIGN AND METHODS: Clinical and immunogenetic markers of autoimmune diabetes were studied in 136 individuals with DSD and compared with 194 age- and sex-matched individuals with type 1 diabetes, 222 with DS, and 671 healthy controls. HLA class II was analyzed by sequence-specific primed PCR. Islet autoantibodies were measured by radioimmunoassay. RESULTS: Age at onset of diabetes was biphasic, with 22% of DS children diagnosed before 2 years of age, compared with only 4% in this age-group with type 1 diabetes in the general population (P < 0.0001). The frequency of the highest-risk type 1 diabetes–associated HLA genotype, DR3-DQ2/DR4-DQ8, was decreased in both early- and later-onset DSD compared with age-matched children with type 1 diabetes (P < 0.0001), although HLA DR3-DQ2 genotypes were increased (P = 0.004). Antibodies to GAD were observed in all five samples tested from children diagnosed at ≤2 years of age, and persistent islet autoantibodies were detected in 72% of DSD cases. Thyroid and celiac disease were diagnosed in 74 and 14%, respectively, of the DSD cohort. CONCLUSIONS: Early-onset diabetes in children with DS is unlikely to be etiologically different from autoimmune diabetes occurring in older DS children. Overall, these studies demonstrate more extreme autoimmunity in DSD typified by early-onset diabetes with multiple autoimmunity, persistent islet autoantibodies, and decreased HLA-mediated susceptibility

Frequency of cytokine gene promoter polymorphisms in the Northern Ireland Cystic Fibrosis population

AbstractBackgroundThe impact of pre-pregnancy pulmonary and nutritional status in pregnancy outcomes of women with cystic fibrosis (CF) is not clearly defined.MethodsA chart review of CF women who attended the University of Washington Medical Center (UWMC), Seattle WA. from January 1989 until May 2004.ResultsThere were 43 pregnancies resulting in 36 live births among 25 of 189 CF women. In the subset of CF women receiving their obstetric care at the UWMC whose FEV1 was <50% predicted, infant weight was lower than in women with a higher FEV1 (2.9 kg±0.4 (range 2.2–3.3 kg) versus 3.4±0.8 kg (range 2.5–5.1 kg)) p=0.05 although the gestational ages were the same (37±2 weeks (range 33–39 weeks) versus to 38±2 weeks (range 35–40 weeks) p=0.17). Infant weight and gestational age of women whose initial BMI was <20 kg/m2 was no different from women with a normal initial BMI (3.0±0.4 kg, range 2.2–3.4 kg versus 3.3±0.8 kg, range 2.6–5.1 kg p=0.29, and 37.7±2.4 weeks, range 33–39 weeks versus 37.2±2.1 weeks, range 34–40 weeks).ConclusionsCF women with severe pulmonary impairment tend to have lower weight babies but it remains difficult to determine prospectively which CF women will tolerate pregnancy well. Aggressive antepartum management is recommended for all CF women

Frontal responses during learning predict vulnerability to the psychotogenic effects of ketamine:linking cognition, brain activity, and psychosis

Context: Establishing a neurobiological account of delusion formation that links cognitive processes, brain activity, and symptoms is important to furthering our understanding of psychosis. Objective: To explore a theoretical model of delusion formation that implicates prediction error - dependent associative learning processes in a pharmacological functional magnetic resonance imaging study using the psychotomimetic drug ketamine. Design: Within-subject, randomized, placebo-controlled study. Setting: Hospital-based clinical research facility, Addenbrooke's Hospital, Cambridge, England. The work was completed within the Wellcome Trust and Medical Research Council Behavioral and Clinical Neuroscience Institute, Cambridge. Participants: Fifteen healthy, right-handed volunteers (8 of whom were male) with a mean +/- SD age of 29 +/- 7 years and a mean +/- SD predicted full-scale IQ of 113 +/- 4 were recruited from within the local community by advertisement. Interventions: Subjects were given low-dose ketamine (100 ng/mL of plasma) or placebo while performing a causal associative learning task during functional magnetic resonance imaging. In a separate session outside the scanner, the dose was increased (to 200 ng/mL of plasma) and subjects underwent a structured clinical interview. Main Outcome Measures: Brain activation, blood plasma levels of ketamine, and scores from psychiatric ratings scales (Brief Psychiatric Ratings Scale, Present State Examination, and Clinician-Administered Dissociative States Scale). Results: Low-dose ketamine perturbs error-dependent learning activity in the right frontal cortex (P = .03). Highdose ketamine produces perceptual aberrations (P = .01) and delusion-like beliefs (P = .007). Critically, subjects showing the highest degree of frontal activation with placebo show the greatest occurrence of drug-induced perceptual aberrations (P = .03) and ideas or delusions of reference (P = .04). Conclusions: These findings relate aberrant prediction error - dependent associative learning to referential ideas and delusions via a perturbation of frontal cortical function. They are consistent with a model of delusion formation positing disruptions in error-dependent learning

Relevance of use-invariant soil properties to assess soil quality of vulnerable ecosystems : the case of Mediterranean vineyards

Vineyard landscapes in Mediterranean areas represent a strong cultural legacy and support a crucial socioeconomic sector. The sustainability of these landscapes is threatened by rapid changes of soil quality, in the context of global change and intensive management practices. Considering the Languedoc-Roussillon region of southern France as representative of Mediterranean soil and climate conditions, we evaluated the topsoil quality of vineyards at the regional scale, based on a set of 31 physical, chemical and biological soil indicators measured on 164 commercial vineyard plots. Almost all soil parameters were highly variable among plots. Biological activity was low but no systematic perturbation of the trophic web was noticed. The regional variability of use-invariant soil properties (such as calcium carbonate content and texture) was characterized and taken into account for the analysis of dynamic indicators. Invariant soil properties explained up to 25% of the variance of dynamic chemical and biological indicators. Consequently as a tool to improve soil management decision and recommendations, we proposed a grouping of the 164 vineyard plots into functional soil groups determined by soil invariant properties. Information redundancy between different dynamic indicators was analyzed, and their interpretation and limitations as indicators of topsoil quality were discussed. Our study has produced detailed topsoil indicator baselines that can be immediately used as references for winegrowers to appraise the topsoil quality of their vineyard in comparison with others