Individual Alpha Peak Frequency Moderates Transfer of Learning in Cognitive Remediation of Schizophrenia.

OBJECTIVE: Meta-analyses report moderate effects across cognitive remediation (CR) trials in schizophrenia. However, individual responses are variable, with some participants showing no appreciable gain in cognitive performance. Furthermore, reasons for heterogeneous outcome are undetermined. We examine the extent to which CR outcome is attributable to near learning-direct gains in trained cognitive tasks-while also exploring factors influencing far transfer of gains during training to external cognitive measures. METHOD: Thirty-seven schizophrenia outpatients were classified as CR responders and non-responders according to change in MATRICS Consensus Cognitive Battery composite score following 20 sessions of computer-based training. Metrics of near learning during training, as well as baseline demographic, clinical, cognitive, and electroencephalographic (EEG) measures, were examined as predictors of responder status. RESULTS: Significant post-training improvement in cognitive composite score (Cohen's d = .41) was observed across the sample, with n = 21 and n = 16 classified as responders and non-responders, respectively. Near learning was evidenced by significant improvement on each training exercise with practice; however, learning did not directly predict responder status. Group-wise comparison of responders and non-responders identified two factors favoring responders: higher EEG individual alpha frequency (IAF) and lower antipsychotic dosing. Tested in moderation analyses, IAF interacted with learning to predict improvement in cognitive outcome. CONCLUSION: CR outcome in schizophrenia is not directly explained by learning during training and appears to depend on latent factors influencing far transfer of trained abilities. Further understanding of factors influencing transfer of learning is needed to optimize CR efficacy.

'25-Hydroxyvitamin D, Autoantigenic and Total Antibody Concentrations: Results from a Danish Case-control Study of Newly Diagnosed Patients with Childhood Type 1 Diabetes and their Healthy Siblings'.

B cells have recently entered the stage as an important accessory player in type 1 diabetes (T1D) etiopathogenesis. Experimental studies suggest regulatory functions of vitamin D on B cells. However, only a few human studies, with considerable methodological limitations, have been conducted within this field. Our objective was to investigate whether higher 25-hydroxyvitamin D (25(OH)D) concentrations were inversely associated with ß-cell autoantigens glutamic acid decarboxylase (isoform 65) (GADA) and insulinoma-associated antigen-2A (IA-2A). Further, we also wanted to examine the relationship between 25(OH)D and total antibody concentrations. We randomly selected 500 patients with newly diagnosed T1D and 500 siblings for 25(OH)D, antibody and genetic analysis from the population-based Danish Registry of Childhood and Adolescent Diabetes. The relative change (RC) in the mean concentration of GADA, IA-2A and antibody isotypes by a 10 nmol/l increase in 25(OH)D concentration was modelled by a robust log-normal regression model. We found no association between 25(OH)D and GADA [adjusted RC per 10 nmol/l increase: 1.00; 95% confidence interval (CI): 0.98-1.02] and IA-2A [adjusted RC per 10 nmol/l increase: 0.92; CI: 0.76-1.12]. Further, 25(OH)D was not associated with the total concentration of antibody isotypes [immunoglobulin (Ig)A, IgE, IgG and IgM]. All null findings were unaltered after adjustment for genetic variation in the vitamin D pathway. Physiological concentrations of 25(OH)D are unlikely to have a clinically important effect on antibody concentrations in a paediatric population of newly diagnosed patients with T1D and their healthy siblings.

Adrenaline and cortisol levels are lower during nighttime than daytime hypoglycaemia in children with type 1 diabetes.

AIM: We investigated children's counter regulatory hormone profiles during a hyperinsulinaemic hypoglycaemic clamp procedure at day and night. METHODS: In 2013, we assessed the counter regulatory response to hypoglycaemia in eight outpatients with type 1 diabetes, recruited from the Herlev Hospital, Denmark, at a mean age of 9.6 ± 2.3 years. Hyperinsulinaemic 80 mU/m2 /min clamps were performed with a stepwise reduction in plasma glucose from euglycaemia (7-9 mmol/L) to hypoglycaemia (<3.5 mmol/L) and the glucose nadir (≤2.2 mmol/L) during the day and night. Adrenaline, cortisol, glucagon and growth hormone levels were assessed. RESULTS: Adrenaline and growth hormone levels were higher during the day versus the night (p = 0.04 and p = 0.01, respectively). However, at the glucose nadir, the level of adrenaline was lower during the night than the day (0.6 ± 0.2 versus 1.9 ± 0.5 nmol/L, p = 0.016) and cortisol was lower during the day than the night (42 ± 15 versus 319 ± 81 nmol/L, p = 0.016). No differences were demonstrated for glucagon and growth hormone levels based on the same criteria. CONCLUSION: The adrenaline response was blunted during nocturnal iatrogenic hypoglycaemia in our study cohort, and no increase in cortisol levels was demonstrated.

Increased mortality in a Danish cohort of young people with Type 1 diabetes mellitus followed for 24 years.

AIM: To determine the mortality rate in a Danish cohort of children and adolescents diagnosed with Type 1 diabetes mellitus compared with the general population. METHODS: In 1987 and 1989 we included 884 children and 1020 adolescents aged 20 years and under, corresponding to 75% of all Danish children and adolescents with Type 1 diabetes, in two nationwide studies in Denmark. Those who had participated in both investigations (n = 720) were followed until 1 January 2014, using the Danish Civil Registration System on death certificates and emigration. We derived the expected number of deaths in the cohort, using population data values from Statistics Denmark to calculate the standardized mortality ratio. Survival analysis was performed using Cox proportional hazards model. RESULTS: During the 24 years of follow-up, 49 (6.8%) patients died, resulting in a standardized mortality ratio of 4.8 (95% confidence interval 3.5, 6.2) compared with the age-standardized general population. A 1% increase in baseline HbA1c (1989), available in 718 of 720 patients, was associated with all-cause mortality (hazard ratio = 1.38; 95% confidence interval 1.2, 1.6; P < 0.0001). Type 1 diabetes with multiple complications was the most common reported cause of death (36.7%). CONCLUSION: We found an increased mortality rate in this cohort of children and adolescents with Type 1 diabetes compared with the general population. The only predictor for increased risk of death up to 24 years after inclusion was the HbA1c level in 1989. This emphasizes the importance of achieving optimal metabolic control in young people with Type 1 diabetes.

Insulin pump treatment; increasing prevalence, and predictors for better metabolic outcome in Danish children and adolescents with type 1 diabetes.

AIMS: Few studies have looked at nationwide data for insulin pump treatment. Since 1996 the Danish Childhood Diabetes Registry (DanDiabKids) has collected data on all Danish diabetic patients aged 0-15 yr. The purpose of this study is to evaluate the prevalence of continuous subcutaneous insulin infusion (CSII) use among Danish children with diabetes and to compare metabolic control in CSII-treated children and adolescents to those treated with MDI. MATERIALS AND METHODS: The Registry collects on a yearly basis data on insulin regimen, central measured hemoglobin A1c (HbA1c), and demographic data on all patients. In the period 2005-2011, 2983 young patients (1721 males) with diabetes were followed in the Registry. Mean observation period was 5.11 yr [standard error (SE) 0.09]. In the total period 1846 patients were treated with MDI and 1493 changed from MDI to CSII. In 2005, less than 5% of children were treated with CSII whereas the percentage of children on CSII increased to approximately 50% in 2011. The patients were divided into age groups, <5 yr, 5-10 yr, and > 15 yr. RESULTS: HbA1c was significantly higher in MDI-treated children, +5.29 (CI 95% 4.29; 6.29 mmol/mol). HbA1c in all age groups was significantly lower in CSII-treated patients, and longitudinally HbA1c continued to be lower in all age groups. In multivariate analysis, a low HbA1c at CSII start, centers with more than 100 pump patients, a more recent year of diabetes onset, a higher number of self-monitoring of blood glucose (SMBG) measurements, a higher number of daily boluses, and a higher percentage of bolus insulin were all related to a lower HbA1c. CONCLUSION: The percentage of children on pumps (CSII) is CSII treatment is associated with a significantly lower Hba1c, achieved just after treatment initiation. In the following years there is a parallel rise in HbA1c in both MDI as well as in MDI treated patients. Patients coming from larger clinics, and patients measuring more blood glucose values and taking more boluses have a better metabolic control.

Systemic levels of CCL2, CCL3, CCL4 and CXCL8 differ according to age, time period and season among children newly diagnosed with type 1 diabetes and their healthy siblings.

The mechanisms by which antigen-specific T cells migrate to the islets of Langerhans in type 1 diabetes (T1D) are largely unknown. Chemokines attract immune cells to sites of inflammation. The aim was to elucidate the role of inflammatory chemokines in T1D at time of diagnosis. From a population-based registry of children diagnosed with T1D from 1997 to 2005, we studied five different inflammatory chemokines (CCL2, CCL3, CCL4, CCL5 and CXCL8). Four hundred and eighty-two cases and 479 sibling frequencies matched on age and sample year distribution were included. Patients showed lower levels of CCL4 compared to siblings, but this result was not significant after correction for multiple testing. CCL2, CCL3, CCL4 and CXCL8 levels were highest in the most recent cohorts (P < 0.01) in both patients and siblings. A significant seasonal variation - for most of the chemokines - was demonstrated with the highest level during the summer period in both patients and siblings. In addition, there was a significant inverse relationship between CCL4 levels and age. When comparing patients and siblings, remarkably few differences were identified, but interestingly chemokine levels varied with age, season and period for the entire study population. Such variations should be taken into account when studying chemokines in paediatric populations.

Diabetic ketoacidosis at the onset of type 1 diabetes is associated with future HbA1c levels.

AIMS/HYPOTHESIS: We investigated the long-term impact of diabetic ketoacidosis (DKA) at onset on metabolic regulation and residual beta cell function in a Danish population with type 1 diabetes. METHODS: The study is based on data from DanDiabKids, a Danish national diabetes register for children. The register provides clinical and biochemical data on patients with type 1 diabetes diagnosed in 1996-2009 and then followed-up until 1 January 2012. Repeated-measurement models were used as statistical methods. RESULTS: The study population comprised 2,964 children <18 years. The prevalence of DKA at diagnosis was 17.9%. Of the total subjects, 8.3% had mild, 7.9% had moderate and 1.7% had severe DKA. DKA (moderate and severe) was associated with increased HbA1c (%) levels (0.24; 95% CI 0.11, 0.36; p = 0.0003) and increased insulin dose-adjusted HbA1c (IDAA1c, 0.51; 95% CI 0.31, 0.70; p < 0.0001) during follow-up, after adjustment for covariates. Children without a family history of diabetes were more likely to present with DKA (19.2% vs 8.8%, p < 0.0001); however, these children had a lower HbA1c (%) level over time (-0.35; 95% CI -0.46, -0.24; p < 0.0001). Continuous subcutaneous insulin infusion (CSII) was associated with a long-term reduction in HbA1c, changing the effect of DKA, after adjustment for covariates (p < 0.0001). CONCLUSIONS/INTERPRETATION: DKA at diagnosis was associated with poor long-term metabolic regulation and residual beta cell function as assessed by HbA1c and IDAA1c, respectively; however, CSII treatment was associated with improvement in glycaemic regulation and residual beta cell function, changing the effect of DKA at onset in our population.

Validation of a suite of ERP and QEEG biomarkers in a pre-competitive, industry-led study in subjects with schizophrenia and healthy volunteers.

OBJECTIVE: Complexity and lack of standardization have mostly limited the use of event-related potentials (ERPs) and quantitative EEG (QEEG) biomarkers in drug development to small early phase trials. We present results from a clinical study on healthy volunteers (HV) and patients with schizophrenia (SZ) that assessed test-retest, group differences, variance, and correlation with functional assessments for ERP and QEEG measures collected at clinical and commercial trial sites with standardized instrumentation and methods, and analyzed through an automated data analysis pipeline. METHODS: 81 HV and 80 SZ were tested at one of four study sites. Subjects were administered two ERP/EEG testing sessions on separate visits. Sessions included a mismatch negativity paradigm, a 40 Hz auditory steady-state response paradigm, an eyes-closed resting state EEG, and an active auditory oddball paradigm. SZ subjects were also tested on the Brief Assessment of Cognition (BAC), Positive and Negative Syndrome Scale (PANSS), and Virtual Reality Functional Capacity Assessment Tool (VRFCAT). RESULTS: Standardized ERP/EEG instrumentation and methods ensured few test failures. The automated data analysis pipeline allowed for near real-time analysis with no human intervention. Test-retest reliability was fair-to-excellent for most of the outcome measures. SZ subjects showed significant deficits in ERP and QEEG measures consistent with published academic literature. A subset of ERP and QEEG measures correlated with functional assessments administered to the SZ subjects. CONCLUSIONS: With standardized instrumentation and methods, complex ERP/EEG testing sessions can be reliably performed at clinical and commercial trial sites to produce high-quality data in near real-time.

Highly asymmetric fine-scale genetic structure between sexes of African striped mice and indication for condition dependent alternative male dispersal tactics.

Sex-biased dispersal is observed in many taxa, but few studies have compared sex-biased dispersal among and within populations. We addressed the magnitude and habitat dependency of sex-biased dispersal in social African striped mice by separating group-related from population-related genetic variance to understand the contribution of each sex to deme structure. As dispersal over unoccupied habitat is likely to be more costly than dispersal within a population, we predicted that individuals leaving the natal population have a lower body condition, being inferior to heavier territorial individuals. Fine-scale genetic structure was detected in both sexes. Female relatedness decreased continuously from R = 0.21 at 25 m to zero at 500 m. Maximum male relatedness R = 0.05 was constant at distances between 25 and 75 m, becoming zero at 100 m. Genetic variance (F(ST) ) among seven locations was significantly higher in females than in males, while inbreeding estimates (F(IS) ) were significantly higher in males than in females. Assignment tests estimated significantly more migrants among males, while Bayesian clustering estimated only a single genetic unit cluster for males among the seven locations. The mean body mass of migrant males (44 g) was significantly lower than for males that remained resident and thus dispersed within their sub-population (48 g). Combined, the results showed habitat-independent male-biased dispersal and high female philopatry, and suggested that body condition was more important than kinship in male dispersal decisions. We suggest that locally inferior males are important for gene flow between sub-populations. Thus, males might follow alternative dispersal tactics.

Species cohesion despite extreme inbreeding in a social spider.

Colonial social spiders experience extreme inbreeding and highly restricted gene flow between colonies; processes that question the genetic cohesion of geographically separated populations and which could imply multiple origins from predecessors with limited gene flow. We analysed species cohesion and the potential for long-distance dispersal in the social spider Stegodyphus dumicola by studying colony structure in eastern South Africa and the cohesion between this population and Namibian populations previously published. Data from both areas were (re)analysed for historic demographic parameters. Eastern South African S. dumicola were closely related to an east Namibian lineage, showing cohesion of S. dumicola relative to its sister species. Colony structure was similar in both areas with mostly monomorphic colonies, but haplotype diversity was much reduced in eastern South Africa. Here, the population structure indicated recent population expansion. By contrast, Namibia constitutes an old population, possibly the geographic origin of the species. Both the comparison of the eastern South African and Namibian lineages and the distribution within eastern South Africa show the potential for long-distance dispersal in few generations via colony propagation.

Measuring quality of life in first-episode psychosis.

Quality of life (QoL) measures are increasingly recognized as necessary parts of outcome assessments in psychosis. The present paper is a comprehensive study of patients with first-episode psychosis where QoL is measured by the commonly used Lehman Quality of Life Interview (L-QoLI). The aim is to examine if the L-QoLI maintain its original structure when used in a group of patients with first-episode psychosis, and to investigate what determines global subjective QoL with a specific emphasis on premorbid adjustment, duration of untreated psychosis (DUP) and clinical symptoms. The study indicates that the psychometric properties of the L-QoLI do not change significantly when used in first-episode samples. The patients report subjective and objective QoL in the fair to good range, with only a moderate association between the objective and subjective measures. Poor global satisfaction is predicted by being single, abusing drugs, being depressed, having a diagnosis of psychotic affective disorder, having poor premorbid social adjustment and DUP over 10 weeks. The study supports the notion that patients with first-episode psychosis construct QoL in the same way as other groups, and that longer durations of compromised function at this stage produces poor satisfaction with life rather than a downward readjustment of expectations.

Characterization of metabolic responders on CSII treatment amongst children and adolescents in Denmark from 2007 to 2013.

AIM: This prospective study aimed to identify and estimate the frequency of responders offered Continuous subcutaneous insulin infusion (CSII) from baseline data and during follow-up, and secondly to characterize CSII users with good adherence to pump therapy among 463 children and adolescents with Type 1 diabetes mellitus. METHODS: A response was defined as lowering HbA1c with 1% or achieving an HbA1c<7.5% (58 mmol/mol). Good adherence was defined as measuring ≥7 self monitored blood glucoses (SMBGs) and taking ≥7 boluses daily. Logistic regression was used to estimate the effect of demographic and clinical variables prior to and during pump treatment. RESULTS: At 24 months follow-up 32% qualified as responders. Stratifying for age at onset, 45% of the children aged <6 yrs qualified as responders vs. 32% and 28% of the youngsters and adolescents aged 6-12 yrs. and 12-19 yrs., respectively (p=0.02). Responders were characterized by their HbA1c-level at pump onset (p=0.001), taking more daily boluses (7.64 ± 3.33 vs. 6.40 ± 3.18 p=0.003) and measuring more SMBGs per day at follow-up (6.88 ± 2.35 vs. 6.31 ± 2.54 p=0.03). The incidence of severe hypoglycemia decreased from 14.3 to 3.3 events per 100 person years (p<0.0001). Twenty percent did not respond despite a good adherence toward CSII therapy. CONCLUSION: Age <6 years, high or low HbA1c at pump initiation and number of daily boluses were associated with improved or sustained near-normal metabolic outcome. The incidence of severe hypoglycemia was significantly reduced. Twenty percent of the population had good adherence without any metabolic improvement.

Nationwide reduction in the frequency of severe hypoglycemia by half.

AIMS: To examine contemporary rates of severe hypoglycemia (SH) and identify the effect of predictors of SH in a pediatric type 1 diabetes population. METHODS: The national diabetes register provided data on children residing in Denmark from 2008 to 2013 in this register-based population study. Robust Poisson regression models were applied. RESULTS: The study population [n = 2,715 (50.9 % boys), mean (SD) age at onset; 8.1 (4.0) years, diabetes duration; 5.6 (4.9) years] comprised 7,390 person-years of data and 561 events of SH. The overall incidence of SH was 7.6 per 100 person-years. The incidence rate peaked with 16.0 per 100 person-years in 2008 reaching a nadir of 4.9 in 2011. Overall, insulin pump reduced the rate of SH with 27 % compared to any pen treatment (P = 0.003). When stratifying pen treatment, premixed insulin increased the rate of SH by 1.9-fold (P = 0.0015) and NPH increased the rate by 1.6-fold (P = 0.003) versus pump treatment, whereas long-acting insulin analogues were comparable with pump treatment (P = 0.1485). We found no association of SH with glycemic control (P > 0.05). CONCLUSIONS: A nationwide halving in rates of severe hypoglycemia was observed during the study period independent of the prevailing average HbA1c level. Changes in diabetes care and successful educational programs may have influenced the lower incidence rate of severe hypoglycemia.

IDDM7 links to insulin-dependent diabetes mellitus in Danish multiplex families but linkage is not explained by novel polymorphisms in the candidate gene GALNT3. The Danish Study Group of Diabetes in Childhood and The Danish IDDM Epidemiology and Genetics Group.

The insulin-dependent diabetes mellitus (IDDM) susceptibility locus IDDM7 on 2q31 links to IDDM in some but not other populations. Linkage of D2S152, the marker for IDDM7, has hitherto not been demonstrated in Danish patients. GALNT3 that encodes the UDP-GalNAc: polypeptide N-acetyl-galactosaminyltransferase-T3 (GalNAc-T3), was recently identified and mapped to a region 5-25 cM from D2S152. The GalNAc transferases may play a role in immune mediated diseases by glycosylating autoantigens. Hence, the aims of the present study were to investigate by means of extended transmission disequilibrium testing (ETDT) and transmission disequilibrium testing (TDT) of the marker for IDDM7, D2S152, the marker for GALNT3, D2S2363, and novel polymorphisms identified through mutation screening of the entire GALNT3 for linkage with IDDM in 241 Danish IDDM multiplex families. ETDT analysis demonstrated linkage between IDDM and D2S152 (P(ETDT)=0.034). A prevalent T-->A polymorphism, T284A, was found in the GALNT3 3'UTR. Analysis of the D2S2363 and the T284A GALNT3 transmission patterns did not show linkage to IDDM in Danish patients (P(ETDT)=0.15 and P(TDT)=0.76, respectively). In conclusion, IDDM7 (D2S152) links to IDDM in Danish patients, but D2S2363 and the identified T284A polymorphism in the GALNT3 3'UTR did not. Hence, it is unlikely that the GALNT3 is an IDDM susceptibility gene.

Linkage of the human inducible nitric oxide synthase gene to type 1 diabetes.

Exposure of human pancreatic islets to a mixture of cytokines induces expression of the inducible nitric oxide synthase (iNOS), impairs beta-cell function, and induces apoptosis. We performed a mutational scanning of all 27 exons of the human NOS2 gene and linkage transmission disequilibrium testing of identified NOS2 polymorphisms in a Danish nationwide type 1 diabetes mellitus (IDDM) family collection. Mutational screening was performed using PCR-amplified exons, followed by single stranded conformation polymorphism and verification of potential polymorphisms by sequencing. The transmission disequilibrium test was performed in an IDDM family material comprising 257 Danish families; 154 families were affected sibling pair families, and 103 families were simplex families. In total, 10 polymorphisms were identified in 8 exons, of which 4 were tested in the family material. A C/T single nucleotide polymorphism in exon 16 resulting in an amino acid substitution, Ser(608)Leu, showed linkage to IDDM in human leukocyte antigen DR3/4-positive affected offspring (P = 0.008; corrected P = 0.024). No other distorted transmission patterns were found for any other tested single nucleotide polymorphism or constructed haplotypes with the exception of those including data from exon 16. In conclusion, linkage of the human NOS2 gene to IDDM in a subset of patients supports a pathogenic role of nitric oxide in human IDDM.

Analysis of an interferon-gamma gene (IFNG) polymorphism in Danish and Finnish insulin-dependent diabetes mellitus (IDDM) patients and control subjects. Danish Study Group of Diabetes in Childhood.

A CA-repeat polymorphism within the first intron of the interferon (IFN)-gamma gene was analyzed. This polymorphism was recently demonstrated to be associated with insulin-dependent diabetes mellitus (IDDM) in Japanese subjects. We typed 266 IDDM patients and 195 control subjects of Danish Caucasoid origin. No significant differences in allele or genotype frequencies between patients and control were observed. In addition, we typed 168 IDDM and 110 control subjects of Finnish origin. A significant disease association of the studied IFN-gamma allelic pattern was found (p = 0.029). Analysis of data according to HLA-DQB1 susceptibility status did not reveal heterogeneity of risk at the IFN-gamma locus in either of the populations. Fifty-five Danish and 94 Finnish IDDM multiplex families with at least two affected siblings (660 individuals) were typed to test for transmission disequilibrium (TDT). No evidence for overall transmission disequilibrium using either an allele-wise (p = 0.42; combined data) or a genotype-wise analysis (p = 0.21; combined data) could be detected. Thus, the modest significance level observed in the Finnish case-control study and the failure to replicate it by the TDT provide little support for the hypothesis that the IFN-gamma gene microsatellite is associated with IDDM.

Intra-peritoneal administration of interleukin-1 beta induces impaired insulin release from the perfused rat pancreas.

Previous studies have demonstrated a stimulatory effect of interleukin-1 beta (IL-1 beta) on insulin and glucagon release from the perfused rat pancreas, accompanied by selective lysis of 20% of beta-cells as assessed by electronmicroscopy. However, we have not observed an inhibitory action of IL-1 beta on insulin release from the perfused pancreas as shown for isolated islets. To test whether periodical exposure of the endocrine pancreas to circulating IL-1 beta in vivo affects insulin release from the intact perfused pancreas, rats were treated with daily intraperitoneal injections of 4 micrograms IL-1 beta/kg or saline for 5 days. On day 5 the pancreata were isolated 2 h after the last injection and perfused from 0 to 72 min with 11 mmol/l D-glucose and from 72 to 84 min with 20 mmol/l D-glucose. Saline or IL-1 beta was added from 12 to 72 min. In pancreata from animals pre-treated with IL-1 beta glucose-stimulated as well as IL-1 beta potentiated glucose-stimulated insulin release was almost completely abolished. Furthermore, a decline in insulin release was observed at 11 mmol/l D-glucose, in contrast to an increase in insulin release in controls. The total extractable insulin content in pancreata from IL-1 beta pre-treated rats was higher than in pancreata from saline-treated controls. In contrast to the inhibitory effect of in vivo administration of IL-1 beta on beta-cell function glucagon secretion was stimulated. These observations suggest that circulating IL-1 beta is an important modulator of alpha- and beta-cell secretory function in vivo and that IL-1 beta should be considered a contributory pathogenetic factor in the development of insulin-dependent (type 1) diabetes mellitus.

Genetic susceptibility markers in Danish patients with type 1 (insulin-dependent) diabetes--evidence for polygenicity in man. Danish Study Group of Diabetes in Childhood.

Fifty-five Danish families with two offspring concordant for type 1 diabetes--identified through a nationwide population-based survey, and 57 "true sporadic" cases--matched with familial cases for age at onset, but with no IDDM-affected first-degree relatives and long disease duration, and 110 control subjects were typed for putative genetic susceptibility markers for type 1 diabetes identified from a pathogenetic model. The markers included MHC class I, II and III loci, the manganese superoxide dismutase (MnSOD) locus (chr. 6q), interleukin-1 beta (IL1B), the IL-1 receptor antagonist (IL1RN), and the IL-1 type 1 receptor (IL1RI) loci (each chr. 2q). No significant differences between familial and sporadic cases were found within the MHC region (including the following loci: HLA-DQ, -DR, heat shock protein (HSP) 70, tumour necrosis factor (TNF), HLA-B and -A). In both groups of patients 11% were negative for both DQA1*0301-DQB1*0302 and DQA1*0501-DQB1*0201 genotypes, and 7% of the type 1 diabetics had genotypes unable to encode a susceptibility DQ alpha beta heterodimer. Disease association was found for the IL1RN (p = 0.04) and for the IL1RI (p = 0.03). When comparing controls and only familial cases with type 1 diabetes for the IL1RN polymorphism a difference was observed (p = 0.003). For the IL1B RFLP a trend for difference was observed between familial cases and control subjects (p = 0.046), whereas no differences between sporadic cases and control subjects could be demonstrated neither at the IL1B nor at the IL1RN loci. A difference in the MnSOD pattern was observed between sporadic cases and controls (p = 0.04).

IDDM12 (CTLA4) on 2q33 and IDDM13 on 2q34 in genetic susceptibility to type 1 diabetes (insulin-dependent).

Type 1 diabetes (insulin-dependent) is a multifactorial disease with polygenic susceptibility. The major genetic component (IDDM1) resides within the HLA region, but several non-HLA loci have been implicated in the genetic susceptibility. In the present study, we have analysed two such loci, IDDM12 (CTLA4) on 2q33 and IDDM13 on 2q34, in Danish (n = 254) and Spanish (n = 39) type 1 diabetic multiplex families. No significant evidence of linkage of IDDM12 was observed in any of the two studied data sets. However, when the present data were combined with previously published data, they strengthened the evidence of linkage at this locus, p = 0.00002. For the IDDM13 region, we found some positive evidence of linkage of the D2S137-D2S164-D2S1471 markers (p-values 0.007, 0.02, and 0.007, respectively) using transmission disequilibrium testing (TDT) and the Tsp version of the TDT. Importantly, random transmission of all tested alleles was observed in unaffected offspring (p > 0.3). Stratification for HLA (high risk and non-high risk genotypes) in the Danish families did not reveal heterogeneity at IDDM12 or IDDM13. In conclusion, our data on an entirely new family data set did not support the existence of IDDM12 as a type 1 diabetes susceptibility locus in the Danish population. In addition, we found support for evidence of linkage and association of the IDDM13/D2S137-D2S1471 region (approximately 3.5 cM) to type 1 diabetes, however, further studies are needed to substantiate this observation.

Group founding and breeding structure in the subsocial spider stegodyphus lineatus (Eresidae)

Co-operative behaviour may evolve by enhancing the genetic similarity of group members. Increased group similarity is thought to be the basis for the 'subsocial route' of social evolution in the spider family Eresidae. Two processes may promote the similarity of individuals within populations or breeding groups, namely philopatry in stable environments and founder events in a stochastic environment. We show that both processes led to genetic differentiation within and among populations of the subsocial spider Stegodyphus lineatus. Within populations we distinguished between the genetic structure caused by random mating and philopatry in old breeding groups and that caused by newly founded groups consisting of sibs. Such sib-groups suggest that new breeding groups are established primarily by single females. The different gene coancestries among breeding groups resulted in high variances among single-locus data. The results imply that sex-specific dispersal behaviour (random male mating-dispersal or female group founding) had different impacts on the population structure. This type of population structure, where within-population philopatry and founder events may lead to differential proliferation of breeding groups, is very similar to that presumed for social spiders, and is also one that could provide the conditions for interdemic selection.