Long-term exposure of mouse pancreatic islets to oleate or palmitate results in reduced glucose-induced somatostatin and oversecretion of glucagon

AIMS/HYPOTHESIS: Long-term exposure to NEFAs leads to inhibition of glucose-induced insulin secretion. We tested whether the release of somatostatin and glucagon, the two other major islet hormones, is also affected. METHODS: Mouse pancreatic islets were cultured for 72 h at 4.5 or 15 mmol/l glucose with or without 0.5 mmol/l oleate or palmitate. The release of glucagon and somatostatin during subsequent 1 h incubations at 1 or 20 mmol/l glucose as well as the islet content of the two hormones were determined. Lipid-induced changes in islet cell ultrastructure were assessed by electron microscopy. RESULTS: Culture at 15 mmol/l glucose increased islet glucagon content by approximately 50% relative to that observed following culture at 4.5 mmol/l glucose. Inclusion of oleate or palmitate reduced islet glucagon content by 25% (at 4.5 mmol/l glucose) to 50% (at 15 mmol/l glucose). Long-term exposure to the NEFA increased glucagon secretion at 1 mmol/l glucose by 50% (when islets had been cultured at 15 mmol/l glucose) to 100% (with 4.5 mmol/l glucose in the culture medium) and abolished the inhibitory effect of 20 mmol/l glucose on glucagon secretion. Somatostatin content was unaffected by glucose and lipids, but glucose-induced somatostatin secretion was reduced by approximately 50% following long-term exposure to either of the NEFA, regardless of whether the culture medium contained 4.5 or 15 mmol/l glucose. Ultrastructural evidence of lipid deposition was seen in <10% of non-beta cells but in >80% of the beta cells. CONCLUSIONS/INTERPRETATION: Long-term exposure to high glucose and/or NEFA affects the release of somatostatin and glucagon. The effects on glucagon secretion are very pronounced and in type 2 diabetes in vivo may aggravate the hyperglycaemic effects due to lack of insulin

Statistical Analysis of Molecular Signal Recording

A molecular device that records time-varying signals would enable new approaches in neuroscience. We have recently proposed such a device, termed a “molecular ticker tape”, in which an engineered DNA polymerase (DNAP) writes time-varying signals into DNA in the form of nucleotide misincorporation patterns. Here, we define a theoretical framework quantifying the expected capabilities of molecular ticker tapes as a function of experimental parameters. We present a decoding algorithm for estimating time-dependent input signals, and DNAP kinetic parameters, directly from misincorporation rates as determined by sequencing. We explore the requirements for accurate signal decoding, particularly the constraints on (1) the polymerase biochemical parameters, and (2) the amplitude, temporal resolution, and duration of the time-varying input signals. Our results suggest that molecular recording devices with kinetic properties similar to natural polymerases could be used to perform experiments in which neural activity is compared across several experimental conditions, and that devices engineered by combining favorable biochemical properties from multiple known polymerases could potentially measure faster phenomena such as slow synchronization of neuronal oscillations. Sophisticated engineering of DNAPs is likely required to achieve molecular recording of neuronal activity with single-spike temporal resolution over experimentally relevant timescales.United States. Defense Advanced Research Projects Agency. Living Foundries ProgramGoogle (Firm)New York Stem Cell Foundation. Robertson Neuroscience Investigator AwardNational Institutes of Health (U.S.) (EUREKA Award 1R01NS075421)National Institutes of Health (U.S.) (Transformative R01 1R01GM104948)National Institutes of Health (U.S.) (Single Cell Grant 1 R01 EY023173)National Institutes of Health (U.S.) (Grant 1R01DA029639)National Institutes of Health (U.S.) (Grant 1R01NS067199)National Science Foundation (U.S.) (CAREER Award CBET 1053233)National Science Foundation (U.S.) (Grant EFRI0835878)National Science Foundation (U.S.) (Grant DMS1042134)Paul G. Allen Family Foundation (Distinguished Investigator in Neuroscience Award

Deviant Peer Affiliation and Antisocial Behavior: Interaction with Monoamine Oxidase A (MAOA) Genotype

Although genetic and environmental factors are separately implicated in the development of antisocial behavior (ASB), interactive models have emerged relatively recently, particularly those incorporating molecular genetic data. Using a large sample of male Caucasian adolescents and young adults from the National Longitudinal Study of Adolescent Health (Add Health), the association of deviant peer affiliation, the 30-base pair variable number tandem repeat polymorphism in promoter region of the monoamine oxidase-A (MAOA) gene, and their interaction, with antisocial behavior (ASB) was investigated. Weighted analyses accounting for over-sampling and clustering within schools as well as controlling for age and wave suggested that deviant peer affiliation and MAOA genotype were each significantly associated with levels of overt ASB across a 6-year period. Only deviant peer affiliation was significantly related to covert ASB, however. Additionally, there was evidence suggestive of a gene-environment interaction (G × E) where the influence of deviant peer affiliation on overt ASB was significantly stronger among individuals with the high-activity MAOA genotype than the low-activity genotype. MAOA was not significantly associated with deviant peer affiliation, thus strengthening the inference of G × E rather than gene-environment correlation (rGE). Different forms of gene-environment interplay and implications for future research on ASB are discussed

Latent Class Analysis of Antisocial Behavior: Interaction of Serotonin Transporter Genotype and Maltreatment

To improve understanding about genetic and environmental influences on antisocial behavior (ASB), we tested the association of the 44-base pair polymorphism of the serotonin transporter gene (5-HTTLPR) and maltreatment using latent class analysis in 2,488 boys and girls from Wave 1 of the National Longitudinal Study of Adolescent Health. In boys, ASB was defined by three classes (Exclusive Covert, Mixed Covert and Overt, and No Problems) whereas in girls, ASB was defined by two classes (Exclusive Covert, No Problems). In boys, 5-HTTLPR and maltreatment were not significantly related to ASB. However, in girls, maltreatment, but not 5-HTTLPR, was significantly associated with ASB. A significant interaction between 5-HTTLPR and maltreatment was also observed, where maltreated girls homozygous for the short allele were 12 times more likely to be classified in the Exclusive Covert group than in the No Problems group. Structural differences in the latent structure of ASB at Wave 2 and Wave 3 prevented repeat LCA modeling. However, using counts of ASB, 5-HTTLPR, maltreatment, and its interaction were unrelated to overt and covert ASB at Wave 2 and only maltreatment was related to covert ASB at Wave 3. We discuss these findings within the context of sex differences in ASB and relevant models of gene-environment interplay across developmental periods

The parallel development of ODD and CD symptoms from early childhood to adolescence

This study examined the developmental relations between symptoms of oppositional defiant disorder (ODD) and conduct disorder (CD) from early childhood to adolescence. Specifically we tested, according to parent-reported problems, whether symptoms of ODD precede the development of CD symptoms, whether ODD and CD symptoms are reciprocally associated across time, or whether ODD and CD symptoms develop parallel to each other across time. Participants were a community-based sample (at time 1: N = 485, 48% boys) assessed biannually five times from age 4 to 6 until age 12-14. The findings suggested that, with control for stability effects, baseline SES, and symptoms of attention deficit hyperactivity disorder, ODD and CD symptoms develop parallel to each other. No gender differences were obtained. We conclude that without the initial presence of CD symptoms, ODD symptoms are not developmental precursors to CD symptoms

Childhood Predictors of Desistance and Level of Persistence in Offending in Early Onset Offenders

Childhood predictors of adolescent offending careers were studied in 310 boys from the longitudinal Pittsburgh Youth Study who started offending prior to age 12. Three main groups were distinguished: serious persisters (n = 95), moderately serious persisters (n = 117), desisters (n = 63), and an intermittent group (n = 35). Group membership was predicted using risk and promotive factors measured in childhood. Serious and moderately serious persisters could be distinguished well from desisters (29.2% and 32.3% explained variance). Distinction between the two persister groups proved somewhat more difficult (20.9% explained variance). More serious persisters than desisters showed disruptive behavior, while moderately serious persisters fell in between. Further, more moderately serious persisters were marked by social disadvantage. Family involvement, small family and positive peer relationships were promotive of desistance. Concluding, early onset offenders show considerable heterogeneity in their adolescent offending careers which seem to some extent to be predicted by different sets of risk and promotive factors

Developmental trajectories of child to adolescent externalizing behavior and adult DSM-IV disorder: results of a 24-year longitudinal study

Objective: Childhood externalizing behavior is found to be relatively persistent. Developmental pathways within types of externalizing behavior have been recognized from childhood to adolescence. We aimed to describe the prediction of adult DSM-IV disorders from developmental trajectories of externalizing behavior over a period of 24 years on a longitudinal multiple birth cohort study of 2,076 children. This has not been examined yet. Methods: Trajectories of the four externalizing behavior types aggression, opposition, property violations, and status violations were determined separately through latent class growth analysis (LCGA) using data of five waves, covering ages 4-18 years. Psychiatric disorders of 1,399 adults were assessed with the CIDI. We used regression analyses to determine the associations between children's trajectories and adults' psychiatric disorders. Results: All externalizing behavior types showed significant associations with disruptive disorder in adulthood. In all antisocial behavior types high-level trajectories showed the highest probability for predicting adult disorders. Particularly the status violations cluster predicted many disorders in adulthood. The trajectories most often predicted disruptive disorders in adulthood, but predicted also anxiety, mood, and substance use disorders. Conclusions: We can conclude that an elevated level of externalizing behavior in childhood has impact on the long-term outcome, regardless of the developmental course of externalizing behavior. Furthermore, different types of externalizing beh

The impact of ADHD and conduct disorder in childhood on adult delinquency: A 30 years follow-up study using official crime records

<p>Abstract</p> <p>Background</p> <p>Few longitudinal studies have explored lifetime criminality in adults with a childhood history of severe mental disorders. In the present study, we wanted to explore the association between adult delinquency and several different childhood diagnoses in an in-patient population. Of special interest was the impact of disturbance of activity and attention (ADHD) and mixed disorder of conduct and emotions on later delinquency, as these disorders have been variously associated with delinquent development.</p> <p>Methods</p> <p>Former Norwegian child psychiatric in-patients (n = 541) were followed up 19-41 years after hospitalization by record linkage to the National Register of Criminality. On the basis of the hospital records, the patients were re-diagnosed according to ICD-10. The association between diagnoses and other baseline factors and later delinquency were investigated using univariate and multivariate Cox regression analyses.</p> <p>Results</p> <p>At follow-up, 24% of the participants had been convicted of criminal activity.</p> <p>In the multivariate Cox regression analysis, conduct disorder (RR = 2.0, 95%CI = 1.2-3.4) and hyperkinetic conduct disorder (RR = 2.7, 95% CI = 1.6-4.4) significantly increased the risk of future criminal behaviour. Pervasive developmental disorder (RR = 0.4, 95%CI = 0.2-0.9) and mental retardation (RR = 0.4, 95%CI = 0.3-0.8) reduced the risk for a criminal act. Male gender (RR = 3.6, 95%CI = 2.1-6.1) and chronic family difficulties (RR = 1.3, 95% CI = 1.1-1.5) both predicted future criminality.</p> <p>Conclusions</p> <p>Conduct disorder in childhood was highly associated with later delinquency both alone or in combination with hyperactivity, but less associated when combined with an emotional disorder. ADHD in childhood was no more associated with later delinquency than the rest of the disorders in the study population. Our finding strengthens the assumption that there is no direct association between ADHD and criminality.</p

Correlates of self-reported offending in children with a first police contact from distinct socio-demographic and ethnic groups

<p>Abstract</p> <p>Background</p> <p>This study aims to identify risk factors for level of offending among childhood offenders from different socio-economic status (SES) neighborhoods and ethnic origins.</p> <p>Method</p> <p>Three groups of childhood first time police arrestees were studied using standardized instruments for individual and parental characteristics: native Dutch offenders from moderate to high SES neighborhoods, native Dutch offenders from low SES neighborhoods, and offenders of non-Western origin from low SES neighborhoods.</p> <p>Results</p> <p>All subgroups showed high rates of externalizing disorders (27.2% to 41.8%) and familial difficulties (25.7% to 50.5%). Few differences between neighborhoods were found in the prevalence and impact of risk factors. However, the impact of some family risk factors on offending seemed stronger in the low SES groups. Regarding ethnical differences, family risk factors were more prevalent among non-Western childhood offenders. However, the association of these factors with level of offending seemed lower in the non-Western low SES group, while the association of some individual risk factors were stronger in the non-Western low SES group. Turning to the independent correlation of risk factors within each of the groups, in the Dutch moderate to high SES group, 23.1% of the variance in level of offending was explained by ADHD and behavioral problems; in the Dutch low SES group, 29.0% of the variance was explained by behavioral problems and proactive aggression; and in the non-Western low SES group, 41.2% of the variance was explained by substance use, sensation seeking, behavioral peer problems, and parental mental health problems.</p> <p>Conclusions</p> <p>Thereby, the study indicates few neighborhood differences in the impact of individual and parental risk factors on offending, while individual and parental risk factors may differ between ethnic groups.</p