The association between repetitive behaviours, impulsivity and hyperactivity in people with intellectual disability

Background There is a need for assessments of psychological difference and disorder in people who have more severe intellectual disability (ID). Hyperactivity and impulsivity are two behavioural domains of importance as they are correlated with self‐injury and aggression and this alludes to a shared cognitive correlate of compromised behavioural inhibition. Additionally, compromised behavioural inhibition is demonstrably related to repetitive behaviour and the latter might be expected to be associated with impulsivity and hyperactivity. Methods The Activity Questionnaire (TAQ) was developed for this study. Three sub‐scales with high levels of face validity were supported by factor analysis of the scoring of 755 intellectually disabled participants on the TAQ items. These sub‐scales mapped onto the constructs of Overactivity, Impulsivity and Impulsive Speech. Test–retest, inter‐rater reliability and internal consistency were robust. TAQ scores and scores on the Repetitive Behaviour Questionnaire (RBQ) were collected for a sample of 136 participants with varying degrees of ID. Results Scores on the TAQ at sub‐scale and full‐scale level were not related to level of adaptive functioning. There were significant positive associations between overactivity (TAQ) and stereotyped behaviour (RBQ), impulsivity (TAQ) and restricted preferences (RBQ), and impulsive speech (TAQ) and repetitive speech (RBQ). Conclusions The TAQ is a reliable assessment of hyperactivity and impulsivity for people with ID with robust factor structure. Validity requires evaluation. The relationship between impulsivity and restricted preferences may result from a common cognitive impairment in inhibition, which may underpin these two classes of behaviour.     

Effects of social context on social interaction and self-injurious behavior in Cornelia de Lange syndrome

Cornelia de Lange syndrome is reported to be associated with self-injurious behavior (SIB) and social avoidance. We used analog methodology to examine the effect of manipulating adult social contact on social communicative behaviors and SIB in 16 children with this syndrome. For 9 participants engagement behavior was related to levels of adult attention, and SIB showed significant variability across conditions for 3 participants. These findings indicate that SIB can be affected by environmental factors, even though it is thought to be part of the behavioral phenotype of Cornelia de Lange syndrome and suggest that individuals with this syndrome show socially motivated attention-soliciting behaviors. The implications for gene-environment interactions are discussed.     

Fronto‐insular‐parietal network engagement underlying arithmetic word problem solving

Mathematical word problems are ubiquitous and standard for teaching and evaluating generalization of mathematical knowledge for real‐world contexts. It is therefore concerning that the neural mechanisms of word problem solving are not well understood, as these insights represent strong potential for improving education and remediating deficits in this domain. Here, we investigate neural response to word problems via functional magnetic resonance imaging (fMRI). Healthy adults performed sentence judgment tasks on word problems that either contained one‐step mathematical operations, or nonarithmetic judgments on parallel narratives without any numerical information. Behavioral results suggested that the composite efficiency measurement of combining accuracy and RT did not differ between the two problem types. Arithmetic sentence judgments elicited greater activation in the fronto‐insular‐parietal network including intraparietal sulcus (IPS), dorsolateral prefrontal cortex (PFC), and anterior insula (AI) than narrative sentence judgment. Narrative sentence judgments, conversely, resulted in greater activation predominantly in the left ventral PFC, angular gyrus and perisylvian cortex compared with reading arithmetic sentences. Moreover, task‐dependent functional connectivity analyses showed the AI circuits were more strongly coupled with IPS during arithmetic sentence judgments than nonarithmetic sentences. Finally, activations in the IPS during arithmetic were highly correlated with out‐of‐scanner performance on a distinct set of problems with the same characteristics. These results show arithmetic word problem performance differences may rely more heavily on fronto‐insular‐parietal circuits for mathematical model building than narrative text comprehension of similar difficulty. More broadly, our study suggests that quantitative measurements of brain mechanisms can provide pivotal role for uncovering crucial arithmetic skills.     

Apo-AII is an elevated biomarker of chronic non-human primate ethanol self-administration

AIMS: Serum protein profiles were examined in na?ve, ethanol self-administering and ethanol abstinent cynomolgus monkeys (Macaca fasicularis) to search for differences in protein expression which could possibly serve as biomarkers of heavy ethanol consumption. METHODS: Surface-enhanced laser desorption ionization time-of-flight (SELDI-ToF) mass spectrometry was used for proteomic profiling of serum. RESULTS: Two proteins were identified by SELDI-ToF to be increased in ethanol self-administering compared with abstinent animals. These proteins were identified to be apolipoprotein AI (Apo-AI) and apolipoprotein AII (Apo-AII) by peptide mass fingerprinting and comparison with spectra of purified human Apo-AI and AII proteins. Immunoblot analysis of Apo-AI and Apo-AII was performed on a separate group of animals (within-animal ethanol-na?ve and self-administering) and confirmed a statistically significant increase in Apo-AII, while Apo-AI was unchanged. CONCLUSIONS: An open proteomic screen of serum and confirmation in a separate set of animals found Apo-AII to be increased in the serum of ethanol self-administering monkeys. These results are consistent with previous clinical studies of human ethanol consumption and serum apolipoprotein expression. Moreover, these results validate the use of non-human primates as a model organism for proteomic analysis of ethanol self-administration biomarkers.     

Sialylated core 1 based O-linked glycans enhance the growth rate of mammary carcinoma cells in MUC1 transgenic mice

The MUC1 mucin, found on the luminal surface of simple epithelial cells is upregulated and aberrantly glycosylated in many carcinomas particularly breast and ovarian. MUC1 expressed by normal mammary epithelial cells, carries core 2 glycans but in breast carcinomas the simple core 1 based glycans are added. The binding of the monoclonal antibody SM3 to its peptide epitope in the tandem repeat of MUC1 is blocked by the branched core 2 glycans found on MUC1 expressed by normal cells. Thus SM3 does not bind to MUC1 expressed by normal mammary epithelial cells but reacts with more than 90% of breast carcinomas, suggesting that the loss of at least some core 2 glycans is a very common event in breast carcinogenesis. To determine if the change in glycosylation observed in breast carcinomas confers an advantage to cancer cells, murine mammary carcinoma cell lines were developed that express MUC1 carrying core 2 or core 1 linked glycans. The in vivo growth rate in wild-type and nude mice were identical regardless of the O-glycosylation patterns. However, the tumors that grew out of wild-type mice lost most of their MUC1 expression. In contrast, in MUC1 transgenic mice, where expression of MUC1 was retained by the tumor, a striking difference in growth rate was observed. In these mice, cells expressing core 1 glycans grew significantly faster than cells expressing core 2 glycans. These data suggest that MUC1 transgenic mice are more tolerant to core 1 expressing tumors than to tumors expressing core 2.     

Enhanced delivery of exogenous peptides into the class I antigen processing and presentation pathway

Current immunization strategies, using peptide or protein antigens, generally fail to elicit cytotoxic-T-lymphocyte responses, since these antigens are unable to access intracellular compartments where loading of major histocompatibility complex class I (MHC-I) molecules occurs. In an attempt to circumvent this, we investigated whether the GM1 receptor-binding B subunit of Escherichia coli heat-labile toxin (EtxB) could be used to deliver class I epitopes. When a class I epitope was conjugated to EtxB, it was delivered into the MHC-I presentation pathway in a GM1-binding-dependent fashion and resulted in the appearance of MHC-I-epitope complexes at the cell surface. Importantly, we show that the efficiency of EtxB-mediated epitope delivery could be strikingly enhanced by incorporating, adjacent to the class I epitope, a 10-amino-acid segment from the C terminus of the DNA polymerase (Pol) of herpes simplex virus. The replacement of this 10-amino-acid segment by a heterologous sequence or the introduction of specific amino acid substitutions within this segment either abolished or markedly reduced the efficiency of class I epitope delivery. If the epitope was extended at its C terminus, EtxB-mediated delivery into the class I presentation pathway was found to be completely dependent on proteasome activity. Thus, by combining the GM1-targeting function of EtxB with the 10-amino-acid Pol segment, highly efficient delivery of exogenous epitopes into the endogenous pathway of class I antigen processing and presentation can be achieved.     

Natural endogenous adjuvants

It has long been known that immunization with a protein by itself is often not sufficient to stimulate immunity, and may instead induce tolerance. To elicit productive immune responses exogenous adjuvants need to be co-injected with an antigen. One important class of adjuvants are the unique (non-mammalian) components of microbes. It is now believed that an adjuvant is required for immunity because the immune system evolved to respond to dangerous situations such as infections, and the presence of an adjuvant is the mechanism used to identify these situations. However, there are some circumstances where immune responses are generated in the apparent absence of any microbial or other exogenous adjuvant. Such situations include immune responses to transplants, tumors, autoimmunity and possibly certain viral infections. It has been postulated that in these situations the danger signals come from endogenous adjuvants that are released from dying cells. There is abundant evidence that dead cells are immunogenic, and recently it has been shown that cells contain endogenous adjuvant activities that are released after death. Some actual and putative endogenous adjuvants, such as monosodium urate and heat shock proteins, have been identified and there are others whose identities are not yet known. The potential biological roles of this class of adjuvants are discussed.     

Stimulation of malignant growth in rodents by antidepressant drugs at clinically relevant doses.

Tricyclic antidepressants, such as amitriptyline (Elavil), and the nontricyclic agent, fluoxetine (Prozac), bind to growth-regulatory intracellular histamine receptors, associated with anti-estrogen binding sites in microsomes and nuclei. The prototype anti-estrogen binding site/intracellular histamine receptor ligand, N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine HCl, inhibits normal cell proliferation in vitro but stimulates tumor growth in vivo. Because of their structural similarity to N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine HCl, we carried out studies to determine whether amitriptyline and fluoxetine stimulate tumor growth and/or development in rodents at concentrations relevant to the treatment of human depression (equivalent human dose range, approximately 100-150 mg/day for amitriptyline and approximately 20-80 mg/day for fluoxetine). All experiments were performed blinded. In studies of growth stimulation of transplantable syngeneic tumors, groups of mice were inoculated s.c. with C-3 fibrosarcoma cells or given i.v. or s.c. injections of B16f10 melanoma cells, followed 24 h later by daily i.p. injections of saline, amitriptyline, or fluoxetine. Tumor latency (fibrosarcoma), aggregate tumor weight (s.c. injected melanoma), or time to death from pulmonary metastasis (i.v. injected melanoma) was determined; drug-induced stimulation of DNA synthesis in C-3 fibrosarcoma cells in vitro was correlated with tumor growth acceleration in vivo. In a mammary carcinogenesis model, the effects of chronic saline, amitriptyline, or fluoxetine administration on the rate and frequency of development of mammary tumors in rats fed dimethylbenzanthracene (DMBA) were compared. Eight of 20 amitriptyline- or fluoxetine-treated mice developed fibrosarcoma tumors by day 5, as compared to none of 20 saline controls (P less than 0.002). Similarly, 20 of 21 DMBA-treated rats receiving the antidepressant drugs developed 33 mammary tumors by week 15 as compared to 5 tumors in 4 of 7 DMBA-treated rats receiving saline (P less than 0.001). For both models, tumor latency decreased 30-40% and, in the DMBA model, tumor frequency increased greater than 2-fold in the antidepressant-treated rats as compared to controls. Stimulation of fibrosarcoma growth in vivo correlated with a corresponding bell-shaped drug-induced increase in DNA synthesis in vitro. While the median time to death from pulmonary metastases did not differ among groups given i.v. injections of melanoma cells, a significant (P less than 0.01) stimulation of growth of s.c. injected melanoma was observed in mice receiving the antidepressants.(ABSTRACT TRUNCATED AT 400 WORDS)