Beta-catenin abnormalities and associated insulin-like growth factor overexpression are important in phyllodes tumours and fibroadenomas of the breast

The aim of this study was to assess the expression of IGF-I and IGF-II in phyllodes tumours and fibroadenomas and to see if there is any correlation between nuclear beta-catenin expression and IGF-I and IGF-II expression in these tumours. In a previous study, it has been shown that Wnt signalling is important in the pathogenesis of phyllodes tumours of the breast. Epithelial Wnt5a overexpression and stromal Wnt2 overexpression were associated with abnormal, nuclear localization of beta-catenin in the stromal cells of these tumours. However, not all tumours with beta-catenin accumulation showed Wnt overexpression. One other possible cause of beta-catenin accumulation is overexpression of insulin-like growth factors (IGFs), as both IGF-I and IGF-II have been shown to stabilize beta-catenin. In this study, 30 fibroadenomas of the breast were assessed for beta-catenin expression using immunohistochemistry and the results were compared with previous data from 119 phyllodes tumours. In situ hybridization was used to assess IGF-I and IGF-II expression in 23 phyllodes tumours and 16 fibroadenomas. Nineteen phyllodes tumours (83%) showed widespread overexpression of IGF-II and 5/23 (22%) showed widespread overexpression of IGF-I. IGF-I expression correlated with nuclear beta-catenin staining in phyllodes tumours. Malignant phyllodes tumours showed no or little IGF-I expression. There was a degree of nuclear beta-catenin expression in the stroma (weak in 33%, moderate in 27%, and strong in 40%) in all fibroadenomas and nuclear beta-catenin staining correlated with IGF-I overexpression. Extensive IGF-II overexpression was also found in the majority of fibroadenomas (12/16). These results support the hypothesis that IGF-I and IGF-II overexpression may be important in the pathogenesis of fibroepithelial neoplasms of the breast and that IGF-I overexpression is likely to be contributing to the nuclear beta-catenin localization observed in the tumours.     

Self-perceptions of competence in children with ADHD and comparison children

The self-perceptions of children with attention-deficit/hyperactivity disorder (ADHD; n = 487) were compared with those of children in a local normative comparison group (n = 287), relative to teacher- and parent-rated perceptions of their competence. Children were participants in the ongoing follow-up portion of the Multimodal Treatment Study of Children with ADHD. Children with ADHD were much more likely than comparison children to overestimate their competence relative to adult report, regardless of who was used as the criterion rater (teacher, mother, or father). Examination by comorbidity subgroups revealed that children with ADHD inflated their self-perceptions the most in domains of greatest deficit. Gender effects also are reported.     

Generating Attention,Inhibition, and Memory: A Pilot Randomized Trial for Preschoolers With Executive Functioning Deficits

This goal of this study was to assess the initial feasibility and efficacy of a play-based intervention targeting executive functions (EF) and parent–child relationships in preschoolers compared with an active control group. Preschoolers with EF deficits (M age = 3.7 ± 0.47, predominantly White boys) and their parents were randomized to intervention (n = 36) or active control (n = 32) conditions. Child performance on EF tasks, parent and masked teacher ratings of EF and behavior, and masked clinician ratings of severity were collected at baseline and at 3 and 6 months postbaseline. Partial eta-squared effect sizes at .02 or higher comparing performance across the two groups was considered evidence of meaningful, albeit small, intervention effects. Intervention effects were observed for parent ratings of inattention, hyperactivity/impulsivity, and number/severity of problems experienced in various home situations, teacher ratings of severity of problems in various school situations, parent and teacher ratings of overall impairment, and clinician ratings of impairment. Intervention effects for functional improvements were maintained at the 6-month follow-up. No effect of the intervention was observed on the objective EF measures, although parent ratings of emotional control were improved for children in the intervention group. An intervention utilizing play-based activities targeting EF, when administered in a structured way by parents, is a promising approach for improving behavior in preschoolers with self-regulation deficits. More work is needed to investigate potential impact on EF and to disentangle mechanisms of action. It may be that the intervention’s focus on the structure and quality of parent–child interactions is a mediator of outcomes, rather than improved EFs.     

Energetic characteristics of the new transthyretin variant A25T may explain its atypical central nervous system pathology

Transthyretin (TTR) is a tetrameric protein that must misfold to form amyloid fibrils. Misfolding includes rate-limiting tetramer dissociation, followed by fast tertiary structural changes that enable aggregation. Amyloidogenesis of wild-type (WT) TTR causes a late-onset cardiac disease called senile systemic amyloidosis. The aggregation of one of > 80 TTR variants leads to familial amyloidosis encompassing a collection of disorders characterized by peripheral neuropathy and/or cardiomyopathy. Prominent central nervous system (CNS) impairment is rare in TTR amyloidosis. Herein, we identify a new A25T TTR variant in a Japanese patient who presented with CNS amyloidosis at age 42 and peripheral neuropathy at age 44. The A25T variant is the most destabilized and fastest dissociating TTR tetramer published to date, yet, surprising, disease onset is in the fifth decade. Quantification of A25T TTR in the serum of this heterozygote reveals low levels relative to WT, suggesting that protein concentration influences disease phenotype. Another recently characterized TTR CNS variant (D18G TTR) exhibits strictly analogous characteristics, suggesting that instability coupled with low serum concentrations is the signature of CNS pathology and protects against early-onset systemic amyloidosis. The low A25T serum concentration may be explained either by impaired secretion from the liver or by increased clearance, both scenarios consistent with A25T's low kinetic and thermodynamic stability. Liver transplantation is the only known treatment for familial amyloid polyneuropathy. This is a form of gene therapy that removes the variant protein from serum preventing systemic amyloidosis. Unfortunately, the choroid plexus would have to be resected to remove A25T from the CSF-the source of the CNS TTR amyloid. Herein we demonstrate that small-molecule tetramer stabilizers represent an attractive therapeutic strategy to inhibit A25T misfolding and CNS amyloidosis. Specifically, 2-[(3,5-dichlorophenyl)amino]benzoic acid is an excellent inhibitor of A25T TTR amyloidosis in vitro.     

Very low doses of X-rays can cause human lymphocytes to become less susceptible to ionizing radiation

Cultured human lymphocytes exposed to very low doses of X-raysbecome less susceptible to subsequent higher doses of X-rays.Cells exposed to doses as low as 0.5 rad (cGy) or 1 rad of X-raysat 32–34 h of culture become adapted so that less cytogeneticdamage in the from of chromosome breakage is induced by 150rad administered at 48 h. This response, which does not occurafter high inital doses of X-rays, can be eliminated by 3-aminobenzamide,an inhibitor of poly(ADP-ribose) polymerase.     

Inflammatory pseudotumor of lymph node and spleen: An entity biologically distinct from inflammatory myofibroblastic tumor

Inflammatory pseudotumors (IPTs) of the lymph node and spleen are an uncommon, benign cause of lymphadenopathy and/or splenomegaly that often bear striking clinicopathologic similarities to the inflammatory myofibroblastic tumors (IMTs) found in soft tissues. These tumors have classically been grouped together under the umbrella category of "inflammatory pseudotumor." Recent evidence shows that IMTs are in fact neoplastic processes that often harbor balanced chromosomal translocations involving the ALK kinase gene. These translocations result in expression of ALK kinase in IMTs as assessed by immunohistochemical studies. However, the relationship between IMT and IPT of the lymph node and spleen is uncertain. To determine if ALK tyrosine kinase expression is also present in IPT, 13 cases of IPT (9 involving lymph nodes, 4 splenic lesions) were examined for the presence of ALK tyrosine kinase by immunohistochemical staining on paraffin-embedded tissue. In addition, in situ hybridization studies for Epstein-Barr virus--encoded RNAs (EBER) and immunoperoxidase studies for human herpesvirus-8 (HHV8)--specific proteins were performed. All cases had clinical, morphologic, and immunophenotypic findings typical of IPT and had varying proportions of fibroblastic and inflammatory components. Age ranged from 11 to 75 (median, 40) years; 8 subjects were male, and 5 were female. None of the cases (0 of 13) had positive staining for ALK kinase or HHV8, and in 1 a lymph node (1 of 13) was focally positive for EBV (EBER) by in situ hybridization. The absence of ALK kinase as detected by immunohistochemical studies in IPT of the lymph node and spleen suggests that this entity is biologically distinct from the histologically similar IMT.     

Cortical mechanisms of cocaine sensitization

Behavioral sensitization is the augmented motor-stimulant response that occurs with repeated, intermittent exposure to most drugs of abuse, including cocaine. Sensitization, which is a long-lasting phenomenon, is thought to underlie drug craving and relapse to drug use. Much research has been conducted to determine the neural mechanisms of sensitization. The bulk of this effort has focused on the nucleus accumbens and ventral tegmental area (VTA) that comprise a portion of the mesolimbic dopamine system. Recently, studies have begun to also explore the role of the medial prefrontal cortex (mPFC) in sensitization, in part because this region provides glutamatergic innervation to the VTA and nucleus accumbens. The present review will coalesce these studies into a working hypothesis that states that cocaine sensitization results from a decrease in inhibitory modulation of excitatory transmission from the mPFC to the VTA and nucleus accumbens. The discussion will revolve around how repeated cocaine exposure alters dopamine, gamma-aminobutyric acid (GABA), and glutamate regulation of pyramidal cell activity. It will be proposed that cocaine-induced alterations in cortical transmission occur in two phases. During early withdrawal from repeated cocaine exposure, changes in neurotransmitter release are thought to underlie the decreased inhibitory modulation of pyramidal projection neurons. Following more prolonged withdrawal, the attenuation in inhibitory transmission appears to occur at the receptor level. A model will be presented that may serve to direct future studies on the involvement of the mPFC in the development of cocaine sensitization, which ultimately could lead to development of pharmacotherapies for cocaine addiction.