How does a phonological dyslexic read words she has never seen?

In literate people the visual input logogen system contains roughly the same number of words as the auditory input and phonological output logogen systems. An exception is represented by literate people who speak a dialect which has no written tradition. An Italian phonological dyslexic patient (ML), speaking Italian and Friulan dialect, is described. Her performance in reading Friulan was less good than her reading of Italian words but substantially better than her nonword reading.

It is suggested that dialect words are read less well than Italian words because on the only reading route which is intact in a phonological dyslexic (a lexical one), no orthographic entry is represented for dialect words, since there has been no previous exposure to dialect in the written modality.

On the other side the advantage shown for reading of dialect words over nonwords, which is in some respects similar to the advantage demonstrated in English and French phonological dyslexics for reading pseudohomophones over ordinary nonwords, may have several explanations. A first possibility is that information coming from the phonological output lexicon would enhance the phonological assembly of real dialect words. A second and third explanation consider the possible intervention of a top-down mechanism: in one case the helping information would come again from the phonological output lexicon, in the other case from a store consisting of potential graphemic forms generated by long auditory exposure to a word. This latter mechanism would be more likely to work in a speaker whose language has regular phoneme-to-grapheme correspondences.     

Specific order impairment in arabic number writing: A case‐study

The present study examines the transitory deficit in transcoding verbal to Arabic numbers in an aphasic patient, TM. She showed a mild syntactic impairment in syntactic comprehension of verbal numbers, with preserved performance in comprehension of Arabic numbers, in access to semantic representation, as well as in reading of Arabic numbers, but she committed 75% of errors when required to write numbers in the Arabic format to dictation. In conformity to the previous literature on transcoding deficits, the majority of her errors were syntactic (60%). However, most of them were unusual “order errors” (50%) in which lexical digits (e.g., 1 to 9) were written on the left and zeros on the right of the number, which contained in the majority of the cases the correct number of digits. A similar type of errors has been reported in only one previous case study (Delazer & Denes, 1998), but not specifically studied. We discuss hypotheses concerning its origins as stemming from a syntactic disorder within existing models of transcoding (McCloskey, Caramazza, & Basili, 1985; Power & Dal Martello, 1990). We also report kinematic assessment of the patient's handwriting before and after recovery. At time of the second examination, results show that her pattern of movement fluency parallels that of healthy subjects and supports a distinction between two types of zeros within Arabic numbers, in relation to the verbal code and the rules required to produce them. This paper thus also highlights the potential usefulness of using a digitising tablet in the study of transcoding deficits.     

Short exposure of albumin to high concentrations of malondialdehyde does not mimic physiological conditions

Malondialdehyde (MDA), a major lipid peroxidation product, spontaneously binds to, and modifies proteins. In vivo, proteins are physiologically exposed to micromolar MDA concentrations for long periods. In order to mimic this process in vitro, protein modification is often performed by short exposure to millimolar MDA concentrations, also in order to generate antigenic structures for antibody production.     

Dysregulation of the epigenome in triple-negative breast cancers: Basal-like and claudin-low breast cancers express aberrant DNA hypermethylation

A subset of human breast cancer cell lines exhibits aberrant DNA hypermethylation that is characterized by hyperactivity of the DNA methyltransferase enzymes, overexpression of DNMT3b, and concurrent methylation-dependent silencing of numerous epigenetic biomarker genes. The objective of this study was to determine if this aberrant DNA hypermethylation (i) is found in primary breast cancers, (ii) is associated with specific breast cancer molecular subtypes, and (iii) influences patient outcomes. Analysis of epigenetic biomarker genes (CDH1, CEACAM6, CST6, ESR1, GNA11, MUC1, MYB, SCNN1A, and TFF3) identified a gene expression signature characterized by reduced expression levels or loss of expression among a cohort of primary breast cancers. The breast cancers that express this gene expression signature are enriched for triple-negative subtypes — basal-like and claudin-low breast cancers. Methylation analysis of primary breast cancers showed extensive promoter hypermethylation of epigenetic biomarker genes among triple-negative breast cancers, compared to other breast cancer subclasses where promoter hypermethylation events were less frequent. Furthermore, triple-negative breast cancers either did not express or expressed significantly reduced levels of protein corresponding to methylation-sensitive biomarker gene products. Together, these findings suggest strongly that loss of epigenetic biomarker gene expression is frequently associated with gene promoter hypermethylation events. We propose that aberrant DNA hypermethylation is a common characteristic of triple-negative breast cancers and may represent a fundamental biological property of basal-like and claudin-low breast cancers. Kaplan–Meier analysis of relapse-free survival revealed a survival disadvantage for patients with breast cancers that exhibit aberrant DNA hypermethylation. Identification of this distinguishing trait among triple-negative breast cancers forms the basis for development of new rational therapies that target the epigenome in patients with basal-like and claudin-low breast cancers.     

Best Self Visualization Method With High‐Risk Youth

The healing process of the Best Self Visualization Method (BSM) is described within the framework of meditation, neuroscience, and psychodynamic theory. Cases are drawn from the treatment of high‐risk youth, who have histories of poverty, survival of sexual and physical abuse, and/or current risk for perpetrating abuse. Clinical use of BSM is demonstrated in two case illustrations, one of group psychotherapy and another of individual therapy.     

Ultra‐deep T cell receptor sequencing reveals the complexity and intratumour heterogeneity of T cell clones in renal cell carcinomas

The recognition of cancer cells by T cells can impact upon prognosis and be exploited for immunotherapeutic approaches. This recognition depends on the specific interaction between antigens displayed on the surface of cancer cells and the T cell receptor (TCR), which is generated by somatic rearrangements of TCR α‐ and β‐chains (TCRb). Our aim was to assess whether ultra‐deep sequencing of the rearranged TCRb in DNA extracted from unfractionated clear cell renal cell carcinoma (ccRCC) samples can provide insights into the clonality and heterogeneity of intratumoural T cells in ccRCCs, a tumour type that can display extensive genetic intratumour heterogeneity (ITH). For this purpose, DNA was extracted from two to four tumour regions from each of four primary ccRCCs and was analysed by ultra‐deep TCR sequencing. In parallel, tumour infiltration by CD4, CD8 and Foxp3 regulatory T cells was evaluated by immunohistochemistry and correlated with TCR‐sequencing data. A polyclonal T cell repertoire with 367–16 289 (median 2394) unique TCRb sequences was identified per tumour region. The frequencies of the 100 most abundant T cell clones/tumour were poorly correlated between most regions (Pearson correlation coefficient, –0.218 to 0.465). 3–93% of these T cell clones were not detectable across all regions. Thus, the clonal composition of T cell populations can be heterogeneous across different regions of the same ccRCC. T cell ITH was higher in tumours pretreated with an mTOR inhibitor, which could suggest that therapy can influence adaptive tumour immunity. These data show that ultra‐deep TCR‐sequencing technology can be applied directly to DNA extracted from unfractionated tumour samples, allowing novel insights into the clonality of T cell populations in cancers. These were polyclonal and displayed ITH in ccRCC. TCRb sequencing may shed light on mechanisms of cancer immunity and the efficacy of immunotherapy approaches. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

The matricellular protein CCN3 regulates NOTCH1 signalling in chronic myeloid leukaemia

Deregulated NOTCH1 has been reported in lymphoid leukaemia, although its role in chronic myeloid leukaemia (CML) is not well established. We previously reported BCR‐ABL down‐regulation of a novel haematopoietic regulator, CCN3, in CML; CCN3 is a non‐canonical NOTCH1 ligand. This study characterizes the NOTCH1–CCN3 signalling axis in CML. In K562 cells, BCR‐ABL silencing reduced full‐length NOTCH1 (NOTCH1‐FL) and inhibited the cleavage of NOTCH1 intracellular domain (NOTCH1‐ICD), resulting in decreased expression of the NOTCH1 targets c‐MYC and HES1. K562 cells stably overexpressing CCN3 (K562/CCN3) or treated with recombinant CCN3 (rCCN3) showed a significant reduction in NOTCH1 signalling (> 50% reduction in NOTCH1‐ICD, p < 0.05). Gamma secretase inhibitor (GSI), which blocks NOTCH1 signalling, reduced K562/CCN3 colony formation but increased that of K562/control cells. GSI combined with either rCCN3 or imatinib reduced K562 colony formation with enhanced reduction of NOTCH1 signalling observed with combination treatments. We demonstrate an oncogenic role for NOTCH1 in CML and suggest that BCR‐ABL disruption of NOTCH1–CCN3 signalling contributes to the pathogenesis of CML. © 2013 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

LONGITUDINAL AND CONCURRENT PATHWAYS TO ALCOHOLISM: THE IMPORTANCE OF PERCEPTION OF NEIGHBORHOOD DISORDER

Neighborhood‐level and individual‐level variables from childhood and adulthood were examined in relation to alcoholism in adulthood. In 1976–1978, children from working‐class neighborhood schools in Montreal, Canada participated in a study examining the outcomes of childhood behaviors. At this time, peer nominations of childhood aggression were collected. In 1999–2003, these participants were contacted during mid‐adulthood (N = 676) and asked to complete measures of perception of neighborhood disorder as well as a structured clinical interview assessing their lifetime history of alcoholism. Measures of participants’ neighborhood socioeconomic status (SES) from adolescence and adulthood were retrieved from Canadian census tract data and included in the model. Findings supported an association between neighborhood disorder and alcoholism, such that perceived disorder mediated the association between census‐based assessments of neighborhood SES and alcoholism, but not when examined within a larger model. These findings supported the importance of the individual's interpretation of their environment in relation to alcoholism.