ERRORLESS ESTABLISHMENT OF A RIGHT-LEFT DISCRIMINATION IN RETARDATES

This study was concerned with the task of determining necessary steps for establishing an errorless method of discrimination training in a right-left problem. It was designed to establish a terminal motor response of the S placing the correct hand on a blank stimulus board in response to an auditory stimulus of Left or Right. To achieve this terminal response in a group of institutionalized retardates, stimuli of a previously learned color discrimination (pink and blue) were presented immediately following the corresponding auditory stimulus of Left or Right during each of the initial discrimination trials. To preclude or greatly diminish errors during the establishment of this discrimination, fading techniques were used to move the Ss from a discrimination controlled by visual (color) stimuli to one controlled by auditory stimuli ( Left or Right ). Results indicated the designed program, i.e. fading procedures, to be effective for precluding or diminishing errors to less than 10% for five of the nine Ss and for maintaining a correct response level of 70% or above for all Ss throughout procedures of fading. For three Ss who experienced difficulty, i .e. the correct response level fell below 90% at some point in fading, remedial manipulations of the visual and/or auditory stimuli were incorporated. The remedial procedures used for these Ss proved effective and the resultant data revealed possible considerations for redesigning the program. Remedial techniques were employed if Ss did not meet the response criterion while: 1) Generalizing from one set of stimulus components (experimental) to another (testing), 2) Fading from visual to auditory stimuli, 3) Discriminating initial differences between both visual and auditory stimuli, 4) Differentiating the motor response corresponding to the presented auditory and visual stimuli, and 5) Discriminating the reinforcing stimuli as discriminating stimuli for correct responses. The design of the present study was one which attempted to measure behavior before learning began and after a program had been completed, in addition to demonstrating that behavior can be successful while change is being implemented. This was an analytic task set by E in attempt to establish observable functional relations between S\u27s behavior (the dependent variable) and the program as originally designed (the independent variable). The individual analysis of behavior has as its primary concern the initiation of effective procedures. Therefore, this thesis dealt with a detailed analysis of the methodology involved in learning a right-left discrimination

The Parental Concerns Questionnaire: A Brief Screening Instrument for Potentially Severe Behavior Problems in Infants and Toddlers At-Risk for Developmental Delays

The Parental Concerns Questionnaire (PCQ) was designed as a parent-interview screening instrument for young children with developmental concerns at risk for potentially severe behavior problems (SBDs). Parents of 262 young children (4 to 48 months) answered to the 15 dichotomous PCQ items interviewed by trained staff. Cluster analysis for items revealed three item clusters, which we labeled Developmental/Social (8 items), Biomedical (3 items), and Behavior Problems (3 items). This paper discussed primarily the Behavior Problems cluster, with items referring to self-injurious, aggressive, and destructive behaviors. Parents' concerns about behavior problems were high, with item-endorsements of the Behavior Problems cluster ranging from 41.8 % to 68.8 %. The Behavior Problems cluster was significantly correlated with all three subscales of the Behavior Problems Inventory (BPI-01), with select subscales of the Aberrant Behavior Checklist (ABC), and with the Repetitive Behavior Scale-Revised (RBS-R) providing some evidence for concurrent validity. Sensitivity and specificity data were computed for the three PCQ items as well as for the cluster score in comparison with the BPI-01, ABC, and RBS-R showing strong sensitivity. The PCQ Behavior Problems cluster is a useful screening checklist with high sensitivity for potential SBDs in young children at-risk for developmental delays

Intervenção precoce à distância e acompanhamento por familiares de crianças e bebês em situação de risco de problemas de desenvolvimento e de comportamento agressivo no Peru

http://dx.doi.org/10.5902/1984686X9946A major barrier to meeting the needs of low-income children and families with disabilities is distance from a center providing the diagnostics and treatment. In the U.S. several innovative ways of overcoming this difficulty have emerged, e.g. Call-In, Come-In Services in a Pediatric Psychology Practice, diagnostics and consultation via telemedicine, use of the Internet for webcasting conferences, library resources over the Internet, etc. These services are not yet available in many developing countries or in rural areas of the U.S., however.  We report below an inexpensive and effective method of early distance intervention using workshops every two months and monthly telephone follow-up at the Centro Ann Sullivan del Peru in Lima, Peru. While many poor families may not have regular access to radio, television, or the Internet, we and others (Bigelow, Carta, & LeFever, 2008) have found that almost all have cell phones, and they can be followed regularly. In our project on early prevention of severe aggression, self-injury, and stereotyped behavior among infants and toddlers at risk for developmental disabilities, monthly telephone follow-up attendance remained high throughout the one-year follow-up period (92%), while family attendance at the six bi-monthly workshops dropped off (75% to 28%). Mean BPI frequency scores decreased significantly over the year. BPI scores were significantly higher, and they decreased more in the high-attendance group than in the low-attendance group.  Family stress was reduced by 65%. Consumer satisfaction was 98%.A very similar workshop package has been given to many orphanages and to remote areas in Peru, where there is not any kind of education about disabilities and where parents have to be the best teachers. Having such tools gives them knowledge of what their children can achieve, so they would not relinquish them to government orphanages.  http://dx.doi.org/10.5902/1984686X9946A maior barreira para atender às necessidades de crianças com deficiência de baixa renda e suas famílias é a distância suas casas e um centro que ofereça diagnóstico e tratamento. Nos EUA várias maneiras inovadoras para superar essa dificuldade surgiram. Por exemplo, o Call-In, Come-In serviços em prática de Psicologia pediátrica, diagnóstico e consulta através de telemedicina, o uso da Internet para conferências, recursos de biblioteca através da Internet, etc. No entanto, estes serviços ainda não estão disponíveis em muitos países em desenvolvimento ou em áreas rurais os EUA. Apresentamos a seguir um método barato e eficaz de intervenção precoce à distância utilizando oficinas a cada dois meses e acompanhamento mensal por telefone no Centro Ann Sullivan do Peru, em Lima. Enquanto muitas famílias pobres não têm acesso regular à rádio, televisão ou da Internet, nós e outros (Bigelow, Carta, e LeFever, 2008) evidenciamos que quase todas as famílias têm telefones celulares, e elas podem ser acompanhados regularmente através dos mesmos. Em nosso projeto para prevenção precoce de agressão grave, autoagressão e comportamento estereotipado, entre as crianças e bebês em situação de risco de vir a apresentar um desenvolvimento atípico, o atendimento por telefone para acompanhamento mensal manteve-se em nível elevado durante todo o período de seguimento de um ano (92%), enquanto atendimento às famílias nas seis oficinas bimestrais teve uma queda (de 75% para 28%). Os escores médios de freqüência BPI diminuíram significativamente ao longo do ano. Pontuações BPI foram significativamente elevadas, e diminuíram mais no grupo de alta freqüência que no grupo de baixo comparecimento. Estresse familiar foi reduzido em 65% e a satisfação dos consumidores foi de 98%. Um pacote de oficinas muito semelhante foi dado em diversos orfanatos de áreas remotas no Peru, onde não há qualquer tipo de educação sobre deficiência e onde os pais têm de ser os melhores professores. Ter essas ferramentas lhes dá conhecimento daquilo que os seus filhos podem alcançar, de modo que eles não venham a abandoná-los nos orfanatos do governo

Protein misfolding in neurodegenerative diseases : implications and strategies

A hallmark of neurodegenerative proteinopathies is the formation of misfolded protein aggregates that cause cellular toxicity and contribute to cellular proteostatic collapse. Therapeutic options are currently being explored that target different steps in the production and processing of proteins implicated in neurodegenerative disease, including synthesis, chaperone-assisted folding and trafficking, and degradation via the proteasome and autophagy pathways. Other therapies, like mTOR inhibitors and activators of the heat shock response, can rebalance the entire proteostatic network. However, there are major challenges that impact the development of novel therapies, including incomplete knowledge of druggable disease targets and their mechanism of action as well as a lack of biomarkers to monitor disease progression and therapeutic response. A notable development is the creation of collaborative ecosystems that include patients, clinicians, basic and translational researchers, foundations and regulatory agencies to promote scientific rigor and clinical data to accelerate the development of therapies that prevent, reverse or delay the progression of neurodegenerative proteinopathies.Peer reviewe

Risk Factors for Self-Injury, Aggression, and Stereotyped Behavior Among Young Children At Risk for Intellectual and Developmental Disabilities

Before the 1990s, research on the early identification and prevention of severe behavior disorders (SBDs), such as aggression, self-injury, and stereotyped behavior, among young children with intellectual and developmental disabilities (IDD), was mostly done with children 3 years or older. More recent work suggests that signs of SBDs may occur as early as 6 months in some infants. The present study combined a cross-sectional and longitudinal approach to examine SBDs in 180 young children aged 4–48 months recruited through mass screening, then receiving an interdisciplinary evaluation and six-month follow-ups for one year. Twelve potential risk factors related to SBDs were examined. Eight of these risk factors, including age, gender, diagnosis, intellectual and communication levels, visual impairment, parent education, family income, were differentially related to scores for Aggression, SIB, and Stereotyped Behavior subscales on the Behavior Problems Inventory (BPI-01) at initial interdisciplinary evaluation. BPI-01 scores decreased over the year for 57% of the children and increased for 43%. The amount of decrease on each BPI-01 subscale varied with age, gender, and diagnosis

Interleukin-18 produced by bone marrow- derived stromal cells supports T-cell acute leukaemia progression

International audienceDevelopment of novel therapies is critical for T-cell acute leukae-mia (T-ALL). Here, we investigated the effect of inhibiting the MAPK/MEK/ERK pathway on T-ALL cell growth. Unexpectedly, MEK inhibitors (MEKi) enhanced growth of 70% of human T-ALL cell samples cultured on stromal cells independently of NOTCH activa-tion and maintained their ability to propagate in vivo. Similar results were obtained when T-ALL cells were cultured with ERK1/ 2-knockdown stromal cells or with conditioned medium from MEKi-treated stromal cells. Microarray analysis identified interleu-kin 18 (IL-18) as transcriptionally up-regulated in MEKi-treated MS5 cells. Recombinant IL-18 promoted T-ALL growth in vitro, whereas the loss of function of IL-18 receptor in T-ALL blast cells decreased blast proliferation in vitro and in NSG mice. The NFKB pathway that is downstream to IL-18R was activated by IL-18 in blast cells. IL-18 circulating levels were increased in T-ALL-xeno-grafted mice and also in T-ALL patients in comparison with controls. This study uncovers a novel role of the pro-inflammatory cytokine IL-18 and outlines the microenvironment involvement in human T-ALL development

Differentiation between rebound thymic hyperplasia and thymic relapse after chemotherapy in pediatric Hodgkin lymphoma

Rebound thymic hyperplasia (RTH) is a common phenomenon caused by stress factors such as chemotherapy (CTX) or radiotherapy, with an incidence between 44% and 67.7% in pediatric lymphoma. Misinterpretation of RTH and thymic lymphoma relapse (LR) may lead to unnecessary diagnostic procedures including invasive biopsies or treatment intensification. The aim of this study was to identify parameters that differentiate between RTH and thymic LR in the anterior mediastinum. After completion of CTX, we analyzed computed tomographies (CTs) and magnetic resonance images (MRIs) of 291 patients with classical Hodgkin lymphoma (CHL) and adequate imaging available from the European Network for Pediatric Hodgkin lymphoma C1 trial. In all patients with biopsy-proven LR, an additional fluorodeoxyglucose (FDG)-positron emission tomography (PET)-CT was assessed. Structure and morphologic configuration in addition to calcifications and presence of multiple masses in the thymic region and signs of extrathymic LR were evaluated. After CTX, a significant volume increase of new or growing masses in the thymic space occurred in 133 of 291 patients. Without biopsy, only 98 patients could be identified as RTH or LR. No single finding related to thymic regrowth allowed differentiation between RTH and LR. However, the vast majority of cases with thymic LR presented with additional increasing tumor masses (33/34). All RTH patients (64/64) presented with isolated thymic growth. Isolated thymic LR is very uncommon. CHL relapse should be suspected when increasing tumor masses are present in distant sites outside of the thymic area. Conversely, if regrowth of lymphoma in other sites can be excluded, isolated thymic mass after CTX likely represents RTH

Response-adapted omission of radiotherapy and comparison of consolidation chemotherapy in intermediate- and advanced-stage children and adolescents with classic Hodgkin lymphoma: a titration study with an embedded non-inferiority randomised controlled trial

BACKGROUND: Children and adolescents with intermediate-stage and advanced-stage classical Hodgkin lymphoma achieve an event-free survival at 5 years of about 90% after treatment with vincristine, etoposide, prednisone, and doxorubicin (OEPA) followed by cyclophosphamide, vincristine, prednisone, and procarbazine (COPP) and radiotherapy, but long-term treatment effects affect survival and quality of life. We aimed to investigate whether radiotherapy can be omitted in patients with morphological and metabolic adequate response to OEPA and whether modified consolidation chemotherapy reduces gonadotoxicity. METHODS: Our study was designed as a titration study with an open-label, embedded, multinational, non-inferiority, randomised controlled trial, and was carried out at 186 hospital sites across 16 European countries. Children and adolescents with newly diagnosed intermediate-stage (treatment group 2) and advanced-stage (treatment group 3) classical Hodgkin lymphoma who were younger than 18 years and stratified according to risk using Ann Arbor disease stages IIAE, IIB, IIBE, IIIA, IIIAE, IIIB, IIIBE, and all stages IV (A, B, AE, and BE) were included in the study. Patients with early disease (treatment group 1) were excluded from this analysis. All patients were treated with two cycles of OEPA (1·5 mg/m(2) vincristine taken intravenously capped at 2 mg, on days 1, 8, and 15; 125 mg/m(2) etoposide taken intravenously on days 1–5; 60 mg/m(2) prednisone taken orally on days 1–15; and 40 mg/m(2) doxorubicin taken intravenously on days 1 and 15). Patients were randomly assigned to two (treatment group 2) or four (treatment group 3) cycles of COPP (500 mg/m(2) cyclophosphamide taken intravenously on days 1 and 8; 1·5 mg/m(2) vincristine taken intravenously capped at 2 mg, on days 1 and 8; 40 mg/m(2) prednisone taken orally on days 1 to 15; and 100 mg/m(2) procarbazine taken orally on days 1 to 15) or COPDAC, which was identical to COPP except that 250 mg/m(2) dacarbazine administered intravenously on days 1 to 3 replaced procarbazine. The method of randomisation (1:1) was minimisation with stochastic component and was centrally stratified by treatment group, country, trial sites, and sex. The primary endpoint was event-free survival, defined as time from treatment start until the first of the following events: death from any cause, progression or relapse of classical Hodgkin lymphoma, or occurrence of secondary malignancy. The primary objectives were maintaining 90% event-free survival at 5 years in patients with adequate response to OEPA treated without radiotherapy and to exclude a decrease of 8% in event-free survival at 5 years in the embedded COPDAC versus COPP randomisation to show non-inferiority of COPDAC. Efficacy analyses are reported per protocol and safety in the intention-to-treat population. The trial is registered with ClinicalTrials.gov (trial number NCT00433459) and EUDRACT (trial number 2006-000995-33), and is closed to recruitment. FINDINGS: Between Jan 31, 2007, and Jan 30, 2013, 2102 patients were recruited. 737 (35%) of the 2102 recruited patients were in treatment group 1 (early-stage disease) and were not included in our analysis. 1365 (65%) of the 2102 patients were in treatment group 2 (intermediate-stage disease; n=455) and treatment group 3 (advanced-stage disease; n=910). Of these 1365, 1287 (94%) patients (435 [34%] of 1287 in treatment group 2 and 852 [66%] of 1287 in treatment group 3) were included in the titration trial per-protocol analysis. 937 (69%) of 1365 patients were randomly assigned to COPP (n=471) or COPDAC (n=466) in the embedded trial. Median follow-up was 66·5 months (IQR 62·7–71·7). Of 1287 patients in the per-protocol group, 514 (40%) had an adequate response to treatment and were not treated with radiotherapy (215 [49%] of 435 in treatment group 2 and 299 [35%] of 852 in treatment group 3). 773 (60%) of 1287 patients with inadequate response were scheduled for radiotherapy (220 [51%] of 435 in the treatment group 2 and 553 [65%] of 852 in treatment group 3. In patients who responded adequately, event-free survival rates at 5 years were 90·1% (95% CI 87·5–92·7). event-free survival rates at 5 years in 892 patients who were randomly assigned to treatment and analysed per protocol were 89·9% (95% CI 87·1–92·8) for COPP (n=444) versus 86·1% (82·9–89·4) for COPDAC (n=448). The COPDAC minus COPP difference in event-free survival at 5 years was −3·7% (−8·0 to 0·6). The most common grade 3–4 adverse events (intention-to-treat population) were decreased haemoglobin (205 [15%] of 1365 patients during OEPA vs 37 [7%] of 528 treated with COPP vs 20 [2%] of 819 treated with COPDAC), decreased white blood cells (815 [60%] vs 231 [44%] vs 84 [10%]), and decreased neutrophils (1160 [85%] vs 223 [42%] vs 174 [21%]). One patient in treatment group 2 died of sepsis after the first cycle of OEPA; no other treatment-related deaths occurred. INTERPRETATION: Our results show that radiotherapy can be omitted in patients who adequately respond to treatment, when consolidated with COPP or COPDAC. COPDAC might be less effective, but is substantially less gonadotoxic than COPP. A high proportion of patients could therefore be spared radiotherapy, eventually reducing the late effects of treatment. With more refined criteria for response assessment, the number of patients who receive radiotherapy will be further decreased. FUNDING: Deutsche Krebshilfe, Elternverein für Krebs-und leukämiekranke Kinder Gießen, Kinderkrebsstiftung Mainz, Tour der Hoffnung, Menschen für Kinder, Programme Hospitalier de Recherche Clinique, and Cancer Research UK