Prevalence, phenomenology, aetiology and predictors of challenging behaviour in Smith-Magenis syndrome

Background

The prevalence, phenomenology aetiology and correlates of four forms of challenging behaviour in 32 children and adults with Smith-Magenis syndrome (SMS) were investigated.

Methods

Cognitive assessments, questionnaires and semi-structured interviews were used to gather data on intellectual disability, verbal and physical aggression, destructive behaviour and self-injury and on characteristics known to be associated with aggression.

Results

Aggression in SMS was more prevalent (87%), but not more severe than aggression in contrast groups. Aggressive behaviour was more frequently associated with environmental contingencies (e.g. attention, escape and access to tangibles) than self-injury and destructive behaviours. Severity of challenging behaviours was associated with high impulsivity.

Conclusion

Aggression is seen in the majority of people with SMS. Results suggest that behavioural disinhibition and operant social reinforcement are associated with the manifestation of aggression.

The relationship between specific cognitive impairment and behaviour in Prader-Willi syndrome

Background

Individuals with Prader-Willi syndrome (PWS) have been shown to demonstrate a particular cognitive deficit in attention switching and high levels of preference for routine and temper outbursts. This study assesses whether a specific pathway between a cognitive deficit and behaviour via environmental interaction can exist in individuals with PWS.

Methods

Four individuals with PWS participated in a series of three single-case experiments including laboratory-based and natural environment designs. Cognitive (computer-based) challenges placed varying demands on attention switching or controlled for the cognitive demands of the tasks while placing no demands on switching. Unexpected changes to routines or expectations were presented in controlled games, or imposed on participants' natural environments and compared with control conditions during which no unexpected changes occurred. Behaviour was observed and heart rate was measured.

Results

Participants showed significantly increased temper outburst related behaviours during cognitive challenges that placed demands on attention switching, relative to the control cognitive challenges. Participants showed significantly increased temper outburst related behaviours when unexpected changes occurred in an experimental or the natural environment compared with when no changes occurred.

Conclusions

Difficult behaviours that could be triggered reliably in an individual by a specific cognitive demand could also be triggered via manipulation of the environment. Results suggest that a directional relationship between a specific cognitive deficit and behaviour, via environmental interaction, can exist in individuals with PWS.

Neural correlates of task switching in paternal 15q11-q13 deletion Prader-Willi syndrome

We report a first study of brain activity linked to task switching in individuals with Prader-Willi syndrome (PWS) PWS individuals show a specific cognitive deficit in task switching which may be associated with the display of temper outbursts and repetitive questioning The performance of participants with PWS and typically developing controls was matched in a cued task switching procedure and brain activity was contrasted on switching and non switching blocks using SARI Individuals with PWS did not show the typical frontal-parietal pattern of neural activity associated with switching blocks, with significantly reduced activation in regions of the posterior parietal and ventromedial prefrontal cortices We suggest that this is linked to a difficulty in PWS in setting appropriate attentional weights to enable task set reconfiguration In addition to this, PWS individuals did not show the typical pattern of deactivation, with significantly less deactivation in an anterior region of the ventromedial prefrontal cortex One plausible explanation for this is that individuals with PWS show dysfunction within the default mode network which has been linked to attentional control The data point to functional changes in the neural circuitry supporting task switching in PWS even when behavioural performance is matched to controls and thus highlight neural mechanisms that may be involved in a specific pathway between genes cognition and behaviour (C) 2010 Elsevier B V All rights reserved

Dorsal and ventral stream mediated visual processing in genetic subtypes of Prader-Willi syndrome

Previous work has suggested that there are specific deficits in dorsal stream processing in a variety of developmental disorders. Prader-Willi syndrome (PWS) is associated with two main genetic subtypes, deletion and disomy. Relative strengths in visual processing are shown in PWS, although these strengths may be specific to the deletion subtype. We investigated visual processing in PWS using an adapted Simon task which contrasted location (dorsal stream) and shape identity (ventral stream) tasks. Compared to a group of typically developing children, children with PWS deletion showed a greater degree of impairment in the dorsal stream task than in the ventral stream task, a pattern similar to that shown in a group of boys with Fragile-X syndrome. When matched on a measure of non-verbal ability, children with PWS disomy showed the opposite pattern with better performance in the location compared to the shape task, although these task performance asymmetries may have been linked to executive control processes. It is proposed that children with PWS deletion show a relative strength in visual processing in the ventral stream along with a specific deficit in dorsal stream processing. In contrast, children with PWS disomy show neither effect. (C) 2009 Published by Elsevier Ltd.

The Relationship between Components of the Behavioural Phenotype in Prader-Willi Syndrome

Background

Repetitive questions and temper outbursts form part of the behavioural phenotype of Prader-Willi syndrome (PWS). We investigated the phenomenology of temper outbursts in PWS and their relationship with other PWS behavioural characteristics.

Method

Four individuals with PWS were observed (5-10 h), during a number of experimental and natural environment challenges, some of which were expected to trigger temper outbursts. Individual behaviours including crying, ignoring, arguing, questioning, stereotypy, frowning and posture changes were recorded and subjected to lag sequential analysis.

Results

All participants were significantly more likely to show repetitive questioning before more challenging behaviours such as crying, arguing or ignoring requests. Precursor behaviours such as frowning and stereotypical behaviour were identified in three participants.

Conclusions

Temper outbursts in PWS may be associated with other PWS behavioural phenotypic characteristics such as repetitive questions and 'stubbornness'. A progression of behaviours may lead up to the most challenging temper outburst behaviours. This may have important implications for effective coping strategies.

A specific pathway can be identified between genetic characteristics and behaviour profiles in Prader-Willi syndrome via cognitive, environmental and physiological mechanisms

Behavioural phenotypes associated with genetic syndromes have been extensively investigated in order to generate rich descriptions of phenomenology, determine the degree of specificity of behaviours for a particular syndrome, and examine potential interactions between genetic predispositions for behaviour and environmental influences. However, relationships between different aspects of behavioural phenotypes have been less frequently researched and although recent interest in potential cognitive phenotypes or endophenotypes has increased, these are frequently studied independently of the behavioural phenotypes.

Taking Prader-Willi syndrome (PWS) as an example, we discuss evidence suggesting specific relationships between apparently distinct aspects of the PWS behavioural phenotype and relate these to specific endophenotypic characteristics.

The framework we describe progresses through biological, cognitive, physiological and behavioural levels to develop a pathway from genetic characteristics to behaviour with scope for interaction with the environment at any stage.

We propose this multilevel approach as useful in setting out hypotheses in order to structure research that can more rapidly advance theory.

Task-switching deficits and repetitive behaviour in genetic neurodevelopmental disorders: Data from children with Prader-Willi syndrome chromosome 15 q11-q13 deletion and boys with Fragile X syndrome

Prader-Willi syndrome (PWS) and Fragile X syndrome (FraX) are associated with distinctive cognitive and behavioural profiles. We examined whether repetitive behaviours in the two syndromes were associated with deficits in specific executive functions. PWS, FraX, and typically developing (TD) children were assessed for executive functioning using the Test of Everyday Attention for Children and an adapted Simon spatial interference task. Relative to the TD children, children with PWS and FraX showed greater costs of attention switching on the Simon task, but after controlling for intellectual ability, these switching deficits were only significant in the PWS group. Children with PWS and FraX also showed significantly increased preference for routine and differing profiles of other specific types of repetitive behaviours. A measure of switch cost from the Simon task was positively correlated to scores on preference for routine questionnaire items and was strongly associated with scores on other items relating to a preference for predictability. It is proposed that a deficit in attention switching is a component of the endophenotypes of both PWS and FraX and is associated with specific behaviours. This proposal is discussed in the context of neurocognitive pathways between genes and behaviour.

Further refinement of the nature of the communication impairment in Cornelia de Lange syndrome

Purpose – Research into the communication skills of individuals with Cornelia de Lange syndrome (CdLS) is extremely limited. This paper aims to evaluate the nature of these skills and impairments in CdLS using a detailed informant assessment of pre-verbal communication skills.
Design/methodology/approach – The study used the Pre-verbal Communication Schedule to evaluate communication skills in individuals with CdLS (n ¼ 14), aged five to14 years. The group was compared with a contrast group of individuals with Cri du Chat syndrome (CdCS; n ¼ 14) who were matched for age and intellectual ability.
Findings – A significant difference was identified in understanding non-vocal communication (p , 0.005), with the CdLS group showing a greater deficit. These findings indicate the presence of a syndrome-specific deficit in understanding non-verbal communication in individuals with CdLS and suggest that there may be a dissociation between the processing of verbal and non-verbal communication.
Originality/value – The findings indicate that, in many ways, these two syndrome groups are not dissimilar in terms of their communication skills. However, individuals with CdLS show a syndrome-specific deficit in understanding non-vocal communication relative to the CdCS group.

The Beta Agonist Lung Injury Trial Prevention:A Randomized Controlled Trial

Rationale: Experimental studies suggest that pretreatment with b-agonists might prevent acute lung injury (ALI).

Objectives: To determine if in adult patients undergoing elective esophagectomy, perioperative treatment with inhaled b-agonists effects the development of early ALI.

Methods:We conducted a randomized placebo-controlled trial in 12 UK centers (2008-2011). Adult patients undergoing elective esophagectomy were allocated to prerandomized, sequentially numbered treatment packs containing inhaled salmeterol (100 mg twice daily) or a matching placebo. Patients, clinicians, and researchers were masked to treatment allocation. The primary outcome was development of ALI within 72 hours of surgery. Secondary outcomes were ALI within 28 days, organ failure, adverse events, survival, and health-related quality of life. An exploratory substudy measured biomarkers of alveolar-capillary inflammation and injury.

Measurements and Main Results: A total of 179 patients were randomized to salmeterol and 183 to placebo. Baseline characteristics were similar. Treatment with salmeterol did not prevent early lung injury (32 [19.2%] of 168 vs. 27 [16.0%] of 170; odds ratio [OR], 1.25; 95% confidence interval [CI], 0.71-2.22). There was no difference in organ failure, survival, or health-related quality of life.Adverse events were less frequent in the salmeterol group (55 vs. 70; OR, 0.63; 95% CI, 0.39-0.99), predominantly because of a lower number of pneumonia (7 vs. 17; OR, 0.39; 95% CI, 0.16-0.96). Salmeterol reduced some biomarkers of alveolar inflammation and epithelial injury.

Conclusion: Perioperative treatment with inhaled salmeterol was well tolerated but did not prevent ALI.

Clinical trial registered with International Standard Randomized Controlled Trial Register (ISRCTN47481946) and European Union database of randomized Controlled Trials (EudraCT 2007-004096-19).Copyright © 2014 by the American Thoracic Society.

Respiratory syncytial virus infections enhance cigarette smoke induced COPD in mice

Respiratory syncytial viral (RSV) infections are a frequent cause of chronic obstructive pulmonary disease (COPD) exacerbations, which are a major factor in disease progression and mortality. RSV is able to evade antiviral defenses to persist in the lungs of COPD patients. Though RSV infection has been identified in COPD, its contribution to cigarette smoke-induced airway inflammation and lung tissue destruction has not been established. Here we examine the long-term effects of cigarette smoke exposure, in combination with monthly RSV infections, on pulmonary inflammation, protease production and remodeling in mice. RSV exposures enhanced the influx of macrophages, neutrophils and lymphocytes to the airways of cigarette smoke exposed C57BL/6J mice. This infiltration of cells was most pronounced around the vasculature and bronchial airways. By itself, RSV caused significant airspace enlargement and fibrosis in mice and these effects were accentuated with concomitant smoke exposure. Combined stimulation with both smoke and RSV synergistically induced cytokine (IL-1a, IL-17, IFN-c, KC, IL-13, CXCL9, RANTES, MIF and GM-CSF) and protease (MMP-2, -8, -12, -13, -16 and cathepsins E, S, W and Z) expression. In addition, RSV exposure caused marked apoptosis within the airways of infected mice, which was augmented by cigarette smoke exposure. RSV and smoke exposure also reduced protein phosphatase 2A (PP2A) and protein tyrosine phosphates (PTP1B) expression and activity. This is significant as these phosphatases counter smoke-induced inflammation and protease expression. Together, these findings show for the first time that recurrent RSV infection markedly enhances inflammation, apoptosis and tissue destruction in smoke-exposed mice. Indeed, these results indicate that preventing RSV transmission and infection has the potential to significantly impact on COPD severity and progression.

Keratinocyte Growth-Factor Promotes Epithelial Survival and Resolution in a Human Model of Lung Injury

Rationale: Increasing epithelial repair and regeneration may hasten resolution of lung injury in patients with the Acute Respiratory Distress Syndrome (ARDS). In animal models of ARDS, Keratinocyte Growth Factor (KGF) reduces injury and increases epithelial proliferation and repair. The effect of KGF in the human alveolus is unknown.

Objectives: To test whether KGF can attenuate alveolar injury in a human model of ARDS.

Methods: Volunteers were randomized to intravenous KGF (60 μg/kg) or placebo for 3 days, before inhaling 50μg lipopolysaccharide. Six hours later, subjects underwent bronchoalveolar lavage (BAL) to quantify markers of alveolar inflammation and cell-specific injury.

Measurements and Main Results: KGF did not alter leukocyte infiltration or markers of permeability in response to LPS. KGF increased BAL concentrations of Surfactant Protein D (SP-D), MMP-9, IL-1Ra, GM-CSF and CRP. In vitro, BAL fluid from KGF-treated subjects (KGF BAL) inhibited pulmonary fibroblast proliferation, but increased alveolar epithelial proliferation. Active MMP-9 increased alveolar epithelial wound repair. Finally, BAL from the KGF pre-treated group enhanced macrophage phagocytic uptake of apoptotic epithelial cells and bacteria compared with BAL from the placebo-treated group. This effect was blocked by inhibiting activation of the GM-CSF receptor.

Conclusions: KGF treatment increases BAL SP-D, a marker of type II alveolar epithelial cell proliferation in a human model of ALI. Additionally KGF increases alveolar concentrations of the anti-inflammatory cytokine IL-1Ra, and mediators that drive epithelial repair (MMP-9) and enhance macrophage clearance of dead cells and bacteria (GM-CSF).