A longitudinal comparison of emotional, behavioral and attention problems in autistic and typically developing children.

BACKGROUND: Mental health problems are elevated in autistic individuals but there is limited evidence on the developmental course of problems across childhood. We compare the level and growth of anxious-depressed, behavioral and attention problems in an autistic and typically developing (TD) cohort. METHODS: Latent growth curve models were applied to repeated parent-report Child Behavior Checklist data from age 2-10 years in an inception cohort of autistic children (Pathways, N = 397; 84% boys) and a general population TD cohort (Wirral Child Health and Development Study; WCHADS; N = 884, 49% boys). Percentile plots were generated to quantify the differences between autistic and TD children. RESULTS: Autistic children showed elevated levels of mental health problems, but this was substantially reduced by accounting for IQ and sex differences between the autistic and TD samples. There was small differences in growth patterns; anxious-depressed problems were particularly elevated at preschool and attention problems at late childhood. Higher family income predicted lower base-level on all three dimensions, but steeper increase of anxious-depressed problems. Higher IQ predicted lower level of attention problems and faster decline over childhood. Female sex predicted higher level of anxious-depressed and faster decline in behavioral problems. Social-affect autism symptom severity predicted elevated level of attention problems. Autistic girls' problems were particularly elevated relative to their same-sex non-autistic peers. CONCLUSIONS: Autistic children, and especially girls, show elevated mental health problems compared to TD children and there are some differences in predictors. Assessment of mental health should be integrated into clinical practice for autistic children.

The role of infants' mother-directed gaze, maternal sensitivity, and emotion recognition in childhood callous unemotional behaviours.

While some children with callous unemotional (CU) behaviours show difficulty recognizing emotional expressions, the underlying developmental pathways are not well understood. Reduced infant attention to the caregiver's face and a lack of sensitive parenting have previously been associated with emerging CU features. The current study examined whether facial emotion recognition mediates the association between infants' mother-directed gaze, maternal sensitivity, and later CU behaviours. Participants were 206 full-term infants and their families from a prospective longitudinal study, the Durham Child Health and Development Study (DCHDS). Measures of infants' mother-directed gaze, and maternal sensitivity were collected at 6 months, facial emotion recognition performance at 6 years, and CU behaviours at 7 years. A path analysis showed a significant effect of emotion recognition predicting CU behaviours (ß = -0.275, S.E. = 0.084, p = 0.001). While the main effects of infants' mother-directed gaze and maternal sensitivity were not significant, their interaction significantly predicted CU behaviours (ß = 0.194, S.E. = 0.081, p = 0.016) with region of significance analysis showing a significant negative relationship between infant gaze and later CU behaviours only for those with low maternal sensitivity. There were no indirect effects of infants' mother-directed gaze, maternal sensitivity or the mother-directed gaze by maternal sensitivity interaction via emotion recognition. Emotion recognition appears to act as an independent predictor of CU behaviours, rather than mediating the relationship between infants' mother-directed gaze and maternal sensitivity with later CU behaviours. This supports the idea of multiple risk factors for CU behaviours.

Failure to learn from feedback underlies word learning difficulties in toddlers at risk for autism.

Children's assignment of novel words to nameless objects, over objects whose names they know (mutual exclusivity; ME) has been described as a driving force for vocabulary acquisition. Despite their ability to use ME to fast-map words (Preissler & Carey, 2005), children with autism show impaired language acquisition. We aimed to address this puzzle by building on studies showing that correct referent selection using ME does not lead to word learning unless ostensive feedback is provided on the child's object choice (Horst & Samuelson, 2008). We found that although toddlers aged 2;0 at risk for autism can use ME to choose the correct referent of a word, they do not benefit from feedback for long-term retention of the word-object mapping. Further, their difficulty using feedback is associated with their smaller receptive vocabularies. We propose that difficulties learning from social feedback, not lexical principles, limits vocabulary building during development in children at risk for autism.

The subcortical correlates of autistic traits in school-age children: a population-based neuroimaging study.

BACKGROUND: There is emerging evidence that the neuroanatomy of autism forms a spectrum which extends into the general population. However, whilst several studies have identified cortical morphology correlates of autistic traits, it is not established whether morphological differences are present in the subcortical structures of the brain. Additionally, it is not clear to what extent previously reported structural associations may be confounded by co-occurring psychopathology. To address these questions, we utilised neuroimaging data from the Adolescent Brain Cognitive Development Study to assess whether a measure of autistic traits was associated with differences in child subcortical morphology, and if any observed differences persisted after adjustment for child internalising and externalising symptoms. METHODS: Our analyses included data from 7005 children aged 9-10 years (female: 47.19%) participating in the Adolescent Brain Cognitive Development Study. Autistic traits were assessed using scores from the Social Responsiveness Scale (SRS). Volumes of subcortical regions of interest were derived from structural magnetic resonance imaging data. RESULTS: Overall, we did not find strong evidence for an association of autistic traits with differences in subcortical morphology in this sample of school-aged children. Whilst lower absolute volumes of the nucleus accumbens and putamen were associated with higher scores of autistic traits, these differences did not persist once a global measure of brain size was accounted for. LIMITATIONS: It is important to note that autistic traits were assessed using the SRS, of which higher scores are associated with general behavioural problems, and therefore may not be wholly indicative of autism-specific symptoms. In addition, individuals with a moderate or severe autism diagnosis were excluded from the ABCD study, and thus, the average level of autistic traits will be lower than in the general population which may bias findings towards the null. CONCLUSIONS: These findings from our well-powered study suggest that other metrics of brain morphology, such as cortical morphology or shape-based phenotypes, may be stronger candidates to prioritise when attempting to identify robust neuromarkers of autistic traits.

A multi-organ, lung-derived inflammatory response following in vitro airway exposure to cigarette smoke and next-generation nicotine delivery products.

Despite increasing use of in vitro models that closely resemble in vivo human biology, their application in understanding downstream effects of airway toxicity, such as inflammation, are at an early stage. In this study, we used various assays to examine the inflammatory response induced in MucilAir™ tissues and A549 cells exposed to three products known to induce toxicity. Reduced barrier integrity was observed in tissues following exposure to each product, with reduced viability and increased cytotoxicity also shown. Similar changes in viability were also observed in A549 cells. Furthermore, whole cigarette smoke (CS) induced downstream phenotypic THP-1 changes and endothelial cell adhesion, an early marker of atherosclerosis. In contrast, exposure to next-generation delivery product (NGP) aerosol did not induce this response. Cytokine, histological and RNA analysis highlighted increased biomarkers linked to inflammatory pathways and immune cell differentiation following exposure to whole cigarette smoke, including GM-CSF, IL-1ß, cleaved caspase-3 and cytochrome P450 enzymes. As a result of similar observations in human airway inflammation, we propose that our exposure platform could act as a representative model for studying such events in vitro. Furthermore, this model could be used to test the inflammatory or anti-inflammatory impact posed by inhaled compounds delivered to the lung.

Gap junction mediated bioelectric coordination is required for slow muscle development, organization, and function.

Bioelectrical signaling, intercellular communication facilitated by membrane potential and electrochemical coupling, is emerging as a key regulator of animal development. Gap junction (GJ) channels can mediate bioelectric signaling by creating a fast, direct pathway between cells for the movement of ions and other small molecules. In vertebrates, GJ channels are formed by a highly conserved transmembrane protein family called the Connexins. The connexin gene family is large and complex, presenting a challenge in identifying the specific Connexins that create channels within developing and mature tissues. Using the embryonic zebrafish neuromuscular system as a model, we identify a connexin conserved across vertebrate lineages, gjd4, which encodes the Cx46.8 protein, that mediates bioelectric signaling required for appropriate slow muscle development and function. Through a combination of mutant analysis and in vivo imaging we show that gjd4/Cx46.8 creates GJ channels specifically in developing slow muscle cells. Using genetics, pharmacology, and calcium imaging we find that spinal cord generated neural activity is transmitted to developing slow muscle cells and synchronized activity spreads via gjd4/Cx46.8 GJ channels. Finally, we show that bioelectrical signal propagation within the developing neuromuscular system is required for appropriate myofiber organization, and that disruption leads to defects in behavior. Our work reveals the molecular basis for GJ communication among developing muscle cells and reveals how perturbations to bioelectric signaling in the neuromuscular system_may contribute to developmental myopathies. Moreover, this work underscores a critical motif of signal propagation between organ systems and highlights the pivotal role played by GJ communication in coordinating bioelectric signaling during development.

Recent advancements and application of in vitro models for predicting inhalation toxicity in humans.

Animals have been indispensable in testing chemicals that can pose a risk to human health, including those delivered by inhalation. In recent years, the combination of societal debate on the use of animals in research and testing, the drive to continually enhance testing methodologies, and technology advancements have prompted a range of initiatives to develop non-animal alternative approaches for toxicity testing. In this review, we discuss emerging in vitro techniques being developed for the testing of inhaled compounds. Advanced tissue models that are able to recreate the human response to toxic exposures alongside examples of their ability to complement in vivo techniques are described. Furthermore, technology being developed that can provide multi-organ toxicity assessments are discussed.

Non-verbal IQ and change in restricted and repetitive behavior throughout childhood in autism: a longitudinal study using the Autism Diagnostic Interview-Revised.

BACKGROUND: Restricted and repetitive behavior (RRB) is one of the characteristic features of Autism Spectrum Disorder. This domain of symptoms includes a broad range of behaviors. There is a need to study each behavior individually to better understand the role of each in the development of autistic children. Moreover, there are currently no longitudinal studies investigating change in these behaviors over development. METHODS: The goal of the present study was to explore the association between age and non-verbal IQ (NVIQ) on 15 RRB symptoms included in the Autism Diagnostic Interview-Revised (ADI-R) over time. A total of 205 children with ASD were assessed using the ADI-R at time of diagnosis, at age 6 years, and at age 11 years, and with the Wechsler Intelligence Scales for Children-Fourth Edition (WISC-IV) at age 8 years. RESULTS: The proportion of children showing each RRB tended to diminish with increasing age, except for sensitivity to noise and circumscribed interests, where the proportion increased over time. Although there was no significant main effect of NVIQ, there was a significant interaction between age and NVIQ. This was mainly driven by Difficulties with change in routine, for which higher NVIQ was associated with the behavior remaining relatively stable with age, while lower NVIQ was associated with the behavior becoming more prevalent with age. LIMITATIONS: The study focused on the presence/absence of each RRB but did not account for potential changes in frequency or severity of the behaviors over development. Furthermore, some limitations are inherent to the measures used. The ADI-R relies on parent report and hence has some level of subjectivity, while the Wechsler intelligence scales can underestimate the intellectual abilities of some autistic children. CONCLUSIONS: These results confirm that specific RRB are differentially linked to age and NVIQ. Studying RRB individually is a promising approach to better understanding how RRB change over the development of autistic children and are linked to other developmental domains.

Report on the joint IBEPAG/ICCBBA survey on import/export and blood component labelling.

A survey of blood centre organizations was carried out to establish the degree of progress towards the implementation of global standards for coding and labelling blood components. The survey was performed through questionnaires completed by blood organizations. Of nearly 32 million blood donations collected annually by the participants, 43% are identified with ISBT 128 donation numbers and 36% are fully compliant with the ISBT 128 Standard. Planned implementations indicate that 85% of donations will be identified by ISBT 128 donation numbers by 2011.

Visual search performance in infants associates with later ASD diagnosis.

An enhanced ability to detect visual targets amongst distractors, known as visual search (VS), has often been documented in Autism Spectrum Disorders (ASD). Yet, it is unclear when this behaviour emerges in development and if it is specific to ASD. We followed up infants at high and low familial risk for ASD to investigate how early VS abilities links to later ASD diagnosis, the potential underlying mechanisms of this association and the specificity of superior VS to ASD. Clinical diagnosis of ASD as well as dimensional measures of ASD, attention-deficit/hyperactivity disorder (ADHD) and anxiety symptoms were ascertained at 3 years. At 9 and 15 months, but not at age 2 years, high-risk children who later met clinical criteria for ASD (HR-ASD) had better VS performance than those without later diagnosis and low-risk controls. Although HR-ASD children were also more attentive to the task at 9 months, this did not explain search performance. Superior VS specifically predicted 3 year-old ASD but not ADHD or anxiety symptoms. Our results demonstrate that atypical perception and core ASD symptoms of social interaction and communication are closely and selectively associated during early development, and suggest causal links between perceptual and social features of ASD.

Alternative reagents to antibodies in imaging applications.

Antibodies have been indispensable tools in molecular biology, biochemistry and medical research. However, a number of issues surrounding validation, specificity and batch variation of commercially available antibodies have prompted research groups to develop novel non-antibody binding reagents. The ability to select highly specific monoclonal non-antibody binding proteins without the need for animals, the ease of production and the ability to site-directly label has enabled a wide variety of applications to be tested, including imaging. In this review, we discuss the success of a number of non-antibody reagents in imaging applications, including the recently reported Affimer.

Callous-unemotional traits moderate executive function in children with ASD and ADHD: A pilot event-related potential study.

Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are associated with varied executive function (EF) difficulties. Callous-unemotional (CU) traits, a proposed antecedent of adult psychopathy, are often associated with intact or enhanced EF. Here we test whether CU traits may therefore modulate EF in ASD and ADHD, in which EF is typically impaired. We collected CU traits and measured event-related potentials (ERPs) that index EF during a cued-continuous performance test (CPT-OX) in boys with ASD, ADHD, comorbid ASD+ADHD and typical controls. We examined attentional orienting at cues (Cue-P3), inhibitory processing at non-targets (NoGo-P3) and conflict monitoring between target and non-target trials (Go-N2 vs. NoGo-N2). In children with ASD, higher CU traits were associated with an enhanced increase in N2 amplitude in NoGo trials compared to Go trials, which suggests relatively superior conflict monitoring and a potential cognitive strength associated with CU traits. The results emphasise the importance of considering the effects of co-occurring traits in the assessment of heterogeneity of EF profiles in neurodevelopmental disorders.

Highly active catalysts for the Suzuki coupling of aryl chlorides.

Simple tricyclohexylphosphine adducts of palladium complexes with orthometallated N-donor ligands show by far the highest activity yet reported in the Suzuki coupling of aryl chlorides, even under aerobic conditions.

Intraoperative measurement of cerebral and tumor blood flow with laser-Doppler flowmetry.

A new technique, laser-Doppler flowmetry, has been used intraoperatively to measure blood flow responses in normal brain tissue and brain tumor to blood pressure and arterial blood gas alterations. We have observed that blood flow is reduced in most cerebral tumors, and that most tumors retain the normal response to changes in arterial blood gas; however, these responses are varied. One group of tumors in our study demonstrated an autoregulatory capacity; a second behaved passively--that is, blood flow changes followed blood pressure--while a third showed no response.

Modified prone position for cranial remodeling procedures in children with craniofacial dysmorphism: a technical note.

A new head position for use during operation on young children with cranial deformities is described. The position allows exposure of the entire calvarium from the supraorbital ridges to the posterior rim of the foramen magnum. It is a modification of the conventional prone position involving hyperextension of the neck. The authors have safely used this position to perform one-stage radical cranial remodeling procedures that previously required two stages. The advantages of this position and the methods for achieving it are discussed.

Tension pneumocephalus: treatment with controlled decompression via a closed water-seal drainage system. Case report.

The successful treatment of a patient with tension pneumocephalus by controlled decompression via external drainage is described. The advantage of the technique includes the immediate release of high pressure and the capability of maintaining constant low pressure to enable and facilitate sealing of dural tears. The method has been used in three other patients, leading to resolution of the tension pneumocephalus without recurrence or other complications.

Changes in superior sagittal sinus pressure in children with head elevation, jugular venous compression, and PEEP.

Air embolism is a potential hazard during craniotomy whenever intracranial venous pressure is subatmospheric. In order to better understand both the risk of air embolism and its treatment in neurosurgical patients, the authors have investigated the relationship of superior sagittal sinus pressure (SSP) to head position in 15 children and examined the effects of both jugular venous compression and positive end-expiratory airway pressure (PEEP) on SSP. Progressive head elevation significantly decreased mean SSP and, in five patients, SSP was less than 0 mm Hg at 90 degrees torso elevation. A PEEP of 10 cm H2O was ineffective in significantly increasing SSP at any degree of head elevation, whereas bilateral internal jugular compression always caused a significant increase in SSP. The authors conclude that children are at risk for venous air embolism when undergoing suboccipital craniectomy in the sitting position because intracranial venous pressure is often subatmospheric when the head is elevated. Furthermore, maintaining PEEP does not appear to be a reliable treatment for increasing SSP, whereas bilateral internal jugular compression is effective.

Adverse impact of a calcium entry-blocker (verapamil) on intracranial pressure in patients with brain tumors.

In order to examine the effects of verapamil on intracranial pressure (ICP) in patients with compromised intracranial compliance, five hypertensive patients with supratentorial tumors were given verapamil, 5 mg intravenously, at the time of anesthesia induction. Within 4 minutes, ICP increased 67% from 18 +/- 4 mm Hg (standard error) to 27 +/- 5 mm Hg (p less than 0.05), whereas mean arterial pressure decreased 20% from 111 +/- 7 mm Hg to 89 +/- 4 mm Hg (p less than 0.05), and cerebral perfusion pressure (CPP) decreased 33% from 93 +/- 11 mm Hg to 62 +/- 6 mm Hg (p less than 0.05). The increases in ICP responded promptly to hyperventilation and intravenous lidocaine (1.5 mg/kg). A control group of five hypertensive patients with supratentorial tumors received the same anesthetic agents without verapamil. In this group, ICP and CPP were unchanged. The authors conclude that calcium entry-blockers, such as verapamil, should be avoided in patients with compromised intracranial compliance unless ICP is being monitored and proper therapy for intracranial hypertension can be rapidly instituted.

Cardiac catheters for diagnosis and treatment of venous air embolism: a prospective study in man.

One hundred consecutive patients undergoing neurosurgical procedures in the seated position were monitored for venous air embolism with a Swan-Ganz pulmonary artery (PA) catheter, precordial Doppler ultrasound device, and continuous end-tidal CO2 (FETCO2) analysis. Simultaneous determinations of right atrial and pulmonary capillary wedge pressures were also performed during each operation. Although 80 episodes of air embolism were detected by changes in Doppler sounds, only 36 were associated with increased PA pressure, and only 30 developed a decrease in FETCO2. Changes in PA pressure and FETCO2 agreed closely (r = 0.86), and only marked changes were associated with systemic hypotension. Air was recovered from the right atrium and PA only in small amounts (2 to 20 ml) during air embolism, although it was possible to aspirate large quantities of blood. Twenty-nine patients were found to have right atrial pressures that were higher than pulmonary capillary wedge pressures. Paradoxical air embolism from a probe-patent foramen ovale was possible in these patients, and one developed signs and symptoms of systemic air embolism postoperatively. We conclude that noninvasive monitoring with the combination of a precordial Doppler device and end-tidal CO2 analysis is satisfactory for rapid detection of clinically significant venous air embolism. The unique advantage of Swan-Ganz monitoring, however, is that it permits identification of patients who may sustain paradoxical air embolism, and that it differentiates the hemodynamic effects of brain-stem manipulation from those caused by air embolism.