The effect of functioning on Quality of Life Inventory-Disability measured quality of life is not mediated or moderated by parental psychological distress.

PURPOSE: The measurement of quality of life (QOL) in children with intellectual disability often relies upon proxy report via caregivers. The current study investigated whether caregiver psychological distress mediates or moderates the effects of impairment on their ratings of QOL in children with intellectual disability. METHODS: Caregivers of 447 children with an intellectual disability reported their child's day-to-day functioning, their own psychological distress using the Kessler Psychological Distress Scale, and the Quality of Life Inventory-Disability (QI-Disability), a measure of QOL for proxy report of a child's observable behaviours that indicate quality of life. Linear regression was used to assess the effects of the child's functional abilities on their QI-Disability score and causal mediation analysis to estimate the extent to which these effects were mediated by caregivers' psychological distress. RESULTS: A minority of caregivers (n = 121, 27.1%) reported no psychological distress. Lower day-to-day functional abilities, such as being fully dependent on others to manage their personal needs were associated with lower total QOL scores. There was no significant mediation effect of caregiver psychological distress on the association between child functioning and total QOL scores. Moderation analyses revealed small and largely nonsignificant interaction coefficients, indicating that caregiver psychological distress did not influence the strength of the relationship between child functioning and total QOL scores. CONCLUSION: Caregiver psychological distress did not mediate or moderate the relationship between the level of functional abilities and QOL in children with intellectual disability. QI-Disability measured observable child behaviours which may reduce the influence of caregiver factors on the accurate measure of QOL for children with intellectual disability.

Difficulties in developmental follow-up of preterm neonates in a randomised-controlled trial of Bifidobacterium breve M16-V - Experience from Western Australia.

BACKGROUND: Probiotics may be neuroprotective for preterm neonates due to their anti-inflammatory effects and ability to facilitate nutrition. AIM: To assess long-term effects of early probiotic supplementation on neuropsychological development in preterm infants. STUDY DESIGN: Follow up study. SUBJECTS: Children at age 3 to 5 years who had participated as preterm infants (<33 week) in the randomised controlled trial. OUTCOMES: Primary: Continuous early learning composite measure derived from the Mullen's Scale of Early Learning (MSEL). Other outcomes were assessed by the Developmental, Dimensional and Diagnostic Interview, Developmental NEuroPSYchological assessment-2nd Edition, Parental questionnaires using children's communication checklist-2nd edition, social responsiveness scale, and Vineland Adaptive Behavioural Scales-2nd edition. MEASURES: Continuous scores derived from all the measures. RESULTS: 67 children of the 159 participants (42%) (Probiotic: 36/79, Placebo: 31/80) were followed-up for at least one neuropsychological assessment. All six assessments were completed in 18/31 (58.1%) of the control vs. 11/36 (30.6%) probiotic group children. Multivariable analysis of MSEL composite score showed no evidence of probiotic effect univariately, or after adjustment for gestation, intrauterine growth restriction, Apgar <7 at 5 min and age at assessment (adjusted mean effect in probiotic group: -2.7, 95% CI -8.5-3.0, p = 0.349). CONCLUSION: There was no significant effect on neurodevelopment of children assessed at the age of 3 to 5 years who participated as preterm neonates in the RCT of B. breve M-16V. The validity of these results is limited by the reduced sample size due to high rate of loss to follow up.

Deep Eutectic Solvents Based on Natural Ascorbic Acid Analogues and Choline Chloride.

Deep eutectic solvents (DES) are one of the most promising green technologies to emerge in recent years given their combination of environmentally friendly credentials and useful functionalities. Considering the continued search for new DES - especially those that exemplify the aforementioned characteristics, we report the preparation of DES based on natural analogues of l-ascorbic acid for the first time. The onset of eutectic melting occurred at temperatures far below the melting point of the individual components and resulted in the generation of glass forming fluids with glass transition temperatures, viscosities and flow behavior that are comparable to similar systems. This work expands the current array of DES that can be produced using naturally occurring components, which given their potential to be bio-derived, interesting physicochemical properties (e. g. propensity to supercool and vitrify) and apparent antibacterial nature, may provide utility within a range of applications.

Unforeseen crystal forms of the natural osmolyte floridoside.

Floridoside (2-α-O-D-galactopyranosyl glycerol) is a glycerol glycoside that is biosynthesised by most species of red algae and has been implicated as an intracellular regulator of various homeostatic functions. Here, we report the identification of two unforeseen crystal forms of the ubiquitous natural osmolyte floridoside including a seemingly unheralded second anhydrous conformational polymorph and the unambiguous description of an elusive monohydrated variant. By employing a variety of thermal and spectroscopic techniques, we begin to explore both their macro and molecular physicochemical properties, which are notably different to that of the previously reported polymorph. This work advances the characterisation of this important natural biomolecule which could aid in facilitating optimised utilisation across a variety of anthropocentric applications and improve comprehension of its role in-vivo as a preeminent compatible solute.

Does otitis media in early childhood affect later behavioural development? Results from the Western Australian Pregnancy Cohort (Raine) Study.

OBJECTIVES: To examine the relationship between early life episodes of otitis media and later behavioural development with adjustment for confounders. DESIGN: Longitudinal cohort study. SETTING: The Western Australian Pregnancy Cohort (Raine) Study recruited 2900 pregnant women from King Edward Memorial Hospital (KEMH) in Perth, Western Australia, between 1989 and 1991. PARTICIPANTS: Data from the children born were collected at both the Year 3 and Year 5 follow-up. At Year 3, n = 611 were diagnosed with recurrent otitis media through parent-report and clinical examination. At Year 5, n = 299 were considered exposed to otitis media based upon tympanometry results. MAIN OUTCOME MEASURES: Performance in the Child Behaviour Checklist (CBCL), a questionnaire completed by the primary caregiver at Year 10. RESULTS: Significant associations were found between recurrent otitis media at Year 3 and internalising behaviours (P = .011), and the somatic (P = .011), withdrawn (P = .014), attention (P = .003) and thought problems domains (P = .021), and the total CBCL score (P = .010). A significant association was also found between exposure to otitis media at Year 5 and externalising behaviours (P = .026). CONCLUSIONS: A modest association was seen between recurrent otitis media at Year 3 and exposure to otitis media at Year 5 and a number of behaviour domains at Year 10.

Social impairments in autism spectrum disorder are related to maternal immune history profile.

Maternal immune activation has been highlighted as a factor that might increase the risk and severity of autism spectrum disorder (ASD) in children. Preclinical animal evidence shows that immune activation in mothers during pregnancy causes ASD-like behavioural traits in offspring. To this point, there has been no investigation of whether immune system activation in human mothers during pregnancy is associated with more severe symptoms in children with ASD. In this study, data from an existing ASD cohort (N=220) were analysed to investigate whether immune conditions in the mother were associated with greater severity of autism-related symptoms. Results showed that children whose mothers reported a history of immune activation (allergies and asthma) had significantly higher scores on the Social Responsiveness Scale (SRS; P=0.016), suggesting more severe social impairment symptoms in these children. This increasing severity of social impairment symptoms was further shown on the SRS cognition (P=0.007) and mannerisms (P=0.002) subscales. While immune history was associated with an increase in the severity of social impairment symptoms, history of autoimmune conditions in the mother did not have any effect in this cohort. To the best of our knowledge, this study is the first to show an association between immune activation history in the mother and increased ASD symptom severity in children with ASD. These findings support the idea of an immune system-mediated subtype in ASD, where the immune history of the mother may be an important factor.

Duration of general anaesthetic exposure in early childhood and long-term language and cognitive ability.

BACKGROUND: The anaesthetic dose causing neurotoxicity in animals has been evaluated, but the relationship between duration of volatile anaesthetic (VA) exposure and neurodevelopment in children remains unclear. METHODS: Data were obtained from the Western Australian Pregnancy Cohort (Raine) Study, with language (Clinical Evaluation of Language Fundamentals: Receptive [CELF-R] and Expressive [CELF-E] and Total [CELF-T]) and cognition (Coloured Progressive Matrices [CPM]) assessed at age 10 yr. Medical records were reviewed, and children divided into quartiles based on total VA exposure duration before age three yr. The association between test score and exposure duration quartile was evaluated using linear regression, adjusting for patient characteristics and comorbidity. RESULTS: Of 1622 children with available test scores, 148 had documented VA exposure and were split into the following quartiles: ≤25, >25 to ≤35, >35 to ≤60 and >60 min. Compared with unexposed children, CELF-T scores for children in the first and second quartiles did not differ, but those in the third and fourth quartiles had significantly lower scores ([3 rd quartile - Unexposed] -5.3; 95% confidence interval [CI], (-10.2 - -0.4), [4 th quartile - Unexposed] -6.2; 95% CI, (-11.6 - -0.9). CELF-E showed similar findings, but significant differences were not found in CELF-R or CPM for any quartile. CONCLUSIONS: Children with VA exposures ≤35 min did not differ from unexposed children, but those with exposures >35 min had lower total and expressive language scores. It remains unclear if this is a dose-response relationship, or if children requiring longer exposures for longer surgeries have other clinical reasons for lower scores.

Exploring quality of life of children with cerebral palsy and intellectual disability: What are the important domains of life?

BACKGROUND: Although it is estimated that half of all children with cerebral palsy also have comorbid intellectual disability, the domains of quality of life (QOL) important for these children are not well understood. The aim of this study was to identify important domains of QOL for these children and adolescents. METHODS: Due to the children's communication impairments, qualitative semi-structured interviews were conducted with 18 parents. The children (9 males) had a median age of 12 (range 7 to 17) years at interview and nearly two thirds were classified as Gross Motor Function Classification System IV or V. A grounded theory approach was used to identify domains of QOL. RESULTS: The 11 domains identified as important to QOL were physical health, body comfort, behaviour and emotion, communication, predictability and routine, movement and physical activity, nature and outdoors, variety of activity, independence and autonomy, social connectedness, and access to services. CONCLUSIONS: The domains of QOL that emerged from this study will be useful for professionals who support children with cerebral palsy and their families. They will also be important for developing a QOL instrument essential for informing the development of interventions and their monitoring and evaluation.

Protective benefit of predominant breastfeeding against otitis media may be limited to early childhood: results from a prospective birth cohort study.

OBJECTIVES: To examine the long-term effects of predominant breastfeeding on incidence of otitis media. DESIGN: Prospective birth cohort study. SETTING: The West Australian Pregnancy Cohort (Raine) Study recruited 2900 mothers through antenatal clinics at the major tertiary obstetric hospital in Perth, Western Australia, between 1989 and 1992. PARTICIPANTS: In total, 2237 children participated in a 6-year cohort follow-up, and a subset of 1344 were given ear and hearing assessments. MAIN OUTCOME MEASURES: OM diagnosis at 6 years of age (diagnosed by low-compliance tympanograms, 0-0.1 mmho). This was compared to OM diagnosed at the 3-year cohort follow-up using parent-report measures. Main exposure measures were duration of predominant breastfeeding (defined as the age other milk was introduced) and duration of partial (any) breastfeeding (defined as the age breastfeeding was stopped). RESULTS: There was a significant, independent association between predominant breastfeeding (OR = 1.33 [1.04, 1.69]; P = 0.02) and OM, and breastfeeding duration (OR = 1.35 [1.08, 1.68]; P = 0.01) with OM at 3 years of age. However, at 6 years of age, this relationship was no longer statistically significant (predominant breastfeeding OR = 0.78 [0.48, 1.06]; P = 0.09; duration of breastfeeding, OR = 1.34 [0.81, 2.23]; P = 0.25). CONCLUSIONS: Our findings are in line with a number of epidemiological studies which show a positive association between breastfeeding and OM in early childhood. However, the long-term follow-up of these children revealed that by 6 years of age, there was no significant influence of breastfeeding on presence of OM. These results suggest that the protective effect of predominant breastfeeding for at least 6 months does not extend to school-age children, where other social and environmental factors may be stronger predictors of OM.

Lack of replication for the myosin-18B association with mathematical ability in independent cohorts.

Twin studies indicate that dyscalculia (or mathematical disability) is caused partly by a genetic component, which is yet to be understood at the molecular level. Recently, a coding variant (rs133885) in the myosin-18B gene was shown to be associated with mathematical abilities with a specific effect among children with dyslexia. This association represents one of the most significant genetic associations reported to date for mathematical abilities and the only one reaching genome-wide statistical significance. We conducted a replication study in different cohorts to assess the effect of rs133885 maths-related measures. The study was conducted primarily using the Avon Longitudinal Study of Parents and Children (ALSPAC), (N = 3819). We tested additional cohorts including the York Cohort, the Specific Language Impairment Consortium (SLIC) cohort and the Raine Cohort, and stratified them for a definition of dyslexia whenever possible. We did not observe any associations between rs133885 in myosin-18B and mathematical abilities among individuals with dyslexia or in the general population. Our results suggest that the myosin-18B variant is unlikely to be a main factor contributing to mathematical abilities.

Towards a molecular characterization of autism spectrum disorders: an exome sequencing and systems approach.

The hypothetical 'AXAS' gene network model that profiles functional patterns of heterogeneous DNA variants overrepresented in autism spectrum disorder (ASD), X-linked intellectual disability, attention deficit and hyperactivity disorder and schizophrenia was used in this current study to analyze whole exome sequencing data from an Australian ASD cohort. An optimized DNA variant filtering pipeline was used to identify loss-of-function DNA variations. Inherited variants from parents with a broader autism phenotype and de novo variants were found to be significantly associated with ASD. Gene ontology analysis revealed that putative rare causal variants cluster in key neurobiological processes and are overrepresented in functions involving neuronal development, signal transduction and synapse development including the neurexin trans-synaptic complex. We also show how a complex gene network model can be used to fine map combinations of inherited and de novo variations in families with ASD that converge in the L1CAM pathway. Our results provide an important step forward in the molecular characterization of ASD with potential for developing a tool to analyze the pathogenesis of individual affected families.

Autism spectrum disorder in children born preterm-role of exposure to perinatal inflammation.

Autism Spectrum Disorder (ASD) is the collective term for neurodevelopmental disorders characterized by qualitative impairments in social interaction, communication, and a restricted range of activities and interests. Many countries, including Australia, have reported a dramatic increase in the number of diagnoses over the past three decades, with current prevalence of ASD at 1 in every 110 individuals (~1%). The potential role for an immune-mediated mechanism in ASD has been implicated by several studies, and some evidence suggests a potential link between prenatal infection-driven inflammation and subsequent development of ASD. Furthermore, a modest number of contemporary studies have reported a markedly increased prevalence of ASD in children born preterm, who are at highest risk of exposure to perinatal inflammation. However, the mechanisms that underpin the susceptibility to infection-driven inflammation during pregnancy and risk of preterm birth, and how these intersect with the subsequent development of ASD in the offspring, is not understood. This review aims to summarize and discuss the potential mechanisms and evidence for the role of prenatal infection on the central nervous system, and how it may increase the susceptibility for ASD pathogenesis in children born preterm.

A microsatellite linkage map for the cultivated strawberry (Fragaria × ananassa) suggests extensive regions of homozygosity in the genome that may have resulted from breeding and selection.

The linkage maps of the cultivated strawberry, Fragaria × ananassa (2n = 8x = 56) that have been reported to date have been developed predominantly from AFLPs, along with supplementation with transferrable microsatellite (SSR) markers. For the investigation of the inheritance of morphological characters in the cultivated strawberry and for the development of tools for marker-assisted breeding and selection, it is desirable to populate maps of the genome with an abundance of transferrable molecular markers such as microsatellites (SSRs) and gene-specific markers. Exploiting the recent release of the genome sequence of the diploid F. vesca, and the publication of an extensive number of polymorphic SSR markers for the genus Fragaria, we have extended the linkage map of the 'Redgauntlet' × 'Hapil' (RG × H) mapping population to include a further 330 loci, generated from 160 primer pairs, to create a linkage map for F. × ananassa containing 549 loci, 490 of which are transferrable SSR or gene-specific markers. The map covers 2140.3 cM in the expected 28 linkage groups for an integrated map (where one group is composed of two separate male and female maps), which represents an estimated 91% of the cultivated strawberry genome. Despite the relative saturation of the linkage map on the majority of linkage groups, regions of apparent extensive homozygosity were identified in the genomes of 'Redgauntlet' and 'Hapil' which may be indicative of allele fixation during the breeding and selection of modern F. × ananassa cultivars. The genomes of the octoploid and diploid Fragaria are largely collinear, but through comparison of mapped markers on the RG × H linkage map to their positions on the genome sequence of F. vesca, a number of inversions were identified that may have occurred before the polyploidisation event that led to the evolution of the modern octoploid strawberry species.

Nucleolar NF-κB/RelA mediates apoptosis by causing cytoplasmic relocalization of nucleophosmin.

In a number of contexts, and particularly in response to cellular stress, stimulation of the NF-kappaB (NF-κB) pathway promotes apoptosis. One mechanism underlying this pro-apoptotic activity is nucleolar sequestration of RelA, which is reported to cause cell death by repressing NF-κB-driven transcription. Here, we identify a novel and distinct nucleolar activity of RelA that induces apoptosis. We demonstrate, using a viral nucleolar localization signal (NoLS)-RelA fusion protein, that direct targeting of RelA to the nucleolus mediates apoptosis, independent of NF-κB transcriptional activity. We demonstrate a requirement for nucleophosmin (NPM, B23.1) in this apoptotic effect, and the apoptotic effect of stress-induced nucleolar RelA. We show by multiple approaches that nucleolar translocation of RelA is causally involved in the relocalization of NPM from the nucleolus to the cytoplasm and that RelA-induced cytoplasmic NPM mediates apoptosis by facilitating the mitochondrial accumulation of BAX. These data uncover a novel stress-response pathway and mechanism by which RelA promotes apoptosis, independent of its effects on NF-κB transcriptional activity. These findings are relevant to the design of novel anticancer agents that target RelA to this compartment.

CNTNAP2 variants affect early language development in the general population.

Early language development is known to be under genetic influence, but the genes affecting normal variation in the general population remain largely elusive. Recent studies of disorder reported that variants of the CNTNAP2 gene are associated both with language deficits in specific language impairment (SLI) and with language delays in autism. We tested the hypothesis that these CNTNAP2 variants affect communicative behavior, measured at 2 years of age in a large epidemiological sample, the Western Australian Pregnancy Cohort (Raine) Study. Singlepoint analyses of 1149 children (606 males and 543 females) revealed patterns of association which were strikingly reminiscent of those observed in previous investigations of impaired language, centered on the same genetic markers and with a consistent direction of effect (rs2710102, P = 0.0239; rs759178, P = 0.0248). On the basis of these findings, we performed analyses of four-marker haplotypes of rs2710102-rs759178-rs17236239-rs2538976 and identified significant association (haplotype TTAA, P = 0.049; haplotype CGAG, [corrected] P = .0014). Our study suggests that common variants in the exon 13-15 region of CNTNAP2 influence early language acquisition, as assessed at age 2, in the general population. We propose that these CNTNAP2 variants increase susceptibility to SLI or autism when they occur together with other risk factors.

Analysis of dyslexia candidate genes in the Raine cohort representing the general Australian population.

Several genes have been suggested as dyslexia candidates. Some of these candidate genes have been recently shown to be associated with literacy measures in sample cohorts derived from the general population. Here, we have conducted an association study in a novel sample derived from the Australian population (the Raine cohort) to further investigate the role of dyslexia candidate genes. We analysed markers, previously reported to be associated with dyslexia, located within the MRPL19/C2ORF3, KIAA0319, DCDC2 and DYX1C1 genes in a sample of 520 individuals and tested them for association with reading and spelling measures. Association signals were detected for several single nucleotide polymorphisms (SNPs) within DYX1C1 with both the reading and spelling tests. The high linkage disequilibrium (LD) we observed across the DYX1C1 gene suggests that the association signal might not be refined by further genetic mapping.

Progress and prospects: human artificial chromosomes.

Artificial chromosomes (ACs) are highly promising vectors for use in gene therapy applications. They are able to maintain expression of genomic-sized exogenous transgenes within target cells, without integrating into the host genome. Although these vectors have huge potential and benefits when compared against normal expression constructs, they are highly complex, technically challenging to construct and difficult to deliver to target cells. This review focuses on the current progress in the field of ACs and discusses the recent advances in purification, construction, delivery and potential new molecular therapies.

Quality of in-hospital care for adults with acute bacterial meningitis: a national retrospective survey.

BACKGROUND: Most adults with bacterial meningitis and meningococcal septicaemia present to junior doctors who have limited experience of these conditions. In contrast to paediatric practice, data from industrialized countries with regard to current hospital management practice are lacking. AIM: To examine whether current practice meets recommended standards in hospital management of community-acquired bacterial meningitis and meningococcal septicaemia among adults. DESIGN: National audit of medical records. METHODS: We conducted a survey of all patients with acute bacterial meningitis and meningococcal septicaemia admitted to 18 randomly selected acute hospitals in England and Wales between 1 January 2000 and 31 December 2001. All stages of care, including pre-hospital management, initial hospital assessment, record keeping, and ongoing hospital and public health management, were assessed. RESULTS: We identified 212 cases of bacterial meningitis and meningococcal septicaemia; 190 cases remained in the final analysis. Clinical record keeping did not meet acceptable standards in 33% of cases. Parenteral antibiotics were given within 1 h of hospital arrival in 56% of cases, increasing to 79% among those with an initial differential diagnosis that included bacterial meningitis or meningococcal septicaemia. A full severity of illness assessment was made in 27%. The quality of clinical practice varied widely between hospitals. This was most pronounced in the timeliness of consultant review (p < 0.0005). DISCUSSION: The quality of adult clinical practice for bacterial meningitis and meningococcal septicaemia needs improvement. This study provides a tool for developing targeted interventions to improve quality of care and outcome among adults with life-threatening infections, both in the UK and in other countries.

gamma-2 Herpes virus post-transcriptional gene regulation.

gamma-2 herpes viruses, which include Kaposi's sarcoma-associated herpes virus, are an important subfamily of herpes virus because of their oncogenic potential. Herpes virus saimiri (HVS) is the prototype gamma-2 herpes virus and is a useful model to study the basic mechanisms of lytic replication in this subfamily. Like all herpes viruses, HVS has two distinct life cycles, latent persistence and lytic replication. Analysis of herpes virus genomes has demonstrated that, in contrast to cellular genes, most virus genes that are expressed lytically do not have introns. Herpes viruses replicate in the nucleus of the host cell, and therefore require that the viral intron-lacking mRNAs are exported from the nucleus to allow virus mRNA translation. This review focuses upon the role of HVS ORF 57, a post-transcriptional regulatory protein, which is conserved in all herpes viruses. HVS ORF 57 is a multifunctional protein involved in both trans-activation and trans-repression of target mRNAs. The major role of the ORF 57 protein in mediating viral mRNA export is considered, and the ORF 57-host cell interactions that are required for this function are discussed.