The impact of stroke: are people with aphasia different to those without?

Purpose. Stroke rehabilitation programmes aim to improve functional outcomes and quality of life. This study explored long-term outcomes in a cohort of people admitted to two acute stroke units with stroke. Comparisons were drawn between people with aphasia (PWA) and people without aphasia. Methods. People admitted to hospital with a first stroke were assessed at 2-weeks, 3-months and 6-months post-stroke. Measures included: the Barthel Index for Activities of Daily Living (ADL), the Frenchay Aphasia Screening Test, the General Health Questionnaire-12 for emotional well-being and the Stroke and Aphasia Quality of Life Scale-39g. Extended ADL and social support were also measured at 3 and 6 months, with the Frenchay Activities Index and the Social Support Survey, respectively. Results. Of 126 eligible participants, 96(76%) took part and 87(69%) were able to self-report. Self-report data are reported here. Although outcomes improved significantly across time, at 6 months people continued to experience substantial functional limitations (16% aphasic; 32% dependent on basic ADL); participation limitations (79% ≤30 on the FAI); high psychological distress (45%) and compromised quality of life (54% ≤4 on the SAQOL-39g). Levels of social support remained relatively stable. Though at 3-months post-stroke PWA were significantly more likely to experience high psychological distress (93% versus 50% for those without), across time, there were no significant differences between PWA and those without on psychological distress and also ADL and social support. There were, however, significant differences on extended ADL (F(1,68) = 7.80, p < 0.01) and quality of life (F(1,69) = 6.30, p < 0.05). Conclusion. PWA participated in fewer activities and reported worse quality of life after stroke than people without aphasia, even when their physical abilities, well-being and social support were comparable. Implications for clinical practice and future research are discussed

Stigmergy co-ordinates multicellular collective behaviours during Myxococcus xanthus surface migration

Surface translocation by the soil bacterium Myxococcus xanthus is a complex multicellular phenomenon that entails two motility systems. However, the mechanisms by which the activities of individual cells are coordinated to manifest this collective behaviour are currently unclear. Here we have developed a novel assay that enables detailed microscopic examination of M. xanthus motility at the interstitial interface between solidified nutrient medium and a glass coverslip. Under these conditions, M. xanthus motility is characterised by extensive micro-morphological patterning that is considerably more elaborate than occurs at an air-surface interface. We have found that during motility on solidified nutrient medium, M. xanthus forges an interconnected furrow network that is lined with an extracellular matrix comprised of exopolysaccharides, extracellular lipids, membrane vesicles and an unidentified slime. Our observations have revealed that M. xanthus motility on solidified nutrient medium is a stigmergic phenomenon in which multi-cellular collective behaviours are co-ordinated through trail-following that is guided by physical furrows and extracellular matrix materials

Six years beyond pediatric trauma: child and parental ratings of children’s health-related quality of life in relation to parental mental health

Purpose: To examine the relationship between child self-report and parent proxy report of health-related quality of life (HRQL) and how parents’ mental health status relates to the HRQL ratings 6 years after minor to severe injury of the child. Materials and methods: This cross-sectional cohort study was performed at a regional pediatric trauma center in Stockholm, Sweden. The PedsQL 4.0 versions for ages 5–7, 8–12, and 13–18 years were completed by 177 child–parent dyads 6 years after injury to the child. The parents also rated their own mental health through the mental health domain (MH) in the SF-36 Health Survey. Results: The children’s median age was 13 years (IQR 10–16 years), 54 % were males, and the median ISS was 5 (IQR 2–9). Most of the parents were female (77 %), born in Sweden (79 %), and half had university degrees. There was no statistically significant difference between child self-report and parent proxy report in any of the PedsQL 4.0 scales or summary scales. The levels of agreement between child self-report and parent proxy reports were excellent (ICC ≥ 0.80) for all scales with the exception of emotional functioning (ICC 0.53) which also was the scale with the lowest internal consistency in child self-report (α 0.60). Multiple regression analyses showed that worse parental mental health status correlated with worse child self-report and parent proxy report of children’s HRQL. Conclusions: Children and their parents’ reports on child’s HRQL were in agreement. Decreased mental health in parents was associated with lower scores on parent proxy reports and child self-reports of HRQL after injury. The current investigation highlights the possible relationship between parent’s mental health status and children’s HRQL long after an injury, which should be considered in future investigations and in clinical care

Upregulation of the cell-cycle regulator RGC-32 in Epstein-Barr virus-immortalized cells

Epstein-Barr virus (EBV) is implicated in the pathogenesis of multiple human tumours of lymphoid and epithelial origin. The virus infects and immortalizes B cells establishing a persistent latent infection characterized by varying patterns of EBV latent gene expression (latency 0, I, II and III). The CDK1 activator, Response Gene to Complement-32 (RGC-32, C13ORF15), is overexpressed in colon, breast and ovarian cancer tissues and we have detected selective high-level RGC-32 protein expression in EBV-immortalized latency III cells. Significantly, we show that overexpression of RGC-32 in B cells is sufficient to disrupt G2 cell-cycle arrest consistent with activation of CDK1, implicating RGC-32 in the EBV transformation process. Surprisingly, RGC-32 mRNA is expressed at high levels in latency I Burkitt's lymphoma (BL) cells and in some EBV-negative BL cell-lines, although RGC-32 protein expression is not detectable. We show that RGC-32 mRNA expression is elevated in latency I cells due to transcriptional activation by high levels of the differentially expressed RUNX1c transcription factor. We found that proteosomal degradation or blocked cytoplasmic export of the RGC-32 message were not responsible for the lack of RGC-32 protein expression in latency I cells. Significantly, analysis of the ribosomal association of the RGC-32 mRNA in latency I and latency III cells revealed that RGC-32 transcripts were associated with multiple ribosomes in both cell-types implicating post-initiation translational repression mechanisms in the block to RGC-32 protein production in latency I cells. In summary, our results are the first to demonstrate RGC-32 protein upregulation in cells transformed by a human tumour virus and to identify post-initiation translational mechanisms as an expression control point for this key cell-cycle regulator

Building Babies - Chapter 16

In contrast to birds, male mammals rarely help to raise the offspring. Of all mammals, only among rodents, carnivores, and primates, males are sometimes intensively engaged in providing infant care (Kleiman and Malcolm 1981). Male caretaking of infants has long been recognized in nonhuman primates (Itani 1959). Given that infant care behavior can have a positive effect on the infant’s development, growth, well-being, or survival, why are male mammals not more frequently involved in “building babies”? We begin the chapter defining a few relevant terms and introducing the theory and hypotheses that have historically addressed the evolution of paternal care. We then review empirical findings on male care among primate taxa, before focusing, in the final section, on our own work on paternal care in South American owl monkeys (Aotus spp.). We conclude the chapter with some suggestions for future studies.Deutsche Forschungsgemeinschaft (HU 1746/2-1) Wenner-Gren Foundation, the L.S.B. Leakey Foundation, the National Geographic Society, the National Science Foundation (BCS-0621020), the University of Pennsylvania Research Foundation, the Zoological Society of San Dieg

Ferritins: furnishing proteins with iron

Ferritins are a superfamily of iron oxidation, storage and mineralization proteins found throughout the animal, plant, and microbial kingdoms. The majority of ferritins consist of 24 subunits that individually fold into 4-α-helix bundles and assemble in a highly symmetric manner to form an approximately spherical protein coat around a central cavity into which an iron-containing mineral can be formed. Channels through the coat at inter-subunit contact points facilitate passage of iron ions to and from the central cavity, and intrasubunit catalytic sites, called ferroxidase centers, drive Fe2+ oxidation and O2 reduction. Though the different members of the superfamily share a common structure, there is often little amino acid sequence identity between them. Even where there is a high degree of sequence identity between two ferritins there can be major differences in how the proteins handle iron. In this review we describe some of the important structural features of ferritins and their mineralized iron cores and examine in detail how three selected ferritins oxidise Fe2+ in order to explore the mechanistic variations that exist amongst ferritins. We suggest that the mechanistic differences reflect differing evolutionary pressures on amino acid sequences, and that these differing pressures are a consequence of different primary functions for different ferritins

Modulation of enhancer looping and differential gene targeting by Epstein-Barr virus transcription factors directs cellular reprogramming

Epstein-Barr virus (EBV) epigenetically reprogrammes B-lymphocytes to drive immortalization and facilitate viral persistence. Host-cell transcription is perturbed principally through the actions of EBV EBNA 2, 3A, 3B and 3C, with cellular genes deregulated by specific combinations of these EBNAs through unknown mechanisms. Comparing human genome binding by these viral transcription factors, we discovered that 25% of binding sites were shared by EBNA 2 and the EBNA 3s and were located predominantly in enhancers. Moreover, 80% of potential EBNA 3A, 3B or 3C target genes were also targeted by EBNA 2, implicating extensive interplay between EBNA 2 and 3 proteins in cellular reprogramming. Investigating shared enhancer sites neighbouring two new targets (WEE1 and CTBP2) we discovered that EBNA 3 proteins repress transcription by modulating enhancer-promoter loop formation to establish repressive chromatin hubs or prevent assembly of active hubs. Re-ChIP analysis revealed that EBNA 2 and 3 proteins do not bind simultaneously at shared sites but compete for binding thereby modulating enhancer-promoter interactions. At an EBNA 3-only intergenic enhancer site between ADAM28 and ADAMDEC1 EBNA 3C was also able to independently direct epigenetic repression of both genes through enhancer-promoter looping. Significantly, studying shared or unique EBNA 3 binding sites at WEE1, CTBP2, ITGAL (LFA-1 alpha chain), BCL2L11 (Bim) and the ADAMs, we also discovered that different sets of EBNA 3 proteins bind regulatory elements in a gene and cell-type specific manner. Binding profiles correlated with the effects of individual EBNA 3 proteins on the expression of these genes, providing a molecular basis for the targeting of different sets of cellular genes by the EBNA 3s. Our results therefore highlight the influence of the genomic and cellular context in determining the specificity of gene deregulation by EBV and provide a paradigm for host-cell reprogramming through modulation of enhancer-promoter interactions by viral transcription factors

Genome-Wide Association Studies in Dogs and Humans Identify ADAMTS20 as a Risk Variant for Cleft Lip and Palate

Cleft lip with or without cleft palate (CL/P) is the most commonly occurring craniofacial birth defect. We provide insight into the genetic etiology of this birth defect by performing genome-wide association studies in two species: dogs and humans. In the dog, a genome-wide association study of 7 CL/P cases and 112 controls from the Nova Scotia Duck Tolling Retriever (NSDTR) breed identified a significantly associated region on canine chromosome 27 (unadjusted p=1.1 x 10-13; adjusted p= 2.2 x 10-3). Further analysis in NSDTR families and additional full sibling cases identified a 1.44 Mb homozygous haplotype (chromosome 27: 9.29 – 10.73 Mb) segregating with a more complex phenotype of cleft lip, cleft palate, and syndactyly (CLPS) in 13 cases. Whole-genome sequencing of 3 CLPS cases and 4 controls at 15X coverage led to the discovery of a frameshift mutation within ADAMTS20 (c.1360_1361delAA (p.Lys453Ilefs*3)), which segregated concordant with the phenotype. In a parallel study in humans, a family-based association analysis (DFAM) of 125 CL/P cases, 420 unaffected relatives, and 392 controls from a Guatemalan cohort, identified a suggestive association (rs10785430; p =2.67 x 10-6) with the same gene, ADAMTS20. Sequencing of cases from the Guatemalan cohort was unable to identify a causative mutation within the coding region of ADAMTS20, but four coding variants were found in additional cases of CL/P. In summary, this study provides genetic evidence for a role of ADAMTS20 in CL/P development in dogs and as a candidate gene for CL/P development in humans

Changes in catastrophizing and kinesiophobia are predictive of changes in disability and pain after treatment in patients with anterior knee pain

Purpose. The purpose of the study was to investigate if changes in psychological variables are related to the outcome in pain and disability in patients with chronic anterior knee pain. Methods. A longitudinal observational study on 47 patients with chronic anterior knee pain was performed in a secondary healthcare setting. Pain was measured with the visual analogue scale and disability with the Lysholm scale. The psychological variables, such as anxiety, depression, pain coping strategies, catastrophizing and fear to movement beliefs, were studied by using self-administered questionnaires. Results. Among the pain coping strategies, only the catastrophizing subscale showed a significant reduction. Similarly, anxiety, depression and kinesiophobia were significantly reduced after treatment. Those patients who decreased the catastrophizing, kinesiophobia, anxiety and depression showed a greater improvement in pain and disability after a purely biomedical treatment. A multiple regression analysis revealed that changes in catastrophizing predicted the amount of improvement in pain severity and that changes in both catastrophizing and anxiety predicted changes in disability after treatment. Conclusion. What has been found suggests that clinical improvement in pain and disability is associated with a reduction in catastrophizing and kinesiophobia. Therefore, co-interventions to reduce catastrophizing thinking and kinesiophobia may enhance the results. Level of evidence. Prospective Cohort Study, Level I for prognosis