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Proficient use of spatial terms such as under, to the left of or in front of is a central component of daily communication and is important in the development of language and spatial cognition. Here we examine spatial language abilities in intellectually high-functioning individuals with autism spectrum disorder, an area previously overlooked in autism research. Twenty-five high-functioning individuals with ASD and 25 typically developing controls, matched for chronological age and cognitive abilities, completed a novel battery tapping a broad range of spatial language abilities. We report selective difficulties in the production of spatial terms and spatial description recall in high-functioning ASD. Overall verbal abilities did not account for the observed group differences. Crucially, however, the intensity of autism spectrum traits predicted individual performance in both spatial language production and spatial description recall. We discuss the theoretical implications of these findings and explore their significance for both clinical practice and intervention. Lay abstract How we think and talk about space is an essential ability, necessary for understanding the world around us. We recruit spatial thinking every day when finding our way or using tools but also in more advanced tasks, such as reading complex graphs or maps. We do so also in daily communication when we use spatial language, terms such as under, over, to the left of or in front of, and when we give instructions. Spatial terms appear in children’s early vocabularies and continue to develop until late childhood or even early adolescence. Because spatial language develops over many years, some spatial terms are mastered very early, whereas others take longer to acquire. In the current set of studies, we tested how intellectually high-functioning children and adults on the autism spectrum use and understand these early- and late-acquired spatial terms in comparison to typically developing age-matched individuals. We found that children and adults on the autism spectrum experience difficulties with the use of some spatial terms (e.g. near and far or out of and down off) but not with others, which are acquired early (e.g. in and on or over and under). We also found that remembering spatial terms from short stories was more difficult for the individuals on the autism spectrum compared with typically developing individuals. These results reveal difficulties that can profoundly affect everyday communication of children and adults on the autism spectrum but also open new directions of research on language development in autism spectrum disorders.

The ability to mentally rotate objects in space is a fundamental cognitive capacity. Previous studies showed that the time to rotate the image of a figure to match another increases progressively with angular disparity. It remains unclear whether this increase in response time with angular disparity could reflect increased processing operations or more cognitive effort instead of a sustained use of a ‘rotate’ mechanism without a change in workload. We collected response times as well as pupillary responses that index cognitive workload and activity in the brainstem’s locus coeruleus, from a sample of 38 young adults performing a chronometric mental rotations task. The results showed the expected increase in response times but no increase in pupil diameters between 60, 120, and 180 degrees of rotation, suggesting no significant changes in arousal levels when rotating figures near and far. This indicates that during mental rotation the load on cognitive resources remains constant irrespective of angular distance. © 2020 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/

Current treatment methods to repair meniscal tears do not bring fully satisfactory results. Tissue adhesives are considered promising alternatives, since they are easy to apply and cause minimal tissue trauma. The first aim of this study was to analyze the adhesive properties of and tissue response to two recently developed biodegradable block copolymeric three-armed- and hyper-branched tissue adhesives. The second aim was to investigate if tissue surface modification with collagenase improves the attachment of the adhesives and increases the healing potential of the tissue. Cylindrical explants were harvested from bovine menisci. The central core of the explants was removed and glued back into the defect, with or without incubation in collagenase solution prior to gluing, using one of the novel glues, Dermabond® or fibrin glue. The repair constructs were cultured in vitro for 1 and 28 days. Adhesion tests and histology were performed to analyze the effects of the glue in combination with the additional treatment. The adhesive strength of the novel glues was 40-50 kPa, which was significantly higher than that of fibrin glue (15 kPa). Cells were present in direct contact with the glues, and the tissue remained vital during the whole culture period. Increased cellularity around the tear in the collagenase treated explants was observed after 1 day. The two newly developed tissue adhesives are attractive materials to be used for repair of meniscal tears. The beneficial influence of collagenase treatment in treating meniscal tears with glues still needs to be confirmed in more clinical relevant studies. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1405-1411, 2017.

Post-translational modifications of core histones participate in controlling the expression of genes. Methylation of lysine 4 of histone H3 (H3K4), together with acetylation of H3K27, is closely associated with open chromatin and gene transcription. H3K4 methylation is catalyzed by KMT2 lysine methyltransferases that include the mixed-lineage leukemia 1–4 (MLL1-4) and SET1A and B enzymes. For efficient catalysis, all six require a core complex of four proteins, WDR5, RBBP5, ASH2L, and DPY30. We report that targeted disruption of Ash2l in the murine hematopoietic system results in the death of the mice due to a rapid loss of mature hematopoietic cells. However, lin−Sca1+Kit+ (LSK) cells, which are highly enriched in hematopoietic stem and multi-potent progenitor cells, accumulated in the bone marrow. The loss of Ash2l resulted in global reduction of H3K4 methylation and deregulated gene expression, including down-regulation of many mitosis-associated genes. As a consequence, LSK cells accumulated in the G2-phase of the cell cycle and were unable to proliferate and differentiate. In conclusion, Ash2l is essential for balanced gene expression and for hematopoietic stem and multi-potent progenitor cell physiology.

9 p., Background: Stroke disproportionately affects people in low-income and middle-income countries. Although improvements in stroke care and outcomes have been reported in high-income countries, little is known about practice and outcomes in low and middle-income countries. We aimed to compare patterns of care available and their association with patient outcomes across countries at different economic levels. Methods: We studied the patterns and effect of practice variations (ie, treatments used and access to services) among participants in the INTERSTROKE study, an international observational study that enrolled 13 447 stroke patients from 142 clinical sites in 32 countries between Jan 11, 2007, and Aug 8, 2015. We supplemented patient data with a questionnaire about health-care and stroke service facilities at all participating hospitals. Using univariate and multivariate regression analyses to account for patient casemix and service clustering, we estimated the association between services available, treatments given, and patient outcomes (death or dependency) at 1 month. Findings: We obtained full information for 12 342 (92%) of 13 447 INTERSTROKE patients, from 108 hospitals in 28 countries; 2576 from 38 hospitals in ten high-income countries and 9766 from 70 hospitals in 18 low and middle-income countries. Patients in low-income and middle-income countries more often had severe strokes, intracerebral haemorrhage, poorer access to services, and used fewer investigations and treatments (p

Study Design. A biodegradable glue was biomechanically tested for annulus closure using nondegenerated goat intervertebral discs. Ultimate strength and endurance tests were performed using native and punctured discs as positive and negative controls, respectively.Objective. The aim of this study was to investigate the feasibility and biomechanical properties of a biodegradable glue for annulus closure.Summary of Background Data. There is an unmet clinical need for annulus closure techniques. Isocyanate-terminated tissue glues show potential because they adhere to annulus tissue, have an elastic modulus similar to the annulus, and show limited cytotoxicity to human annulus fibrosus cells.Methods. Three biomechanical tests were performed divided in 2 parts: part 1: ultimate strength tests comparing native, punctured (2.4-mm needle), and glued caprine intervertebral discs (n = 11 per group); part 2: 10 discs per group were subjected to a 10-day ex vivo endurance test of 864,000 load cycles, followed by ultimate strength tests. Outcome parameters include the restoration of strength after puncture, reduction of herniation in the endurance test, and conservation of glue strength after endurance testing.Results. Part 1: The glue partially restored subsidence to failure and yield strength/ultimate strength ratio of intervertebral discs. Part 2: During endurance testing, 40% of punctured discs failed compared with none of the glued discs. Endurance testing did not affect glue strength, and pooling of ultimate strength tests showed that the glue restored ultimate strength, work to failure, and yield strength/ultimate strength to 79%, 75%, and 119% of native values, respectively.Conclusion. A biodegradable isocyanate-terminated glue increases the force at which nucleus protrusion occurs, and it limits herniations during endurance or ultimate strength tests. Biomechanical tests in a bioreactor provide a low-cost assessment for annulus repair strategies; however, the clinical efficacy needs to be further addressed using long-term in vivo studies.

Regenerative medicine and cell therapy are the most growing fields of medical sciences in the last decade. The successes in development of scaffolds for three-dimensional cells and tissue breeding are one of the key factors of this progress. A broad spectrum of synthetic polymers, natural biopolymers and their combinations are available for testing and applications. Growing knowledge of biological and physicochemical properties of various (bio-) polymers allow tailoring macromolecules to particular medical application.

Menisci are crucial structures in the knee joint as they play functions in load transfer, maintaining joint stability and in homeostasis of articular cartilage. Most injuries of the knee are associated with meniscus trauma; the meniscus tears which lead to pain, swelling and locking of the joint. Current treatment methods do not bring fully satisfactory results. The ultimate goal of the PhD project was to develop novel tissue adhesives (glues) for repair of meniscal tears. Such glues, once deposited in meniscal tear, fill the tear, bind to meniscus tissue and hold the torn region together during the healing period. Within this project, we have designed and developed biodegradable tissue adhesives composed of biocompatible polymers: trimethylene carbonate (TMC), polyethylene glycol (PEG) and citric acid (CA). These copolymers were finally end-functionalized with isocyanate groups in order to achieve strong covalent attachment of the glues to meniscus tissue as well as curing of the glue in the wet environment of the knee joint. The developed materials were tested in terms of both their chemical structure and physical, mechanical and adhesive properties. Moreover, their biocompatibility was evaluated in vitro in cellular assays and bovine meniscus explants culture. Furthermore, materials were implanted in rats, in order to evauate their biocompatibility and degradation profile in vivo. The obtained results showed satisfactory adhesive strength of the glues to meniscus tissue, which was significantly higher than that of adhesives used nowadays in clinics. In vitro cellular tests as well as explant tissue culture confirmed that the materials were not toxic to the cells. The results of the in vivo implantation are showed moderate inflammatory response, which is expected to be less prominent when applied in physiologically relevant amounts in a meniscus tissue. Moreover, the materials proved to be biodegradable with degradation profile suitable for meniscus repair application. The developed tissue glues hold great potentials to be applied for meniscal tear repair as a replace or support for sutures and staples. They have satisfactory both mechanical, adhesive, and biological properties.

Objective: The objective of this article is to determine the prevalence of parents of children (aged 0–17 years) within a mental health service system and gather contextual data regarding this population. Method: The study uses a census approach. The Census is conducted annually across Central Coast Adult Mental Health Services, NSW, Australia. All five community mental health teams and four acute inpatient units within the service participate, with each team completing Census forms for active clients identified as parents on Census day. The Census form collects data on parents and children including demographic data, parental diagnosis, parental contact and risk factors. Results: Consecutive data shows 25–28% of active clients are parents. Annually, at least 400 children are identified; approximately 60% reside permanently with their parent with a mental illness. Conclusions: The Census is a valuable tool to determine the prevalence of parenthood. Moreover, it collects contextual data on this population. Data show an emerging relationship between parental diagnosis and parental contact. A picture of level of risk across the system has also been highlighted. Results add to the evidence regarding parental mental illness and circumstances of these families. The data clearly articulate a large need for interventions for children of parents with a mental illness (COPMI) within this population, given the high proportion of children who permanently reside with their parent with a mental illness.

In this study, injectable hydrogels were prepared by the horseradish peroxidase mediated co-crosslinking of dextran-tyramine (Dex-TA) and hyaluronic acid-tyramine (HA-TA) conjugates intended for cartilage tissue engineering. In general the gelation times of 10 wt% polysaccharide solutions are < 20 seconds and their storage moduli can be adjusted by varying the composition between Dex-TA and HA-TA. Dex-TA/HA-TA (50/50) hydrogels were fully degradable in the presence of hyaluronidase. Chondrocytes incorporated in 10 wt% Dex-TA and Dex-TA/HA-TA (50/50) gels showed good viability after 28 days. These results indicate that Dex-TA/HA-TA (50/50) hydrogels are promising injectable and biodegradable hydrogels for cartilage repair.

The National Mental Health Plan 2003–2008 identified that consumer and carer participation and partnership at all levels of policy, planning and treatment should be a hallmark of a quality mental h...

Gene transcription is controlled by post-translational modifications of core histones. Methylation of lysine 4 of histone H3 (H3K4), together with acetylation of H3K27, is closely associated with open chromatin and gene transcription. H3K4 methylation is catalyzed by KMT2 lysine methyltransferases that include the mixed-lineage leukemia 1-4 (MLL1-4) and SET1A and B enzymes. For efficient catalysis all six require a core complex of four proteins, WDR5, RBBP5, ASH2L, and DPY30. In a newly-generated pIC-inducible Mx1-Cre mouse model, we report that targeted disruption of Ash2l in the hematopoietic system results in death of the mice due to a rapid loss of mature hematopoietic cells in the bone marrow and the spleen, associated with a significant reduction of the RBC, WBC and platelets. However, Lin-Sca1+Kit+ (LSK) cells, which are highly enriched in hematopoietic stem and multi-potent progenitor cells, were significantly increased in the bone marrow (18-fold increase). This increase was associated with a 15-fold loss of the myeloid progenitor (MP) population (p < 0.001). In detail, total cell number of granulocyte-macrophage progenitors (GMPs), megakaryocyte-erythrocyte progenitors (MEPs) and common-myeloid progenitors (CMPs) was significantly reduced, while the relative proportion remained essentially unchanged. In LSK cells, Ash2l loss interfered with H3K4 methylation and resulted in broadly deregulated gene expression, including down-regulation of mitosis-associated genes. As a consequence, LSK cells accumulated in the G2/M-phase of the cell cycle and were unable to proliferate and form colonies in semi-solid medium. Lentiviral complementation with human ASH2L in the lineage-negative population partly but not entirely restored colony forming capacity, suggesting that ASH2L-mediated shaping of hematopoietic differentiation is a very early process. In addition, we demonstrated that those genes that harbor H3K4me3 and H3K27ac marks at their promoters were preferentially transcriptionally down-regulated. In contrast, up-regulated genes were characterized by low H3K4me3 and H3K27ac. Thus, these findings suggest that H3K4me3 and H3K27ac are not essential for transcription of all genes and that other, so far unidentified chromatin marks, allow recruitment of the RNA polymerase complex and transcription. Together, our data identify Ash2l as a novel essential factor for balanced gene expression and for hematopoietic stem and multi-potent progenitor cell physiology. These data may have important implications for future therapies of hematopoietic malignancies, including epigenetic targeting of malignant stem cells. Disclosures No relevant conflicts of interest to declare.

The few studies reporting the prevalence of parental mental problems or mental illness estimate that anywhere between 20-50% of clients of mental health services may be parents. The studies often fail to fully describe the population, the children involved, and their exposure to potential risk factors. A recent Department of Community Services review identified that parents with mental health issues are over-represented among maltreating families, and the National Framework for Protecting Australia's Children emphasised the need to increase the capacity and capability of adult services to identify and respond to the needs of children at risk. This paper describes the historical context, development, and implementation of the Mental Health and Parenting Census which is conducted annually across Central Coast Mental Health Services in New South Wales. In 2008 and 2009, almost one third of clients were identified as parents of children aged 0-17 years. The majority of parents were female, and the most common diagnoses were mood and psychotic disorders. Almost 60% of children were living with the parent with a mental illness on a permanent basis, and over 40% of parents experience low levels of support. The Mental Health and Parenting Census is thought to be the first of its kind to not only determine the prevalence of parenthood amongst active clients of an adult mental health service on a given day, but also to generate contextual information about the parents and the children, including exposure of children to risk factors.

Herein, the synthesis and biological evaluation of dual opioid agonists-neurokinin 1 receptor (NK1R) antagonists is described. In these multitarget ligands, the two pharmacophores do not overlap, and this allowed maintaining high NK1R affinity and antagonist potency in compounds 12 and 13. Although the fusion of the two ligands resulted in slightly diminished opioid agonism at the μ- and δ-opioid receptors (MOR and DOR, respectively), as compared to the opioid parent peptide, balanced MOR/DOR activities were obtained. Compared to morphine, compounds 12 and 13 produced more potent antinociceptive effects in both acute (tail-flick) and neuropathic pain models (von Frey and cold plate). Similarly to morphine, analgesic tolerance developed after repetitive administration of these compounds. To our delight, compound 12 did not produce cross-tolerance with morphine and high antihyperalgesic and antiallodynic effects could be reinstated after chronic administration of each of the two compounds.

Contains fulltext : 170599.pdf (Publisher’s version ) (Open Access) The aim of the current in vitro study was to investigate if tissue surface modification with collagenase and addition of the TGF-beta3 can increase the number of cells present in meniscus tears repaired with the use of newly developed tissue adhesives based on isocyanate-terminated block copolymers. Cylindrical explants were harvested from the inner part of bovine menisci. To simulate a full-thickness tear, the central core of the explants was removed and glued back into the defect, with or without incubation in collagenase solution prior to gluing. The repair constructs were then cultured with or without addition of TGF-beta3, and assessed for their histological appearance. The histological staining of the constructs confirmed that both developed adhesives were not cytotoxic. After 28 days, meniscus cells were present in direct contact with the glues. The addition of TGF-beta3 to the culture medium resulted in the presence of cells that formed a sheath inside the simulated tear and in increased cell numbers at the edges of annulus of the explants. In the group in which the tissue was incubated in collagenase and cultured in medium containing TGF-beta3, thicker layers of cells were observed. These results suggest that repairing the torn meniscus with tissue adhesives after pre-treatment of the tissue with collagenase and stimulation with TGF-beta3 is a very promising treatment method, especially when treating the inner avascular part of the meniscus. Nevertheless, longer-term in vitro and in vivo studies are needed to confirm the beneficial effects of this combination therapy.