Genetic contributions to visuospatial cognition in Williams syndrome: insights from two contrasting partial deletion patients

Background Williams syndrome (WS) is a rare neurodevelopmental disorder arising from a hemizygotic deletion of approximately 27 genes on chromosome 7, at locus 7q11.23. WS is characterised by an uneven cognitive profile, with serious deficits in visuospatial tasks in comparison to relatively proficient performance in some other cognitive domains such as language and face processing. Individuals with partial genetic deletions within the WS critical region (WSCR) have provided insights into the contribution of specific genes to this complex phenotype. However, the combinatorial effects of different genes remain elusive. Methods We report on visuospatial cognition in two individuals with contrasting partial deletions in the WSCR: one female (HR), aged 11 years 9 months, with haploinsufficiency for 24 of the WS genes (up to GTF2IRD1), and one male (JB), aged 14 years 2 months, with the three most telomeric genes within the WSCR deleted, or partially deleted. Results Our in-depth phenotyping of the visuospatial domain from table-top psychometric, and small- and large-scale experimental tasks reveal a profile in HR in line with typically developing controls, albeit with some atypical features. These data are contrasted with patient JB’s atypical profile of strengths and weaknesses across the visuospatial domain, as well as with more substantial visuospatial deficits in individuals with the full WS deletion. Conclusions Our findings point to the contribution of specific genes to spatial processing difficulties associated with WS, highlighting the multifaceted nature of spatial cognition and the divergent effects of genetic deletions within the WSCR on different components of visuospatial ability. The importance of general transcription factors at the telomeric end of the WSCR, and their combinatorial effects on the WS visuospatial phenotype are also discussed

Amelogenesis imperfecta

Amelogenesis imperfecta (AI) represents a group of developmental conditions, genomic in origin, which affect the structure and clinical appearance of enamel of all or nearly all the teeth in a more or less equal manner, and which may be associated with morphologic or biochemical changes elsewhere in the body. The prevalence varies from 1:700 to 1:14,000, according to the populations studied. The enamel may be hypoplastic, hypomineralised or both and teeth affected may be discoloured, sensitive or prone to disintegration. AI exists in isolation or associated with other abnormalities in syndromes. It may show autosomal dominant, autosomal recessive, sex-linked and sporadic inheritance patterns. In families with an X-linked form it has been shown that the disorder may result from mutations in the amelogenin gene, AMELX. The enamelin gene, ENAM, is implicated in the pathogenesis of the dominant forms of AI. Autosomal recessive AI has been reported in families with known consanguinity. Diagnosis is based on the family history, pedigree plotting and meticulous clinical observation. Genetic diagnosis is presently only a research tool. The condition presents problems of socialisation, function and discomfort but may be managed by early vigorous intervention, both preventively and restoratively, with treatment continued throughout childhood and into adult life. In infancy, the primary dentition may be protected by the use of preformed metal crowns on posterior teeth. The longer-term care involves either crowns or, more frequently these days, adhesive, plastic restorations

Immunization of Chickens with Newcastle Disease Virus Expressing H5 Hemagglutinin Protects against Highly Pathogenic H5N1 Avian Influenza Viruses

Highly-pathogenic avian influenza virus (HPAIV) and Newcastle disease virus (NDV) are the two most important poultry viruses in the world. Natural low-virulence NDV strains have been used as vaccines over the past 70 years with proven track records. We have previously developed a reverse genetics system to produce low-virulent NDV vaccine strain LaSota from cloned cDNA. This system allows us to use NDV as a vaccine vector for other avian pathogens.Here, we constructed two recombinant NDVs (rNDVs) each of which expresses the hemagglutinin (HA) gene of HPAIV H5N1 strain A/Vietnam/1203/2004 from an added gene. In one, rNDV (rNDV-HA), the open reading frame (ORF) of HA gene was expressed without modification. In the second, rNDV (rNDV-HAF), the ORF was modified so that the transmembrane and cytoplasmic domains of the encoded HA gene were replaced with those of the NDV F protein. The insertion of either version of the HA ORF did not increase the virulence of the rNDV vector. The HA protein was found to be incorporated into the envelopes of both rNDV-HA and rNDV-HAF. However, there was an enhanced incorporation of the HA protein in rNDV-HAF. Chickens immunized with a single dose of either rNDV-HA or rNDV-HAF induced a high titer of HPAIV H5-specific antibodies and were completely protected against challenge with NDV as well as lethal challenges of both homologous and heterologous HPAIV H5N1.Our results suggest that these chimeric viruses have potential as safe and effective bivalent vaccines against NDV and. HPAIV. These vaccines will be convenient and affordable, which will be highly beneficial to the poultry industry. Furthermore, immunization with these vaccines will permit serological differentiation of vaccinated and avian influenza field virus infected animals

CHAMP: Cognitive behaviour therapy for health anxiety in medical patients, a randomised controlled trial

BACKGROUND: Abnormal health anxiety, also called hypochondriasis, has been successfully treated by cognitive behaviour therapy (CBT) in patients recruited from primary care, but only one pilot trial has been carried out among those attending secondary medical clinics where health anxiety is likely to be more common and have a greater impact on services. The CHAMP study extends this work to examine both the clinical and cost effectiveness of CBT in this population. METHOD/DESIGN: The study is a randomized controlled trial with two parallel arms and equal randomization of 466 eligible patients (assuming a 20% drop-out) to an active treatment group of 5-10 sessions of cognitive behaviour therapy and to a control group. The aim at baseline, after completion of all assessments but before randomization, was to give a standard simple explanation of the nature of health anxiety for all participants. Subsequently the control group was to receive whatever care might usually be available in the clinics, which is normally a combination of clinical assessment, appropriate tests and reassurance. Those allocated to the active treatment group were planned to receive between 5 and 10 sessions of an adapted form of cognitive behaviour therapy based on the Salkovskis/Warwick model, in which a set of treatment strategies are chosen aimed at helping patients understand the factors that drive and maintain health anxiety. The therapy was planned to be given by graduate research workers, nurses or other health professionals trained for this intervention whom would also have their competence assessed independently during the course of treatment. The primary outcome is reduction in health anxiety symptoms after one year and the main secondary outcome is the cost of care after two years. DISCUSSION: This represents the first trial of adapted cognitive behaviour therapy in health anxiety that is large enough to test not only the clinical benefits of treatment but also whether the cost of treatment is offset by savings from reduced use of other health services in comparison to the control group.Cognitive behaviour therapy for Health Anxiety in Medical Patients (CHAMP) TRIAL REGISTRATION: Current Controlled Trials ISRCTN14565822

Erythropoietin: A potent inducer of peripheral immuno/inflammatory modulation in autoimmune EAE

Background: Beneficial effects of short-term erythropoietin (EPO) theraphy have been demonstrated in several animal models of acute neurologic injury, including experimental autoimmune encephalomyelitis(EAE)-the animal model of multiple sclerosis. We have found that EPO treatment substantially reduces the acute clinical paralysis seen EAE mice and this improvements is accompanied by a large reduction in the mononuclear cell infiltration and downregulation of glial MHC class II expression within the inflamed CNS. Other reports have recently indicated that peripherally generated anti-inflammatory CD4 +Foxp3 3 regulatory T cells (Tregs) and the IL17-producing CD4+ T helper cell (Th17) subpopulations play key antagonistic roles in EAE pathogenesis. However, no information regardind the effects of EPO theraphy on the behavior of the general mononuclear-lymphocyte population, Tregs or Th17 cells in EAE has emerged. Methods and Findings: We first determined in vivo that EPO theraphy markedly suppressed MOG specific T cell proliferation and sharply reduced the number of reactive dendritic cells (CD11c positive) in EAE lumph modes during both inductive and later symptomatic phases of MOG 35-55 induced EAE. We then determined the effect in vivo of EPO on numbers of peripheral Treg cells and Th17 cells. We found that EPO treatment modulated immune balance in both the periphery and the inflamed spinal cord by promoting a large expansion in Treg cells, inhibiting Th17 polarization and abrogating proliferation of the antigen presenting dendritic cell population. Finally we utilized tissue culture assays to show that exposure to EPO in vitro similarly downregulated MOG-specific T cell proliferation and also greatly suppressed T cell production of pro-inflammatory cytokines. Conclusions: Taken together, our findings reveal an important new locus whereby EPO induces substantial long-term tissue protection in the host through signalling to several critical subsets of immune cells that reside in the peripheral lymphatic system.published_or_final_versio

Australian chiropractic sports medicine: half way there or living on a prayer?

Sports chiropractic within Australia has a chequered historical background of unorthodox individualistic displays of egocentric treatment approaches that emphasise specific technique preference and individual prowess rather than standardised evidence based management. This situation has changed in recent years with the acceptance of many within sports chiropractic to operate under an evidence informed banner and to embrace a research culture. Despite recent developments within the sports chiropractic movement, the profession is still plagued by a minority of practitioners continuing to espouse certain marginal and outlandish technique systems that beleaguer the mainstream core of sports chiropractic as a cohesive and homogeneous group. Modern chiropractic management is frequently multimodal in nature and incorporates components of passive and active care. Such management typically incorporates spinal and peripheral manipulation, mobilisation, soft tissue techniques, rehabilitation and therapeutic exercises. Externally, sports chiropractic has faced hurdles too, with a lack of recognition and acceptance by organized and orthodox sports medical groups. Whilst some arguments against the inclusion of chiropractic may be legitimate due to its historical baggage, much of the argument appears to be anti-competitive, insecure and driven by a closed-shop mentality.sequently, chiropractic as a profession still remains a pariah to the organised sports medicine world. Add to this an uncertain continuing education system, a lack of protection for the title 'sports chiropractor', a lack of a recognized specialist status and a lack of support from traditional chiropractic, the challenges for the growth and acceptance of the sports chiropractor are considerable. This article outlines the historical and current challenges, both internal and external, faced by sports chiropractic within Australia and proposes positive changes that will assist in recognition and inclusion of sports chiropractic in both chiropractic and multi-disciplinary sports medicine alike

The use of opioids at the end of life: knowledge level of pharmacists and cooperation with physicians

Contains fulltext : 96464.pdf (publisher's version ) (Open Access)PURPOSE: What is the level of knowledge of pharmacists concerning pain management and the use of opioids at the end of life, and how do they cooperate with physicians? METHODS: A written questionnaire was sent to a sample of community and hospital pharmacists in the Netherlands. The questionnaire was completed by 182 pharmacists (response rate 45%). RESULTS: Pharmacists were aware of the most basic knowledge about opioids. Among the respondents, 29% erroneously thought that life-threatening respiratory depression was a danger with pain control, and 38% erroneously believed that opioids were the preferred drug for palliative sedation. One in three responding pharmacists did not think his/her theoretical knowledge was sufficient to provide advice on pain control. Most pharmacists had working agreements with physicians on euthanasia (81%), but fewer had working agreements on palliative sedation (46%) or opioid therapy (25%). Based on the experience of most of responding pharmacists (93%), physicians were open to unsolicited advice on opioid prescriptions. The majority of community pharmacists (94%) checked opioid prescriptions most often only after dispensing, while it was not a common practice among the majority of hospital pharmacists (68%) to check prescriptions at all. CONCLUSIONS: Although the basic knowledge of most pharmacists was adequate, based on the responses to the questionnaire, there seems to be a lack of knowledge in several areas, which may hamper pharmacists in improving the quality of care when giving advice to physicians and preventing or correcting mistakes if necessary. If education is improved, a more active role of the pharmacist may improve the quality of end-of-life pharmacotherapy

Functional Hair Cell Mechanotransducer Channels Are Required for Aminoglycoside Ototoxicity

Aminoglycosides (AG) are commonly prescribed antibiotics with potent bactericidal activities. One main side effect is permanent sensorineural hearing loss, induced by selective inner ear sensory hair cell death. Much work has focused on AG's initiating cell death processes, however, fewer studies exist defining mechanisms of AG uptake by hair cells. The current study investigated two proposed mechanisms of AG transport in mammalian hair cells: mechanotransducer (MET) channels and endocytosis. To study these two mechanisms, rat cochlear explants were cultured as whole organs in gentamicin-containing media. Two-photon imaging of Texas Red conjugated gentamicin (GTTR) uptake into live hair cells was rapid and selective. Hypocalcemia, which increases the open probability of MET channels, increased AG entry into hair cells. Three blockers of MET channels (curare, quinine, and amiloride) significantly reduced GTTR uptake, whereas the endocytosis inhibitor concanavalin A did not. Dynosore quenched the fluorescence of GTTR and could not be tested. Pharmacologic blockade of MET channels with curare or quinine, but not concanavalin A or dynosore, prevented hair cell loss when challenged with gentamicin for up to 96 hours. Taken together, data indicate that the patency of MET channels mediated AG entry into hair cells and its toxicity. Results suggest that limiting permeation of AGs through MET channel or preventing their entry into endolymph are potential therapeutic targets for preventing hair cell death and hearing loss

Sustainable Urban Systems: Co-design and Framing for Transformation

Rapid urbanisation generates risks and opportunities for sustainable development. Urban policy and decision makers are challenged by the complexity of cities as social–ecological–technical systems. Consequently there is an increasing need for collaborative knowledge development that supports a whole-of-system view, and transformational change at multiple scales. Such holistic urban approaches are rare in practice. A co-design process involving researchers, practitioners and other stakeholders, has progressed such an approach in the Australian context, aiming to also contribute to international knowledge development and sharing. This process has generated three outputs: (1) a shared framework to support more systematic knowledge development and use, (2) identification of barriers that create a gap between stated urban goals and actual practice, and (3) identification of strategic focal areas to address this gap. Developing integrated strategies at broader urban scales is seen as the most pressing need. The knowledge framework adopts a systems perspective that incorporates the many urban trade-offs and synergies revealed by a systems view. Broader implications are drawn for policy and decision makers, for researchers and for a shared forward agenda

Characterizing Associations and SNP-Environment Interactions for GWAS-Identified Prostate Cancer Risk Markers—Results from BPC3

Genome-wide association studies (GWAS) have identified multiple single nucleotide polymorphisms (SNPs) associated with prostate cancer risk. However, whether these associations can be consistently replicated, vary with disease aggressiveness (tumor stage and grade) and/or interact with non-genetic potential risk factors or other SNPs is unknown. We therefore genotyped 39 SNPs from regions identified by several prostate cancer GWAS in 10,501 prostate cancer cases and 10,831 controls from the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). We replicated 36 out of 39 SNPs (P-values ranging from 0.01 to 10−28). Two SNPs located near KLK3 associated with PSA levels showed differential association with Gleason grade (rs2735839, P = 0.0001 and rs266849, P = 0.0004; case-only test), where the alleles associated with decreasing PSA levels were inversely associated with low-grade (as defined by Gleason grade <8) tumors but positively associated with high-grade tumors. No other SNP showed differential associations according to disease stage or grade. We observed no effect modification by SNP for association with age at diagnosis, family history of prostate cancer, diabetes, BMI, height, smoking or alcohol intake. Moreover, we found no evidence of pair-wise SNP-SNP interactions. While these SNPs represent new independent risk factors for prostate cancer, we saw little evidence for effect modification by other SNPs or by the environmental factors examined