Problematic clinical features of powered wheelchair users with severely disabling multiple sclerosis

This article is made available through the Brunel Open Access Publishing Fund. Copyright @ 2014 Informa UK Ltd.Purpose: The aim of this study is to describe the clinical features of powered wheelchair users with severely disabling multiple sclerosis (MS) and explore the problematic clinical features influencing prescription. Method: Retrospective review of electronic and case note records of recipients of electric-powered indoor/outdoor powered wheelchairs (EPIOCs) attending a specialist wheelchair service between June 2007 and September 2008. Records were reviewed by a consultant in rehabilitation medicine, data systematically extracted and entered into a computer database. Further data were entered from clinical records. Data were extracted under three themes; demographic, diagnostic, clinical and wheelchair factors. Results: Records of 28 men mean age 57 (range 37–78, SD 12) years and 63 women mean age 57 (range 35–81, SD 11) years with MS were reviewed a mean of 64 (range 0–131) months after receiving their wheelchair. Twenty two comorbidities, 11 features of MS and 8 features of disability were thought to influence wheelchair prescription. Fifteen users were provided with specialised seating and 46 with tilt-in-space seats. Conclusions: Our findings suggest that people with severe MS requiring an EPIOC benefit from a holistic assessment to identify problematic clinical features that influence the prescription of the EPIOC and further medical and therapeutic interventions

Restoring unitarity in the q-deformed world-sheet S-matrix

The world-sheet S-matrix of the string in AdS5 x S5 has been shown to admit a q-deformation that relates it to the S-matrix of a generalization of the sine-Gordon theory, which arises as the Pohlmeyer reduction of the superstring. Whilst this is a fascinating development the resulting S-matrix is not explicitly unitary. The problem has been known for a long time in the context of S-matrices related to quantum groups. A braiding relation often called "unitarity" actually only corresponds to quantum field theory unitarity when the S-matrix is Hermitian analytic and quantum group S-matrices manifestly violate this. On the other hand, overall consistency of the S-matrix under the bootstrap requires that the deformation parameter is a root of unity and consequently one is forced to perform the "vertex" to IRF, or SOS, transformation on the states to truncate the spectrum consistently. In the IRF formulation unitarity is now manifest and the string S-matrix and the S-matrix of the generalised sine-Gordon theory are recovered in two different limits. In the latter case, expanding the Yang-Baxter equation we find that the tree-level S-matrix of the Pohlmeyer-reduced string should satisfy a modified classical Yang-Baxter equation explaining the apparent anomaly in the perturbative computation. We show that the IRF form of the S-matrix meshes perfectly with the bootstrap equations.Comment: 52 pages, some additional comments and clarifications for the published versio

A comparison of sunlight exposure in men with prostate cancer and basal cell carcinoma

Ultraviolet radiation exposure increases basal cell carcinoma (BCC) risk, but may be protective against prostate cancer. We attempted to identify exposure patterns that confer reduced prostate cancer risk without increasing that of BCC. We used a questionnaire to assess exposure in 528 prostate cancer patients and 442 men with basal cell carcinoma, using 365 benign prostatic hypertrophy patients as controls. Skin type 1 (odds ratio (OR)=0.47, 95% CI=0.26–0.86), childhood sunburning (OR=0.38, 95% CI=0.26–0.57), occasional/frequent sunbathing (OR=0.21, 95% CI=0.14–0.31), lifetime weekday (OR=0.85, 95% CI=0.80–0.91) and weekend exposure (OR=0.79, 95% CI=0.73–0.86) were associated with reduced prostate cancer risk. Skin type 1 (OR=4.00, 95% CI=2.16–7.41), childhood sunburning (OR=1.91, 95% CI=1.36–2.68), regular foreign holidays (OR=6.91, 95% CI=5.00-9.55) and weekend (OR=1.17, 95% CI=1.08–1.27) but not weekday exposure were linked with increased BCC risk. Combinations of one or two parameters were associated with a progressive decrease in the ORs for prostate cancer risk (OR=0.54–0.25) with correspondingly increased BCC risk (OR=1.60–2.54). Our data do not define exposure patterns that reduce prostate cancer risk without increasing BCC risk

Thiopurine Methyltransferase Predicts the Extent of Cytotoxicty and DNA Damage in Astroglial Cells after Thioguanine Exposure

Thiopurine methyltransferase (Tpmt) is the primary enzyme responsible for deactivating thiopurine drugs. Thiopurine drugs (i.e., thioguanine [TG], mercaptopurine, azathioprine) are commonly used for the treatment of cancer, organ transplant, and autoimmune disorders. Chronic thiopurine therapy has been linked to the development of brain cancer (most commonly astrocytomas), and Tpmt status has been associated with this risk. Therefore, we investigated whether the level of Tpmt protein activity could predict TG-associated cytotoxicity and DNA damage in astrocytic cells. We found that TG induced cytotoxicity in a dose-dependent manner in Tpmt+/+, Tpmt+/− and Tpmt−/− primary mouse astrocytes and that a low Tpmt phenotype predicted significantly higher sensitivity to TG than did a high Tpmt phenotype. We also found that TG exposure induced significantly more DNA damage in the form of single strand breaks (SSBs) and double strand breaks (DSBs) in primary astrocytes with low Tpmt versus high Tpmt. More interestingly, we found that Tpmt+/− astrocytes had the highest degree of cytotoxicity and genotoxicity (i.e., IC50, SSBs and DSBs) after TG exposure. We then used human glioma cell lines as model astroglial cells to represent high (T98) and low (A172) Tpmt expressers and found that A172 had the highest degree of cytoxicity and SSBs after TG exposure. When we over-expressed Tpmt in the A172 cell line, we found that TG IC50 was significantly higher and SSB's were significantly lower as compared to mock transfected cells. This study shows that low Tpmt can lead to greater sensitivity to thiopurine therapy in astroglial cells. When Tpmt deactivation at the germ-line is considered, this study also suggests that heterozygosity may be subject to the greatest genotoxic effects of thiopurine therapy

Lymphomas driven by Epstein-Barr virus nuclear antigen-1 (EBNA1) are dependant upon Mdm2

Epstein-Barr virus (EBV)-associated Burkitt's lymphoma is characterised by the deregulation of c-Myc expression and a restricted viral gene expression pattern in which the EBV nuclear antigen-1 (EBNA1) is the only viral protein to be consistently expressed. EBNA1 is required for viral genome propagation and segregation during latency. However, it has been much debated whether the protein plays a role in viral-associated tumourigenesis. We show that the lymphomas which arise in EµEBNA1 transgenic mice are unequivocally linked to EBNA1 expression and that both C-Myc and Mdm2 deregulation are central to this process. Tumour cell survival is supported by IL-2 and there is a skew towards CD8-positive T cells in the tumour environment, while the immune check-point protein PD-L1 is upregulated in the tumours. Additionally, several isoforms of Mdm2 are upregulated in the EµEBNA1 tumours, with increased phosphorylation at ser166, an expression pattern not seen in Eµc-Myc transgenic tumours. Concomitantly, E2F1, Xiap, Mta1, C-Fos and Stat1 are upregulated in the tumours. Using four independent inhibitors of Mdm2 we demonstrate that the EµEBNA1 tumour cells are dependant upon Mdm2 for survival (as they are upon c-Myc) and that Mdm2 inhibition is not accompanied by upregulation of p53, instead cell death is linked to loss of E2F1 expression, providing new insight into the underlying tumourigenic mechanism. This opens a new path to combat EBV-associated disease

Chd8 mediates cortical neurogenesis via transcriptional regulation of cell cycle and Wnt signaling

De novo mutations in CHD8 are strongly associated with autism spectrum disorder, but the basic biology of CHD8 remains poorly understood. Here we report that Chd8 knockdown during cortical development results in defective neural progenitor proliferation and differentiation that ultimately manifests in abnormal neuronal morphology and behaviors in adult mice. Transcriptome analysis revealed that while Chd8 stimulates the transcription of cell cycle genes, it also precludes the induction of neural-specific genes by regulating the expression of PRC2 complex components. Furthermore, knockdown of Chd8 disrupts the expression of key transducers of Wnt signaling, and enhancing Wnt signaling rescues the transcriptional and behavioral deficits caused by Chd8 knockdown. We propose that these roles of Chd8 and the dynamics of Chd8 expression during development help negotiate the fine balance between neural progenitor proliferation and differentiation. Together, these observations provide new insights into the neurodevelopmental role of Chd8.National Institutes of Health (U.S.) (Grant UH1-MH106018-03

Is there a common water-activity limit for the three domains of life?

Archaea and Bacteria constitute a majority of life systems on Earth but have long been considered inferior to Eukarya in terms of solute tolerance. Whereas the most halophilic prokaryotes are known for an ability to multiply at saturated NaCl (water activity (a w) 0.755) some xerophilic fungi can germinate, usually at high-sugar concentrations, at values as low as 0.650-0.605 a w. Here, we present evidence that halophilic prokayotes can grow down to water activities of <0.755 for Halanaerobium lacusrosei (0.748), Halobacterium strain 004.1 (0.728), Halobacterium sp. NRC-1 and Halococcus morrhuae (0.717), Haloquadratum walsbyi (0.709), Halococcus salifodinae (0.693), Halobacterium noricense (0.687), Natrinema pallidum (0.681) and haloarchaeal strains GN-2 and GN-5 (0.635 a w). Furthermore, extrapolation of growth curves (prone to giving conservative estimates) indicated theoretical minima down to 0.611 a w for extreme, obligately halophilic Archaea and Bacteria. These were compared with minima for the most solute-tolerant Bacteria in high-sugar (or other non-saline) media (Mycobacterium spp., Tetragenococcus halophilus, Saccharibacter floricola, Staphylococcus aureus and so on) and eukaryotic microbes in saline (Wallemia spp., Basipetospora halophila, Dunaliella spp. and so on) and high-sugar substrates (for example, Xeromyces bisporus, Zygosaccharomyces rouxii, Aspergillus and Eurotium spp.). We also manipulated the balance of chaotropic and kosmotropic stressors for the extreme, xerophilic fungi Aspergillus penicilloides and X. bisporus and, via this approach, their established water-activity limits for mycelial growth (∼0.65) were reduced to 0.640. Furthermore, extrapolations indicated theoretical limits of 0.632 and 0.636 a w for A. penicilloides and X. bisporus, respectively. Collectively, these findings suggest that there is a common water-activity limit that is determined by physicochemical constraints for the three domains of life

The genetics and neuropathology of frontotemporal lobar degeneration

Frontotemporal lobar degeneration (FTLD) is a heterogeneous group of disorders characterized by disturbances of behavior and personality and different types of language impairment with or without concomitant features of motor neuron disease or parkinsonism. FTLD is characterized by atrophy of the frontal and anterior temporal brain lobes. Detailed neuropathological studies have elicited proteinopathies defined by inclusions of hyperphosphorylated microtubule-associated protein tau, TAR DNA-binding protein TDP-43, fused-in-sarcoma or yet unidentified proteins in affected brain regions. Rather than the type of proteinopathy, the site of neurodegeneration correlates relatively well with the clinical presentation of FTLD. Molecular genetic studies identified five disease genes, of which the gene encoding the tau protein (MAPT), the growth factor precursor gene granulin (GRN), and C9orf72 with unknown function are most frequently mutated. Rare mutations were also identified in the genes encoding valosin-containing protein (VCP) and charged multivesicular body protein 2B (CHMP2B). These genes are good markers to distinguish underlying neuropathological phenotypes. Due to the complex landscape of FTLD diseases, combined characterization of clinical, imaging, biological and genetic biomarkers is essential to establish a detailed diagnosis. Although major progress has been made in FTLD research in recent years, further studies are needed to completely map out and correlate the clinical, pathological and genetic entities, and to understand the underlying disease mechanisms. In this review, we summarize the current state of the rapidly progressing field of genetic, neuropathological and clinical research of this intriguing condition

Synaptic Wnt signaling—a contributor to major psychiatric disorders?

Wnt signaling is a key pathway that helps organize development of the nervous system. It influences cell proliferation, cell fate, and cell migration in the developing nervous system, as well as axon guidance, dendrite development, and synapse formation. Given this wide range of roles, dysregulation of Wnt signaling could have any number of deleterious effects on neural development and thereby contribute in many different ways to the pathogenesis of neurodevelopmental disorders. Some major psychiatric disorders, including schizophrenia, bipolar disorder, and autism spectrum disorders, are coming to be understood as subtle dysregulations of nervous system development, particularly of synapse formation and maintenance. This review will therefore touch on the importance of Wnt signaling to neurodevelopment generally, while focusing on accumulating evidence for a synaptic role of Wnt signaling. These observations will be discussed in the context of current understanding of the neurodevelopmental bases of major psychiatric diseases, spotlighting schizophrenia, bipolar disorder, and autism spectrum disorder. In short, this review will focus on the potential role of synapse formation and maintenance in major psychiatric disorders and summarize evidence that defective Wnt signaling could contribute to their pathogenesis via effects on these late neural differentiation processes

Human factors and ergonomics design principles and guidelines : helping designers to be more creative

This is a pre-copyedited version of a contribution published in: Proceedings of the 20th Congress of the International Ergonomics Association (IEA 2018). IEA 2018. Advances in Intelligent Systems and Computing, vol 824, edited by Bagnara S., Tartaglia R., Albolino S., Alexander T., Fujita Y., published by Springer, Cham. The definitive authenticated version is available online via https://doi.org/10.1007/978-3-319-96071-5_17.The knowledge and application of Human Factors/Ergonomics (HFE) principles and guidelines can help designers to develop better products and services. However, they may also include design constraints that may affect designers’ creativity. Although both HFE principles and guidelines and creativity are considered essential in the design of products and services, the link between them is little researched. In this article a discussion is presented on the influence that HFE principles and guidelines can exert on the creativity of designers. It also presents case studies of HFE principles and guidelines and discusses how they can influence designers’ creativity. In addition, a set of recommendations is suggested to help designers apply ergonomic design principles and guidelines to stimulate creativity. It is concluded that HFE principles and guidelines can assist designers in creating safer and more efficient products and services and can also broaden their creative process and therefore the originality and appropriateness of products and services