Viral delivery of antioxidant genes as a therapeutic strategy in experimental models of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with no effective treatment to date. Despite its multi-factorial aetiology, oxidative stress is hypothesized to be one of the key pathogenic mechanisms. It is thus proposed that manipulation of the expression of antioxidant genes that are downregulated in the presence of mutant SOD1 may serve as a therapeutic strategy for motor neuronal protection. Lentiviral vectors expressing either PRDX3 or NRF2 genes were tested in the motor neuronal-like NSC34 cell line, and in the ALS tissue culture model, NSC34 cells expressing the human SOD1(G93A) mutation. The NSC34 SOD1(G93A) cells overexpressing either PRDX3 or NRF2 showed a significant decrease in endogenous oxidation stress levels by 40 and 50% respectively compared with controls, whereas cell survival was increased by 30% in both cases. The neuroprotective potential of those two genes was further investigated in vivo in the SOD1(G93A) ALS mouse model, by administering intramuscular injections of adenoassociated virus serotype 6 (AAV6) expressing either of the target genes at a presymptomatic stage. Despite the absence of a significant effect in survival, disease onset or progression, which can be explained by the inefficient viral delivery, the promising in vitro data suggest that a more widespread CNS delivery is needed

When sitting becomes sport: life stories in sitting volleyball

Results of recent studies support a growing literature which indicates that exercise and physical activity are associated with better quality of life and health outcomes. The purpose of the present qualitative study is to gain a deeper insight into how sitting volleyball players perceive the impact of the sport on their lives. So far, the research in the field of disability and sport has tended to focus on ideological approaches rather than empiricism. Thus, the present study explores how the participants experience their disability and their involvement in sport. The research was conducted with a group of 5 male sitting volleyball players (aged 32 to 61 years old) in Athens, Greece. Data were collected primarily through audio-recorded, semi-structured in-depth interviews and enriched with participant observation field notes. Data was analysed following an Interpretative Phenomenological Analysis (IPA) as the aim of the research was to capture the players’ perceptions of their participation in sitting volleyball

A novel splice variant of the DNA-PKcs gene is associated with clinical and cellular radiosensitvity in a xeroderma pigmentosum patient

This article has been made available through the Brunel Open Access Publishing Fund.Background: Radiotherapy-induced DNA double strand breaks (DSB) are critical cytotoxic lesions. Inherited defects in DSB DNA repair pathways lead to hypersensitivity to ionising radiation, immunodeficiency and increased cancer incidence. A patient with xeroderma pigmentosum complementation group C, with a scalp angiosarcoma exhibited dramatic clinical radiosensitivity following radiotherapy, resulting in death. A fibroblast cell line from non-affected skin (XP14BRneo17) was hypersensitive to ionising radiation and defective in DNA double strand break repair. Aim: To determine the genetic defect causing cellular radiation hypersensitivity in XP14BRneo17 cells. Methods: Functional genetic complementation whereby copies of human chromosomes containing genes involved in DNA DSB repair (chromosomes 2, 5, 8 10, 13 and 22) were individually transferred to XP14BRneo17 cells in an attempt to correct the radiation hypersensitivity. Clonogenic survival assays and γ-H2AX immunofluorescence were conducted to measure radiation sensitivity and repair of DNA DSBs. DNA sequencing of defective DNA repair genes was performed. Results: Transfer of chromosome 8 (location of DNA-PKcs gene), and transfection of a mammalian expression construct containing the DNA-PKcs cDNA restored normal ionising radiation sensitivity and repair of DNA DSBs in XP14BRneo17 cells. DNA sequencing of the DNA-PKcs coding region revealed a 249 bp deletion (between base pairs 3656-3904) encompassing exon 31 of the gene. Conclusion: We provide evidence of a novel splice variant of the DNA-PKcs gene associated with radiosensitivity in a xeroderma pigmentosum patient and report the first double mutant in distinct DNA repair pathways being consistent with viability.Brunel Open Access Publishing Fun

Experimental hut comparisons of nets treated with carbamate or pyrethroid insecticides, washed or unwashed, against pyrethroid-resistant mosquitoes.

The efficacy against mosquitoes (Diptera: Culicidae) of a bednet treated with carbamate insecticide [carbosulfan capsule suspension (CS) 200 mg/m(2)] was compared with four types of pyrethroid-treated nets in veranda-trap huts at Yaokoffikro near Bouaké, Côte d'Ivoire, where the malaria vector Anopheles gambiae Giles carries the kdr gene (conferring pyrethroid resistance) at high frequency and Culex quinquefasciatus Say is also pyrethroid resistant. Pyrethroids compared were lambdacyhalothrin CS 18 mg/m(2), alphacypermethrin water dispersible granules (WG) 20 mg/m(2), deltamethrin 50 mg/m(2) (Permanet) and permethrin emulsifiable concentrate (EC) 500 mg/m(2). Insecticidal power and personal protection from mosquito bites were assessed before and after the nets were used for 8 months and hand washed five times in cold soapy water. Before washing, all treatments except permethrin significantly reduced blood-feeding and all had significant insecticidal activity against An. gambiae. The carbosulfan net gave significantly higher killing of An. gambiae than all pyrethroid treatments except the Permanet. Against Culex spp., carbosulfan was more insecticidal and gave a significantly better protective effect than any of the pyrethroid treatments. After washing, treated nets retained various degrees of efficacy against both mosquito genera - but least for the carbosulfan net. Washed nets with three types of pyrethroid treatment (alphacypermethrin, lambdacyhalothrin, permethrin) gave significantly higher mortality rates of Culex than in huts with the same pyrethroid-treated nets before washing. After five washes, the Permanet, which is sold as a long-lasting insecticidal product, performed no better than the other nets in our experimental conditions

Recognizing the Valentinians--now and then

Peer reviewe

Origin of the 2009 Mexico influenza virus: a comparative phylogenetic analysis of the principal external antigens and matrix protein

Triple-reassortant swine influenza A (H1) viruses, containing genes from avian, human, and swine influenza viruses, emerged and became an outbreak among humans worldwide. Over a 1,000 cases were identified within the first month, chiefly in Mexico and the United States. Here, the phylogenetic analysis of haemagglutin (HA), neuraminidase (NA), and matrix protein (MP) was carried out. The analysis showed that the H1 of this reassortant originated from American pigs, while NA and MP were more likely from European pigs. All of the 2009 isolates appear homogeneous and cluster together, although they are distinct from classical human A (H1N1) viruses

Elevated expression of artemis in human fibroblast cells is associated with cellular radiosensitivity and increased apoptosis

Copyright @ 2012 Nature Publishing GroupThis article has been made available through the Brunel Open Access Publishing Fund.Background: The objective of this study was to determine the molecular mechanism(s) responsible for cellular radiosensitivity in two human fibroblast cell lines 84BR and 175BR derived from two cancer patients. Methods: Clonogenic assays were performed following exposure to increasing doses of gamma radiation to confirm radiosensitivity. γ-H2AX foci assays were used to determine the efficiency of DNA double strand break (DSB) repair in cells. Quantitative-PCR (Q-PCR) established the expression levels of key DNA DSB repair proteins. Imaging flow cytometry using Annexin V-FITC was used to compare artemis expression and apoptosis in cells. Results: Clonogenic cellular hypersensitivity in the 84BR and 175BR cell lines was associated with a defect in DNA DSB repair measured by the γ-H2AX foci assay. Q-PCR analysis and imaging flow cytometry revealed a two-fold overexpression of the artemis DNA repair gene which was associated with an increased level of apoptosis in the cells before and after radiation exposure. Over-expression of normal artemis protein in a normal immortalised fibroblast cell line NB1-Tert resulted in increased radiosensitivity and apoptosis. Conclusion: We conclude elevated expression of artemis is associated with higher levels of DNA DSB, radiosensitivity and elevated apoptosis in two radio-hypersensitive cell lines. These data reveal a potentially novel mechanism responsible for radiosensitivity and show that increased artemis expression in cells can result in either radiation resistance or enhanced sensitivity.This work was supported in part by The Vidal Sassoon Foundation USA. This article is made available through the Brunel Open Access Publishing Fund

A Trial of a 7-Valent Pneumococcal Conjugate Vaccine in HIV-Infected Adults.

BACKGROUND: Streptococcus pneumoniae is a leading and serious coinfection in adults with human immunodeficiency virus (HIV) infection, particularly in Africa. Prevention of this disease by vaccination with the current 23-valent polysaccharide vaccine is suboptimal. Protein conjugate vaccines offer a further option for protection, but data on their clinical efficacy in adults are needed. METHODS: In this double-blind, randomized, placebo-controlled clinical efficacy trial, we studied the efficacy of a 7-valent conjugate pneumococcal vaccine in predominantly HIV-infected Malawian adolescents and adults who had recovered from documented invasive pneumococcal disease. Two doses of vaccine were given 4 weeks apart. The primary end point was a further episode of pneumococcal infection caused by vaccine serotypes or serotype 6A. RESULTS: From February 2003 through October 2007, we followed 496 patients (of whom 44% were male and 88% were HIV-seropositive) for 798 person-years of observation. There were 67 episodes of pneumococcal disease in 52 patients, all in the HIV-infected subgroup. In 24 patients, there were 19 episodes that were caused by vaccine serotypes and 5 episodes that were caused by the 6A serotype. Of these episodes, 5 occurred in the vaccine group and 19 in the placebo group, for a vaccine efficacy of 74% (95% confidence interval [CI], 30 to 90). There were 73 deaths from any cause in the vaccine group and 63 in the placebo group (hazard ratio in the vaccine group, 1.18; 95% CI, 0.84 to 1.66). The number of serious adverse events within 14 days after vaccination was significantly lower in the vaccine group than in the placebo group (3 vs. 17, P=0.002), and the number of minor adverse events was significantly higher in the vaccine group (41 vs. 13, P=0.003). CONCLUSIONS: The 7-valent pneumococcal conjugate vaccine protected HIV-infected adults from recurrent pneumococcal infection caused by vaccine serotypes or serotype 6A. (Current Controlled Trials number, ISRCTN54494731.) Copyright 2010 Massachusetts Medical Society

Geographically weighted correspondence matrices for local error reporting and change analyses: mapping the spatial distribution of errors and change

This letter describes and applies generic methods for generating local measures from the correspondence table. These were developed by integrating the functionality of two existing R packages: gwxtab and diffeR. They demonstrate how spatially explicit accuracy and error measures can be generated from local geographically weighted correspondence matrices, for example to compare classified and reference data (predicted and observed) for error analyses, and classes at times t1 and t2 for change analyses. The approaches in this letter extend earlier work that considered the measures derived from correspondence matrices in the context of generalized linear models and probability. Here the methods compute local, geographically weighted correspondence matrices, from which local statistics are directly calculated. In this case a selection of the overall and categorical difference measures proposed by Pontius and Milones (2011) and Pontius and Santacruz (2014), as well as spatially distributed estimates of kappa coefficients, User and Producer accuracies. The discussion reflects on the use of the correspondence matrix in remote sensing research, the philosophical underpinnings of local rather than global approaches for modelling landscape processes and the potential for policy and scientific benefits that local approaches support

A review of landslide problems and mitigation measures in Chongqing and Hong Kong: Similarities and differences

The cities of Chongqing and Hong Kong are both located at hilly areas which are highly populated, with buildings and major highways located very close to slopes and earth-retaining structures. Landslides and rockfalls are very common in both cities, and large expenditures are being incurred by both Governments on the investigation, design and implementation of mitigation and preventive measures to reduce the likelihood of the loss of life and economic losses due to landslides. As a result of the collaborative studies and technical exchange programs between the University of Hong Kong and the Chongqing Jianzhu University, a more in-depth understanding of the landslide problem, methodology and mitigation measures in Chongqing and Hong Kong was achieved. The objective of this paper is therefore to: (1) highlight the similarities and differences of the slope safety problems which these cities have been facing and (2) present and compare the key technical approaches these two cities have been undertaken to reduce the risk of landslide and rockfalls, so that both cities could benefit from the experience and lesson learnt. Based on the review of literature and published case records, it is concluded that the city of Chongqing has to deal with natural hazards such as earthquake, river erosion and flooding more than that in Hong Kong, but both cities have been applying practical and latest technology to mitigating the landslide problem. It is recommended that the city of Chongqing should consider establishing a sustainable long-term landslide management plan and that the landslide prevention system being used in Hong Kong could be a good reference starting point. © 2004 Elsevier B.V. All rights reserved.postprin