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

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

Advanced structural characterisation of pharmaceuticals using nano-thermal analysis (nano-TA)

The production of drug delivery systems fabricated at the nano scale comes with the challenges of identifying reliable characterisation tools, especially for solid dosage forms. A full understanding of physicochemical properties of solid-state systems at a high spatial resolution is essential to monitor their manufacturability, processability, performance (dissolution) and stability. Nano-thermal analysis (nano-TA), a hybrid of atomic force microscopy (AFM) and thermal analysis, has emerged as a solution to address the need for complete characterisation of samples with surface heterogeneity. Nano-TA provides not only physical information using conventional AFM but also the thermal behaviour of these systems as an additional chemical dimension. In this review, the principles and techniques of nano-TA are discussed with emphasis on recent pharmaceutical applications. Building on nano-TA, the combination of this approach with infrared spectroscopic analysis is briefly introduced. The challenges and considerations for future development of nano-TA characterisation are also outlined

AAV9-based gene therapy partially ameliorates the clinical phenotype of a mouse model of Leigh syndrome

Leigh syndrome (LS) is the most common infantile mitochondrial encephalopathy. No treatment is currently available for this condition. Mice lacking $\textit{Ndufs4}$, encoding NADH: ubiquinone oxidoreductase iron-sulfur protein 4 recapitulates the main findings of complex I related LS, including severe multisystemic complex I deficiency and progressive neurodegeneration. In order to develop a gene therapy approach for LS, we used here an AAV2/9 vector carrying the human $\textit{NDUFS4}$ coding sequence (hNDUFS4). We administered AAV2/9-$\textit{hNDUFS4}$ by intravenous (IV) and/or intracerebroventricular (ICV) routes to either newborn or young $\textit{Ndufs4}$$^{-/-}$ mice. We found that IV administration alone was only able to correct the complex I deficiency in peripheral organs, while ICV administration partially corrected the deficiency in the brain. However, both treatments failed to improve the clinical phenotype or to prolong the lifespan of $\textit{Ndufs4}$$^{-/-}$ mice. In contrast, combined IV and ICV treatments resulted, along with increased complex I activity, in the amelioration of the rotarod performance, and in a significant prolongation of the lifespan. Our results indicate that extraneurological organs play an important role in LS pathogenesis, and provide an insight into current limitations of AAV-mediated gene therapy in multisystem disorders. These findings warrant future investigations to develop new vectors able to efficiently target multiple organs.This work was supported by the Core Grant from the MRC, ERC advanced grant FP7- 322424 and NRJ-Institut de France Grant (to MZ) and by the grant [GR-2010-2306- 756] from the Italian Ministry of Health (to CV)

Magnetization reversal and local switching fields of ferromagnetic Co/Pd microtubes with radial magnetization

Three-dimensional nanomagnetism is a rapidly growing field of research covering both noncollinear spin textures and curved magnetic geometries including microtubular structures. We spatially resolve the field-induced magnetization reversal of free-standing ferromagnetic microtubes utilizing multifrequency magnetic force microscopy (MFM). The microtubes are composed of Co/Pd multilayer films with perpendicular magnetic anisotropy that translates to an anisotropy with radial easy axis upon rolling-up. Simultaneously mapping the topography and the perpendicular magnetostatic force derivative, the relation between surface angle and local magnetization configuration is evaluated for a large number of locations with slopes exceeding 45 degrees. The angle-dependence of the switching field is concurrent with the Kondorsky model, i.e., the rolled-up nanomembrane behaves like a planar magnetic film with perpendicular anisotropy and a pinning dominated magnetization reversal. Additionally, we discuss methodological challenges when detecting magnetostatic force derivatives near steep surfaces

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

Predation contributes to invasion resistance of benthic communities against the non-indigenous tunicate Ciona intestinalis

Marine anthropogenic structures offer novel niches for introduced species but their role in the subsequent invasion to natural habitats remains unknown. Upon arrival in new environments, invaders must overcome biotic resistance from native competitors and predators if they are to establish successfully in natural habitats. We tested the hypotheses that (1) artificial structures (e. g., suspended aquaculture installations) present a niche opportunity for invasive species by providing a refuge from native benthic predators, and (2) native predators in natural benthic habitats suppress successful colonization by invaders. A recruitment experiment showed that the ascidians Pyura chilensis (native) and Ciona intestinalis (invasive) could recruit to both suspended artificial structures and natural benthic habitats. Ciona, however, was only able to establish adult populations on artificial structures. In natural benthic habitats Ciona only recruited and grew in predator-exclusion cages, because without this protection predation prevented its establishment. In predation experiments, native invertebrate and fish predators removed all invasive ascidians (recruits and adults) in benthic habitats, which contrasted with the high adult survival of the native ascidian P. chilensis. The refuge from a number of benthic predators facilitates the establishment of large populations of invasive species on suspended structures. We present a conceptual model of the invasion processes that includes the anthropogenic structures as a transitional stepping-stone that facilitates invasion by enhancing and prolonging propagule supply to surrounding natural communities. Those established invaders might then overcome biotic resistance during time periods when populations of consumers or competitors are weakened by natural or anthropogenic disturbances. Our results suggest that the conservation of natural habitats with a high diversity of native predators can be an effective means to prevent the spread of invasive species growing on suspended structures. © 2011 The Author(s).published_or_final_versionSpringer Open Choice, 21 Feb 201

Recognizing the Valentinians--now and then

Peer reviewe

Quality of glycaemic control in ambulatory diabetics at the out-patient clinic of Kenyatta National Hospital, Nairobi

Background: Treatment of diabetes mellitus is based on the evidence that lowering blood glucose as close to normal range as possible is a primary strategy for reducing or preventing complications or early mortality from diabetes. This suggests poorer glycaemic control would be associated with excess of diabetes-related morbidity and mortality. This presumption is suspected to reach high proportions in developing countries where endemic poverty abets poor glycaemic control. There is no study published on Kenyan patients with diabetes mellitus about their glycaemic control as an audit of diabetes care. Objective: To determine the glycaemic control of ambulatory diabetic patients. Design: Cross-sectional study on each clinic day of a randomly selected sample of both type I and 2 diabetic patients. Setting: Kenyatta National Hospital. Methods: Over a period of six months, January 1998 to June 1998. During routine diabetes care in the clinic, mid morning random blood sugar and glycated haemoglobin (HbAI c)were obtained. Results: A total of 305 diabetic patients were included, 52.8% were females and 47.2% were males. 58.3% were on Oral Hypoglycaemic Agent (OHA) only, 22.3% on insulin only; 9.2% on OHA and insulin and 4.6% on diet only. 39.5% had mean HbAlc £ 8% while 60.5% had HbAlc ³ 8%. Patients on diet-only therapy had the best mean HbAlc=7.04% while patients on OHA-only had the worst mean HbAlc=9.06%. This difference was significant (p=0.01). The former group, likely, had better endogenous insulin production. The influence of age, gender and duration of diabetes on the level of glycaemic control observed did not attain statistically significant proportions. Conclusion: The majority of ambulatory diabetic patients attending the out-patient diabetic clinic had poor glycaemic control. The group with the poorest level of glycaemic control were on OHA-only, while best control was observed amongst patients on diet-only, because of possible fair endogenous insulin production. Poor glycaemic control was presumed to be due to sub-optimal medication and deteriorating diabetes. There is need to empower patients with knowledge and resources to enhance their individual participation in diabetes self-care. Diabetes care providers and facilities also need capacity building to improve care of patients with diabetes. East African Medical Journal Vol.80(8) 2003: 406-41

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