Activities of Rifampin, Rifapentine and Clarithromycin Alone and in Combination against Mycobacterium ulcerans Disease in Mice

Buruli ulcer (BU) is found throughout the world but is particularly prevalent in West Africa. Until 2004, treatment for this disfiguring disease was surgical excision followed by skin grafting, procedures often requiring months of hospitalization. More recently, an 8-week regimen of oral rifampin and streptomycin administered by injection has become the standard of care recommended by the World Health Organization. However, daily injections require sterile needles and syringes to prevent spread of blood borne pathogens and streptomycin has potentially serious side effects, most notably hearing loss. We tested an entirely oral regimen, substituting the long acting rifapentine for rifampin and clarithromycin for streptomycin. We also evaluated each drug separately. We found that rifapentine alone is as good as rifampin plus streptomycin, but the simultaneous addition of effective clarithromycin doses, at least in the mouse, reduces the activity of both rifampin and rifapentine, making it difficult to assess the efficacy of the oral regimens in the model. Studies of serum drug concentrations indicated that separating treatment times by one hour or reducing the clarithromycin dose to one active in humans should overcome this issue in experimental and clinical BU treatment, respectively

Identifying and evaluating field indicators of urogenital schistosomiasis-related morbidity in preschool-aged children

BACKGROUND:Several studies have been conducted quantifying the impact of schistosome infections on health and development in school-aged children. In contrast, relatively little is known about morbidity levels in preschool-aged children (≤ 5 years) who have been neglected in terms of schistosome research and control. The aim of this study was to compare the utility of available point-of-care (POC) morbidity diagnostic tools in preschool versus primary school-aged children (6-10 years) and determine markers which can be used in the field to identify and quantify Schistosoma haematobium-related morbidity. METHODS/PRINCIPAL FINDINGS:A comparative cross-sectional study was conducted to evaluate the performance of currently available POC morbidity diagnostic tools on Zimbabwean children aged 1-5 years (n=104) and 6-10 years (n=194). Morbidity was determined using the POC diagnostics questionnaire-based reporting of haematuria and dysuria, clinical examination, urinalysis by dipsticks, and urine albumin-to-creatinine ratio (UACR). Attributable fractions were used to quantify the proportion of morbidity attributable to S. haematobium infection. Based on results of attributable fractions, UACR was identified as the most reliable tool for detecting schistosome-related morbidity, followed by dipsticks, visual urine inspection, questionnaires, and lastly clinical examination. The results of urine dipstick attributes showed that proteinuria and microhaematuria accounted for most differences between schistosome egg-positive and negative children (T=-50.1; p<0.001). These observations were consistent in preschool vs. primary school-aged children. CONCLUSIONS/SIGNIFICANCE:Preschool-aged children in endemic areas can be effectively screened for schistosome-related morbidity using the same currently available diagnostic tools applicable to older children. UACR for detecting albuminuria is recommended as the best choice for rapid assessment of morbidity attributed to S. haematobium infection in children in the field. The use of dipstick microhaematuria and proteinuria as additional indicators of schistosome-related morbidity would improve the estimation of disease burden in young children

Postcopulatory sexual selection

The female reproductive tract is where competition between the sperm of different males takes place, aided and abetted by the female herself. Intense postcopulatory sexual selection fosters inter-sexual conflict and drives rapid evolutionary change to generate a startling diversity of morphological, behavioural and physiological adaptations. We identify three main issues that should be resolved to advance our understanding of postcopulatory sexual selection. We need to determine the genetic basis of different male fertility traits and female traits that mediate sperm selection; identify the genes or genomic regions that control these traits; and establish the coevolutionary trajectory of sexes

Thioredoxin Glutathione Reductase as a Novel Drug Target: Evidence from Schistosoma japonicum

Background: Schistosomiasis remains a major public health concern affecting billions of people around the world. Currently, praziquantel is the only drug of choice for treatment of human schistosomiasis. The emergence of drug resistance to praziquantel in schistosomes makes the development of novel drugs an urgent task. Thioredoxin glutathione reductase (TGR) enzymes in Schistosoma mansoni and some other platyhelminths have been identified as alternative targets. The present study was designed to confirm the existense and the potential value of TGR as a target for development of novel antischistosomal agents in Schistosoma japonicum, a platyhelminth endemic in Asia. Methods and Findings: After cloning the S. japonicum TGR (SjTGR) gene, the recombinant SjTGR selenoprotein was purified and characterized in enzymatic assays as a multifunctional enzyme with thioredoxin reductase (TrxR), glutathione reductase (GR) and glutaredoxin (Grx) activities. Immunological and bioinformatic analyses confirmed that instead of having separate TrxR and GR proteins in mammalian, S. japonicum only encodes TGR, which performs the functions of both enzymes and plays a critical role in maintaining the redox balance in this parasite. These results were in good agreement with previous findings in Schistosoma mansoni and some other platyhelminths. Auranofin, a known inhibitor against TGR, caused fatal toxicity in S. japonicum adult worms in vitro and reduced worm and egg burdens in S. japonicum infected mice. Conclusions: Collectively, our study confirms that a multifunctional enzyme SjTGR selenoprotein, instead of separate Trx

Preferential Amplification of CD8 Effector-T Cells after Transcutaneous Application of an Inactivated Influenza Vaccine: A Randomized Phase I Trial

Background: Current conventional vaccination approaches do not induce potent CD8 T-cell responses for fighting mostly variable viral diseases such as influenza, avian influenza viruses or HIV. Following our recent study on vaccine penetration by targeting of vaccine to human hair follicular ducts surrounded by Langerhans cells, we tested in the first randomized Phase-Ia trial based on hair follicle penetration (namely transcutaneous route) the induction of virus-specific CD8 T cell responses. Methods and Findings: We chose the inactivated influenza vaccine – a conventional licensed tetanus/influenza (TETAGRIP®) vaccine – to compare the safety and immunogenicity of transcutaneous (TC) versus IM immunization in two randomized controlled, multi-center Phase I trials including 24 healthy-volunteers and 12 HIV-infected patients. Vaccination was performed by application of inactivated influenza vaccine according to a standard protocol allowing the opening of the hair duct for the TC route or needle-injection for the IM route. We demonstrated that the safety of the two routes was similar. We showed the superiority of TC application, but not the IM route, to induce a significant increase in influenza-specific CD8 cytokine-producing cells in healthy-volunteers and in HIV-infected patients. However, these routes did not differ significantly for the induction of influenza-specific CD4 responses, and neutralizing antibodies were induced only by the IM route. The CD8 cell response is thus the major immune response observed after TC vaccination. Conclusions: This Phase Ia clinical trial (Manon05) testing an anti-influenza vaccine demonstrated that vaccines designed for antibody induction by the IM route, generate vaccine-specific CD8 T cells when administered transcutaneously. These results underline the necessity of adapting vaccination strategies to control complex infectious diseases when CD8 cellular responses are crucial. Our work opens up a key area for the development of preventive and therapeutic vaccines for diseases in which CD8 cells play a crucial role

Beyond equilibrium climate sensitivity

ISSN:1752-0908ISSN:1752-089

Splicing Deregulation and Splicing Modulation in Acute Myeloid Leukemia: DNA is not Destiny

Cancer is thought to arise from accumulation of DNA mutations. However, AML is a heterogeneous disease characterized by diverse mutations each occurring at low frequencies. Actually, AML is a subtype with a relatively low mutational load compared to other cancer types. In addition, in children, DNA is far less damaged by exposure or age. Thus, also AML might not only be driven by differences in genomic content but also by transcriptomic heterogeneity. In this thesis we aimed to study deregulated splicing in AML and uncover its role in leukemogenesis

Environmental burdens of producing bread wheat, oilseed rape and potatoes in England and Wales using simulation and system modelling

Background, aims and scope Food production is essential to life. Modern farming uses considerable resources to produce arable crops. Analysing the environmental burdens of alternative crop production methods is a vital tool for policymakers. The paper describes the production burdens (calculated by life cycle analysis) of three key arable crops: bread wheat, oilseed rape and potatoes as grown in England and Wales using organic and non-organic (contemporary conventional) systems. Resource use (e.g. abiotic and energy) and burdens from emissions are included (e.g. global warming potential on a 100-year basis, global warming potential (GWP), and eutrophication and acidification potentials). Methods Crop production was analysed, using systems models, so that the effects of factors like changing N fertiliser application rates or irrigation could be examined. Emissions of nitrate were derived from a simulation model in which soil organic N was driven to steady state so that all long-term effects were properly accounted for. Yield response curves to N were similarly derived from long-term experiments. Crop nutrient inputs and plant protection applications were derived from national survey data and the literature. All major inputs were accounted for including fertiliser extraction, manufacture and delivery; pesticide manufacture; field fuel use; machinery and building manufacture; crop drying, cooling and storage. The current balance of production systems were found from survey data. The weighted mean national production was calculated froma combination of three rainfall levels and soil textures. The system boundary is the farm gate. The functional unit is 1 t marketable fresh weight of each product. Results and discussion The primary energy needs for the producing the three main crops were 2.4, 4.9 and 1.4 GJ/t for bread wheat, oilseed rape and potatoes, respectively. When expressed in terms of dry matter, protein or energy, wheat incurred smaller burdens than oilseed rape, which incurred lower burdens than potatoes. The crops do, of course, all play different roles. Organically produced bread wheat needed about 80% of the energy of non-organic, while organic potatoes needed 13% more energy than nonorganically produced ones. While pesticide use was always lower in organic production, other burdens were generally inconsistently higher or lower. Land occupation was always higher for organic production. Lower fertiliser use (and hence energy use) in organic systems is offset by more energy for fieldwork and lower yields. Main crop potato energy needs are dominated by cold storage. Reducing the N application rate for bread wheat production reduces energy use and GWP. The optimum for energy is with N at about 70% of the current level. It seems to be lower for GWP, but the sub-models used are beyond their range of reliability. The results are generally of the same order as those from other European studies. Conclusions Arable crop production depends heavily on fossil fuel in current major production systems. The emissions causing GWP are very dependent on nitrous oxide, more so than fuel consumption. That, together with emissions of ammonia and nitrate, means that agriculture has a C-N footprint rather than the C footprint that typifies most industrial life. Recommendations and perspectives With the large influence of nitrous oxide on GWP, evaluation of nitrous oxide emissions by another method, e.g. crop-soil simulation modelling instead of the more rigid IPCC method would improve the robustness of the analysis. The transition betweenfarming systems was not included in this study, but there could be short to medium term benefits of converting from nonorganic to organic methods that should be evaluated. System modelling allows alternative production methods to be readily explored and this greatly enhances LCA methodology