Telomere length regulation: coupling DNA end processing to feedback regulation of telomerase

The conventional DNA polymerase machinery is unable to fully replicate the ends of linear chromosomes. To surmount this problem, nearly all eukaryotes use the telomerase enzyme, a specialized reverse transcriptase that utizes its own RNA template to add short TG-rich repeats to chromosome ends, thus reversing their gradual erosion occurring at each round of replication. This unique, non-DNA templated mode of telomere replication requires a regulatory mechanism to ensure that telomerase acts at telomeres whose TG tracts are too short, but not at those with long tracts, thus maintaining the protective TG repeat cap at an appropriate average length. The prevailing notion in the field is that telomere length regulation is brought about through a negative feedback mechanism that counts TG repeat-bound protein complexes to generate a signal that regulates telomerase action. This review summarizes experiments leading up to this model and then focuses on more recent experiments, primarily from yeast, that begin to suggest how this counting mechanism might work. The emerging picture is that of a complex interplay between the conventional DNA replication machinery, DNA damage response factors, and a specialized set of proteins that help to recruit and regulate the telomerase enzyme

Assessment of the conservation priority status of South African estuaries for use in management and water allocation

The future health and productivity of South Africa's approximately 250 estuaries is dependent on two main factors: management and freshwater inputs. Both management and water allocation decisions involve trade-offs between conservation and various types of utilisation. In order to facilitate decision-making in both of these spheres, it is necessary to understand the relative conservation importance of different estuaries. This study devises a method for prioritising South African estuaries on the basis of conservation importance, and presents the results of a ranking based on the collation of existing data for all South African estuaries. Estuaries are scored in terms of their size, type and biogeographical zone, habitats and biota (plants, invertebrates, fish and birds). Thirtythree estuaries are currently under formal protection, but they are not representative of all estuarine biodiversity. We performed a complementarity analysis, incorporating data on abundance where available, to determine the minimum set of estuaries that includes all known species of plants, invertebrates, fishes and birds. In total, 32 estuaries were identified as 'required protected areas', including 10 which are already protected. An estuary's importance status (including 'required protected area' status) will influence the choice of management class and hence freshwater allocation under the country's new Water Act, and can be used to assist the development of a new management strategy for estuaries, which is currently underway. WaterSA Vol.28(2) 2002: 191-20

The Leeds Evaluation of Efficacy of Detoxification Study (LEEDS) project: An open-label pragmatic randomised control trial comparing the efficacy of differing therapeutic agents for primary care detoxification from either street heroin or methadone [ISRCTN07752728]

BACKGROUND: Heroin is a synthetic opioid with an extensive illicit market leading to large numbers of people becoming addicted. Heroin users often present to community treatment services requesting detoxification and in the UK various agents are used to control symptoms of withdrawal. Dissatisfaction with methadone detoxification [8] has lead to the use of clonidine, lofexidine, buprenorphine and dihydrocodeine; however, there remains limited evaluative research. In Leeds, a city of 700,000 people in the North of England, dihydrocodeine is the detoxification agent of choice. Sublingual buprenorphine, however, is being introduced. The comparative value of these two drugs for helping people successfully and comfortably withdraw from heroin has never been compared in a randomised trial. Additionally, there is a paucity of research evaluating interventions among drug users in the primary care setting. This study seeks to address this by randomising drug users presenting in primary care to receive either dihydrocodeine or buprenorphine. METHODS/DESIGN: The Leeds Evaluation of Efficacy of Detoxification Study (LEEDS) project is a pragmatic randomised trial which will compare the open use of buprenorphine with dihydrocodeine for illicit opiate detoxification, in the UK primary care setting. The LEEDS project will involve consenting adults and will be run in specialist general practice surgeries throughout Leeds. The primary outcome will be the results of a urine opiate screening at the end of the detoxification regimen. Adverse effects and limited data to three and six months will be acquired

A space-time continuous finite element method for 2D viscoelastic wave equation

International audienceA widespread approach to software service analysis uses session types. Very different type theories for binary and multiparty protocols have been developed; establishing precise connections between them remains an open problem. We present the first formal relation between two existing theories of binary and multiparty session types: a binary system rooted in linear logic, and a multiparty system based on automata theory. Our results enable the analysis of multiparty protocols using a (much simpler) type theory for binary protocols, ensuring protocol fidelity and deadlock-freedom. As an application, we offer the first theory of multiparty session types with behavioral genericity. This theory is natural and powerful; its analysis techniques reuse results for binary session types

Treatment of an Intramammary Bacterial Infection with 25-Hydroxyvitamin D3

Deficiency of serum levels of 25-hydroxyvitamin D3 has been correlated with increased risk of infectious diseases such as tuberculosis and influenza. A plausible reason for this association is that expression of genes encoding important antimicrobial proteins depends on concentrations of 1,25-dihydroxyvitamin D3 produced by activated immune cells at sites of infection, and that synthesis of 1,25-dihydroxyvitamin D3 is dependent on the availability of 25-hydroxyvitamin D3. Thus, increasing the availability of 25(OH)D3 for immune cell synthesis of 1,25-dihydroxyvitamin D3 at sites of infection has been hypothesized to aid in clearance of the infection. This report details the treatment of an acute intramammary infection with infusion of 25-hydroxyvitamin D3 to the site of infection. Ten lactating cows were infected with in one quarter of their mammary glands. Half of the animals were treated intramammary with 25-hydroxyvitamin D3. The 25-hydroxyvitamin D3 treated animal showed significantly lower bacterial counts in milk and showed reduced symptomatic affects of the mastitis. It is significant that treatment with 25-hydroxyvitamin D3 reduced the severity of an acute bacterial infection. This finding suggested a significant non-antibiotic complimentary role for 25-hydroxyvitamin D3 in the treatment of infections in compartments naturally low in 25-hydroxyvitamin D3 such as the mammary gland and by extension, possibly upper respiratory tract infections

Evolution of Mycobacterium tuberculosis complex lineages and their role in an emerging threat of multidrug resistant tuberculosis in Bamako, Mali

In recent years Bamako has been faced with an emerging threat from multidrug resistant TB (MDR-TB). Whole genome sequence analysis was performed on a subset of 76 isolates from a total of 208 isolates recovered from tuberculosis patients in Bamako, Mali between 2006 and 2012. Among the 76 patients, 61(80.3%) new cases and 15(19.7%) retreatment cases, 12 (16%) were infected by MDR-TB. The dominant lineage was the Euro-American lineage, Lineage 4. Within Lineage 4, the Cameroon genotype was the most prevalent genotype (n=20, 26%), followed by the Ghana genotype (n=16, 21%). A sub-clade of the Cameroon genotype, which emerged ~22 years ago was likely to be involved in community transmission. A sub-clade of the Ghana genotype that arose approximately 30 years ago was an important cause of MDR-TB in Bamako. The Ghana genotype isolates appeared more likely to be MDR than other genotypes after controlling for treatment history. We identifed a clade of four related Beijing isolates that included one MDR-TB isolate. It is a major concern to fnd the Cameroon and Ghana genotypes involved in community transmission and MDR-TB respectively. The presence of the Beijing genotype in Bamako remains worrying, given its high transmissibility and virulence

“Even if You Know Everything You Can Forget”: Health Worker Perceptions of Mobile Phone Text-Messaging to Improve Malaria Case-Management in Kenya

This paper presents the results of a qualitative study to investigate the perceptions and experiences of health workers involved in a a cluster-randomized controlled trial of a novel intervention to improve health worker malaria case-management in 107 government health facilities in Kenya. The intervention involved sending text-messages about paediatric outpatient malaria case-management accompanied by “motivating” quotes to health workers’ mobile phones. Ten malaria messages were developed reflecting recommendations from the Kenyan national guidelines. Two messages were delivered per day for 5 working days and the process was repeated for 26 weeks (May to October 2009). The accompanying quotes were unique to each message. The intervention was delivered to 119 health workers and there were significant improvements in correct artemether-lumefantrine (AL) management both immediately after the intervention (November 2009) and 6 months later (May 2010). In-depth interviews with 24 health workers were undertaken to investigate the possible drivers of this change. The results suggest high acceptance of all components of the intervention, with the active delivery of information in an on the job setting, the ready availability of new and stored text messages and the perception of being kept ‘up to date’ as important factors influencing practice. Applying the construct of stages of change we infer that in this intervention the SMS messages were operating primarily at the action and maintenance stages of behaviour change achieving their effect by creating an enabling environment and providing a prompt to action for the implementation of case management practices that had already been accepted as the clinical norm by the health workers. Future trials testing the effectiveness of SMS reminders in creating an enabling environment for the establishment of new norms in clinical practice as well as in providing a prompt to action for the implementation of the new case-management guidelines are justified

Investigating the Therapeutic Potential of a Probiotic in a Rat Model for Infection Following Fracture Fixation

Background: Staphylococcus aureus (S. aureus) is the most common pathogen responsible for osteomyelitis. Objectives: Our objective was to investigate the potential of a probiotic as a treatment for S. aureus-induced infection following fracture fixation in a rat model. Methods: Fifty male Sprague-Dawley rats were assigned to five groups (Control, S. aureus, S. aureus +ceftriaxone, S. aureus + once weekly probiotic, and S. aureus + twice weekly probiotic). Lactobacillus casei subsp. casei (ATCC: 39392) was selected from eight strains of probiotic bacteria with anti-staphylococcal activity. Infection was induced by inoculation with106 colony-forming units (CFU) of S. aureus in a closed femur fracture model stabilized with an intramedullary pin. Three weeks after the surgery, the development of infection and response to the therapy was documented using radiographs, microbiological and histopathological analysis. Results: No bacteria were recovered from rats in the Control group. The analysis of variance revealed a significant difference in the CFU/femur (P < 0.001) and CFU/pin (P = 0.001) across all five treatment groups. When the results were compared, the CFU/femur was significantly lower in the S. aureus + Probiotic twice weekly in comparison with S. aureus (P = 0.008) and the S. aureus + ceftriaxone (P = 0.012) groups. Repeated measure ANOVA to test the radiographic scores during the follow-up time between the intervention groups revealed no significant differences (P = 0.179). Conclusions: Parenteral administration of viable L. casei inhibits S. aureus-induced infection as shown by the bacteriologic analysis, but makes no difference to the radiological union rates. This could be the first step towards developing an effective, biologic adjunctive therapy for the management of osteomyelitis following fracture fixation