Monensin causes dose dependent inhibition of Mycobacterium avium subspecies paratuberculosis in radiometric culture

<p>Abstract</p> <p>Background</p> <p><it>Mycobacterium avium </it>subspecies <it>paratuberculosis </it>(MAP) causes a chronic wasting diarrheal disease in ruminants called Johne's disease, that is evocative of human inflammatory bowel disease (IBD). Agents used to treat IBD, called "anti-inflammatories", immuno-modulators" and "immuno-suppressants" inhibit MAP growth in culture. We concluded that, unknowingly, the medical profession has been treating MAP since sulfasalazine's introduction in 1942. Monensin, called a "Growth Enhancer" in cattle, ameliorates Johne's disease without a documented mechanism of action. We hypothesized that Monensin would inhibit MAP in culture.</p> <p>Methods</p> <p>Using the radiometric ¹⁴CO₂Bactec^®system, that expresses mycobacterial growth in arbitrary growth index (GI) units, we studied the effect of Monensin on the growth kinetic of MAP isolated from humans with IBD ("Dominic", "Ben" & UCF-4) and cattle with Johne's disease (303 & ATCC 19698.) Results are expressed as percent inhibition of cumulative GI (%–ΔcGI).</p> <p>Results</p> <p>The positive control Clofazimine inhibits every strain tested. The negative controls Cycloheximide & Phthalimide, have no inhibition on any MAP strain. Monensin has dose dependent inhibition on every MAP strain tested. The most susceptible human isolate was UCF-4 (73% – ΔcGI at 1 μg/ml) and bovine isolate was 303 (73% – ΔcGI at 4 μg/ml.) Monensin additionally inhibits <it>M. avium </it>ATCC 25291 (87% – ΔcGI at 64 μg/ml) & BCG (92% – ΔcGI at 16 μg/ml).</p> <p>Discussion</p> <p>We show that in radiometric culture the "Growth Enhancer" Monensin causes dose dependent inhibition of mycobacteria including MAP. We posit that the "Growth Enhancer" effect of Monensin may, at least in part, be due to inhibition of MAP in clinical or sub-clinical Johne's disease.</p

Why alternative teenagers self-harm: exploring the link between non-suicidal self-injury, attempted suicide and adolescent identity

Background: The term ‘self-harm’ encompasses both attempted suicide and non-suicidal self-injury (NSSI). Specific adolescent subpopulations such as ethnic or sexual minorities, and more controversially, those who identify as ‘Alternative’ (Goth, Emo) have been proposed as being more likely to self-harm, while other groups such as ‘Jocks’ are linked with protective coping behaviours (for example exercise). NSSI has autonomic (it reduces negative emotions) and social (it communicates distress or facilitates group ‘bonding’) functions. This study explores the links between such aspects of self-harm, primarily NSSI, and youth subculture.&lt;p&gt;&lt;/p&gt; Methods: An anonymous survey was carried out of 452 15 year old German school students. Measures included: identification with different youth cultures, i.e. Alternative (Goth, Emo, Punk), Nerd (academic) or Jock (athletic); social background, e.g. socioeconomic status; and experience of victimisation. Self-harm (suicide and NSSI) was assessed using Self-harm Behavior Questionnaire and the Functional Assessment of Self-Mutilation (FASM).&lt;p&gt;&lt;/p&gt; Results: An “Alternative” identity was directly (r ≈ 0.3) and a “Jock” identity inversely (r ≈ -0.1) correlated with self-harm. “Alternative” teenagers self-injured more frequently (NSSI 45.5% vs. 18.8%), repeatedly self-injured, and were 4–8 times more likely to attempt suicide (even after adjusting for social background) than their non-Alternative peers. They were also more likely to self-injure for autonomic, communicative and social reasons than other adolescents.&lt;p&gt;&lt;/p&gt; Conclusions: About half of ‘Alternative’ adolescents’ self-injure, primarily to regulate emotions and communicate distress. However, a minority self-injure to reinforce their group identity, i.e. ‘To feel more a part of a group’

DNDI-6148:A novel benzoxaborole preclinical candidate for the treatment of visceral leishmaniasis

Visceral leishmaniasis (VL) is a parasitic disease endemic across multiple regions of the world and is fatal if untreated. Current therapies are unsuitable, and there is an urgent need for safe, short-course, and low-cost oral treatments to combat this neglected disease. The benzoxaborole chemotype has previously delivered clinical candidates for the treatment of other parasitic diseases. Here, we describe the development and optimization of this series, leading to the identification of compounds with potent in vitro and in vivo antileishmanial activity. The lead compound (DNDI-6148) combines impressive in vivo efficacy (>98% reduction in parasite burden) with pharmaceutical properties suitable for onward development and an acceptable safety profile. Detailed mode of action studies confirm that DNDI-6148 acts principally through the inhibition of Leishmania cleavage and polyadenylation specificity factor (CPSF3) endonuclease. As a result of these studies and its promising profile, DNDI-6148 has been declared a preclinical candidate for the treatment of VL

Can fisheries-induced evolution shift reference points for fisheries management?

Heino, M., Baulier, L., Boukal, D. S., Ernande, B., Johnston, F. D., Mollet, F. M., Pardoe, H., Therkildsen, N. O., Uusi-Heikkilä, S., Vainikka, A., Arlinghaus, R., Dankel, D. J., Dunlop, E. S., Eikeset, A. M., Enberg, K., Engelhard G. H., Jørgensen, C., Laugen, A. T., Matsumura, S., Nusslé, S., Urbach, D., Whitlock, R., Rijnsdorp, A. D., and Dieckmann, U. 2013. Can fisheries-induced evolution shift reference points for fisheries management? - ICES Journal of Marine Science, 70: 707-721. Biological reference points are important tools for fisheries management. Reference points are not static, but may change when a population's environment or the population itself changes. Fisheries-induced evolution is one mechanism that can alter population characteristics, leading to "shifting” reference points by modifying the underlying biological processes or by changing the perception of a fishery system. The former causes changes in "true” reference points, whereas the latter is caused by changes in the yardsticks used to quantify a system's status. Unaccounted shifts of either kind imply that reference points gradually lose their intended meaning. This can lead to increased precaution, which is safe, but potentially costly. Shifts can also occur in more perilous directions, such that actual risks are greater than anticipated. Our qualitative analysis suggests that all commonly used reference points are susceptible to shifting through fisheries-induced evolution, including the limit and "precautionary” reference points for spawning-stock biomass, Blim and Bpa, and the target reference point for fishing mortality, F0.1. Our findings call for increased awareness of fisheries-induced changes and highlight the value of always basing reference points on adequately updated information, to capture all changes in the biological processes that drive fish population dynamic

Development of a DNA Barcoding System for Seagrasses: Successful but Not Simple

Seagrasses, a unique group of submerged flowering plants, profoundly influence the physical, chemical and biological environments of coastal waters through their high primary productivity and nutrient recycling ability. They provide habitat for aquatic life, alter water flow, stabilize the ground and mitigate the impact of nutrient pollution. at the coast region. Although on a global scale seagrasses represent less than 0.1% of the angiosperm taxa, the taxonomical ambiguity in delineating seagrass species is high. Thus, the taxonomy of several genera is unsolved. While seagrasses are capable of performing both, sexual and asexual reproduction, vegetative reproduction is common and sexual progenies are always short lived and epimeral in nature. This makes species differentiation often difficult, especially for non-taxonomists since the flower as a distinct morphological trait is missing. Our goal is to develop a DNA barcoding system assisting also non-taxonomists to identify regional seagrass species. The results will be corroborated by publicly available sequence data. The main focus is on the 14 described seagrass species of India, supplemented with seagrasses from temperate regions. According to the recommendations of the Consortium for the Barcoding of Life (CBOL) rbcL and matK were used in this study. After optimization of the DNA extraction method from preserved seagrass material, the respective sequences were amplified from all species analyzed. Tree- and character-based approaches demonstrate that the rbcL sequence fragment is capable of resolving up to family and genus level. Only matK sequences were reliable in resolving species and partially the ecotype level. Additionally, a plastidic gene spacer was included in the analysis to confirm the identification level. Although the analysis of these three loci solved several nodes, a few complexes remained unsolved, even when constructing a combined tree for all three loci. Our approaches contribute to the understanding of the morphological plasticity of seagrasses versus genetic differentiation

The Eat Smart Study: A randomised controlled trial of a reduced carbohydrate versus a low fat diet for weight loss in obese adolescents

Background Despite the recognition of obesity in young people as a key health issue, there is limited evidence to inform health professionals regarding the most appropriate treatment options. The Eat Smart study aims to contribute to the knowledge base of effective dietary strategies for the clinical management of the obese adolescent and examine the cardiometablic effects of a reduced carbohydrate diet versus a low fat diet. Methods and design Eat Smart is a randomised controlled trial and aims to recruit 100 adolescents over a 2½ year period. Families will be invited to participate following referral by their health professional who has recommended weight management. Participants will be overweight as defined by a body mass index (BMI) greater than the 90th percentile, using CDC 2000 growth charts. An accredited 6-week psychological life skills program ‘FRIENDS for Life’, which is designed to provide behaviour change and coping skills will be undertaken prior to volunteers being randomised to group. The intervention arms include a structured reduced carbohydrate or a structured low fat dietary program based on an individualised energy prescription. The intervention will involve a series of dietetic appointments over 24 weeks. The control group will commence the dietary program of their choice after a 12 week period. Outcome measures will be assessed at baseline, week 12 and week 24. The primary outcome measure will be change in BMI z-score. A range of secondary outcome measures including body composition, lipid fractions, inflammatory markers, social and psychological measures will be measured. Discussion The chronic and difficult nature of treating the obese adolescent is increasingly recognised by clinicians and has highlighted the need for research aimed at providing effective intervention strategies, particularly for use in the tertiary setting. A structured reduced carbohydrate approach may provide a dietary pattern that some families will find more sustainable and effective than the conventional low fat dietary approach currently advocated. This study aims to investigate the acceptability and effectiveness of a structured reduced dietary carbohydrate intervention and will compare the outcomes of this approach with a structured low fat eating plan. Trial Registration: The protocol for this study is registered with the International Clinical Trials Registry (ISRCTN49438757)

Millennial changes in North American wildfire and soil activity over the last glacial cycle

Climate changes in the North Atlantic region during the last glacial cycle were dominated by the slow waxing and waning of the North American ice sheet as well as by intermittent Dansgaard-­‐Oeschger (DO) events. However prior to the last deglaciation, little is known about the response of North American vegetation to such rapid climate changes and especially about the response of biomass burning, an important factor for regional changes in radiative forcing. Here we use continuous, high-­‐resolution ammonium (NH4+) records derived from the NGRIP and GRIP ice cores to document both North American NH4+ background emissions from soils and wildfire frequency over the last 110,000 yr. Soil emissions increased on orbital timescales with warmer climate, related to the northward expansion of vegetation due to reduced ice-­‐covered areas. During Marine Isotope Stage (MIS) 3 DO warm events, a higher fire recurrence rate is recorded, while NH4+ soil emissions rose only slowly during longer interstadial warm periods, in line with slow ice sheet shrinkage and delayed ecosystem changes. Our results indicate that sudden warming events had little impact on NH4+ soil emissions and NH4+ aerosol transport to Greenland during the glacial but triggered a significant increase in the frequency of fire occurrence.This paper has greatly benefitted from the Sir Nicholas Shackleton fellowship, Clare Hall, University of Cambridge, U.K., awarded to HF in 2014. The Division for Climate and Environmental Physics, Physics Institute, University of Bern acknowledges the long-­‐term financial support of ice core research by the Swiss National Science Foundation (SNSF) and the Oeschger Centre for Climate Change Research. EW is supported by a Royal Society professorship. NGRIP is directed and organized by the Department of Geophysics at the Niels Bohr Institute for Astronomy, Physics and Geophysics, University of Copenhagen. It is supported by funding agencies in Denmark (SNF), Belgium (FNRS-­‐CFB), France (IPEV and INSU/CNRS), Germany (AWI), Iceland (RannIs), Japan (MEXT), Sweden (SPRS), Switzerland (SNSF) and the USA (NSF, Office of Polar Programs).This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ngeo249

Life Expectancy at Birth for People with Serious Mental Illness and Other Major Disorders from a Secondary Mental Health Care Case Register in London

Despite improving healthcare, the gap in mortality between people with serious mental illness (SMI) and general population persists, especially for younger age groups. The electronic database from a large and comprehensive secondary mental healthcare provider in London was utilized to assess the impact of SMI diagnoses on life expectancy at birth.People who were diagnosed with SMI (schizophrenia, schizoaffective disorder, bipolar disorder), substance use disorder, and depressive episode/disorder before the end of 2009 and under active review by the South London and Maudsley NHS Foundation Trust (SLAM) in southeast London during 2007-09 comprised the sample, retrieved by the SLAM Case Register Interactive Search (CRIS) system. We estimated life expectancy at birth for people with SMI and each diagnosis, from national mortality returns between 2007-09, using a life table method.A total of 31,719 eligible people, aged 15 years or older, with SMI were analyzed. Among them, 1,370 died during 2007-09. Compared to national figures, all disorders were associated with substantially lower life expectancy: 8.0 to 14.6 life years lost for men and 9.8 to 17.5 life years lost for women. Highest reductions were found for men with schizophrenia (14.6 years lost) and women with schizoaffective disorders (17.5 years lost).The impact of serious mental illness on life expectancy is marked and generally higher than similarly calculated impacts of well-recognised adverse exposures such as smoking, diabetes and obesity. Strategies to identify and prevent causes of premature death are urgently required