New approaches to measuring anthelminthic drug efficacy: parasitological responses of childhood schistosome infections to treatment with praziquantel

By 2020, the global health community aims to control and eliminate human helminthiases, including schistosomiasis in selected African countries, principally by preventive chemotherapy (PCT) through mass drug administration (MDA) of anthelminthics. Quantitative monitoring of anthelminthic responses is crucial for promptly detecting changes in efficacy, potentially indicative of emerging drug resistance. Statistical models offer a powerful means to delineate and compare efficacy among individuals, among groups of individuals and among populations.; We illustrate a variety of statistical frameworks that offer different levels of inference by analysing data from nine previous studies on egg counts collected from African children before and after administration of praziquantel.; We quantify responses to praziquantel as egg reduction rates (ERRs), using different frameworks to estimate ERRs among population strata, as average responses, and within strata, as individual responses. We compare our model-based average ERRs to corresponding model-free estimates, using as reference the World Health Organization (WHO) 90 % threshold of optimal efficacy. We estimate distributions of individual responses and summarize the variation among these responses as the fraction of ERRs falling below the WHO threshold.; Generic models for evaluating responses to anthelminthics deepen our understanding of variation among populations, sub-populations and individuals. We discuss the future application of statistical modelling approaches for monitoring and evaluation of PCT programmes targeting human helminthiases in the context of the WHO 2020 control and elimination goals

Benefits and risks of the hormetic effects of dietary isothiocyanates on cancer prevention

The isothiocyanate (ITC) sulforaphane (SFN) was shown at low levels (1-5 µM) to promote cell proliferation to 120-143% of the controls in a number of human cell lines, whilst at high levels (10-40 µM) it inhibited such cell proliferation. Similar dose responses were observed for cell migration, i.e. SFN at 2.5 µM increased cell migration in bladder cancer T24 cells to 128% whilst high levels inhibited cell migration. This hormetic action was also found in an angiogenesis assay where SFN at 2.5 µM promoted endothelial tube formation (118% of the control), whereas at 10-20 µM it caused significant inhibition. The precise mechanism by which SFN influences promotion of cell growth and migration is not known, but probably involves activation of autophagy since an autophagy inhibitor, 3-methyladenine, abolished the effect of SFN on cell migration. Moreover, low doses of SFN offered a protective effect against free-radical mediated cell death, an effect that was enhanced by co-treatment with selenium. These results suggest that SFN may either prevent or promote tumour cell growth depending on the dose and the nature of the target cells. In normal cells, the promotion of cell growth may be of benefit, but in transformed or cancer cells it may be an undesirable risk factor. In summary, ITCs have a biphasic effect on cell growth and migration. The benefits and risks of ITCs are not only determined by the doses, but are affected by interactions with Se and the measured endpoint

Study of Peri-Articular Anaesthetic for Replacement of the Knee (SPAARK): study protocol for a patient-blinded, randomised controlled superiority trial of liposomal bupivacaine

Background: Optimising the management of peri-operative pain and recovery following knee replacement has been identified as a patient priority. Current pain relief strategies use opiate-based analgesia; however, up to 50% of patients experience significant side effects. Local anaesthetic incisional infiltration is one alternative. The length of the duration of action is a major limiting factor of current local anaesthetic techniques. Liposomal bupivacaine has been reported to be effective for up to 72 h. This randomised controlled trial will evaluate the clinical and cost effectiveness of liposomal bupivacaine. Methods: SPAARK is a patient-blinded, multi-centre, active comparator, superiority, two-arm, parallel-group randomised controlled trial. Five hundred patients undergoing knee replacement will be recruited and randomised to liposomal bupivacaine plus bupivacaine hydrochloride or bupivacaine hydrochloride alone. The co-primary outcomes are the Quality of Recovery 40 measured at 72 h post-surgery and also cumulative pain measured daily using a 0–10 visual analogue scale for the first 3 days following surgery. Secondary outcomes include cumulative opioid consumption, fitness for discharge, functional outcomes assessed using the Oxford Knee Score and American Knee Society Score, the EuroQol five dimensions instrument and complications. A cost utility analysis is also planned. Discussion: The clinical effectiveness and cost effectiveness of liposomal bupivacaine have yet to be evaluated in the National Health Service, making this trial appropriate and timely. Trial registration: ISRCTN registry, ISRCTN54191675. Registered on 14 November 2017

Genetic variation in leaf and stem glucosinolates in resynthesized lines of winter rapeseed (Brassica napus L.)

Glucosinolates are secondary components characteristic for the Brassicaceae with complex biological functions. Glucosinolates in the seeds are anti-nutritive when feeding animals and their inheritance have been extensively investigated. Much less is known about the genetics of glucosinolates in leaves and stems, which may attract some insects, while repelling others. They may also inhibit bacterial processes of importance when using green biomass for the production of biogas. The objective of this study was to analyse the genetic variation of total and individual glucosinolates in the green material of rapeseed. For this 28 resynthesized winter rapeseed lines were tested at two locations. There was a large variation in leaf glucosinolate content between 0.10 and 4.75 mu mol/g dry matter. The predominant leaf glucosinolates are the alkenyle glucosinolates progoitrin, gluconapin and glucobrassicanapin. The line R53 is exceptional, while combining a relative high content of the indole glucosinolate glucobrassicin with low alkenyle glucosinolates in the leaves. The total glucosinolate concentration in the stems and leaves is not correlated with the seed glucosinolate concentrations. Heritabilities are above hA(2)A = 0.60 for progoitrin, hA(2)A = 0.65 for gluconapin, hA(2)A = 0.30 for glucobrassicanapin and hA(2)A = 0.52 for total glucosinolate content in the leaves. In conclusion, resynthesized rapeseed is an important genetic resource to modify the leaf glucosinolate content and composition of rapeseed.Deutsche Bundesstiftung Umwelt (DBU

Which New Approaches to Tackling Neglected Tropical Diseases Show Promise?

This PLoS Medicine Debate examines the different approaches that can be taken to tackle neglected tropical diseases (NTDs). Some commentators, like Jerry Spiegel and colleagues from the University of British Columbia, feel there has been too much focus on the biomedical mechanisms and drug development for NTDs, at the expense of attention to the social determinants of disease. Burton Singer argues that this represents another example of the inappropriate “overmedicalization” of contemporary tropical disease control. Peter Hotez and colleagues, in contrast, argue that the best return on investment will continue to be mass drug administration for NTDs

Dietary phenethylisothiocyanate attenuates bowel inflammation in mice

<p>Abstract</p> <p>Background</p> <p>Phenethylisothiocyanate (PEITC) is produced by Brassica food plants. PEO is a <b>P</b>EITC <b>E</b>ssential <b>O</b>il containing >95% natural PEITC. PEITC is known to produce various health benefits but its effect in alleviation of ulcerative colitis signs is unknown.</p> <p>Results</p> <p>In two efficacy studies (acute and chronic) oral administration of PEO was effective at remitting acute and chronic signs of ulcerative colitis (UC) in mice. Disease activity, histology and biochemical characteristics were measured in the treated animals and were compared with appropriate controls. PEO treatment significantly improved body weights and stool consistency as well as decreased intestinal bleeding. PEO treatment also reduced mucosal inflammation, depletion of goblet cells and infiltration of inflammatory cells. Attenuation of proinflammatory interleukin1β production was observed in the colons of PEO-treated animals. Expression analyses were also carried out for immune function related genes, transcription factors and cytokines in lipopolysaccharide-activated mouse macrophage cells. PEO likely affects an intricate network of immune signaling genes including a novel concentration dependent reduction of total cellular Signal Transducer and Activator of Transcription 1 (STAT1) as well as nuclear phosphorylated-STAT1 (activated form of STAT1). A PEO-concentration dependent decrease of mRNA of C-X-C motif ligand 10 (a STAT1 responsive chemokine) and Interleukin 6 were also observed.</p> <p>Conclusions</p> <p>PEO might be a promising candidate to develop as a treatment for ulcerative colitis patients. The disease attenuation by PEO is likely associated with suppression of activation of STAT1 transcription and inhibition of pro-inflammatory cytokines.</p

Mapping Helminth Co-Infection and Co-Intensity: Geostatistical Prediction in Ghana

Urinary schistosomiasis and hookworm infections cause considerable morbidity in school age children in West Africa. Severe morbidity is predominantly observed in individuals infected with both parasite types and, in particular, with heavy infections. We investigated for the first time the distribution of S. haematobium and hookworm co-infections and distribution of co-intensity of these parasites in Ghana. Bayesian geostatistical models were developed to generate a national co-infection map and national intensity maps for each parasite, using data on S. haematobium and hookworm prevalence and egg concentration (expressed as eggs per 10 mL of urine for S. haematobium and expressed as eggs per gram of faeces for hookworm), collected during a pre-intervention baseline survey in Ghana, 2008. In contrast with previous findings from the East Africa region, we found that both S. haematobium and hookworm infections are highly focal, resulting in small, localized clusters of co-infection and areas of high co-intensity. Overlaying on a single map the co-infection and the intensity of multiple parasite infections allows identification of areas where parasite environmental contamination and morbidity are at its highest, while providing an evidence base for the assessment of the progress of successive rounds of mass drug administration (MDA) in integrated parasitic disease control programs

Triple Co-Administration of Ivermectin, Albendazole and Praziquantel in Zanzibar: A Safety Study

This paper describes how the use of three drugs which are used separately in mass drug distribution programmes when given together appear safe for use in large populations which have been previously treated with the same drugs separately (Mectizan [ivermectin], albendazole and praziquantel). The target diseases—lymphatic filariasis, soil-transmitted worms and schistosomiasis—were prevalent in Zanzibar up to 2000 but have been largely controlled by mass drug administration. The Ministry of Health and Social Welfare, with the support of WHO, initiated a small scale trial in a population of triple therapy in over 5,000 people initially in two sites, and having found there were no severe adverse events associated with the combined treatment then upscaled to treat the whole of the eligible population of over 700,000. Similarly, there were no severe adverse events. This is the first time the three drugs have been used together at the same time at scale in Africa and provide a basis for expansion of integrated preventive chemotherapy of helminths (worms). The next steps need to be initiated in populations which have heavier worm loads and such interventions need to be subject to close monitoring and ethical review

Mass Mortality of Adult Male Subantarctic Fur Seals: Are Alien Mice the Culprits?

Background: Mass mortalities of marine mammals due to infectious agents are increasingly reported. However, in contrast to previous die-offs, which were indiscriminate with respect to sex and age, here we report a land-based mass mortality of Subantarctic fur seals with apparent exclusivity to adult males. An infectious agent with a male-predilection is the most plausible explanation for this die-off. Although pathogens with gender-biased transmission and pathologies are unusual, rodents are known sources of male-biased infectious agents and the invasive Mus musculus house mouse, occurs in seal rookeries. Methodology / Principal Findings: Molecular screening for male-biased pathogens in this potential rodent reservoir host revealed the absence of Cardiovirus and Leptospirosis genomes in heart and kidney samples, respectively, but identified a novel Streptococcus species with 30 % prevalence in mouse kidneys. Conclusions / Significance: Inter-species transmission through environmental contamination with this novel bacterium, whose congenerics display male-bias and have links to infirmity in seals and terrestrial mammals (including humans)

Benzyl Isothiocyanate, a Major Component from the Roots of Salvadora Persica Is Highly Active against Gram-Negative Bacteria

Plants produce a number of antimicrobial substances and the roots of the shrub Salvadora persica have been demonstrated to possess antimicrobial activity. Sticks from the roots of S. persica, Miswak sticks, have been used for centuries as a traditional method of cleaning teeth. Diverging reports on the chemical nature and antimicrobial repertoire of the chewing sticks from S. persica led us to explore its antibacterial properties against a panel of pathogenic or commensal bacteria and to identify the antibacterial component/s by methodical chemical characterization. S. persica root essential oil was prepared by steam distillation and solid-phase microextraction was used to sample volatiles released from fresh root. The active compound was identified by gas chromatography-mass spectrometry and antibacterial assays. The antibacterial compound was isolated using medium-pressure liquid chromatography. Transmission electron microscopy was used to visualize the effect on bacterial cells. The main antibacterial component of both S. persica root extracts and volatiles was benzyl isothiocyanate. Root extracts as well as commercial synthetic benzyl isothiocyanate exhibited rapid and strong bactericidal effect against oral pathogens involved in periodontal disease as well as against other Gram-negative bacteria, while Gram-positive bacteria mainly displayed growth inhibition or remained unaffected. The short exposure needed to obtain bactericidal effect implies that the chewing sticks and the essential oil may have a specific role in treatment of periodontal disease in reducing Gram-negative periodontal pathogens. Our results indicate the need for further investigation into the mechanism of the specific killing of Gram-negative bacteria by S. persica root stick extracts and its active component benzyl isothiocyanate