Potential Drug Development Candidates for Human Soil-Transmitted Helminthiases

There are few drugs - none ideal - for the treatment and control of gastrointestinal helminths (soil-transmitted nematodes) which, as chronic infections jeopardize children's growth, learning and ultimately individual, community and country development. Drugs for helminths are not attractive in human medicine, but are lucrative in animal health. Traditionally, investment in veterinary medicines has benefited humans for these diseases. With modern regulations an approved veterinary medicine can be tested in humans with little adaptation, reducing time and cost of development. We searched for products that could easily be transitioned into humans, having the necessary characteristics for use in communities exposed to these infections. A limited number of candidates met the main criteria for selection. We provide here a detailed analysis of two veterinary products, emodepside and monepantel, and nitazoxanide, which is approved for human use. In addition we include a less detailed analysis of all products examined, and the criteria on which the analysis was based. It is clear that the pipeline of easily obtainable human anthelminthics remains extremely limited, and further efforts are needed to find replacements for the inadequate number of products available today

Self-reported data: a major tool to assess compliance with anti-malarial combination therapy among children in Senegal

Background: Although there are many methods available for measuring compliance, there is no formal gold standard. Different techniques used to measure compliance were compared among children treated by the anti-malarial amodiaquine/sulphadoxine-pyrimethamine (AQ/SP) combination therapy, in use in Senegal between 2004 and 2006. Methods: The study was carried out in 2004, in five health centres located in the Thies region (Senegal). Children who had AQ/SP prescribed for three and one day respectively at the health centre were recruited. The day following the theoretical last intake of AQ, venous blood, and urine samples were collected for anti-malarial drugs dosage. Caregivers and children above five years were interviewed concerning children's drug intake. Results: Among the children, 64.7% adhered to 80% of the prescribed dose and only 37.7% were strict full adherent to the prescription. There was 72.7% agreement between self-reported data and blood drug dosage for amodiaquine treatment. Concerning SP, results found that blood dosages were 91.4% concordant with urine tests and 90% with self-reported data based on questionnaires. Conclusion: Self-reported data could provide useful quantitative information on drug intake and administration. Under strict methodological conditions this method, easy to implement, can be used to describe patients' behaviors and their use of new anti-malarial treatment. Self-reported data is a major tool for assessing compliance in resource poor countries. Blood and urine drug dosages provide qualitative results that confirm any drug intake. Urine assays for SP could be useful to obtain public health data, for example on chemoprophylaxis among pregnant women

Citizen science in schools: Engaging students in research on urban habitat for pollinators

Citizen science can play an important role in school science education. Citizen science is particularly relevant to addressing current societal environmental sustainability challenges, as it engages the students directly with environmental science and gives students an understanding of the scientific process. In addition, it allows students to observe local representations of global challenges. Here, we report a citizen science programme designed to engage school-age children in real-world scientific research. The programme used standardized methods deployed across multiple schools through scientist–school partnerships to engage students with an important conservation problem: habitat for pollinator insects in urban environments. Citizen science programmes such as the programme presented here can be used to enhance scientific literacy and skills. Provided key challenges to maintain data quality are met, this approach is a powerful way to contribute valuable citizen science data for understudied, but ecologically important study systems, particularly in urban environments across broad geographical areas

Computational Identification of Uncharacterized Cruzain Binding Sites

Chagas disease, caused by the unicellular parasite Trypanosoma cruzi, claims 50,000 lives annually and is the leading cause of infectious myocarditis in the world. As current antichagastic therapies like nifurtimox and benznidazole are highly toxic, ineffective at parasite eradication, and subject to increasing resistance, novel therapeutics are urgently needed. Cruzain, the major cysteine protease of Trypanosoma cruzi, is one attractive drug target. In the current work, molecular dynamics simulations and a sequence alignment of a non-redundant, unbiased set of peptidase C1 family members are used to identify uncharacterized cruzain binding sites. The two sites identified may serve as targets for future pharmacological intervention

Structural Characterization of CYP51 from Trypanosoma cruzi and Trypanosoma brucei Bound to the Antifungal Drugs Posaconazole and Fluconazole

Chagas Disease is caused by kinetoplastid protozoa Trypanosoma cruzi, whose sterols resemble those of fungi, in both composition and biosynthetic pathway. Azole inhibitors of sterol 14α-demethylase (CYP51), such as fluconazole, itraconazole, voriconazole, and posaconazole, successfully treat fungal infections in humans. Efforts have been made to translate anti-fungal azoles into a second-use application for Chagas Disease. Ravuconazole and posaconazole have been recently proposed as candidates for clinical trials with Chagas Disease patients. However, the widespread use of posaconazole for long-term treatment of chronic infections may be limited by hepatic and renal toxicity, a requirement for simultaneous intake of a fatty meal or nutritional supplement to enhance absorption, and cost. To aid our search for structurally and synthetically simple CYP51 inhibitors, we have determined the crystal structures of the CYP51 targets in T. cruzi and T. brucei, both bound to the anti-fungal drugs fluconazole or posaconazole. The structures provide a basis for a design of new drugs targeting Chagas Disease, and also make it possible to model the active site characteristics of the highly homologous Leishmania CYP51. This work provides a foundation for rational synthesis of new therapeutic agents targeting the three kinetoplastid parasites

Within- and cross-language contributions of morphological awareness to word reading development in Chinese-English bilingual children

A growing body of cross-linguistic research has suggested that morphological awareness plays a key role in both L1 and L2 word reading among bilingual readers. However, little is known about the interaction and development of L1 and L2 morphological awareness in relation to word reading. We addressed this issue by evaluating the unique contributions of L1 Chinese and L2 English morphological awareness to word reading in both Chinese and English across Grades 2 (N = 150), 5 (N = 158), and 8 (N = 159) Hong Kong Chinese–English bilingual children. Children completed five tasks of Chinese morphological awareness which tapped for compounding awareness, homophone awareness, homographic awareness, semantic radical awareness, and affix awareness, and six English morphological judgment and analogy tasks that assessed morphological awareness at three levels: inflection, derivation, and compounding. English phonological awareness, Chinese and English vocabulary, and nonverbal ability were measured as controls. Word reading was assessed in both languages. Within-language analyses revealed that Chinese morphological awareness accounted for 27, 22, and 12% of unique variances in Chinese word reading above the control measures in Grades 2, 5, and 8 respectively. In contrast, English morphological awareness explained small but significant unique variances in English word reading, i.e., 4, 8, and 2%, across Grades 2, 5, and 8 respectively. Critically, there were cross-language influences: Chinese morphological awareness explained 4% of unique variance in English word reading in Grade 2 after controlling for IQ, English vocabulary, English phonological awareness, and English morphological awareness; English morphological awareness explained significant variances in Chinese word reading, i.e., 4, 3, and 4% in Grades 2, 5, and 8 respectively, after the relevant controls. These findings suggest a bi-directional cross-language transfer of morphological awareness to word reading in L1 Chinese and L2 English. However, the direction of its transfer may be constrained by some language-specific morphological features