Transcriptional phenotype of the anti-parasitic benzodiazepine meclonazepam on the blood fluke .

There are limited control measures for the disease schistosomiasis, despite the fact that infection with parasitic blood flukes affects hundreds of millions of people worldwide. The current treatment, praziquantel, has been in use since the 1980's and there is a concern that drug resistance may emerge with continued monotherapy. Given the need for additional antischistosomal drugs, we have re-visited an old lead, meclonazepam.

Development of non-sedating benzodiazepines with antischistosomal activity.

The neglected tropical disease schistosomiasis infects over 200 million people worldwide and is treated with just one broad-spectrum antiparasitic drug (praziquantel). Alternative drugs are needed in the event of emerging praziquantel resistance or treatment failure. One promising lead that has shown efficacy in animal models and a human clinical trial is the benzodiazepine meclonazepam, discovered by Roche in the 1970s.

Neoblast-like stem cells of Fasciola hepatica.

The common liver fluke (Fasciola hepatica) causes the disease fasciolosis, which results in considerable losses within the global agri-food industry. There is a shortfall in the drugs that are effective against both the adult and juvenile life stages within the mammalian host, such that new drug targets are needed. Over the last decade the stem cells of parasitic flatworms have emerged as reservoirs of putative novel targets due to their role in development and homeostasis, including at host-parasite interfaces.

Transcriptomic analysis supports a role for the nervous system in regulating growth and development of Fasciola hepatica juveniles.

Fasciola spp. liver flukes have significant impacts in veterinary and human medicine. The absence of a vaccine and increasing anthelmintic resistance threaten sustainable control and underscore the need for novel flukicides.

Schistosoma mansoni alter transcription of immunomodulatory gene products following in vivo praziquantel exposure.

Control of the neglected tropical disease schistosomiasis relies almost entirely on praziquantel (PZQ) monotherapy. How PZQ clears parasite infections remains poorly understood. Many studies have examined the effects of PZQ on worms cultured in vitro, observing outcomes such as muscle contraction.

Molecular characterisation and vaccine efficacy of two novel developmentally regulated surface tegument proteins of Fasciola hepatica.

The surface tegument of Fasciola hepatica is a crucial tissue due to its key role at the host-parasite interface. We characterised three novel proteins, termed Fhteg1, Fhteg5 and Fhteg8, that are found in the tegument membrane fraction of adult F. hepatica.

RNA interference dynamics in juvenile Fasciola hepatica are altered during in vitro growth and development.

For over a decade RNA interference (RNAi) has been an important molecular tool for functional genomics studies in parasitic flatworms. Despite this, our understanding of RNAi dynamics in many flatworm parasites, such as the temperate liver fluke (Fasciola hepatica), remains rudimentary. The ability to maintain developing juvenile fluke in vitro provides the opportunity to perform functional studies during development of the key pathogenic life stage.

Non-sedating benzodiazepines cause paralysis and tissue damage in the parasitic blood fluke Schistosoma mansoni.

Parasitic flatworm infections (e.g. tapeworms and fluke worms) are treated by a limited number of drugs.

The anthelmintic drug praziquantel activates a schistosome transient receptor potential channel.

The anthelmintic drug praziquantel (PZQ) is used to treat schistosomiasis, a neglected tropical disease that affects over 200 million people worldwide. PZQ causes Ca influx and spastic paralysis of adult worms and rapid vacuolization of the worm surface. However, the mechanism of action of PZQ remains unknown even after 40 years of clinical use.

Anti-schistosomal action of the calcium channel agonist FPL-64176.

Subversion of parasite neuromuscular function is a key strategy for anthelmintic drug development. Schistosome Ca signaling has been an area of particular interest for decades, with a specific focus on L-type voltage-gated Ca channels (Cas). However, the study of these channels has been technically challenging.

Profiling G protein-coupled receptors of Fasciola hepatica identifies orphan rhodopsins unique to phylum Platyhelminthes.

G protein-coupled receptors (GPCRs) are established drug targets. Despite their considerable appeal as targets for next-generation anthelmintics, poor understanding of their diversity and function in parasitic helminths has thwarted progress towards GPCR-targeted anti-parasite drugs. This study facilitates GPCR research in the liver fluke, Fasciola hepatica, by generating the first profile of GPCRs from the F.

Reasons to Be Nervous about Flukicide Discovery.

The majority of anthelmintics dysregulate neuromuscular function, a fact most prominent for drugs against nematode parasites. In contrast to the strong knowledge base for nematode neurobiology, resource and tool deficits have prevented similar advances in flatworm parasites since those driven by bioimaging, immunocytochemistry, and neuropeptide biochemistry 20-30 years ago. However, recent developments are encouraging a renaissance in liver fluke neurobiology that can now support flukicide discovery.

Stimulating Neoblast-Like Cell Proliferation in Juvenile Fasciola hepatica Supports Growth and Progression towards the Adult Phenotype In Vitro.

Fascioliasis (or fasciolosis) is a socioeconomically important parasitic disease caused by liver flukes of the genus Fasciola. Flukicide resistance has exposed the need for new drugs and/or a vaccine for liver fluke control. A rapidly improving 'molecular toolbox' for liver fluke encompasses quality genomic/transcriptomic datasets and an RNA interference platform that facilitates functional genomics approaches to drug/vaccine target validation.

Calmodulin disruption impacts growth and motility in juvenile liver fluke.

Background: Deficiencies in effective flukicide options and growing issues with drug resistance make current strategies for liver fluke control unsustainable, thereby promoting the need to identify and validate new control targets in Fasciola spp. parasites. Calmodulins (CaMs) are small calcium-sensing proteins with ubiquitous expression in all eukaryotic organisms and generally use fluctuations in intracellular calcium levels to modulate cell signalling events.

RNAi dynamics in Juvenile Fasciola spp. Liver flukes reveals the persistence of gene silencing in vitro.

Background: Fasciola spp. liver fluke cause pernicious disease in humans and animals. Whilst current control is unsustainable due to anthelmintic resistance, gene silencing (RNA interference, RNAi) has the potential to contribute to functional validation of new therapeutic targets.

Malingering as a categorical or dimensional construct: the latent structure of feigned psychopathology as measured by the SIRS and MMPI-2.

The 6 nonoverlapping primary scales of the Structured Interview of Reported Symptoms (SIRS) were subjected to taxometric analysis in a group of 1,211 criminal and civil examinees in order to investigate the latent structure of feigned psychopathology. Both taxometric procedures used in this study, mean above minus below a cut (MAMBAC) and maximum covariance (MAXCOV), produced dimensional results. A subgroup of participants (n = 711) with valid Minnesota Multiphasic Personality Inventory-2 (MMPI-2) protocols were included in a second round of analyses in which the 6 nonoverlapping primary scales of the SIRS and the Infrequency (F), Infrequency-Psychopathology (Fp), and Dissimulation (Ds) scales of the MMPI-2 served as indicators.

Issues regarding the clinical use of the Classification of Violence Risk (COVR) assessment instrument.

The MacArthur Study of Mental Disorder and Violence produced an instrument for classifying hospitalized psychiatric patients according to their risk of behaving violently following discharge. The instrument, Classification of Violence Risk (COVR) has been computerized and is now commercially available to clinicians. A validation study performed by the original researchers showed that when the instrument was applied to a new sample of patients, it demonstrated a considerable reduction in positive predictive power.

Comparability of the MMPI-2 F(p) and F scales and the SIRS in clinical use with suspected malingerers.

Relationships among Structured Interview of Reported Symptoms (SIRS) scores and Minnesota Multiphasic Personality Inventory--2 (MMPI-2) F(p) and F scores were examined for 63 suspected malingerers evaluated at either of two psychiatric facilities. Despite differences between facilities in terms of seriousness of subjects' offenses, mean scores on the malingering tests were similar. Cutting scores for F(p) and F resulting in substantial correspondence between these scales and the SIRS were derived.