Development of mavoglurant and its potential for the treatment of fragile X syndrome.

Introduction: Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. With no curative treatment available, current therapeutic approaches are aimed at symptom management. FXS is caused by silencing the FMR1 gene, which encodes FMRP; as loss of FMRP leads to the development of symptoms associated with FXS. Areas covered: In this evaluation, the authors examine the role of the metabotropic glutamate receptor 5 (mGluR5) in the pathophysiology of FXS, and its suitability as a target for rescuing the disease state. Furthermore, the authors review the evidence from preclinical studies of pharmacological interventions targeting mGluR5 in FXS. Lastly, the authors assess the findings from clinical studies in FXS, in particular the use of the Aberrant Behavior Checklist-Community Edition (ABC-C) and the recently developed ABC-C for FXS scale, as clinical endpoints to assess disease modification in this patient population. Expert opinion: There is cautious optimism for the successful treatment of the core behavioral and cognitive symptoms of FXS based on preclinical data in animal models and early studies in humans. However, the association between mGluR5-heightened responsiveness and the clinical phenotype in humans remains to be demonstrated. Many questions regarding the optimal treatment and outcome measures of FXS remain unanswered.

Potential schistosome-vector snails and associated trematodes in ricefields of Corrients province, Argentina: preliminary results

Considering the possibility of introduction of schistosomiasis mansoni into Argentina as a consequence of dam construction on the Rio De La Plata basin, preliminary studies have been carried out on agrosystems such as ricefields in Corrientes province with the following purposes: 1) to survey and estimate the relative abundance of planorbids and identify potential vector species; 2) to identify environmental factors capable of influencing Biomphalaria population dynamics; and 3) to find out snail-parasite associations and estimate snail infection rates in order to detect possible competitive interactions between larval stages of native trematodes that could be used in biological control of Schistosoma mansoni. Three potential schistosome vectors were detected in ricefields, namely Biomphalaria straminea, B. tenagophila and B. peregrina, although B. orbignyi, a species refractory to infection with S. mansoni, proved the most frequent and abundant. Positive correlations (P<0.05) were found between Biomphalaria abundance and some environmental parameters: conductivity, hardness, calcium, nitrites plus nitrates, ammonium and bicarbonates. Water temperature correlation was negative (P<0.05). No correlation (P>0.05) was found in total iron, phosphates (SRP), pH and soil granulometry. Echinocercariae developed from rediae and belonging to Petasiger sp., Paryphostomum sp., and other undetermined species were found.

Pharmacokinetic drug interaction potential of risperidone with cytochrome p450 isozymes as assessed by the dextromethorphan, the caffeine, and the mephenytoin test.

Two published case reports showed that addition of risperidone (1 and 2 mg/d) to a clozapine treatment resulted in a strong increase of clozapine plasma levels. As clozapine is metabolized by cytochrome P450 isozymes, a study was initiated to assess the in vivo interaction potential of risperidone on various cytochrome P450 isozymes. Eight patients were phenotyped with dextromethorphan (CYP2D6), mephenytoin (CYP2C19), and caffeine (CYP1A2) before and after the introduction of risperidone. Before risperidone, all eight patients were phenotyped as being extensive metabolizers of CYP2D6 and CYP2C19. Risperidone at dosages between 2 and 6 mg/d does not appear to significantly inhibit CYP1A2 and CYP2C19 in vivo (median plasma paraxanthine/caffeine ratios before and after risperidone: 0.65, 0.69; p = 0.89; median urinary (S)/(R) mephenytoin ratios before and after risperidone:0.11, 0.12; p = 0.75). Although dextromethorphan metabolic ratio is significantly increased by risperidone (median urinary dextromethorphan/dextrorphan ratios before and after risperidone: 0.010, 0.018; p = 0.042), risperidone can be considered a weak in vivo CYP2D6 inhibitor, as this increase is modest and none of the eight patients was changed from an extensive to a poor metabolizer. The reported increase of clozapine concentrations by risperidone can therefore not be explained by an inhibition of CYP1A2, CYP2D6, CYP2C19 or by any combination of the three.

Separation of free amino acids in human plasma by capillary electrophoresis with laser induced fluorescence: potential for emergency diagnosis of inborn errors of metabolism.

Free amino acids (AAs) in human plasma are derivatized with 3-(4-carboxybenzoyl)quinoline-2-carboxaldehyde (CBQCA) and analyzed by capillary electrophoresis (CE) with laser induced fluorescence (LIF) detection. The labeling procedure is significantly improved over results reported previously. Derivatization can be completed in 40 min, with concentrations as low as 4 x 10(-8) M successfully labeled in favourable cases. Twenty-nine AAs (including 2 internal standards) are identified and can be reproducibly separated in 70 min. Migration time RSD values for 23 of these AAs were calculated and found in the range from 0.5 to 4%. The rapid derivatization procedure and the resolution obtained in the separation are sufficient for a semi-quantitative, emergency diagnosis of several inborn errors of metabolism (IEM). Amino acid profiles for both normal donor plasma samples and plasma samples of patients suffering from phenylketonuria, tyrosinemia, maple syrup urinary disease, hyperornithinemia, and citrullinemia are studied.

Potential sources of biodynamically active natural products in Brazil

In contrast to China where vegatation is predominantly herbaceous, vegetation in Brazil is commonly arboreous. This fact may explain why Chinese drugs are usually acetate derived, while actual and potential natural therapeutic agents from Brazil are mostly shikimate derived. Only relatively few compounds isolated from Brazilian plants have been submitted to adequate pharmacological testing

Siliceous deep-sea sponge Monorhaphis chuni: A potential paleoclimate archive in ancient animals

The deep-sea sponge Monorhaphis chuni forms giant basal spicules, which can reach lengths of 3 m; they represent the largest biogenic silica structures on Earth that is formed from an individual metazoan. The spicules offer a unique opportunity to record environmental change of past oceanic and climatic conditions. A giant spicule collected in the East China Sea in a depth of 1110 m was investigated. The oxygen isotopic composition and Mg/Ca ratios determined along center-to-surface segments are used as geochemical proxies for the assessment of seawater paleotemperatures. Calculations are based on the assumption that the calculated temperature near the surface of the spicule is identical with the average ambient temperature of 4 degrees C. A seawater temperature of 1.9 degrees C is inferred for the beginning of the lifespan of the Monorhaphis specimen. The temperature increases smoothly to 2.3 degrees C, to be followed by sharply increased and variable temperatures up to 6-10 degrees C. In the outer part of the spicule, the inferred seawater temperature is about 4 degrees C. The lifespan of the spicule can be estimated to 11,000 +/- 3000 years using the long-term trend of the inferred temperatures fitted to the seawater temperature age relationships since the Last Glacial Maximum. Specimens of Monorhaphis therefore represents one the oldest living animals on Earth. The remarkable temperature spikes of the ambient seawater occurring 9500-3100 years B.P. are explained by discharges of hydrothermal fluids in the neighborhood of the spicule. The irregular lamellar organization of the spicule and the elevated Mn concentrations during the high-temperature growth are consistent with a hydrothermal fluid input. (C) 2012 Elsevier B.V. All rights reserved.

Evaluation of acute administration of natural products with potential diuretic effects, in humans

In order to evaluate the potential diuretic effect of two natural products, Elephantopus scaber and Alpinia speciosa, a trial administration was carried out in ten healthy volunteers and the effects compared to the those of a placebo. The substances were given on different days, with a seven day interval between doses. The amount of substance administered to the subjects was five times the usual dose i.e. 7.5 g/100 ml and 0.8 g/100 ml respectively. The following parameters parameteres were measured: urinary and plasma sodium, potassium, uric acid, calcium, phosphate, urea, creatinine. The subjects were also examined clinically and total urinary volume was assessed. The only significant finding (p < 0.05) was a slight diuresis with Alpinia speciosa, which also lowered the diastolic (p < 0.05) and systolic (p < 0.01) blood pressures. No effect on electrolytes or renal function parameters was observed, and this probably excludes any renal tubular or glomerular effect from these substances.

Derivation of soil-specific streaming potential electrical parameters from hydrodynamic characteristics of partially saturated soils

Water movement in unsaturated soils gives rise to measurable electrical potential differences that are related to the flow direction and volumetric fluxes, as well as to the soil properties themselves. Laboratory and field data suggest that these so-called streaming potentials may be several orders of magnitudes larger than theoretical predictions that only consider the influence of the relative permeability and electrical conductivity on the self potential (SP) data. Recent work has improved predictions somewhat by considering how the volumetric excess charge in the pore space scales with the inverse of water saturation. We present a new theoretical approach that uses the flux-averaged excess charge, not the volumetric excess charge, to predict streaming potentials. We present relationships for how this effective excess charge varies with water saturation for typical soil properties using either the water retention or the relative permeability function. We find large differences between soil types and the predictions based on the relative permeability function display the best agreement with field data. The new relationships better explain laboratory data than previous work and allow us to predict the recorded magnitudes of the streaming potentials following a rainfall event in sandy loam, whereas previous models predict values that are three orders of magnitude too small. We suggest that the strong signals in unsaturated media can be used to gain information about fluxes (including very small ones related to film flow), but also to constrain the relative permeability function, the water retention curve, and the relative electrical conductivity function.

Oral insecticidal activity of root colonizing Pseudomonas fluorescens CHA0: a biocontrol agent with potential to control plant pests and diseases

The application of microbial biocontrol agents for the control of fungal plant diseases and plant insect pests is a promising approach in the development of environmentally benign pest management strategies. The ideal biocontrol organism would be a bacterium or a fungus with activity against both, insect pests and fungal pathogens. Here we demonstrate the oral insecticidal activity of the root colonizing Pseudomonas fluorescens CHA0, which is so far known for its capacity to efficiently suppress fungal plant pathogens. Feeding assays with CHA0-sprayed leaves showed that this strain displays oral insecticidal activity and is able to efficiently kill larvae of three important insect pests. We further show data indicating that the Fit insect toxin produced by CHA0 and also metabolites controlled by the global regulator GacA contribute to oral insect toxicity.

Comment on "Streaming potential dependence on water-content in Fontainebleau sand" by V. Allegre, L. Jouniaux, F. Lehmann and P. Sailhac

Allegre et al. recently presented new experimental data regarding the dependence of the streaming potential coupling coefficient with the saturation of the water phase. Such experiments are important to model the self-potential response associated with the flow of water in the vadose zone and the electroseismic/seismoelectric conversions in unsaturated porous media. However, the approach used to interpret the data is questionable and the conclusions reached by Allegre et al. likely incorrect

Efficacy of niclosamide as a potential antipenetrant (TAP) against cercariae of Schistosoma mansoni monkeys

A 1% (W/V) formulation of Niclosamide (2', 5-Dichloro-4-nitrosalicylanilide) (TAP) was tested on Cebus apella monkeys as a topical prophylatic against schistosomiasis mansoni. Two experiments were conducted using the same formulation. In the first experiment, the TAP provided complete protection against schistosomiasis for 3 days. Of the 4 monkeys treated with TAP 7 days before exposure to Schistosoma mansoni cercariae, 2 were completely protected. The remaining 2 monkeys of the 7 day treatment group had a 78% or greater reduction in adult worm buderns when compared to the placebo treated monkeys. The second experiment was designed determine the time between day 3 and 7 when the TAP no longer provided complete protection. However, all of the TAP treated monkeys in this experiment were completely protected, even the monkeys treated 7 days earlier. In both experiments, all monkeys used as infection controls and those receiving only the placebo became infected and showed typical experimental schistosomiasis. These results demonstrate that the TAP could provide fast acting, short-term protection to people who must enter cercariae infested water.

Peri-insular hemispherotomy: potential pitfalls and avoidance of complications.

Techniques for cerebral hemispherectomy have progressively evolved towards more disconnection and less excision over the last 50 years. Peri-insular hemispherotomy (PIH), as described by the senior author, has the maximal ratio of disconnection to excision among all procedures for hemispheric epilepsy. In this study, we focus on surgical complications and intraoperative anatomical observations during PIH over the last 10 years. Based on this experience, the procedure has undergone some modifications, which we detail herein.