Multidisciplinary approach to assess the seasonal effect on redox processes occurring in a tropical alluvial aquifer

Iron, Manganese, alluvial aquifer, Hondura

Efficacy of APX2039 in a Rabbit Model of Cryptococcal Meningitis

Cryptococcal Meningitis (CM) is uniformly fatal if not treated, and treatment options are limited. We previously reported on the activity of APX2096, the prodrug of the novel Gwt1 inhibitor APX2039, in a mouse model of CM. Here, we investigated the efficacy of APX2039 in mouse and rabbit models of CM. In the mouse model, the controls had a mean lung fungal burden of 5.95 log10 CFU/g, whereas those in the fluconazole-, amphotericin B-, and APX2039-treated mice were 3.56, 4.59, and 1.50 log10 CFU/g, respectively. In the brain, the control mean fungal burden was 7.97 log10 CFU/g, while the burdens were 4.64, 7.16, and 1.44 log10 CFU/g for treatment with fluconazole, amphotericin B, and APX2039, respectively. In the rabbit model of CM, the oral administration of APX2039 at 50 mg/kg of body weight twice a day (BID) resulted in a rapid decrease in the cerebrospinal fluid (CSF) fungal burden, and the burden was below the limit of detection by day 10 postinfection. The effective fungicidal activity (EFA) was -0.66 log10 CFU/mL/day, decreasing from an average of 4.75 log10 CFU/mL to 0 CFU/mL, over 8 days of therapy, comparing favorably with good clinical outcomes in humans associated with reductions of the CSF fungal burden of -0.4 log10 CFU/mL/day, and, remarkably, 2-fold the EFA of amphotericin B deoxycholate in this model (-0.33 log10 CFU/mL/day). A total drug exposure of the area under the concentration-time curve from 0 to 24 h (AUC0-24) of 25 to 50 mg · h/L of APX2039 resulted in near-maximal antifungal activity. These data support the further preclinical and clinical evaluation of APX2039 as a new oral fungicidal monotherapy for the treatment of CM. IMPORTANCE Cryptococcal meningitis (CM) is a fungal disease with significant global morbidity and mortality. The gepix Gwt1 inhibitors are a new class of antifungal drugs. Here, we demonstrated the efficacy of APX2039, the second member of the gepix class, in rabbit and mouse models of cryptococcal meningitis. We also analyzed the drug levels in the blood and cerebrospinal fluid in the highly predictive rabbit model and built a mathematical model to describe the behavior of the drug with respect to the elimination of the fungal pathogen. We demonstrated that the oral administration of APX2039 resulted in a rapid decrease in the CSF fungal burden, with an effective fungicidal activity of -0.66 log10 CFU/mL/day, comparing favorably with good clinical outcomes in humans associated with reductions of -0.4 log10 CFU/mL/day. The drug APX2039 had good penetration of the central nervous system and is an excellent candidate for future clinical testing in humans for the treatment of CM

Ring maps applied to hydrogeological and environmental studies in alluvial aquifers, central Italy

<p>Analysis of hydrogeological data of aquifers requires assessment of multiple variables and this is difficult to visualise in a single map with commonly used techniques. Ring maps are presented in this paper as a useful option to overcome this limitation.</p> <p>Four alluvial aquifers from Central Italy were assessed and are presented as case studies, evaluating the hydrogeological setting, the groundwater chemistry and the distribution of representative contaminants (Boron, Iron, Manganese and Nitrates). The final result is a graphical representation showing the ring maps, which simultaneously depict 12 numerical variables and two other variables: the geographical position and the main lithological properties of the aquifers.</p> <p>The research indicates that coastal alluvial aquifers show higher contamination when compared to the intramontane alluvial aquifers. Boron is exclusively present in the coastal alluvial aquifers where maximum concentrations are associated with the uprising of deeper saline groundwater with a chloride-sodium chemistry. Iron and manganese are generally associated and their presence is inversely correlated to that of nitrates. The presence of Nitrates is less common in the intramontane aquifers.</p> <p>The ring maps presented in this paper have been effectively used as a geovisualisation tool for multivariate hydrogeological and environmental data. The technique simultaneously and clearly shows several variables in one single graphical representation.</p

Statistical and Fractal Approaches on Long Time-Series to Surface-Water/Groundwater Relationship Assessment: A Central Italy Alluvial Plain Case Study

In this research, univariate and bivariate statistical methods were applied to rainfall, river and piezometric level datasets belonging to 24-year time series (1986–2009). These methods, which often are used to understand the effects of precipitation on rivers and karstic springs discharge, have been used to assess piezometric level response to rainfall and river level fluctuations in a porous aquifer. A rain gauge, a river level gauge and three wells, located in Central Italy along the lower Pescara River valley in correspondence of its important alluvial aquifer, provided the data. Statistical analysis has been used within a known hydrogeological framework, which has been refined by mean of a photo-interpretation and a GPS survey. Water–groundwater relationships were identified following the autocorrelation and cross-correlation analyses. Spectral analysis and mono-fractal features of time series were assessed to provide information on multi-year variability, data distributions, their fractal dimension and the distribution return time within the historical time series. The statistical–mathematical results were interpreted through fieldwork that identified distinct groundwater flowpaths within the aquifer and enabled the implementation of a conceptual model, improving the knowledge on water resources management tools

Pharmacodynamics of ATI-2307 in a rabbit model of cryptococcal meningoencephalitis.

Cryptococcal meningoencephalitis (CM) is a devastating fungal disease with high morbidity and mortality. The current regimen that is standard-of-care involves a combination of three different drugs administered for up to one year. There is a critical need for new therapies due to both toxicity and inadequate fungicidal activity of the currently available antifungal drugs. ATI-2307 is a novel aryl amidine that disrupts the mitochondrial membrane potential and inhibits the respiratory chain complexes of fungi-it thus represents a new mechanism for direct antifungal action. Furthermore, ATI-2307 selectively targets fungal mitochondria via a fungal-specific transporter that is not present in mammalian cells. It has very potent in vitro anticryptococcal activity. In this study, the efficacy of ATI-2307 was tested in a rabbit model of CM. ATI-2307 demonstrated significant fungicidal activity at dosages between 1 and 2 mg/kg/d, and these results were superior to fluconazole and similar to amphotericin B treatment. When ATI-2307 was combined with fluconazole, the antifungal effect was greater than either therapy alone. While ATI-2307 has potent anticryptococcal activity in the subarachnoid space, its ability to reduce yeasts in the brain parenchyma was relatively less over the same study period. This new drug, with its unique mechanism of fungicidal action and ability to positively interact with an azole, has demonstrated sufficient anticryptococcal potential in this experimental setting to be further evaluated in clinical studies

Phosphorylated neurofilament heavy chain: A biomarker of survival for C9ORF72-associated amyotrophic lateral sclerosis

As potential treatments for C9ORF72-associated amyotrophic lateral sclerosis (c9ALS) approach clinical trials, the identification of prognostic biomarkers for c9ALS becomes a priority. We show that levels of phosphorylated neurofilament heavy chain (pNFH) in cerebrospinal fluid (CSF) predict disease status and survival in c9ALS patients, and are largely stable over time. Moreover, c9ALS patients exhibit higher pNFH levels, more rapid disease progression, and shorter survival after disease onset than ALS patients without C9ORF72 expansions. These data support the use of CSF pNFH as a prognostic biomarker for clinical trials, which will increase the likelihood of successfully developing a treatment for c9ALS. Ann Neurol 2017;82:139–146

Phosphorylated neurofilament heavy chain: A biomarker of survival for C9ORF72-associated amyotrophic lateral sclerosis

© 2017 The Authors Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association As potential treatments for C9ORF72-associated amyotrophic lateral sclerosis (c9ALS) approach clinical trials, the identification of prognostic biomarkers for c9ALS becomes a priority. We show that levels of phosphorylated neurofilament heavy chain (pNFH) in cerebrospinal fluid (CSF) predict disease status and survival in c9ALS patients, and are largely stable over time. Moreover, c9ALS patients exhibit higher pNFH levels, more rapid disease progression, and shorter survival after disease onset than ALS patients without C9ORF72 expansions. These data support the use of CSF pNFH as a prognostic biomarker for clinical trials, which will increase the likelihood of successfully developing a treatment for c9ALS. Ann Neurol 2017;82:139–146