Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

SSVEP detection assessment by combining visual stimuli paradigms and no-training detection methods

IntroductionBrain-Computer Interfaces (BCI) based on Steady-State Visually Evoked Potentials (SSVEP) have great potential for use in communication applications because of their relatively simple assembly and in some cases the possibility of bypassing the time-consuming training stage. However, among multiple factors, the efficient performance of this technology is highly dependent on the stimulation paradigm applied in combination with the SSVEP detection algorithm employed. This paper proposes the performance assessment of the classification of target events with respect to non-target events by applying four types of visual paradigms, rectangular modulated On-Off (OOR), sinusoidal modulated On-Off (OOS), rectangular modulated Checkerboard (CBR), and sinusoidal modulated Checkerboard (CBS), with three types of SSVEP detection methods, Canonical Correlation Analysis (CCA), Filter-Bank CCA (FBCCA), and Minimum Energy Combination (MEC).MethodsWe set up an experimental protocol in which the four types of visual stimuli were presented randomly to twenty-seven participants and after acquiring their electroencephalographic responses to five stimulation frequencies (8.57, 10.909, 15, 20, and 24 Hz), the three detection methods were applied to the collected data.ResultsThe results are conclusive, obtaining the best performance with the combination of either OOR or OOS visual stimulus and the FBCCA as a detection method, however, this finding contrasts with the opinion of almost half of the participants in terms of visual comfort, where the 51.9% of the subjects felt more comfortable and focused with CBR or CBS stimulation.DiscussionFinally, the EEG recordings correspond to the SSVEP response of 27 subjects to four visual paradigms when selecting five items on a screen, which is useful in BCI navigation applications. The dataset is available to anyone interested in studying and evaluating signal processing and machine-learning algorithms for SSVEP-BCI systems

Repurposed Drugs That Activate Autophagy in Filarial Worms Act as Effective Macrofilaricides

Onchocerciasis and lymphatic filariasis are two neglected tropical diseases caused by filarial nematodes that utilize insect vectors for transmission to their human hosts. Current control strategies are based on annual or biannual mass drug administration (MDA) of the drugs Ivermectin or Ivermectin plus Albendazole, respectively. These drug regimens kill the first-stage larvae of filarial worms (i.e., microfilariae) and interrupt the transmission of infections. MDA programs for these microfilaricidal drugs must be given over the lifetime of the filarial adult worms, which can reach 15 years in the case of Onchocerca volvulus. This is problematic because of suboptimal responses to ivermectin in various endemic regions and inefficient reduction of transmission even after decades of MDA. There is an urgent need for the development of novel alternative treatments to support the 2030 elimination goals of onchocerciasis and lymphatic filariasis. One successful approach has been to target Wolbachia, obligatory endosymbiotic bacteria on which filarial worms are dependent for their survival and reproduction within the human host. A 4–6-week antibiotic therapy with doxycycline, for example, resulted in the loss of Wolbachia that subsequently led to extensive apoptosis of somatic cells, germline, embryos, and microfilariae, as well as inhibition of fourth-stage larval development. However, this long-course regimen has limited use in MDA programs. As an alternative approach to the use of bacteriostatic antibiotics, in this study, we focused on autophagy-inducing compounds, which we hypothesized could disturb various pathways involved in the interdependency between Wolbachia and filarial worms. We demonstrated that several such compounds, including Niclosamide, an FDA-approved drug, Niclosamide ethanolamine (NEN), and Rottlerin, a natural product derived from Kamala trees, significantly reduced the levels of Wolbachia in vitro. Moreover, when these compounds were used in vivo to treat Brugia pahangi-infected gerbils, Niclosamide and NEN significantly decreased adult worm survival, reduced the release of microfilariae, and decreased embryonic development depending on the regimen and dose used. All three drugs given orally significantly reduced Wolbachia loads and induced an increase in levels of lysosome-associated membrane protein in worms from treated animals, suggesting that Niclosamide, NEN, and Rottlerin were effective in causing drug-induced autophagy in these filarial worms. These repurposed drugs provide a new avenue for the clearance of adult worms in filarial infections

Ultrastructural Analysis of a Forming Embryonic Embodiment in the Adult Zebrafish Optic Tectum Surviving in Organotypic Culture

It has been shown that adult zebrafish are capable of regenerating regions of the central nervous system (CNS) after insult. Unlike in higher-order vertebrates where damage to the CNS leads to glial scar formation and permanent functional deficits, damage to the adult zebrafish CNS is transient and followed by nearly complete reconstitution of both function and anatomy. Our lab’s previous work has shown that explants of zebrafish optic tectum can survive in organotypic culture for up to 7 days, and that at 96 h in culture, regenerating cells of the tectum begin to form structures that resemble the embryonic neural tube seen in vertebrate development. The current project aims to elucidate the cellular and ultrastructural components of the formation of this neural tube-like structure using scanning and transmission electron microscopy. Our results show that after injury and cultivation for 96 h, the explants contained differentiating cells that were undergoing several cellular events, such as neovascularization, and rosette/cisternae formation, leading to the formation of a structure resembling the embryonic neural tube. Additionally, we demonstrate healthy cellular ultrastructures in both degenerated and regenerated areas of the explant

Farmacopea vegetal caribeña

En la presente edición, producto del trabajo colectivo del programa, han sido sometidos a la metodología de validación científica TRAMIL, 399 usos significativos de partes de 130 especies reportadas en 11.004 encuestas etnofarmacológicas, llevadas a cabo en 64 comunidades incluyendo la mayor parte de los países de la cuenca del Caribe. De los usos sometidos a validación, 393 han sido clasificados en la categoría REC y 6 en TOX. Además, se han realizado 529 ensayos de laboratorio: fitoquímicos (49), de actividad biológica (213) y evaluación de toxicidad (267). Más del 90% de estos ensayos se han realizado en laboratorios universitarios de los países participantes de la cuenca del Caribe. Los contenidos que se encuentran en esta Farmacopea están dirigidos fundamentalmente a personas involucradas en atención primaria de salud. La información que suministramos no debe ser utilizada, bajo ninguna circunstancia, como base para realizar diagnósticos médicos, procedimientos clínicos o quirúrgicos, ni análisis de laboratorio. Esta edición se imprime con el auspicio del Centro de Investigaciones científicas de Yucatan-México, la Universidad de Cartagena-Colombia y COLCIENCIAS-Colombia: Proyecto de Investigación No. 512-2012.Departamento Administrativo de Ciencia, Tecnología e Innovación [CO] Colciencias1107-569-33684Aislamiento y purificación de compuestos con potencial actividad antileishmanial a partir de Cordia dentada Poir. y Heliotropium indicum L.n

Assessing seed desiccation responses of native trees in the Caribbean

Native trees from the Caribbean were tested for seed desiccation responses, by adapting the “100-seed test” protocol. Ninety-seven seed lots of 91 species were collected in the Dominican Republic and tested for germination immediately after collecting, and after drying and moist storage. Seed desiccation sensitivity was assessed as a continuous variable (Viability Loss Index; VLI), based on seed germination values before and after drying. The results were compared with predictions of seed desiccation responses based on seed lot traits (initial moisture content and thousand-seed weight) and with those of published predictive models based on plant and seed traits. VLI could be calculated for seed lots of 40 species. 80% of these seed lots showed consistent results among experiments and predictive models. Issues on the set up of the experiments were discussed, as well as the species for which experimental results and predictions led to contrasting results. Overall, the “100-seed test” confirmed to be an effective tool for assessing seed desiccation responses of a diverse under-investigated woody flora, guiding the seed conservation of trees and their use in reforestation programmes. In addition, by providing new data, it might improve the performance of available predictive models

Discovery of New Broad-Spectrum Anti-Infectives for Eukaryotic Pathogens Using Bioorganometallic Chemistry.

Drug resistance observed with many anti-infectives clearly highlights the need for new broad-spectrum agents to treat especially neglected tropical diseases (NTDs) caused by eukaryotic parasitic pathogens, including fungal infections. Herein, we show that the simple modification of one of the most well-known antifungal drugs, fluconazole, with organometallic moieties not only improves the activity of the parent drug but also broadens the scope of application of the new derivatives. These compounds were highly effective in vivo against pathogenic fungal infections and potent against parasitic worms such as Brugia, which causes lymphatic filariasis and Trichuris, one of the soil-transmitted helminths that infects millions of people globally. Notably, the identified molecular targets indicate a mechanism of action that differs greatly from that of the parental antifungal drug, including targets involved in biosynthetic pathways that are absent in humans, offering great potential to expand our armamentarium against drug-resistant fungal infections and neglected tropical diseases (NTDs) targeted for elimination by 2030.</p

Discovery of new broad-spectrum anti-infectives for eukaryotic pathogens using bioorganometallic chemistry

Drug resistance observed with many anti-infectives clearly highlights the need for new broad-spectrum agents to treat especially neglected tropical diseases (NTDs)caused by eukaryotic parasitic pathogens, including fungal infections. Herein, we show that the simple modification of one of the most well-known antifungal drugs, fluconazole, with organometallic moieties not only improves the activity of the parent drug but also broadens the scope of application of the new derivatives. These compounds were highly effective in vivo against pathogenic fungal infections and potent against parasitic worms such as Brugia, which causes lymphatic filariasis and Trichuris, one of the soil-transmitted helminths that infects millions of people globally. Notably, the identified molecular targets indicate a mechanism of action that differs greatly from that of the parental antifungal drug, including targets involved in biosynthetic pathways that are absent in humans, offering great potential to expand our armamentarium against drug-resistant fungal infections and neglected tropical diseases (NTDs) targeted for elimination by 203