Safety, Pharmacokinetics, and Pharmacodynamics of a First-in-Class ClC-1 Inhibitor to Enhance Muscle Excitability: Phase I Randomized Controlled Trial.

NMD670 is a first-in-class inhibitor of skeletal muscle-specific chloride channel ClC-1, developed to improve muscle weakness and fatigue in neuromuscular diseases. Preclinical studies show that ClC-1 inhibition enhances muscle excitability, improving muscle contractility and strength. We describe the first-in-human, randomized, double-blind, placebo-controlled study, which evaluated the safety, pharmacokinetics, and pharmacodynamics of single and multiple doses of NMD670 in healthy male and female subjects.

TMS and EEG Pharmacodynamic Effects of a Selective Sphingosine-1-Phosphate Subtype 1 Receptor Agonist on Cortical Excitability in Healthy Subjects.

Current anti-epileptic drugs lack efficacy, cause many side effects and one third of all patients are treatment-resistant. Drugs targeting the sphingosine-1-phosphate receptor show potential anti-convulsant effects in animal models and decrease cortical excitability in patients with multiple sclerosis, but available compounds alter lymphocyte trafficking and cause immunosuppression, limiting their clinical anti-epileptic potential. TRV045 is a selective sphingosine-1-phosphate subtype 1 receptor agonist without effects on lymphocyte trafficking, demonstrating efficacy in animal models of epilepsy, with the potential to target abnormal cortical excitability.

The ClC-1 chloride channel inhibitor NMD670 improves skeletal muscle function in rat models and patients with myasthenia gravis.

Myasthenia gravis (MG) is a neuromuscular disease that results in compromised transmission of electrical signals at the neuromuscular junction (NMJ) from motor neurons to skeletal muscle fibers. As a result, patients with MG have reduced skeletal muscle function and present with symptoms of severe muscle weakness and fatigue. ClC-1 is a skeletal muscle specific chloride (Cl) ion channel that plays important roles in regulating neuromuscular transmission and muscle fiber excitability during intense exercise.

Automated diagnosis of intestinal parasites: A new hybrid approach and its benefits.

Intestinal parasites are responsible for several diseases in human beings. In order to eliminate the error-prone visual analysis of optical microscopy slides, we have investigated automated, fast, and low-cost systems for the diagnosis of human intestinal parasites. In this work, we present a hybrid approach that combines the opinion of two decision-making systems with complementary properties: (DS) a simpler system based on very fast handcrafted image feature extraction and support vector machine classification and (DS) a more complex system based on a deep neural network, Vgg-16, for image feature extraction and classification.

Author Correction: Surveillance of vector-borne pathogens under imperfect detection: lessons from Chagas disease risk (mis)measurement.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

Synanthropic triatomines as potential vectors of Trypanosoma cruzi in Central Brazil.

Introduction: Chagas disease surveillance requires current knowledge on synanthropic triatomines. We analyzed the occurrence and Trypanosoma cruzi infection rates of triatomine bugs in central Brazil, during 2012-2014.

Methods: Triatomines were collected inside or around houses, and T.

Surveillance of vector-borne pathogens under imperfect detection: lessons from Chagas disease risk (mis)measurement.

Vector-borne pathogens threaten human health worldwide. Despite their critical role in disease prevention, routine surveillance systems often rely on low-complexity pathogen detection tests of uncertain accuracy. In Chagas disease surveillance, optical microscopy (OM) is routinely used for detecting Trypanosoma cruzi in its vectors.

Idiopathic delayed-onset edema surrounding deep brain stimulation leads: Insights from a case series and systematic literature review.

Introduction: Deep brain stimulation (DBS) is effective for some neurological and psychiatric conditions. Idiopathic delayed-onset edema (IDE) surrounding the leads has been anecdotally reported. The etiology, predisposing factors and prognosis of this complication are unknown.

Vector-borne transmission of Trypanosoma cruzi among captive Neotropical primates in a Brazilian zoo.

Background: Neotropical primates are important sylvatic hosts of Trypanosoma cruzi, the etiological agent of Chagas disease. Infection is often subclinical, but severe disease has been described in both free-ranging and captive primates. Panstrongylus megistus, a major T.

Influence of parameter values on the oscillation sensitivities of two p53-Mdm2 models.

Biomolecular networks that present oscillatory behavior are ubiquitous in nature. While some design principles for robust oscillations have been identified, it is not well understood how these oscillations are affected when the kinetic parameters are constantly changing or are not precisely known, as often occurs in cellular environments. Many models of diverse complexity level, for systems such as circadian rhythms, cell cycle or the p53 network, have been proposed.

Building a Synthetic Transcriptional Oscillator.

Reaction circuits mimicking genetic oscillators can be realized with synthetic, switchable DNA genes (so-called genelets), and two enzymes only, an RNA polymerase and a ribonuclease. The oscillatory behavior of the genelets is driven by the periodic production and degradation of RNA effector molecules. Here, we describe the preparation, assembly, and testing of a synthetic, transcriptional two-node negative-feedback oscillator, whose dynamics can be followed in real-time by fluorescence read-out.

Occurrence and characterization of Acanthamoeba similar to genotypes T4, T5, and T2/T6 isolated from environmental sources in Brasília, Federal District, Brazil.

Species of Acanthamoeba can cause keratitis and brain infections. The characterization of environmental isolates is necessary to analyze the risk of human infection. We aimed at identifying and genotyping Acanthamoeba isolates from soil, swimming pools, and water features in Brasília, Federal District, Brazil, as well as determining their physiological characteristics and pathogenic potential.

Infestation of Mauritia flexuosa palms by triatomines (Hemiptera: Reduviidae), vectors of Trypanosoma cruzi and Trypanosoma rangeli in the Brazilian savanna.

To determine the infestation and trypanosome infection of triatomines captured in Mauritia flexuosa palm trees across its geographic distribution in the Brazilian savanna (Cerrado), we sampled 42 localities in eight states and in the Federal District, Brazil, between July 2005 and January 2010. Overall, 2154 specimens of the species Rhodnius neglectus, Psammolestes tertius, Triatoma sordida, and Microtriatoma borbai, were collected. Among the 341 palms sampled, 182 (53.

[Comparative biology and feeding behavior of Rhodnius neglectus and Rhodnius robustus (Triatominae) under laboratory conditions].

Introduction: The vector competence of triatomine insects is determined by studying their biology and feeding behavior under field and/or laboratory conditions. Factors including the number of bites, the amount of blood ingested and defecation time have implications for trypanosome transmission. The biological and behavioral parameters of Rhodnius neglectus and R.

Trypanosoma cruzi I genotypes in different geographical regions and transmission cycles based on a microsatellite motif of the intergenic spacer of spliced-leader genes.

The intergenic region of spliced-leader (SL-IR) genes from 105 Trypanosoma cruzi I (Tc I) infected biological samples, culture isolates and stocks from 11 endemic countries, from Argentina to the USA were characterised, allowing identification of 76 genotypes with 54 polymorphic sites from 123 aligned sequences. On the basis of the microsatellite motif proposed by Herrera et al. (2007) to define four haplotypes in Colombia, we could classify these genotypes into four distinct Tc I SL-IR groups, three corresponding to the former haplotypes Ia (11 genotypes), Ib (11 genotypes) and Id (35 genotypes); and one novel group, Ie (19 genotypes).

Predicting the potential geographical distribution of Rhodnius neglectus (Hemiptera, Reduviidae) based on ecological niche modeling.

Rhodnius neglectus is frequently found in palm trees and bird nests in sylvatic environments. However, adult specimens infected by Trypanosoma cruzi have been invading houses in central Brazil. Analyzing and predicting the geographical distribution of this species may improve vector surveillance strategies for Chagas disease.

Arthropods associated with the crown of Mauritia flexuosa (Arecaceae) palm trees in three different environments from Brazilian Cerrado.

Canopy arthropods, mainly from palm trees, are little known in the Brazilian Cerrado. In order to describe the arthropod community structure associated with the crown of Mauritia flexuosa (Arecaceae), we sampled 150 palm trees in six "veredas" of the Federal District, Brazil, in wild, rural and periurban areas in the rainy season. The arthropods within abandoned bird nests, mammal refuges, leaves and organic matter were manually collected, preserved in ethanol 70% and separated by order, family, morphospecies and feeding guilds.

Is Rhodnius prolixus (Triatominae) invading houses in central Brazil?

Sylvatic triatomines of the genus Rhodnius commonly fly into houses in Latin America, maintaining the risk of Chagas disease transmission in spite of control efforts. In the recent past, adult bugs collected inside houses in central Brazil were identified as R. prolixus, a primary disease vector whose natural geographical range excludes this region.

[Intra-domiciliary capture of Panstrongylus rufotuberculatus (Champion, 1899) (Hemiptera, Reduviidae, Triatominae) in Piura, Peru].

Panstrongylus rufotuberculatus is widely distributed in Central and South America. In Peru, it has been found in Tumbes, Piura, and Cuzco. The authors report the presence of P.

Molecular characterisation of Trypanosoma rangeli strains isolated from Rhodnius ecuadoriensis in Peru, R. colombiensis in Colombia and R. pallescens in Panama, supports a co-evolutionary association between parasites and vectors.

We present data on the molecular characterisation of strains of Trypanosoma rangeli isolated from naturally infected Rhodnius ecuadoriensis in Peru, from Rhodnius colombiensis, Rhodnius pallescens and Rhodnius prolixus in Colombia, and from Rhodnius pallescens in Panama. Strain characterisation involved a duplex PCR with S35/S36/KP1L primers. Mini-exon gene analysis was also carried out using TrINT-1/TrINT-2 oligonucleotides.

Sampling Rhodnius neglectus in Mauritia flexuosa palm trees: a field study in the Brazilian savanna.

Two sampling methods (manual capture and live-baited adhesive traps) were compared for collecting the bug Rhodnius neglectus Lent (Hemiptera: Reduviidae: Triatominae) from palm trees, Mauritia flexuosa L. (Arecaceae), in the savanna of Brasília DF. R.

The triatomines of northern Peru, with emphasis on the ecology and infection by trypanosomes of Rhodnius ecuadoriensis (Triatominae).

Information on the distribution and synanthropic behaviour of triatomines is essential for Chagas disease vector control. This work summarises such information from northern Peru, and presents new data on Rhodnius ecuadoriensis - an important local vector infesting 10-35% of dwellings in some zones. Three species are strongly synanthropic and may be suitable targets for chemical control of domestic/peridomestic bug populations.

Biogeography of Triatominae (Hemiptera: Reduviidae) in Ecuador: implications for the design of control strategies.

Chagas disease control strategies strongly depend on the triatomine vector species involved in Trypanosoma cruzi transmission within each area. Here we report the results of the identification of specimens belonging to various species of Triatominae captured in Ecuador (15 species from 17 provinces) and deposited in the entomological collections of the Catholic University of Ecuador (Quito), Instituto Oswaldo Cruz (Brazil), the Natural History Museum London (UK), the London School of Hygiene and Tropical Medicine (UK), the National Institute of Hygiene (Quito), and the Vozandes Hospital (Quito). A critical review of published information and new field records are presented.

Clinical observations of unresponsive mucosal leishmaniasis.

We report the long-term clinical follow-up of two patients with unresponsive mucosal leishmaniasis due to Leishmania (Viannia) braziliensis from the Três Braços area in Bahia State, Brazil. Both were agricultural male workers with extensive upper respiratory mucosal involvement that was not cured with conventional and experimental therapy.

Human cutaneous leishmaniasis caused by Leishmania (Viannia) braziliensis in Santiago del Estero, Argentina: identification of parasites by monoclonal antibodies and isoenzymes.

Diagnostic and parasite characterization and identification studies were carried out in human patients with cutaneous leishmaniasis lesions in Santiago del Estero, Northern Province of Argentina. Diagnostic procedures were biopsies of lesions for smears and inoculations in hamster, needle aspirations of material from ulcers for "in vitro" cultures. Immunodiagnostic techniques applied were IFAT-IgG and Montenegro skin test.