Animal models for exploring Chagas disease pathogenesis and supporting drug discovery.

Infections with the parasitic protozoan cause Chagas disease, which results in serious cardiac and/or digestive pathology in 30%-40% of individuals. However, symptomatic disease can take decades to become apparent, and there is a broad spectrum of possible outcomes. The complex and long-term nature of this infection places a major constraint on the scope for experimental studies in humans.

A panel of phenotypically and genotypically diverse bioluminescent:fluorescent Trypanosoma cruzi strains as a resource for Chagas disease research.

Chagas disease is caused by Trypanosoma cruzi, a protozoan parasite that displays considerable genetic diversity. Infections result in a range of pathological outcomes, and different strains can exhibit a wide spectrum of anti-parasitic drug tolerance. The genetic determinants of infectivity, virulence and therapeutic susceptibility remain largely unknown.

Bis-6-amidino-benzothiazole Derivative that Cures Experimental Stage 1 African Trypanosomiasis with a Single Dose.

We designed and synthesized a series of symmetric bis-6-amidino-benzothiazole derivatives with aliphatic central units and evaluated their efficacy against bloodstream forms of the African trypanosome . Of these, a dicationic benzothiazole compound () exhibited sub-nanomolar in vitro potency with remarkable selectivity over mammalian cells (>26,000-fold). Unsubstituted 5-amidine groups and a cyclohexyl spacer were the crucial determinants of trypanocidal activity.

Dissecting the interstrand crosslink DNA repair system of Trypanosoma cruzi.

DNA interstrand crosslinks (ICLs) are toxic lesions that can block essential biological processes. Here we show Trypanosoma cruzi, the causative agent of Chagas disease, is susceptible to ICL-inducing compounds including mechlorethamine and novel nitroreductase-activated prodrugs that have potential in treating this infection. To resolve such lesions, cells co-opt enzymes from "classical" DNA repair pathways that alongside dedicated factors operate in replication-dependent and -independent mechanisms.

Impact of urban aerosols on the cloud condensation activity using a clustering model.

The indirect effect of aerosols on climate through aerosol-cloud-interactions is still highly uncertain and limits our ability to assess anthropogenic climate change. The foundation of this uncertainty is in the number of cloud condensation nuclei (CCN), which itself mainly stems from uncertainty in aerosol sources and how particles evolve to become effective CCN. We analyze particle number size distribution (PNSD) and CCN measurements from an urban site in a two-step method: (1) we use an unsupervised clustering model to classify the main aerosol categories and processes occurring in the urban atmosphere and (2) we explore the influence of the identified aerosol populations on the CCN properties.

Local association of Trypanosoma cruzi chronic infection foci and enteric neuropathic lesions at the tissue micro-domain scale.

Digestive Chagas disease (DCD) is an enteric neuropathy caused by Trypanosoma cruzi infection. The mechanism of pathogenesis is poorly understood and the lack of a robust, predictive animal model has held back research. We screened a series of mouse models using gastrointestinal tracer assays and in vivo infection imaging systems to discover a subset exhibiting chronic digestive transit dysfunction and significant retention of faeces in both sated and fasted conditions.

Image-Based In Vitro Screening Reveals the Trypanostatic Activity of Hydroxymethylnitrofurazone against .

Hydroxymethylnitrofurazone (NFOH) is a therapeutic candidate for Chagas disease (CD). It has negligible hepatotoxicity in a murine model compared to the front-line drug benznidazole (BZN). Here, using strains that express bioluminescent and/or fluorescent reporter proteins, we further investigated the in vitro and in vivo activity of NFOH to define whether the compound is trypanocidal or trypanostatic.

Antipsychotic Use and Bloodstream Infections Among Adult Patients With Chronic Obstructive Pulmonary Disease: A Cohort Study.

Objective: Mounting evidence suggests that antipsychotics may have immunomodulatory effects, but their impact on disseminated infections remains unknown. This study thus sought to estimate the effect of antipsychotic treatment on the occurrence of bloodstream infection during long-term follow-up in adult patients with chronic obstructive pulmonary disease.

Methods: This retrospective cohort study, with new user and active comparator design, included adult patients seen from January 2008 to June 2018 in a tertiary teaching hospital in Buenos Aires, Argentina.

Quantifying traffic, biomass burning and secondary source contributions to atmospheric particle number concentrations at urban and suburban sites.

In this study, we propose a new approach to determine the contributions of primary vehicle exhaust (N), primary biomass burning (N) and secondary (N) particles to mode segregated particle number concentrations. We used simultaneous measurements of aerosol size distribution in the 12-600 nm size range and black carbon (BC) concentration obtained during winter period at urban and suburban sites influenced by biomass burning (BB) emissions. As expected, larger aerosol number concentrations in the 12-25 and 25-100 nm size ranges are observed at the urban site compared to the suburban site.

amastigotes that persist in the colon during chronic stage murine infections have a reduced replication rate.

Chronic infections are typically lifelong, with small numbers of parasites surviving in restricted tissue sites, which include the gastrointestinal tract. There is considerable debate about the replicative status of these persistent parasites and whether there is a role for dormancy in long-term infection. Here, we investigated proliferation in the colon of chronically infected mice using 5-ethynyl-2'deoxyuridine incorporation into DNA to provide 'snapshots' of parasite replication status.

Bioluminescent:Fluorescent Trypanosoma cruzi Reporter Strains as Tools for Exploring Chagas Disease Pathogenesis and Drug Activity.

Chagas disease results from infection with the trypanosomatid parasite Trypanosoma cruzi. Progress in developing new drugs has been hampered by the long term and complex nature of the condition and by our limited understanding of parasite biology. Technical difficulties in assessing the parasite burden during the chronic stage of infection have also proven to be a particular challenge.

Activation properties of aerosol particles as cloud condensation nuclei at urban and high-altitude remote sites in southern Europe.

Understanding the activation properties of aerosol particles as cloud condensation nuclei (CCN) is important for the climate and hydrological cycle, but their properties are not fully understood. In this study, the CCN activation properties of aerosols are investigated at two different sites in southern Spain: an urban background station in Granada and a high altitude mountain station in the Sierra Nevada National Park, with a horizontal separation of 21 km and vertical separation of 1820 m. CCN activity at the urban environment is driven by primary sources, mainly road traffic.

Spectroelectrochemical Determination of Isoprenaline in a Pharmaceutical Sample.

UV/Vis absorption spectroelectrochemistry (SEC) is a multi-response technique that has been commonly used for the characterization of materials and the study of reaction mechanisms. However, it has been scarcely used for quantitative purposes. SEC allows us to obtain two analytical signals simultaneously, yielding a dual sensor in just one experiment.

Non-invasive monitoring of drug action: A new live in vitro assay design for Chagas' disease drug discovery.

New assay designs are needed to improve the predictive value of the Trypanosoma cruzi in vitro tests used as part of the Chagas' disease drug development pipeline. Here, we employed a green fluorescent protein (eGFP)-expressing parasite line and live high-content imaging to monitor the growth of T. cruzi amastigotes in mouse embryonic fibroblasts.

Best Practice Framework of Fracture Liaison Services in Spain and their coordination with Primary Care.

Unlabelled: The coordination of Fracture Liaison Services (FLS) with Primary Care (PC) is necessary for the continuity of care of patients with fragility fractures. This study proposes a Best Practice Framework (BPF) and performance indicators for the implementation and follow-up of FLS-PC coordination in clinical practice in Spain.

Purpose: To develop a BPF for the coordination of FLS with PC in Spain and to improve the continuity of care for patients with fragility fractures.

Derivative UV/Vis spectroelectrochemistry in a thin-layer regime: deconvolution and simultaneous quantification of ascorbic acid, dopamine and uric acid.

In this work, UV/Vis spectroelectrochemistry (SEC), in a thin-layer regime and parallel configuration, is selected to solve a complex mixture that contains dopamine (DA), ascorbic acid (AA) and uric acid (UA). These molecules, like many other biological compounds, are assuming a highly important place in analytical and biomedical fields due to the fundamental role that they play in human metabolism. In addition, low or high levels of these compounds are associated with diseases such as Parkinson's disease.

Drug-cured experimental Trypanosoma cruzi infections confer long-lasting and cross-strain protection.

Background: The long term and complex nature of Chagas disease in humans has restricted studies on vaccine feasibility. Animal models also have limitations due to technical difficulties in monitoring the extremely low parasite burden that is characteristic of chronic stage infections. Advances in imaging technology offer alternative approaches that circumvent these problems.

Intracellular DNA replication and differentiation of Trypanosoma cruzi is asynchronous within individual host cells in vivo at all stages of infection.

Investigations into intracellular replication and differentiation of Trypanosoma cruzi within the mammalian host have been restricted by limitations in our ability to detect parasitized cells throughout the course of infection. We have overcome this problem by generating genetically modified parasites that express a bioluminescent/fluorescent fusion protein. By combining in vivo imaging and confocal microscopy, this has enabled us to routinely visualise murine infections at the level of individual host cells.

Test-retest reliability of stride length-cadence gait relationship in Parkinson's disease.

Introduction: The gait pattern in Parkinson´s disease (PD) subjects is characterized by a specific deficit of the internal regulation of the stride length (SL), while the control of the cadence (Cad) remains intact. The purpose of the present study was to evaluate the reliability of the stride length-cadence relationship (SLCrel) in a group of PD subjects.

Methods: Thirty five PD subjects performed two sessions, separated by a three month resting period.

Dying in the Intensive Care Unit.

Objective: To document (using available data) the profile of the patients seen by the hospital's palliative service (PS) and who died in the medicine intensive care unit (ICU) of the Veterans Affairs Caribbean Healthcare System.

Methods: A record review of subjects who died in the ICU from January 1, 2012, to December 31, 2014. Demographic data, underlying comorbidities, the cause of death, the length of stay, evaluation made by the PS, and the withdrawal of life support (when such occurred) were recorded for each patient.

Exploiting Genetically Modified Dual-Reporter Strains to Monitor Experimental Trypanosoma cruzi Infections and Host-Parasite Interactions.

Trypanosoma cruzi is the causative agent of Chagas disease, the most important parasitic infection in Latin America. Despite a global research effort, there have been no significant treatment advances for at least 40 years. Gaps in our knowledge of T.