The burden of congenital Chagas disease and implementation of molecular diagnostic tools in Latin America

It is estimated that between 8000 and 15 000 Trypanosoma cruzi infected babies are born every year to infected mothers in Chagas disease endemic countries. Currently, poor access to and performance of the current diagnostic algorithm, based on microscopy at birth and serology at 8-12 months after delivery, is one of the barriers to congenital Chagas disease (CCD) control. Detection of parasite DNA using molecular diagnostic tools could be an alternative or complement to current diagnostic methods, but its implementation in endemic regions remains limited. Prompt diagnosis and treatment of CCD cases would have a positive clinical and epidemiological impact. In this paper, we analysed the burden of CCD in Latin America, and the potential use of molecular tests to improve access to early diagnosis and treatment of T. cruzi infected newborns.Fil: Picado, Albert. Foundation for Innovative New Diagnostics; SuizaFil: Cruz, Israel. Foundation for Innovative New Diagnostics; SuizaFil: Redard Jacot, Maël. Foundation for Innovative New Diagnostics; SuizaFil: Schijman, Alejandro Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Torrico, Faustino. Universidad Mayor de San Simón; Bolivia. Fundación CEADES; BoliviaFil: Sosa-Estani, Sergio Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Epidemiología y Salud Pública. Instituto de Efectividad Clínica y Sanitaria. Centro de Investigaciones en Epidemiología y Salud Pública; Argentina. Drugs for Neglected Diseases initiative; BrasilFil: Katz, Zachary. Foundation for Innovative New Diagnostics; SuizaFil: Ndung'u, Joseph Mathu. Foundation for Innovative New Diagnostics; Suiz

Electronic clinical decision support algorithms incorporating point-of-care diagnostic tests in low-resource settings: a target product profile

Health workers in low-resource settings often lack the support and tools to follow evidence-based clinical recommendations for diagnosing, treating and managing sick patients. Digital technologies, by combining patient health information and point-of-care diagnostics with evidence-based clinical protocols, can help improve the quality of care and the rational use of resources, and save patient lives. A growing number of electronic clinical decision support algorithms (CDSAs) on mobile devices are being developed and piloted without evidence of safety or impact. Here, we present a target product profile (TPP) for CDSAs aimed at guiding preventive or curative consultations in low-resource settings. This document will help align developer and implementer processes and product specifications with the needs of end users, in terms of quality, safety, performance and operational functionality. To identify the characteristics of CDSAs, a multidisciplinary group of experts (academia, industry and policy makers) with expertise in diagnostic and CDSA development and implementation in low-income and middle-income countries were convened to discuss a draft TPP. The TPP was finalised through a Delphi process to facilitate consensus building. An agreement greater than 75% was reached for all 40 TPP characteristics. In general, experts were in overwhelming agreement that, given that CDSAs provide patient management recommendations, the underlying clinical algorithms should be human-interpretable and evidence-based. Whenever possible, the algorithm's patient management output should take into account pretest disease probabilities and likelihood ratios of clinical and diagnostic predictors. In addition, validation processes should at a minimum show that CDSAs are implementing faithfully the evidence they are based on, and ideally the impact on patient health outcomes. In terms of operational needs, CDSAs should be designed to fit within clinic workflows and function in connectivity-challenged and high-volume settings. Data collected through the tool should conform to local patient privacy regulations and international data standards

Quantifying protein-mRNA interactions in single live cells.

ZBP1 interaction with b-actin mRNA was enhanced perinuclearly in neurons compared to fibroblasts. Cytoplasmic ZBP1 and ribosome binding to the mRNA were anti-correlated depending on their location in the cell. These measurements support a mechanism whereby ZBP1 inhibits translation of localizing mRNA until its release from the mRNA peripherally, allowing ribosome binding

Energy Dose-Response in Selective Laser Trabeculoplasty: A Review

PRCIS: A literature review of SLT energy dose response found no definitive relationship between IOP reduction with respect to total or pulse energy, race, pigmentation, or application pattern. PURPOSE: Selective laser trabeculoplasty (SLT) is a safe and effective treatment for lowering intraocular pressure (IOP). While evidence is mounting for the advantage of its use as a first-line treatment for IOP reduction, the SLT procedures in use vary widely. The purpose of this literature review was to investigate if there were any relationships between SLT energy and efficacy for lowering IOP in the published literature. METHODS: A literature review was undertaken that included studies in which energy levels required for successful SLT treatment were investigated: in general, with respect to angle pigmentation, race or ethnicity, and treatment arc extent. RESULTS: There was no indication that higher (or lower) energy used in the treatment leads to greater (or less) IOP reduction. Similar results were obtained regarding level of trabecular meshwork (TM) pigmentation. Race was not found to be associated with altered dose response in SLT. There were indications that treating the full 360 degrees, as opposed to smaller arcs, could be beneficial for more IOP reduction. IOP reduction from SLT was found to be similar to that provided by topical medications. CONCLUSIONS: The optimal energy level of SLT needed for IOP reduction has not yet been definitively established, with all reported pulse energies resulting in similar IOP reduction. Furthermore, similar lack of conclusive findings exists regarding optimal SLT energy dosage for use in different races and degrees of TM pigmentation. This parameter, as well as each of the above-mentioned factors, requires further research

A Proposal for the Use of a Fixed Low-Energy Selective Laser Trabeculoplasty for Open Angle Glaucoma

Selective laser trabeculoplasty (SLT) has been in routine clinical use for over 20 years with millions of patients successfully treated and a low rate of clinically significant complications. The procedure requires the clinician to manually position the laser beam on the trabecular meshwork using a gonioscopy lens and to titrate the SLT laser energy based on the amount of pigmentation in the angle, as well as the observation of small bubbles produced by the laser effect. We propose that SLT energy titration is unnecessary either to achieve intraocular pressure (IOP) reduction or to minimize potential side effects. Ample evidence to support our proposal includes multiple clinical reports demonstrating comparable levels of IOP reduction resulting from different laser energies, a large variety of energy and other laser parameters used in commercially available SLT lasers, and the nature of the laser-induced changes in the trabecular meshwork tissue with respect to energy. Despite these variations in laser parameters, SLT consistently reduces IOP with a low complication rate. We propose that using low fixed energy for all patients will effectively and safely lower patients' IOP while reducing the complexity of the SLT procedure, potentially making SLT accessible to more patients

Transmission and Pathogenesis of Swine-Origin 2009 A(H1N1) Influenza Viruses in Ferrets and Mice

available in PMC 2010 October 12Recent reports of mild to severe influenza-like illness in humans caused by a novel swine-origin 2009 A(H1N1) influenza virus underscore the need to better understand the pathogenesis and transmission of these viruses in mammals. In this study, selected 2009 A(H1N1) influenza isolates were assessed for their ability to cause disease in mice and ferrets and compared with a contemporary seasonal H1N1 virus for their ability to transmit to naïve ferrets through respiratory droplets. In contrast to seasonal influenza H1N1 virus, 2009 A(H1N1) influenza viruses caused increased morbidity, replicated to higher titers in lung tissue, and were recovered from the intestinal tract of intranasally inoculated ferrets. The 2009 A(H1N1) influenza viruses exhibited less efficient respiratory droplet transmission in ferrets in comparison with the highly transmissible phenotype of a seasonal H1N1 virus. Transmission of the 2009 A(H1N1) influenza viruses was further corroborated by characterizing the binding specificity of the viral hemagglutinin to the sialylated glycan receptors (in the human host) by use of dose-dependent direct receptor-binding and human lung tissue–binding assays

Mechanisms of amphetamine action illuminated through optical monitoring of dopamine synaptic vesicles in Drosophila brain

Amphetamines elevate extracellular dopamine, but the underlying mechanisms remain uncertain. Here we show in rodents that acute pharmacological inhibition of the vesicular monoamine transporter (VMAT) blocks amphetamine-induced locomotion and self-administration without impacting cocaine-induced behaviours. To study VMAT’s role in mediating amphetamine action in dopamine neurons, we have used novel genetic, pharmacological and optical approaches in Drosophila melanogaster. In an ex vivo whole-brain preparation, fluorescent reporters of vesicular cargo and of vesicular pH reveal that amphetamine redistributes vesicle contents and diminishes the vesicle pH-gradient responsible for dopamine uptake and retention. This amphetamine-induced deacidification requires VMAT function and results from net H+ antiport by VMAT out of the vesicle lumen coupled to inward amphetamine transport. Amphetamine-induced vesicle deacidification also requires functional dopamine transporter (DAT) at the plasma membrane. Thus, we find that at pharmacologically relevant concentrations, amphetamines must be actively transported by DAT and VMAT in tandem to produce psychostimulant effects

Regulation of local expression of cell adhesion and motility-related mRNAs in breast cancer cells by IMP1/ ZBP1

Summary Metastasis involves tumor cell detachment from the primary tumor, and acquisition of migratory and invasive capabilities. These capabilities are mediated by multiple events, including loss of cell-cell contact, an increase in focal adhesion turnover and failure to maintain a normal cell polarity. We have previously reported that silencing of the expression of the zipcode-binding protein IMP1/ZBP1 in breast tumor patients is associated with metastasis. IMP1/ZBP1 selectively binds to a group of mRNAs that encode important mediators for cell adhesion and motility. Here, we show that in both T47D and MDA231 human breast carcinoma cells IMP1/ZBP1 functions to suppress cell invasion. Binding of ZBP1 to the mRNAs encoding E-cadherin, b-actin, a-actinin and the Arp2/3 complex facilitates localization of the mRNAs, which stabilizes cell-cell connections and focal adhesions. Our studies suggest a novel mechanism through which IMP1/ZBP1 simultaneously regulates the local expression of many cell-motility-related mRNAs to maintain cell adherence and polarity, decrease focal adhesion turnover and maintain a persistent and directional motility