Sub-cortical and brainstem sites associated with chemo-stimulated increases in ventilation in humans

We investigated the neural basis for spontaneous chemo-stimulated increases in ventilation in awake, healthy humans. Blood oxygen level dependent (BOLD) functional MRI was performed in nine healthy subjects using T2weighted echo planar imaging. Brain volumes (52 transverse slices, cortex to high spinal cord) were acquired every 3.9 s. The 30 min paradigm consisted of six, 5-min cycles, each cycle comprising 45 s of hypoxic-isocapnia, 45 s of isooxic-hypercapnia and 45 s of hypoxic-hypercapnia, with 55 s of non-stimulatory hyperoxic-isocapnia (control) separating each stimulus period. Ventilation was significantly (p < 0.001) increased during hypoxic-isocapnia, isooxic-hypercapnia and hypoxic-hypercapnia (17.0, 13.8, 24.9 L/min respectively) vs. control (8.4 L/min) and was associated with significant (p < 0.05, corrected for multiple comparisons) signal increases within a bilateral network that included the basal ganglia, thalamus, red nucleus, cerebellum, parietal cortex, cingulate and superior mid pons. The neuroanatomical structures identified provide evidence for the spontaneous control of breathing to be mediated by higher brain centres, as well as respiratory nuclei in the brainstem

Pediatric Emergency Care Capacity in a Low-Resource Setting: An assessment of district hospitals in Rwanda

BACKGROUND: Health system strengthening is crucial to improving infant and child health outcomes in low-resource countries. While the knowledge related to improving newborn and child survival has advanced remarkably over the past few decades, many healthcare systems in such settings remain unable to effectively deliver pediatric advance life support management. With the introduction of the Emergency Triage, Assessment and Treatment plus Admission care (ETAT+)-a locally adapted pediatric advanced life support management program-in Rwandan district hospitals, we undertook this study to assess the extent to which these hospitals are prepared to provide this pediatric advanced life support management. The results of the study will shed light on the resources and support that are currently available to implement ETAT+, which aims to improve care for severely ill infants and children. METHODS: A cross-sectional survey was undertaken in eight district hospitals across Rwanda focusing on the availability of physical and human resources, as well as hospital services organizations to provide emergency triage, assessment and treatment plus admission care for severely ill infants and children. RESULTS: Many of essential resources deemed necessary for the provision of emergency care for severely ill infants and children were readily available (e.g. drugs and laboratory services). However, only 4/8 hospitals had BVM for newborns; while nebulizer and MDI were not available in 2/8 hospitals. Only 3/8 hospitals had F-75 and ReSoMal. Moreover, there was no adequate triage system across any of the hospitals evaluated. Further, guidelines for neonatal resuscitation and management of malaria were available in 5/8 and in 7/8 hospitals, respectively; while those for child resuscitation and management of sepsis, pneumonia, dehydration and severe malnutrition were available in less than half of the hospitals evaluated. CONCLUSIONS: Our assessment provides evidence to inform new strategies to enhance the capacity of Rwandan district hospitals to provide pediatric advanced life support management. Identifying key gaps in the health care system is required in order to facilitate the implementation and scale up of ETAT+ in Rwanda. These findings also highlight a need to establish an outreach/mentoring program, embedded within the ongoing ETAT+ program, to promote cross-hospital learning exchanges

Increased Expression of Simple Ganglioside Species GM2 and GM3 Detected by MALDI Imaging Mass Spectrometry in a Combined Rat Model of A beta Toxicity and Stroke

The aging brain is often characterized by the presence of multiple comorbidities resulting in synergistic damaging effects in the brain as demonstrated through the interaction of Alzheimer\u27s disease (AD) and stroke. Gangliosides, a family of membrane lipids enriched in the central nervous system, may have a mechanistic role in mediating the brain\u27s response to injury as their expression is altered in a number of disease and injury states. Matrix-Assisted Laser Desorption Ionization (MALDI) Imaging Mass Spectrometry (IMS) was used to study the expression of A-series ganglioside species GD1a, GM1, GM2, and GM3 to determine alteration of their expression profiles in the presence of beta-amyloid (A beta) toxicity in addition to ischemic injury. To model a stroke, rats received a unilateral striatal injection of endothelin-1 (ET-1) (stroke alone group). To model A beta toxicity, rats received intracerebralventricular (icv) injections of the toxic 25-35 fragment of the A beta peptide (A beta alone group). To model the combination of A beta toxicity with stroke, rats received both the unilateral ET-1 injection and the bilateral icv injections of A beta(25-35) (combined A beta/ET-1 group). By 3 d, a significant increase in the simple ganglioside species GM2 was observed in the ischemic brain region of rats who received a stroke (ET-1), with or without A beta. By 21 d, GM2 levels only remained elevated in the combined A beta/ET-1 group. GM3 levels however demonstrated a different pattern of expression. By 3 d GM3 was elevated in the ischemic brain region only in the combined A beta/ET-1 group. By 21 d, GM3 was elevated in the ischemic brain region in both stroke alone and A beta/ET-1 groups. Overall, results indicate that the accumulation of simple ganglioside species GM2 and GM3 may be indicative of a mechanism of interaction between AD and stroke

Soil carbon fractions in response to mineral and organic fertilizer types and rates.

Abstract: The use of organic fertilizers from pig slurry and poultry litter can increase soil organic carbon and crop productivity. This study aimed to evaluate soil organic carbon fractions and corn yield after applying organic and mineral fertilizers. The experiment was conducted in the western region of Santa Catarina State, southern Brazil on a Nitossolo Vermelho Eutroférrico típico (Rhodic Kandiudox). The production system was an integrated crop-livestock using corn and soybean in the summer and black oat and rye with grazing by sheep in the winter. The experimental design was randomized blocks, with treatments in factorial 5 × 3 + 1, with four replications, five sources of fertilizers, three rates and the control with no fertilization. The treatments were three organic fertilizers: poultry litter, pig slurry and compost from pig slurry and two minerals fertilizer (M1 and M2). Mineral fertilizers were formulated from pig slurry (M1) and poultry litter (M2), with the application of three rates, which represent 75, 100 and 150 % of the recommendation for the crop, based on the element that is most demanding by the plant (K for soybeans and N for corn). Soil samples were collected at the layers of 0.00-0.05, 0.05-0.10 and 0.10-0.20 m in which fractions of total soil organic carbon (TOC), namely particulate (POC) and mineral-associated organic carbon (MAC) were determined. Corn yield was evaluated in the 2018/2019 and 2019/2020 seasons. The results were analyzed through analysis of variance to compare sources and polynomial regression analysis for fertilizer rates. The MAC fraction has a higher proportion of TOC and its contents were higher with increasing rates of organic and mineral fertilizers, mainly in the surface layer. Poultry litter and compost fertilizers increased TOC’s particulate fraction (POC), showing the highest levels at the highest fertilization recommendation rate. Organic and mineral fertilizers positively increase corn yield, and animal-derived fertilizers show that they can be an alternative for high crop yields

Immunoproteomics of Plasmodium falciparum-infected red blood cell membrane fractions

BACKGROUND The surface of infected red blood cells (iRBCs) has been widely investigated because of the molecular complexity and pathogenesis mechanisms involved. Asymptomatic individuals are important in the field because they can perpetuate transmission as natural reservoirs and present a challenge for diagnosing malaria because of their low levels of circulating parasites. Recent studies of iRBC antibody recognition have shown that responses are quantitatively similar in symptomatic and asymptomatic infections, but no studies have characterised the plasmodial proteins targeted by this response. OBJECTIVES Our main objective was to identify Plasmodium falciparum proteins associated with iRBC ghosts recognised by antibodies in the sera of symptomatic and asymptomatic individuals in the Brazilian Amazon. METHODS We collected symptomatic and asymptomatic sera from patients residing in the Brazilian Amazon and P. falciparum iRBC ghosts to identify the proteins involved in natural antibody recognition by 2D-electrophoresis, western blotting, and highresolution mass spectrometry. FINDINGS 2D gel-based immunoproteome analysis using symptomatic and asymptomatic sera identified 11 proteins with at least one unique peptide, such as chaperones HSP70-1 and HSP70-x, which likely are components of the secretion machinery/PTEX translocon. PfEMP1 is involved in antigenic variation in symptomatic infections and we found putative membrane proteins whose functions are unknown. MAIN FINDINGS Our results suggest a potential role of old and new proteins, such as antigenic variation proteins, iRBC remodelling, and membrane proteins, with no assigned functions related to the immune response against P. falciparum, providing insights into the pathogenesis, erythrocyte remodelling, and secretion machinery important for alternative diagnosis and/or malaria therapy.publishersversionpublishe

Epidemiological Pathology of Dementia: Attributable-Risks at Death in the Medical Research Council Cognitive Function and Ageing Study

Researchers from the Medical Research Council Cognitive Function and Ageing Neuropathology Study carry out an analysis of brain pathologies contributing to dementia, within a cohort of elderly individuals in the UK who agreed to brain donation

Cytoarchitectonic and chemoarchitectonic characterization of the prefrontal cortical areas in the mouse

This study describes cytoarchitectonic criteria to define the prefrontal cortical areas in the mouse brain (C57BL/6 strain). Currently, well-illustrated mouse brain stereotaxic atlases are available, which, however, do not provide a description of the distinctive cytoarchitectonic characteristics of individual prefrontal areas. Such a description is of importance for stereological, neuronal tracing, and physiological, molecular and neuroimaging studies in which a precise parcellation of the prefrontal cortex (PFC) is required. The present study describes and illustrates: the medial prefrontal areas, i.e., the infralimbic, prelimbic, dorsal and ventral anterior cingulate and Fr2 area; areas of the lateral PFC, i.e., the dorsal agranular insular cortical areas and areas of the ventral PFC, i.e., the lateral, ventrolateral, ventral and medial orbital areas. Each cytoarchitectonically defined boundary is corroborated by one or more chemoarchitectonic stainings, i.e., acetylcholine esterase, SMI32, SMI311, dopamine, parvalbumin, calbindin and myelin staining

Antileishmanial High-Throughput Drug Screening Reveals Drug Candidates with New Scaffolds

Drugs currently available for leishmaniasis treatment often show parasite resistance, highly toxic side effects and prohibitive costs commonly incompatible with patients from the tropical endemic countries. In this sense, there is an urgent need for new drugs as a treatment solution for this neglected disease. Here we show the development and implementation of an automated high-throughput viability screening assay for the discovery of new drugs against Leishmania. Assay validation was done with Leishmania promastigote forms, including the screening of 4,000 compounds with known pharmacological properties. In an attempt to find new compounds with leishmanicidal properties, 26,500 structurally diverse chemical compounds were screened. A cut-off of 70% growth inhibition in the primary screening led to the identification of 567 active compounds. Cellular toxicity and selectivity were responsible for the exclusion of 78% of the pre-selected compounds. The activity of the remaining 124 compounds was confirmed against the intramacrophagic amastigote form of the parasite. In vitro microsomal stability and cytochrome P450 (CYP) inhibition of the two most active compounds from this screening effort were assessed to obtain preliminary information on their metabolism in the host. The HTS approach employed here resulted in the discovery of two new antileishmanial compounds, bringing promising candidates to the leishmaniasis drug discovery pipeline

An Image-Based High-Content Screening Assay for Compounds Targeting Intracellular Leishmania donovani Amastigotes in Human Macrophages

Leishmaniasis is a tropical disease threatening 350 million people from endemic regions. The available drugs for treatment are inadequate, with limitations such as serious side effects, parasite resistance or high cost. Driven by this need for new drugs, we developed a high-content, high-throughput image-based screening assay targeting the intracellular amastigote stage of different species of Leishmania in infected human macrophages. The in vitro infection protocol was adapted to a 384-well-plate format, enabling acquisition of a large amount of readouts by automated confocal microscopy. The reading method was based on DNA staining and required the development of a customized algorithm to analyze the images, which enabled the use of non-modified parasites. The automated analysis generated parameters used to quantify compound activity, including infection ratio as well as the number of intracellular amastigote parasites and yielded cytotoxicity information based on the number of host cells. Comparison of this assay with one that used the promastigote form to screen 26,500 compounds showed that 50% of the hits selected against the intracellular amastigote were not selected in the promastigote screening. These data corroborate the idea that the intracellular amastigote form of the parasite is the most appropriate to be used in primary screening assay for Leishmania