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Paediatric sepsis remains an important cause of morbidity and mortality in children. This review will summarize the main aspects of the definition, current evidence-base for interventions and suggest possible areas of improvement. Controversy remains regarding accurate definitions for paediatric sepsis, resuscitation fluid volume and type, choice of vasoactive agents for use in resuscitation and antibiotic choices. Many adjunctive therapies have been suggested with theoretical benefit, although few have proven beneficial. Definitive recommendations are not yet supported by data. We describe best practice recommendations based on international guidelines, a review of primary literature, and a discussion of ongoing clinical trials and the nuances of therapeutic choices. Early diagnosis and aggressive intervention with timely antibiotics, fluid resuscitation and vasoactive medications are the most important interventions in to improve outcomes. The implementation of protocols, resource-adjusted sepsis bundles and advanced technologies will impact on reducing sepsis mortality. [ABSTRACT FROM AUTHOR]

Highlights: [•] We studied the effect of pentamidine against Trypanosoma cruzi both in vitro and in vivo. [•] Pentamidine decreases the viability of isolated trypomastigotes of T. cruzi. [•] Pentamidine decreases the parasite burden in T. cruzi-infected cells. [•] Pentamidine improves the disease outcome in T. cruzi-infected mice. [•] Pentamidine inhibits the polyamine transport in isolated parasites. [Copyright &y& Elsevier]

Abstract: Nucleoside diphosphate kinases (NDPKs) are enzymes required to preserve the intracellular nucleoside phosphate equilibrium. Trypanosoma cruzi has four putative nucleoside diphosphate kinases with unidentified biological roles and subcellular localization. TcNDPK2 has an N-terminal domain (DM10) with unknown function, which defines a subgroup of NDPKs distributed in a wide variety of organisms. Digitonin extraction demonstrated that this isoform is distributed in detergent soluble and insoluble fractions. Fluorescence microscopy showed that TcNDPK2 alone or fused to GFP was localized in cytoskeleton and flagella. TcNDPK2 was also detected by Western blot in purified polymerized tubulin and flagellar samples. In parasites expressing DM10 fused with GFP, the fluorescence was localized in cytoskeleton and flagellum with an identical pattern to TcNDPK2. This constitutes the first report that could give insights on the role of DM10 domains in NDPKs and also the identification of the first T. cruzi peptide that contains a microtubule association domain. [Copyright &y& Elsevier]

Abstract: Adenylate kinases supply energy routes in cellular energetic homeostasis. In this work, we identified and characterized the adenylate kinase activity in extracts from the flagellated parasite Trypanosoma cruzi, the causative agent of Chagas'' disease. Adenylate kinase activity was detected in different subcellular fractions and the cytosolic isoform was biochemically characterized. Cytosolic adenylate kinase specific activity increases continuously during the epimastigote growth and is down-regulated when other soluble phosphotransferase, arginine kinase, is overexpressed. Six different genes of adenylate kinase isoforms were identified and the mRNA expression was confirmed by RT-PCR and Northern Blot. Three open reading frames coding for different enzyme isoforms named TzADK1, TzADK2 and TzADK5 were cloned and functionally expressed in E. coli. This work reports an unusually large number of genes of adenylate kinases and suggests a coordinated regulation of phosphotransferase-mediated ATP regenerating pathways in the unicellular parasite Trypanosoma cruzi. [Copyright &y& Elsevier]

• A DPSIR analysis is presented on the topic of microplastics pollution. • EU regulatory and policy instruments concerning microplastics are identified. • Current and developing upstream and downstream responses are reviewed. This review organizes key information about microplastic pollution through a DPSIR (driving forces, pressures, states, impacts and responses) analysis, namely the current knowledge on the sources of microplastics in the environment, the abundance, mobility and fate of microplastics distributed across the different environmental compartments, as well as their socio-economic and environmental impacts. The available or developing upstream and downstream responses to the microplastic pollution are also reviewed as part of the DPSIR analysis. These include the regulatory and policy instruments, environmental education campaigns, product design, the development of biodegradable plastics, environmental cleanups, waste management, drinking water and wastewater treatment plants, and other treatment technologies and processes. Whenever possible, the current trends and discerning gaps in the research conducted so far by the scientific community are identified, giving some clues to what is going to be the future research on this topic and into new lines of research. [ABSTRACT FROM AUTHOR]

Polyamines play critical roles as regulators of cell growth and differentiation. In contrast with other protozoa, the human parasite Trypanosoma cruzi , the etiological agent of Chagas disease, is auxotrophic for polyamines. Therefore, their intracellular availability depends exclusively on polyamine transport and inhibition of these uptake processes can alter the viability of the parasite. The polyamine analogues used in this work were successfully tested as antiproliferative agents in cancer cells, bacteria, fungi and also showed a potent antiplasmodial effect. We evaluated the activity of these compounds on polyamine transport in T. cruzi and assessed the effects on parasite viability. Three polyamine derivatives, AMXT1501, Ant4 and Ant44, inhibited the putrescine transport in epimastigotes (the insect stage of T. cruzi ) with calculated IC 50 values of 2.43, 5.02 and 3.98 μM, respectively. In addition, only Ant4 and Ant44 inhibited spermidine transport with IC 50 of 8.78 μM and 13.34 μM, respectively. The Ant4 analogue showed a high trypanocidal effect on trypomastigotes (the bloodstream stage of T. cruzi ) with an IC 50 of 460 nM, (SI = 12.7) while in epimastigotes the IC 50 was significantly higher (16.97 μM). In addition, we studied the effect of the combination of benznidazole, a drug used in treating Chagas disease, with Ant4 on the viability of epimastigotes. The combined treatment produced a significant increase on the inhibition of parasites growth compared with individual treatments. In summary, these results suggest that Ant4, a putrescine conjugate, is a promising compound for the treatment of Chagas disease because it showed a potent trypanocidal effect via its inhibition of polyamine import. [ABSTRACT FROM AUTHOR]

Belief in a Just World research found evidence that one feels threatened whenever one witnesses an innocent victim suffering, often resorting to secondary victimization to neutralize the observed injustice. However, literature has neglected the explanatory power of adolescent deviant behavior in victimization processes. This study (n = 284 students) aims to determine the impact of the adolescents' deviant behavior, BJW and victim's innocence on secondary victimization. Additionally, we analyzed juvenile deviant behavior's impact on victim identification. Juveniles who committed more deviant behaviors identified less with the victim than those with lower deviance levels. The interaction effects show that juveniles who are strong just world believers and have higher delinquency engaged significantly more in secondary victimization when confronted with an innocent victim. These results clarify the role played by adolescent deviant behavior and BJW in secondary victimization judgments regarding situations with innocent and non-innocent victims. [ABSTRACT FROM AUTHOR]

Abstract: Phytomonas are trypanosomatid plant parasites closely related to parasites that cause several human diseases. Little is known about the biology of these organisms including aspects of their metabolism. Arginine kinase (E.C. 2.7.3.3) is a phosphotransferase which catalyzes the interconversion between the phosphagen phosphoarginine and ATP. This enzyme is present in some invertebrates and is a homolog of another widely distributed phosphosphagen kinase, creatine kinase. In this work, a single canonical arginine kinase isoform was detected in Phytomonas Jma by enzymatic activity assays, PCR, and Western Blot. This arginine kinase is very similar to the canonical isoforms found in T. cruzi and T. brucei, presenting about 70% of amino acid sequence identity and a very similar molecular weight (40kDa). The Phytomonas phosphagen system seems to be very similar to T. cruzi, which has only one isoform, or T. brucei (three isoforms); establishing a difference with other trypanosomatids, such as Leishmania, which completely lacks phosphagen kinases, probably by the presence of the arginine-consuming enzyme, arginase. Finally, phylogenetic analysis suggests that Kinetoplastids'' arginine kinase was acquired, during evolution, from the arthropod vectors by horizontal gene transfer. [Copyright &y& Elsevier]

Arginine kinase (AK) is an enzyme present in various invertebrates, as well as in some trypanosomatids such as T. cruzi , the etiological agent that causes Chagas disease. In invertebrates, this protein acts as an allergen inducing an IgE-type humoral immune response. Since AK is a highly conserved protein, we decided to study whether patients with chronic Chagas disease (CCD) produce specific antibodies against T. cruzi AK (Tc AK). Plasma from patients with CCD, with and without cardiac alterations and non-infected individuals were evaluated for the presence of anti- Tc AK IgG and IgE antibodies by ELISA, including detection of specific IgG subclasses. Our results showed that the levels of specific anti- Tc AK IgG and IgE were different between infected and non-infected individuals, but comparable between those with different clinical manifestations. Interestingly, anti- Tc AK IgG4 antibodies associated with IgE-mediated allergenic processes were also increased in CCD patients. Finally, we found that several of the predicted B cell epitopes in Tc AK matched allergenic peptides previously described for its homologues in other organisms. Our results revealed for the first time a parasite's specific IgE antibody target and suggest that Tc AK could contribute to delineate an inefficient B cell response by prompting a bias towards a Th2 profile. These findings also shed light on a potential allergenic response in the context of T. cruzi infection. [ABSTRACT FROM AUTHOR]

[Display omitted] Trypanosoma cruzi is the causative agent of Chagas' disease, an endemic and neglected disease. The treatment is limited to only two drugs, benznidazole (BZL) and nifurtimox (NFX), introduced more than fifty years ago and no new advances have been made since then. Nucleoside diphosphate kinases (NDPK) are key metabolic enzymes which have gained interest as drug targets of pathogen organisms. Taking advantage of the computer-assisted drug repurposing approaches, in the present work we initiate a search of potential T. cruzi nucleoside diphosphate kinase 1 (TcNDPK1) inhibitors over an ∼ 12,000 compound structures database to find drugs targeted to this enzyme with trypanocidal activity. Four medicines were selected and evaluated in vitro , ketorolac (KET, an anti-inflamatory), dutasteride (DUT, used to treat benign prostatic hyperplasia), nebivolol and telmisartan (NEB and TEL, used to treat high blood pressure). The four compounds were weak inhibitors and presented different trypanocidal effect on epimastigotes, trypomastigotes and intracellular stages. NEB and TEL were the most active drugs with increased effect on intracellular stages, (IC 50 = 2.25 µM and 13.21 µM respectively), and selectivity indexes of 13.01 and 8.59 respectively, showing comparable effect to BZL, the first line drug for Chagas' disease treatment. In addition, both presented positive interactions when combined with BZL. Finally, transgenic epimastigotes with increased expression of TcNDPK1 were more resistant to TEL and NEB, suggesting that TcNDPK1 is at least one of the molecular targets. In view of the results, NEB and TEL could be repurposed medicines for Chagas' disease therapy. [ABSTRACT FROM AUTHOR]

Very few studies have investigated cognition and impulsivity following mild traumatic brain injury (mTBI) in the general population. Furthermore, the neurobiological mechanisms underlying post-TBI neurobehavioral syndromes are complex and remain to be fully clarified. Herein, we took advantage of machine learning based-modeling to investigate potential biomarkers of mTBI-associated impulsivity. Twenty-one mTBI patients were assessed within one-month post-TBI and their data were compared to 19 healthy controls on measures of impulsivity (Barratt Impulsiveness Scale – BIS), executive functioning, episodic memory, self-report cognitive failures and blood biomarkers of inflammation, vascular and neuronal damage. mTBI patients were significantly more impulsive than controls in BIS total and subscales. Serum levels of sCD40L, Cathepsin D, IL-4, Neuropilin-1, IFN-α2, and Copeptin were associated with impulsivity in mTBI patients. Besides showing that mTBI are associated with impulsivity in non-military people, we unveiled different pathophysiological pathways potentially implicated in mTBI-related impulsivity. • mTBI patients from general population display high levels of impulsivity. • mTBI-related impulsivity was successfully detected by self-report measures. • Inflammatory, vascular, and neuronal/glial mediators are associated with mTBI impulsivity. • Serum molecules might be potential biomarkers of post-mTBI impulsivity. [ABSTRACT FROM AUTHOR]

Arginine kinase catalyzes the reversible transphosphorylation between ADP and phosphoarginine which plays a critical role in the maintenance of cellular energy homeostasis. Arginine kinase from the protozoan parasite Trypanosoma cruzi , the etiologic agent of Chagas disease, meets the requirements to be considered as a potential therapeutic target for rational drug design including being absent in its mammalian hosts. In this study a group of polyphenolic compounds was evaluated as potential inhibitors of arginine kinase using molecular docking techniques. Among the analyzed compounds with the lowest free binding energy to the arginine kinase active site (<−6.96 kcal/mol), resveratrol was chosen for subsequent assays. Resveratrol inhibits 50% of recombinant arginine kinase activity at 325 μM. The trypanocidal effect of resveratrol was evaluated on the T. cruzi trypomastigotes bursting from infected CHO K1 cells, with IC 50 = 77 μM. Additionally epimastigotes overexpressing arginine kinase were 5 times more resistant to resveratrol compared to controls. Taking into account that: (1) resveratrol is considered as completely nontoxic; (2) is easily accessible due to its low market price; and (3) has as a well-defined target enzyme which is absent in the mammalian host, it is a promising compound as a trypanocidal drug for Chagas disease. [ABSTRACT FROM AUTHOR]

The healing capacity of bones after fracture implies the existence of adult regenerative cells. However, information on identification and functional role of fracture-induced progenitors is still lacking. Paired-related homeobox 1 (Prx1) is expressed during skeletogenesis. We hypothesize that fracture recapitulates Prx1's expression, and Prx1 expressing cells are critical to induce repair. To address our hypothesis, we used a combination of in vivo and in vitro approaches, short and long-term cell tracking analyses of progenies and actively expressing cells, cell ablation studies, and rodent animal models for normal and defective fracture healing. We found that fracture elicits a periosteal and endosteal response of perivascular Prx1+ cells that participate in fracture healing and showed that Prx1-expressing cells have a functional role in the repair process. While Prx1-derived cells contribute to the callus, Prx1's expression decreases concurrently with differentiation into cartilaginous and bone cells, similarly to when Prx1+ cells are cultured in differentiating conditions. We determined that bone morphogenic protein 2 (BMP2), through C-X-C motif-ligand-12 (CXCL12) signaling, modulates the downregulation of Prx1. We demonstrated that fracture elicits an early increase in BMP2 expression, followed by a decrease in CXCL12 that in turn down-regulates Prx1, allowing cells to commit to osteochondrogenesis. In vivo and in vitro treatment with CXCR4 antagonist AMD3100 restored Prx1 expression by modulating the BMP2-CXCL12 axis. Our studies represent a shift in the current research that has primarily focused on the identification of markers for postnatal skeletal progenitors, and instead we characterized the function of a specific population (Prx1+ cells) and their expression marker (Prx1) as a crossroad in fracture repair. The identification of fracture-induced perivascular Prx1+ cells and regulation of Prx1's expression by BMP2 and in turn by CXCL12 in the orchestration of fracture repair, highlights a pathway in which to investigate defective mechanisms and therapeutic targets for fracture non-union. • The regenerative capacity of bones after fractures implies the existence of adult progenitor cells. • In fracture repair, the nature and regulation of progenitor cells remain elusive. • Our studies identified the functional role of Prx1expressing cells in fracture. • Our studies characterized a novel BMP-CXCL12-Prx1 regulatory cascade in fracture. • Additional supporting information may be found in the online version of this article. [ABSTRACT FROM AUTHOR]

Enolase is a glycolytic enzyme that catalyzes the interconversion between 2-phosphoglycerate and phosphoenolpyruvate. In trypanosomatids, enolase was proposed as a key enzyme after in silico and in vivo analysis and it was validated as a protein essential for the survival of the parasite. Therefore, enolase constitutes an interesting enzyme target for the identification of drugs against Chagas disease. In this work, a combined virtual screening strategy was implemented, employing similarity virtual screening, molecular docking, and molecular dynamics. First, two known enolase inhibitors and the enzyme substrates were used as queries for the similarity screening on the Sweetlead database using five different algorithms. Compounds retrieved in the top 10 of at least three search algorithms were selected for further analysis, resulting in six compounds of medical use (etidronate, pamidronate, fosfomycin, acetohydroxamate, triclofos, and aminohydroxybutyrate). Molecular docking simulations and pose re-scoring predicted that binding with acetohydroxamate and triclofos would be weak, while fosfomycin and aminohydroxybutyrate predicted binding is experimentally implausible. Docking poses obtained for etidronate, pamidronate, and PEP were used for molecular dynamics calculations to describe their mode of binding. From the obtained results, we propose etidronate as a potential Tc ENO inhibitor and describe molecular motifs to be taken into account in the repurposing or design of drugs targeting this enzyme active site. Image 1 [ABSTRACT FROM AUTHOR]