Severe malaria: what's new on the pathogenesis front?

Plasmodium falciparum causes the most severe and fatal form of malaria in humans with over half a million deaths each year. Cerebral malaria, a complex neurological syndrome of severe falciparum malaria, is often fatal and represents a major public health burden. Despite vigorous efforts, the pathophysiology of cerebral malaria remains to be elucidated, thereby hindering the development of adjunctive therapies. In recent years, multidisciplinary and collaborative approaches have led to groundbreaking progress both in the laboratory and in the field. Here we review the latest breakthroughs in severe malaria pathogenesis, with a specific focus on new pathogenetic mechanisms leading to cerebral malaria. The most recent findings point towards specific parasite phenotypes targeting brain microvasculature, endothelial dysfunction and subsequent oedema-induced brain swelling

Cellular communication via microparticles: Role in transfer of multidrug resistance in cancer

Multidrug resistance (MDR) continues to be a major impediment to the successful treatment of cancer. The two efflux transporters, P-glycoprotein (P-gp) and MRP1 are major contributors to cancer MDR clinically. The upregulation of P-gp leading to MDR was initially understood to occur via pre- and post-transcriptional mechanisms only. However, we demonstrated that microparticles mediate the intercellular exchange and trafficking of bioactive material, including functional P-gp and selected modulatory miRNAs. This exchange of P-gp leads to the dissemination of MDR within a cancer cell population. These findings have significant implications in understanding the cellular basis governing the intercellular acquisition of deleterious traits in cancers, serving to substantially advance our understanding of the molecular basis of the emergence of MDR in cancer clinically. © 2014 Future Medicine Ltd

Potential Efficacy of Citicoline as Adjunct Therapy in Treatment of Cerebral Malaria

Cerebral malaria (CM) is characterized by a dysregulated immune response that results in endothelial membrane destabilization and increased microparticle (MP) production. Citicoline (CTC) is a membrane stabilizer used for the treatment of neurological disorders. We evaluated the efficacy of CTC as adjunct therapy to aid recovery from experimental CM. We show that CTC reduces MP production in vitro; in combination with artesunate in vivo, confers partial protection against CM; and prolongs survival. © 2014, American Society for Microbiology. All Rights Reserved

Elevated Cell-Specific Microparticles Are a Biological Marker for Cerebral Dysfunctions in Human Severe Malaria

Cerebral malaria (CM) and severe anemia (SA) are the most severe complications of Plasmodium falciparum infections. Although increased release of endothelial microparticles (MP) correlates with malaria severity, the full extent of vascular cell vesiculation remains unknown. Here, we characterize the pattern of cell-specific MP in patients with severe malaria. We tested the hypothesis that systemic vascular activation contributes to CM by examining origins and levels of plasma MP in relation to clinical syndromes, disease severity and outcome. Patients recruited in Douala, Cameroon, were assigned to clinical groups following WHO criteria. MP quantitation and phenotyping were carried out using cell-specific markers by flow cytometry using antibodies recognizing cell-specific surface markers. Platelet, erythrocytic, endothelial and leukocytic MP levels were elevated in patients with cerebral dysfunctions and returned to normal by discharge. In CM patients, platelet MP were the most abundant and their levels significantly correlated with coma depth and thrombocytopenia. This study shows for the first time a widespread enhancement of vesiculation in the vascular compartment appears to be a feature of CM but not of SA. Our data underpin the role of MP as a biomarker of neurological involvement in severe malaria. Therefore, intervention to block MP production in severe malaria may provide a new therapeutic pathway

Indirect determination of biochemistry reference intervals using outpatient data

Creatinine; Urea; Clinical chemistryCreatinina; Urea; Química clínicaCreatinina; Urea; Química clínicaThe aim of this study was to determine reference intervals in an outpatient population from Vall d’Hebron laboratory using an indirect approach previously described in a Dutch population (NUMBER project). We used anonymized test results from individuals visiting general practitioners and analysed during 2018. Analytical quality was assured by EQA performance, daily average monitoring and by assessing longitudinal accuracy between 2018 and 2020 (using trueness verifiers from Dutch EQA). Per test, outliers by biochemically related tests were excluded, data were transformed to a normal distribution (if necessary) and means and standard deviations were calculated, stratified by age and sex. In addition, the reference limit estimator method was also used to calculate reference intervals using the same dataset. Finally, for standardized tests reference intervals obtained were compared with the published NUMBER results. Reference intervals were calculated using data from 509,408 clinical requests. For biochemical tests following a normal distribution, similar reference intervals were found between Vall d’Hebron and the Dutch study. For creatinine and urea, reference intervals increased with age in both populations. The upper limits of Gamma-glutamyl transferase were markedly higher in the Dutch study compared to Vall d’Hebron results. Creatine kinase and uric acid reference intervals were higher in both populations compared to conventional reference intervals. Medical test results following a normal distribution showed comparable and consistent reference intervals between studies. Therefore a simple indirect method is a feasible and cost-efficient approach for calculating reference intervals. Yet, for generating standardized calculated reference intervals that are traceable to higher order materials and methods, efforts should also focus on test standardization and bias assessment using commutable trueness verifiers

Minimizing conservativity violations in ontology alignments: algorithms and evaluation

In order to enable interoperability between ontology-based systems, ontology matching techniques have been proposed. However, when the generated mappings lead to undesired logical consequences, their usefulness may be diminished. In this paper, we present an approach to detect and minimize the violations of the so-called conservativity principle where novel subsumption entailments between named concepts in one of the input ontologies are considered as unwanted. The practical applicability of the proposed approach is experimentally demonstrated on the datasets from the Ontology Alignment Evaluation Initiative

Measurement of the inclusive and dijet cross-sections of b-jets in pp collisions at sqrt(s) = 7 TeV with the ATLAS detector

The inclusive and dijet production cross-sections have been measured for jets containing b-hadrons (b-jets) in proton-proton collisions at a centre-of-mass energy of sqrt(s) = 7 TeV, using the ATLAS detector at the LHC. The measurements use data corresponding to an integrated luminosity of 34 pb^-1. The b-jets are identified using either a lifetime-based method, where secondary decay vertices of b-hadrons in jets are reconstructed using information from the tracking detectors, or a muon-based method where the presence of a muon is used to identify semileptonic decays of b-hadrons inside jets. The inclusive b-jet cross-section is measured as a function of transverse momentum in the range 20 < pT < 400 GeV and rapidity in the range |y| < 2.1. The bbbar-dijet cross-section is measured as a function of the dijet invariant mass in the range 110 < m_jj < 760 GeV, the azimuthal angle difference between the two jets and the angular variable chi in two dijet mass regions. The results are compared with next-to-leading-order QCD predictions. Good agreement is observed between the measured cross-sections and the predictions obtained using POWHEG + Pythia. MC@NLO + Herwig shows good agreement with the measured bbbar-dijet cross-section. However, it does not reproduce the measured inclusive cross-section well, particularly for central b-jets with large transverse momenta.Comment: 10 pages plus author list (21 pages total), 8 figures, 1 table, final version published in European Physical Journal

Jet energy measurement with the ATLAS detector in proton-proton collisions at root s=7 TeV

The jet energy scale and its systematic uncertainty are determined for jets measured with the ATLAS detector at the LHC in proton-proton collision data at a centre-of-mass energy of √s = 7TeV corresponding to an integrated luminosity of 38 pb-1. Jets are reconstructed with the anti-kt algorithm with distance parameters R=0. 4 or R=0. 6. Jet energy and angle corrections are determined from Monte Carlo simulations to calibrate jets with transverse momenta pT≥20 GeV and pseudorapidities {pipe}η{pipe}<4. 5. The jet energy systematic uncertainty is estimated using the single isolated hadron response measured in situ and in test-beams, exploiting the transverse momentum balance between central and forward jets in events with dijet topologies and studying systematic variations in Monte Carlo simulations. The jet energy uncertainty is less than 2. 5 % in the central calorimeter region ({pipe}η{pipe}<0. 8) for jets with 60≤pT<800 GeV, and is maximally 14 % for pT<30 GeV in the most forward region 3. 2≤{pipe}η{pipe}<4. 5. The jet energy is validated for jet transverse momenta up to 1 TeV to the level of a few percent using several in situ techniques by comparing a well-known reference such as the recoiling photon pT, the sum of the transverse momenta of tracks associated to the jet, or a system of low-pT jets recoiling against a high-pT jet. More sophisticated jet calibration schemes are presented based on calorimeter cell energy density weighting or hadronic properties of jets, aiming for an improved jet energy resolution and a reduced flavour dependence of the jet response. The systematic uncertainty of the jet energy determined from a combination of in situ techniques is consistent with the one derived from single hadron response measurements over a wide kinematic range. The nominal corrections and uncertainties are derived for isolated jets in an inclusive sample of high-pT jets. Special cases such as event topologies with close-by jets, or selections of samples with an enhanced content of jets originating from light quarks, heavy quarks or gluons are also discussed and the corresponding uncertainties are determined. © 2013 CERN for the benefit of the ATLAS collaboration

Search for direct production of charginos and neutralinos in events with three leptons and missing transverse momentum in √s = 7 TeV pp collisions with the ATLAS detector

A search for the direct production of charginos and neutralinos in final states with three electrons or muons and missing transverse momentum is presented. The analysis is based on 4.7 fb−1 of proton–proton collision data delivered by the Large Hadron Collider and recorded with the ATLAS detector. Observations are consistent with Standard Model expectations in three signal regions that are either depleted or enriched in Z-boson decays. Upper limits at 95% confidence level are set in R-parity conserving phenomenological minimal supersymmetric models and in simplified models, significantly extending previous results

Single hadron response measurement and calorimeter jet energy scale uncertainty with the ATLAS detector at the LHC

The uncertainty on the calorimeter energy response to jets of particles is derived for the ATLAS experiment at the Large Hadron Collider (LHC). First, the calorimeter response to single isolated charged hadrons is measured and compared to the Monte Carlo simulation using proton-proton collisions at centre-of-mass energies of sqrt(s) = 900 GeV and 7 TeV collected during 2009 and 2010. Then, using the decay of K_s and Lambda particles, the calorimeter response to specific types of particles (positively and negatively charged pions, protons, and anti-protons) is measured and compared to the Monte Carlo predictions. Finally, the jet energy scale uncertainty is determined by propagating the response uncertainty for single charged and neutral particles to jets. The response uncertainty is 2-5% for central isolated hadrons and 1-3% for the final calorimeter jet energy scale.Comment: 24 pages plus author list (36 pages total), 23 figures, 1 table, submitted to European Physical Journal