A Novel High Throughput Assay for Anthelmintic Drug Screening and Resistance Diagnosis by Real-Time Monitoring of Parasite Motility

Parasitic worms cause untold morbidity and mortality on billions of people and livestock. Drugs are available but resistance is problematic in livestock parasites and is a looming threat for human helminths. Currently, new drug discovery and resistance monitoring is hindered as drug efficacy is assessed by observing motility or development of parasites using laborious, subjective, low-throughput methods evaluated by eye using microscopy. Here we describe a novel application for a cell monitoring device (xCELLigence) that can simply and objectively assess real time anti-parasite efficacy of drugs on eggs, larvae and adults in a fully automated, label-free, high-throughput fashion. This technique overcomes the current low-throughput bottleneck in anthelmintic drug development and resistance detection pipelines. The widespread use of this device to screen for new therapeutics or emerging drug resistance will be an invaluable asset in the fight against human, animal and plant parasitic helminths and other pathogens that plague our planet

Associations between Active Trachoma and Community Intervention with Antibiotics, Facial Cleanliness, and Environmental Improvement (A,F,E)

Trachoma is an infectious disease that is cased by a bacterium, Chlamydia trachomatis, and is the leading cause of preventable blindness estimated to be responsible for 3.6% of blindness globally. The World Health Organization (WHO) recommends a strategy for trachoma control known as SAFE—surgery, antibiotics, facial cleanliness, and environmental improvement. Regular evaluations of trachoma control activities are advocated for by the WHO for decision making, programme planning, and the rational use of programme resources. We undertook a survey to evaluate the effectiveness of the SAFE strategy following three years of interventions in four districts in Southern Sudan. In this paper, we aimed to find out the relationship between the antibiotics, facial cleanliness, and environmental improvement (A,F,E) and active trachoma signs. Our study revealed that prevalence of active trachoma was less in children who had received treatment with azithromycin, had clean faces, had faces washed more frequently, and used latrines compared to children who had not received these interventions. The study findings are important since they make the case for implementing the A,F,E interventions together

The role for osmotic agents in children with acute encephalopathies: a systematic review

Background: Raised intracranial pressure (ICP) is known to complicate both traumatic and non-traumatic encephalopathies. It impairs cerebral perfusion and may cause death due to global ischaemia and intracranial herniation. Osmotic agents are widely used to control ICP. In children, guidelines for their use are mainly guided by adult studies. We conducted this review to determine the current evidence of the effectiveness of osmotic agents and their effect on resolution of coma and outcome in children with acute encephalopathy.Methods: We searched several databases for published and unpublished studies in English and French languages, between January 1966 and March 2009. We considered studies on the use of osmotic agents in children aged between 0 and 16 years with acute encephalopathies. We examined reduction in intracranial pressure, time to resolution of coma, and occurrence of neurological sequelae and death.Results: We identified four randomized controlled trials, three prospective studies, two retrospective studies and one case report. Hypertonic saline (HS) achieved greater reduction in intracranial pressure (ICP) compared to mannitol and other fluids; normal saline or ringer's lactate. This effect was sustained for longer when it was given as continuous infusion. Boluses of glycerol and mannitol achieved transient reduction in ICP. Oral glycerol was associated with lower mortality and neurological sequelae when compared to placebo in children with acute bacterial meningitis. HS was associated with lower mortality when compared to mannitol in children with non-traumatic encephalopathies.Conclusion: HS appears to achieve a greater reduction in ICP than other osmotic agents. Oral glycerol seems to improve outcome among children with acute bacterial meningitis. A sustained reduction in ICP is desirable and could be achieved by modifying the modes and rates of administration of these osmotic agents, but these factors need further investigation

FHL2 interacts with CALM and is highly expressed in acute erythroid leukemia

The t(10;11)(p13;q14) translocation results in the fusion of the CALM (clathrin assembly lymphoid myeloid leukemia protein) and AF10 genes. This translocation is observed in acute myeloblastic leukemia (AML M6), acute lymphoblastic leukemia (ALL) and malignant lymphoma. Using a yeast two-hybrid screen, the four and a half LIM domain protein 2 (FHL2) was identified as a CALM interacting protein. Recently, high expression of FHL2 in breast, gastric, colon, lung as well as in prostate cancer was shown to be associated with an adverse prognosis. The interaction between CALM and FHL2 was confirmed by glutathione S-transferase-pulldown assay and co-immunoprecipitation experiments. The FHL2 interaction domain of CALM was mapped to amino acids 294–335 of CALM. The transcriptional activation capacity of FHL2 was reduced by CALM, but not by CALM/AF10, which suggests that regulation of FHL2 by CALM might be disturbed in CALM/AF10-positive leukemia. Extremely high expression of FHL2 was seen in acute erythroid leukemia (AML M6). FHL2 was also highly expressed in chronic myeloid leukemia and in AML with complex aberrant karyotype. These results suggest that FHL2 may play an important role in leukemogenesis, especially in the case of AML M6

Identification of Novel Human Damage Response Proteins Targeted through Yeast Orthology

Studies in Saccharomyces cerevisiae show that many proteins influence cellular survival upon exposure to DNA damaging agents. We hypothesized that human orthologs of these S. cerevisiae proteins would also be required for cellular survival after treatment with DNA damaging agents. For this purpose, human homologs of S. cerevisiae proteins were identified and mapped onto the human protein-protein interaction network. The resulting human network was highly modular and a series of selection rules were implemented to identify 45 candidates for human toxicity-modulating proteins. The corresponding transcripts were targeted by RNA interference in human cells. The cell lines with depleted target expression were challenged with three DNA damaging agents: the alkylating agents MMS and 4-NQO, and the oxidizing agent t-BuOOH. A comparison of the survival revealed that the majority (74%) of proteins conferred either sensitivity or resistance. The identified human toxicity-modulating proteins represent a variety of biological functions: autophagy, chromatin modifications, RNA and protein metabolism, and telomere maintenance. Further studies revealed that MMS-induced autophagy increase the survival of cells treated with DNA damaging agents. In summary, we show that damage recovery proteins in humans can be identified through homology to S. cerevisiae and that many of the same pathways are represented among the toxicity modulators

Reductions in malaria and anaemia case and death burden at hospitals following scale-up of malaria control in Zanzibar, 1999-2008

Background: In Zanzibar, the Ministry of Health and partners accelerated malaria control from September 2003 onwards. The impact of the scale-up of insecticide-treated nets (ITN), indoor-residual spraying (IRS) and artemisinin-combination therapy (ACT) combined on malaria burden was assessed at six out of seven in-patient health facilities. Methods. Numbers of outpatient and inpatient cases and deaths were compared between 2008 and the pre-intervention period 1999-2003. Reductions were estimated by segmented log-linear regression, adjusting the effect size for time trends during the pre-intervention period. Results: In 2008, for all age groups combined, malaria deaths had fallen by an estimated 90% (95% confidence interval 55-98%)(p < 0.025), malaria in-patient cases by 78% (48-90%), and parasitologically- confirmed malaria out-patient cases by 99.5% (92-99.9%). Anaemia in-patient cases decreased by 87% (57-96%); anaemia deaths and out-patient cases declined without reaching statistical significance due to small numbers. Reductions were similar for children under-five and older ages. Among under-fives, the proportion of all-cause deaths due to malaria fell from 46% in 1999-2003 to 12% in 2008 (p < 0.01) and that for anaemia from 26% to 4% (p < 0.01). Cases and deaths due to other causes fluctuated or increased over 1999-2008, without consistent difference in the trend before and after 2003. Conclusions: Scaling-up effective malaria interventions reduced malaria-related burden at health facilities by over 75% within 5 years. In high-malaria settings, intensified malaria control can substantially contribute to reaching the Millennium Development Goal 4 target of reducing under-five mortality by two-thirds between 1990 and 2015

A diagnosis of the plasma waves responsible for the explosive energy release of substorm onset

During geomagnetic substorms, stored magnetic and plasma thermal energies are explosively converted into plasma kinetic energy. This rapid reconfiguration of Earth’s nightside magnetosphere is manifest in the ionosphere as an auroral display that fills the sky. Progress in understanding of how substorms are initiated is hindered by a lack of quantitative analysis of the single consistent feature of onset; the rapid brightening and structuring of the most equatorward arc in the ionosphere. Here, we exploit state-of-the-art auroral measurements to construct an observational dispersion relation of waves during substorm onset. Further, we use kinetic theory of high-beta plasma to demonstrate that the shear Alfven wave dispersion relation bears remarkable similarity to the auroral dispersion relation. In contrast to prevailing theories of substorm initiation, we demonstrate that auroral beads seen during the majority of substorm onsets are likely the signature of kinetic Alfven waves driven unstable in the high-beta magnetotail

ChemR23 Dampens Lung Inflammation and Enhances Anti-viral Immunity in a Mouse Model of Acute Viral Pneumonia

Viral diseases of the respiratory tract, which include influenza pandemic, children acute bronchiolitis, and viral pneumonia of the elderly, represent major health problems. Plasmacytoid dendritic cells play an important role in anti-viral immunity, and these cells were recently shown to express ChemR23, the receptor for the chemoattractant protein chemerin, which is expressed by epithelial cells in the lung. Our aim was to determine the role played by the chemerin/ChemR23 system in the physiopathology of viral pneumonia, using the pneumonia virus of mice (PVM) as a model. Wild-type and ChemR23 knock-out mice were infected by PVM and followed for functional and inflammatory parameters. ChemR23−/− mice displayed higher mortality/morbidity, alteration of lung function, delayed viral clearance and increased neutrophilic infiltration. We demonstrated in these mice a lower recruitment of plasmacytoid dendritic cells and a reduction in type I interferon production. The role of plasmacytoid dendritic cells was further addressed by performing depletion and adoptive transfer experiments as well as by the generation of chimeric mice, demonstrating two opposite effects of the chemerin/ChemR23 system. First, the ChemR23-dependent recruitment of plasmacytoid dendritic cells contributes to adaptive immune responses and viral clearance, but also enhances the inflammatory response. Second, increased morbidity/mortality in ChemR23−/− mice is not due to defective plasmacytoid dendritic cells recruitment, but rather to the loss of an anti-inflammatory pathway involving ChemR23 expressed by non-leukocytic cells. The chemerin/ChemR23 system plays important roles in the physiopathology of viral pneumonia, and might therefore be considered as a therapeutic target for anti-viral and anti-inflammatory therapies

Ageing exacerbates damage of systemic and salivary neutrophils from patients presenting Candida-related denture stomatitis

<p>Abstract</p> <p>Background</p> <p>Ageing leads to a decline in the function of the immune system, increasing the body's susceptibility to infections through the impairment of T-cells, macrophages, neutrophils and dendritic cells Denture stomatitis is a primary oral disease affecting elderly denture wearers. The major etiologic factor involved in this pathology is the infection by <it>Candida albicans</it>, an opportunistic pathogen that causes local and disseminated diseases in immunosuppressed humans. Neutrophils play a critical role in the immune response against <it>C. albicans </it>and are continually present in the salivary fluid and in the blood. The aim of this study was to determine ageing-related changes in salivary and blood neutrophils and their potential implications in <it>Candida</it>-related denture stomatitis.</p> <p>Results</p> <p>Our results showed a lower number of neutrophils in the saliva from patients presenting <it>Candida</it>-related denture stomatitis in comparison to their matched controls. Furthermore, fewer neutrophils were isolated from the saliva of aged control individuals in comparison to matched younger subjects. CXCR1, CD62L and CD11b expression were significantly greater on systemic neutrophils from younger control individuals. Elderly individuals showed more apoptotic salivary neutrophils and lower GM-CSF levels than younger ones, regardless of the occurrence of <it>Candida </it>infection. On the other hand, CXCL-8 concentrations were higher in the saliva from elderly individuals. Besides, TNF-α was detected at elevated levels in the saliva from infected elderly subjects. Salivary neutrophils from elderly and young patients presented impaired phagocytic activity against <it>C. albicans</it>. However, just systemic neutrophils from elderly showed decreased phagocytosis when compared to the younger ones, regardless of the occurrence of infection. In addition, neutrophils from aged individuals and young patients presented low fungicidal activity.</p> <p>Conclusion</p> <p>The data suggests that the <it>Candida </it>related-denture stomatitis is associated to neutrophils function deficiency, and ageing drastically appears to alter important characteristics of such cells, facilitating the establishment of this infection.</p