Interventions to treat cutaneous leishmaniasis in children: A systematic review

by Andrés Uribe-Restrepo, Alexandra Cossio, Mayur M. Desai, Diana Dávalos, María del Mar Castro

Background

Case management in children with cutaneous leishmaniasis (CL) is mainly based on studies performed in adults. We aimed to determine the efficacy and harms of interventions to treat CL in children.

Methods

We conducted a systematic review of clinical trials and cohort studies, assessing treatments of CL in children (≤12 years old). We performed structured searches in PubMed, CENTRAL, LILACS, SciELO, Scopus, the International Clinical Trials Registry Platform (ICTRP), clinicaltrials.gov and Google Scholar. No restrictions regarding ethnicity, country, sex or year of publication were applied. Languages were limited to English, Spanish and Portuguese. Two reviewers screened articles, completed the data extraction and assessment of risk of bias. A qualitative summary of the included studies was performed.

Results

We identified 1092 records, and included 8 manuscripts (6 Randomized Clinical Trials [RCT] and 2 non-randomized studies). Most of the articles excluded in full-text review did not report outcomes separately for children. In American CL (ACL), 5 studies evaluated miltefosine and/or meglumine antimoniate (MA). Their efficacy varied from 68–83% and 17–69%, respectively. In Old-World CL (OWCL), two studies evaluated systemic therapies: rifampicin and MA; and one study assessed efficacy of cryotherapy (42%, Per Protocol [PP]) vs intralesional MA (72%, PP). Few studies (4) provided information on adverse events (AEs) for children, and no serious AEs were reported in participants. Risk of bias was generally low to unclear in ACL studies, and unclear to high in OWCL studies.

Conclusion

Information on efficacy of treatment for CL in children is scarce. There is an unmet need to develop specific formulations, surveillance of AEs, and guidelines both for the management of CL and clinical trials involving the pediatric population.

Registration

The protocol of this review was registered in the PROSPERO International register of systematic reviews, number CRD42017062164.

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Novel mass spectrometry based detection and identification of variants of rabies virus nucleoprotein in infected brain tissues

by Matthew Reed, Olga Stuchlik, William C. Carson, Lillian Orciari, Pamela A. Yager, Victoria Olson, Yu Li, Xianfu Wu, Jan Pohl, Panayampalli Subbian Satheshkumar

Human rabies is an encephalitic disease transmitted by animals infected with lyssaviruses. The most common lyssavirus that causes human infection is rabies virus (RABV), the prototypic member of the genus. The incubation period of RABV in humans varies from few weeks to several months in some instances. During this prodromal period, neither antibodies nor virus is detected. Antibodies, antigen and nucleic acids are detectable only after the onset of encephalitic symptoms, at which point the outcome of the disease is nearly 100% fatal. Hence, the primary intervention for human RABV exposure and subsequent post-exposure prophylaxis relies on testing animals suspected of having rabies. The most widely used diagnostic tests in animals focus on antigen detection, RABV-encoded nucleoprotein (N protein) in brain tissues. N protein accumulates in the cytoplasm of infected cells as large and granular inclusions, which are visualized in infected brain tissues by immuno-microscopy using anti-N protein antibodies. In this study, we explored a mass spectrometry (MS) based method for N protein detection without the need for any specific antibody reagents or microscopy. The MS-based method described here is unbiased, label-free, requires no amplification and determines any previously sequenced N protein available in the database. The results demonstrate the ability of MS/MS based method for N protein detection and amino acid sequence determination in animal diagnostic samples to obtain RABV variant information. This study demonstrates a potential for future developments of rabies diagnostic tests based on MS platforms.

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Translating preventive chemotherapy prevalence thresholds for <i>Schistosoma mansoni</i> from the Kato-Katz technique into the point-of-care circulating cathodic antigen diagnostic test

by Oliver Bärenbold, Amadou Garba, Daniel G. Colley, Fiona M. Fleming, Ayat A. Haggag, Reda M. R. Ramzy, Rufin K. Assaré, Edridah M. Tukahebwa, Jean B. Mbonigaba, Victor Bucumi, Biruck Kebede, Makoy S. Yibi, Aboulaye Meité, Jean T. Coulibaly, Eliézer K. N’Goran, Louis-Albert Tchuem Tchuenté, Pauline Mwinzi, Jürg Utzinger, Penelope Vounatsou

Background

Intervention guidelines against Schistosoma mansoni are based on the Kato-Katz technique. However, Kato-Katz thick smears show low sensitivity, especially for light-intensity infections. The point-of-care circulating cathodic antigen (POC-CCA) is a promising rapid diagnostic test detecting antigen output of living worms in urine and results are reported as trace, 1+, 2+, and 3+. The use of POC-CCA for schistosomiasis mapping, control, and surveillance requires translation of the Kato-Katz prevalence thresholds into POC-CCA relative treatment cut-offs. Furthermore, the infection status of egg-negative but antigen-positive individuals and the intensity-dependent sensitivity of POC-CCA should be estimated to determine its suitability for verification of disease elimination efforts.

Methodology

We used data from settings in Africa and the Americas characterized by a wide range of S. mansoni endemicity. We estimated infection intensity-dependent sensitivity and specificity of each test at the unit of the individual, using a hierarchical Bayesian egg-count model that removes the need to define a ‘gold’ standard applied to data with multiple Kato-Katz thick smears and POC-CCA urine cassette tests. A simulation study was carried out based on the model estimates to assess the relation of the two diagnostic tests for different endemicity scenarios.

Principal findings

POC-CCA showed high specificity (> 95%), and high sensitivity (> 95%) for moderate and heavy infection intensities, and moderate sensitivity (> 75%) for light infection intensities, and even for egg-negative but antigen-positive infections. A 10% duplicate slide Kato-Katz thick smear prevalence corresponded to a 15–40% prevalence of ≥ trace-positive POC-CCA, and 10–20% prevalence of ≥ 1+ POC-CCA. The prevalence of ≥ 2+ POC-CCA corresponded directly to single slide Kato-Katz prevalence for all prevalence levels.

Conclusions/significance

The moderate sensitivity of POC-CCA, even for very light S. mansoni infections where the sensitivity of Kato-Katz is very low, and the identified relationship between Kato-Katz and POC-CCA prevalence thresholds render the latter diagnostic tool useful for surveillance and initial estimation of elimination of S. mansoni. For prevalence below 10% based on a duplicate slide Kato-Katz thick smear, we suggest using POC-CCA including trace results to evaluate treatment needs and propose new intervention thresholds that need to be validated in different settings.

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Economic impact of dengue in Mexico considering reported cases for 2012 to 2016

by Adriana Zubieta-Zavala, Malaquias López-Cervantes, Guillermo Salinas-Escudero, Adrian Ramírez-Chávez, José Ramos Castañeda, Sendy Isarel Hernández-Gaytán, Juan Guillermo López Yescas, Luis Durán-Arenas

Background

Given that dengue disease is growing and may progress to dengue hemorrhagic fever (DHF), data on economic cost and disease burden are important. However, data for Mexico are limited.

Methodology/Principal findings

Burden of dengue fever (DF) and DHF in Mexico was assessed using official databases for epidemiological information, disabilities weights from Shepard et al, the reported number of cases and deaths, and costs. Overall costs of dengue were summed from direct medical costs to the health system, cost of dengue to the patient (out-of-pocket expenses [medical and non-medical], indirect costs [loss of earnings, patient and/or caregiver]), and other government expenditures on prevention/surveillance. The first three components, calculated as costs per case by a micro-costing approach (PAATI; program, actions, activities, tasks, inputs), were scaled up to overall cost using epidemiology data from official databases. PAATI was used to calculate cost of vector control and prevention, education, and epidemiological surveillance, based on an expert consensus and normative construction of an ideal scenario.Disability-adjusted life years (DALYs) for Mexico in 2016 were calculated to be 2283.46 (1.87 per 100,000 inhabitants). Overall economic impact of dengue in Mexico for 2012 was US$144 million, of which US$44 million corresponded to direct medical costs and US$5 million to the costs from the patient’s perspective. The estimated cost of prevention/surveillance was calculated with information provided by federal government to be US$95 million. The overall economic impact of DF and DHF showed an increase in 2013 to US$161 million and a decrease to US$133, US$131 and US$130 million in 2014, 2015 and 2016, respectively.

Conclusions/Significance

The medical and economic impact of dengue were in agreement with other international studies, and highlight the need to include governmental expenditure for prevention/surveillance in overall cost analyses given the high economic impact of these, increasing the necessity to evaluate its effectiveness.

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Enteropathogenic <i>E</i>. <i>coli</i> relies on collaboration between the formin mDia1 and the Arp2/3 complex for actin pedestal biogenesis and maintenance

by Katrina B. Velle, Kenneth G. Campellone

Enteropathogenic and enterohemorrhagic E. coli (EPEC and EHEC) are closely related extracellular pathogens that reorganize host cell actin into “pedestals” beneath the tightly adherent bacteria. This pedestal-forming activity is both a critical step in pathogenesis, and it makes EPEC and EHEC useful models for studying the actin rearrangements that underlie membrane protrusions. To generate pedestals, EPEC relies on the tyrosine phosphorylated bacterial effector protein Tir to bind host adaptor proteins that recruit N-WASP, a nucleation-promoting factor that activates the Arp2/3 complex to drive actin polymerization. In contrast, EHEC depends on the effector EspFU to multimerize N-WASP and promote Arp2/3 activation. Although these core pathways of pedestal assembly are well-characterized, the contributions of additional actin nucleation factors are unknown. We investigated potential cooperation between the Arp2/3 complex and other classes of nucleators using chemical inhibitors, siRNAs, and knockout cell lines. We found that inhibition of formins impairs actin pedestal assembly, motility, and cellular colonization for bacteria using the EPEC, but not the EHEC, pathway of actin polymerization. We also identified mDia1 as the formin contributing to EPEC pedestal assembly, as its expression level positively correlates with the efficiency of pedestal formation, and it localizes to the base of pedestals both during their initiation and once they have reached steady state. Collectively, our data suggest that mDia1 enhances EPEC pedestal biogenesis and maintenance by generating seed filaments to be used by the N-WASP/Arp2/3-dependent actin nucleation machinery and by sustaining Src-mediated phosphorylation of Tir.

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Multiscale computational model of Achilles tendon wound healing: Untangling the effects of repair and loading

by Kellen Chen, Xiao Hu, Silvia S. Blemker, Jeffrey W. Holmes

Mechanical stimulation of the healing tendon is thought to regulate scar anisotropy and strength and is relatively easy to modulate through physical therapy. However, in vivo studies of various loading protocols in animal models have produced mixed results. To integrate and better understand the available data, we developed a multiscale model of rat Achilles tendon healing that incorporates the effect of changes in the mechanical environment on fibroblast behavior, collagen deposition, and scar formation. We modified an OpenSim model of the rat right hindlimb to estimate physiologic strains in the lateral/medial gastrocnemius and soleus musculo-tendon units during loading and unloading conditions. We used the tendon strains as inputs to a thermodynamic model of stress fiber dynamics that predicts fibroblast alignment, and to determine local collagen synthesis rates according to a response curve derived from in vitro studies. We then used an agent-based model (ABM) of scar formation to integrate these cell-level responses and predict tissue-level collagen alignment and content. We compared our model predictions to experimental data from ten different studies. We found that a single set of cellular response curves can explain features of observed tendon healing across a wide array of reported experiments in rats–including the paradoxical finding that repairing transected tendon reverses the effect of loading on alignment–without fitting model parameters to any data from those experiments. The key to these successful predictions was simulating the specific loading and surgical protocols to predict tissue-level strains, which then guided cellular behaviors according to response curves based on in vitro experiments. Our model results provide a potential explanation for the highly variable responses to mechanical loading reported in the tendon healing literature and may be useful in guiding the design of future experiments and interventions.

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Prediction of antibiotic resistance in <i>Escherichia coli</i> from large-scale pan-genome data

by Danesh Moradigaravand, Martin Palm, Anne Farewell, Ville Mustonen, Jonas Warringer, Leopold Parts

The emergence of microbial antibiotic resistance is a global health threat. In clinical settings, the key to controlling spread of resistant strains is accurate and rapid detection. As traditional culture-based methods are time consuming, genetic approaches have recently been developed for this task. The detection of antibiotic resistance is typically made by measuring a few known determinants previously identified from genome sequencing, and thus requires the prior knowledge of its biological mechanisms. To overcome this limitation, we employed machine learning models to predict resistance to 11 compounds across four classes of antibiotics from existing and novel whole genome sequences of 1936 E. coli strains. We considered a range of methods, and examined population structure, isolation year, gene content, and polymorphism information as predictors. Gradient boosted decision trees consistently outperformed alternative models with an average accuracy of 0.91 on held-out data (range 0.81–0.97). While the best models most frequently employed gene content, an average accuracy score of 0.90 could be obtained using population structure information alone. Single nucleotide variation data were less useful, and significantly improved prediction only for two antibiotics, including ciprofloxacin. These results demonstrate that antibiotic resistance in E. coli can be accurately predicted from whole genome sequences without a priori knowledge of mechanisms, and that both genomic and epidemiological data can be informative. This paves way to integrating machine learning approaches into diagnostic tools in the clinic.

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Dissecting the regulation and function of ATP at the single-cell level

by Jianhan Zhang, Xu Han, Yihan Lin

Regulation of cellular ATP level is critical for diverse biological processes and may be defective in diseases such as cancer and mitochondrial disorders. While mitochondria play critical roles in ATP level regulation, we still lack a systematic and quantitative picture of how individual mitochondrial-related genes contribute to cellular ATP level and how dysregulated ATP levels may affect downstream cellular processes. Advances in genetically encoded ATP biosensors have provided new opportunities for addressing these issues. ATP biosensors allow researchers to quantify the changes of ATP levels in real time at the single-cell level and characterize corresponding effects at the cellular, tissue, and organismal level. Along this direction, several recent single-cell studies using ATP biosensors, including the work by Mendelsohn and colleagues, have started to uncover the principles for how genetic and nongenetic parameters may modulate ATP levels to affect cellular functions and human health.

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CD71<sup>+</sup>VISTA<sup>+</sup> erythroid cells promote the development and function of regulatory T cells through TGF-β

by Shima Shahbaz, Najmeh Bozorgmehr, Petya Koleva, Afshin Namdar, Juan Jovel, Roy A. Fava, Shokrollah Elahi

Cell-surface transferrin receptor (CD71+) erythroid cells are abundant in newborns with immunomodulatory properties. Here, we show that neonatal CD71+ erythroid cells express significant levels of V-domain Immunoglobulin (Ig) Suppressor of T Cell Activation (VISTA) and, via constitutive production of transforming growth factor (TGF)- β, play a pivotal role in promotion of naïve CD4+ T cells into regulatory T cells (Tregs). Interestingly, we discovered that CD71+VISTA+ erythroid cells produce significantly higher levels of TGF-β compared to CD71+VISTA erythroid cells and CD71+ erythroid cells from the VISTA knock-out (KO) mice. As a result, CD71+VISTA+ erythroid cells—compared to CD71+VISTA and CD71+ erythroid cells from the VISTA KO mice—significantly exceed promotion of naïve CD4+ T cells into induced Tregs (iTreg) via TGF-β in vitro. However, depletion of CD71+ erythroid cells had no significant effects on the frequency of Tregs in vivo. Surprisingly, we observed that the remaining and/or newly generated CD71+ erythroid cells following anti-CD71 antibody administration exhibit a different gene expression profile, evidenced by the up-regulation of VISTA, TGF-β1, TGF-β2, and program death ligand-1 (PDL-1), which may account as a compensatory mechanism for the maintenance of Treg population. We also observed that iTreg development by CD71+ erythroid cells is mediated through the inhibition of key signaling molecules phosphorylated protein kinase B (phospho-Akt) and phosphorylated mechanistic target of rapamycin (phospho-mTOR). Finally, we found that elimination of Tregs using forkhead box P3 (FOXP3)-diptheria toxin receptor (DTR) mice resulted in a significant expansion in the frequency of CD71+ erythroid cells in vivo. Collectively, these studies provide a novel, to our knowledge, insight into the cross-talk between CD71+ erythroid cells and Tregs in newborns. Our results highlight the biological role of CD71+ erythroid cells in the neonatal period and possibly beyond.

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O.D.G. Giunte e Commissioni: Commissione di inchiesta sul fenomeno delle mafie – dal 19/12/2018 al 20/12/2018

O.D.G. Giunte e Commissioni

Commissione di inchiesta sul fenomeno delle mafie

Seduta/e: 5,6 (19/12/2018 – 20/12/2018)

odgmafia_5_1 e 6.pdf

N.B.: Testo sottolineato (1)


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