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[PMID]: 29470556
[Au] Autor:Kimuda MP; Noyes H; Mulindwa J; Enyaru J; Alibu VP; Sidibe I; Mumba Ngoyi D; Hertz-Fowler C; MacLeod A; Tastan Bishop Ö; Matovu E; TrypanoGEN Research Group as members of The H3Africa Consortium
[Ad] Address:College of Veterinary Medicine, Animal Resources and Biosecurity (COVAB), Makerere University, Kampala, Uganda.
[Ti] Title:No evidence for association between APOL1 kidney disease risk alleles and Human African Trypanosomiasis in two Ugandan populations.
[So] Source:PLoS Negl Trop Dis;12(2):e0006300, 2018 Feb.
[Is] ISSN:1935-2735
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:BACKGROUND: Human African trypanosomiasis (HAT) manifests as an acute form caused by Trypanosoma brucei rhodesiense (Tbr) and a chronic form caused by Trypanosoma brucei gambiense (Tbg). Previous studies have suggested a host genetic role in infection outcomes, particularly for APOL1. We have undertaken candidate gene association studies (CGAS) in a Ugandan Tbr and a Tbg HAT endemic area, to determine whether polymorphisms in IL10, IL8, IL4, HLAG, TNFA, TNX4LB, IL6, IFNG, MIF, APOL1, HLAA, IL1B, IL4R, IL12B, IL12R, HP, HPR, and CFH have a role in HAT. METHODOLOGY AND RESULTS: We included 238 and 202 participants from the Busoga Tbr and Northwest Uganda Tbg endemic areas respectively. Single Nucleotide Polymorphism (SNP) genotype data were analysed in the CGAS. The study was powered to find odds ratios > 2 but association testing of the SNPs with HAT yielded no positive associations i.e. none significant after correction for multiple testing. However there was strong evidence for no association with Tbr HAT and APOL1 G2 of the size previously reported in the Kabermaido district of Uganda. CONCLUSIONS/SIGNIFICANCE: A recent study in the Soroti and Kaberamaido focus in Central Uganda found that the APOL1 G2 allele was strongly associated with protection against Tbr HAT (odds ratio = 0.2, 95% CI: 0.07 to 0.48, p = 0.0001). However, in our study no effect of G2 on Tbr HAT was found, despite being well powered to find a similar sized effect (OR = 0.9281, 95% CI: 0.482 to 1.788, p = 0.8035). It is possible that the G2 allele is protective from Tbr in the Soroti/Kabermaido focus but not in the Iganga district of Busoga, which differ in ethnicity and infection history. Mechanisms underlying HAT infection outcome and virulence are complex and might differ between populations, and likely involve several host, parasite or even environmental factors.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180309
[Lr] Last revision date:180309
[St] Status:In-Data-Review
[do] DOI:10.1371/journal.pntd.0006300

  2 / 19818 MEDLINE  
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[PMID]: 29396200
[Au] Autor:Büscher P; Bart JM; Boelaert M; Bucheton B; Cecchi G; Chitnis N; Courtin D; Figueiredo LM; Franco JR; Grébaut P; Hasker E; Ilboudo H; Jamonneau V; Koffi M; Lejon V; MacLeod A; Masumu J; Matovu E; Mattioli R; Noyes H; Picado A; Rock KS; Rotureau B; Simo G; Thévenon S; Trindade S; Truc P; Van Reet N; Informal Expert Group on Gambiense HAT Reservoirs
[Ad] Address:Department of Biomedical Sciences, Institute of Tropical Medicine, Nationalestraat 155, 2000 Antwerp, Belgium. Electronic address: pbuscher@itg.be.
[Ti] Title:Do Cryptic Reservoirs Threaten Gambiense-Sleeping Sickness Elimination?
[So] Source:Trends Parasitol;34(3):197-207, 2018 Mar.
[Is] ISSN:1471-5007
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Trypanosoma brucei gambiense causes human African trypanosomiasis (HAT). Between 1990 and 2015, almost 440000 cases were reported. Large-scale screening of populations at risk, drug donations, and efforts by national and international stakeholders have brought the epidemic under control with <2200 cases in 2016. The World Health Organization (WHO) has set the goals of gambiense-HAT elimination as a public health problem for 2020, and of interruption of transmission to humans for 2030. Latent human infections and possible animal reservoirs may challenge these goals. It remains largely unknown whether, and to what extend, they have an impact on gambiense-HAT transmission. We argue that a better understanding of the contribution of human and putative animal reservoirs to gambiense-HAT epidemiology is mandatory to inform elimination strategies.
[Pt] Publication type:JOURNAL ARTICLE; REVIEW
[Em] Entry month:1802
[Cu] Class update date: 180310
[Lr] Last revision date:180310
[St] Status:In-Data-Review

  3 / 19818 MEDLINE  
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[PMID]: 29247858
[Au] Autor:Palace-Berl F; Pasqualoto KFM; Zingales B; Moraes CB; Bury M; Franco CH; da Silva Neto AL; Murayama JS; Nunes SL; Silva MN; Tavares LC
[Ad] Address:Department of Biochemical and Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, University of São Paulo, SP, Brazil. Electronic address: palaceberlf@usp.br.
[Ti] Title:Investigating the structure-activity relationships of N'-[(5-nitrofuran-2-yl) methylene] substituted hydrazides against Trypanosoma cruzi to design novel active compounds.
[So] Source:Eur J Med Chem;144:29-40, 2018 Jan 20.
[Is] ISSN:1768-3254
[Cp] Country of publication:France
[La] Language:eng
[Ab] Abstract:Chagas disease, caused by the protozoan Trypanosoma cruzi, is a neglected chronic tropical infection endemic in Latin America. New and effective treatments are urgently needed because the two available drugs - benznidazole (BZD) and nifurtimox (NFX) - have limited curative power in the chronic phase of the disease. We have previously reported the design and synthesis of N'-[(5-nitrofuran-2-yl) methylene] substituted hydrazides that showed high trypanocidal activity against axenic epimastigote forms of three T. cruzi strains. Here we show that these compounds are also active against a BZD- and NFX-resistant strain. Herein, multivariate approaches (hierarchical cluster analysis and principal component analysis) were applied to a set of thirty-six formerly characterized compounds. Based on the findings from exploratory data analysis, novel compounds were designed and synthesized. These compounds showed two-to three-fold higher trypanocidal activity against epimastigote forms than the previous set and were 25-30-fold more active than BZD. Their activity was also evaluated against intracellular amastigotes by high content screening (HCS). The most active compounds (BSF-38 to BSF-40) showed a selective index (SI') greater than 200, in contrast to the SI' values of reference drugs (NFX, 16.45; BZD, > 3), and a 70-fold greater activity than BZD. These findings indicate that nitrofuran compounds designed based on the activity against epimastigote forms show promising trypanocidal activity against intracellular amastigotes, which correspond to the predominant parasite stage in the chronic phase of Chagas disease.
[Mh] MeSH terms primary: Nitrofurans/chemistry
Nitrofurans/pharmacology
Trypanocidal Agents/chemistry
Trypanocidal Agents/pharmacology
Trypanosoma cruzi/drug effects
[Mh] MeSH terms secundary: Cell Line
Chagas Disease/drug therapy
Drug Design
Humans
Models, Molecular
Structure-Activity Relationship
[Pt] Publication type:JOURNAL ARTICLE
[Nm] Name of substance:0 (Nitrofurans); 0 (Trypanocidal Agents)
[Em] Entry month:1803
[Cu] Class update date: 180309
[Lr] Last revision date:180309
[Js] Journal subset:IM
[Da] Date of entry for processing:171217
[St] Status:MEDLINE

  4 / 19818 MEDLINE  
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[PMID]: 28456430
[Au] Autor:Seiringer P; Pritsch M; Flores-Chavez M; Marchisio E; Helfrich K; Mengele C; Hohnerlein S; Bretzel G; Löscher T; Hoelscher M; Berens-Riha N
[Ad] Address:Division of Infectious Diseases and Tropical Medicine, Medical Center of the University of Munich (LMU), Leopoldstr. 5, 80802 Munich, Germany; German Center for Infection Research (DZIF), partner site Munich, Munich, Germany. Electronic address: peter.seiringer@lrz.uni-muenchen.de.
[Ti] Title:Comparison of four PCR methods for efficient detection of Trypanosoma cruzi in routine diagnostics.
[So] Source:Diagn Microbiol Infect Dis;88(3):225-232, 2017 Jul.
[Is] ISSN:1879-0070
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Due to increased migration, Chagas disease has become an international health problem. Reliable diagnosis of chronically infected people is crucial for prevention of non-vectorial transmission as well as treatment. This study compared four distinct PCR methods for detection of Trypanosoma cruzi DNA for the use in well-equipped routine diagnostic laboratories. DNA was extracted of T. cruzi-positive and negative patients' blood samples and cultured T. cruzi, T. rangeli as well as Leishmania spp. One conventional and two real-time PCR methods targeting a repetitive Sat-DNA sequence as well as one conventional PCR method targeting the variable region of the kDNA minicircle were compared for sensitivity, intra- and interassay precision, limit of detection, specificity and cross-reactivity. Considering the performance, costs and ease of use, an algorithm for PCR-diagnosis of patients with a positive serology for T. cruzi antibodies was developed.
[Mh] MeSH terms primary: Chagas Disease/diagnosis
Molecular Diagnostic Techniques/methods
Polymerase Chain Reaction/methods
Trypanosoma cruzi/isolation & purification
[Mh] MeSH terms secundary: Adolescent
Adult
Blood/parasitology
Child, Preschool
Female
Humans
Male
Middle Aged
Sensitivity and Specificity
Trypanosoma cruzi/genetics
Young Adult
[Pt] Publication type:COMPARATIVE STUDY; EVALUATION STUDIES; JOURNAL ARTICLE
[Em] Entry month:1803
[Cu] Class update date: 180309
[Lr] Last revision date:180309
[Js] Journal subset:IM
[Da] Date of entry for processing:170501
[St] Status:MEDLINE

  5 / 19818 MEDLINE  
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[PMID]: 29521209
[Au] Autor:Cardona-G W; Yepes AF; Herrera-R A
[Ad] Address:Universidad de Antioquia-UdeA, Calle 70 No. 52-21, A.A 1226, Medellín, Colombia, Chemistry of Colombian Plants, Institute of Chemistry, Exact and Natural Sciences School. Colombia.
[Ti] Title:Hybrid Molecules: Promising Compounds for the Development of New Treatments against Leishmaniasis and Chagas Disease.
[So] Source:Curr Med Chem;, 2018 Mar 08.
[Is] ISSN:1875-533X
[Cp] Country of publication:Netherlands
[La] Language:eng
[Ab] Abstract:Leishmaniasis and Chagas disease are endemic pathologies in tropical countries. These cause high morbidity and a public health problem. Current chemotherapies are based on conventional drugs with variable efficacy and toxicity related with length of therapeutic schemes and high doses. When two pharmacological agents are combined into a single molecule, the result is the so-called hybrid molecule. In the search for new treatments against Chagas disease and leishmaniasis, several studies have shown that hybrid molecules display high antiprotozoal activity and this emerging strategy is quite promising in the field of new drug discovery and development. This review focuses on the antiprotozoal activity of different hybrids obtained from the hybridization of pharmacophores, showing that the most of the efforts have been concentrated in the molecular hybridization of quinoline, chalcone and hydrazone moieties.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1803
[Cu] Class update date: 180309
[Lr] Last revision date:180309
[St] Status:Publisher
[do] DOI:10.2174/0929867325666180309111428

  6 / 19818 MEDLINE  
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[PMID]: 29481567
[Au] Autor:Dolezelová E; Terán D; Gahura O; Kotrbová Z; Procházková M; Keough D; Spacek P; Hocková D; Guddat L; Zíková A
[Ad] Address:Institute of Parasitology, Biology Centre, Czech Academy of Sciences, Branisovská, Ceské Budejovice, Czech Republic.
[Ti] Title:Evaluation of the Trypanosoma brucei 6-oxopurine salvage pathway as a potential target for drug discovery.
[So] Source:PLoS Negl Trop Dis;12(2):e0006301, 2018 Feb.
[Is] ISSN:1935-2735
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Due to toxicity and compliance issues and the emergence of resistance to current medications new drugs for the treatment of Human African Trypanosomiasis are needed. A potential approach to developing novel anti-trypanosomal drugs is by inhibition of the 6-oxopurine salvage pathways which synthesise the nucleoside monophosphates required for DNA/RNA production. This is in view of the fact that trypanosomes lack the machinery for de novo synthesis of the purine ring. To provide validation for this approach as a drug target, we have RNAi silenced the three 6-oxopurine phosphoribosyltransferase (PRTase) isoforms in the infectious stage of Trypanosoma brucei demonstrating that the combined activity of these enzymes is critical for the parasites' viability. Furthermore, we have determined crystal structures of two of these isoforms in complex with several acyclic nucleoside phosphonates (ANPs), a class of compound previously shown to inhibit 6-oxopurine PRTases from several species including Plasmodium falciparum. The most potent of these compounds have Ki values as low as 60 nM, and IC50 values in cell based assays as low as 4 µM. This data provides a solid platform for further investigations into the use of this pathway as a target for anti-trypanosomal drug discovery.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1802
[Cu] Class update date: 180308
[Lr] Last revision date:180308
[St] Status:In-Data-Review
[do] DOI:10.1371/journal.pntd.0006301

  7 / 19818 MEDLINE  
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[PMID]: 29191556
[Au] Autor:Thompson AM; Marshall AJ; Maes L; Yarlett N; Bacchi CJ; Gaukel E; Wring SA; Launay D; Braillard S; Chatelain E; Mowbray CE; Denny WA
[Ad] Address:Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. Electronic address: am.thompson@auckland.ac.nz.
[Ti] Title:Assessment of a pretomanid analogue library for African trypanosomiasis: Hit-to-lead studies on 6-substituted 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine 8-oxides.
[So] Source:Bioorg Med Chem Lett;28(2):207-213, 2018 01 15.
[Is] ISSN:1464-3405
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:A 900 compound nitroimidazole-based library derived from our pretomanid backup program with TB Alliance was screened for utility against human African trypanosomiasis (HAT) by the Drugs for Neglected Diseases initiative. Potent hits included 2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazine 8-oxides, which surprisingly displayed good metabolic stability and excellent cell permeability. Following comprehensive mouse pharmacokinetic assessments on four hits and determination of the most active chiral form, a thiazine oxide counterpart of pretomanid (24) was identified as the best lead. With once daily oral dosing, this compound delivered complete cures in an acute infection mouse model of HAT and increased survival times in a stage 2 model, implying the need for more prolonged CNS exposure. In preliminary SAR findings, antitrypanosomal activity was reduced by removal of the benzylic methylene but enhanced through a phenylpyridine-based side chain, providing important direction for future studies.
[Mh] MeSH terms primary: Nitroimidazoles/pharmacology
Small Molecule Libraries/pharmacology
Trypanosomiasis, African/drug therapy
[Mh] MeSH terms secundary: Administration, Oral
Animals
Disease Models, Animal
Dose-Response Relationship, Drug
Humans
Mice
Molecular Structure
Nitroimidazoles/administration & dosage
Nitroimidazoles/chemistry
Small Molecule Libraries/administration & dosage
Small Molecule Libraries/chemistry
Structure-Activity Relationship
[Pt] Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Name of substance:0 (2-nitro-6-(4-(trifluoromethoxy)benzyloxy)-6,7-dihydro-5H-imidazo(2,1-b)(1,3)oxazine); 0 (Nitroimidazoles); 0 (Small Molecule Libraries)
[Em] Entry month:1802
[Cu] Class update date: 180309
[Lr] Last revision date:180309
[Js] Journal subset:IM
[Da] Date of entry for processing:171202
[St] Status:MEDLINE

  8 / 19818 MEDLINE  
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[PMID]: 29514668
[Au] Autor:Meyer A; Holt HR; Oumarou F; Chilongo K; Gilbert W; Fauron A; Mumba C; Guitian J
[Ad] Address:Department of Pathobiology and Population Sciences, Royal Veterinary College, Hatfield, UK.
[Ti] Title:Integrated cost-benefit analysis of tsetse control and herd productivity to inform control programs for animal African trypanosomiasis.
[So] Source:Parasit Vectors;11(1):154, 2018 Mar 07.
[Is] ISSN:1756-3305
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:BACKGROUND: Animal African trypanosomiasis (AAT) and its tsetse vector are responsible for annual losses estimated in billions of US dollars ($). Recent years have seen the implementation of a series of multinational interventions. However, actors of AAT control face complex resource allocation decisions due to the geographical range of AAT, diversity of ecological and livestock systems, and range of control methods available. METHODS: The study presented here integrates an existing tsetse abundance model with a bio-economic herd model that captures local production characteristics as well as heterogeneities in AAT incidence and breed. These models were used to predict the impact of tsetse elimination on the net value of cattle production in the districts of Mambwe, in Zambia, and Faro et Déo in Cameroon. The net value of cattle production under the current situation was used as a baseline, and compared with alternative publicly funded control programmes. In Zambia, the current baseline is AAT control implemented privately by cattle owners (Scenario Z0). In Cameroon, the baseline (Scenario C0) is a small-scale publicly funded tsetse control programme and privately funded control at farm level. The model was run for 10 years, using a discount rate of 5%. RESULTS: Compared to Scenario C0, benefit-cost ratios (BCR) of 4.5 (4.4-4.7) for Scenario C1 (tsetse suppression using insecticide treatment of cattle (ITC) and traps + maintenance with ITC barrier), and 3.8 (3.6-4.0) for Scenario C2 (tsetse suppression using ITC and traps + maintenance with barrier of targets), were estimated in Cameroon. For Zambia, the benefit-cost ratio calculated for Scenarios Z1 (targets, ITC barrier), Z2 (targets, barrier traps), Z3 (aerial spraying, ITC barrier), and Z4 (aerial spraying, barrier traps) were 2.3 (1.8 - 2.7), 2.0 (1.6-2.4), 2.8 (2.3-3.3) and 2.5 (2.0-2.9), respectively. Sensitivity analysis showed that the profitability of the projects is relatively resistant to variations in the costs of the interventions and their technical efficiency. CONCLUSIONS: It is envisioned that the methodologies presented here will be useful for the evaluation and design of existing and future control programmes, ensuring they have tangible benefits in the communities they are targeting.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1803
[Cu] Class update date: 180308
[Lr] Last revision date:180308
[St] Status:In-Data-Review
[do] DOI:10.1186/s13071-018-2679-x

  9 / 19818 MEDLINE  
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[PMID]: 29302035
[Au] Autor:Rijo-Ferreira F; Carvalho T; Afonso C; Sanches-Vaz M; Costa RM; Figueiredo LM; Takahashi JS
[Ad] Address:Graduate Program in Areas of Basic and Applied Biology, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, 4099-002, Porto, Portugal.
[Ti] Title:Sleeping sickness is a circadian disorder.
[So] Source:Nat Commun;9(1):62, 2018 01 04.
[Is] ISSN:2041-1723
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Sleeping sickness is a fatal disease caused by Trypanosoma brucei, a unicellular parasite that lives in the bloodstream and interstitial spaces of peripheral tissues and the brain. Patients have altered sleep/wake cycles, body temperature, and endocrine profiles, but the underlying causes are unknown. Here, we show that the robust circadian rhythms of mice become phase advanced upon infection, with abnormal activity occurring during the rest phase. This advanced phase is caused by shortening of the circadian period both at the behavioral level as well as at the tissue and cell level. Period shortening is T. brucei specific and independent of the host immune response, as co-culturing parasites with explants or fibroblasts also shortens the clock period, whereas malaria infection does not. We propose that T. brucei causes an advanced circadian rhythm disorder, previously associated only with mutations in clock genes, which leads to changes in the timing of sleep.
[Mh] MeSH terms primary: Sleep Disorders, Circadian Rhythm/physiopathology
Sleep/physiology
Trypanosoma brucei brucei/physiology
Trypanosomiasis, African/parasitology
[Mh] MeSH terms secundary: Animals
Body Temperature/physiology
Circadian Rhythm/physiology
Fibroblasts/metabolism
Fibroblasts/parasitology
Gene Expression
Host-Parasite Interactions
Humans
Male
Mice, Inbred C57BL
Mice, Transgenic
Period Circadian Proteins/genetics
Sleep Disorders, Circadian Rhythm/complications
Time Factors
Trypanosomiasis, African/complications
[Pt] Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Name of substance:0 (Period Circadian Proteins)
[Em] Entry month:1803
[Cu] Class update date: 180305
[Lr] Last revision date:180305
[Js] Journal subset:IM
[Da] Date of entry for processing:180106
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02484-2

  10 / 19818 MEDLINE  
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[PMID]: 29256285
[Au] Autor:Carnevali V; Nogueda-Torres B; Villagrán-Herrera ME; De Diego-Cabrera JA; Rocha-Chávez G; Martínez-Ibarra JA
[Ad] Address:1 Department of Public Health and Infectious Diseases, University of Rome , Rome , Italy.
[Ti] Title:Prevalence of Trypanosoma cruzi and organ alterations in Virginia opossums (Didelphis virginiana) from western Mexico - short communication.
[So] Source:Acta Vet Hung;65(4):505-509, 2017 12.
[Is] ISSN:0236-6290
[Cp] Country of publication:Hungary
[La] Language:eng
[Ab] Abstract:Small populations of Virginia opossum (Didelphis virginiana) in western Mexico are endangered by hunting and natural predators as well as by different kinds of diseases. After two serological analyses using Serodia® latex particle agglutination and indirect haemagglutination (IHA) tests, 35 (53.03%) of 66 collected opossums in two small towns in western Mexico were positive for the presence of Trypanosoma cruzi. Twenty-eight of the 35 seropositive opossums had pathological lesions: 11 had changes in only one organ, 13 in two organs, and four had pathological changes in three organs. Splenomegaly was the most common finding in the examined opossums, followed by hepatomegaly. These potentially fatal pathological changes could contribute to the scarcity of the opossum population, even leading to the extinction of this species in western Mexico.
[Mh] MeSH terms primary: Didelphis/parasitology
Trypanosoma cruzi/isolation & purification
Trypanosomiasis/veterinary
[Mh] MeSH terms secundary: Animals
Cardiomegaly/epidemiology
Cardiomegaly/parasitology
Cardiomegaly/veterinary
Esophageal Achalasia/epidemiology
Esophageal Achalasia/parasitology
Esophageal Achalasia/veterinary
Hepatomegaly/epidemiology
Hepatomegaly/parasitology
Hepatomegaly/veterinary
Mexico/epidemiology
Splenomegaly/epidemiology
Splenomegaly/parasitology
Splenomegaly/veterinary
Trypanosomiasis/epidemiology
Trypanosomiasis/pathology
[Pt] Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Em] Entry month:1803
[Cu] Class update date: 180305
[Lr] Last revision date:180305
[Js] Journal subset:IM
[Da] Date of entry for processing:171220
[St] Status:MEDLINE
[do] DOI:10.1556/004.2017.048


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