Efficacy of Proveblue (Methylene Blue) in an Experimental Cerebral Malaria Murine Model

ABSTRACTAlthough 100% of untreated mice infected withPlasmodium bergheidied with specific signs of cerebral malaria and 100% of mice treated with 3 mg/kg dihydroartemisinin, the active metabolite of artesunate, which is used as the first-line treatment for severe malaria, also died but showed no specific signs of cerebral malaria, 78% of mice treated with 10 mg/kg Proveblue (methylene blue) and 78% of mice treated with a combination of 3 mg dihydroartemisinin and 10 mg/kg Proveblue survived and showed no specific signs of cerebral malaria or detectable parasites.

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In VitroAntimicrobial Susceptibility Patterns of Blastocystis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.04832-14 ◽

2015 ◽

Vol 59 (8) ◽

pp. 4417-4423 ◽

Cited By ~ 4

Author(s):

Tamalee Roberts ◽

Stephen Bush ◽

John Ellis ◽

John Harkness ◽

Damien Stark

Keyword(s):

Current Treatment ◽

Line Treatment ◽

First Line ◽

Content Type ◽

Treatment Regimens ◽

Drug Treatments ◽

Resistant Strains ◽

Susceptibility Patterns ◽

First Line Treatment

ABSTRACTBlastocystisis the most common human enteric protist with controversial clinical significance. Metronidazole is considered a first-line treatment forBlastocystisinfection; however, there has been increasing evidence for the lack of efficacy of this treatment. Treatment failure has been reported in several clinical cases, and recentin vitrostudies have suggested the occurrence of metronidazole-resistant strains. In this study, we tested 12Blastocystisisolates from 4 commonBlastocystissubtypes (ST1, ST3, ST4, and ST8) against 12 commonly used antimicrobials (metronidazole, paromomycin, ornidazole, albendazole, ivermectin, trimethoprim-sulfamethoxazole [TMP-SMX], furazolidone, nitazoxanide, secnidazole, fluconazole, nystatin, and itraconazole) at 10 different concentrationsin vitro. It was found that each subtype showed little sensitivity to the commonly used metronidazole, paromomycin, and triple therapy (furazolidone, nitazoxanide, and secnidazole). This study highlights the efficacy of other potential drug treatments, including trimethoprim-sulfamethoxazole and ivermectin, and suggests that current treatment regimens be revised.

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Mycobacterium tuberculosis Coinfection Has No Impact on Plasmodium berghei ANKA-Induced Experimental Cerebral Malaria in C57BL/6 Mice

Infection and Immunity ◽

10.1128/iai.01290-15 ◽

2015 ◽

Vol 84 (2) ◽

pp. 502-510 ◽

Cited By ~ 5

Author(s):

Jannike Blank ◽

Jochen Behrends ◽

Thomas Jacobs ◽

Bianca E. Schneider

Keyword(s):

Mycobacterium Tuberculosis ◽

Immune Responses ◽

Cerebral Malaria ◽

Plasmodium Berghei ◽

Parasite Clearance ◽

Human Infection ◽

Experimental Cerebral Malaria ◽

Content Type ◽

Cell Responses ◽

The Tropics

Cerebral malaria (CM) is the most severe complication of human infection withPlasmodium falciparum. The mechanisms predisposing to CM are still not fully understood. Proinflammatory immune responses are required for the control of blood-stage malaria infection but are also implicated in the pathogenesis of CM. A fine balance between pro- and anti-inflammatory immune responses is required for parasite clearance without the induction of host pathology. The most accepted experimental model to study human CM isPlasmodium bergheiANKA (PbANKA) infection in C57BL/6 mice that leads to the development of a complex neurological syndrome which shares many characteristics with the human disease. We applied this model to study the outcome ofPbANKA infection in mice previously infected withMycobacterium tuberculosis, the causative agent of tuberculosis. Tuberculosis is coendemic with malaria in large regions in the tropics, and mycobacteria have been reported to confer some degree of unspecific protection against rodentPlasmodiumparasites in experimental coinfection models. We found that concomitantM. tuberculosisinfection did not change the clinical course ofPbANKA-induced experimental cerebral malaria (ECM) in C57BL/6 mice. The immunological environments in spleen and brain did not differ between singly infected and coinfected animals; instead, the overall cytokine and T cell responses in coinfected mice were comparable to those in animals solely infected withPbANKA. Our data suggest thatM. tuberculosiscoinfection is not able to change the outcome ofPbANKA-induced disease, most likely because the inflammatory response induced by the parasite rapidly dominates in mice previously infected withM. tuberculosis.

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The Glycosylphosphatidylinositol Transamidase Complex Subunit PbGPI16 of Plasmodium berghei Is Important for Inducing Experimental Cerebral Malaria

Infection and Immunity ◽

10.1128/iai.00929-17 ◽

2018 ◽

Vol 86 (8) ◽

Cited By ~ 2

Author(s):

Qingyang Liu ◽

Yan Zhao ◽

Li Zheng ◽

Xiaotong Zhu ◽

Liwang Cui ◽

...

Keyword(s):

Cerebral Malaria ◽

Plasmodium Berghei ◽

Surface Display ◽

Surface Proteins ◽

Experimental Cerebral Malaria ◽

Content Type ◽

T Complex ◽

Proinflammatory Responses ◽

Major Factors ◽

Gpi Transamidase

ABSTRACT In animal models of experimental cerebral malaria (ECM), the glycosylphosphatidylinositols (GPIs) and GPI anchors are the major factors that induce nuclear factor kappa B (NF-κB) activation and proinflammatory responses, which contribute to malaria pathogenesis. GPIs and GPI anchors are transported to the cell surface via a process called GPI transamidation, which involves the GPI transamidase (GPI-T) complex. In this study, we showed that GPI16, one of the GPI-T subunits, is highly conserved among Plasmodium species. Genetic knockout of pbgpi16 (Δpbgpi16) in the rodent malaria parasite Plasmodium berghei strain ANKA led to a significant reduction of the amounts of GPIs in the membranes of merozoites, as well as surface display of several GPI-anchored merozoite surface proteins. Compared with the wild-type parasites, Δpbgpi16 parasites in C57BL/6 mice caused much less NF-κB activation and elicited a substantially attenuated T helper type 1 response. As a result, Δpbgpi16 mutant-infected mice displayed much less severe brain pathology, and considerably fewer Δpbgpi16 mutant-infected mice died from ECM. This study corroborated the GPI toxin as a significant inducer of ECM and further suggested that vaccines against parasite GPIs may be a promising strategy to limit the severity of malaria.

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A Loop-Mediated Isothermal Amplification Assay Targeting Neisseria gonorrhoeae penA-60.001

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01663-19 ◽

2019 ◽

Vol 64 (1) ◽

Author(s):

Ken Shimuta ◽

Shu-ichi Nakayama ◽

Hideyuki Takahashi ◽

Makoto Ohnishi

Keyword(s):

Neisseria Gonorrhoeae ◽

Lamp Assay ◽

Isothermal Amplification ◽

Assay System ◽

Line Treatment ◽

First Line ◽

Content Type ◽

Loop Mediated Isothermal Amplification ◽

Amplification Assay ◽

First Line Treatment

ABSTRACT Ceftriaxone (CRO) is widely used as the first-line treatment for gonococcal infections. However, CRO-resistant Neisseria gonorrhoeae strains carrying mosaic penA-60.001 have emerged recently and disseminated worldwide. To meet the urgent need to detect these strains, we report here a loop-mediated isothermal amplification (LAMP) assay system that targets N. gonorrhoeae penA-60.001. This assay system can differentiate N. gonorrhoeae strains carrying mosaic penA-60.001 from strains carrying other penA alleles.

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Baseline Ex Vivo and Molecular Responses of Plasmodium falciparum Isolates to Piperaquine before Implementation of Dihydroartemisinin-Piperaquine in Senegal

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02445-18 ◽

2019 ◽

Vol 63 (5) ◽

Cited By ~ 5

Author(s):

Marie Gladys Robert ◽

Francis Foguim Tsombeng ◽

Mathieu Gendrot ◽

Silman Diawara ◽

Marylin Madamet ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Copy Number ◽

Ex Vivo ◽

Line Treatment ◽

First Line ◽

Molecular Responses ◽

Content Type ◽

Number Variation ◽

Plasmepsin Ii ◽

First Line Treatment

ABSTRACT Dihydroartemisinin-piperaquine, which was registered in 2017 in Senegal, is not currently used as the first-line treatment against uncomplicated malaria. A total of 6.6% to 17.1% of P. falciparum isolates collected in Dakar in 2013 to 2015 showed ex vivo-reduced susceptibility to piperaquine. Neither the exonuclease E415G mutation nor the copy number variation of the plasmepsin II gene (Pfpm2), associated with piperaquine resistance in Cambodia, was detected in Senegalese parasites.

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Disruption of Parasitehmgb2Gene Attenuates Plasmodium berghei ANKA Pathogenicity

Infection and Immunity ◽

10.1128/iai.03129-14 ◽

2015 ◽

Vol 83 (7) ◽

pp. 2771-2784 ◽

Cited By ~ 8

Author(s):

Sylvie Briquet ◽

Nadou Lawson-Hogban ◽

Bertrand Boisson ◽

Miguel P. Soares ◽

Roger Péronet ◽

...

Keyword(s):

Cerebral Malaria ◽

Plasmodium Berghei ◽

Inflammatory Diseases ◽

High Mobility ◽

Experimental Cerebral Malaria ◽

Content Type ◽

Extracellular Milieu ◽

Nuclear Factors ◽

Immune Mediated ◽

The Brain

Eukaryotic high-mobility-group-box (HMGB) proteins are nuclear factors involved in chromatin remodeling and transcription regulation. When released into the extracellular milieu, HMGB1 acts as a proinflammatory cytokine that plays a central role in the pathogenesis of several immune-mediated inflammatory diseases. We found that thePlasmodiumgenome encodes two genuine HMGB factors,PlasmodiumHMGB1 and HMGB2, that encompass, like their human counterparts, a proinflammatory domain. Given that these proteins are released from parasitized red blood cells, we then hypothesized thatPlasmodiumHMGB might contribute to the pathogenesis of experimental cerebral malaria (ECM), a lethal neuroinflammatory syndrome that develops in C57BL/6 (susceptible) mice infected withPlasmodium bergheiANKA and that in many aspects resembles human cerebral malaria elicited byP. falciparuminfection. The pathogenesis of experimental cerebral malaria was suppressed in C57BL/6 mice infected withP. bergheiANKA lacking thehmgb2gene (Δhmgb2ANKA), an effect associated with a reduction of histological brain lesions and with lower expression levels of several proinflammatory genes. The incidence of ECM inpbhmgb2-deficient mice was restored by the administration of recombinantPbHMGB2. Protection from experimental cerebral malaria in Δhmgb2ANKA-infected mice was associated with reduced sequestration in the brain of CD4+and CD8+T cells, including CD8+granzyme B+and CD8+IFN-γ+cells, and, to some extent, neutrophils. This was consistent with a reduced parasite sequestration in the brain, lungs, and spleen, though to a lesser extent than in wild-typeP. bergheiANKA-infected mice. In summary,PlasmodiumHMGB2 acts as an alarmin that contributes to the pathogenesis of cerebral malaria.

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Toxoplasma gondii Upregulates Interleukin-12 To Prevent Plasmodium berghei-Induced Experimental Cerebral Malaria

Infection and Immunity ◽

10.1128/iai.01259-13 ◽

2014 ◽

Vol 82 (3) ◽

pp. 1343-1353 ◽

Cited By ~ 7

Author(s):

Erik W. Settles ◽

Lindsey A. Moser ◽

Tajie H. Harris ◽

Laura J. Knoll

Keyword(s):

Toxoplasma Gondii ◽

Cerebral Malaria ◽

Plasmodium Berghei ◽

Serum Levels ◽

Interleukin 12 ◽

Experimental Cerebral Malaria ◽

Content Type ◽

T Cell Infiltration ◽

Ifn Γ ◽

Deficient Mice

ABSTRACTA chronic infection with the parasiteToxoplasma gondiihas previously been shown to protect mice against subsequent viral, bacterial, or protozoal infections. Here we have shown that a chronicT. gondiiinfection can preventPlasmodium bergheiANKA-induced experimental cerebral malaria (ECM) in C57BL/6 mice. Treatment with solubleT. gondiiantigens (STAg) reduced parasite sequestration and T cell infiltration in the brains ofP. berghei-infected mice. Administration of STAg also preserved blood-brain barrier function, reduced ECM symptoms, and significantly decreased mortality. STAg treatment 24 h post-P. bergheiinfection led to a rapid increase in serum levels of interleukin 12 (IL-12) and gamma interferon (IFN-γ). By 5 days afterP. bergheiinfection, STAg-treated mice had reduced IFN-γ levels compared to those of mock-treated mice, suggesting that reductions in IFN-γ at the time of ECM onset protected against lethality. Using IL-10- and IL-12βR-deficient mice, we found that STAg-induced protection from ECM is IL-10 independent but IL-12 dependent. Treatment ofP. berghei-infected mice with recombinant IL-12 significantly decreased parasitemia and mortality. These data suggest that IL-12, either induced by STAg or injected as a recombinant protein, mediates protection from ECM-associated pathology potentially through early induction of IFN-γ and reduction in parasitemia. These results highlight the importance of early IL-12 induction in protection against ECM.

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Ten-Day Quadruple Therapy Comprising Low-Dose Rabeprazole, Bismuth, Amoxicillin, and Tetracycline Is an Effective and Safe First-Line Treatment for Helicobacter pylori Infection in a Population with High Antibiotic Resistance: a Prospective, Multicenter, Randomized, Parallel-Controlled Clinical Trial in China

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00432-18 ◽

2018 ◽

Vol 62 (9) ◽

Cited By ~ 1

Author(s):

Yong Xie ◽

Zhenhua Zhu ◽

Jiangbin Wang ◽

Lingxia Zhang ◽

Zhenyu Zhang ◽

...

Keyword(s):

Antibiotic Resistance ◽

Low Dose ◽

Controlled Clinical Trial ◽

Line Treatment ◽

First Line ◽

Content Type ◽

Quadruple Therapy ◽

Treatment Groups ◽

H Pylori ◽

First Line Treatment

ABSTRACT The objective of this study was to investigate the efficacy and safety of 10-day bismuth quadruple therapy with amoxicillin, tetracycline, or clarithromycin and different doses of rabeprazole for first-line treatment of Helicobacter pylori infection. This multicenter, randomized, parallel-controlled clinical trial was conducted between March 2013 and August 2014. A total of 431 H. pylori-infected patients with duodenal ulcers were enrolled and randomized into four treatment groups (1:1:1:1) for 10 days, as follows: (i) a group receiving a low dose of rabeprazole of 10 mg twice a day (b.i.d.) (LR dose) plus bismuth, amoxicillin, and clarithromycin (LR-BAC); (ii) a group receiving LR plus bismuth, amoxicillin, and tetracycline (LR-BAT); (iii) a group receiving a high dose of rabeprazole of 20 mg b.i.d. (HR dose) plus bismuth, amoxicillin, and clarithromycin (HR-BAC); and (iv) a group receiving HR-BAT. Antimicrobial susceptibility was assessed by the Etest method. The primary outcome was H. pylori eradication at 4 weeks after the treatment. The per-protocol (PP) eradication rates in the LR-BAC, LR-BAT, HR-BAC, and HR-BAT groups were 94.1%, 91.9%, 94.8%, and 91.9%, respectively, while the intention-to-treat (ITT) eradication rates in those groups were 87.2%, 87.2%, 87.7%, and 86%, respectively. There was no significant difference between the four groups in PP analysis (P = 0.799) and ITT analysis (P = 0.985). The efficacies of four-treatment therapy were not affected by antibiotic resistance. The adverse events in the four treatment groups were similar; central nervous system (CNS) and gastrointestinal symptoms were the most common reported. Bismuth-containing quadruple therapy with low-dose rabeprazole, amoxicillin, and tetracycline is a good option for first-line treatment of H. pylori infection in a population with high antibiotic resistance. (This study is registered at Chinese Clinical Trials Registry [www.chictr.org.cn] under number ChiCTR1800014832.)

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