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2021 ◽  
Vol 17 (9) ◽  
pp. e1009633
Christina L. Hutson ◽  
Ashley V. Kondas ◽  
Jana M. Ritter ◽  
Zachary Reed ◽  
Sharon Dietz Ostergaard ◽  

Smallpox, caused by the solely human pathogen Variola virus (VARV), was declared eradicated in 1980. While known VARV stocks are secure, smallpox remains a bioterrorist threat agent. Recent U.S. Food and Drug Administration approval of the first smallpox anti-viral (tecovirimat) therapeutic was a successful step forward in smallpox preparedness; however, orthopoxviruses can become resistant to treatment, suggesting a multi-therapeutic approach is necessary. Animal models are required for testing medical countermeasures (MCMs) and ideally MCMs are tested directly against the pathogen of interest. Since VARV only infects humans, a representative animal model for testing therapeutics directly against VARV remains a challenge. Here we show that three different humanized mice strains are highly susceptible to VARV infection, establishing the first small animal model using VARV. In comparison, the non-humanized, immunosuppressed background mouse was not susceptible to systemic VARV infection. Following an intranasal VARV challenge that mimics the natural route for human smallpox transmission, the virus spread systemically within the humanized mouse before mortality (~ 13 days post infection), similar to the time from exposure to symptom onset for ordinary human smallpox. Our identification of a permissive/representative VARV animal model can facilitate testing of MCMs in a manner consistent with their intended use.

Sepideh Shabani ◽  
Fahimeh Kaveh Baghbahadorani ◽  
Farahnaz Jazaeri ◽  
Foruzan Ganji ◽  
Nayyereh Sadat Mortazavi ◽  

Background: Silymarin and N-acetylcysteine are antioxidant supplements with protective effects on the liver and kidneys. The aim of this study was to investigate the effect of silymarin and N-acetylcysteine on liver and kidney disorders against severe pre-eclampsia. Methods: In the present single-blind clinical trial, 60 mothers who underwent termination of pregnancy due to severe pre-eclampsia were divided into two groups. The first group received 70 mg of silymarin and the second group received 600 mg of N-acetylcysteine at 3 doses immediately, 12 and 24 hours after delivery. Patients were monitored for blood pressure, platelet and biochemical markers of liver injury and kidney function 12, 36 and 60 hours after drug administration. Results: Over time, the mean Alanine Transaminase (ALT), Aspartate Transaminase (AST), Lactate Dehydrogenase (LDH) and Alkaline Phosphatase (ALP), levels in the two groups of silymarin and N-acetylcysteine significantly decreased (p<0.001). Silymarin and N-acetylcysteine were not significantly different in reducing the increased creatinine and BUN levels. Conclusion: N-acetylcysteine and silymarin help patients with pre-eclampsia to improve kidney and hepatic dysfunction; however, silymarin was more effective in decreasing ALT, AST, ALP, and LDH levels than N-acetylcysteine. N-acetylcysteine was more effective in decreasing BUN and creatinine levels than silymarin.

2021 ◽  
Vol 19 (1) ◽  
Tim Jang ◽  
Maria Poplawska ◽  
Emanuela Cimpeanu ◽  
George Mo ◽  
Dibyendu Dutta ◽  

AbstractPainful vaso-occlusive crisis (VOC) remains the most common reason for presenting to the Emergency Department and hospitalization in patients with sickle cell disease (SCD). Although two new agents have been approved by the Food and Drug Administration for treating SCD, they both target to reduce the frequency of VOC. Results from studies investigating various approaches to treat and shorten VOC have so far been generally disappointing. In this paper, we will summarize the complex pathophysiology and downstream events of VOC and discuss the likely reasons for the disappointing results using monotherapy. We will put forward the rationale for exploring some of the currently available agents to either protect erythrocytes un-involved in the hemoglobin polymerization process from sickling induced by the secondary events, or a multipronged combination approach that targets the complex downstream pathways of VOC.

2021 ◽  
Vol 15 (9) ◽  
pp. e0009596
Reza A. Niles ◽  
Charles R. Thickstun ◽  
Horace Cox ◽  
Daniel Dilliott ◽  
Clara R. Burgert-Brucker ◽  

Background Guyana is one of four countries in the Latin American Region where lymphatic filariasis (LF) remains endemic. In preparation for the introduction of a new triple drug therapy regimen (ivermectin, diethylcarbamazine, and albendazole (IDA)) in 2019, an acceptability study was embedded within sentinel site mapping in four regions to assess mass drug administration (MDA) coverage and compliance, acceptability, and perceptions about treatment and disease. The results from this survey would inform the rollout of IDA in Guyana in 2019. Methods Data collection for the study occurred in August 2019, using a validated questionnaire administered by trained enumerators. Across all regions, a total of 1,248 participants were sampled by the Filarial Mapping team. Four-hundred and fifty-one participants aged over 18 years were randomly selected for participation in an expanded acceptability questionnaire. All data were captured in Secure Data Kit (SDK). Results Acceptability was measured using a mean acceptability score. Unadjusted mean scores ranged from 24.6 to 29.3, with 22.5 as the threshold of acceptability. Regional variation occurred across many indicators of interest: self-rated understanding about LF, mechanisms of LF transmission, LF drug safety and history of treatment during MDA. Region IV (Georgetown) recorded higher knowledge about LF, but lower compliance and acceptability. Number of pills was not perceived as a concern. Conclusion Acceptability of MDA was good across all four regions under study. Results from this study set a baseline level for key indicators and acceptability, from which the acceptability of IDA can be measured. Regional variations across indicators suggest that localized approaches should be considered for social mobilization and MDA delivery to capture these contextual differences.

2021 ◽  
Stella de Jesus Lourenço da Silva ◽  
Alícia De Souza Santos ◽  
Derly Rodrigues De Souza ◽  
Raquel Lira Lustosa Carvalho

Introdução: A anemia falciforme é uma doença causada por uma mutação na cadeia β da hemoglobina (Hb) que leva à produção da hemoglobina falciforme (HbS), resultando na falcização dos eritrócitos. Essa alteração pode causar crise vaso-oclusiva dolorosa, lesão vascular e dano ao órgão-alvo. O tratamento atual é feito com hidroxiuréia e L-glutamina, que tratam apenas os sintomas da doença, além disso, a hidroxiuréia apresenta efeitos adversos significativos. O voxelotor foi aprovado em 2019 pela US Food and Drug Administration. Esse medicamento forma uma ligação covalente reversível com a valina N-terminal da cadeia α da Hb e modula sua afinidade pelo oxigênio que, uma vez oxigenada, previne a falcização. Objetivo: Analisar a eficácia e os resultados obtidos na fase de teste deste medicamento através da análise de artigos disponíveis na literatura. Metodologia: A pesquisa foi realizada nas bases Biblioteca Virtual em Saúde, PubMed, SciELO e Google acadêmico. A seleção dos artigos foi realizada de acordo com título, resumo, palavras-chave e ano de publicação (2016-2021). Resultados: O voxelotor apresentou boa tolerância, perfil farmacocinético linear e meia-vida variando de 61 a 85 horas. O medicamento conseguiu aumentar os níveis de hemoglobina, reduzir os marcadores de hemólise de maneira dose-dependente e diminuiu os danos vasculares induzidos por hemólise em pacientes com anemia falciforme. Ademais, a droga inibiu a falcização das hemácias e diminuiu a viscosidade do sangue, reduzindo o risco de anemia e hemólise. Alguns pacientes apresentaram efeitos leves a moderados, como diarreia, náuseas e vômitos, entretanto, estes podem não estar diretamente relacionados ao tratamento. Conclusões: O voxelotor foi bem tolerado pelos usuários, aumentou os níveis de hemoglobina, a afinidade pelo oxigênio, diminuiu a hemólise em pacientes com anemia falciforme e exibiu apenas efeitos colaterais leves a moderados, mostrando-se ser um medicamento promissor no tratamento da anemia falciforme.

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