scholarly journals Hematological consequences of malaria in mice previously treated for visceral leishmaniasis

2021 ◽  
Vol 6 ◽  
pp. 83
Author(s):  
Gulab Fatima Rani ◽  
Helen Ashwin ◽  
Najmeeyah Brown ◽  
Ian S. Hitchcock ◽  
Paul M. Kaye
Keyword(s):  
Leishmania Donovani ◽  
Severe Disease ◽  
Parasite Burden ◽  
Subsequent Development ◽  
Blood Parameters ◽  
Inos Expression ◽  
Infection Model ◽  
Plasmodium Infection ◽  
Previously Treated ◽  
The Impact

Background: Polyparasitism is commonplace in countries where endemicity for multiple parasites exists, and studies in animal models of coinfection have made significant inroads into understanding the impact of often competing demands on the immune system. However, few studies have addressed how previous exposure to and treatment for one infection impacts a subsequent heterologous infection.   Methods: We used a C57BL/6 mouse model of drug-treated Leishmania donovani infection followed by experimental Plasmodium chabaudi AS malaria, focusing on hematological dysfunction as a common attribute of both infections. We measured parasite burden, blood parameters associated with anemia and thrombocytopenia, and serum thrombopoietin. In addition, we quantified macrophage iNOS expression through immunohistological analysis of the liver and spleen.   Results: We found that the thrombocytopenia and anemia that accompanies primary L. donovani infection was rapidly reversed following single dose AmBisome® treatment, along with multiple other markers associated with immune activation (including restoration of tissue microarchitecture and reduced macrophage iNOS expression). Compared to naive mice, mice cured of previous L. donovani infection showed comparable albeit delayed clinical responses (including peak parasitemia and anemia) to P. chabaudi AS infection. Thrombocytopenia was also evident in these sequentially infected mice, consistent with a decrease in circulating levels of thrombopoietin. Architectural changes to the spleen were also comparable in sequentially infected mice compared to those with Plasmodium infection alone. Conclusions: Our data suggest that in this sequential infection model, previously-treated L. donovani infection has limited impact on the subsequent development of Plasmodium infection, but this issue deserves further attention in models of more severe disease or through longitudinal population studies in humans.

scholarly journals Hematological consequences of malaria infection in mice previously treated for visceral leishmaniasis

2021 ◽  
Vol 6 ◽  
pp. 83
Author(s):  
Gulab Fatima Rani ◽  
Helen Ashwin ◽  
Najmeeyah Brown ◽  
Ian S. Hitchcock ◽  
Paul M. Kaye
Keyword(s):  
Leishmania Donovani ◽  
Severe Disease ◽  
Parasite Burden ◽  
Subsequent Development ◽  
Blood Parameters ◽  
Inos Expression ◽  
Infection Model ◽  
Clinical Responses ◽  
Previously Treated ◽  
The Impact

Background: Polyparasitism is commonplace in countries where endemicity for multiple parasites exists, and studies in animal models of coinfection have made significant inroads into understanding the impact of often competing demands on the immune system. However, few studies have addressed how previous exposure to and treatment for one infection impacts a subsequent heterologous infection.   Methods: We used a C57BL/6 mouse model of drug-treated Leishmania donovani infection followed by experimental Plasmodium chabaudi AS malaria, focusing on hematological dysfunction as a common attribute of both infections. We measured parasite burden, blood parameters associated with anemia and thrombocytopenia, and serum thrombopoietin. In addition, we quantified macrophage iNOS expression through immunohistological analysis of the liver and spleen.   Results: We found that the thrombocytopenia and anemia that accompanies primary L. donovani infection was rapidly reversed following single dose AmBisome® treatment, along with multiple other markers associated with immune activation (including restoration of tissue microarchitecture and reduced macrophage iNOS expression). Compared to naive mice, mice cured of previous VL showed comparable albeit delayed clinical responses (including peak parasitemia and anemia) to P. chabaudi AS infection. Thrombocytopenia was also evident in these sequentially infected mice, consistent with a decrease in circulating levels of thrombopoietin. Architectural changes to the spleen were also comparable in sequentially infected mice compared to those with malaria alone. Conclusions: Our data suggest that in this sequential infection model, previously-treated VL has limited impact on the subsequent development of malaria, but this issue deserves further attention in models of more severe disease or through longitudinal population studies in humans.

scholarly journals Evaluation of modulators of cAMP-response in terms of their impact on cell cycle and mitochondrial activity of Leishmania donovani

2020 ◽  
Author(s):  
Amrita Saha ◽  
Anindita Bhattacharjee ◽  
Amit Vij ◽  
Pijush K. Das ◽  
Arijit Bhattacharya ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Leishmania Donovani ◽  
Parasite Burden ◽  
Careful Examination ◽  
Mammalian Host ◽  
Infection Model ◽  
Mitochondrial Activity ◽  
Macrophage Infection ◽  
Pde Inhibitors

AbstractWith the identification of novel cAMP binding effecter molecules in Trypanosoma, role of cAMP in kinetopalstida parasites gained an intriguing break through. Despite earlier demonstrations of role of cAMP in survival of Leishmania during macrophage infection, there is essential need to specifically clarify involvement of cAMP in various cellular processes in the parasite. In this context, we sought to gain a comprehensive understanding of the effect of cAMPanalogs and cAMP-phosphodiesterase (PDE) inhibitors on proliferation of log phase parasites. Administration of both hydrolysable (8-pCPT-cAMP) and non-hydrolysable analogs (Sp-8-pCPT-cAMPS) of cAMP resulted in significant decrease of Leishmania proliferation. Amongst the various PDE inhibitors, etazolate was found to be potently anti-proliferative. BrdU cell proliferation and K/N/F-enumeration microscopic study revealed that both cAMP analogues and selective PDE inhibitors resulted in significant cell cycle arrest at G1 phase with reduced S-phase population. Furthermore, careful examination of the flagellar motility patterns revealed significantly reduced coordinated forward flagellar movement of the promastigotes with a concomitant decrease in cellular ATP levels. Alongside, 8-pCPT-cAMP and PDE inhibitors etazolate and trequinsin showed marked reduction in mitochondrial membrane potential. Treatment of etazolate at subcytotoxic concentration to infected macrophages significantly reduced parasite burden and administration of etazolate to Leishmania-infected BALB/c mice showed reduced liver and spleen parasite burden. Collectively, these results imply involvement of cAMP in various crucial processes paving the avenue for developing potent anti-leishmanial agent.Author SummaryLeishmania donovani is the causative agent of fatal Visceral Leishmaniasis. The current available medications are toxic, expensive and require long term daily administrations. With an aim to develop improved therapeutic, components of cAMP homeostasis, particularly cAMP-phosphodiesteares, has been targeted for Leishmania and other kinetoplastid pathogens. cAMP plays diverse roles in functional processes involved in cell division, transition into different stages of the life cycle of Leishmania and motility. In this study, the authors found administration of both hydrolysable and non-hydrolysable analogs of cAMP and certain PDE inhibitors resulted in remarkable decrease proliferation with considerable cytopathic impact on promastigotes. The mammalian phosphodiestearse inhibitor etazolate caused significant reduction in parasite load in L. donovani infected macrophages and demonstrated considerable reduction of liver and spleen parasite burden in in vivo mouse infection model. The study suggested that etazolate, with its slightest impact on mammalian host, can be repurposed for developing effective anti-leishmanials.

scholarly journals Leishmania donovani metacyclic promastigotes impair phagosome properties in inflammatory monocytes

2021 ◽  
Author(s):  
Christine Matte ◽  
Guillermo Arango Duque ◽  
Albert Descoteaux
Keyword(s):  
Nadph Oxidase ◽  
Leishmania Donovani ◽  
Parasitophorous Vacuole ◽  
Clinical Manifestations ◽  
Parasite Burden ◽  
Surface Coat ◽  
Self Healing ◽  
Inflammatory Monocytes ◽  
Metacyclic Promastigotes ◽  
The Impact

Leishmaniasis, a debilitating disease with clinical manifestations ranging from self-healing ulcers to life-threatening visceral pathologies, is caused by protozoan parasites of the Leishmania genus. These professional vacuolar pathogens are transmitted by infected sand flies to mammalian hosts as metacyclic promastigotes and are rapidly internalized by various phagocyte populations. Classical monocytes are among the first myeloid cells to migrate to infection sites. Recent evidence shows that recruitment of these cells contributes to parasite burden and to the establishment of chronic disease. However, the nature of Leishmania-inflammatory monocyte interactions during the early stages of host infection has not been well investigated. Here, we aimed to assess the impact of Leishmania donovani metacyclic promastigotes on antimicrobial responses within these cells. Our data showed that inflammatory monocytes are readily colonized by L. donovani metacyclic promastigotes, while infection with Escherichia coli is efficiently cleared. Upon internalization, metacyclic promastigotes inhibited superoxide production at the parasitophorous vacuole (PV) through a mechanism involving exclusion of NADPH oxidase subunits gp91phox and p47phox from the PV membrane. Moreover, we observed that unlike phagosomes enclosing zymosan particles, vacuoles containing parasites acidify poorly. Interestingly, whereas the parasite surface coat virulence glycolipid lipophosphoglycan (LPG) was responsible for the inhibition of PV acidification, impairment of the NADPH oxidase assembly was independent of LPG and GP63. Collectively, these observations indicate that permissiveness of inflammatory monocytes to L. donovani may thus be related to the ability of this parasite to impair the microbicidal properties of phagosomes.

scholarly journals PREPARATION AND CHARACTERIZATION OF ANDROGRAPHOLIDE NANOPARTICLES FOR VISCERAL LEISHMANIASIS CHEMOTHERAPY: IN VITRO AND IN VIVO EVALUATIONS

2016 ◽  
Vol 8 (12) ◽  
pp. 102
Author(s):  
Pallab Ghosh ◽  
Subhasish Mondal ◽  
Tanmoy Bera
Keyword(s):  
Visceral Leishmaniasis ◽  
Leishmania Donovani ◽  
Parasite Burden ◽  
Plga Nanoparticles ◽  
Antileishmanial Activity ◽  
Infection Model ◽  
Vitamin E Tpgs ◽  
Polyethylene Glycol 1000

<p><strong>Objective: </strong>To overcome low physiological solubility, poor bioavailability, the short plasma half-life of andrographolide (AG), a delivery system based on poly (D, L-lactide-co-glycolide) (PLGA) nanoparticles (NPs) were developed to increase the efficiency of AG against visceral leishmaniasis (VL).<strong> </strong></p><p><strong>Methods: </strong>Andrographolide-PLGA nanoparticles (AGnp) were prepared with Pgp efflux inhibitor vitamin E TPGS (D-α-tocopheryl polyethylene glycol 1000 succinate) by emulsion solvent evaporation method and characterized. Antileishmanial activity was evaluated using<em> in vitro</em> and<em> in vivo</em> VL infection model. <strong></strong></p><p><strong>Results: </strong>The particle size of AGnp was found to be171.4±11.5 nm with an encapsulation efficiency of 81%. The AGnp reduced AG cellular toxicity, retained it's<em> in vitro</em> antileishmanial activity and lead to a reduction (99.9%) of parasite burden in the <em>Leishmania donovani</em> infected spleen and liver. AGnp was more active in infected mice liver at low dose than in spleen. Therapeutic indexes (TI) were 6.9-fold greater in AG and 68-fold in AGnp compared to amphotericin B (AmB) when evaluated in <em>L. donovani</em> infected spleen.<strong> </strong></p><p><strong>Conclusion: </strong>Incorporation of AG in PLGA nanoparticles, provided controlled and improved <em>in vivo</em> performance against VL</p>

scholarly journals Leishmania donovani metacyclic promastigotes impair phagosome properties in inflammatory monocytes

2021 ◽  
Author(s):  
Christine Matte ◽  
Guillermo Arango Duque ◽  
Albert Descoteaux
Keyword(s):  
Nadph Oxidase ◽  
Leishmania Donovani ◽  
Parasitophorous Vacuole ◽  
Clinical Manifestations ◽  
Parasite Burden ◽  
Surface Coat ◽  
Self Healing ◽  
Inflammatory Monocytes ◽  
Metacyclic Promastigotes ◽  
The Impact

Leishmaniasis, a debilitating disease with clinical manifestations ranging from self-healing ulcers to life-threatening visceral pathologies, is caused by protozoan parasites of the Leishmania genus. These professional vacuolar pathogens are transmitted by infected sand flies to mammalian hosts as metacyclic promastigotes and are rapidly internalized by various phagocyte populations. Classical monocytes are among the first myeloid cells to migrate to infection sites. Recent evidence shows that recruitment of these cells contributes to parasite burden and to the establishment of chronic disease. However, the nature of Leishmania-inflammatory monocyte interactions during the early stages of host infection has not been well investigated. Here, we aimed to assess the impact of Leishmania donovani metacyclic promastigotes on antimicrobial responses within these cells. Our data showed that inflammatory monocytes were readily colonized by L. donovani metacyclic promastigotes, while infection with Escherichia coli was efficiently cleared. Upon internalization, metacyclic promastigotes inhibited superoxide production at the parasitophorous vacuole (PV) through a mechanism involving exclusion of NADPH oxidase subunits gp91 phox and p47phox from the PV membrane. Moreover, we observed that unlike phagosomes enclosing zymosan particles, vacuoles containing parasites acidified poorly. Interestingly, whereas the parasite surface coat virulence glycolipid lipophosphoglycan was responsible for the inhibition of PV acidification, impairement of the NADPH oxidase assembly was independent of lipophosphoglycan and of the metalloprotease GP63. Collectively, these observations indicate that permissiveness of inflammatory monocytes to L. donovani may thus be related to the ability of this parasite to impair the microbicidal properties of phagosomes.

scholarly journals Outcomes of COVID-19 Hospitalized Patients Previously Treated with Renin-Angiotensin System Inhibitors

2020 ◽  
Vol 9 (11) ◽  
pp. 3472 ◽  
Author(s):  
Elena-Mihaela Cordeanu ◽  
Lucas Jambert ◽  
Francois Severac ◽  
Hélène Lambach ◽  
Jonathan Tousch ◽  
...  
Keyword(s):  
Renin Angiotensin System ◽  
Severe Pneumonia ◽  
University Hospital ◽  
Angiotensin System ◽  
Angiotensin Converting Enzyme 2 ◽  
Renin Angiotensin ◽  
Previously Treated ◽  
The Impact ◽  
Harmful Effects ◽  
Observation Period

(1) Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) penetrates respiratory epithelium through angiotensin-converting enzyme-2 binding, raising concerns about the potentially harmful effects of renin–angiotensin system inhibitors (RASi) on Human Coronavirus Disease 2019 (COVID-19) evolution. This study aimed to provide insight into the impact of RASi on SARS-CoV-2 outcomes in patients hospitalized for COVID-19. (2) Methods: This was a retrospective analysis of hospitalized adult patients with SARS-CoV-2 infection admitted to a university hospital in France. The observation period ended at hospital discharge. (3) Results: During the study period, 943 COVID-19 patients were admitted to our institution, of whom 772 were included in this analysis. Among them, 431 (55.8%) had previously known hypertension. The median age was 68 (56–79) years. Overall, 220 (28.5%) patients were placed under mechanical ventilation and 173 (22.4%) died. According to previous exposure to RASi, we defined two groups, namely, “RASi” (n = 282) and “RASi-free” (n = 490). Severe pneumonia (defined as leading to death and/or requiring intubation, high-flow nasal oxygen, noninvasive ventilation, and/or oxygen flow at a rate of ≥5 L/min) and death occurred more frequently in RASi-treated patients (64% versus 53% and 29% versus 19%, respectively). However, in a propensity score-matched cohort derived from the overall population, neither death (hazard ratio (HR) 0.93 (95% confidence interval (CI) 0.57–1.50), p = 0.76) nor severe pneumonia (HR 1.03 (95%CI 0.73–1.44), p = 0.85) were associated with RASi therapy. (4) Conclusion: Our study showed no correlation between previous RASi treatment and death or severe COVID-19 pneumonia after adjustment for confounders.

scholarly journals Vitamin D and Blood Parameters

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 1017
Author(s):  
Thomas Müller ◽  
Lutz Lohse ◽  
Andreas Blodau ◽  
Katja Frommholz
Keyword(s):  
Vitamin D ◽  
Mean Corpuscular Volume ◽  
Plasma Concentrations ◽  
Blood Parameters ◽  
Vitamin D Supplementation ◽  
Mean Corpuscular Hemoglobin ◽  
Corpuscular Volume ◽  
Corpuscular Haemoglobin ◽  
Mean Corpuscular Haemoglobin ◽  
The Impact

Background: Vitamin D has a steroid- and an anabolic-resembling chemical structure. Vitamin D is essential for many processes in the human body after hydroxylation. Aims of the Study: To investigate the impact of 25-hydroxy-vitamin D plasma concentrations on the blood parameters number of erythrocytes, hematocrit, mean corpuscular hemoglobin and mean corpuscular volume. Methods: Serial assessments were done in 290 patients with multiple sclerosis and repeated after a mean interval of 245 days. A recommendation for vitamin D supplementation was given in case of a concentration lower than 20 ng/mL combined with a prescription of a formulation containing vitamin D but not vitamin K. Results: There was a fall of vitamin D in 119 subjects and a rise in 164, while no change appeared in 7 participants. When vitamin D values went down between both assessments moments, the computed increase of mean corpuscular haemoglobin was significantly lower compared with the rise of mean corpuscular haemoglobin associated with a vitamin D elevation. When vitamin D declined, the computed fall of mean corpuscular volume fall was significantly lower compared with the decrease of mean corpuscular volume, when vitamin D rose. Positive correlations were found between differences of vitamin D and mean corpuscular haemoglobin, respectively mean corpuscular volume. Inverse relations appeared between disparities of vitamin D and erythrocytes, respectively haematocrit. Conclusions: The elevation of vitamin D plasma levels provides enhanced preconditions for a better tissue oxygenation on a cellular level.

scholarly journals Baicalin Represses Type Three Secretion System of Pseudomonas aeruginosa through PQS System

Molecules ◽  
2021 ◽  
Vol 26 (6) ◽  
pp. 1497
Author(s):  
Pansong Zhang ◽  
Qiao Guo ◽  
Zhihua Wei ◽  
Qin Yang ◽  
Zisheng Guo ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Virulence Factors ◽  
Mammalian Cells ◽  
Secretion System ◽  
Chinese Herbs ◽  
Infection Model ◽  
Lung Pathology ◽  
Promising Alternative ◽  
The Impact

Therapeutics that target the virulence of pathogens rather than their viability offer a promising alternative for treating infectious diseases and circumventing antibiotic resistance. In this study, we searched for anti-virulence compounds against Pseudomonas aeruginosa from Chinese herbs and investigated baicalin from Scutellariae radix as such an active anti-virulence compound. The effect of baicalin on a range of important virulence factors in P. aeruginosa was assessed using luxCDABE-based reporters and by phenotypical assays. The molecular mechanism of the virulence inhibition by baicalin was investigated using genetic approaches. The impact of baicalin on P. aeruginosa pathogenicity was evaluated by both in vitro assays and in vivo animal models. The results show that baicalin diminished a plenty of important virulence factors in P. aeruginosa, including the Type III secretion system (T3SS). Baicalin treatment reduced the cellular toxicity of P. aeruginosa on the mammalian cells and attenuated in vivo pathogenicity in a Drosophila melanogaster infection model. In a rat pulmonary infection model, baicalin significantly reduced the severity of lung pathology and accelerated lung bacterial clearance. The PqsR of the Pseudomonas quinolone signal (PQS) system was found to be required for baicalin’s impact on T3SS. These findings indicate that baicalin is a promising therapeutic candidate for treating P. aeruginosa infections.

scholarly journals The impact of quarantine on Covid-19 infections

2021 ◽  
Vol 10 (s1) ◽  
Author(s):  
Pablo Marshall
Keyword(s):  
Health System ◽  
Infection Rate ◽  
District Level ◽  
Infection Model ◽  
Social Distancing ◽  
Proposed Model ◽  
Lower Infection ◽  
The Impact ◽  
Lower Infection Rate ◽  
Over Time

Abstract Objectives: Coronavirushas had profound effects on people’s lives and the economy of many countries, generating controversy between the need to establish quarantines and other social distancing measures to protect people’s health and the need to reactivate the economy. This study proposes and applies a modification of the SIR infection model to describe the evolution of coronavirus infections and to measure the effect of quarantine on the number of people infected. Methods: Two hypotheses, not necessarily mutually exclusive, are proposed for the impact of quarantines. According to the first hypothesis, quarantine reduces the infection rate, delaying new infections over time without modifying the total number of people infected at the end of the wave. The second hypothesis establishes that quarantine reduces the population infected in the wave. The two hypotheses are tested with data for a sample of 10 districts in Santiago, Chile. Results: The results of applying the methodology show that the proposed model describes well the evolution of infections at the district level. The data shows evidence in favor of the first hypothesis, quarantine reduces the infection rate; and not in favor of the second hypothesis, that quarantine reduces the population infected. Districts of higher socio-economic levels have a lower infection rate, and quarantine is more effective. Conclusions: Quarantine, in most districts, does not reduce the total number of people infected in the wave; it only reduces the rate at which they are infected. The reduction in the infection rate avoids peaks that may collapse the health system.

scholarly journals Splanchnic Vein Thrombosis in Acute Pancreatitis and Its Consequences

2021 ◽  
Vol 27 ◽  
pp. 107602962110102
Author(s):  
Łukasz Nawacki ◽  
Jarosław Matykiewicz ◽  
Ewa Stochmal ◽  
Stanisław Głuszek
Keyword(s):  
Acute Pancreatitis ◽  
Severe Disease ◽  
Vascular Complication ◽  
Strong Positive Correlation ◽  
Splanchnic Vein Thrombosis ◽  
Vein Thrombosis ◽  
Computed Tomography Scans ◽  
Negative Effect ◽  
Medical Histories ◽  
The Impact

Splanchnic vein thrombosis (SVT) is a serious vascular complication that can occur in patients with acute pancreatitis. We assessed the incidence of SVT and its relationship with acute pancreatitis (AP) and associated complications. We carried out a retrospective analysis of medical histories from patients hospitalized with AP in a single surgical center. Histories were acquired from patients with abdominal and pelvic computed tomography scans performed between the 2nd and 3rd day of hospitalization. We assessed the impact and extent of thrombosis over the disease course. We found a strong positive correlation (Cramer’s V coefficient = 0.34) between SVT and disease severity. Mortality in the study group was 7.2% (8 patients) of which 5 patients (62.5%) were diagnosed with SVT. We observed an increased incidence of death among patients with thrombosis, with results approaching significance ( P = 0.056). In our study, we found that SVT has a negative effect on the course of AP and is associated with more severe disease and increased mortality.

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