scholarly journals MRI demonstrates glutamine antagonist-mediated reversal of cerebral malaria pathology in mice

2018 ◽  
Vol 115 (51) ◽  
pp. E12024-E12033 ◽  
Author(s):  
Brittany A. Riggle ◽  
Sanhita Sinharay ◽  
William Schreiber-Stainthorp ◽  
Jeeva P. Munasinghe ◽  
Dragan Maric ◽  
...  
Keyword(s):  
Cerebral Malaria ◽  
Fatal Outcome ◽  
Case Fatality ◽  
Adjunctive Treatment ◽  
Brain Pathology ◽  
Brain Swelling ◽  
Disease Markers ◽  
The Impact ◽  
Antimalarial Chemotherapy

The deadliest complication of Plasmodium falciparum infection is cerebral malaria (CM), with a case fatality rate of 15 to 25% in African children despite effective antimalarial chemotherapy. No adjunctive treatments are yet available for this devastating disease. We previously reported that the glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) rescued mice from experimental CM (ECM) when administered late in the infection, a time by which mice had already suffered blood–brain barrier (BBB) dysfunction, brain swelling, and hemorrhaging. Herein, we used longitudinal MR imaging to visualize brain pathology in ECM and the impact of a new DON prodrug, JHU-083, on disease progression in mice. We demonstrate in vivo the reversal of disease markers in symptomatic, infected mice following treatment, including the resolution of edema and BBB disruption, findings usually associated with a fatal outcome in children and adults with CM. Our results support the premise that JHU-083 is a potential adjunctive treatment that could rescue children and adults from fatal CM.

scholarly journals Reversible brain edema in experimental cerebral malaria is associated with transcellular blood-brain barrier disruption and delayed microhemorrhages

2021 ◽  
Author(s):  
Angelika Hoffmann ◽  
Jessica Jin ◽  
Mame Aida ◽  
Chi Ho Wai ◽  
Sanjib Mohanty ◽  
...  
Keyword(s):  
Cerebral Malaria ◽  
Blood Brain Barrier ◽  
Fatal Outcome ◽  
Brain Barrier ◽  
Brain Swelling ◽  
Experimental Cerebral Malaria ◽  
Barrier Disruption ◽  
Blood Brain Barrier Disruption ◽  
Blood Brain ◽  
Brain Barrier Disruption

Brain swelling occurs in cerebral malaria (CM) and may either reverse or result in fatal outcome. It is currently unknown how brain swelling in CM reverses, as investigations have been hampered by inadequate animal models. In this study, we show that reversible brain swelling in experimental murine cerebral malaria (ECM) can be induced reliably after single vaccination with radiation-attenuated sporozoites as revealed by in vivo high-field (9.4T) magnetic resonance imaging. Our results provide evidence that parenchymal fluid increase and consecutive brain swelling results from transcellular blood-brain barrier disruption (BBBD), as revealed by electron microscopy. This mechanism enables reversal of brain swelling but does not prevent persistent focal brain damage, evidenced by microhemorrhages, in areas of most severe BBBD. In a cohort of 27 pediatric and adult CM patients (n=4 fatal, n=23 non-fatal) two out of four fatal CM patients (50%) and 8 out of 23 non-fatal CM patients (35%) showed microhemorrhages on MRI at clinical field strength of 1.5T, emphasizing the translational potential of the experimental model.

Fatal outcomes of imported dengue fever in adult travelers from non-endemic areas are associated with primary infections

2021 ◽  
Author(s):  
Ralph Huits ◽  
Eli Schwartz
Keyword(s):  
Health Care Providers ◽  
Case Reports ◽  
Secondary Infection ◽  
Fatal Outcome ◽  
Case Fatality ◽  
Severe Dengue ◽  
Care Providers ◽  
Denv Serotypes ◽  
Secondary Infections ◽  
The Impact

Abstract Background The case-fatality rate of dengue in travelers is low. Secondary dengue virus (DENV) infections are considered a risk factor for fatal outcome in endemic populations; however, the impact of secondary infections on mortality in travelers has not been studied systematically. We performed a descriptive analysis of case reports of dengue fatalities in travelers. Methods We searched Medline for clinical case reports, using the free terms and MeSH headings: ‘Dengue’ OR ‘Severe Dengue’ AND ‘Travel-Related Illness’ OR ‘travel’ AND ‘Mortality’ OR ‘Fatal Outcome’. We analyzed case reports of fatal dengue in returning travelers published from 1995 to 2020, with the objective to detail risk factors for dengue mortality in this population. We verified the authors’ classifications of primary or secondary dengue infections; infections were considered as primary by absence of anti-DENV immunoglobulin (Ig)G or by IgM-to-IgG ratios greater than or equal to 1.8 in the first 7 days post symptom onset. Results We identified nine detailed reports of dengue with fatal outcome among travelers from non-endemic countries. Eight fatalities were female. The median age was 32 years (range 21–63). Out of nine fatal cases, seven travelers had a primary DENV infection, one had a secondary infection and, in one, these data were not reported. The infecting DENV serotypes were DENV-1 (n = 2), DENV-2 (n = 2) and DENV-3 (n = 3); DENV-1 or 2 (n = 1) and in one case, the serotype could not be determined. Conclusions Dengue-related deaths in travelers are rare. Most dengue cases in travelers are primary infections. Contrary to prevailing conceptions, we found that fatal outcomes of dengue in travelers from non-endemic countries were reported mainly with primary DENV infections. We alert health care providers that primary DENV infections are not always harmless and that in adult travelers from non-endemic countries, primary infections may contribute more to dengue-related mortality than secondary infections.

scholarly journals Targeting glutamine metabolism rescues mice from late-stage cerebral malaria

2015 ◽  
Vol 112 (42) ◽  
pp. 13075-13080 ◽  
Author(s):  
Emile B. Gordon ◽  
Geoffrey T. Hart ◽  
Tuan M. Tran ◽  
Michael Waisberg ◽  
Munir Akkaya ◽  
...  
Keyword(s):  
T Cells ◽  
Cerebral Malaria ◽  
Blood Brain Barrier ◽  
Case Fatality ◽  
Glutamine Metabolism ◽  
Brain Barrier ◽  
Brain Swelling ◽  
African Children ◽  
Blood Brain ◽  
The Brain

The most deadly complication of Plasmodium falciparum infection is cerebral malaria (CM) with a case fatality rate of 15–25% in African children despite effective antimalarial chemotherapy. There are no adjunctive treatments for CM, so there is an urgent need to identify new targets for therapy. Here we show that the glutamine analog 6-diazo-5-oxo-l-norleucine (DON) rescues mice from CM when administered late in the infection a time at which mice already are suffering blood–brain barrier dysfunction, brain swelling, and hemorrhaging accompanied by accumulation of parasite-specific CD8+ effector T cells and infected red blood cells in the brain. Remarkably, within hours of DON treatment mice showed blood–brain barrier integrity, reduced brain swelling, decreased function of activated effector CD8+ T cells in the brain, and levels of brain metabolites that resembled those in uninfected mice. These results suggest DON as a strong candidate for an effective adjunctive therapy for CM in African children.

scholarly journals Brain Magnetic Resonance Imaging Reveals Different Courses of Disease in Pediatric and Adult Cerebral Malaria

2020 ◽  
Author(s):  
Praveen K Sahu ◽  
Angelika Hoffmann ◽  
Megharay Majhi ◽  
Rajyabardhan Pattnaik ◽  
Catriona Patterson ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Magnetic Resonance ◽  
Cerebral Malaria ◽  
Brain Volume ◽  
Fatal Outcome ◽  
Brain Magnetic Resonance Imaging ◽  
Quantitative Mri ◽  
Resonance Imaging ◽  
Brain Swelling ◽  
Brain Volumes

Abstract Background Cerebral malaria is a common presentation of severe Plasmodium falciparum infection and remains an important cause of death in the tropics. Key aspects of its pathogenesis are still incompletely understood, but severe brain swelling identified by magnetic resonance imaging (MRI) was associated with a fatal outcome in African children. In contrast, neuroimaging investigations failed to identify cerebral features associated with fatality in Asian adults. Methods Quantitative MRI with brain volume assessment and apparent diffusion coefficient (ADC) histogram analyses were performed for the first time in 65 patients with cerebral malaria to compare disease signatures between children and adults from the same cohort, as well as between fatal and nonfatal cases. Results We found an age-dependent decrease in brain swelling during acute cerebral malaria, and brain volumes did not differ between fatal and nonfatal cases across both age groups. In nonfatal disease, reversible, hypoxia-induced cytotoxic edema occurred predominantly in the white matter in children, and in the basal ganglia in adults. In fatal cases, quantitative ADC histogram analyses also demonstrated different end-stage patterns between adults and children: Severe hypoxia, evidenced by global ADC decrease and elevated plasma levels of lipocalin-2 and microRNA-150, was associated with a fatal outcome in adults. In fatal pediatric disease, our results corroborate an increase in brain volume, leading to augmented cerebral pressure, brainstem herniation, and death. Conclusions Our findings suggest distinct pathogenic patterns in pediatric and adult cerebral malaria with a stronger cytotoxic component in adults, supporting the development of age-specific adjunct therapies.

scholarly journals The impact of COVID-19 in diabetic kidney disease and chronic kidney disease: A population-based study

2020 ◽  
Author(s):  
Juan Alonso Leon-Abarca ◽  
Roha Saeed Memon ◽  
Bahar Rehan ◽  
Maimoona Iftikhar ◽  
Antara Chatterjee
Keyword(s):  
Chronic Kidney Disease ◽  
Diabetic Nephropathy ◽  
Kidney Disease ◽  
Fatal Outcome ◽  
Case Fatality ◽  
Population Based ◽  
Continuous Variable ◽  
Binomial Regression ◽  
Robust Poisson Regression ◽  
The Impact

Background: The spectrum of pre-existing renal disease is known as a risk factor for severe COVID-19 outcomes. However, little is known about the impact of COVID-19 on patients with diabetic nephropathy in comparison to patients with chronic kidney disease. Methods: We used the Mexican Open Registry of COVID-19 patients 11 to analyze anonymized records of those who had symptoms related to COVID-19 to analyze the rates of SARS-CoV-2 infection, development of COVID-19 pneumonia, admission, intubation, Intensive Care Unit admission and mortality. Robust Poisson regression was used to relate sex and age to each of the six outcomes and find adjusted prevalences and adjusted prevalence ratios. Also, binomial regression models were performed for those outcomes that had significant results to generate probability plots to perform a fine analysis of the results obtained along age as a continuous variable. Results: The adjusted prevalence analysis revealed that that there was a a 87.9% excess probability of developing COVID-19 pneumonia in patients with diabetic nephropathy, a 5% excess probability of being admitted, a 101.7% excess probability of intubation and a 20.8% excess probability of a fatal outcome due to COVID-19 pneumonia in comparison to CKD patients (p<0.01). Conclusions: Patients with diabetic nephropathy had nearly a twofold rate of COVID-19 pneumonia, a higher probability of admission, a twofold probability of intubation and a higher chance of death once admitted compared to patients with chronic kidney disease alone. Also, both diseases had higher COVID-19 pneumonia rates, intubation rates and case-fatality rates compared to the overall population. Keywords: COVID-19, SARS-CoV-2, Chronic Kidney Disease, diabetic nephropathy

scholarly journals Parasite histones mediate leak and coagulopathy in cerebral malaria

2019 ◽  
Author(s):  
Christopher A Moxon ◽  
Yasir Alhamdi ◽  
Janet Storm ◽  
Julien MH Toh ◽  
Joo Yeon Ko ◽  
...  
Keyword(s):  
Cerebral Malaria ◽  
Fatal Outcome ◽  
Endothelial Activation ◽  
Host Cells ◽  
Brain Swelling ◽  
Coagulation Activation ◽  
Brain Vasculature ◽  
Vascular Surface ◽  
Extracellular Histones ◽  
The Brain

AbstractCoagulopathy and leak, specific to the brain vasculature, are central pathogenetic components of cerebral malaria (CM). It is unclear how the parasite, Plasmodium falciparum, triggers these processes. Extracellular histones, released from damaged host cells, bind to cell membranes and cause coagulation activation, platelet aggregation and vascular leak in diverse critical illnesses. In CM patients with P. falciparum, serum histones correlate with fibrin formation, thrombocytopenia, and endothelial activation and predict brain swelling on magnetic resonance imaging and fatal outcome. Post-mortem, histones bind to the luminal vascular surface, co-localizing with P. falciparum-infected erythrocytes (IE), and with thrombosis and leak. Purified P. falciparum histones cause toxicity and barrier disruption in cultured human brain microvascular endothelial cells, as does serum from CM patients, reversed by anti-histone antibodies and non-anticoagulant heparin. These data implicate parasite histones as a key trigger of fatal brain swelling in CM. Neutralizing histones with agents such as non-anticoagulant heparin warrant exploration to prevent brain swelling and improve outcome.

scholarly journals The impact of the global distribution of bats on mortality in COVID-19 patients

2020 ◽  
Vol 7 (1) ◽  
pp. 42-48
Author(s):  
Andrej Egorov ◽  
◽  
Julia Romanova ◽  
Keyword(s):  
Neutralizing Antibodies ◽  
Viral Infections ◽  
Fatal Outcome ◽  
Case Fatality ◽  
Epidemiological Data ◽  
Significant Heterogeneity ◽  
Large Reservoir ◽  
Inflammatory Reactions ◽  
The World ◽  
The Impact

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) originated in November 2019 in China and quickly spread throughout the world causing a disease named COVID-19. An analysis of the epidemiological data on morbidity and mortality caused by SARS-CoV-2 shows that, in some countries, namely Belgium, UK, France, Italy, the Netherlands, and Spain, an increased case fatality rate (CFR) was noticed compared to the rest of the world. The CFR, calculated as the number of deaths from the total number of the cases, ranges in these countries from 10.22% to 15.8% according to the Center for Evidence-Based Medicine (CEBM). At the same time, in the countries of Central and Northern Europe, this parameter varies between 3.78% and 4.94%. This significant heterogeneity in CFR between countries has not been given a convincing explanation yet. It was found that the precursor of SARS-CoV-2 is a virus circulating in bats in China. The mutations that occurred in this virus altered its receptor specificity, thereby enabling viral infection in humans. Bats are highly resistant to viral infections due to their robust interferon system and a reduced level of inflammatory reactions. Viruses replicate in these animals up to high titers without any substantial harm to their health. As a result, bats represent a large reservoir of viruses with the potential to infect other animals, including humans. The infection of people with bat (or human) betacoronaviruses can lead to the formation of memory B-cells that provide an accelerated antibody response to cross-reactive epitopes upon subsequent infection. The early emergence of neutralizing antibodies in SARS-CoV-2 patients correlates with the severity of the disease and the likelihood of a fatal outcome. The antibody-dependent enhancement (ADE) of infection/disease known for various viruses, including SARS-CoV-1 and MERS-CoV, may be a possible cause of this phenomenon. In this article, we suggest a close connection between the distribution areas of bats carrying SARS-CoV-1-like viruses and the CFR from COVID-19.

Experimental Study of the Impact of Alisma plantago-aquatica Secretions on Pathogenic Bacteria

2014 ◽  
Vol 1 (3) ◽  
pp. 3-7
Author(s):  
O. Zhukorskyy ◽  
O. Hulay
Keyword(s):  
Pathogenic Bacteria ◽  
Initial Density ◽  
Biologically Active ◽  
Erysipelothrix Rhusiopathiae ◽  
Natural Focus ◽  
Test Species ◽  
Popula Tions ◽  
And Control ◽  
The Impact

Aim. To estimate the impact of in vivo secretions of water plantain (Alisma plantago-aquatica) on the popula- tions of pathogenic bacteria Erysipelothrix rhusiopathiae. Methods. The plants were isolated from their natural conditions, the roots were washed from the substrate residues and cultivated in laboratory conditions for 10 days to heal the damage. Then the water was changed; seven days later the selected samples were sterilized using fi lters with 0.2 μm pore diameter. The dilution of water plantain root diffusates in the experimental samples was 1:10–1:10,000. The initial density of E. rhusiopathiae bacteria populations was the same for both experimental and control samples. The estimation of the results was conducted 48 hours later. Results. When the dilution of root diffusates was 1:10, the density of erysipelothrixes in the experimental samples was 11.26 times higher than that of the control, on average, the dilution of 1:100 − 6.16 times higher, 1:1000 – 3.22 times higher, 1:10,000 – 1.81 times higher, respectively. Conclusions. The plants of A. plantago-aquatica species are capable of affecting the populations of E. rhusiopathiae pathogenic bacteria via the secretion of biologically active substances into the environment. The consequences of this interaction are positive for the abovementioned bacteria, which is demon- strated by the increase in the density of their populations in the experiment compared to the control. The intensity of the stimulating effect on the populations of E. rhusiopathiae in the root diffusates of A. plantago-aquatica is re- ciprocally dependent on the degree of their dilution. The investigated impact of water plantain on erysipelothrixes should be related to the topical type of biocenotic connections, the formation of which between the test species in the ecosystems might promote maintaining the potential of natural focus of rabies. Keywords: Alisma plantago-aquatica, in vivo secretions, Erysipelothrix rhusiopathiae, population density, topical type of connections.

Curcumin-containing Silver Nanoparticles prevent carbon tetrachlorideinduced hepatotoxicity in mice

2020 ◽  
Vol 23 ◽  
Author(s):  
Hossam Ebaid ◽  
Mohamed Habila ◽  
Iftekhar Hassan ◽  
Jameel Al-Tamimi ◽  
Mohamed S. Omar ◽  
...  
Keyword(s):  
Dna Damage ◽  
Silver Nanoparticles ◽  
Nuclear Dna ◽  
Liquid Paraffin ◽  
Tail Length ◽  
Hepatic Tissue ◽  
Tissue Destruction ◽  
Group 2 ◽  
The Impact

Background: Hepatotoxicity remains an important clinical challenge. Hepatotoxicity observed in response to toxins and hazardous chemicals may be alleviated by delivery of the curcumin in silver nanoparticles (AgNPs-curcumin). In this study, we examined the impact of AgNPs-curcumin in a mouse model of carbon tetrachloride (CCl4)-induced hepatic injury. Methods: Male C57BL/6 mice were divided into three groups (n=8 per group). Mice in group 1 were treated with vehicle control alone, while mice in Group 2 received a single intraperitoneal injection of 1 ml/kg CCl4 in liquid paraffin (1:1 v/v). Mice in group 3 were treated with 2.5 mg/kg AgNPs-curcumin twice per week for three weeks after the CCl4 challenge. Results: Administration of CCL4 resulted in oxidative dysregulation, including significant reductions in reduced glutathione and concomitant elevations in the level of malondialdehyde (MDA). CCL4 challenge also resulted in elevated levels of serum aspartate transaminase (AST) and alanine transaminase (ALT); these findings were associated with the destruction of hepatic tissues. Treatment with AgNPs-curcumin prevented oxidative imbalance, hepatic dysfunction, and tissue destruction. A comet assay revealed that CCl4 challenge resulted in significant DNA damage as documented by a 70% increase in nuclear DNA tail-length; treatment with AgNPs-curcumin inhibited the CCL4-mediated increase in nuclear DNA tail-length by 34%. Conclusion: Administration of AgNPs-curcumin resulted in significant antioxidant activity in vivo. This agent has the potential to prevent the hepatic tissue destruction and DNA damage that results from direct exposure to CCL4.

Impact of hydroxychloroquin/azithromycin protocol on COVID-19 case-fatality rate reduction in Algeria. (Preprint)

2020 ◽  
Author(s):  
Ahmed Youssef Kada
Keyword(s):  
Case Fatality Rate ◽  
Doubling Time ◽  
Case Fatality ◽  
World Health ◽  
Fatality Rate ◽  
Therapeutic Protocol ◽  
First Case ◽  
The World ◽  
The Impact ◽  
At Home

BACKGROUND Covid-19 is an emerging infectious disease like viral zoonosis caused by new coronavirus SARS CoV 2. On December 31, 2019, Wuhan Municipal Health Commission in Hubei province (China) reported cases of pneumonia, the origin of which is a new coronavirus. Rapidly extendable around the world, the World Health Organization (WHO) declares it pandemic on March 11, 2020. This pandemic reaches Algeria on February 25, 2020, date on which the Algerian minister of health, announced the first case of Covid-19, a foreign citizen. From March 1, a cluster is formed in Blida and becomes the epicentre of the coronavirus epidemic in Algeria, its total quarantine is established on March 24, 2020, it will be smoothly alleviated on April 24. A therapeutic protocol based on hydroxychloroquine and azithromycin was put in place on March 23, for complicated cases, it was extended to all the cases confirmed on April 06. OBJECTIVE This study aimed to demonstrate the effectiveness of hydroxychloroquin/azithromycin protocol in Algeria, in particular after its extension to all patients diagnosed COVID-19 positive on RT-PCR test. We were able to illustrate this fact graphically, but not to prove it statistically because the design of our study, indeed in the 7 days which followed generalization of therapeutic protocol, case fatality rate decrease and doubling time increase, thus confirming the impact of wide and early prescription of hydroxychloroquin/azithromycin protocol. METHODS We have analyzed the data collected from press releases and follow-ups published daily by the Ministry of Health, we have studied the possible correlations of these data with certain events or decisions having a possible impact on their development, such as confinement at home and its reduction, the prescription of hydroxychloroquine/azithromycin combination for serious patients and its extension to all positive COVID subjects. Results are presented in graphics, the data collection was closed on 31/05/2020. RESULTS Covid-19 pandemic spreads from February 25, 2020, when a foreign citizen is tested positive, on March 1 a cluster is formed in the city of Blida where sixteen members of the same family are infected during a wedding party. Wilaya of Blida becomes the epicentre of coronavirus epidemic in Algeria and lockdown measures taken, while the number of national cases diagnosed begins to increases In any event, the association of early containment measures combined with a generalized initial treatment for all positive cases, whatever their degree of severity, will have contributed to a reduction in the fatality rate of COVID 19 and a slowing down of its doubling time. CONCLUSIONS In Algeria, the rapid combination of rigorous containment measure at home and early generalized treatment with hydroxychloroquin have demonstrated their effectiveness in terms of morbidity and mortality, the classic measures of social distancing and hygiene will make it possible to perpetuate these results by reducing viral transmission, the only unknown, the reopening procedure which can only be started after being surrounded by precautions aimed at ensuring the understanding of the population. CLINICALTRIAL Algeria, Covid-19, pandemic, hydroxychloroquin, azithromycin, case fatality rate

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