Malaria-induced NLRP12/NLRP3-dependent caspase-1 activation mediates inflammation and hypersensitivity to bacterial superinfection.

Cyclic paroxysm and high fever are hallmarks of malaria and are associated with high levels of pyrogenic cytokines, including IL-1ß. In this report, we describe a signature for the expression of inflammasome-related genes and caspase-1 activation in malaria. Indeed, when we infected mice, Plasmodium infection was sufficient to promote MyD88-mediated caspase-1 activation, dependent on IFN-γ-priming and the expression of inflammasome components ASC, P2X7R, NLRP3 and/or NLRP12. Pro-IL-1ß expression required a second stimulation with LPS and was also dependent on IFN-γ-priming and functional TNFR1. As a consequence of Plasmodium-induced caspase-1 activation, mice produced extremely high levels of IL-1ß upon a second microbial stimulus, and became hypersensitive to septic shock. Therapeutic intervention with IL-1 receptor antagonist prevented bacterial-induced lethality in rodents. Similar to mice, we observed a significantly increased frequency of circulating CD14(+)CD16(-)Caspase-1(+) and CD14(dim)CD16(+)Caspase-1(+) monocytes in peripheral blood mononuclear cells from febrile malaria patients. These cells readily produced large amounts of IL-1ß after stimulation with LPS. Furthermore, we observed the presence of inflammasome complexes in monocytes from malaria patients containing either NLRP3 or NLRP12 pyroptosomes. We conclude that NLRP12/NLRP3-dependent activation of caspase-1 is likely to be a key event in mediating systemic production of IL-1ß and hypersensitivity to secondary bacterial infection during malaria.

Painless Aortic Dissection with Catastrophic Consequences Presenting as Sudden Loss of Consciousness with no Prodromal Symptoms.

This case report presents a complex clinical scenario involving a 71-year-old female with aortic dissection accompanied by hypotension. The patient's initial presentation of sudden loss of consciousness unveiled a large pericardial effusion and cardiac tamponade, leading to emergency surgery. Subsequent diagnostic findings revealed an intramural haematoma with an intimal tear in the ascending aorta. Postoperatively, the patient experienced an ischaemic stroke, necessitating prompt neurology consultation and treatment. This report underscores the significance of early recognition and collaborative management in achieving positive patient outcomes. LEARNING POINTS: Early identification of aortic dissection symptoms, such as sudden loss of consciousness and hypotension, is crucial for effective management.Managing aortic dissection involves a multidisciplinary effort with emergency medicine, cardiology and surgical teams working together for optimal patient outcomes.After aortic dissection surgery, staying attentive to potential neurological complications such as ischaemic strokes is essential.

Oral treatment with Saccharomyces cerevisiae strain UFMG 905 modulates immune responses and interferes with signal pathways involved in the activation of inflammation in a murine model of typhoid fever.

Salmonella spp. are Gram-negative, facultative, intracellular pathogens that cause several diarrheal diseases ranging from self-limiting gastroenteritis to typhoid fever. Previous results from our laboratory showed that Saccharomyces cerevisiae strain UFMG 905 isolated from 'cachaça' production presented probiotic properties due to its ability to protect against experimental infection with Salmonella enterica serovar Typhimurium. In this study, the effects of oral treatment with S. cerevisiae 905 were evaluated at the immunological level in a murine model of typhoid fever. Treatment with S. cerevisiae 905 inhibited weight loss and increased survival rate after Salmonella challenge. Immunological data demonstrated that S. cerevisiae 905 decreased levels of proinflammatory cytokines and modulated the activation of mitogen-activated protein kinases (p38 and JNK, but not ERK1/2), NF-κB and AP-1, signaling pathways which are involved in the transcriptional activation of proinflammatory mediators. Experiments in germ-free mice revealed that probiotic effects were due, at least in part, to the binding of Salmonella to the yeast. In conclusion, S. cerevisiae 905 acts as a potential new biotherapy against S. Typhimurium infection due to its ability to bind bacteria and modulate signaling pathways involved in the activation of inflammation in a murine model of typhoid fever.

Management of stable coronary artery disease and atrial fibrillation with anti-thrombotic therapy: A systematic review and meta-analysis.

INTRODUCTION: Long term management of patients with stable coronary artery disease of >1 year after myocardial infarction (MI) or percutaneous coronary intervention and atrial fibrillation is unclear. Current guidelines recommend using oral anti-coagulation (OAC) alone although the recommendation is weak and there is low quality evidence. Two new randomized control trials (RCTs) were published recently. We conducted an updated meta-analysis to evaluate the effect of these studies on patient outcomes. OBJECTIVE: To conduct a systematic review and meta-analysis of published RCTs and observational studies to compare OAC alone versus OAC plus single anti-platelet therapy. METHODS: Electronic searches were conducted using appropriate terms from 3 databases. Relevant studies included. Data extracted and analysis were performed using STATA. MEASUREMENTS: Summary statistics were pooled and measured for primary and secondary outcomes of both treatment arms. MAIN RESULTS: Eight studies involving 10,120 patients were included for the analysis. Five thousand two hundred thirty-seven patients were on combination therapy while 4883 were on OAC alone. There was no statistically significant difference in the primary outcome of major adverse cardiac events (hazard ratio [HR] 1.067; 95% confidence interval [CI] 0.912-1.249; P value .417). There was no statistically significant difference even in the measured secondary outcomes namely all cause mortality (HR 1.048; 95% CI 0.830-1.323; P value .695), cardiovascular mortality (HR 0.863; 95% CI 0.593-1.254; P value .439). However, we found statistically significant difference between the 2 groups in the incidence of MI with higher incidence in mono therapy group (HR 1.229; 95% CI 1.011-1.495; P value .039) and higher incidence of major bleeding in the combination therapy group in the subgroup analysis (HR 0.649; 95% CI 0.464-0.907; P value .011). CONCLUSION: We found no reduction of major adverse cardiac event between combination therapy and mono therapy. Although mono therapy showed increased risk of major bleeding overall, subgroup analysis of the RCTs showed increased risk of major bleeding in the combination therapy group. MI was higher in the mono therapy group compared to the combination therapy group, however this outcome was not reproducible in the subgroup analysis of the RCTs.

Evaluation of in vitro antagonism and of in vivo immune modulation and protection against pathogenic experimental challenge of two probiotic strains of Bifidobacterium animalis var. lactis.

The aim of the present study was to compare the effect of intragastric administration with two strains of Bifidobacterium animalis subsp. lactis (Bifido A and Bifido B), in gnotobiotic and conventional mice, challenged with Salmonella Typhimurium. In vitro antagonism test showed that the two strains were able to produce antagonistic substances against various pathogenic microorganisms. In an ex vivo antagonism test the production of antagonistic substances was observed only against three out ten pathogens tested. Both Bifidobacterium strains were able to colonize and to maintain high population levels in the digestive tract of gnotobiotic mice. In addition, the two strains had low and limited translocation ability and did not cause any histological lesion in any of the organs analyzed. Both strains were able to reduce the fecal number of Salmonella in gnotobiotic mice challenged with the pathogen, but only Bifido B was able to confer a protection as demonstrated by a lower mortality. Higher levels of sIgA and IL-10 were observed only in Bifido B mono-associated mice when compared to germ free group. We could conclude that, among the parameters analyzed, the strain Bifido B exhibited the more desirable characteristics to be used as a probiotic.

Cocaine-induced Type-A Aortic Dissection Extending to the Common Iliac Arteries.

Aortic dissection is a rare and fatal complication of cocaine-induced hypertension. The injury mechanism is through shear stress that penetrates the intimal vessel layer, allowing blood flow to separate intimal and medial layers. Due to its scarcity and the paucity of related literature, our knowledge of this condition is limited. We present a rare case of a cocaine-induced aortic dissection, which extended continuously from the aortic root to the common iliacs, along with a literature review of similar cases. A 48-year-old male with recent cocaine use presented with left-sided chest-pain, which radiated to the back with nausea, diaphoresis, and shortness of breath. The patient was hypotensive. The initial radiographs and computed tomography were negative. The cardiac enzymes were elevated and the patient was admitted to rule out acute coronary syndrome. Next day echocardiogram and computed tomography revealed a Type-A aortic dissection continuously extending from the aortic root to the left common iliac artery. The patient was immediately transferred for surgery. Postoperatively, he developed acute kidney injury and shock liver. The patient status continued to deteriorate and he expired on postoperative day four. This case demonstrates the importance of prompt and thorough diagnostic evaluation, despite subjective history and initially negative imaging that might point towards other conditions. Unlike the previous cases, our case failed to identify the positive history of cocaine until nearly 24 hours into the patient's hospital course, suggesting a need for close monitoring in these patients and a possible need for repeat imaging.​​​​​​​.

Escherichia coli strain Nissle 1917 ameliorates experimental colitis by modulating intestinal permeability, the inflammatory response and clinical signs in a faecal transplantation model.

Inflammatory bowel diseases (IBDs) are a group of inflammatory conditions of the gut that include ulcerative colitis and Crohn's disease. Probiotics are live micro-organisms that may be used as adjuvant therapy for patients with IBD. The aim of this study was to evaluate the effect of prophylactic ingestion of Escherichia coli strain Nissle 1917 (EcN) in a murine model of colitis. For induction of colitis, mice were given a 3.5% dextran sodium sulfate (DSS) solution for 7 days in drinking water. EcN administration to mice subjected to DSS-induced colitis resulted in significant reduction in clinical and histopathological signs of disease and preservation of intestinal permeability. We observed reduced inflammation, as assessed by reduced levels of neutrophils, eosinophils, chemokines and cytokines. We observed an increase in the number of regulatory T-cells in Peyer's patches. Germ-free mice received faecal content from control or EcN-treated mice and were then subjected to DSS-induced colitis. We observed protection from colitis in animals that were colonized with faecal content from EcN-treated mice. These results suggest that preventative oral administration of EcN or faecal microbiota transplantation with EcN-containing microbiota ameliorates DSS-induced colitis by modifying inflammatory responsiveness to DSS.

Inhibition of tissue inflammation and bacterial translocation as one of the protective mechanisms of Saccharomyces boulardii against Salmonella infection in mice.

Growing evidences suggest that Saccharomyces boulardii (SB) is efficacious against bacterial infections and inflammatory bowel diseases. This study investigated the effects of treatment with SB provided in a murine model of typhoid fever. Mice were divided into two groups: (1) control animals challenged with Salmonella Typhimurium (ST), and (2) animals receiving SB, and then challenged with ST. At days 0, 1, 5, 10 and 15 post-challenge, animals were euthanized and tissues collected to analyze bacterial translocation, cytokines, signaling pathways and histological analysis. Survival rate and animal weight were also evaluated. Treatment with SB increased survival rate and inhibited translocation of bacteria after ST challenge. Histological data showed that SB also protected mice against liver damage induced by ST. SB decreased levels of inflammatory cytokines and activation of mitogen-activated protein kinases (p38, JNK and ERK1/2), phospho-IκB, p65-RelA, phospho-jun and c-fos in the colon, signal pathways involved in the activation of inflammation induced by ST. Further experiments revealed that probiotic effects were due, at least in part, to the binding of ST to the yeast. Such binding diminishes ST translocation, resulting in decreased activation of signaling pathways which lead to intestinal inflammation in a murine model of typhoid fever.