The Systemic Inflammation Hypothesis: Towards a New Paradigm of Acute Decompensation and Multiorgan Failure in Cirrhosis

Lipocalin-2 (LCN2), also known as neutrophil gelatinase-associated lipocalin (NGAL), is released by various cell types and is an attractive biomarker of inflammation, ischemia, infection, and kidney damage. Both intestinal and metabolic inflammation, as observed in obesity and related disorders, are associated with increased LCN2 synthesis. While LCN2 in the intestinal tract regulates the composition of the gut microbiota and shows anti-inflammatory activities, it also exhibits proinflammatory activities in other experimental settings. In animal models of metabolic inflammation, type 2 diabetes mellitus (T2DM), or nonalcoholic steatohepatitis (NASH), increased LCN2 expression favors inflammation via the recruitment of inflammatory cells, such as neutrophils, and the induction of proinflammatory cytokines. A better understanding of this crucial marker of innate immunity might pave the way for targeting this pathway in future therapies.

Lipocalin-2: A Master Mediator of Intestinal and Metabolic Inflammation.

Abstract Metabolic abnormalities lead to the dysfunction of metabolic pathways and metabolite accumulation or deficiency which is well-recognized hallmarks of diseases. Metabolite signatures that have close proximity to subject’s phenotypic informative dimension, are useful for predicting diagnosis and prognosis of diseases as well as monitoring treatments. The lack of early biomarkers could lead to poor diagnosis and serious outcomes. Therefore, noninvasive diagnosis and monitoring methods with high specificity and selectivity are desperately needed. Small molecule metabolites-based metabolomics has become a specialized tool for metabolic biomarker and pathway analysis, for revealing possible mechanisms of human various diseases and deciphering therapeutic potentials. It could help identify functional biomarkers related to phenotypic variation and delineate biochemical pathways changes as early indicators of pathological dysfunction and damage prior to disease development. Recently, scientists have established a large number of metabolic profiles to reveal the underlying mechanisms and metabolic networks for therapeutic target exploration in biomedicine. This review summarized the metabolic analysis on the potential value of small-molecule candidate metabolites as biomarkers with clinical events, which may lead to better diagnosis, prognosis, drug screening and treatment. We also discuss challenges that need to be addressed to fuel the next wave of breakthroughs. 

/pdf/small-molecule-metabolites-discovery-of-biomarkers-and-3d30vx3k.pdf

Small molecule metabolites: discovery of biomarkers and therapeutic targets

While mesenchymal stem cells (MSCs)-based therapy appears to be promising, there are concerns regarding possible side effects related to the unwanted suppression of antimicrobial immunity leading to an increased risk of infection. Conversely, recent data show that MSCs exert strong antimicrobial effects through indirect and direct mechanisms, partially mediated by the secretion of antimicrobial peptides and proteins (AMPs). In fact, MSCs have been reported to increase bacterial clearance in pre-clinical models of sepsis, acute respiratory distress syndrome and cystic fibrosis related infections. This article reviews the current evidence regarding the direct antimicrobial effector function of MSCs, focusing mainly on the role of MSCs-derived AMPs. The strategies that might modulate the expression and secretion of these AMPs, leading to enhanced antimicrobial effect are highlighted. Furthermore, studies evaluating the presence of AMPs in the cargo of extracellular vesicles (EVs) are underlined as perspective opportunities to develop new drug delivery tools. The antimicrobial potential of MSCs-derived EVs can also be heightened through cell conditioning and/or drug loading. Finally, improving the pharmacokinetics and delivery, in addition to deciphering the multi-target drug status of AMPs, should synergistically lead to key advances against infections caused by drug resistant strains.

/pdf/antimicrobial-activity-of-mesenchymal-stem-cells-current-s45e6fb6if.pdf

Antimicrobial Activity of Mesenchymal Stem Cells: Current Status and New Perspectives of Antimicrobial Peptide-Based Therapies.

Pathophysiology of decompensated cirrhosis: Portal hypertension, circulatory dysfunction, inflammation, metabolism and mitochondrial dysfunction.

Patients with COVID-19 present with low plasma citrulline concentrations that associate with systemic inflammation and gastrointestinal symptoms.

BACKGROUND: Severe acute respiratory syndrome caused by the novel coronavirus (SARS-CoV-2) is frequently associated with gastrointestinal manifestations. Herein we evaluated the interest in measuring the intestinal fatty acid-binding protein (I-FABP), a biomarker of intestinal injury, in COVID-19 patients. METHODS: Serum I-FABP was analyzed in 28 consecutive patients hospitalized for a PCR-confirmed COVID-19, in 24 hospitalized patients with non-COVID-19 pulmonary diseases, and 79 patients admitted to the emergency room for abdominal pain. RESULTS: I-FABP serum concentrations were significantly lower in patients with COVID-19, as compared to patients with non-COVID-19 pulmonary diseases [70.3 pg/mL (47-167.9) vs. 161.1 pg/mL (88.98-305.2), respectively, p = 0.008]. I-FABP concentrations in these two populations were significantly lower than in patients with abdominal pain without COVID-19 [344.8 pg/mL (268.9-579.6)]. I-FABP was neither associated with severity nor the duration of symptoms. I-FABP was correlated with polymorphonuclear cell counts. CONCLUSIONS: In this pilot study, we observed a low I-FABP concentration in COVID-19 patients either with or without gastrointestinal symptoms, of which the pathophysiological mechanisms and clinical impact remain to be established. Further explorations on a larger cohort of patients will be needed to unravel the molecular mechanism of such observation, including the effects of malabsorption and/or abnormal lipid metabolism.

/pdf/i-fabp-is-decreased-in-covid-19-patients-independently-of-1uwinkb3q9.pdf

I-FABP is decreased in COVID-19 patients, independently of the prognosis.

Invasive candidiasis (IC) is a leading cause of morbidity and mortality among nonneutropenic ICU patients and these life-threatening nosocomial infections require early diagnosis and prompt treatment. However, none of the predictive tools are sufficiently accurate to identify high-risk patients and the potential interest of IC prophylactic, empirical and preemptive treatment in the nonneutropenic ICU population has not yet been demonstrated. In the case of nosocomial severe sepsis after necrotizing pancreatitis or upper digestive anastomotic leakage, early probabilistic antifungals are probably indicated. In the remaining ICU surgical and medical patients, prophylactic and empirical strategies are highly debated because they may promote antifungal selective pressure through an overuse of these molecules. In this context, non-culture-based methods such as mannan or β-D glucan or polymerase chain reaction tests are promising. However, none of these tests used alone in ICU patients is sufficiently accurate to avoid overuse of empirical/preemptive treatment. The interest of strategies associating predictive clinical scores and non-culture-based methods still needs to be demonstrated by well-conducted randomized, controlled trials. While awaiting these studies, we consider that probabilist treatment should be stopped earlier if IC is not proven.

https://journals.sagepub.com/doi/pdf/10.1177/2049936114562586

Management of invasive candidiasis in nonneutropenic ICU patients.

mong the different liver transplantation (LT) techniques develA oped to date, LT with preservation of the inferior vena cava (IVC) has gained wide acceptance as it enables the maintenance of hemodynamic stability without a need for a venous bypass. However, techniques of caval preservation present a risk of hepatic venous outflow obstruction (HVOO), which ranges from 2 to 10%. HVOO may occur as a consequence of liver graft rotation, thus resulting in smaller caliber anastomosis leading to partial or total thrombosis of the anastomosis. A donor–recipient body weight mismatch, a split graft, or a relatively small liver graft placed in a large peritoneal cavity may further accentuate the risk of graft torsion and kinking of the venous anastomosis. In this setting, we have developed a modified technique of piggyback anastomosis between the suprahepatic donor IVC and the right hepatic vein from the recipient, enlarged by a cavotomy. In this study, we report the critical technical aspects and results of this anastomosis referred to as the ‘‘one-vein technique’’ (OVT).

Further to the Right: Piggyback Anastomosis on the Right Hepatic Vein Facilitates the Implantation of Small Liver Grafts (the One-vein Technique).

/pdf/focus-on-gastrointestinal-system-in-critically-ill-patients-ulj7ukjcur.pdf

Focus on gastrointestinal system in critically ill patients.

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