172 research outputs found
'Equity' and 'Justice' for patients with acute-on chronic liver failure: A call to action
Acute-on chronic liver failure (ACLF) occurs in hospitalised patients with cirrhosis and is characterised by multiorgan failures and high rates of short-term mortality. Without liver transplantation (LT), the 28-day mortality of patients with ACLF ranges between 18-25% in those with ACLF Grade 1 to 68-89% in those with ACLF Grade 3. It has become clear that there is lack of equity of access to LT for patients with ACLF across the world due to the current allocation policies, which are based on prognostic scores that underestimate the risk of death of these patients and lack of appreciation that there is clear evidence of transplant benefit for carefully selected patients as they can have excellent post-LT outcomes. This expert opinion provides evidence supporting the argument that patients with ACLF should be given priority for LT using prognostic models that define the risk of death for these patients, pinpoint risk factors for poor post-LT outcomes, identify unanswered questions and describe the design of a global study, the CHANCE study, which will provide answers to the outstanding issues. It also suggests widespread adoption of pilot programmes across the world as have been initiated in the UK and recommended in Spain to introduce new policies for organ allocation for patients with ACLF
AMP-activated protein kinase controls liposaccharide-induced hyperpermeability
Organ dysfunction determines the severity of sepsis and is correlated to mortality. Endothelial increased permeability contributes to the development of organ failure. AMP-activated protein kinase (AMPK) has been shown to modulate cytoskeleton and could mediate endothelial permeability. Our hypothesis is that AMPK controls sepsis-induced hyperpermeability in the heart and is involved in septic cardiomyopathy. Sepsis was induced by intraperitoneal injection of liposaccharide, 10 mg/kg (LPS). Alpha-1 AMPK knockout mice (α1KO) were compared with wild-type. Vascular permeability was characterized by Evans blue extravasation. Inflammatory cytokine mRNA expression was determined by qPCR analysis. Left ventricular mass was assessed by echocardiography. In addition, to emphasize the beneficial role of AMPK on heart vascular permeability, AMPK activator (acadesine) was administered to C57Bl6 mice before LPS injection. The ANOVA test with Bonferroni's post hoc test and the log-rank test were used. P < 0.05 was considered as significant. Increased cardiac vascular permeability was observed in the LPS group in comparison to untreated animals (2.5% vs. 16%; P < 0.05). The α1KO mice exhibited an increase vascular permeability after LPS injection in comparison to wild-type mice (41.5% vs. 16%; P < 0.05). α1KO animals had a significant mortality increase after LPS injection (70% vs. 10%; P < 0.05). LPS markedly induced the production of proinflammatory cytokines (TNFα, IL-1β, IL-6) that were significantly higher in the α1KO animals. More importantly, LPS treatment leads to an increased left ventricular mass in the α1KO mice within 24 hours, suggesting the onset of edema. Finally LPS-induced vascular hyperpermeability was greatly reduced after AMPK activation by acadesine (13.2% vs. 40%; P < 0.05). AMPK importantly regulates cardiac vascular permeability and could control the sepsis-induced cardiomyopathy. AMPK could represent a new pharmacological target of sepsis
The systemic inflammation hypothesis: Towards a new paradigm of acute decompensation and multiorgan failure in cirrhosis
Acute decompensation (AD) of cirrhosis is defined by the development of ascites, hepatic encephalopathy and/or variceal bleeding. Ascites is traditionally attributed to splanchnic arterial vasodilation and
left ventricular dysfunction, hepatic encephalopathy to hyperammonaemia, and variceal haemorrhage to
portal hypertension. Recent large-scale European observational studies have shown that systemic
inflammation is a hallmark of AD. Here we present a working hypothesis, the systemic inflammation
hypothesis, suggesting that systemic inflammation through an impairment of the functions of one or
more of the major organ systems may be a common theme and act synergistically with the traditional
mechanisms involved in the development of AD. Systemic inflammation may impair organ system
function through mechanisms which are not mutually exclusive. The first mechanism is a nitric oxidemediated accentuation of the preexisting splanchnic vasodilation, resulting in the overactivation of
the endogenous vasoconstrictor systems which elicit intense vasoconstriction and hypoperfusion in
certain vascular beds, in particular the renal circulation. Second, systemic inflammation may cause
immune-mediated tissue damage, a process called immunopathology. Finally, systemic inflammation
may induce important metabolic changes. Indeed, systemic inflammatory responses are energetically
expensive processes, requiring reallocation of nutrients (glucose, amino acids and lipids) to fuel immune
activation. Systemic inflammation also inhibits nutrient consumption in peripheral (non-immune) organs, an effect that may provide one mechanism of reallocation and prioritisation of metabolic fuels for
inflammatory responses. However, the decrease in nutrient consumption in peripheral organs may result
in decreased mitochondrial production of ATP (energy) and subsequently impaired organ functio
Bacterial and fungal infections in acute-on-chronic liver failure: prevalence, characteristics and impact on prognosis
Liver grafts procured and discarded by all Belgian centers and transplanted within Eurotransplant network: analysis of cause to decline, a Be-LIAC study
The annual balance between imports and exports of grafts is a matter of debate. We examined the Eurotransplant database of all liver grafts procured within Belgium and Luxemburg which were exported and transplanted abroad. The aim of our study was to analyse the reasons for graft refusal by all Belgian transplant centres and early postoperative evolution. Database between 2015 and 2019 included donor characteristics, reason of offer decline, graft and recipient survival. During the 4 year period 329 grafts were procured in Belgium and transplanted abroad. 163 were exported for HU recipients, 17 no national match recipients (8 AB group, 2 pediatric and 7 other reasons), 19 pay back, 15 splits, 11 not mentioned. Hundred and four grafts were declined by all Belgian centres. Forty seven were declined primary offers and fifty seven livers were distributed by extended allocation. Between them we find out four DCD donors, 83 for medical reasons (age, cytolysis, size mismatch and steatosis). Thirteen livers were accepted and declined at arrival for size mismatch (kept as rescue offer in the same centre). One donor was unstable and two were rejected for positive HCV virology. Only one liver who was primary accepted for a split was transplanted as a whole liver. Two patients presented primary graft nonfunction and three primary graft dysfunction. All of them were retransplanted. Thirteen patients died in the early 3 month postoperative period. Even though higher mortality is expected from marginal grafts, better acceptance rate could be achieved at a national level
T-5224, a selective inhibitor of c-Fos/activator protein-1, improves survival by inhibiting serum high mobility group box-1 in lethal lipopolysaccharide-induced acute kidney injury model
MMP-8 Deficiency Increases TLR/RAGE Ligands S100A8 and S100A9 and Exacerbates Lung Inflammation during Endotoxemia
Matrix metalloproteinase-8, released mainly from neutrophils, is a critical regulator of the inflammatory response by its ability to cleave multiple mediators. Herein, we report the results of a model of endotoxemia after intraperitoneal LPS injection in mice lacking MMP-8 and their wildtype counterparts. Control, saline-treated animals showed no differences between genotypes. However, there was an increased lung inflammatory response, with a prominent neutrophilic infiltration in mutant animals after LPS treatment. Using a proteomic approach, we identify alarmins S100A8 and S100A9 as two of the main differences between genotypes. Mice lacking MMP-8 showed a significant increase in these two molecules in lung homogenates, but not in spleen and serum. Mice lacking MMP-8 also showed an increase in MIP-1α levels and a marked activation of the non-canonical NF-κB pathway, with no differences in CXC-chemokines such as MIP-2 or LIX. These results show that MMP-8 can modulate the levels of S100A8 and S100A9 and its absence promotes the lung inflammatory response during endotoxemia
Intensive enteral nutrition is ineffective for individuals with severe alcoholic hepatitis treated with corticosteroids.
peer reviewedBACKGROUND & AIMS: Severe alcoholic hepatitis (AH) is a lifethreatening
disease for which adequate oral nutritional support
is recommended. We performed a randomized controlled trial to
determine whether the combination of corticosteroid and
intensive enteral nutrition therapy is more effective than corticosteroid
therapy alone in patients with severe AH. METHODS:
We enrolled 136 heavy consumers of alcohol (age, 18–75 y)
with recent onset of jaundice and biopsy-proven severe AH in
our study, performed at 18 hospitals in Belgium and 2 in
France, from February 2010 through February 2013. Subjects
were assigned randomly (1:1) to groups that received either
intensive enteral nutrition plus methylprednisolone or conventional
nutrition plus methylprednisolone (controls). In the
intensive enteral nutrition group, enteral nutrition was given
via feeding tube for 14 days. The primary end point was patient
survival for 6 months. RESULTS: In an intention-to-treat analysis,
we found no significant difference between groups in
6-month cumulative mortality: 44.4% of patients died in the
intensive enteral nutrition group (95% confidence interval [CI],
32.2%–55.9%) and 52.1% of controls died (95% CI, 39.4%–
63.4%) (P ¼ .406). The enteral feeding tube was withdrawn
prematurely from 48.5% of patients, and serious adverse
events considered to be related to enteral nutrition occurred in
5 patients. Regardless of group, a greater proportion of patients
with a daily calorie intake less than 21.5 kcal/kg/day died
(65.8%; 95% CI, 48.8–78.4) than patients with a higher intake
of calories (33.1%; 95% CI, 23.1%–43.4%) (P < .001).
CONCLUSIONS: In a randomized trial of patients with severe AH
treated with corticosteroids, we found that intensive enteral
nutrition was difficult to implement and did not increase survival.
However, low daily energy intake was associated with greater
mortality, so adequate nutritional intake should be a main goal for
treatment
Inhibition of glutamine synthetase in monocytes from patients with acute-on-chronic liver failure resuscitates their antibacterial and inflammatory capacity
OBJECTIVE: Acute-on-chronic liver failure (ACLF) is associated with dysfunctional circulating monocytes whereby patients become highly susceptible to bacterial infections. Here, we identify the pathways underlying monocyte dysfunction in ACLF and we investigate whether metabolic rewiring reinstates their phagocytic and inflammatory capacity. //
DESIGN: Following phenotypic characterisation, we performed RNA sequencing on CD14+CD16- monocytes from patients with ACLF and decompensated alcoholic cirrhosis. Additionally, an in vitro model mimicking ACLF patient-derived features was implemented to investigate the efficacy of metabolic regulators on monocyte function. //
RESULTS: Monocytes from patients with ACLF featured elevated frequencies of interleukin (IL)-10-producing cells, reduced human leucocyte antigen DR isotype (HLA-DR) expression and impaired phagocytic and oxidative burst capacity. Transcriptional profiling of isolated CD14+CD16- monocytes in ACLF revealed upregulation of an array of immunosuppressive parameters and compromised antibacterial and antigen presentation machinery. In contrast, monocytes in decompensated cirrhosis showed intact capacity to respond to inflammatory triggers. Culturing healthy monocytes in ACLF plasma mimicked the immunosuppressive characteristics observed in patients, inducing a blunted phagocytic response and metabolic program associated with a tolerant state. Metabolic rewiring of the cells using a pharmacological inhibitor of glutamine synthetase, partially restored the phagocytic and inflammatory capacity of in vitro generated- as well as ACLF patient-derived monocytes. Highlighting its biological relevance, the glutamine synthetase/glutaminase ratio of ACLF patient-derived monocytes positively correlated with disease severity scores. //
CONCLUSION: In ACLF, monocytes feature a distinct transcriptional profile, polarised towards an immunotolerant state and altered metabolism. We demonstrated that metabolic rewiring of ACLF monocytes partially revives their function, opening up new options for therapeutic targeting in these patients
Multicenter evaluation of a lateral-flow device test for diagnosing invasive pulmonary aspergillosis in ICU patients
Introduction: The incidence of invasive pulmonary aspergillosis (IPA) in intensive care unit (ICU) patients is increasing, and early diagnosis of the disease and treatment with antifungal drugs is critical for patient survival. Serum biomarker tests for IPA typically give false-negative results in non-neutropenic patients, and galactomannan (GM) detection, the preferred diagnostic test for IPA using bronchoalveolar lavage (BAL), is often not readily available. Novel approaches to IPA detection in ICU patients are needed. In this multicenter study, we evaluated the performance of an Aspergillus lateral-flow device (LFD) test for BAL IPA detection in critically ill patients. Methods: A total of 149 BAL samples from 133 ICU patients were included in this semiprospective study. Participating centers were the medical university hospitals of Graz, Vienna and Innsbruck in Austria and the University Hospital of Mannheim, Germany. Fungal infections were classified according to modified European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria. Results: Two patients (four BALs) had proven IPA, fourteen patients (sixteen BALs) had probable IPA, twenty patients (twenty-one BALs) had possible IPA and ninety-seven patients (one hundred eight BALs) did not fulfill IPA criteria. Sensitivity, specificity, negative predictive value, positive predictive value and diagnostic odds ratios for diagnosing proven and probable IPA using LFD tests of BAL were 80%, 81%, 96%, 44% and 17.6, respectively. Fungal BAL culture exhibited a sensitivity of 50% and a specificity of 85%. Conclusion: LFD tests of BAL showed promising results for IPA diagnosis in ICU patients. Furthermore, the LFD test can be performed easily and provides rapid results. Therefore, it may be a reliable alternative for IPA diagnosis in ICU patients if GM results are not rapidly available. Trial registration: ClinicalTrials.gov NCT02058316. Registered 20 January 2014
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