Ultrasmall gold nanoparticles (2 nm) easily penetrate the membranes of intestinal murine epithelial cells (MODE‐K) and colorectal cancer cells (CT‐26). They are also taken up by 3D spheroids (400 µm) ...of these cell types and primary gut organoids (500 µm). In contrast, dissolved dyes are not taken up by any of these cells or 3D structures. The distribution of fluorescent ultrasmall gold nanoparticles inside cells, spheroids, and gut organoids is examined by confocal laser scanning microscopy. Nanoparticles conjugated with the cytostatic drug doxorubicin and a fluorescent dye exhibit significantly greater cytotoxicity toward CT‐26 tumor spheroids than equally concentrated dissolved doxorubicin, probably because they enter the interior of a spheroid much more easily than dissolved doxorubicin. Comprehensive analyses show that the cellular uptake of ultrasmall gold nanoparticles occurs by different endocytosis pathways.
Ultrasmall gold nanoparticles (2 nm) are easily taken up by 3D spheroids and primary gut organoids. Nanoparticles conjugated with the cytostatic drug doxorubicin exhibit a significantly greater cytotoxicity toward tumor spheroids than equally concentrated dissolved doxorubicin. They can also enter the spheroid more easily than dissolved doxorubicin.
Background & Aims
Acute‐on‐chronic liver failure (ACLF) is characterized by an acute deterioration of liver function in patients with cirrhosis in combination with recently defined organ failures. ...Our aim was to independently validate the prognostic value of the recently established EASL‐CLIF‐Consortium definition of ACLF and to identify new predictors of short‐term mortality.
Methods
Patients with cirrhosis and the International Classification of Diseases, Tenth Revision diagnosis of (sub)acute liver failure were retrospectively categorized according to the EASL‐CLIF‐Consortium definition. Logistic regression analyses were performed to identify clinical and epidemiological predictors of 30‐ and 90‐day mortality.
Results
From 2008 to 2015, 257 patients were included. Overall, 173 (67%) patients met the EASL criteria for ACLF (grade 1: n = 43 25%, grade 2: n = 52 30%, grade 3: n = 79 45%). Mortality within 30 days in patients without ACLF was 3.6%, and 18.6%, 37.3% and 62.0% in patients with ACLF grades 1, 2 and 3 respectively. Outcome of patients with bacterial infection‐triggered ACLF was distinct from non‐infection‐triggered ACLF (71.6% vs 33.8% 30‐day survival, P < .001), and infection‐triggered ACLF was independently associated with increased mortality (odds ratio OR = 4.28, P < .001). Pneumonia was a particularly frequent infection and burdened with high mortality. In addition, infections with multidrug‐resistant organisms were frequent and independently associated with mortality (P = .030, OR = 4.41), as was glycopeptide antibiotic therapy as initial empirical antibiotic therapy (P = .005).
Conclusions
This study confirmed the EASL‐CLIF‐Consortium definition of ACLF as strong predictor of mortality in patients with acute decompensation of cirrhosis. However, we have observed a remarkably higher mortality in infection‐triggered ACLF compared to other precipitating events.
Abstract
Transjugular intrahepatic portosystemic shunt (TIPS) is one of the main treatment options in patients with decompensated liver cirrhosis but is still associated with partly severe ...complications. For adequate patient selection, prognostic parameters are of crucial importance. The liver maximum capacity (LiMAx) breath test measures enzymatic liver function and could potentially represent an efficient prognostic marker. We therefore aimed to assess the role of LiMAx in predicting survival of TIPS patients in a prospective analysis. LiMAx was performed for patients who underwent TIPS implantation between October 2016 and February 2018. Associations with transplant-free survival after 24 weeks were assessed by logistic regression. A total number of 30 patients were included, of whom seven received liver transplantation (N = 2) or died (N = 5) during follow-up. LiMAx values after (
P
= 0.01, OR = 1.24, 95% CI = 1.04–1.47) and before (
P
= 0.03, OR 1.21, 95% CI = 1.02–1.43) TIPS implantation and MELD score (
P
= 0.03, OR = 0.79, 95% CI = 0.63–0.98) were significantly associated with transplant-free survival according to univariate logistic regression. In AUROC analysis, LiMAx at day one after TIPS (sensitivity 85.7%, specificity 78.3%, AUROC 0.85, cut-off ≤ 165 µg/kg/h), LiMAx value at the day before TIPS (sensitivity 100%, specificity 73.9%, AUROC 0.82, cut-off ≤ 205 µg/kg/h) and MELD score (sensitivity 71.4%, specificity 73.9%, AUROC 0.82, cut-off ≥ 15) had the highest prognostic accuracy. LiMAx values prior and after TIPS procedure seem to be good prognostic parameters regarding prediction of transplant-free survival of patients undergoing TIPS implantation.
In cirrhotic patients with hepatocellular carcinoma (HCC), right-sided radioembolization (RE) with Yttrium-90-loaded microspheres is an established palliative therapy and can be considered a ..."curative intention" treatment when aiming for sequential tumor resection. To become surgical candidate, hypertrophy of the left liver lobe to > 40% (future liver remnant, FLR) is mandatory, which can develop after RE. The amount of radiation-induced shrinkage of the right lobe and compensatory hypertrophy of the left lobe is difficult for clinicians to predict. This study aimed to utilize machine learning to predict left lobe liver hypertrophy in patients with HCC and cirrhosis scheduled for right lobe RE, with external validation. The results revealed that machine learning can accurately predict relative and absolute volume changes of the left liver lobe after right lobe RE. This prediction algorithm could help to estimate the chances of conversion from palliative RE to curative major hepatectomy following significant FLR hypertrophy.
Background and Aims
Given the early response of neutrophil granulocytes to infections, detection of pathological neutrophil migration might help in predicting adverse events in patients with liver ...cirrhosis.
Methods
Migration of blood neutrophils in hospitalized patients with cirrhosis was characterized by a novel standardized migration assay. Pathological neutrophil migration patterns were associated with a composite endpoint of ACLF, sepsis or death within 7 or 30 days.
Results
Overall, 125 patients were included, of whom 11 (8.8%) had compensated cirrhosis, 84 (67.2%) had acute decompensation (AD) and 30 (24%) had acute‐on‐chronic liver failure (ACLF). The migration response of neutrophils from patients with AD or ACLF to stimulation with the chemotactic formylpeptide f‐Met‐Leu‐Phe (fMLP) was significantly impaired, while the response to chemokine (C‐X‐C motif)‐ligand 8 (CXCL8) was affected less pronouncedly. In contrast, no relevant differences in response to CXCL1 were observed. Of note, neutrophils of a number of patients with AD and ACLF were largely immotile at resting and stimulated conditions. Patients with non‐migrating neutrophils at unstimulated conditions were at high risk to develop the composite endpoint of ACLF, sepsis or death. Moreover, expression of chemokine receptors CXCR1 and CXCR2 was significantly decreased in patients with ACLF. Interestingly, the expression of chemokine receptors did not correlate with neutrophil migration patterns, but—based on the increased expression of the cell surface markers CD66b and CD177—neutrophils of patients with AD and ACLF were strongly pre‐activated.
Conclusion
Pathological neutrophil migration in patients with cirrhosis indicates a high risk of developing adverse outcomes.
Primary and recurrent cytomegalovirus (CMV) infections frequently cause CMV colitis in immunocompromised as well as inflammatory bowel disease (IBD) patients. Additionally, colitis occasionally ...occurs upon primary CMV infection in patients who are apparently immunocompetent. In both cases, the underlying pathophysiologic mechanisms are largely elusive ‐ in part due to the lack of adequate access to specimens. We employed the mouse cytomegalovirus (MCMV) model to assess the association between CMV and colitis. During acute primary MCMV infection of immunocompetent mice, the gut microbial composition was affected as manifested by an altered ratio of the Firmicutes to Bacteroidetes phyla. Interestingly, these microbial changes coincided with high‐titer MCMV replication in the colon, crypt hyperplasia, increased colonic pro‐inflammatory cytokine levels, and a transient increase in the expression of the antimicrobial protein Regenerating islet‐derived protein 3 gamma (Reg3γ). Further analyses revealed that murine and human intestinal epithelial cell lines, as well as primary intestinal crypt cells and organoids represent direct targets of CMV infection causing increased cell death. Accordingly, in vivo MCMV infection disrupted the intestinal epithelial barrier and increased apoptosis of intestinal epithelial cells. In summary, our data show that CMV transiently induces colitis in immunocompetent hosts by altering the intestinal homeostasis.
Acute cytomegalovirus (CMV) infection of immunocompetent mice alters the gut microbiota, involves high‐titer CMV replication in the colon, andepithelial barrier disruption. In vitro studies employing murine and human primary intestinal organoids reveal epithelial cells as a direct target of CMV with high rates of cell mortality upon CMV infection.
Inactivating mutations in
NPC1L1
were identified on exon sequencing and genotyping in 16 cohorts of patients with coronary heart disease and controls. Mutation carriers had lower LDL cholesterol ...levels and a lower risk of coronary heart disease than did noncarriers.
Ezetimibe, a drug that is commonly prescribed to reduce plasma levels of low-density lipoprotein (LDL) cholesterol, inhibits the function of the protein encoded by the Niemann–Pick C1-like 1 gene (
NPC1L1
).
1
NPC1L1 protein, which is expressed in the small intestine and liver, functions as a transporter of dietary cholesterol from the gut lumen into intestinal enterocytes.
2
,
3
Because of its ability to block sterol absorption by about 50%,
4
ezetimibe lowers plasma LDL cholesterol levels by 15 to 20%.
5
However, it is uncertain whether inhibiting NPC1L1 — either through ezetimibe treatment or by other means — reduces the risk of . . .
Background & Aims Recent studies have described a major impact of genetic variations near the IL28B gene on the natural course and outcome of antiviral therapy in chronic hepatitis C. We therefore, ...aimed to explore the impact of donor and recipient genotypes of these polymorphisms on hepatitis C virus (HCV) liver graft reinfection. Methods Donor and recipient genotypes of IL28B rs12979860C>T single nucleotide polymorphism were determined in 91 patients with HCV liver graft reinfection, 47 of whom were treated with pegylated interferon-α (PEG-IFN-α) and ribavirin. IL28B genetic polymorphisms were correlated with the natural course and treatment outcome of recurrent hepatitis C. Results Patients requiring liver transplantation due to end-stage chronic hepatitis C appeared to be selected toward the adverse genotypes rs12979860 CT/TT compared to non-transplanted HCV-infected patients ( p = 0.046). Patients with the donor genotype rs12979860 CC had higher peak ALT and HCV RNA serum concentrations than those with CT/TT ( p = 0.04 and 0.06, respectively). No association was observed between ALT/HCV RNA serum concentrations and recipient genotypes ( p >0.3). More important, donor IL28B rs12979860 CC vs . CT/TT genotypes were associated with rapid, complete early, and sustained virologic response (RVR, cEVR, SVR) to treatment with PEG-IFN-α and ribavirin ( p = 0.003, 0.0012, 0.008, respectively), but weaker associations of recipient genotypes with RVR, cEVR, and SVR were observed as well ( p = 0.0046, 0.115, 0.118, respectively). Conclusions We provide evidence for a dominant, but not exclusive impact of the donor rather than the recipient IL28B genetic background on the natural course and treatment outcome of HCV liver graft reinfection.
Vitamin D is an important immune modulator that plays an emerging role in inflammatory and metabolic liver diseases, including infection with hepatitis C virus (HCV). In contrast, the relationship ...between vitamin D metabolism and chronic hepatitis B (CHB) is less well characterized. Therefore, we quantified 25(OH)D3 serum levels in a cohort of 203 treatment‐naïve patients with chronic hepatitis B virus (HBV) infection and tested for their association with clinical parameters of CHB. Of 203 patients, 69 (34%), 95 (47%), and 39 (19%) had severe vitamin D deficiency (25(OH)D3 <10 ng/mL), vitamin D insufficiency (25(OH)D3 ≥10 and <20 ng/mL), or adequate vitamin D serum levels (25(OH)D3 ≥20 ng/mL), respectively. In both uni‐ and multivariate analyses, HBV DNA viral load (log10 IU/mL) was a strong predictor of low 25(OH)D3 serum levels (P = 0.0007 and P = 0.000048, respectively) and vice versa. Mean 25(OH)D3 serum concentrations in patients with HBV DNA <2,000 versus ≥2,000 IU/mL were 17 versus 11 ng/mL, respectively (P < 0.00001). In addition, hepatitis B early antigen (HBeAg)‐positive patients had lower 25(OH)D3 serum levels than HBeAg‐negative patients (P = 0.0013). Finally, 25(OH)D3 and HBV DNA serum levels showed inverse seasonal fluctuations. Conclusion: Low 25(OH)D3 serum levels are associated with high levels of HBV replication in patients with CHB. This represents a major difference from chronic hepatitis C, where numerous previous studies have shown a lack of correlation between HCV viral load and vitamin D serum levels. Inverse seasonal fluctuations of 25(OH)D3 and HBV DNA serum levels are suggestive of a functional relationship between both variables. (Hepatology 2013;58:1270–1276)
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