Substantial Fibrosis Research Articles

Comparison of the diagnostic performance of shear wave elastography with shear wave dispersion for pre-operative staging of hepatic fibrosis in patients with hepatocellular carcinoma

PurposeThis prospective study aimed to compare the diagnostic accuracy of shear wave elastography (SWE) with that of shear wave dispersion (SWD) in evaluation of hepatic fibrosis in patients with hepatocellular carcinoma before resection. MethodA total of 210 consecutive patients with hepatocellular carcinoma (HCC) who were scheduled to undergo hepatectomy were prospectively enrolled, pre-operative SWE and SWD examinations were performed. Fibrosis staging and necroinflammatory activity were determined histopathologically according to the Scheuer standard. Multivariate linear regression analysis was used to identify factors associated with SWE and SWD values. The performance of SWE and SWD were determined by receiver operating characteristic (ROC) analysis. ResultsBoth SWE and SWD values of liver were highly correlated with liver fibrosis stage and necroinflammatory activity (p < 0.05). Both SWE and SWD values were significantly different among the patients with different stages of liver fibrosis (p < 0.001). ROC analysis revealed that SWE that predicted substantial fibrosis (S ≥ 2), severe fibrosis (S ≥ 3) and cirrhosis (S = 4) were 0.895, 0.877 and 0.854, the SWD that predicted substantial fibrosis (S ≥ 2), severe fibrosis (S ≥ 3) and cirrhosis (S = 4) were 0.857, 0.815 and 0.791. SWE had better diagnostic performance than SWD in predicting severe fibrosis (S ≥ 3) and cirrhosis (S = 4). ConclusionsBoth SWE and SWD are useful, accurate and non-invasive methods for evaluating hepatic fibrosis in patients with hepatocellular carcinoma adapted to hepatectomy, SWE is a more accurate imaging modality than SWD in predicting severe fibrosis (S ≥ 3) and cirrhosis (S = 4).

Retrospective Evaluation of Non-Invasive Assessment Based on Routine Laboratory Markers for Assessing Advanced Liver Fibrosis in Chronic Hepatitis B Patients.

BackgroundAt present, there is a lack of cheap, effective and convenient detection methods for hepatitis B-related liver fibrosis, especially in the developing area.AimTo evaluate the non-invasive methods for the significant and advanced fibrosis stage in chronic hepatitis B virus (HBV) patients in basic hospitals and to assess their diagnostic utility.MethodsThe study included 436 consecutive naive HBV individuals who had their livers biopsied. They were examined in one week using aspartate aminotransferase-to-aspartate aminotransferase ratio (AAR), age-platelet index (API), aspartate aminotransferase-to-platelet ratio index (APRI), fibrosis-4 (FIB-4), Forns, gamma-glutamyl transpeptidase-to-platelet ratio (GPR), S-index and transient elastography (TE). Scheuer scoring system was used to determine the histologic fibrosis grades (S0–S4). The diagnostic effectiveness was assessed using AUROCs and the DeLong test, both of which were based on statistical comparisons.ResultsFor both substantial (≧S2) and advanced (≧S3) fibrosis phases, TE had good diagnostic performance in determining the hepatic fibrosis. Similar diagnostic performance was shown with Forns and S-index when it came to detecting fibrosis stages lower than S3. One model’s diagnostic value was not significantly improved by combining serum models. Correlation coefficients between clinical features and fibrosis phases were greatest for Forns (r = 0.397), S-index (r = 0.382) and TE (r = 0.535) when compared to other variables.ConclusionThis investigation showed that Forns and S-index may be helpful strategies for detecting advanced fibrosis in HBV patients admitted to community hospitals.

Soluble CD163 and CD163 Expression on Monocytes Associated with Chronic Hepatitis B Inflammation and HBsAg Loss.

Monocyte/macrophage-associated CD163 is an indicator of the severity of liver inflammation and cirrhosis, but the difference of soluble CD163 (sCD163) levels in chronic hepatitis B (CHB) patients and hepatitis B surface antigen (HBsAg)-loss patients is unclear. Herein, we aimed to compare the sCD163 levels in CHB patients and HBsAg-loss patients with or without antiviral treatment. sCD163 and CD163 expression on monocytes were compared among four groups, healthy subjects, treatment-naïve CHB patients, spontaneous HBsAg-loss patients, and treatment-related HBsAg-loss patients. The correlation between sCD163 levels and clinical parameters in CHB patients was analyzed. A group of 80 patients with hepatitis B virus (HBV) infection and liver biopsy were recruited. sCD163 levels were higher in the CHB group than in the other three groups. sCD163 levels were higher in treatment-related HBsAg-loss patients than in spontaneous HBsAg-loss patients. sCD163 levels were negatively correlated with hepatitis B e-antigen (HBeAg) and HBsAg levels in HBeAg-positive patients. Liver biopsy results further demonstrated that sCD163 levels were elevated in CHB patients with substantial inflammation (A≥2) or fibrosis (F≥2). The sCD163 model was more sensitive in predicting inflammation than other noninvasive models. Its levels were higher in patients with normal alanine aminotransferase levels and significant inflammation (A≥2) than in patients with no or mild inflammation. sCD163 and CD163 expression on monocytes were associated with CHB inflammation and HBsAg loss, and may be used as markers to predict HBV-specific immune activation.

Extracellular vesicles improve diastolic function and substructure in normal and high-fat diet models of chronic myocardial ischemia

ObjectiveThe burden of mortality and morbidity of cardiovascular disease is in part due to substantial fibrosis accelerated by coexisting risk factors. This study aims to evaluate the effect of extracellular vesicle therapy on diastolic function and myocardial fibrosis in the setting of chronic myocardial ischemia with and without a high-fat diet. MethodsForty male Yorkshire swine were administered a normal or high-fat diet. At 11 weeks of age, they underwent placement of an ameroid constrictor on their left circumflex coronary artery. Both dietary groups then received either intramyocardial injection of vehicle saline as controls or extracellular vesicles as treatment into the ischemic territory (normal diet control, n = 8; high-fat diet controls, n = 11) or extracellular vesicles (normal diet extracellular vesicles, n = 9; high-fat diet extracellular vesicles, n = 12). Five weeks later, hemodynamic parameters, histology, and selected protein expression were evaluated. ResultsExtracellular vesicles reduced end-diastolic pressure volume relationship (P = .002), perivascular collagen density (P = .031), calcium mineralization (P = .026), and cardiomyocyte diameter (P < .0001), and upregulated osteopontin (P = .0046) and mechanistic target of rapamycin (P = .021). An interaction between extracellular vesicles and diet was observed in the vimentin area (P = .044) and fraction of myofibroblast markers to total vimentin (P = .049). Significant changes across diet were found with reductions in muscle fiber area (P = .026), tumor necrosis factor α (P = .0002), NADPH oxidase 2 and 4 (P = .0036, P = .008), superoxide dismutase 1 (P = .034), and phosphorylated glycogen synthase kinase 3β (P = .020). ConclusionsExtracellular vesicle therapy improved the myocardium's ability to relax and is likely due to structural improvements at the extracellular matrix and cellular levels.

Quantitative T1 mapping MRI for the assessment of extraocular muscle fibrosis in thyroid-associated ophthalmopathy.

We aimed to investigate the performance of T1 mapping and its histological correlation with extraocular muscle fibrosis in thyroid-associated ophthalmopathy (TAO). We prospectively recruited 12 cases of active TAO, 12 cases of inactive TAO, and 15 cases of control subjects. All participants underwent magnetic resonance imaging (MRI) scan with pre-/postcontrast T1 mapping and short-time inversion-recovery (STIR) sequence. The images were analyzed to obtain precontrast T1, extracellular-volume (ECV) fraction on T1 mapping, and signal-intensity ratio (SIR) on STIR for each rectus. Muscle biopsy was performed at lateral rectus to quantify-collagen volume fraction, glycosaminoglycan (GAG)-volume fraction, and extracellular space component. The relationship between MRI and histopathology was examined with Pearson correlation coefficient. The active TAO group was characterized with GAG accumulation, while the inactive TAO group presented with substantial fibrosis. The MRI parameters achieved acceptable interobserver and intraobserver agreement. The precontrast T1 and ECV remarkably increased in the TAO groups than the control group, and ECV positively correlated with collagen-volume fraction (r = 0.913) and extracellular-space component (r = 0.886) in the inactive TAO group. The SIR statistically increased in the active TAO group, and SIR positively correlated with GAG-volume fraction in all three groups. The performance of ECV (cutoff > 48.1%) to screen out extraocular muscle fibrosis in inactive TAO was 60.9% sensitivity and 93.3% specificity. The ECV parameter on T1 mapping MRI is a reliable tool to quantify extraocular muscle fibrosis, providing insights into noninvasive evaluation of pathological changes in TAO orbit. ChiCTR2000040394; Date of registration: 28 November 2020.

Higher liver stiffness in patients with chronic congestive heart failure: data from NHANES with liver ultrasound transient elastography.

Liver stiffness in patients with chronic congestive heart failure (CCHF) is poorly understood and liver ultrasound transient elastography (LUTE) is a new non-invasive method to detect this condition. In this cross-sectional study we explored liver stiffness and secondary congestive hepatopathy in patients with CCHF detected by LUTE. Data from the National Health and Nutrition Examination Survey (NHANES 2017-2018) were analyzed. All participants undergoing LUTE and without liver disease were included, among whom, 110 participants were diagnosed with CCHF. The cut-off values of stiffness for fibrosis and cirrhosis were above 7.65 and 13.01 kPa, respectively. Data regarding liver stiffness were compared between the participants with and without CCHF. Among patients with CCHF, the median liver stiffness was 6.0 kPa, above 7.65 kPa in 32.7% of patients, and above 13.01 kPa in 14.6% of patients. The mean liver stiffness was 5.0 kPa in the control group and was significantly lower than that of patients with CCHF (P<0.001). The ratio of serum albumin/globulin (A/G) gradually decreased according to the liver stiffness of patients with CCHF (P=0.03). Patients with CCHF had higher liver stiffness values than controls, nearly one-third had substantial fibrosis, and more than one in seven patients progressed to cirrhosis. The A/G ratio may be a potential biomarker for liver stiffness caused by CCHF.

From the Literature

From the Literature

Therapeutic effect of adipose-derived regenerative cells on bladder function in rats with underactive bladder.

ABSTRACTWe examined the effect of adipose-derived regenerative cells (ADRC) on bladder functions in a rat model of detrusor underactivity (DU) induced by bladder over-distention.Adult female Sprague Dawley rats were divided into 3 groups: sham group (control); over-distention group; and over-distention with ADRC treatment group. Bladder was over-distended with saline (2.7mL) on day 1, 8, 15 and 22 of the study. ADRCs, which were harvested from male F344 rats, expanded via culture, were injected into the bladder wall at day 15. Cystometry and in vitro organ bath functional studies were performed on day 28. Moreover, histological assessment of the bladder was performed.In cystometry, significant prolongation of the inter-contraction interval (ICI) and decrease of voiding efficiency (VE) were observed in the over-distention group, compared to that in the control group. Significant improvement in ICI and VE was seen in the ADRC treatment group in comparison with the over-distention group. The over-distention group showed significantly weaker bladder contractile responses to carbachol and electrical field stimulation than the control group, while bladder contractile responses were significantly stronger in the ADRC treatment group than that in the over-distention group. The over-distention group showed substantial fibrosis of the bladder compared to the control group, whereas bladder fibrosis was alleviated in the ADRC treatment group.In conclusion, the injection of ADRC into bladder wall improved bladder dysfunction and histological changes induced by bladder over-distention. ADRCs-based regenerative therapy could be novel treatment for DU.

Decellularized Fetal Matrix Suppresses Fibrotic Gene Expression and Promotes Myogenesis in a Rat Model of Volumetric Muscle Loss.

Traumatic muscle loss often results in poor functional restoration. Skeletal muscle injuries cannot be repaired without substantial fibrosis and loss of muscle function. Given its regenerative properties, the authors evaluated outcomes of fetal tissue-derived decellularized matrix for skeletal muscle regeneration. The authors hypothesized that fetal matrix would lead to enhanced myogenesis and suppress inflammation and fibrosis. Composite tissue composed of dermis, subcutaneous tissue, and panniculus carnosus was harvested from the trunk of New Zealand White rabbit fetuses on gestational day 24 and from Sprague-Dawley rats on gestational day 18 and neonatal day 3, and decellularized using a sodium dodecyl sulfate-based negative-pressure protocol. Six, 10-mm-diameter, full-thickness rat latissimus dorsi wounds were created for each treatment, matrix was implanted (excluding the defect groups), and the wounds were allowed to heal for 60 days. Analyses were performed to characterize myogenesis, neovascularization, inflammation, and fibrosis at harvest. Significant myocyte ingrowth was visualized in both allogeneic and xenogeneic fetal matrix groups compared to neonatal and defect groups based on myosin heavy chain immunofluorescence staining. Microvascular networks were appreciated within all implanted matrices. At day 60, expression of Ccn2, Col1a1, and Ptgs2 were decreased in fetal matrix groups compared to defect. Neonatal matrix-implanted wounds failed to show decreased expression of Col1a1 or Ptgs2, and demonstrated increased expression of Tnf, but also demonstrated a significant reduction in Ccn2 expression. Initial studies of fetal matrices demonstrate promise for muscle regeneration in a rat latissimus dorsi model. Further research is necessary to evaluate fetal matrix for future translational use and better understand its effects.

High-trans fatty acid and high-sugar diets can cause mice with non-alcoholic steatohepatitis with liver fibrosis and potential pathogenesis

Background and aimsEven Non-alcoholic steatohepatitis (NASH) has been becoming the key role in process of liver fibrosis or cirrhosis, no any NASH involving liver fibrosis mice model which consistent with the mechanisms of fatty acid and glucose metabolism disorder was widely accepted. Here, we established a mouse model of nonalcoholic steatohepatitis (NASH) with liver fibrosis using a high-fat, high-carbohydrate diet (HFHC) and analyzed the potential pathogenesis using a transcriptome microarray.MethodsFifty mice were stratified by weight and randomly divided into the HFHC model and control (Con) groups. Ten mice were sacrificed at the beginning of the experiments, 10 mice of HFHC and Con group were euthanized at the end of 20 and 30 weeks. The following analyses were performed: biochemical analysis; histological assessment; evaluation of hepatic type I collagen (Col-I), α-smooth muscle actin (α-SMA) and transforming growth factor-β1 (TGF-β1) protein and mRNA expression levels; and transcriptomic gene chip analysis.ResultsCompared with the Con group at each time point, the body weight and liver wet weight of the HFHC model group of mice were significantly higher. At 30th weeks, alanine aminotransferase (ALT), aspartate aminotransferase (AST), fasting blood glucose (FBG) and fasting insulin (FINS) levels or activities and the triglyceride (TG) and hydroxyproline (HYP) content in the HFHC model group were significantly elevated. Severe steatosis was present in the liver tissues contributed from the HFHC group of mice. Typically, substantial perisinusoidal fibrosis with a cage-like structure and bridging formations were observed in the mice liver in HFHC group. Col-I, α-SMA and TGF-β1 protein and mRNA expression levels in liver tissues of HFHC mice dramatically increased over time. Compared with the Con group, the HFHC group had 151 differentially expressed genes that were involved in 41 signaling pathways.ConclusionsAfter keeping 30 weeks HFHC diet treatment, the mice exhibited substantial liver fibrosis, hepatic steatosis, ballooning degeneration and inflammation. Basing on the transcriptome microarray assays, the experimental NASH involving liver fibrosis potentially related to dramatically changed ECM-receptor interaction, Toll-like receptor signaling and other signaling pathways.

Metabolic Alterations in Cardiomyocytes are Associated with Methamphetamine‐Induced Cardiomyopathy

IntroductionIllicit use of Methamphetamine (METH) in humans is associated with cardiac dysfunction known as METH‐induced cardiomyopathy. Specifically, the stimulant inhibits mitochondrial bioenergetics, resulting in energy deprivation, which may ultimately lead to the activation of the adaptive autophagy process.ObjectivesWe aim to determine the METH‐induced metabolic alterations in cardiomyocytes leading to the development of the METH‐associated cardiomyopathy.Methods and ResultsAutopsy heart samples from humans with a positive toxicology for METH use showed substantial fibrosis in the heart. ‘Binge’ METH‐administration in mice for four weeks developed cardiac hypertrophy and fibrosis in the heart. Mitochondria isolated from the METH‐treated heart showed defects in mitochondrial respiration. Western blot analysis of autophagy regulatory protein expression ‘Binge’ METH‐treated mice showed increased expression of LC3B‐II and p62 proteins. To determine the direct non‐catecholamine dependent effect of METH on cardiomyocytes, we treated primary cardiomyocytes with different doses of METH (100 and 250 μM). Western Blot analysis showed a dose and time‐dependent increase in the expression of LC3B‐II and autophagy‐related protein 7 (Atg7). We also observed increased phosphorylation of cellular metabolism‐related proteins, i.e., phosphorylated FOXO1 (at Ser 256) and FOXO3a (at Ser 253). We conducted autophagy flux assay to confirm the METH‐induced activation of autophagy exposing cardiomyocytes with METH (250 μM for 24 hours) followed by treatment with lysosomal inhibitor BafilomycinA1 (50nM for 3 hours). Western Blot analysis showed increased expression of LC3B‐II in BafA1 treated cardiomyocytes suggesting activation of autophagy following METH‐exposure.ConclusionsWe report that METH use causes adverse fibrotic remodeling in hearts from both human and pre‐clinical mouse model. We found that METH suppresses mitochondrial respiration in cardiomyocytes that elicit adaptive activation of autophagy and autophagy regulatory proteins as a response to METH‐induced energy deprivation.Support or Funding InformationThis project was performed as part of the CURIOUS program supported by grant R25HL147665 from the NIH/NHLBI. This work was further supported by NIH/NHLBI grants R00 HL122354, R01HL145753, R01HL145753‐01S1 and PGM121307A to Dr. Bhuiyan. American Heart Association postdoctoral fellowship to Dr. Alam; Malcolm Fiest post‐ and pre‐doctoral fellowships to Dr. Abdullah and Aishwarya by CCDS, LSUHSC‐S.

Electrocardiographic associations with myocardial fibrosis among sudden cardiac death victims

ObjectiveA major challenge in reducing the incidence of sudden cardiac death (SCD) is the identification of patients at risk. Myocardial fibrosis has a substantial association with SCD risk but is...

The MRL/MpJ Mouse Strain Is Not Protected From Muscle Atrophy and Weakness After Rotator Cuff Tear.

Chronic rotator cuff tears are a common source of shoulder pain and disability. Patients with rotator cuff tears often have substantial weakness, fibrosis, and fat accumulation, which limit successful surgical repair and postoperative rehabilitation. The Murphy Roths Large (MRL) strain of mice have demonstrated superior healing and protection against pathological changes in several disease and injury conditions. We tested the hypothesis that, compared with the commonly used C57Bl/6 (B6) strain, MRL mice would have less muscle fiber atrophy and fat accumulation, and be protected against the loss in force production that occurs after cuff tear. Adult male B6 and MRL mice were subjected to a rotator cuff tear, and changes in muscle fiber contractility and histology were measured. RNA sequencing and shotgun metabolomics and lipidomics were also performed. The muscles were harvested one month after tear. B6 and MRL mice had a 40% reduction in relative muscle force production after rotator cuff tear. RNA sequencing identified an increase in fibrosis-associated genes and a reduction in mitochondrial metabolism genes. The markers of glycolytic metabolism increased in B6 mice, while MRL mice appeared to increase amino acid metabolism after tear. There was an accumulation of lipid after injury, although there was a divergent response between B6 and MRL mice in the types of lipid species that accrued. There were strain-specific differences between the transcriptome, metabolome, and lipidome of B6 and MRL mice, but these differences did not protect MRL mice from weakness and pathological changes after rotator cuff tear. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:811-822, 2020.

3254Manifestations of myocardial fibrosis in the standard 12-lead electrocardiogram

Abstract Background Myocardial fibrosis has substantial role in sudden cardiac deaths (SCD). Major challenge in preventing SCDs is early recognition of vulnerable patients with fibrotic cardiomyopathy. Our aim was to find manifestations of myocardial fibrosis in 12-lead electrocardiogram (ECG). Methods Study population is based on the Fingesture study, which has gathered data from 5,869 consecutive autopsied SCD victims between 1998 and 2017 in Finland. The degree of fibrosis was determined based on the histological samples taken from the heart during autopsy and was categorized into four groups; 1) no fibrosis, 2) scattered mild fibrosis, 3) moderate patchy fibrosis and 4) substantial fibrosis. We were able to collect pre-mortem 12-lead ECGs from 1,100 SCD victims. Ischemic cardiomyopathy was the cause of death in 689 cases and 411 had nonischemic cardiomyopathy at autopsy in the group where ECG was available. Results Mean age of the study subjects was 66±13 years and 75% were male. At least some amount of myocardial fibrosis was present in 92% of the victims. QRS duration in ECG correlated with the degree of fibrosis in autopsy as follows; 96±21ms in group 1 (n=93), 97±20ms in group 2 (n=357), 103±26ms in group 3 (n=506) and 108±27ms in group 4 (n=144; p&lt;0.001, β=0.153). Prevalence of fragmented QRS complex was higher among victims with severe fibrosis (40% in group 1, 43% in group 2, 60% in group 3 and 65% in group 4; p&lt;0.001). Additionally, inferolateral T-wave inversions were more common in groups with increasing amount of myocardial fibrosis (5.4% in group 1, 13.2% in group 2, 20.4% in group 3 and 31.9% in group 4; p&lt;0.001). Associations were visible in both ischemic and nonischemic SCDs but reached statistical significance only among ischemic SCD victims. Heart rate corrected JT interval and Sokolow-Lyon index had no linear correlation with the degree of fibrosis. Conclusions Myocardial fibrosis was associated with QRS prolongation, T-wave inversions and QRS fragmentation among SCD victims. Fibrosis did not manifest as clearly in ECG among patients with nonischemic cardiomyopathies as among ischemic SCD victims. The results may explain the increased risk for SCD in patients with abnormal QRS complex or inverted T waves providing means for recognizing patients with underlying fibrotic cardiomyopathy. Acknowledgement/Funding Sigrid Juselius Foundation, Foundation of Cardiac Research, Paavo Nurmi Foundation and Paulo foundation, Finland

Proof of concept, design, and manufacture via 3‐D printing of a mesh with bactericidal capacity: Behaviour in vitro and in vivo

Currently, hernia treatment involves implantation of a mesh prosthesis, usually made of polypropylene, and the primary complication is infection of the device, which leads to an exponential increase in morbidity. Three-dimensional printing offers a method of dealing with complications of this magnitude. Therefore, in this study, the bactericidal properties and effectiveness of three-dimensional-printed meshes with polycaprolactone (PCL) and gentamicin were evaluated in vitro in Escherichia coli cultures, and their histological behaviour was examined in vivo. Different PCL meshes were implanted into four groups of rats, with 10 rats in each group: PCL meshes, PCL meshes with alginate and calcium chloride, PCL meshes with gentamicin, and PCL meshes with alginate and gentamicin. Thirty-six microporous meshes were manufactured, and their bactericidal properties were assessed. When the meshes did not include an antibiotic, an inhibition halo was not observed; when the gentamicin was free, an asymmetric inhibition area of 5.65 ± 0.46 cm2 was present; when the gentamicin was encapsulated, a rectangular area of 5.40 ± 0.38 cm2 was observed. In the rats, macroporous and microporous mesh implants produced mild inflammation and substantial fibrosis with collagen and neovascular foci. A significant difference was observed in fibroblastic activity between the PCL with alginate group and the PCL with alginate and gentamicin group microporous meshes (p = .013) and in collagen deposits between the macroporous and microporous meshes in the PCL mesh group (p = .033). The feasibility of manufacturing drug-doped printed PCL meshes containing alginate and gentamicin was verified, and the meshes exhibited bactericidal effects and good histopathological behaviour.

Grouping of carbonaceous nanomaterials based on association of patterns of inflammatory markers in BAL fluid with adverse outcomes in lungs

Carbonaceous nanomaterials (CNMs) are universally being used to make commodities, as they present unique opportunities for development and innovation in the fields of engineering, biotechnology, etc. As technology advances to incorporate CNMs in industry, the potential exposures associated with these particles also increase. CNMs have been found to be associated with substantial pulmonary toxicity, including inflammation, fibrosis, and/or granuloma formation in animal models. This study attempts to categorize the toxicity profiles of various carbon allotropes, in particular, carbon black, different multi-walled carbon nanotubes, graphene-based materials, and their derivatives. Statistical and machine learning-based approaches were used to identify groups of CNMs with similar pulmonary toxicity responses from a panel of proteins measured in bronchoalveolar lavage (BAL) fluid samples and with similar pathological outcomes in the lungs. Thus, grouped particles, based on their pulmonary toxicity profiles, were used to select a small set of proteins that could potentially identify and discriminate between the toxicity profiles associated within each group. Specifically, MDC/CCL22 and MIP-3β/CCL19 were identified as common protein markers associated with both toxicologically distinct groups of CNMs. In addition, the persistent expression of other selected protein markers in BAL fluid from each group suggested their ability to predict toxicity in the lungs, i.e. fibrosis and microgranuloma formation. The advantages of such approaches can have positive implications for further research in toxicity profiling.

Flagellin-mediated activation of IL-33-ST2 signaling by a pathobiont promotes intestinal fibrosis.

Intestinal fibrosis is a severe complication in patients with Crohn’s disease (CD). Unfortunately, the trigger leading to the development of intestinal fibrosis in the context of CD remains elusive. Here, we show that colonization by a CD-associated pathobiont adherent-invasive Escherichia coli (AIEC) promotes the development of intestinal fibrosis. Exogenously inoculated AIEC strain LF82 and commensal E. coli HS were gradually eradicated from the intestine in healthy mice. In Salmonella- or dextran sodium sulfate-induced colitis models, AIEC exploited inflammation and stably colonize the gut. Consequently, persistent colonization by AIEC LF82 led to substantial fibrosis. In contrast, commensal E. coli HS was unable to derive a growth advantage from inflammation, thereby failing to colonize the inflamed intestine or promote intestinal fibrosis. AIEC colonization potentiated the expression of the IL-33 receptor ST2 in the intestinal epithelium, which is crucial for the development of intestinal fibrosis. The induction of ST2 by AIEC LF82 was mediated by flagellin, as the FliC mutant failed to induce ST2. These observations provide novel insights into pathobiont-driven intestinal fibrosis and can lead to the development of novel therapeutic approaches for the treatment of intestinal fibrosis in the context of CD that target AIEC and/or its downstream IL-33-ST2 signaling.

Comparison of Two-Dimensional Shear Wave Elastography with NineSerum Fibrosis Indices to Assess Liver Fibrosis in Patients with Chronic Hepatitis B: A Prospective Cohort Study.

To prospectively assess liver fibrosis with two-dimensional shear wave elastography (2D-SWE) in patients with chronic hepatitis B (CHB) and to compare the performance of this modality with that of serum indices using Scheuer scoring from liver biopsies as the reference standard. 123 patients with CHB underwent 2D-SWE measurements and serological tests between April 2016 and February 2018. The 2D-SWE and serum indices in the diagnosis of liver fibrosis were assessed using receiver operating characteristic (ROC) analyses. The areas under ROC (AUCs) for 2D-SWE, aspartate transaminase-to-platelet ratio index, fibrosis index based on the four factors, Forns score, King's score, FibroIndex, red cell distribution width-to-platelet ratio, Hepascore, type IV collagen, and hyaluronic acid were 0.851, 0.738, 0.701, 0.739, 0.734, 0.711, 0.692, 0.601, 0.640, and 0.522, respectively, in the diagnosis of substantial fibrosis, 0.975, 0.819, 0.792, 0.829, 0.818, 0.807, 0.732, 0.572, 0.676, and 0.544, respectively, in the diagnosis of severe fibrosis, and 0.972, 0.883, 0.862, 0.908, 0.889, 0.918, 0.808, 0.601, 0.807, and 0.775, respectively, in the diagnosis of cirrhosis. The AUCs of 2D-SWE in the diagnosis of substantial fibrosis, severe fibrosis, and cirrhosis were significantly higher than those of the serum indices (p < 0.05). 2D-SWE is a reliable noninvasive method for theassessment of liver fibrosis in patients with CHB with better diagnostic performance than that of nine serum fibrosis indices.

Diagnostic Accuracy of 2‐Dimensional Shear Wave Elastography for the Staging of Liver Fibrosis: A Meta‐analysis

ObjectivesTo evaluate the overall accuracy of 2‐dimensional shear wave elastography (SWE) for the staging of liver fibrosis.MethodsLiterature databases and conference abstracts were searched from 2000 to September 2017. Sensitivity, specificity, and other information were extracted from the included studies. Methodological quality was assessed with Quality Assessment of Diagnostic Accuracy Studies 2 tools. Data were synthesized by a bivariate hierarchical model.ResultsThe summary sensitivity and specificity were 0.85 (95% confidence interval [CI], 0.80–0.89) and 0.79 (95% CI, 0.72–0.85) for fibrosis stage F≥2, 0.90 (95% CI, 0.87–0.93) and 0.85 (95% CI, 0.80–0.89) for F≥3, and 0.89 (95% CI, 0.84–0.93) and 0.92 (95% CI, 0.89–0.95) for F=4, respectively. The areas under the summary receiver operating characteristic curve for F≥2, F≥3, and F=4 was 0.81, 0.77, and 0.84.ConclusionsTwo‐dimensional SWE is a good noninvasive method for the diagnosis of substantial liver fibrosis and cirrhosis. Further studies are needed to assess severe fibrosis and to perform head‐to‐head comparisons of 2‐dimensional SWE and other imaging modalities for the evaluation of liver fibrosis.

Laparoscopic Transplant Nephrectomy for Failed Renal Allograft

Traditionally, transplant nephrectomy for a failed renal allograft is performed using open surgery. This approach is associated with bleeding during surgery or infected hematoma, postoperatively. Minimally invasive surgery for removal of a failed renal allograft has previously been reported using robotic technique. These procedures are challenging due to the substantial fibrosis that forms around a retroperitoneal allograft. We report our experience with two cases, using laparoscopic approach. A 47-year-old female lost function of his deceased donor allograft after 1,5 year due rejection and infection, presented with fever, pain in renal fossa and hematuria. The operation was performed intra-abdominally using the laparoscopic with four trocars. The total operative time was 300 min and the estimated blood loss was 250 cm. A 46 year old female patient lost function of his deceased donor allograft after 2 year due atypical hemolytic uremic syndrome. The operative time was 340 min, intraoperative blood loss -150 ml. There were no peri-operative complications observed and the patients were discharged to home in 4 days postoperatively. This method is technically demanding and surgeon needs considerable laparoscopic experience to try this approach.