Different Degrees Of Fibrosis Research Articles

Role of transforming growth factor beta in assessment of severity of hypersensitivity pneumonitis: a single center study

BackgroundHypersensitivity pneumonitis (HP) is a more frequently diagnosed picture of diffuse parenchymal lung disease. It is an inflammation of the lung tissue, provoked by immune mechanisms, which happens to prone individuals as a reaction to a wide range of antigens. There are different degrees of fibrosis and inflammation. A group of extracellular mediators both proinflammatory and profibrotic claimed to be involved in the pathogenesis of HP. Among these mediators, a significant role is played by transforming growth factor-beta (TGF-β).AimCorrelation between the severity of hypersensitivity pneumonitis and the serum level of TGF beta.Patients and methodsSixty subjects were included in the study who were classified into 30 patients newly diagnosed with hypersensitivity pneumonitis and 30 healthy subjects served as controls. All the participants were subjected to complete history taking, physical examination, spirometry, 6-min walk distance test, HRCT, and serum levels of TGF-β.ResultsThe serum level of TGF beta is elevated in newly diagnosed HP cases (fibrotic and non-fibrotic) in relation to control participants showing statistical significance p value < 0.001, and the serum level of TGF beta in the fibrotic group of HP patients is more than that in non-fibrotic group with statistical significance p value 0.012.ConclusionThe serum level of transforming growth factor can be used in the assessment of the severity of hypersensitivity pneumonitis as regards the intensity of lung parenchymal changes.

Diagnostic performance of shear wave measurement in the detection of hepatic fibrosis: A multicenter prospective study.

This study aimed to establish the shear wave measurement (SWM) cut-off value for each fibrosis stage using magnetic resonance (MR) elastography values as a reference standard. We prospectively analyzed 594 patients with chronic liver disease who underwent SWM and MR elastography. Correlation coefficients (were analyzed, and the diagnostic value was evaluated by the area under the receiver operating characteristic curve. Liver stiffness was categorized by MR elastography as F0 (<2.61kPa), F1 (≥2.61kPa, <2.97kPa, any fibrosis), F2 (≥2.97kPa, <3.62kPa, significant fibrosis), F3 (≥3.62kPa, <4.62kPa, advanced fibrosis), or F4 (≥4.62kPa, cirrhosis). The median SWM values increased significantly with increasing fibrosis stage (p<0.001). The correlation coefficient between SWM and MR elastography values was 0.793 (95% confidence interval 0.761-0.821). The correlation coefficients between SWM and MR elastography values significantly decreased with increasing body mass index and skin-capsular distance; skin-capsular distance values were associated with significant differences in sensitivity, specificity, accuracy, or positive predictive value, whereas body mass index values were not. The best cut-off values for any fibrosis, significant fibrosis, advanced fibrosis, and cirrhosis were 6.18, 7.09, 8.05, and 10.89kPa, respectively. This multicenter study in a large number of patients established SWM cut-off values for different degrees of fibrosis in chronic liver diseases using MR elastography as a reference standard. It is expected that these cut-off values will be applied to liver diseases in the future.

Assessment of compensated advanced chronic liver disease based on serum bile acids in chronic hepatitis B patients

Patients with chronic liver disease progressed to compensated advanced chronic liver disease (cACLD), the risk of liver-related decompensation increased significantly. This study aimed to develop prediction model based on individual bile acid (BA) profiles to identify cACLD. This study prospectively recruited 159 patients with hepatitis B virus (HBV) infection and 60 healthy volunteers undergoing liver stiffness measurement (LSM). With the value of LSM, patients were categorized as three groups: F1 [LSM ≤ 7.0 kilopascals (kPa)], F2 (7.1 < LSM ≤ 8.0 kPa), and cACLD group (LSM ≥ 8.1 kPa). Random forest (RF) and support vector machine (SVM) were applied to develop two classification models to distinguish patients with different degrees of fibrosis. The content of individual BA in the serum increased significantly with the degree of fibrosis, especially glycine-conjugated BA and taurine-conjugated BA. The Marco-Precise, Marco-Recall, and Marco-F1 score of the optimized RF model were all 0.82. For the optimized SVM model, corresponding score were 0.86, 0.84, and 0.85, respectively. RF and SVM models were applied to identify individual BA features that successfully distinguish patients with cACLD caused by HBV. This study provides a new tool for identifying cACLD that can enable clinicians to better manage patients with chronic liver disease.

Emerging Therapies and Therapeutic Targets for Composite Liver Disease: NASH.

Liver diseases continue to destroy the lives of people, one of which is known as Non-alcoholic Steatohepatitis (NASH) that becomes a serious liver disease all around the world over the last few years. Non-alcoholic Steatohepatitis (NASH) is a progressive form of Nonalcoholic Fatty Liver Disease (NAFLD) and is characterized by liver steatosis, inflammation, different degrees of fibrosis, and hepatocellular injury. The inflammatory mediators play a vital role in the transition of Non-alcoholic Fatty Liver (NAFL) to Non-alcoholic Steatohepatitis (NASH), which further leads to Hepatocellular Carcinoma (HCC) and becomes a cause of liver transplantation. Considering the severity and complexity of the disease, we aim to summarize the works of various research groups that are working in the area of NASH to find a sophisticated treatment. The present review focused on various factors that are responsible for the development and progression of this prevalent disease, emerging pharmacotherapies as well as therapeutic targets that have been utilized for the treatment of NASH. We also have conducted the structural analysis of available targets, which will be helpful for the enhancement of drug discovery through the implementation of in silico methods. Efforts have been made to provide an update on research in the area of NASH, including the pharmacological agents that are currently undergoing clinical trials for the treatment of NASH. Besides the massive research, still, gaps and challenges are there in the drug development for NASH that also have been discussed.

Endometrial fibrosis in mares: Picrosirius Red and Collagen-2 and 3

In mares, endometrial fibrosis results from abnormal collagen deposition in the stroma and around the endometrial glands. The pathogenesis of endometrial fibrosis remains unknown, but the different types of collagens are a fundamental part of the process. The Picrosirius Red (PSR) staining is widely studied and necessary for collagen fiber and tissue remodeling. The present study aimed to determine the collagen deposition and the gene expression of collagen-2(COL-2) and collagen-3(COL-3) in the endometrium of mares with different degrees of fibrosis. Cyclic mares (n = 34) with a mean age of 14 ± 6.4 years old were used. A uterine biopsy from each mare was obtained at diestrus (D5–D10). Mares were grouped according to the degree of uterine fibrosis described by Kenney (1978): Grade I (n = 12), Grade II (n = 12), and Grade III (n = 10). Collagen in the equine endometrium was morphometrically quantified under PSR staining. The morphometric quantification of the images was performed from each sample after digital microphotographs were taken at 200x magnification, processed, and evaluated using the ImageJ 1.52a software. COL-2 and COL-3 expression was performed using qPCR. Grades were considered independent factors. Collagen-stained area and transcript expression were considered dependent factors. Data were analyzed with ANOVA andt-test. A Pearson correlation was performed between age and collagen deposition. The percentage of tissue collagen area stained with PSR revealed a significant increase between all groups in collagen deposition according to the degree of fibrosis: Grade I (11.7 ± 1.4%), Grade II (17.8 ± 1.3%), and Grade III (24.1 ± 1.9%). Age and the percentage of collagen deposited in the endometrial tissue correlated (r = 0.5) (P = 0.015). Grade II samples presented higher expression of COL-2 transcripts compared to Grade I (P = 0.026) and Grade III (P = 0.003). However, COL-3 did not show differences between groups. This study agrees with other studies that indicate that the worsening of degenerative changes coincides with advanced mare age. Sample evaluations emphasizing degenerative changes rely on an experienced evaluator, while the PSR, followed by computerized analysis, presents quantitative data. In conclusion, the increase in PSR analysis in Grade II and Grade III mares compared to Grade I demonstrates that this technique could play an important role in routine analyses for the detection, quantification, and dynamics of collagen in specific tissues. The study revealed that COL-2 might be involved in the progression and differentiation of healthy endometrium into an endometrium with severe fibrosis.

Macrophages modulate stiffness-related foreign body responses through plasma membrane deformation

Implants are widely used in medical applications and yet macrophage-mediated foreign body reactions caused by implants severely impact their therapeutic effects. Although the extensive use of multiple surface modifications has been introduced to provide some mitigation of fibrosis, little is known about how macrophages recognize the stiffness of the implant and thus influence cell behaviors. Here, we demonstrated that macrophage stiffness sensing leads to differential inflammatory activation, resulting in different degrees of fibrosis. The potential mechanism for macrophage stiffness sensing in the early adhesion stages tends to involve cell membrane deformations on substrates with different stiffnesses. Combining theory and experiments, we show that macrophages exert traction stress on the substrate through adhesion and altered membrane curvature, leading to the uneven distribution of the curvature-sensing protein Baiap2, resulting in cytoskeleton remodeling and inflammation inhibition. This study introduces a physical model feedback mechanism for early cellular stiffness sensing based on cell membrane deformation, offering perspectives for future material design and targeted therapies.

Rol kyshkovoi mikrobioty, endotoksemii ta systemnoho zapalennia u patohenezi nealkoholnoi zhyrovoi khvoroby pechinky

Introduction. Currently there are few and contradictory data concerning the influence of intestinal microbiota (IM) disturbances on the nature and severity of inflammatory processes in the liver tissue, the role of microbial metabolites in the activation of steatosis and fibrosis processes in patients with non-alcoholic fatty liver disease (NAFLD). The aim of the study. To clarify the role of intestinal microbiota, endotoxemia and systemic inflammation in the development and progression of nonalcoholic fatty liver disease. Materials and methods. 108 patients with NAFLD were examined, control group included 30 people. Detection of CRP and TNF-alpha levels, endotoxin in blood serum was carried out by the immunoenzymatic method. Determination of IM composition at the level of the main phylotypes was carried out by the method of quantitative polymerase chain reaction in real time. Results. A weak direct correlation between TNF-alpha, CRP and endotoxin with Firmicutes content (F), and an inverse correlation between CRP with Bacteroidetes content (B) was revealed. The dependence of the ratio of main intestinal phyla (F/B) on markers of systemic inflammation in NAFLD patients with different levels of endotoxin was evaluated. In patients with NAFLD, as endotoxin concentration increased, a deeper imbalance of IM was observed. In the group of patients with NAFLD with a high level of endotoxin, the maximum values of the F/B index were observed. Also, the increase in the intestinal permeability of the mucous barrier depended not only on changes in the IM, but also on systemic inflammation. The highest levels of endotoxemia were observed in patients with a high F/B index and increased activity of pro-inflammatory markers. In patients with NAFLD with varying degrees of fatty infiltration of the liver, an imbalance of IM was detected in comparison with the control group. As the degree of steatosis increased in NAFLD patients, an increase in Firmicutes content was observed. The maximum shift in the balance of the main phyla towards a decrease in the relative content of Bacteroidetes and an increase in Firmicutes was determined in patients with 3rd degree of steatosis (p-value less than 0.05). In the group of patients with a low and moderate degree of steatosis, a similar trend of IM disorders was observed, but these changes were insignificant. The relative number of Actinobacteria exposed no differences between the examined patients. The analysis of changes in IM in patients with NAFLD depending on the stage of liver fibrosis revealed no significant differences both from the control group and between groups with different degrees of fibrosis. The obtained data indicate that the imbalance of IM makes a significant contribution to the development of liver steatosis, while other important factors are involved in the formation of fibrosis processes, in particular, inflammation, the activity of intestinal metabolites and regulatory molecules. Conclusions.The imbalance of the intestinal microbiota towards an increase in Firmicutes leads to an increase in the production of intestinal metabolites with subsequent initiation of systemic inflammation, which stimulates the accumulation of fat in hepatocytes, affecting the progression of steatosis and the processes of fibrosis in the liver.

The clinicopathological features of adult orbital xanthogranulomatous disease with lacrimal gland reactive lymphoid hyperplasia

Objective: To investigate the clinicopathological features of adult orbital xanthogranulomatous disease (AOXGD) with lacrimal gland reactive lymphoid hyperplasia. Methods: Retrospective case series study. The clinical and pathological data of AOXGD cases diagnosed and treated in Tianjin Eye Hospital from January 2002 to December 2021 was reviewed, and the clinical characteristics, radiologic findings and pathological characteristics of periocular and lacrimal gland lesions of 5 cases were retrospectively analyzed. The expression of IgG4 and IgG protein in periocular and lacrimal gland lesions was detected by immunohistochemical staining, and the role of IgG4 in AOXGD was preliminarily studied. Results: There were four females and one male with an average age of 53.8 years (39 to 77 years). Among the five AOXGD cases, there were three cases of adult-onset xanthogranuloma, one case of adult-onset asthma and periocular xanthogranuloma, and one case of necrobiotic xanthogranuloma. All cases involved both eyes. The swelling of eyelids was observed in five cases, and the yellow or pale yellow eyelid skin was found in two cases. Imaging examinations showed the tumor mainly involved the eyelids, subcutaneous tissues, anterior orbit and lacrimal gland. A large number of foam cells and typical Touton giant cells were found in the periorbital lesions, accompanied by different degrees of fibrosis. The fibrinoid necrosis was detected in one case of necrobiotic xanthogranuloma. The lacrimal gland lesions showed different types of reactive lymphoid hyperplasia, including IgG4-related disease in two cases, follicular lymphoid hyperplasia in two cases and focal lymphoid hyperplasia in one case. IgG4 levels of periorbital and lacrimal gland lesions were elevated in four cases. Asthma and elevated serum IgG4 were found in one case of adult-onset periocular xanthogranuloma. Three patients underwent surgical resection and adjuvant hormone or immunosuppressive therapy, and two patients underwent simple surgical resection. The patients were followed up for 1.5 to 10.0 years, one patient was lost, and four patients had no recurrence. Conclusions: AOXGD with lacrimal gland reactive lymphoid hyperplasia is a group of rare diseases. The periorbital lesions of that are characterized by proliferation of foamy histiocytes and Touton giant cells, and the lacrimal gland lesions of that manifest as IgG4-related disease in some cases.

Non-Invasive Diagnostic Test for Advanced Fibrosis in Adolescents With Non-Alcoholic Fatty Liver Disease.

IntroductionNon-alcoholic fatty liver disease (NAFLD) is a multifaceted disease that includes a wide spectrum of liver damage. The presence and the degree of fibrosis are considered important factors for the prognosis of NAFLD and in predicting the risk of developing cirrhosis. Our aim was to evaluate the usefulness of four fibrosis scores (aspartate aminotransferase/Platelet Index [APRI], FIB-4, NAFLD Fibrosis Score [NFS], and Hepamet) in predicting different degrees of fibrosis among children with biopsy-proven NAFLD.MethodsAbout 286 adolescents [mean age 14.3 years ± 2.5; 154 (53.6%) males], referred between January 2014 and December 2019, with biopsy-proven NAFLD were enrolled.ResultsAbout 173 (60.4%) patients presented fibrosis at histological analysis. In particular: 140 (49.3%) patients had F = 1, 31 (10.8%), had F = 2 and 2 (0.66%) had F = 3. APRI (AUROC 0.619, 95% CI 0.556–0.679) and Hepamet (AUROC 0.778, 95% CI 0.722–0.828) scores had significant (p < 0.001) accuracy to distinguish subjects with fibrosis; while NFS and FIB-4 had not. APRI had a positive predictive value (PPV) of 62.77% (95% CI 57.96–67.35) and an negative predictive value (NPV) of 52.01% (95% CI 46.54–57.43); Hepamet a PPV of 63.24% (95% CI 59.95–66.41) and an NPV of 61.29% (52.9–69.01).ConclusionsOur study showed that Hepamet and APRI perform better than NFS and FIB-4 for identifying fibrosis in patients with NAFLD, but do not have PPVs so high to be considered diagnostic. Therefore, they cannot be employed, in children, for a certain diagnosis of fibrosis or its progression and cannot replace liver biopsy as the gold diagnostic standard. It is, therefore, necessary to continue to research and develop new markers of exclusive fibrosis.

Comparing shear wave elastography with liver biopsy in the assessment of liver fibrosis at King Hussein Medical Center

Background and study aimsThe aim of this prospective study is to compare the sensitivity and specificity of the liver shear wave elastography to the golden standard liver biopsy in staging liver fibrosis.Patients and methodsNinety-five patients were included in this study. These patients were sent for liver biopsy as a possible living liver donor or because of different pathologies including viral and autoimmune hepatitis and congenital liver diseases. A shear wave elastography and US-guided liver biopsy were done at the same setting by one experienced radiologist. One experienced histopathologist, blinded to SWE results, read the specimens.ResultsWe included 95 patients in the study with a mean age of 30 years (range 3–65 years). We had 15/95 (16%) patients with hepatitis B/C, 61/95 (64%) patients with another liver disease, and 19/95 (20%) were donors. The mean of liver stiffness measured by elastography in patients was 6.5±0.19 kPa. The mean liver stiffness measured by elastography in patients with F0–F1 fibrosis was 5.39 ± 0.62 kPa, F2 was 7.32 ± 0.41, at stage F3 was 8.46 ± 0.33, and in the F4 stage, it was 11.42 ± 2.8 kPa. We found a significant difference in the mean level of liver stiffness in different degrees of fibrosis (p = 0.0001).ConclusionThe shear wave elastography could be used to assess liver fibrosis regardless of the cause.

STUDY OF CONCORDANCE BETWEEN THE DEGREE OF LIVER FIBROSIS ESTIMATED THROUGH APRI AND FIB-4 BIOCHEMICAL SCORES, AND ELASTORESONANCE IN PATIENTS WITH AUTOIMMUNE HEPATITIS

Autoimmune hepatitis is a chronic and progressive necroinflammatory disease with a fluctuating course of activity and affects more frequently the female sex. The etiopathogenesis is still unknown and may be the result of an interaction between factors: genetic, immunological, autoantigens; Therefore, the interaction of genetic predisposition with an environmental trigger and the disorder in immunoregulation would result in chronic inflammation of the hepatocytes and with it the development of hepatic fibrosis. Diagnostic tests for the evaluation of liver fibrosis include liver biopsy and non-invasive elastographic methods, such as transition elastography and elastoresonance, as well as serum biomarkers, composed of different variables that help predict the degree of liver fibrosis. Compare the concordance between the results obtained for the diagnosis of liver fibrosis by the APRI and FIB-4 score, with the elastoresonance, in patients with HAI. Elastoresonance, APRI and FIB-4 were performed in 6 patients to assess the concordance between different degrees of fibrosis. A total of 6 patients with a recent diagnosis of HAI were included in the study. The mean age was 50.33 years and 100% were women. 66.66% of the patients presented an advanced degree of fibrosis (F2-F3-F4) due to elastoresonance. The values ​​for the APRI index were: 3 patients (50%) had an advanced degree of fibrosis, 1 patient had a low degree of fibrosis (6%) and 2 patients (33.33%) had intermediate. The findings for the FIB-4 values ​​were exactly the same. The agreement of elastoresonance in the different degrees of fibrosis against the APRI and FIB-4 score was 100%. Non-invasive methods to measure the degree of liver fibrosis in patients with chronic liver disease have shown to be useful, and in this study, it transcends that the correlation with the degree of fibrosis obtained by elastoresonance with the APRI and FIB-4 scores is 100%, this could avoid reaching the liver biopsy, which although it is the gold standard in measuring the degree of liver fibrosis, is an invasive and expensive method, which involves risks for the patient (puncture of other internal organs, infection and adverse reaction to contrast material). In patients classified with advanced fibrosis, the concordance between the estimates obtained using the elastoMR and those derived from the APRI and FIB-4 scores are high. However, a limitation of this study is the size of the sample. The authors declare that there is no conflict of interest.

CONNECTIVE TISSUE GROWTH FACTOR (CTGF) AS A PROMOTER IN THE DEVELOPMENT OF FIBROSIS IN PATIENTS WITH PRIMARY BILIARY CHOLANGITIS

Primary biliary cholangitis (PBC), an immune-mediated disease, is characterized by destroying the intrahepatic bile ducts, leading to progressive damage to the biliary tree, cholestasis, and development of progressive fibrosis leading to cirrhosis with all its complications. The development of fibrosis is multifactorial and includes connective tissue growth factor (CTGF). in a mouse model of cholestasis by bile duct ligation, the hepatic and serum increase in CTGF associated with the progression of fibrosis was demonstrated. Our goal was to determine the relationship between CTGF levels and their association with the development of fibrosis in patients with PBC. Prospective, cross-sectional, and analytical study, including patients with PBC. The degree of fibrosis was determined by transient elastography (Fibroscan). Serum concentrations of FCTC-8pg/ml were quantified, for statistical analysis, the SPSS version 25.0 software was used; the medians (Q3, Q1) of CTGF, alkaline phosphatase, gamma-glutamyl-transpeptidase, and degree of fibrosis were compared with the Mann-Whitney U test with significantly less than 0.05. We included 30 patients, 29 women (96.6%) and 1 man (3.4%), with a mean age of 55.5±12.4 years. Overexpression of CTGF protein was shown in 28 subjects (93.3%). Regarding the degree of fibrosis, all patients were categorized into one of two stages: Significant fibrosis (F2) and cirrhosis (F4). The F2 group had 11 patients with a median and standard deviation for CTGF of 915.9 and 522.9, respectively; The F4 group had 19 patients who showed a median: 945.7 (1313.85-738.32); p :0.025 . In relation to the differences between fibrosis levels and markers of alkaline phosphatase cholestasis, the median and interquartile ranges F2: 79 (180.60) F4: 169(266-5.84) p : 0.066 ; GGT: F2: 1.51(7.7-1,04); F4: 1.2(2-1.92) p:0.746 In (Figure 1) The difference in medians of patients with different degrees of fibrosis and different concentration of CTGF is shown, confirming the association between peptide and the development and progression of fibrosis. According to the results obtained in patients with CBP and chronic cholestasis, the increase in CTGF showed significant differences between the degree of fibrosis and its levels; this could perhaps be interpreted as if it were an important factor for the development and progression of liver fibrosis, taking into account the antecedent of the initial study in mice with bile duct ligation and secondary cholestasis, where this factor was overexpressed at the hepatic and serum level in subjects with advanced fibrosis. It will be important to add more samples to this work and compare it with healthy controls to have better evidence. Connective tissue growth factor (CTGF) probably participates directly in the processes of synthesis of extracellular matrix and therefore in the progression of fibrosis in subjects with primary biliary cholangitis, which makes it a possibility of a therapeutic target to develop in future studies. The authors declare that there is no conflict of interest.

GLP-1 mimetics as a potential therapy for nonalcoholic steatohepatitis.

Nonalcoholic steatohepatitis (NASH), as a severe form of nonalcoholic fatty liver disease (NAFLD), is characterized by liver steatosis, inflammation, hepatocellular injury and different degrees of fibrosis. The pathogenesis of NASH is complex and multifactorial, obesity and type 2 diabetes mellitus (T2DM) have been implicated as major risk factors. Glucagon-like peptide-1 receptor (GLP-1R) is one of the most successful drug targets of T2DM and obesity, and its peptidic ligands have been proposed as potential therapeutic agents for NASH. In this article we provide an overview of the pathophysiology and management of NASH, with a special focus on the pharmacological effects and possible mechanisms of GLP-1 mimetics in treating NAFLD/NASH, including dual and triple agonists at GLP-1R, glucose-dependent insulinotropic polypeptide receptor or glucagon receptor.

Expression and significance of TGF-β1, p38MAPK and BMP-7 protein in liver specimens of patients with alveolar hepatic echinococcosis

To detect the expression of transforming growth factor-β1 (TGF-β1), p38MAPK and bone morphogenetic protein-7 (BMP-7) protein in the liver specimens of patients with hepatic alveolar echinococcosis, and to investigate the potential role of TGF-β1, p38MAPK and BMP-7 protein in hepatic fibrosis caused by hepatic alveolar echinococcosis. A total of 20 patients with hepatic alveolar echinococcosis were enrolled as study subjects, and hepatic specimens were sampled from the sites within 0.5 cm (Group A) and 0.5 to 1.5 cm from hepatic alveolar echinococcosis lesions (Group B), while normal liver specimens sampled from the sites 2 cm and greater from hepatic alveolar echinococcosis lesions served as controls (Group C). The fibrosis of liver specimens was pathological examined using HE and Masson staining, and the expression of TGF-β1, p38MAPK and BMP-7 protein was quantified in liver tissues using Western blotting. The associations of TGF-β1, p38MAPK and BMP-7 protein expression with hepatic fibrosis were assessed. HE staining showed the malaligned structure of hepatocytes and destruction of the structure of hepatic lobules at various degrees in liver specimens in groups A and B, with hepatocyte degeneration, atrophy and necrosis, hyperplasia of fibrous tissues and eosinophilic granulocyte infiltration seen, while no abnormal pathological alterations of liver tissues, normal hepatocyte structure and morphology and uniform size, no malaligned structure of hepatocytes, clear structure of hepatic lobules, no or mild hepatocyte degeneration or necrosis, and no eosinophilic granulocyte infiltration were seen in Group C. Masson staining showed that there was hyperplasia of multiple fibrous connective tissues in the liver portal areas in groups A and B, with fibrosis seen in hepatic lobules, while no obvious pathological changes were seen in Group C. There were significant differences seen in TGF-β1 (P < 0.001), p38MAPK (P < 0.01) and BMP-7 protein (P < 0.05) expression in liver tissues in groups A, B and C, and higher TGF-β1, p38MAPK and BMP-7 protein expression was quantified in groups A and B than in Group C (all P values < 0.05), while greater TGF-β1, p38MAPK and BMP-7 protein expression was detected in Group B than in Group C (all P values < 0.05). The expression of TGF-β1, p38MAPK and BMP-7 protein correlated positively with the severity of hepatic fibrosis (r = 0.866, 0.702 and 0.801, all P values < 0.05), and there were significant differences in TGF-β1 (F = 72.580, P < 0.01), p38MAPK (χ2 = 31.705, P < 0.01) and BMP-7 protein expression (χ2 = 48.388, P < 0.01) among liver tissues with different degrees of fibrosis. The TGF-β1 protein expression correlated positively with p38MAPK and BMP-7 protein expression (r = 0.607 and 0.702, both P values < 0.001), and the BMP-7 protein expression also correlated positively with p38MAPK protein expression (r = 0.456, P < 0.001). The interaction among TGF-β1, p38MAPK and BMP-7 jointly participates in the development of hepatic fibrosis induced hepatic alveolar echinococcosis.

Cordycepin Ameliorates Nonalcoholic Steatohepatitis by Activation of the AMP-Activated Protein Kinase Signaling Pathway.

Background and AimsNonalcoholic fatty liver disease, especially nonalcoholic steatohepatitis (NASH), has become a major cause of liver transplantation and liver‐associated death. NASH is the hepatic manifestation of metabolic syndrome and is characterized by hepatic steatosis, inflammation, hepatocellular injury, and different degrees of fibrosis. However, there is no US Food and Drug Administration–approved medication to treat this devastating disease. Therapeutic activators of the AMP‐activated protein kinase (AMPK) have been proposed as a potential treatment for metabolic diseases such as NASH. Cordycepin, a natural product isolated from the traditional Chinese medicine Cordyceps militaris, has recently emerged as a promising drug candidate for metabolic diseases.Approach and ResultsWe evaluated the effects of cordycepin on lipid storage in hepatocytes, inflammation, and fibrosis development in mice with NASH. Cordycepin attenuated lipid accumulation, inflammation, and lipotoxicity in hepatocytes subjected to metabolic stress. In addition, cordycepin treatment significantly and dose‐dependently decreased the elevated levels of serum aminotransferases in mice with diet‐induced NASH. Furthermore, cordycepin treatment significantly reduced hepatic triglyceride accumulation, inflammatory cell infiltration, and hepatic fibrosis in mice. In vitro and in vivo mechanistic studies revealed that a key mechanism linking the protective effects of cordycepin were AMPK phosphorylation–dependent, as indicated by the finding that treatment with the AMPK inhibitor Compound C abrogated cordycepin‐induced hepatoprotection in hepatocytes and mice with NASH.ConclusionCordycepin exerts significant protective effects against hepatic steatosis, inflammation, liver injury, and fibrosis in mice under metabolic stress through activation of the AMPK signaling pathway. Cordycepin might be an AMPK activator that can be used for the treatment of NASH.

Continuous diffusion spectrum computation for diffusion-weighted magnetic resonance imaging of the kidney tubule system

The use of rigid multi-exponential models (with a priori predefined numbers of components) is common practice for diffusion-weighted MRI (DWI) analysis of the kidney. This approach may not accurately reflect renal microstructure, as the data are forced to conform to the a priori assumptions of simplified models. This work examines the feasibility of less constrained, data-driven non-negative least squares (NNLS) continuum modelling for DWI of the kidney tubule system in simulations that include emulations of pathophysiological conditions. Non-linear least squares (LS) fitting was used as reference for the simulations. For performance assessment, a threshold of 5% or 10% for the mean absolute percentage error (MAPE) of NNLS and LS results was used. As ground truth, a tri-exponential model using defined volume fractions and diffusion coefficients for each renal compartment (tubule system: Dtubules , ftubules ; renal tissue: Dtissue , ftissue ; renal blood: Dblood , fblood ;) was applied. The impact of: (I) signal-to-noise ratio (SNR) =40-1,000, (II) number of b-values (n=10-50), (III) diffusion weighting (b-rangesmall =0-800 up to b-rangelarge =0-2,180 s/mm2), and (IV) fixation of the diffusion coefficients Dtissue and Dblood was examined. NNLS was evaluated for baseline and pathophysiological conditions, namely increased tubular volume fraction (ITV) and renal fibrosis (10%: grade I, mild) and 30% (grade II, moderate). NNLS showed the same high degree of reliability as the non-linear LS. MAPE of the tubular volume fraction (ftubules ) decreased with increasing SNR. Increasing the number of b-values was beneficial for ftubules precision. Using the b-rangelarge led to a decrease in MAPE ftubules compared to b-rangesmall. The use of a medium b-value range of b=0-1,380 s/mm2 improved ftubules precision, and further bmax increases beyond this range yielded diminishing improvements. Fixing Dblood and Dtissue significantly reduced MAPE ftubules and provided near perfect distinction between baseline and ITV conditions. Without constraining the number of renal compartments in advance, NNLS was able to detect the (fourth) fibrotic compartment, to differentiate it from the other three diffusion components, and to distinguish between 10% vs. 30% fibrosis. This work demonstrates the feasibility of NNLS modelling for DWI of the kidney tubule system and shows its potential for examining diffusion compartments associated with renal pathophysiology including ITV fraction and different degrees of fibrosis.

Synergistic antiarrhythmic effect of inward rectifier current inhibition and pulmonary vein isolation in a 3D computer model for atrial fibrillation.

Recent clinical studies showed that antiarrhythmic drug (AAD) treatment and pulmonary vein isolation (PVI) synergistically reduce atrial fibrillation (AF) recurrences after initially successful ablation. Among newly developed atrial-selective AADs, inhibitors of the G-protein-gated acetylcholine-activated inward rectifier current (IKACh) were shown to effectively suppress AF in an experimental model but have not yet been evaluated clinically. We tested in silico whether inhibition of inward rectifier current or its combination with PVI reduces AF inducibility. We simulated the effect of inward rectifier current blockade (IK blockade), PVI, and their combination on AF inducibility in a detailed three-dimensional model of the human atria with different degrees of fibrosis. IK blockade was simulated with a 30% reduction of its conductivity. Atrial fibrillation was initiated using incremental pacing applied at 20 different locations, in both atria. IK blockade effectively prevented AF induction in simulations without fibrosis as did PVI in simulations without fibrosis and with moderate fibrosis. Both interventions lost their efficacy in severe fibrosis. The combination of IK blockade and PVI prevented AF in simulations without fibrosis, with moderate fibrosis, and even with severe fibrosis. The combined therapy strongly decreased the number of fibrillation waves, due to a synergistic reduction of wavefront generation rate while the wavefront lifespan remained unchanged. Newly developed blockers of atrial-specific inward rectifier currents, such as IKAch, might prevent AF occurrences and when combined with PVI effectively supress AF recurrences in human.

Histology and immunohistochemical evaluation of phimotic prepuce: The role of steroid therapy

Phimosis is one of the most frequent andrological diseases in paediatric age. Steroids are useful to treat phimosis. Through a retrospective study of histological and immunohistochemical analysis, we evaluated the effectiveness of topical steroid treatment in patients undergoing circumcision. Cases of patients treated for phimosis were selected during the two-year study period. All patients underwent circumcision and were divided into four groups: groups A (religiously circumcised patients), B (phimotic patients not undergoing steroid treatment), C (phimotic patients who do not respond to cortisone treatment) and D (hypospadic patients undergoing urethroplasty). An histological evaluation of the degree of fibrosis and an immunohistochemical evaluation of collagen IV and tenascin were carried out. Study results demonstrate that the grade of fibrosis is age-related. On histological and immunohistochemical evaluation, fibrosis was found to be lower in patients receiving steroids; higher degrees of fibrosis were found in older patients (p<.05). Different degrees of fibrosis have also been found in hypospadic patients. We can conclude that study results correlated with the clinical history of the patients. The success rate of medical therapy seems to be age-related.

The Predictive Value of Mean Platelet Volume for Liver Fibrosis in Children With Chronic Liver Diseases

Introduction: Almost all causes of chronic liver damage can culminate in liver fibrosis and ultimately cirrhosis. Studies have suggested a relationship between mean platelet volume (MPV) and liver fibrosis; however, this needs confirmation by further studies. We here assessed the predictive value of MPV for liver fibrosis in children with chronic liver diseases. Methods: In this study, children &lt;18 years old with chronic liver diseases referred to the Nemazee Hospital of Shiraz during 2013-2016 were studied. The patients underwent liver biopsy for assessing liver fibrosis. Statistical analyses were conducted in SPSS 23. Results: From 368 studied children, 52.2% were boys. The patients’ mean age was 4.5±3.9 years old. Most patients had grade 6 fibrosis (36.7%). Cryptogenic (42.7%) was the most common cause of chronic liver disease, and jaundice was the most prevalent clinical presentation (53%). There was a significant association between the liver fibrosis and MPV (P=0.025). Conclusion: MPV was significantly different between patients with different severities of liver fibrosis. However, assigning an appropriate cut off value to distinguish different degrees of fibrosis requires more studies.

Left Atrial Appendage Electrical Isolation Reduces Atrial Fibrillation Recurrences: A Simulation Study.

Left Atrial Appendage Electrical Isolation Reduces Atrial Fibrillation Recurrences: A Simulation Study.