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Lysosomal acid lipase (LAL) deficiency is a rare, autosomal recessive disease caused by mutations in the LIPA gene, which produces cholesteryl ester and triglyceride accumulation predominantly in hepatocytes, adrenal glands, and gastrointestinal tract. We describe two new cases occurring in siblings, aged 5 and 7 years, who presented with hepatomegaly, dyslipidemia, and abnormal liver function. Percutaneous liver biopsy revealed portal inflammation, hypertrophic Kupffer cells with a foamy appearance and microvesicular steatosis with fibrosis. Immunostaining for lysosomal markers, cathepsin D and LAMP1 reflected the lysosomal nature of the lipid vacuoles. After enzymatic confirmation, enzyme replacement therapy was initiated for both siblings. Follow-up transaminase levels and lipid profiles showed a notable decrease in AST and ALT and a slight increase in HDL cholesterol. It is crucial to increase awareness of this rare condition among clinicians and pathologists. The expression of lysosomal markers around the lipid vacuoles might help diagnose LAL deficiency in pediatric patients.

A 67-year-old man was referred to the renal team following an episode of acute kidney injury on a background of chronic kidney disease. He had a 9-year history of steroid-sensitive arthritis, epigastric pain and isolated submandibular gland enlargement. He was noted to have a raised eosinophil count, total serum protein and total immunoglobulin G4 (IgG4) level as well as a serum hypocomplementaemia. A renal biopsy showed a tubulointerstitial nephritis with lymphoplasmacytic infiltrates, fibrosis and IgG4-positive plasma cells on immunohistochemistry. A diagnosis of IgG4-related disease was made based on clinical presentation and pathology. Renal function improved with glucocorticoids and the patient was successfully transitioned to azathioprine as a steroid-sparing agent.

Objective: Radiation therapy is commonplace for cancer treatment but often results in fibrosis and atrophy of surrounding soft tissue. Decellularized adipose matrices (DAMs) have been reported to i...

Objectives This study aimed to compare the effects of N-acetylcysteine and benfotiamine in protection of ovarian tissue from ischemia caused by slow neovascularization injury due to intraperitoneal ovarian autotransplant in rats. Materials and methods Twenty-eight female rats were divided into 4 groups, each containing 7 rats. Group 1 only had the abdomen opened and closed, group 2 was the transplant-only group, group 3 received benfotiamine for 3 weeks starting 1 day before the transplant procedure, and group 4 received N-acetylcysteine for 3 weeks starting 1 day before the transplant procedure. At the end of the experimental period, malondialdehyde levels in ovarian tissues together with the apoptosis and fibrosis, proliferating cell nuclear antigen and vascular endothelial growth factor immunoreactivity, and ovarian reserves were investigated. Results Apoptosis was significantly increased in group 2 animals. Primordial follicle count was higher in groups 3 and 4 than in group 2. Vascular endothelial growth factor immunoreactivity was decreased in groups 3 and 4 compared with group 2. Proliferating cell nuclear antigen immunoreactivity was reduced in the secondary follicles in all transplant groups. Conclusions In autologous intraperitoneal ovarian transplant, both benfotiamine and N-acetylcysteine are equal and effective agents in protection of ovarian tissue against ischemic injury.

We report a case of a 62-year-old woman, HIV positive, with a 3-week history of jaundice and elevated cholestatic enzymes. Imaging studies displayed intrahepatic biliary dilatation and a central liver lesion. Pathology described lesions of active cholangitis, lymphoplasmacytic infiltration and fibrosis, suggesting a hepatic inflammatory pseudotumour (IPT) IgG4 related. IgG4-related lymphoplasmacytic form of IPT belongs to IgG4-related diseases. We discuss the importance to include IgG4-related hepatic IPT as part of the differential diagnosis of any liver lesion, highlighting potential imaging clues that may help in establishing the correct diagnosis.

BACKGROUND Burkholderia cepacia complex (BCC) represents a group of multidrug-resistant gram-negative bacteria that cause infections among immunocompromised hosts. Bacteremia occurs in patients who are chronically ill and is associated with substantial morbidity and mortality. The aim of this study was to investigate the clinical characteristics and outcomes of BCC bacteremic patients without cystic fibrosis. METHODS We conducted a retrospective study at the National Taiwan University Hospital. Adults with BCC bacteremia from January 2015 to May 2019 were enrolled. The primary outcome was 14-day mortality. Multivariable logistic regression was performed for outcome analysis. RESULTS One-hundred and ninety-five patients were analyzed and their mean age was 67 years. Over 95% of the BCC isolates were susceptible to trimethoprim/sulfomethoxazole (TMP/SXT). Levofloxacin resistance rates were high, with only 25.1% of isolates being susceptible. Pairwise comparisons were made between different definitive regimens including meropenem-monotherapy, ceftazidime-monotherapy, levofloxacin-monotherapy, TMP/SXT-monotherapy, tigecycline-monotherapy as well as combination versus monotherapy. No regimen was significantly associated with survival in our study. Multivariable logistic regression showed that the Pitt bacteremia score (adjust odds ratio [aOR],1.46; 95% confidence interval [CI],1.19-1.79; p

Background and objectives The highest incidence of death in systemic sclerosis due to pulmonary disease raises the need for early detection and treatment. The study aim is the assessment of interstitial pulmonary disease by Multi Detector High Resolution CT (MDCT) and finds its relationship with the other disease parameters and the Pulmonary Function tests (PFT). Patients and methods A prospective cross-sectional study was performed in Assiut University Hospitals from May 2018 to January 2020 and included 62 consecutive SSc female patients. Demographic, clinical, Laboratory, PFT and MDCT assessment were conducted for all participants. Results The coarseness of fibrosis was 8.32 (range 0.0–17), the average proportion of ground-glass opacification was 28.3% (range, 0.0%–75%). Honey-comb pattern was seen in (52.5%). Mean Extent of disease was 46.25 ± 3.7 (range 5–81). Restrictive deficit found in 42 patients. Significant relation was found between the extent of disease and the percentage predicted FVC (r = 0.373, p 0.018) and FEV1/FVC (r = 0.593, p 0.000) and coarseness of fibrosis and proportion of ground glass opacification correlated inversely with VC (r = −0.385, p = 0.014, r = −0.376, p = 0.017 respectively), Rayanud's phenomena, modified Rodnan Skin Score and Medsger's general are positively correlated with MDCT disease extent. Conclusion Scoring of systemic sclerosis (SSc) related interstitial lung disease (SSc-ILD) could be applicable as one of the important tools for disease assessment.

The use of prosthetic meshes in abdominal wall reconstruction is a well-established approach; however, in certain cases where a bowel resection coexists its application is disputed. Any underlying inflammatory process may augment adhesion formation which is a major postoperative complication. In this animal study, our aim was to investigate the effect of N-acetyl-l-cysteine (NAC) on adhesion formation and the expression of inflammatory markers when a mesh was used in a clean or a potentially contaminated environment.Sixty male Wistar rats were randomly and equally allocated in 3 groups: A, B and C. Animals in all groups underwent laparotomy, a prosthetic mesh was placed and chemoprophylaxis with ciprofloxacin was administered. In groups B and C an enterectomy was also performed. NAC was injected intraperitoneally in group C. Adhesion formation, IL-1a, IL-6, TNF-a and histological data including fibrosis, neutrophils' infiltration and neovascularization were assessed. Mesh samples were sent for cultivation.Adhesion formation was significantly less and inflammation markers were also lower in group C compared to group B (p0.05). Histological findings were significant for greater fibrosis, neutrophils' infiltration and neovascularization in group B compared to both group A and C. Regarding mesh cultures, more specimens were tested positive in group B (p0.05). Outcomes between group A and C did not differ.NAC effectively ameliorated adhesion formation and inflammation in a potentially septic environment where a prosthetic mesh was placed.

Objective To correlate the histopathologic results of conjunctival specimens with clinical findings in patients with conjunctivochalasis and report the results of the paste-pinch-cut technique for management. Design Retrospective chart review. Methods SETTING: Single tertiary ophthalmological centre (Ocular Surface Diseases and Dry Eye Clinic, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Md.). Methods Twenty-five patients (32 eyes) with clinically significant conjunctivochalasis. All patients were referred for clinically significant dry eye without previous diagnosis of chalasis. Sixteen patients had an underlying inflammatory systemic condition. Intervention or Observation Procedure(s): Patients underwent surgery with paste-pinch-cut technique. Subjective dry eye symptoms and ocular surface staining scores (corneal and conjunctival staining using fluorescein and lissamine green respectively) were assessed at every visit. Main outcome measures Change in patient symptoms and ocular surface staining scores and histopathologic findings in conjunctival specimens. Results After surgery, significant improvement was achieved in dry-eye symptoms as well as both corneal and conjunctival staining scores in 29 eyes on reduced topical therapy. Only 3 eyes had persisting conjunctival lissamine staining. Light microscopic examination disclosed mild to moderate lymphoplasmocytic inflammation of the conjunctivae with areas of epithelial goblet cell loss, squamous metaplasia, stromal edema, and fibrosis. Conclusion Conjunctivochalasis appears to be associated with significant inflammation in the setting of dry eye and underlying inflammatory systemic conditions. Although topical anti-inflammatory treatment could be attempted in the initial management, surgical excision should be considered in the absence of clinical response.

Objective: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease that affects 63 in every 100,000 Americans. Its etiology remains unknown, although inflammatory pathways appear...

IgG4 related disease is a term used to describe a fibroinflammatory condition characterized by storiform fibrosis, inflammation with a dense lymphoplasmocytic infiltrate rich in plasma cells expressing IgG4, and often, if not always, raised serum levels of IgG4. We report a case of a patient with a past history of retroperitoneal fibrosis presenting with a swollen left testicle, who underwent an orchidectomy due to suspicion of malignancy. The surgical specimen revealed a paratesticular pseudotumor with histopathological and immunohistochemical characteristics of IgG4 related disease. To the best of our knowledge, just nine such cases have previously been reported, of which only three were manifestations of systemic disease, as in the present case. Whilst it is important to recognize the clinical and radiological features of this entity, histopathology is often essential in order to confirm the diagnosis.

Significance: Wound healing is the largest medical market without an existing small molecule/drug treatment. Both “under-healing” (chronic wounds) and “over-healing” (scarring) cause a substantial ...

Objective: Xenografts of human skin in immunodeficient mice provide a means of assessing human skin physiology and its response to wounding. Approach: We describe a novel xenograft model using full-thickness human neonatal foreskin to examine human skin wound repair. Full-thickness 8 mm human neonatal foreskin biopsies were sutured into the dorsum of NOD scid gamma (NSG; NOD.Cg-Prkdc scidIl2rgtm1Wjl/SzJ) pups as subcutaneous grafts. At postnatal day 21 the subcutaneous grafts were exposed to cutaneous grafts. Following maturation of 2 months, xenografts were then wounded with 5 mm linear incisions and monitored until postwound day (PWD) 14 to study skin repair and fibrosis. To explore whether our model can be used to test the efficacy of topical therapies, wounded xenografts were injected with antifibrotic fibroblast growth factor 2 (FGF2) for the first four consecutive PWDs. Xenografts were harvested for analysis by histology and fluorescence-activated cell sorting (FACS). Results: Xenografts were successfully engrafted with evidence of mouse-human anastomoses and resembled native neonatal foreskin at the gross and microscopic level. Wounded xenografted skin scarred with human collagen and an expansion of CD26-positive human fibroblasts. Collagen scar was quantitated by neural network analysis, which revealed distinct clustering of collagen fiber networks from unwounded skin and wounded skin at PWD7 and PWD14. Collagen fiber networks within FGF2-treated wounds at PWD14 resembled those in untreated wounded xenografts at PWD7, suggesting that FGF2 treatment at time of wounding can reduce fibrosis. Innovation and Conclusion: This novel xenograft model can be used to investigate acute fibrosis, fibroblast heterogeneity, and the efficacy of antifibrotic agents during wound repair in human skin.

Objective To describe the characteristics of the body components and phase angle of patients with MAFLD according to those different to fibrosis and hepatic steatosis. Material and methods Observational and descriptive study in a cohort of 585 volunteers from our center with MAFLD criteria. The risk of liver fibrosis was determined by APRI, NAFLD score and FIB-4; At an indeterminate and high risk of fibrosis, a transient elastography (Fibroscan) were realize. Bioimpedance body composition analysis (SECA®) was performed. Patients with ET and SECA® registry were included. Bioimpedance body composition analysis (SECA®) was performed. Patients with ET and SECA® registry were included. Results 125 participants (21.4%) were evaluated, age 53.9 ± 13.9 years, 62.1% women, BMI 33.2 ± 5.8 kg / m2. The SECA® analysis showed mean fat mass of 42% ± 7.32 and muscle mass 21.18 kg ± 6.6. The PhA was 5.1 ± 0.69, in women 4.92 ± 0.62 and men 5.41 ± 0.70. PhA in patients without fibrosis was 5,091 vs with fibrosis 5,121, (p = 0.813). In advanced fibrosis, it reported a low value compared to the rest of the groups (p = 0.031). The PhA in S3 was higher compared to S1 and S2 (5.3 vs 4.82, 4.81) (p = 0.027). Conclusions In MAFLD the PhA was lower than the healthy Mexican population. In patients without fibrosis and severe steatosis, PhA rises proportionally to the increase in fat mass and BMI and in advanced liver fibrosis, PhA decreases.

Rationale and Objectives To evaluate associations between longitudinal changes of quantitative CT parameters and spirometry in patients with fibrotic hypersensitivity pneumonitis (HP). Materials and Methods Serial CT images and spirometric data were retrospectively collected in a group of 25 fibrotic HP patients. Quantitative CT analysis included histogram parameters (median, interquartile range, skewness, and kurtosis) and a pretrained convolutional neural network (CNN)-based textural analysis, aimed at quantifying the extent of consolidation (C), fibrosis (F), ground-glass opacity (GGO), low attenuation areas (LAA) and healthy tissue (H). Results At baseline, FVC was 61(44-70) %pred. The median follow-up period was 1.4(0.8-3.2) years, with 3(2-4) visits per patient. Over the study, 8 patients (32%) showed a FVC decline of more than 5%, a significant worsening of all histogram parameters (p≤0.015) and an increased extent of fibrosis via CNN (p=0.038). On histogram analysis, decreased skewness and kurtosis were the parameters most strongly associated with worsened FVC (respectively, r2=0.63 and r2=0.54, p

SIGNIFICANCE: Lymphedema is a common disease that affects hundreds of millions of people worldwide with significant financial and social burdens. Despite increasing prevalence and associated morbidities, the mainstay treatment of lymphedema is largely palliative without an effective cure due to incomplete understanding of the disease. RECENT ADVANCES: Recent studies have described key histological and pathological processes that contribute to the progression of lymphedema, including lymphatic stasis, inflammation, adipose tissue deposition, and fibrosis. This review aims to highlight cellular and molecular mechanisms involved in each of these pathological processes. CRITICAL ISSUES: Despite recent advances in the understanding of the pathophysiology of lymphedema, cellular and molecular mechanisms underlying the disease remains elusive due to its complex nature. FUTURE DIRECTIONS: Additional research is needed to gain a better insight into the cellular and molecular mechanisms underlying the pathophysiology of lymphedema, which will guide the development of therapeutic strategies that target specific pathology of the disease.

We herein report a 73-year-old man with isolated hypertrophic pachymeningitis (HP) showing serological and pathological characteristics of both IgG4-related disorders and granulomatosis with polyangiitis. The patient presented with chronic onset headaches and ophthalmalgia. Brain magnetic resonance imaging (MRI) revealed a hypertrophic enhanced dura mater. Serum IgG4 and myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA) levels were elevated. A dura mater biopsy showed infiltration of numerous IgG4-positive plasma cells and granulomatous inflammation without apparent vasculitic lesions, storiform fibrosis, or obstructive phlebitis. Corticosteroid treatments improved his clinical symptoms and MRI findings. There have been reports of MPO-ANCA-positive IgG4-related HP presenting as granulomatous inflammation in the dura mater.

Background The optimal strategy to support primary care practitioners (PCPs) to assess fibrosis severity in nonalcoholic fatty liver disease (NAFLD) and thereby make appropriate management decisions remains unclear. Aims We aimed to examine the feasibility of using a 2-step pathway that combined simple scores (NAFLD Fibrosis Score and Fibrosis-4 Index) with transient elastography (FibroScan®) to streamline NAFLD referrals from a 'routine' primary care population to specialist hepatology management clinics (HMC). Methods The 2-step "Towards Collaborative Management of NAFLD" (TCM-NAFLD) fibrosis risk assessment pathway was implemented at two outer metropolitan primary healthcare practices in Brisbane. Patients aged ≥18 years with a new or established PCP-diagnosis of NAFLD were eligible for assessment. The pathway triaged patients at "high risk" of clinically significant fibrosis to HMC for specialist review, and "low risk" patients to receive ongoing management and longitudinal follow-up in primary care. Results A total of 162 patient assessments between Jun-2019 and Dec-2020 were included. Mean age was 58.7 ± 11.7 years, 30.9% were male, 54.3% had type 2 diabetes or impaired fasting glucose, and mean body mass index was 34.2 ± 6.9 kg/m2 . 122 patients were considered "low risk" for clinically significant fibrosis, two patients had incomplete assessments, and 38 (23.5%) were triaged to HMC. Among 31 completed HMC assessments to date, 45.2% were considered to have clinically significant (or more advanced) fibrosis, representing 9.2% of 153 completed assessments. Conclusion Implementation of the 2-step TCM-NAFLD pathway streamlined hepatology referrals for NAFLD and may facilitate a more cost-effective and targeted use of specialist hepatology resources. This article is protected by copyright. All rights reserved.

Background Serum hepatitis B surface antigen (HBsAg) levels correlate with the duration of chronic hepatitis B virus (HBV) infection and may predict the extent of hepatic fibrosis. Methods We analyzed data from the SONIC-B database, which contains data from 8 global randomized trials and 2 large hepatology centers. Relationship between HBsAg levels and presence of significant fibrosis (Ishak 3–4) or cirrhosis (Ishak 5–6) were explored, and clinically relevant cutoffs were identified to rule out cirrhosis. Results The dataset included 2779 patients: 1866 hepatitis B e antigen (HBeAg)-positive; 322 with cirrhosis. Among HBeAg-positive patients, lower HBsAg levels were associated with higher rates of significant fibrosis (odds ratio [OR], 0.419; P < .001) and cirrhosis (OR, 0.435; P < .001). No relationship was observed among HBeAg-negative patients. Among HBeAg-positive patients, genotype-specific HBsAg cutoffs had excellent negative predictive values (>97%) and low misclassification rates (≤7.1%) and may therefore have utility in ruling out cirrhosis. Diagnostic performance of the HBsAg cutoffs was comparable among patients in whom cirrhosis could not be ruled out with fibrosis 4 (FIB-4). Conclusions Hepatitis B virus genotype-specific HBsAg cutoffs may have utility in ruling out presence of cirrhosis in HBeAg-positive patients with genotypes B, C, and D and can be an adjunct to FIB-4 to reduce the need for further testing.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD), often associated with obesity and metabolic syndrome, manifests itself as steatosis, hepatic fibrosis, cirrhosis, or even end-stage liver disease. NAFLD causes inflammation, insulin resistance and cardiovascular complications. The current study aimed to evaluate the beneficial effects of bariatric surgery on biochemical parameters of hepatic functions in obese patients by comparing them before and one-year after the surgery. METHODS: A total of 72 morbidly obese patients underwent bariatric surgery between 2016 and 2018. The incidence of diabetes mellitus in this group was 29%, median body weight was 124.5 kg (109.0-140.0) and mean body mass index (BMI) was 44.38 ± 6.770 kg/m2. The used surgical procedures included gastric bypass, sleeve gastrectomy, laparoscopic gastric plication, and single anastomosis duodeno-ileal bypass-sleeve gastrectomy. Biochemical parameters including ALT/AST ratio (AAR), NAFLD fibrosis score (NFS), hepatic fibrosis index (FIB-4) and Fatty Liver Index (FLI) were evaluated in all patients at the time of surgery and one year after the intervention. RESULTS: Significant improvement after the intervention was observed in 64 patients. A significant reduction in body weight (P, University of Ostrava in The Czech Republic

BACKGROUND: With new treatments for non-alcoholic fatty liver disease (NAFLD) on the horizon, it will be important to risk-stratify patients based on degree of fibrosis to allocate treatment to those at highest risk. No studies have examined the complication rates of liver biopsies in patients with NAFLD in the outpatient setting. METHODS: We conducted a retrospective chart review of all outpatient elective liver biopsies for NAFLD at a tertiary care centre over a 10-year period. Demographic variables and stage of fibrosis were recorded. Complications up to 1 week post-procedure were recorded. We used univariate logistic regression models to estimate the odds of major complications by fibrosis stage, age, sex, platelets, and international normalized ratio (INR). RESULTS: There were 582 biopsies reviewed in total. The mean age was 53 years. There was an even proportion of males to females. The mean fibrosis stage was 1.9; platelet count was 223.9, INR was 1, and partial thromboplastin time (PTT) was 31. Major complications occurred in 8 out of 582 biopsies (1.4%). Bleeding accounted for 6 of the major complications observed, while infection and pneumoperitoneum each occurred once. There were no statistically significant associations between age (odds ratio [OR] 0.97, 95% CI 0.92–1.03), female sex (OR 1.00, 95% CI 0.25–4.04), platelet count 1.3 (OR 0.47, 95% CI 0.057–3.85), fibrosis stage, and complication rate. CONCLUSIONS: Our results are consistent with previous studies examining complication rates in other patient populations and clinical settings and support the overall safety of liver biopsies.

Cirrhosis is the terminal stage of progressive liver fibrosis, affecting 1%-2% of the global population and accounting for 1.3 million deaths annually.1,2 Median survival for persons with compensated cirrhosis is approximately 12 years, compared with only 2 years for those with hepatic decompensation. Accurate prediction of hepatic decompensation is an unmet need to enable identification of patients with cirrhosis who could benefit from close monitoring and timely medical interventions. Besides, risk stratification of patients with cirrhosis could help inform patient selection for trials evaluating therapies to prevent hepatic decompensation. Although various clinical scores, such as the albumin-bilirubin (ALBI) and fibrosis-4 (FIB-4) indices (ALBI-FIB4 score) have been proposed to predict long-term risk of hepatic decompensation,3 external validation has often shown suboptimal prognostic capability and revealed room for improvement.4.

Background: Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by microangiopathy, inflammation, fibrosis. Interstitial lung disease (ILD) is common among SSc patients. Objective: This study aims to define the clinical, laboratory, and serologic characteristics of SSc patients with ILD and to present the frequency of chest computed tomography features. Methods: Two hundred twenty-six SSc patients who applied to the Rheumatology Department between January 2007 and August 2019 were retrospectively examined. A total of 100 SSc patients with ILD (44.2%) were determined. Clinical, laboratory, and serological features of SSc patients with and without ILD were compared. Results : Both groups had similar characteristics in terms of age and sex. The duration of disease (p=0.001) and follow-up time (p=0.001) were longer in SSc patients with ILD. Multivariable logistic regression analysis indicated that the duration of disease (OR: 1.06 (1.01-1.13), p=0.029), presence of gastrointestinal system involvement (OR: 3.29 (1.28-8.46), p=0.013) and anti-SCL70-positivity (OR: 6.04 (2.35-15.49), p Conclusion: We have shown a relationship between anti-SCL70, disease duration, gastrointestinal system involvement, and ILD in SSc patients.

Objective: This study aims to systematically review the performance of red blood cell distribution width to platelet ratio (RPR) in the diagnosis of significant or advanced fibrosis, and cirrhosis associated with Hepatitis B virus (HBV). Methods: The relevant studies were comprehensively searched in English databases such as Web of Science, PubMed, EMBASE, Cochrane Library, as well as Chinese databases such as China National Knowledge Infrastructure, Wanfang Data from the inception to March 2021. Accuracy of RPR in diagnosing significant or advanced fibrosis and liver cirrhosis was assessed by area under the curve (AUC), pooled sensitivity and specificity, as well as positive and negative likelihood ratios. Stata 15.0 software was applied to analyze the data. Results: In total, 13 literature met the requirements, including patients with significant fibrosis (n=1890), advanced fibrosis (n=645), and cirrhosis (n=499). The prevalence rates of significant fibrosis, advanced fibrosis and cirrhosis were 49.31% (range: 17.25%-84.21%), 37.07% (range: 9.60%-58.20%) and 2.18% (range: 2.78%-44.19%), respectively. The AUCs for predicting significant fibrosis, advanced fibrosis, and cirrhosis by RPR were 0.73 (95%CI: 0.69-0.76),0.80 (95%CI: 0.77-0.84) and 0.80 (95%CI: 0.76-0.83), respectively. Conclusion: RPR is of some diagnostic value to the prediction of HBV-related significant fibrosis, advanced fibrosis and cirrhosis.This conclusion is urgently needed to be verified by further multi-center studies of large sample size and rigorous design.

Fibrosis is a hallmark of adipose tissue (AT) dysfunction and obesity-associated insulin resistance that results from an impaired collagen turnover. Peptidase D (PEPD) plays a vital role in collagen turnover by degrading proline-containing dipeptides. Nevertheless, its specific function and importance in AT is unknown. GWAS identified the rs731839 variant in the locus near PEPD that uncouples obesity from insulin resistance and dyslipidaemia, thus indicating that defective PEPD might impair AT remodelling and exacerbate metabolic complications. Here we show that in human and murine obesity, PEPD expression and activity decrease in AT, coupled to the release of PEPD systemically. Both events, in turn, are associated with the accumulation of fibrosis in AT and insulin resistance. Using pharmacologic and genetic animal models of PEPD down-regulation, we show that whereas dysfunctional PEPD activity provokes AT fibrosis, it is the PEPD secreted by AT the main contributor to inflammation, insulin resistance and metabolic dysfunction. Also, PEPD originated in inflammatory macrophages (Mɸ), plays an essential role promoting fibro-inflammatory responses via activation of EGFR in Mɸ and preadipocytes. Using genetic ablation of pepd in Mɸ that prevents obesity-induced PEPD release, also averts AT fibro-inflammation and obesity-associated metabolic dysfunctions. Taking advantage of factor analysis, we have identified the coupling of prolidase decreased activity and increased systemic levels of PEPD as the essential pathogenic triggers of AT fibrosis and insulin resistance. Thus, PEPD produced by Mɸ qualifies as a biomarker of AT fibro-inflammation and a therapeutic target for AT fibrosis and obesity-associated insulin resistance and type 2 diabetes.

BACKGROUND In recent years, sodium-glucose co-transporter 2 inhibitors (SGLT2is) have been increasingly used in the treatment of patients with non-alcoholic fatty liver disease (NAFLD). This updated meta-analysis aimed to evaluate the efficacy and safety of SGLT2is for patients with NAFLD. METHODS PubMed, Embase, Cochrane Library, Web of Science, Wan Fang, China National Knowledge Infrastructure and VIP databases were searched for relevant studies from inception to April 30, 2021. Values of weighted mean differences (WMDs) and risk ratios (RRs) were determined for continuous and dichotomous outcomes, respectively. RESULTS A total of 1,498 patients with NAFLD from 20 studies were included for further analysis. Pooled analyses indicated significant improvements in body mass index [WMD: -0.84 kg/m2, 95% CI (-1.09, -0.60)], alanine aminotransferase [WMD: -4.36 U/L, 95% CI (-7.17, -1.54)], aspartate aminotransferase [WMD: -2.94 U/L, 95% CI (-5.33, -0.55)], fasting plasma glucose [WMD: -4.08 mmol/L, 95% CI (-6.21, -1.95)] and fibrosis-4 index [WMD: -0.08, 95% CI (-0.11, -0.05)] following SGLT2i treatment (p

Intestinal fibrosis is considered an inevitable complication of Crohn’s disease (CD) that results in symptoms of obstruction and stricture formation. Endoscopic or surgical treatment is required to treat the majority of patients. Progress in the management of stricturing CD is hampered by the lack of effective antifibrotic therapy; however, this situation is likely to change because of recent advances in other fibrotic diseases of the lung, liver, and skin. In this review, we summarize data from randomized controlled trials (RCTs) of antifibrotic therapies in these conditions. Multiple compounds have been tested for antifibrotic effects in other organs. According to their mechanisms, they were categorized into growth factor modulators, inflammation modulators, 5-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, intracellular enzymes and kinases, renin-angiotensin system (RAS) modulators, and others. From our review of the results from the clinical trials and discussion of their implications in the gastrointestinal tract, we have identified several molecular candidates that could serve as potential therapies for intestinal fibrosis in CD.

Rosai-Dorfman-Destombes disease (RDD) is a non-Langerhans cell histiocytosis characterized by the accumulation of histiocytes inside the lymph nodes or extranodally. The association between RDD and IgG4-related disease (IgG4-RD) is discussed. We herein report a case of RDD manifesting as acute tubulointerstitial nephritis mimicking IgG4-RD. The first renal biopsy showed severe tubulointerstitial nephritis with infiltration of S100-positive histiocytes and IgG4-positive plasma cells; storiform fibrosis and obliterative phlebitis were not confirmed. After prednisolone therapy, IgG4-positive cells and S100-positive histiocytes were decreased, but the IgG4/IgG ratio increased despite clinical improvement. These findings indicated extranodal RDD in the kidney presenting as tubulointerstitial nephritis.

Background context Hypertrophy of the ligamentum flavum (LF) is a major contributor to the development of lumbar spinal canal stenosis (LSS). Although previous studies have identified some factors related to hypertrophy of the LF, the etiology remains unclear. It is well known that myofibroblasts have a key role in the pathology of fibrosis in other tissues, including the skin, liver, kidney, and lung. We hypothesized that myofibroblasts were also important players in the pathology of fibrosis in the LF. Purpose To elucidate the distribution and role of myofibroblasts in the hypertrophic LF. Study design A histological, immunohistochemical, and gene expression analysis of the LF in the human lumbar spine. Patient sample Hypertrophic LF tissue samples were collected from patients with LSS. Outcome Measures Histology, immunohistochemistry, microarray, reverse transcription-quantitative polymerase chain reaction, western blotting and enzyme-linked immunosorbent assay. Methods The degree of fibrosis in the dural and dorsal layers of the LF was evaluated by Masson's trichrome tissue staining. Collagen gene expression was evaluated by quantitative reverse transcription polymerase chain reaction. Immunostaining of αSMA was performed to evaluate localization of myofibroblasts in LF tissue. The association between gene expression of alpha-smooth muscle actin (αSMA) and that of several types of collagen was investigated. The signal activated on the dorsal side of LF was examined by gene set enrichment analysis using microarray data. Expression levels of αSMA and several types of collagen in LF fibroblasts were investigated under hypoxic conditions. Results In the histological study using Masson's trichrome staining, the fibrosis score was significantly higher in the dorsal layer than in the dural layer. Gene expression levels for several types of collagen (COL1A1, COL1A2, COL3A1, COL5A1, COL6A1, and COL11A1) and heat shock protein 47 (a collagen-specific chaperone) were significantly higher in the dorsal layer. Furthermore, immunohistochemistry revealed a significantly greater number of αSMA-stained cells in the dorsal layer. There was a strong correlation of αSMA mRNA expression with COL1A-1 in LF fibroblasts. Gene set enrichment analysis showed that the set of fibrosis-related gene signals, including those for epithelial-mesenchymal transition, hypoxia, and inflammation, were significantly upregulated in the dorsal layer compared with the dural layer. Under hypoxic stimulation, expression of αSMA and several types of collagen was increased in LF fibroblasts. Conclusions This study is the first to reveal that myofibroblast expression levels are higher in the dorsal layer of the LF than in the dural layer. We confirmed that hypertrophy of the LF in LSS is associated with increased expression of myofibroblasts in the dorsal layer. Hypoxia could be a cause of expression of myofibroblasts leading to fibrosis and finally to hypertrophy of the LF. Clinical significance The results of this study partially elucidate the molecular mechanisms of LF hypertrophy and suggest that myofibroblasts may be involved in age-related degeneration of the LF.

Drug-induced scleroderma-like lesion is a condition in which administration of a drug induces skin sclerotic lesions similar to systemic sclerosis or morphea. The clinical manifestations of drug-induced scleroderma-like lesion can be divided into two types: scleroderma-like lesions and morphea-like plaques. A wide variety of drugs can cause drug-induced scleroderma-like lesion. Bleomycin, L-tryptophan, vinyl chloride, and phytonadione (vitamin K1) have been reported, but in recent years, cases due to chemotherapeutic agents, such as taxane-based agents, gemcitabine, and tegafur-uracil, and immune checkpoint inhibitors have increased. Drug-induced scleroderma-like lesion differs from systemic sclerosis in that it does not include Raynaud's phenomenon, nail-fold capillary abnormality, organ involvement, such as reflux esophagitis, interstitial pneumonia, renal crisis, or anti-nuclear Abs. On the other hand, there are reports of cases in which Raynaud's phenomenon, positive conversion of anti-nuclear Abs, and development of skin sclerosis from the fingers developed after initiation of the drug. Whether the skin sclerosis improves after discontinuation of the drug depends on the patient. In patients with severe skin sclerosis, functional impairment, such as flexion contracture of the fingers, may occur, and systemic therapy, such as steroids, may be necessary. When treating patients with skin sclerosis, it is important to keep in mind the possibility that the sclerotic lesion may be induced by a drug.

Among the large population of patients with non-alcoholic fatty liver disease (NAFLD), identifying those with fibrotic non-alcoholic steatohepatitis (Fibro-NASH) is a clinical priority, as these patients are at the highest risk of disease progression and will benefit most from pharmacologic treatment. MRI-based proton density fat fraction (MRI-PDFF) and MR elastography (MRE) can risk-stratify patients with NAFLD by assessing steatosis and fibrosis, respectively. We developed a highly specific MRI-based score to identify patients with Fibro-NASH.This analysis included derivation (n = 103) and validation (n = 244) cohorts of patients who underwent MRI, liver biopsy, transient elastography, and laboratory testing for NAFLD from 2016-2020 in 2 tertiary care centers. To identify Fibro-NASH, a formula was developed based on MRI-PDFF, MRE, and a third variable with highest balanced accuracy per logistic regression. The MRI-aspartate aminotransferase (MAST) score was created and compared to NAFLD fibrosis (NFS), Fibrosis-4 (FIB-4), and FibroScan-aspartate aminotransferase (FAST) scores.The MAST score demonstrated high performance and discrimination in the validation cohort (AUC 0.93; 95% CI 0.88-0.97). In the validation cohorts, the 90% specificity cut-off of 0.242 corresponded to a sensitivity of 75.0%, positive predictive value (PPV) of 50.0% and negative predictive value (NPV) of 96.5%, whereas the 90% sensitivity cut-off of 0.165 corresponded to a specificity of 72.2%, PPV of 29.4%, and NPV of 98.1%. Compared to NFS and FIB-4, MAST resulted in fewer patients having indeterminate scores and an overall higher AUC. Compared to FAST, MAST exhibited a higher AUC and overall better discrimination.The MAST score is an accurate, MRI-serum-based score that outperforms previous scores in non-invasively identifying patients at higher risk of Fibro-NASH.Identifying patients with non-alcoholic steatohepatitis and significant fibrosis - who need treatment and are at risk of clinical liver-related outcomes - is a clinical priority. We developed a more accurate score using MRI-based technologies and a laboratory blood test (aspartate aminotransferase) that outperforms previous non-invasive scores for the identification of patients at higher risk of liver disease progression.

Background In erythropoietic protoporphyria (EPP), which presents with severe painful phototoxicity, progressive deposition of protoporphyrins in hepatocytes and bile canaliculi may result in liver disease. Clinically EPP related liver disease ranges from mildly elevated liver enzymes to cirrhosis and acute cholestatic hepatic failure. The prevalence of liver disease in EPP, and factors predicting the risk of developing liver disease, have not been defined in a large series of unselected EPP patients. Aim To determine the prevalence of liver disease in EPP-patients. Methods A single-center prospective unselected cohort study of 114 adult EPP patients, who underwent routine laboratory testing, abdominal ultrasonography and transient elastography to assess the presence of steatosis (controlled attenuation parameter,dB/m) and liver stiffness (kPa). Results 114 adult EPP patients were included. Elevated liver enzymes were found in 6.2% of the patients. Liver steatosis was detected in 29.0%, and significant fibrosis as assessed with liver stiffness measurements was present in 9.6% of patients. BMI positively predicted CAP-values (p = 0.026); and protoporphyrin IX levels (p = 0.043) positively predicted liver stiffness. Conclusions This study demonstrates a prevalence of hepatic steatosis and fibrosis in adult EPP-patients comparable to that found in the general population. Protoporphyrin IX levels correlate with increased liver stiffness in EPP.

Systemic sclerosis (SSc) is a rare autoimmune, connective tissue disorder of unknown aetiology.[1][1] The prevalence of the disease is 19 cases in a million and it is more common in women aged 30–50 years. SSc is characterised by widespread fibrosis of the skin, various internal organs or both of

It is estimated that almost one-third of the United States population will be affected by a vocal fold (VF) disorder during their lifespan. Promising therapies to treat VF injury and scarring are mostly centered on VF tissue engineering strategies such as the injection of engineered biomaterials and cell therapy. VF tissue engineering, however, is a challenging field as the biomechanical properties, structure, and composition of the VF tissue change upon exposure to mechanical stimulation. As a result, the development of long-term VF treatment strategies relies on the characterization of engineered tissues under a controlled mechanical environment. In this review, we highlight the importance of bioreactors as a powerful tool for VF tissue engineering with a focus on the current state of the art of bioreactors designed to mimic phonation in vitro. We discuss the influence of the phonatory environment on the development, function, injury, and healing of the VF tissue and its importance for the development of efficient therapeutic strategies. A concise and comprehensive overview of bioreactor designs, principles, operating parameters, and scalability are presented. An in-depth analysis of VF bioreactor data to date reveals that mechanical stimulation significantly influences cell viability and the expression of proinflammatory and profibrotic genes in vitro. Although the precision and accuracy of bioreactors contribute to generating reliable results, diverse gene expression profiles across the literature suggest that future efforts should focus on the standardization of bioreactor parameters to enable direct comparisons between studies. IMPACT STATEMENT: We present a comprehensive review of bioreactors for vocal fold (VF) tissue engineering with a focus on the influence of the phonatory environment on the development, function, injury, and healing of the VFs and the importance of mimicking phonation on engineered VF tissues in vitro. Furthermore, we put forward a strong argument for the continued development of bioreactors in this area with an emphasis on the standardization of bioreactor designs, principles, operating parameters, and oscillatory regimes to enable comparisons between studies.

Introduction A challenge in phonosurgery is achieving good vocal quality with minimal vocal fold fibrosis. Fibrin glue can be applied to minimize fibrosis; however, its use in the larynx is based primarily on clinical experience, particularly in extensive lesions. Objective The objective of this study was to evaluate the effect of application of fibrin glue on collagen concentration at the late phase of the healing process after detaching a pedicled flap of the vocal fold cover in rabbits. Methods In this prospective animal study, twelve adult male rabbits underwent laryngeal microsurgery, in which an incision was made along the entire length of both vocal folds, followed by extensive mucosal detachment and section of the incision ends. Fibrin glue was applied in the left vocal fold, and the mucosa was repositioned. In the right vocal fold, the mucosa was repositioned without treatment with fibrin glue. After 3-months, the rabbits were euthanized. Histological analyses were performed, and the data collected were subjected to statistical analysis. Results Vocal folds treated with fibrin glue presented higher collagen concentration in Masson trichrome staining and significantly higher (p< 0.05) collagen concentration in picrosirius red staining compared to control vocal folds. Conclusion Treatment with fibrin glue led to greater vocal fold fibrogenesis in the present study. Nonetheless, further studies are necessary to determine the prophylactic effect of sealants in laryngeal surgeries that require extensive detachment of the vocal fold cover. Resumo Introdução Um desafio na fonocirurgia é conseguir uma boa qualidade vocal com o mínimo de fibrose das pregas vocais. A cola de fibrina pode ser aplicada para minimizar a fibrose; porém, seu uso na laringe é baseado principalmente na experiência clínica, particularmente em lesões extensas. Objetivo Avaliar o efeito da aplicação da cola de fibrina na concentração de colágeno na fase tardia do processo de cicatrização, após o descolamento do retalho pediculado da cobertura da prega vocal em coelhos. Método Neste estudo prospectivo com animais, 12 coelhos adultos machos foram submetidos à microcirurgia de laringe, na qual uma incisão foi feita em toda a extensão de ambas as pregas vocais, seguida de extenso descolamento da mucosa e secção das extremidades da incisão. A cola de fibrina foi aplicada na prega vocal esquerda e a mucosa foi reposicionada. Na prega vocal direita, a mucosa foi reposicionada sem tratamento com cola de fibrina. Após três meses, os coelhos foram sacrificados. Análises histológicas foram feitas e os dados coletados foram submetidos à análise estatística. Resultados As pregas vocais tratadas com cola de fibrina apresentaram maior concentração de colágeno na coloração tricrômica de Masson e concentração significativamente maior de colágeno (p < 0,05) na coloração com picrosirius red comparadas às pregas vocais controle. Conclusão O tratamento com cola de fibrina resultou em maior fibrogênese das pregas vocais no presente estudo. Contudo, novos estudos são necessários para determinar o efeito profilático dos selantes em cirurgias de laringe que requerem extenso descolamento da cobertura das pregas vocais.

BackgroundDeceased donor and recipient predictors of posttransplant steatosis/steatohepatitis and fibrosis are not well known. Our aim was to evaluate the prevalence and assess donor and recipient predictors of steatosis, steatohepatitis, and fibrosis in liver transplantation recipients.MethodsUsing the immune tolerance network A-WISH multicenter study (NCT00135694), donor and recipient demographic and clinical features were collected. Liver biopsies were taken from the donor liver at transplant, and from recipients per protocol and for-cause (ie, abnormal transaminases and to rule out rejection) and were interpreted by a central pathologist.ResultsOne hundred eighty-three paired donor/recipients liver biopsies at the time of transplant and posttransplant follow-up (median time 582 d; average time to last biopsies was 704 d [SD ± 402 d]) were analyzed. Donor steatosis did not influence recipient steatosis or fibrosis. Ten of 183 recipients had steatohepatitis on the last biopsy. Recipient body mass index at the time of liver biopsy was the most influential factor associated with posttransplant steatosis. Both donor and recipient metabolic syndrome features were not associated with graft steatosis. Untreated hepatitis C viral (HCV) infection was the most influential factor associated with the development of allograft fibrosis.ConclusionsIn a large experience evaluating paired donor and recipient characteristics, recipient body mass index at the time of liver biopsy was most significantly associated with posttransplant steatosis. Untreated HCV etiology influenced graft fibrosis. Thus relative to untreated HCV, hepatic fibrosis in those with steatosis/steatohepatitis is less common though long-term follow-up is needed to determine the course of posttransplant fibrosis. Emphasis on recipient weight control is essential.

Expression of miR-154 is upregulated in the diseased heart and was previously shown to be upregulated in the lungs of patients with pulmonary fibrosis. However, the role of miR-154 in a model of sustained pressure overload-induced cardiac hypertrophy and fibrosis had not been assessed. To examine the role of miR-154 in the diseased heart, adult male mice were subjected to transverse aortic constriction for four weeks and echocardiography was performed to confirm left ventricular hypertrophy and cardiac dysfunction. Mice were then subcutaneously administered a locked nucleic acid antimiR-154 or control over three consecutive days (25 mg/kg/day) and cardiac function was assessed 8 weeks later. Here, we demonstrate that therapeutic inhibition of miR-154 in mice with pathological hypertrophy was able to protect against cardiac dysfunction and attenuate adverse cardiac remodelling. The improved cardiac phenotype was associated with attenuation of heart and cardiomyocyte size, less cardiac fibrosis, lower expression of atrial and B-type natriuretic peptide genes, attenuation of profibrotic markers and increased expression of p15 (a miR-154 target and cell cycle inhibitor). In summary, this study suggests that miR-154 may represent a novel target for the treatment of cardiac pathologies associated with cardiac fibrosis, hypertrophy and dysfunction.

Liver fibrosis is part of the wound healing process to help the liver recover from the injuries caused by various liver-damaging insults. However, liver fibrosis often progresses to life-threatening cirrhosis and hepatocellular carcinoma. To overcome the limitations of current in vivo liver fibrosis models for studying the pathophysiology of liver fibrosis and establishing effective treatment strategies, we developed a new mouse model of liver fibrosis using polyhexamethylene guanidine phosphate (PHMG-p), a humidifier sterilizer known to induce lung fibrosis in humans. Male C57/BL6 mice were intraperitoneally injected with PHMG-p (0.03% and 0.1%) twice a week for 5 weeks. Subsequently, liver tissues were examined histologically and RNA-sequencing was performed to evaluate the expression of key genes and pathways affected by PHMG-p. PHMG-p injection resulted in body weight loss of ~15% and worsening of physical condition. Necropsy revealed diffuse fibrotic lesions in the liver with no effect on the lungs. Histology, collagen staining, immunohistochemistry for smooth muscle actin and collagen, and polymerase chain reaction analysis of fibrotic genes revealed that PHMG-p induced liver fibrosis in the peri-central, peri-portal, and capsule regions. RNA-sequencing revealed that PHMG-p affected several pathways associated with human liver fibrosis, especially with upregulation of lumican and IRAK3, and downregulation of GSTp1 and GSTp2, which are closely involved in liver fibrosis pathogenesis. Collectively we demonstrated that the PHMG-p-induced liver fibrosis model can be employed to study human liver fibrosis.

BACKGROUND: Diabetes mellitus is associated with an increased risk of development of non-alcoholic fatty liver disease (NAFLD). However, the risk posed by diabetes mellitus in progression of liver disease is uncertain. This study compared the severity of hepatic fibrosis in patients with NAFLD with and without diabetes mellitus. METHODS: Consecutive adult patients with NAFLD undergoing transient elastography [FibroScan Touch 502 (Echosens, Paris, France)] at a tertiary care center in north India were analyzed for severity of hepatic fibrosis. The aspartate aminotransferase (AST) to platelet ratio index (APRI), fibrosis index based on 4 factors (FIB-4), and NAFLD Fibrosis Score (NFS) were calculated. The degree of hepatic fibrosis as determined by FibroScan and non-invasive serum fibrosis models in patients with and without diabetes mellitus were compared. RESULTS: A total of two hundred patients [118 (59%) males, mean age 50.30 ± 11.13 years] were enrolled. Significant hepatic fibrosis was present in 86 (43%) patients [mean age 50.66 ± 10.96 years, 56 (65.11%) males]. The mean FibroScan, APRI, FIB-4, and NFS scores were 9.86 ± 2.97, 0.75 ± 0.47, 2.41 ± 1.41 and −0.24 ± 1.43 in patients with diabetes compared to 5.31 ± 1.09, 0.49 ± 0.27, 1.55 ± 0.85, and −2.12 ± 1.88 in patients without diabetes, respectively (P=

To extend previous molecular analyses of rejection in liver transplant biopsies in the INTERLIVER study (ClinicalTrials.gov #NCT03193151), the present study aimed to define the gene expression selective for parenchymal injury, fibrosis, and steatohepatitis. We analyzed genome-wide microarray measurements from 337 liver transplant biopsies from 13 centers. We examined expression of genes previously annotated as increased in injury and fibrosis using principal component analysis (PCA). PC1 reflected parenchymal injury and related inflammation in the early posttransplant period, slowly regressing over many months. PC2 separated early injury from late fibrosis. Positive PC3 identified a distinct mildly inflamed state correlating with histologic steatohepatitis. Injury PCs correlated with liver function and histologic abnormalities. A classifier trained on histologic steatohepatitis predicted histologic steatohepatitis with cross-validated AUC = 0.83, and was associated with pathways reflecting metabolic abnormalities distinct from fibrosis. PC2 predicted histologic fibrosis (AUC = 0.80), as did a molecular fibrosis classifier (AUC = 0.74). The fibrosis classifier correlated with matrix remodeling pathways with minimal overlap with those selective for steatohepatitis, although some biopsies had both. Genome-wide assessment of liver transplant biopsies can not only detect molecular changes induced by rejection but also those correlating with parenchymal injury, steatohepatitis, and fibrosis, offering potential insights into disease mechanisms for primary diseases.

Frontal fibrosing alopecia (FFA) is a progressive, scarring alopecia of the frontotemporal scalp that poses a substantial burden on quality of life. Large-scale global profiling of FFA is lacking, preventing the development of effective therapeutics.To characterize FFA compared to normal and alopecia areata using broad molecular profiling and to identify biomarkers linked to disease severity.This cross-sectional study assessed 33,118 genes in scalp using RNA sequencing and 350 proteins in serum using OLINK high-throughput proteomics. Disease biomarkers were also correlated with clinical severity and a fibrosis gene set.Genes differentially expressed in lesional FFA included markers related to Th1 (IFNγ/CXCL9/CXCL10), T-cell activation (CD2/CD3/CCL19/ICOS), fibrosis (CXCR3/FGF14/FGF22/VIM/FN1), T-regulatory (FOXP3/TGFB1/TGFB3), and Janus kinase/JAK (JAK3/STAT1/STAT4) (Fold changes [FCH]1.5, FDR.05 for all). Only one protein, ADM, was differentially expressed in FFA serum compared to normal (FCH1.3, FDR.05). Significant correlations were found between scalp biomarkers (IL-36RN/IL-25) and FFA severity, as well as between JAK/STAT and fibrosis gene-sets (r.6; P .05).This study was limited by a small sample size and predominantly female FFA patients.Our data characterize FFA as an inflammatory condition limited to scalp, involving Th1/JAK skewing, with associated fibrosis and elevated T-regulatory markers, suggesting the potential for disease reversibility with JAK/STAT inhibition.

[Background and Aims] Surrogate endpoints that predict complications are necessary for assessment and approval of NASH therapies. We assessed associations between histologic and noninvasive tests (NITs) of fibrosis with liver‐related complications in patients with NASH cirrhosis., [Approach and Results] Patients with compensated cirrhosis due to NASH were enrolled in two placebo‐controlled trials of simtuzumab and selonsertib. Liver fibrosis at baseline and week 48 (W48) was staged by NASH Clinical Research Network (CRN) and Ishak classifications and a machine learning (ML) approach, hepatic collagen and alpha‐smooth muscle actin (α‐SMA) expression were quantified by morphometry, liver stiffness (LS) was measured by transient elastography, and serum NITs (enhanced liver fibrosis [ELF], NAFLD fibrosis score [NFS], and Fibrosis‐4 index [FIB‐4]) were calculated. Cox regression determined associations between these parameters at baseline and their changes over time with adjudicated liver‐related clinical events. Among 1,135 patients, 709 (62%) had Ishak stage 6 fibrosis, and median ELF and LS were 10.66 and 21.1 kPa, respectively. During a median follow‐up of 16.6 months, 71 (6.3%) had a liver‐related event; associated baseline factors included Ishak stage 6 fibrosis, and higher hepatic collagen, α‐SMA expression, ML‐based fibrosis parameters, LS, ELF, NFS, and FIB‐4. Cirrhosis regression observed in 16% (176/1,135) between BL and W48 was associated with a lower risk of events versus nonregression (1.1% [2/176] vs. 7.2% [69/957]; HR, 0.16; 95% CI, 0.04, 0.65 [p = 0.0104]). Conversely, after adjustment for baseline values, increases in hepatic collagen, α‐SMA, ML‐based fibrosis parameters, NFS, and LS were associated with an increased risk of events., [Conclusions] In patients with compensated cirrhosis due to NASH, regression of fibrosis is associated with a reduction in liver‐related complications. These data support the utility of histologic fibrosis regression and NITs as clinical trial endpoints for NASH cirrhosis., This analysis was supported by Gilead Sciences, Inc., Foster City, CA, USA.

Background MicroRNAs are small, endogenous, non-coding RNAs that regulate the expression of many genes. It has recently been shown that circulating microRNAs may be biomarkers of hypertrophy and fibrosis in patients with hypertrophic cardiomyopathy (HCM). Objective To determine whether circulating levels of microRNAs involved in HCM are associated with electrocardiographic and echocardiographic parameters. Methods This study enrolled 20 patients with familial HCM and 20 blood donors. Peripheral serum levels of miR-29a-3p, miR-199a-5p and miR-451a were assessed by quantitative real-time polymerase chain reaction and compared with levels in the control group. Whether circulating levels of miRNAs in HCM patients correlated with electrocardiographic and echocardiographic parameters was also assessed. Results Median circulating levels of miR-29a and miR-451a were significantly higher in HCM than the control group. Median miR-199a levels did not differ between groups. However, circulating levels of miR-199a negatively correlated with corrected QT duration (Bazett formula). Median miR-29a levels positively correlated with QRS duration. In addition, circulating levels of miR-29a correlated with maximal wall thickness, left ventricular mass index and left atrial volume index. Conclusions The data suggested that serum levels of miR-29a and miR-451a were significantly increased in HCM patients. As the circulating level of miR-29a correlated with QRS duration, left ventricular hypertrophy and left atrial dilatation, the serum miR-199a level negatively correlated with corrected QT duration. These miRNAs may be seen as potential biomarkers for further research in HCM pathophysiology.

Tungsten is a naturally occurring transition element used in a broad range of applications. As a result of its extensive use, we are increasingly exposed to tungsten from our environment, including potable water, since tungsten can become bioaccessible in ground sources. The kidneys are particularly susceptible to tungsten exposure as this is the main site for tungsten excretion. In this study, we investigated the prolonged effects of tungsten on the kidneys and how this may impact injury and function. When mice were exposed to tungsten in their drinking water for 1 mo, kidney function had not significantly changed. Following 3-mo exposure, mice were presented with deterioration in kidney function as determined by serum and urine creatinine levels. During 3 mo of tungsten exposure, murine kidneys demonstrated significant increases in the myofibroblast marker α-smooth muscle actin (αSMA) and extracellular matrix products: fibronectin, collagen, and matricellular proteins. In addition, Masson’s trichrome and hematoxylin-eosin (H&E) staining revealed an increase in fibrotic tissue and vacuolization of tubular epithelial cells, respectively, from kidneys of tungsten-treated mice, indicative of renal injury. In vitro treatment of kidney fibroblasts with tungsten led to increased proliferation and upregulation of transforming growth factor β1 (TGFβ1), which was consistent with the appearance of fibroblast-to-myofibroblast transition (FMT) markers. Our data suggest that continuous exposure to tungsten impairs kidney function that may lead to the development of chronic kidney disease (CKD).

Background: In COVID-19, EGFR production is upregulated in the alveolar epithelial cells. EGFR overexpression further activates STAT-3 and increases lung pathology. The EGFR pathway is also one of the major nodes in pulmonary fibrosis. Methods: Nimotuzumab, a humanized anti-EGFR antibody, was used to treat three patients with severe or moderate COVID-19. The antibody was administered in combination with other drugs included in the national COVID-19 protocol. Results: Nimotuzumab was well tolerated. IL-6 decreased from the first antibody infusion. Clinical symptoms significantly improved after nimotuzumab administration, and the CT scans at discharge showed major resolution of the lung lesions and no signs of fibrosis. Conclusion: Safe anti-EGFR antibodies like nimotuzumab may modulate COVID-19-associated hyperinflammation and prevent fibrosis. Clinical Trial Registration: RPCEC00000369 (RPCEC rpcec.sld.cu)., Lay abstract Background: In COVID-19, the protein EGFR is overactive in the infected lung cells. Methods: Nimotuzumab, an anti-EGFR antibody, was used to treat three patients with severe or moderate COVID-19. The antibody was administered in combination with other drugs included in the national COVID-19 protocol. Results: Nimotuzumab was safe. The most important inflammatory markers decreased from the first administration. The patients’ clinical symptoms and imaging results improved significantly. Conclusion: Anti-EGFR antibodies like nimotuzumab may contribute to the recovery of COVID-19 patients without long-term consequences.

The purpose of this study was to evaluate the genetic variation of the PIK3CA gene and the histopathological changes in liver tissue of patients with chronic Schistosomiasis to predict hepatocellular carcinoma. In this retrospective, the study samples were taken from 20 patients, divided into chronic schistosomiasis infected group of people (S) and chronic schistosomiasis uninfected group of people (C). The liver tissue biopsy samples for histological examinations were obtained only from chronic Schistosomiasis patients (n = 9). The blood samples were obtained from groups S and C for the mutational analysis of the PIK3CA and TP53 genes. The results suggest that the patients diagnosed with chronic Schistosomiasis were 9 (55%), and healthy patients without Schistosomiasis were 11 (45%). Histological results found that proliferation of fibrosis was observed in the hepatocytes of schistosomiasis patients. A total of 8 mutations (5 male, 3 female) were detected in PIK3CA and TP53 genes. Including 1634 A > G substitution mutations in PIK3CA, which was the only mutation found in males and females among the 8 mutations, accounting 22.22%. PIK3CA gene mutations were found more predominant in male groups as compared to other TP53 gene mutations. In conclusion, this study found that patients with chronic Schistosomiasis are at risk of PIK3CA gene mutations, eventually leading to hepatocytes fibrosis and liver cancer.

Obesity is a major risk factor for lung disease development. However, little is known about the impact of chronic high-fat and high-fructose (HFHF) diet-induced obesity on lung inflammation and subsequent pulmonary fibrosis. Herein we hypothesized that dedicator of cytokinesis 2 (DOCK2) promotes a proinflammatory phenotype of lung fibroblasts (LFs) to elicit lung injury and fibrosis in chronic HFHF diet-induced obesity. HFHF diet for 20 weeks induced lung inflammation and pro-fibrotic changes in wild-type (WT) C57BL/6 mice. CD68 and monocyte chemoattractant protein-1 (MCP-1) expression were notably increased in the lungs of WT mice fed a HFHF diet. Further, HFHF diet increased lung DOCK2 expression that co-localized with fibroblast-specific protein 1, suggesting a potential role of DOCK2 in regulating proinflammatory phenotype of LFs. Importantly, DOCK2 knockout mice were protected from lung inflammation and fibrosis induced by chronic HFHF diet. In primary human LFs (HLFs), TNF-α and IL-1β induced DOCK2 expression concurrent with MCP-1, IL-6, and matrix metallopeptidase 2. DOCK2 knockdown suppressed TNF-α induced expression of these molecules. DOCK2 knockdown likewise attenuated TNF-α-induced activation of the PI3K/AKT and NF-κB signaling pathways, suggesting a mechanism of DOCK2 mediated proinflammatory and pro-fibrotic changes in HLFs. Taken together, these findings reveal a previously unrecognized role of DOCK2 in regulating proinflammatory phenotype of LFs, potentiation of lung inflammation and pulmonary fibrosis in chronic HFHF diet caused obesity.

Kidney international 101(2), 256-273 (2022). doi:10.1016/j.kint.2021.10.025, Published by Elsevier, New York, NY