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Experimental and Molecular Pathology Aug 2022Mallory-Denk bodies (MDBs) consist of intracellular aggregates of misfolded proteins in ballooned hepatocytes and serve as important markers of progression in certain...
Mallory-Denk bodies (MDBs) consist of intracellular aggregates of misfolded proteins in ballooned hepatocytes and serve as important markers of progression in certain liver diseases. Resident hepatic macrophage-mediated inflammation influences the development of chronic liver diseases and cancer. Here, the first systematic study of macrophages heterogeneity in mice was conducted to illustrate the pathogenesis of MDB formation using single-nucleus RNA sequencing (snRNA-seq). Furthermore, we provided transcriptional profiles of macrophages obtained from the fractionation of mouse liver tissues following chronic injury. We equally identified seven discrete macrophage subpopulations, each involved in specific cellular activated pathways such as basal metabolism, immune regulation, angiogenesis, and cell cycle regulation. Among these, a specific macrophage cluster (Cluster4), a subpopulation specifically expressing genes that regulate cell division and the cell cycle, was identified. Interestingly, we found that CCR2 was significantly induced in Cluster2, thereby inducing monocytes to migrate to macrophages to promote MDB pathogenesis. Thus, our study is the first to demonstrate the heterogeneity of macrophages associated with liver MDB formation in mice through single-cell resolution. This serves as the basis for further insights into the pathogenesis of liver MDB formation and molecular mechanisms of chronic liver disease progression.
Topics: Animals; Hepatocytes; Liver; Liver Diseases; Macrophages; Mallory Bodies; Mice; Transcriptome
PubMed: 35850229
DOI: 10.1016/j.yexmp.2022.104811 -
Cureus Sep 2019Intramural esophageal hematoma (IEH) is a rare cause of submucosal esophageal bleeding and it is on the spectrum of esophageal wall injury along with mucosal tears...
Intramural esophageal hematoma (IEH) is a rare cause of submucosal esophageal bleeding and it is on the spectrum of esophageal wall injury along with mucosal tears (Mallory-Weiss syndrome) and full thickness perforation (Boerhaave's syndrome). Its risk factors include coagulopathy, trauma (foreign body ingestion or esophageal instrumentation) or it can happen spontaneously. It presents with a triad of chest pain, dysphagia, and hematemesis; however, the triad is only present in 35% of patients. We are presenting a case of IEH secondary to food ingestion that was managed successfully by conservative measures.
PubMed: 31696016
DOI: 10.7759/cureus.5623 -
Swiss Medical Weekly Jul 2021During the ongoing COVID-19 pandemic, the launch of a large-scale vaccination campaign and virus mutations have hinted at possible changes in transmissibility and the...
AIMS OF THE STUDY
During the ongoing COVID-19 pandemic, the launch of a large-scale vaccination campaign and virus mutations have hinted at possible changes in transmissibility and the virulence affecting disease progression up to critical illness, and carry potential for future vaccination failure. To monitor disease development over time with respect to critically ill COVID-19 patients, we report near real-time prospective observational data from the RISC-19-ICU registry that indicate changed characteristics of critically ill patients admitted to Swiss intensive care units (ICUs) at the onset of a third pandemic wave.
METHODS
1829 of 3344 critically ill COVID-19 patients enrolled in the international RISC-19-ICU registry as of 31 May 2021 were treated in Switzerland and were included in the present study. Of these, 1690 patients were admitted to the ICU before 1 February 2021 and were compared with 139 patients admitted during the emerging third pandemic wave RESULTS: Third wave patients were a mean of 5.2 years (95% confidence interval [CI] 3.2–7.1) younger (median 66.0 years, interquartile range [IQR] 57.0–73.0 vs 62.0 years, IQR 54.5–68.0; p <0.0001) and had a higher body mass index than patients admitted in the previous pandemic period. They presented with lower SAPS II and APACHE II scores, less need for circulatory support and lower white blood cell counts at ICU admission. P/F ratio was similar, but a 14% increase in ventilatory ratio was observed over time (p = 0.03) CONCLUSION: Near real-time registry data show that the latest COVID-19 patients admitted to ICUs in Switzerland at the onset of the third wave were on average 5 years younger, had a higher body mass index, and presented with lower physiological risk scores but a trend towards more severe lung failure. These differences may primarily be related to the ongoing nationwide vaccination campaign, but the possibility that changes in virus-host interactions may be a co-factor in the age shift and change in disease characteristics is cause for concern, and should be taken into account in the public health and vaccination strategy during the ongoing pandemic. (ClinicalTrials.gov Identifier: NCT04357275).
Topics: COVID-19; Critical Illness; Hospital Mortality; Humans; Intensive Care Units; Pandemics; Prevalence; Prospective Studies; SARS-CoV-2; Switzerland
PubMed: 34291810
DOI: 10.4414/smw.2021.20553 -
The American Journal of Pathology Jun 2020Hepatocellular carcinoma (HCC) is the most common form of liver tumors. Although HCC is associated with chronic viral infections, alcoholic cirrhosis, and nonalcoholic...
Hepatocellular carcinoma (HCC) is the most common form of liver tumors. Although HCC is associated with chronic viral infections, alcoholic cirrhosis, and nonalcoholic fatty liver disease, genetic factors that contribute to the HCC risk remain unknown. The BRCA2 DNA repair associated (BRCA2) and cyclin-dependent kinase inhibitor 1A (CDKN1A) interacting protein, known as BCCIP, are essential for cell viability and maintenance of genomic stability. In this study, we established a new genetically engineered mouse model with Bccip deficiency. Mosaic or heterozygous Bccip deletion conferred an increased risk of spontaneous liver tumorigenesis and B-cell lymphoma development at old age. These abnormalities are accompanied with chronic inflammation, histologic features of nonalcoholic steatohepatitis, keratin and ubiquitin aggregates within cytoplasmic Mallory-Denk bodies, and changes of the intracellular distribution of high-mobility group box 1 protein. Our study suggests BCCIP dysregulation as a risk factor for HCC and offers a novel mouse model for future investigations of nonviral or nonalcoholic causes of HCC development.
Topics: Animals; BRCA2 Protein; Carcinoma, Hepatocellular; Cell Cycle Proteins; Heterozygote; Liver Neoplasms; Lymphoma, B-Cell; Mice; Mice, Knockout; Mosaicism
PubMed: 32201259
DOI: 10.1016/j.ajpath.2020.01.020 -
World Journal of Gastrointestinal... May 2023Mallory-Weiss syndrome (MWS), representing a linear mucosal laceration at the gastroesophageal junction, is a quite frequent cause of upper gastrointestinal bleeding,...
BACKGROUND
Mallory-Weiss syndrome (MWS), representing a linear mucosal laceration at the gastroesophageal junction, is a quite frequent cause of upper gastrointestinal bleeding, usually induced by habitual vomiting. The subsequent cardiac ulceration in this condition is likely due to the concomitance of increased intragastric pressure and inappropriate closure of the gastroesophageal sphincter, collectively inducing ischemic mucosal damage. Usually, MWS is associated with all vomiting conditions, but it has also been described as a complication of prolonged endoscopic procedures or ingested foreign bodies.
CASE SUMMARY
We described herein a case of upper gastrointestinal bleeding in a 16-year-old girl with MWS and chronic psychiatric distress, the latter of which deteriorated following her parents' divorce. The patient, who was residing on a small island during the coronavirus disease 2019 pandemic lockdown period, presented with a 2-mo history of habitual vomiting, hematemesis, and a slight depressive mood. Ultimately, a huge intragastric obstructive trichobezoar was detected and discovered to be due to a hidden habit of continuously eating her own hair; this habit had persisted for the past 5 years until a drastic reduction in food intake and corresponding weight loss occurred. The relative isolation in her living status without school attendance had worsened her compulsory habit. The hair agglomeration had reached such enormous dimensions and its firmness was so hard that its potential for endoscopic treatment was judged to be impossible. The patient underwent surgical intervention instead, which culminated in complete removal of the mass.
CONCLUSION
According to our knowledge, this is the first-ever described case of MWS due to an excessively large trichobezoar.
PubMed: 37342849
DOI: 10.4240/wjgs.v15.i5.972 -
FASEB Journal : Official Publication of... Aug 2019Keratin 8 (K8) and keratin 18 (K18) are the intermediate filament proteins whose phosphorylation/transamidation associate with their aggregation in Mallory-Denk bodies...
Keratin 8 (K8) and keratin 18 (K18) are the intermediate filament proteins whose phosphorylation/transamidation associate with their aggregation in Mallory-Denk bodies found in patients with various liver diseases. However, the functions of other post-translational modifications in keratins related to liver diseases have not been fully elucidated. Here, using a site-specific mutation assay combined with nano-liquid chromatography-tandem mass spectrometry, we identified K8-Lys108 and K18-Lys187/426 as acetylation sites, and K8-Arg47 and K18-Arg55 as methylation sites. Keratin mutation (Arg-to-Lys/Ala) at the methylation sites, but not the acetylation sites, led to decreased stability of the keratin protein. We compared keratin acetylation/methylation in liver disease-associated keratin variants. The acetylation of K8 variants increased or decreased to various extents, whereas the methylation of K18-del65-72 and K18-I150V variants increased. Notably, the highly acetylated/methylated K18-I150V variant was less soluble and exhibited unusually prolonged protein stability, which suggests that additional acetylation of highly methylated keratins has a synergistic effect on prolonged stability. Therefore, the different levels of acetylation/methylation of the liver disease-associated variants regulate keratin protein stability. These findings extend our understanding of how disease-associated mutations in keratins modulate keratin acetylation and methylation, which may contribute to disease pathogenesis.-Jang, K.-H., Yoon, H.-N., Lee, J., Yi, H., Park, S.-Y., Lee, S.-Y., Lim, Y., Lee, H.-J., Cho, J.-W., Paik, Y.-K., Hancock, W. S., Ku, N.-O. Liver disease-associated keratin 8 and 18 mutations modulate keratin acetylation and methylation.
Topics: Acetylation; Amino Acid Sequence; Amino Acid Substitution; Animals; Binding Sites; Cell Line; Cricetinae; HT29 Cells; Humans; Keratin-18; Keratin-8; Liver Diseases; Mallory Bodies; Methylation; Mutant Proteins; Mutation, Missense; Protein Processing, Post-Translational; Protein Stability; Tandem Mass Spectrometry
PubMed: 31199680
DOI: 10.1096/fj.201800263RR -
Scientific Reports Mar 2022Despite the increasing prevalence of Nonalcoholic steatohepatitis (NASH) worldwide, there is no effective treatment available for this disease. "Ballooned hepatocyte" is...
Despite the increasing prevalence of Nonalcoholic steatohepatitis (NASH) worldwide, there is no effective treatment available for this disease. "Ballooned hepatocyte" is a characteristic finding in NASH and is correlated with disease prognosis, but their mechanisms of action are poorly understood; furthermore, neither animal nor in vitro models of NASH have been able to adequately represent ballooned hepatocytes. Herein, we engineered cell sheets to develop a new in vitro model of ballooned hepatocytes. Primary human hepatocytes (PHH) and Hepatic stellate cells (HSC) were co-cultured to produce cell sheets, which were cultured in glucose and lipid containing medium, following which histological and functional analyses were performed. Histological findings showed hepatocyte ballooning, accumulation of fat droplets, abnormal cytokeratin arrangement, and the presence of Mallory-Denk bodies and abnormal organelles. These findings are similar to those of ballooned hepatocytes in human NASH. Functional analysis showed elevated levels of TGFβ-1, SHH, and p62, but not TNF-α, IL-8. Exposure of PHH/HSC sheets to a glucolipotoxicity environment induces ballooned hepatocyte without inflammation. Moreover, fibrosis is an important mechanism underlying ballooned hepatocytes and could be the basis for the development of a new in vitro NASH model with ballooned hepatocytes.
Topics: Animals; Hepatic Stellate Cells; Hepatocytes; Humans; Keratins; Kupffer Cells; Non-alcoholic Fatty Liver Disease
PubMed: 35351975
DOI: 10.1038/s41598-022-09428-x -
Lancet (London, England) May 2024Amblyopia, the most common visual impairment of childhood, is a public health concern. An extended period of optical treatment before patching is recommended by the... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
Extended optical treatment versus early patching with an intensive patching regimen in children with amblyopia in Europe (EuPatch): a multicentre, randomised controlled trial.
BACKGROUND
Amblyopia, the most common visual impairment of childhood, is a public health concern. An extended period of optical treatment before patching is recommended by the clinical guidelines of several countries. The aim of this study was to compare an intensive patching regimen, with and without extended optical treatment (EOT), in a randomised controlled trial.
METHODS
EuPatch was a randomised controlled trial conducted in 30 hospitals in the UK, Greece, Austria, Germany, and Switzerland. Children aged 3-8 years with newly detected, untreated amblyopia (defined as an interocular difference ≥0·30 logarithm of the minimum angle of resolution [logMAR] best corrected visual acuity [BCVA]) due to anisometropia, strabismus, or both were eligible. Participants were randomly assigned (1:1) via a computer-generated sequence to either the EOT group (18 weeks of glasses use before patching) or to the early patching group (3 weeks of glasses use before patching), stratified for type and severity of amblyopia. All participants were initially prescribed an intensive patching regimen (10 h/day, 6 days per week), supplemented with motivational materials. The patching period was up to 24 weeks. Participants, parents or guardians, assessors, and the trial statistician were not masked to treatment allocation. The primary outcome was successful treatment (ie, ≤0·20 logMAR interocular difference in BCVA) after 12 weeks of patching. Two primary analyses were conducted: the main analysis included all participants, including those who dropped out, but excluded those who did not provide outcome data at week 12 and remained on the study; the other analysis imputed this missing data. All eligible and randomly assigned participants were assessed for adverse events. This study is registered with the International Standard Randomised Controlled Trial Number registry (ISRCTN51712593) and is no longer recruiting.
FINDINGS
Between June 20, 2013, and March 12, 2020, after exclusion of eight participants found ineligible after detailed screening, we randomly assigned 334 participants (170 to the EOT group and 164 to the early patching group), including 188 (56%) boys, 146 (44%) girls, and two (1%) participants whose sex was not recorded. 317 participants (158 in the EOT group and 159 in the early patching group) were analysed for the primary outcome without imputation of missing data (median follow-up time 42 weeks [IQR 42] in the EOT group vs 27 weeks [27] in the early patching group). 24 (14%) of 170 participants in the EOT group and ten (6%) of 164 in the early patching group were excluded or dropped out of the study, mostly due to loss to follow-up and withdrawal of consent; ten (6%) in the EOT group and three (2%) in the early patching group missed the 12 week visit but remained on the study. A higher proportion of participants in the early patching group had successful treatment (107 [67%] of 159) than those in the EOT group (86 [54%] of 158; 13% difference; p=0·019) after 12 weeks of patching. No serious adverse events related to the interventions occurred.
INTERPRETATION
The results from this trial indicate that early patching is more effective than EOT for the treatment of most children with amblyopia. Our findings also provide data for the personalisation of amblyopia treatments.
FUNDING
Action Medical Research, NIHR Clinical Research Network, and Ulverscroft Foundation.
Topics: Humans; Amblyopia; Child, Preschool; Female; Male; Child; Eyeglasses; Visual Acuity; Sensory Deprivation; Treatment Outcome; Europe
PubMed: 38704172
DOI: 10.1016/S0140-6736(23)02893-3 -
Journal of Cellular and Molecular... Apr 2024Liver cirrhosis is a silent disease in humans and is experimentally induced by many drugs and toxins as thioacetamide (TAA) in particular, which is the typical model for...
Liver cirrhosis is a silent disease in humans and is experimentally induced by many drugs and toxins as thioacetamide (TAA) in particular, which is the typical model for experimental induction of hepatic fibrosis. Thus, the objective of the present study was to elucidate the possible protective effects of lactéol® forte (LF) and quercetin dihydrate (QD) against TAA-induced hepatic damage in male albino rats. Induction of hepatotoxicity was performed by TAA injection (200 mg/kg I/P, twice/ week) in rats. LF (1 × 10 CFU/rat 5 times/week) and QD (50 mg/kg 5 times/week) treated groups were administered concurrently with TAA injection (200 mg/kg I/P, twice/ week). The experimental treatments were conducted for 12 weeks. Hepatotoxicity was evaluated biochemically by measuring alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transferase (GGT) in the serum and histopathologically with the scoring of histopathological changes besides histochemical assessment of collagen by Masson's trichrome and immunohistochemical analysis for α-smooth muscle actin (α-SMA), Ki67 and caspase-3 expression in liver sections. Our results indicated that LF and QD attenuated some biochemical changes and histochemical markers in TAA-mediated hepatotoxicity in rats by amelioration of biochemical markers and collagen, α-SMA, Ki67 and caspase3 Immunoexpression. Additionally, LF and QD supplementation downregulated the proliferative, necrotic, fibroblastic changes, eosinophilic intranuclear inclusions, hyaline globules and Mallory-like bodies that were detected histopathologically in the TAA group. In conclusion, LF showed better hepatic protection than QD against TAA-induced hepatotoxicity in rats by inhibiting inflammatory reactions with the improvement of some serum hepatic transaminases, histopathological picture and immunohistochemical markers.
Topics: Humans; Rats; Male; Animals; Quercetin; Thioacetamide; Ki-67 Antigen; Liver Cirrhosis; Liver; Flavonoids; Chemical and Drug Induced Liver Injury; Collagen; Oxidative Stress; Calcium Carbonate; Drug Combinations; Lactose
PubMed: 38534093
DOI: 10.1111/jcmm.18196 -
Scientific Reports Aug 2020The current study investigated telocytes (TCs) in the intestinal bulb of Grass carp using light microscopy (LM), Transmission electron microscopy (TEM), scanning...
The current study investigated telocytes (TCs) in the intestinal bulb of Grass carp using light microscopy (LM), Transmission electron microscopy (TEM), scanning electron microscopy, and immunohistochemistry (IHC). By LM, TCs were distinguished by the typical morphological features that had a cell body and telopodes using HE, toluidine blue, methylene blue, Marsland silver stain, Grimelius's silver nitrate, Giemsa, PAS, combined AB pH2,5/PAS, Crossmon's and Mallory triple trichrome, Van Gieson stains, Verhoeff's stain, Sudan black, osmic acid, performic acid with methylene blue and bromophenol blue. TCs were identified under the epithelium as an individual cell or formed a TCs sheath. They detected in the lamina propria, between muscle fibers, around the myenteric plexus and fibrous tissue. TCs acquired immunological features of endocrine cells that exhibited high affinity for silver stain, performic acid with methylene blue, Marsland stain, and immunohistochemical staining using chromogranin A. Sub epithelial TCs were closely related to the endocrine cells. TCs and their secretory activities were recognized using acridine orange. TCs were identified by IHC using CD34, CD117, S100-protein, desmin. TCs formed a3D network that established contact with macrophage, mast cells, dendritic cells, lymphocytes, smooth muscle fibers, fibroblast, Schwann cells and nerve fibers. In conclusion, the localization of TCs in relation to different types of immune cells indicated their potential role in the maintenance of intestinal immunity.
Topics: Animals; Carps; Immunohistochemistry; Intestines; Microscopy, Electron, Transmission; Paraffin Embedding; Telocytes; Telopodes
PubMed: 32820212
DOI: 10.1038/s41598-020-70032-y