Try a new search

Format these results:

Searched for:



Total Results:


The space of Mall confirmed in humans: A response to "Portal venous branches as an anatomic railroad for a gut-bile duct axis" [Letter]

de Jong, Iris E M; Theise, Neil D; Wells, Rebecca G
PMID: 37821022
ISSN: 1600-0641
CID: 5604352

Glisson's capsule matrix structure and function is altered in patients with cirrhosis irrespective of aetiology

Llewellyn, Jessica; Fede, Caterina; Loneker, Abigail E.; Friday, Chet S.; Hast, Michael W.; Theise, Neil D.; Furth, Emma E.; Guido, Maria; Stecco, Carla; Wells, Rebecca G.
Background & Aims: Glisson's capsule is the interstitial connective tissue that surrounds the liver. As part of its normal physiology, it withstands significant daily changes in liver size. The pathophysiology of the capsule in disease is not well understood. The aim of this study was to characterise the changes in capsule matrix, cellular composition, and mechanical properties that occur in liver disease and to determine whether these correlate with disease severity or aetiology. Methods: Samples from ten control patients, and six with steatosis, seven with moderate fibrosis, and 37 with cirrhosis were collected from autopsies, intraoperative biopsies, and liver explants. Matrix proteins and cell markers were assessed by staining and second harmonic generation imaging. Mechanical tensile testing was performed on a test frame. Results: Capsule thickness was significantly increased in cirrhotic samples compared with normal controls irrespective of disease aetiology (70.12 ± 14.16 μm and 231.58 ± 21.82 μm, respectively), whereas steatosis and moderate fibrosis had no effect on thickness (90.91 ± 11.40 μm). Changes in cirrhosis included an increase in cell number (fibroblasts, vascular cells, infiltrating immune cells, and biliary epithelial cells). Key matrix components (collagens 1 and 3, hyaluronan, versican, and elastin) were all deposited in the lower capsule, although only the relative amounts per area of hyaluronan and versican were increased. Organisational features, including crimping and alignment of collagen fibres, were also altered in cirrhosis. Unexpectedly, capsules from cirrhotic livers had decreased resistance to loading compared with controls. Conclusions: The liver capsule, similar to the parenchyma, is an active site of disease, demonstrating changes in matrix and cell composition as well as mechanical properties. Impact and implications: We assessed the changes in composition and response to stretching of the liver outer sheath, the capsule, in human liver disease. We found an increase in key structural components and numbers of cells as well as a change in matrix organisation of the capsule during the later stages of disease. This allows the diseased capsule to stretch more under any given force, suggesting that it is less stiff than healthy tissue.
ISSN: 2589-5559
CID: 5548252

What's old is new again: The anatomical studies of Franklin P. Mall and the fascial-interstitial spaces

Pirri, Carmelo; Wells, Rebecca G; De Caro, Raffaele; Stecco, Carla; Theise, Neil D
Franklin Mall was one of the foremost scientists of the turn of the 19th century, an exemplary mentor as well as researcher, and his revolutionary contributions are still relevant today. Mall's early training in Leipzig with Wilhelm His and Carl Ludwig provided him with an unusual perspective on the integration of anatomy and physiology, and his interest in the links between structure and function guided the work he carried out after joining the faculty of the new Johns Hopkins University School of Medicine. Mall carried out innovative studies on the one hand using dye injection to trace blood and lymphatic supplies to different organs and on the other hand using "putrefaction" to digest tissues and study the organization of the reticular space, demonstrating that it was the underlying source of support for all the organs. These two studies of Mall's, carried out independently, provide the basis for modern studies integrating the understanding of fascia and interstitial spaces.
PMID: 36942935
ISSN: 1098-2353
CID: 5462752

DIAPH1 mediates progression of atherosclerosis and regulates hepatic lipid metabolism in mice

Senatus, Laura; Egaña-Gorroño, Lander; López-Díez, Raquel; Bergaya, Sonia; Aranda, Juan Francisco; Amengual, Jaume; Arivazhagan, Lakshmi; Manigrasso, Michaele B; Yepuri, Gautham; Nimma, Ramesh; Mangar, Kaamashri N; Bernadin, Rollanda; Zhou, Boyan; Gugger, Paul F; Li, Huilin; Friedman, Richard A; Theise, Neil D; Shekhtman, Alexander; Fisher, Edward A; Ramasamy, Ravichandran; Schmidt, Ann Marie
Atherosclerosis evolves through dysregulated lipid metabolism interwoven with exaggerated inflammation. Previous work implicating the receptor for advanced glycation end products (RAGE) in atherosclerosis prompted us to explore if Diaphanous 1 (DIAPH1), which binds to the RAGE cytoplasmic domain and is important for RAGE signaling, contributes to these processes. We intercrossed atherosclerosis-prone Ldlr-/- mice with mice devoid of Diaph1 and fed them Western diet for 16 weeks. Compared to male Ldlr-/- mice, male Ldlr-/- Diaph1-/- mice displayed significantly less atherosclerosis, in parallel with lower plasma concentrations of cholesterol and triglycerides. Female Ldlr-/- Diaph1-/- mice displayed significantly less atherosclerosis compared to Ldlr-/- mice and demonstrated lower plasma concentrations of cholesterol, but not plasma triglycerides. Deletion of Diaph1 attenuated expression of genes regulating hepatic lipid metabolism, Acaca, Acacb, Gpat2, Lpin1, Lpin2 and Fasn, without effect on mRNA expression of upstream transcription factors Srebf1, Srebf2 or Mxlipl in male mice. We traced DIAPH1-dependent mechanisms to nuclear translocation of SREBP1 in a manner independent of carbohydrate- or insulin-regulated cues but, at least in part, through the actin cytoskeleton. This work unveils new regulators of atherosclerosis and lipid metabolism through DIAPH1.
PMID: 36932214
ISSN: 2399-3642
CID: 5449062

Hepatitis Due to Hepatotropic Viruses

Chapter by: Guido, Maria; Mangia, Alessandra; Theise, Neil D.
in: MacSween's Pathology of the Liver, Eighth Edition by
[S.l.] : Elsevier, 2023
pp. 402-447
ISBN: 9780702082290
CID: 5500902

Human hepatocyte PNPLA3-148M exacerbates rapid non-alcoholic fatty liver disease development in chimeric mice

Kabbani, Mohammad; Michailidis, Eleftherios; Steensels, Sandra; Fulmer, Clifton G; Luna, Joseph M; Le Pen, Jérémie; Tardelli, Matteo; Razooky, Brandon; Ricardo-Lax, Inna; Zou, Chenhui; Zeck, Briana; Stenzel, Ansgar F; Quirk, Corrine; Foquet, Lander; Ashbrook, Alison W; Schneider, William M; Belkaya, Serkan; Lalazar, Gadi; Liang, Yupu; Pittman, Meredith; Devisscher, Lindsey; Suemizu, Hiroshi; Theise, Neil D; Chiriboga, Luis; Cohen, David E; Copenhaver, Robert; Grompe, Markus; Meuleman, Philip; Ersoy, Baran A; Rice, Charles M; de Jong, Ype P
Advanced non-alcoholic fatty liver disease (NAFLD) is a rapidly emerging global health problem associated with pre-disposing genetic polymorphisms, most strikingly an isoleucine to methionine substitution in patatin-like phospholipase domain-containing protein 3 (PNPLA3-I148M). Here, we study how human hepatocytes with PNPLA3 148I and 148M variants engrafted in the livers of broadly immunodeficient chimeric mice respond to hypercaloric diets. As early as four weeks, mice developed dyslipidemia, impaired glucose tolerance, and steatosis with ballooning degeneration selectively in the human graft, followed by pericellular fibrosis after eight weeks of hypercaloric feeding. Hepatocytes with the PNPLA3-148M variant, either from a homozygous 148M donor or overexpressed in a 148I donor background, developed microvesicular and severe steatosis with frequent ballooning degeneration, resulting in more active steatohepatitis than 148I hepatocytes. We conclude that PNPLA3-148M in human hepatocytes exacerbates NAFLD. These models will facilitate mechanistic studies into human genetic variant contributions to advanced fatty liver diseases.
PMID: 36103835
ISSN: 2211-1247
CID: 5332872

Etiology, Pathogenesis, Diagnosis, and Practical Implications of Hepatocellular Neoplasms

Hytiroglou, Prodromos; Bioulac-Sage, Paulette; Theise, Neil D; Sempoux, Christine
Hepatocellular carcinoma (HCC), a major global contributor of cancer death, usually arises in a background of chronic liver disease, as a result of molecular changes that deregulate important signal transduction pathways. Recent studies have shown that certain molecular changes of hepatocarcinogenesis are associated with clinicopathologic features and prognosis, suggesting that subclassification of HCC is practically useful. On the other hand, subclassification of hepatocellular adenomas (HCAs), a heterogenous group of neoplasms, has been well established on the basis of genotype-phenotype correlations. Histologic examination, aided by immunohistochemistry, is the gold standard for the diagnosis and subclassification of HCA and HCC, while clinicopathologic correlation is essential for best patient management. Advances in clinico-radio-pathologic correlation have introduced a new approach for the diagnostic assessment of lesions arising in advanced chronic liver disease by imaging (LI-RADS). The rapid expansion of knowledge concerning the molecular pathogenesis of HCC is now starting to produce new therapeutic approaches through precision oncology. This review summarizes the etiology and pathogenesis of HCA and HCC, provides practical information for their histologic diagnosis (including an algorithmic approach), and addresses a variety of frequently asked questions regarding the diagnosis and practical implications of these neoplasms.
PMID: 35954333
ISSN: 2072-6694
CID: 5287222

Pulmonary Pathology of End-Stage COVID-19 Disease in Explanted Lungs and Outcomes After Lung Transplantation

Flaifel, Abdallah; Kwok, Benjamin; Ko, Jane; Chang, Stephanie; Smith, Deane; Zhou, Fang; Chiriboga, Luis A; Zeck, Briana; Theise, Neil; Rudym, Darya; Lesko, Melissa; Angel, Luis; Moreira, Andre; Narula, Navneet
OBJECTIVES/OBJECTIVE:Patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may develop end-stage lung disease requiring lung transplantation. We report the clinical course, pulmonary pathology with radiographic correlation, and outcomes after lung transplantation in three patients who developed chronic respiratory failure due to postacute sequelae of SARS-CoV-2 infection. METHODS:A retrospective histologic evaluation of explanted lungs due to coronavirus disease 2019 was performed. RESULTS:None of the patients had known prior pulmonary disease. The major pathologic findings in the lung explants were proliferative and fibrotic phases of diffuse alveolar damage, interstitial capillary neoangiogenesis, and mononuclear inflammation, specifically macrophages, with varying numbers of T and B lymphocytes. The fibrosis varied from early collagen deposition to more pronounced interstitial collagen deposition; however, pulmonary remodeling with honeycomb change was not present. Other findings included peribronchiolar metaplasia, microvascular thrombosis, recanalized thrombi in muscular arteries, and pleural adhesions. No patients had either recurrence of SARS-CoV-2 infection or allograft rejection following transplant at this time. CONCLUSIONS:The major pathologic findings in the lung explants of patients with SARS-CoV-2 infection suggest ongoing fibrosis, prominent macrophage infiltration, neoangiogenesis, and microvascular thrombosis. Characterization of pathologic findings could help develop novel management strategies.
PMID: 34999755
ISSN: 1943-7722
CID: 5118212

Quantifying cerebrospinal fluid dynamics: A review of human neuroimaging contributions to CSF physiology and neurodegenerative disease

Mehta, Neel H; Suss, Richard A; Dyke, Jonathan P; Theise, Neil D; Chiang, Gloria C; Strauss, Sara; Saint-Louis, Leslie; Li, Yi; Pahlajani, Silky; Babaria, Vivek; Glodzik, Lidia; Carare, Roxana O; de Leon, Mony J
Cerebrospinal fluid (CSF), predominantly produced in the ventricles and circulating throughout the brain and spinal cord, is a key protective mechanism of the central nervous system (CNS). Physical cushioning, nutrient delivery, metabolic waste, including protein clearance, are key functions of the CSF in humans. CSF volume and flow dynamics regulate intracranial pressure and are fundamental to diagnosing disorders including normal pressure hydrocephalus, intracranial hypotension, CSF leaks, and possibly Alzheimer's disease (AD). The ability of CSF to clear normal and pathological proteins, such as amyloid-beta (Aβ), tau, alpha synuclein and others, implicates it production, circulation, and composition, in many neuropathologies. Several neuroimaging modalities have been developed to probe CSF fluid dynamics and better relate CSF volume and flow to anatomy and clinical conditions. Approaches include 2-photon microscopic techniques, MRI (tracer-based, gadolinium contrast, endogenous phase-contrast), and dynamic positron emission tomography (PET) using existing approved radiotracers. Here, we discuss CSF flow neuroimaging, from animal models to recent clinical-research advances, summarizing current endeavors to quantify and map CSF flow with implications towards pathophysiology, new biomarkers, and treatments of neurological diseases.
PMID: 35643187
ISSN: 1095-953x
CID: 5235972

Intrahepatic microbes govern liver immunity by programming NKT cells

Leinwand, Joshua C; Paul, Bidisha; Chen, Ruonan; Xu, Fangxi; Sierra, Maria A; Paluru, Madan M; Nanduri, Sumant; Alcantara Hirsch, Carolina G; Shadaloey, Sorin Aa; Yang, Fan; Adam, Salma A; Li, Qianhao; Bandel, Michelle; Gakhal, Inderdeep; Appiah, Lara; Guo, Yuqi; Vardhan, Mridula; Flaminio, Zia J; Grodman, Emilie R; Mermelstein, Ari; Wang, Wei; Diskin, Brian; Aykut, Berk; Khan, Mohammed; Werba, Gregor; Pushalkar, Smruti; McKinstry, Mia; Kluger, Zachary; Park, Jaimie J; Hsieh, Brandon; Dancel-Manning, Kristen; Liang, Feng-Xia; Park, James S; Saxena, Anjana; Li, Xin; Theise, Neil D; Saxena, Deepak; Miller, George
The gut microbiome shapes local and systemic immunity. The liver is presumed to be a protected sterile site. As such, a hepatic microbiome has not been examined. Here, we showed a liver microbiome in mice and humans that is distinct from the gut and is enriched in Proteobacteria. It undergoes dynamic alterations with age and is influenced by the environment and host physiology. Fecal microbial transfer experiments revealed that the liver microbiome is populated from the gut in a highly selective manner. Hepatic immunity is dependent on the microbiome, specifically Bacteroidetes species. Targeting Bacteroidetes with oral antibiotics reduced hepatic immune cells by ~90%, prevented APC maturation, and mitigated adaptive immunity. Mechanistically, our findings are consistent with presentation of Bacteroidetes-derived glycosphingolipids to NKT cells promoting CCL5 signaling, which drives hepatic leukocyte expansion and activation, among other possible host-microbe interactions. Collectively, we reveal a microbial - glycosphingolipid - NKT - CCL5 axis that underlies hepatic immunity.
PMID: 35175938
ISSN: 1558-8238
CID: 5163572