Mechanism Of Lesion Formation Research Articles

Instrumented Circumferential Fusion in Two Stages for Instable Lumbar Fracture: Long-Term Results of a Series of 74 Patients on Sagittal Balance and Functional Outcomes.

To report the radiologic and functional results of a multicenter, prospective case series of patients with comminuted lumbar fractures treated with 2-stage circumferential arthrodesis. A multicenter prospective case series of 74 patients with comminuted lumbar fractures was analyzed. The strategy entailed initial posterior osteosynthesis, followed by physical replacement with an expandable titanium cage filled with autologous bone via retroperitoneal lumbotomy. The mechanism of lesion formation and epidemiologic characteristics were recorded. Clinical and quality-of-life analyses (visual analog scale [VAS], Oswesty Disability Index [ODI], Short Form 12 [SF-12]) were performed over a minimum observation period of 1 year. Radiologic parameters, including deformity measurements, were recorded at each evaluation. Fusion was analyzed by means of a 1-year monitoring scan. The mean patient age was 38.1 years, and median duration of follow-up was 2.1 years (interquartile range, 1.3-2.9). The distribution of fractures according to the Magerl classification scheme was as follows: A, 64.8%; B, 16.7%; C, 18.5%. At the last follow-up, fusion was considered certain in 57 cases (77%). The mean VAS score was 2.1 ± 1.3, mean ODI was 14.7 ± 8.0, mean SF-12 Physical Component Summary score was 43.2 ± 9.3, and mean SF-12 Mental Component Summary score was 50.8±5.9. Correction of the regional sagittal deformity was significant during the postoperative period, with a mean increase in lordosis of 9.0° (P < 0.0001). The loss of mean correction at the last follow-up (-2.9°) was not significant. Circumferential arthrodesis, including posterior osteosynthesis and physical replacement with an expandable cage and autologous graft, is applicable to the treatment of comminuted lumbar fractures. A high rate of fusion was obtained with significant and long-lasting correction of the sagittal deformity. Functional scores measured at 1 year suggest mild disability. The ODI, SF-12, and VAS scores were positively correlated with fusion at the last follow-up.

Abstract A65: Initiation of pancreatic metaplasia requires ADAM17-mediated autocrine signaling, not paracrine signaling derived from macrophages

Abstract Acinar-to-ductal metaplasia (ADM) has been frequently seen in the damaged pancreatic tissues. It is also associated with PanIN lesions in PDAC samples derived from human and mouse and has been shown to act as a preneoplastic lesion in mice. Therefore, understanding the mechanisms of lesion formation at the earliest phase would provide needed information for studying pancreatic tumorigenesis. Previously, we have shown that EGFR activity is required for metaplastic duct formation and KRas-induced pancreatic tumorigenesis. In addition, a prominent macrophage infiltration has been shown to be important in the early phase of lesion formation. To investigate the origin of EGFR ligands for EGFR activation during ADM formation in vivo, we examined the metaplasia formation by administration of cerulein in the mice with the conditional knockout of a key EGFR ligand sheddase ADAM17 in the pancreas (ADAM17fl/fl;Ptf1aCre/+) or in the myeloid cells (ADAM17fl/fl;LysM-Cre). With 2 weeks cerulein treatment, wild type and ADAM17fl/fl;LysM-Cre mice showed a similar degree of metaplastic and fibrotic response. However, the mice with ADAM17-null pancreas displayed significant protection from chronic pancreatitis induced by cerulein, including a lack of significant macrophage infiltration, making the analysis of any additional contribution from macrophage derived EGFR ligands. To remedy this, we conditionally knocked out HB-EGF (Heparin-binding EGF-like growth factor) one of the most robustly expressed EGFR ligands in macrophages using LysM-Cre. We examined cerulein-induced metaplasia in HB-EGFfl/fl;LysM-Cre mice. Compared to wild type mice, HB-EGFfl/fl;LysM-Cre mice showed a similar degree of metaplastic and fibrotic response and a decrease in cell proliferation; moreover, myeloid cell-specific ablation of HB-EGF dramatically delayed the healing and the restoration of normal pancreatic epithelium after cessation of cerulein treatment. These results indicate that an ADAM17/EGFR ligand/EGFR autocrine loop derived from pancreatic parenchymal cells is required for metaplastic duct formation, and macrophage-derived HBEGF acting in a paracrine fashion contributes to cell survival and tissue remodeling. Citation Format: Hui-Ju Wen, Howard C. Crawford.{Authors}. Initiation of pancreatic metaplasia requires ADAM17-mediated autocrine signaling, not paracrine signaling derived from macrophages. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A65.

Radiation-induced damage to cellular DNA: Chemical nature and mechanisms of lesion formation

This mini-review focuses on the recent identification of several novel radiation-induced single and tandem modifications in cellular DNA. For this purpose accurate high-performance electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) was applied allowing their quantitative measurement and unambiguous characterization. Exposure of human cells to gamma rays led to the formation of several modified bases arising from the rearrangement of the pyrimidine ring of thymine, cytosine and 5-methylcytosine subsequent to initial addition of an hydroxyl radical (•OH) to the 5,6-ethylenic bond. In addition, 5-hydroxymethylcytosine, an novel epigenetic mark, and 5-formylcytosine, were found to be generated consecutively to •OH-mediated hydrogen abstraction from the methyl group of 5-methylcytosine. Relevant mechanistic information on one-oxidation reactions of cellular DNA was also gained from the detection of 5-hydroxycytosine and guanine-thymine intra-strand adducts whose formation is rationalized by the generation of related base radical cation. Attempts to search for the radiation-induced formation of purine 5′,8-cyclo-2′-deoxyribonucleosides were unsuccessful with the exception of trace amounts of (5′S)-5′,8-cyclo-2′-deoxyadenosine.

Book Review: Toxicologic Pathology, Nonclinical Safety Assessment, Edited by Sahota PS, Popp JA, Hardisty JF, and Gopinath C, CRC Press, 1,015 pages, 158 color illustrations, 43 tables, 2013. Hardback version (ISBN 978-1-4398-7210-9; $259.95) and ebook version (ISBN 978-1-4398-7212-3; $181.97).

Various chemicals are used as foods, personal care products and prescription drugs. The effects of many of these chemicals on our health have not been clear, yet we may be exposed to them while manufacturing, using and disposing of them. In general, the goal of toxicologic pathologists is to understand both what the effects of these chemicals and new candidate drugs are and at what levels of exposure they may become hazardous to humans. Recently, some books have been published on the subjects of preclinical histopathology and toxicology, but none have been like the new book edited by Drs. Sahota, Popp, Hardisty and Gopinath (Fig. 1). These editors have contributed to the academic areas of toxicology and toxicologic pathology for many years. Many scientists must know them and collaborate with them in this field worldwide. It could be said that this is the most practical textbook directly available for toxicological research that has been published in recent years. Also, for regulatory scientists and basic researchers involved in drug safety evaluation in government and academic areas, this book will provide valuable information to their work. Fig. 1. This book was prepared by a group of 50 experienced scientists from all over the world. Divided into two sections, it systematically assists pathologists in making a determination concerning the origin and potential importance of a lesion and its relevance for assessing human risk. The first section includes eight chapters for pathologists in areas that are important for effective interaction with many non-pathologists involved in drug development: regulatory issues, general toxicity studies, toxicokinetics, clinical pathology, routine toxicologic pathology, digital imaging, toxicogenomics, and historical control data of laboratory animals. The second section is made up of 18 organ-based chapters (gastrointestinal, respiratory, urinary, hematopoietic, lymphoid, cardiovascular, reproductive, and nervous systems, liver, gallbladder, exocrine pancreas, bone, muscle, tooth, endocrine glands, mammary glands, skin, and special senses). Each section includes embryology, comparative biology, gross and microscopic anatomy, light and electron microscopic descriptions of pathological lesions, mechanism of lesion formation, expected clinical pathology including the biomarkers and/or relevance of chemical-induced lesions to humans. Toxicological lesions of laboratory animals (rats, mice, dogs, monkeys, rabbits, and/or minipigs) are covered in this book. Additionally, all of the over 150 images are in full color and of high quality. Most illustrations exhibit features seen in conventional hematoxylin and eosin–stained tissue sections, although where relevant selected special stains, immunohistochemical stains and electron microscopic figures are included. A minor disappointment is that the total number of figures depends on the chapters, with eight chapters containing less than 10 figures each; however, there are many cases in which multiple illustrations are provided. This book will be a highly valuable aid for toxicologic pathologists working in pharmaceutical drug research at all stages of their training or career. Also, it has been crafted to assist students and residents by serving as a resource that can effectively be used as a ready reference next to the microscope. In order to meet the increasing demand to verify the quality of pathological and toxicological assessments in safety testing for chemicals, three board certification systems have been established in Japan in independent categories of science: one for toxicologic pathologists by the Japanese Society of Toxicologic Pathology (JSTP), one for veterinary pathologists by the Japanese College of Veterinary Pathologists (JCVP), and one for toxicologists by the Japanese Society of Toxicology (JST). This book will be the best text for candidates taking certificate examinations. There are several purchasing options available to readers for this textbook, such as the hardback version, ebook version (full), ebook rental version (6 or 12 months) and PDF version of each chapter ($20.00 for 72 hrs access). Please check the following website for details: http://www.crcpress.com/product/isbn/9781439872109#. While the hard-copy format is useful, searching may be more efficient and comprehensive in the ebook version for readers who want to be able to use the book anytime and anywhere (even in his/her house or while commuting). This really provides advantages to readers. In summary, this is an excellent and very relevant textbook for all new and practicing toxicologic pathologists and indeed, anyone involved in generating, interpreting or reviewing chemical-induced pathological data. The author of this review thoroughly recommends this book for toxicologic pathologists, toxicologists and regulators working with drug and other chemical safety in Japan. It will be a must-have reference book in this scientific field.

The mechanism of lesion formation by focused ultrasound ablation catheter for treatment of atrial fibrillation

The application of therapeutic ultrasound for the treatment of atrial fibrillation (AF) is investigated. The results of theoretical and experimental investigation of ultrasound ablation catheter are presented. The major components of the catheter are the high power cylindrical piezoelectric element and parabolic balloon reflector. Thermal elevation in the ostia of pulmonary veins is achieved by focusing the ultrasound beam in shape of a torus that transverses the myocardial tissue. High intensity ultrasound heating in the focal zone results in a lesion surrounding the pulmonary veins that creates an electrical conduction blocks and relief from AF symptoms. The success of the ablation procedure largely depends on the correct choice of reflector geometry and ultrasonic power. We present a theoretical model of the catheter's acoustic field and bioheat transfer modeling of cardiac lesions. The application of an empirically derived relation between lesion formation and acoustic power is shown to correlate with the experimental data. Developed control methods combine the knowledge of theoretical acoustics and the thermal lesion formation simulations with experiment and thereby establish rigorous dosimetry that contributes to a safe and effective ultrasound ablation procedure.

Differential effects of decoy chemokine (7ND) gene therapy on acute, biphasic and chronic autoimmune encephalomyelitis: Implication for pathomechanisms of lesion formation

Multiple sclerosis (MS) exhibits several clinical subtypes such as the relapsing–remitting (RR) and secondary progressive (SP) forms. In accordance with this, formation of demyelinating plaques in the central nervous system (CNS) occurs by different mechanisms. In the present study, we induced acute, biphasic and chronic (RR or SP) EAE in rats and examined the effects of decoy chemokine (7ND) gene therapy, which inhibits the migration of macrophages, to address the above issue. Interestingly, it was demonstrated that the clinical signs of acute EAE and the first attack of biphasic EAE were minimally affected, whereas chronic EAE and the relapse of biphasic EAE were completely suppressed with 7ND treatment. In the CNS, the number of infiltrating macrophages was reduced in all the stages of the three types of EAE. These findings suggest that in acute EAE and in the first attack of biphasic EAE, where anti-macrophage migration therapy was almost ineffective, pathogenic T cells are mainly involved in lesion formation. In contrast, the relapse of biphasic EAE and chronic EAE macrophages play a major role in the disease process. Thus, the mechanisms of lesion formation are not uniform and immunotherapy should be performed on the basis of information about the pathomechanisms of autoimmune diseases.

Mechanisms of lesion formation in high intensity focused ultrasound therapy

The lesions generated by high intensity ultrasound were studied in transparent tissue phantoms premixed with and without ultrasound contrast agents (UCA) at 1.1- and 3.5-MHz acoustic waves. Generation of small bubbles was observed at the very beginning of exposure, whereas cigar-shaped thermal lesions began to form at the focus after a delay. After further heating, boiling occurred and changed the lesion to tadpole-shape, with advancement toward the transducer. Broadband noise was detected in phantoms with UCA initially. UCA also lowered the pressure threshold and enlarged the lesion. Although thermal and cavitation effects are believed to be both important in lesion formation, tadpole-shaped transformation results from boiling activity.

11. Allergic and immunologic diseases of the skin

Many skin diseases have an inflammatory or immune component, and anti-inflammatory drugs comprise a major portion of a dermatologist's therapeutic armamentarium. Although causes of most of these diseases remain obscure, mechanisms of lesion formation and explanations for symptoms are increasingly well documented. These developments, coupled with the expected availability of novel selective immunomodulatory agents, herald a new era for immunodermatology. Patients with psoriasis, allergic contact dermatitis, atopic dermatitis, urticaria, and autoantibody-mediated blistering diseases are among those who are likely to benefit from advances in the understanding of disease pathogenesis and the emergence of immunotherapeutics. (J Allergy Clin Immunol 2003;111:S560-70.)

Epicardial radiofrequency ablation of ventricular myocardium: mechanisms of lesion formation and damage to adjacent structures

Epicardial radiofrequency ablation of ventricular myocardium: mechanisms of lesion formation and damage to adjacent structures

Induction of Atypical Ductal Hyperplasia in Mouse Mammary Gland Organ Culture

Induction of Atypical Ductal Hyperplasia in Mouse Mammary Gland Organ Culture

Gene Expression and Tibial Dyschondroplasia

Tibial dyschondroplasia (TD) is a skeletal deformity associated with rapid growth in a number of avian species. The disease is the result of a disruption in the cascade of events that occur in the epiphyseal growth plate. Whereas the incidence of TD is susceptible to genetic selection, no specific genetic defect has been identified. Although there are extensive data describing the morphological and biochemical characteristics of the lesion, the mechanism of lesion formation is unknown. However, naturally occurring or induced genetic mutations in other species can provide important clues to possible mechanisms responsible for lesion development. Disruption of normal chondrocyte differentiation by constitutive activation of the parathyroid hormone/parathyroid hormone-related peptide (PTH/PTHrP) receptor, inactivation of the fibroblast growth factor receptor-3 (FGFR-3) receptor, and blocking vascular endothelial growth factor (VEGF) signaling all result in lesions that resemble TD. Impairment of vascular penetration due to the ablation of matrix metalloproteinase-9 (MMP-9) or tartrate-resistant acid phosphatase (TRAP) activity also results in similar cartilage abnormalities. We have integrated these observations with our current knowledge of TD to describe a hypothesis for the sequence of events responsible for the development of tibial dyschondroplastic lesions.

The pathology of murine coxsackievirus B3 myocarditis: An in situ hybridization study

Histologic changes and localization of viral RNA synthesis were studied in cardiac sections of outbred immunocompetent (CD-1) and athymic (nude) Swiss mice infected with a myocardiac variant of coxsackievirus B3 (CVB3). Viral effects in heart tissue sections progressed through four phases in both models. The first phase consisted of histologically normal myocardium with scattered myocytes which were strongly positive for nascent viral RNA by in situ hybridization using a negative strand CVB3 RNA probe. These cells often appeared in clusters. The second phase consisted of focal myocarditic lesions with histologic changes of cell necrosis with accompanying lymphocytes and histiocytes; the in situ hybridization signal was moderate at this stage. Phase 3 demonstrated relatively large lesions with inflammatory infiltrate without recognizable myocyte cytoplasm; these lesions showed a weak hybridization signal. Healed (phase 4) lesions were negative for viral RNA by in situ hybridization and histologically were composed of fibroblast infiltrates with a sparse histiocyte infiltrate. RNA sequences from the enteroviral VP-1 region were detectable by polymerase chain reaction in phases 1 through 3 and some phase 4 lesions in both models. Although the time course of lesion formation was different, lesion development progressed through similar recognizable phasesin both murine models. There is an intimate association between presence of virus and myocarditis lesions in two diverse murine models, indicating that the mechanism of lesion formation is most likely a cytopathic viral effect and not an autoimmune phenomenon. The lack of hybridization signal over healed lesions is most likely attributable to lack of sensitivity of the procedure.

Observation of morphological relationships between angiopathic blood vessels and degenerative neurites in Alzheimer's disease

Two main techniques are used to stain the three types of brain lesions characteristic of Alzheimer's disease: Neurofibrillary tangles (NFT), senile plaques (SP) and congophilic angiopathy. Thioflavine-S is an histochemical marker of the amyloid substance located essentially in the central core of senile plaques and in the walls of the pathological blood vessels. Specific antibodies against Paired Helical Filaments (PHF), the ultrastructural elements of NFT, reveal neuron cell bodies with NFT and numerous dystrophic neurites, mostly around neuritic plaques. Using simultaneous histochemical and immunohistochemical labellings on the same tissue sections of Alzheimer cortex (association cortex and hippocampus), the different lesions were stained with great sensitivity and specificity. Moreover, an unusual morphological relationship between two types of lesions was detected in two Alzheimer brains with prominent congophilic angiopathy: we observed a well marked concentration of dystrophic neurites, immunolabelled with anti-PHF, around blood vessels with Thioflavine-S stained amyloid angiopathy. These lesions were distributed like a sleeve around 1/10 of dyshoric or congophilic blood vessels. The significance of such lesions is unknown but they probably represent a step of the pathogenesis of Alzheimer brain lesions and may explain the general mechanism of lesion formation in Alzheimer's disease.

Cholesterol in the plasma membrane of uterine epithelial cells: A freeze-fracture cytochemical study with digitonin

Freeze-fracture cytochemistry with digitonin has been used to examine the cholesterol content of the plasma membrane of uterine epithelial cells during the early stages of pregnancy in the rat. Lesions caused by digitonin complexing with cholesterol were seen on both lateral and apical portions of the membrane but tight junctions and desmosomes were lesion-free. Compared with day 1 of pregnancy, lesions on the apical plasma membrane were much more extensive and some were of different morphology on day 6 - the day of blastocyst implantation. We consider mechanisms of lesion formation and interpret the results to indicate a higher content and perhaps a different organization of cholesterol in the apical plasma membrane on day 6 of pregnancy. We also suggest how this increase may occur.

Freeze-fracture cytochemistry with polymyxin B. A study on the plasma membrane of uterine epithelial cells.

The peptide antibiotic polymyxin B, has been used as a label in a freeze-fracture cytochemical study of anionic phospholipids in the plasma membrane of uterine epithelial cells. The reagent produces mainly circular lesions visible on both P and E faces of fractured membranes. IMPs are found to be associated with lesions and we consider the possible association of integral membrane proteins with anionic phospholipids as well as the mechanisms of lesion formation.

Kinetics of enamel dissolution during formation of incipient caries-like lesions

The kinetics of enamel dissolution and mechanism of lesion formation were studied using a simple in vitro chemical method for producing lesions in human dental enamel comparable to natural incipient carious lesions, known as white spots. Enamel was exposed to a decalcification medium consisting of an aqueous solution of an acidic buffer plus a soluble organic polymer, hydroxyethyl cellulose, which protects the surface from acid attack during subsurface dissolution. The extent of the lesion was measured by analysis of the decalcification medium for calcium and phosphate dissolved from enamel and by microscopic examination of sections from the enamel. Enamel dissolution was investigated by a differential method to give the initial rate and by an integral method to give the approach to equilibrium. Five buffer acids (chloroacetic, dichloroacetic, lactic, formic, and acetic) were examined at pH's of 3–6 and buffer concentrations of 0–0.5 M. The initial rate increased with decreasing pH, decreasing acid dissociation constant, and nearly lineraly with increasing buffer concentration. The initial rate of enamel dissolution during white spot formation was expressed quantitatively in a single equation for all these acids in terms of undissociated acid concentration, hydrogen ion concentration, acid dissociation constant, and the dissociation constant of the acid anion complex of calcium ion. This equation is similar to that for surface dissolution demonstrating the interrelation of the two processes. The rate of enamel dissolution is controlled principally by the rate of diffusion of undissociated acid into enamel and to a lesser extent by pH and acid strength. Free calcium ion inhibits dissolution and can affect even the initial dissolution rate. Some acids complex calcium, although weakly, enough to eliminate this inhibition and are somewhat more effective in white spot formation.