Initiating Event (initiating + event)

Distribution by Scientific Domains

Selected Abstracts

Initiating events and independent protection layers

John F. Murphy
Abstract Layer of protection analysis (LOPA) is a semiquantitative tool for analyzing and assessing process risk. The tool has grown greatly in popularity and usefulness since the publication of the first CCPS/AIChE guidebook on the subject, Layer of Protection Analysis, Simplified Process Risk Assessment (LOPA). This article is a summary of a new CCPS guideline book that includes the following: Initiating events (IEs). Independent protection layers (IPLs). Criteria for identifying the value of each prospective IE and prospective IPL. Example IE and IPL data. This book is a necessary reference for those applying the LOPA methodology. 2009 American Institute of Chemical Engineers Process Saf Prog, 2009 [source]

Apoptotic and Anti-Apoptotic Synaptic Signaling Mechanisms

Mark P. Mattson
Although several prominent morphological features of apoptosis are evident in the cell body (e.g., cell shrinkage, membrane blebbing, and nuclear DNA condensation and fragmentation) the biochemical and molecular cascades that constitute the cell death machinery can be engaged in synaptic terminals and neurites. Initiating events such as oxyradical production and calcium influx, and effector processes such as Par-4 production, mitochondrial alterations and caspase activation, can be induced in synapses and neurites. Several prominent signal transduction pathways in synaptic terminals play important roles in either promoting or preventing neuronal death in physiological and pathological conditions. For example, activation of glutamate receptors in postsynaptic spines can induce neuronal apoptosis, whereas local activation of neurotrophic factor receptors in presynaptic terminals can prevent neuronal death. Factors capable of inducing nuclear chromatin condensation and fragmentation can be produced locally in synaptic terminals and neurites, and may propogate to the cell body. Recent findings suggest that, beyond their roles in inducing or preventing cell death, apoptotic and anti-apoptotic cascades play roles in synaptic plasticity (structural remodelling and long-term functional changes). For example, caspase activation results in proteolysis of glutamate receptor (AMPA) subunits, which results in altered neuronal responsivity to glutamate. Activation of neurotrophic factor receptors in synaptic terminals can result in local changes in energy metabolism and calcium homeostasis, and can induce long-term changes in synaptic transmission. The emerging data therefore suggest that synapses can be considered as autonomous compartments in which both pro- and anti-apoptotic signaling pathways are activated resulting in structural and functional changes in neuronal circuits. A better understanding of such synaptic signaling mechanisms may reveal novel approaches for preventing and treating an array of neurodegenerative conditions that are initiated by perturbed synaptic homeostasis. [source]

Adverse outcome pathways: A conceptual framework to support ecotoxicology research and risk assessment

Gerald T. Ankley
Abstract Ecological risk assessors face increasing demands to assess more chemicals, with greater speed and accuracy, and to do so using fewer resources and experimental animals. New approaches in biological and computational sciences may be able to generate mechanistic information that could help in meeting these challenges. However, to use mechanistic data to support chemical assessments, there is a need for effective translation of this information into endpoints meaningful to ecological risk,effects on survival, development, and reproduction in individual organisms and, by extension, impacts on populations. Here we discuss a framework designed for this purpose, the adverse outcome pathway (AOP). An AOP is a conceptual construct that portrays existing knowledge concerning the linkage between a direct molecular initiating event and an adverse outcome at a biological level of organization relevant to risk assessment. The practical utility of AOPs for ecological risk assessment of chemicals is illustrated using five case examples. The examples demonstrate how the AOP concept can focus toxicity testing in terms of species and endpoint selection, enhance across-chemical extrapolation, and support prediction of mixture effects. The examples also show how AOPs facilitate use of molecular or biochemical endpoints (sometimes referred to as biomarkers) for forecasting chemical impacts on individuals and populations. In the concluding sections of the paper, we discuss how AOPs can help to guide research that supports chemical risk assessments and advocate for the incorporation of this approach into a broader systems biology framework. Environ. Toxicol. Chem. 2010;29:730,741. 2009 SETAC [source]

Molecular versatility of antibodies

Henry Metzger
Summary: As immunology developed into a discrete discipline, the principal experimental efforts were directed towards uncovering the molecular basis of the specificity exhibited by antibodies and the mechanism by which antigens induced their production. Less attention was given to how antibodies carry out some of their effector functions, although this subject presents an interesting protein-chemical and evolutionary problem; that is, how does a family of proteins that can bind a virtually infinite variety of ligands, many of which the species producing that protein has never encountered, reproducibly initiate an appropriate response? The experimental data persuasively suggested that aggregation of the antibody was a necessary and likely sufficient initiating event, but this only begged the question: how does aggregation induce a response? I used the IgE:mast cell system as a paradigm to investigate this subject. Data from our own group and from many others led to a molecular model that appears to explain how a cell ,senses' that antigen has reacted with the IgE. The model is directly applicable to one of the fundamental questions cited above, i.e. the mechanism by which antigens induce the production of antibodies. Although the model is conceptually simple, incorporating the actual molecular events into a quantitatively accurate scheme represents an enormous challenge. [source]

Induction of hepatic differentiation of mouse bone marrow stromal stem cells by the histone deacetylase inhibitor VPA

Ye Chen
Abstract Bone marrow stromal stem cells (BMSSCs) may have potential to differentiate in vitro and in vivo into hepatocytes. Here, we investigated the effects of valproic acid (VPA) involved in epigenetic modification, a direct inhibitor of histone deacetylase, on hepatic differentiation of mouse BMSSCs. Following the treatment of 2.5 mM VPA for 72 hrs, the in vitro expanded, highly purified and functionally active mouse BMSSCs from bone marrow were either exposed to some well-defined cytokines and growth factors in a sequential way (fibroblast growth factor-4 [FGF-4], followed by HGF, and HGF + OSM + ITS + dexamethasone, resembling the order of secretion during liver embryogenesis) or transplanted (caudal vein) in mice submitted to a protocol of chronic injury (chronic i.p. injection of CCl4). Additional exposure of the cells to VPA considerably improved the in vitro differentiation, as demonstrated by a more homogeneous cell population exhibited epithelial morphology, increasing expression of hepatic special genes and enhanced hepatic functions. Further more, in vivo results indicate that the pre-treatment of VPA significantly increased the homing efficiency of BMSSCs to the site of liver injury and, additionally, for supporting hepatic differentiation as well as in vitro. We have demonstrated the usefulness of VPA in the transdifferentiation of BMSSCs into hepatocytes both in vitro and in vivo, and regulation of fibroblast growth factor receptors (FGFRs) and c-Met gene expression through post-translational modification of core histones might be the primary initiating event for these effects. This mode could be helpful for liver engineering and clinical therapy. [source]

G1 cell cycle regulators in congenital melanocytic nevi.

Comparison with acquired nevi, melanomas
Background:, Congenital nevi are one of the known risk factors for the development of melanoma. However, the magnitude of the risk for both large and small congenital nevi is controversial. Methods:, In order to elucidate the behavior of congenital nevocytes and to define any possible similarities or differences with common nevi and melanomas, we investigated the expression of Ki-67, Rb, p16, cyclin D1, p53 and p21/Waf-1 in 41 congenital nevi, 16 melanomas and 20 acquired common nevi by immunohistochemistry. Results:, Congenital nevi highly expressed p16 (81.82 9.98) but showed limited, if any, reactivity for Ki-67 (1.34% 0.89), Rb (0.76% 0.94), cyclin D1 (0.21% 0.29), p53 (0.54% 0.93) and p21 (0.0609% 0.32). No statistically significant difference was found between giant and nongiant congenital nevi and between congenital and common nevi for any of the markers. The expression of p16 was significantly higher in congenital nevi than in melanomas (p < 0.0001). On the contrary, the expression of Ki-67, p53, p21, Rb and cyclin D1 was significantly higher in melanomas (p < 0.0001). Conclusion:, Our data regarding the immunohistochemical expression of Rb, p16, p53, cyclin D1 and Ki-67 in congenital nevi indicate that either the alteration of their expression is not an initiating event in melanoma formation or, alternatively, congenital melanocytic nevi may not be the first step in malignant transformation. [source]

Chronic wet cough: Protracted bronchitis, chronic suppurative lung disease and bronchiectasis

A.B. Chang PhD
Abstract The role of persistent and recurrent bacterial infection of the conducting airways (endobronchial infection) in the causation of chronic respiratory symptoms, particularly chronic wet cough, has received very little attention over recent decades other than in the context of cystic fibrosis (CF). This is probably related (at least in part) to the (a) reduction in non-CF bronchiectasis in affluent countries and, (b) intense focus on asthma. In addition failure to characterize endobronchial infections has led to under-recognition and lack of research. The following article describes our current perspective of inter-related endobronchial infections causing chronic wet cough; persistent bacterial bronchitis (PBB), chronic suppurative lung disease (CSLD) and bronchiectasis. In all three conditions, impaired muco-ciliary clearance seems to be the common risk factor that provides organisms the opportunity to colonize the lower airway. Respiratory infections in early childhood would appear to be the most common initiating event but other conditions (e.g., tracheobronchomalacia, neuromuscular disease) increases the risk of bacterial colonization. Clinically these conditions overlap and the eventual diagnosis is evident only with further investigations and long term follow up. However whether these conditions are different conditions or reflect severity as part of a spectrum is yet to be determined. Also misdiagnosis of asthma is common and the diagnostic process is further complicated by the fact that the co-existence of asthma is not uncommon. The principles of managing PBB, CSLD and bronchiectasis are the same. Further work is required to improve recognition, diagnosis and management of these causes of chronic wet cough in children. Pediatr Pulmonol. 2008; 43:519,531. 2008 Wiley-Liss, Inc. [source]

Key issues with implementing LOPA

William Bill Bridges
Abstract This article writen by one of the originators of LOPA, focuses on problems observed with LOPA. One the biggest issues is that organizations use LOPA without following the rules for LOPA, especially the rules related to maintaining, testing, and record-keeping for each independent protection layer (IPL) and for each "optimized" initiating event (IE). Another issue is that many companies and analysts overuse LOPA. The LOPA book authors expected the number of scenarios going to LOPA (after a HAZOP/PHA) would be 1 to 10% (max) of those uncovered in a qualitative analysis (maybe after 100 HAZOP nodes, you would do 1,10 LOPA). A PHA team would recommend (or use) LOPA only if the scenario was too complex for the PHA/HAZOP team. It appears that most companies are using LOPA for every scenario that has a severe consequence; this result in doing LOPA on much more than 10% of the scenarios. Many times, there is weak definition of the consequence that is being avoided, so an independent layer of protection does not always match up well with the consequence. LOPA is also overworked when it is used. Many of us on the original LOPA book authorship considered LOPA a single analyst job, after a PHA/HAZOP. Instead, the trend appears to be that companies (or perhaps their consultants) make LOPA part of the PHA (in situ), therefore involving the whole PHA team. LOPA is used in PHA team settings, which distracts PHA teams from their primary task of brainstorming to identify the accident scenarios that can occur. This article focuses on preventing these problems and also summarizes the many benefits LOPA has produced for the industry. 2010 American Institute of Chemical Engineers Process Saf Prog, 2010 [source]

Matrix metalloproteinase 8 (neutrophil collagenase) in the pathogenesis of abdominal aortic aneurysm,

W. R. W. Wilson
Background: Loss of elastin is the initiating event in abdominal aortic aneurysm (AAA) formation, whereas loss of collagen is required for continued expansion. The elastolytic matrix metalloproteinases (MMPs) 2 and 9 are well described, but the source of excessive collagenolysis remains undefined. The aim of this study was to determine the expression of MMP-8, a potent type I collagenase, in normal aorta and AAA. Methods: Infrarenal aortic biopsies were taken from 40 AAA and ten age-matched normal aortas. The concentrations of MMP-8 protein and its inhibitors, tissue inhibitor of metalloproteinase (TIMP) 1 and TIMP-2, were quantified by enzyme-linked immunosorbent assay. Immunohistochemistry was used to localize MMP-8 expression. Results: MMP-8 concentrations were significantly raised in AAA compared with normal aorta (active MMP-8: 45 versus 05 ng per mg protein, P < 0001; total MMP-8: 166 versus 28 ng per mg protein, P < 0001). Levels of TIMP-1 and TIMP-2 were significantly lower in AAA than in normal aortic samples (TIMP-1: 1422 versus 3028 ng per mg protein; P = 0010; TIMP-2: 92 versus 331 ng per mg protein, P < 0001). Immunohistochemistry localized MMP-8 to mesenchymal cells within the adventitia of the aortic wall. Conclusion: The high concentration of MMP-8 in aortic aneurysms represents a potent pathway for collagen degradation, and hence aneurysm formation and expansion. Copyright 2005 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd. [source]

Myeloperoxidase and chlorinated peptides in osteoarthritis: potential biomarkers of the disease

Marla J. Steinbeck
Abstract Osteoarthritis (OA) is a disabling condition in which multiple initiating events or conditions (heritable and nonheritable) result in eventual loss of articular cartilage. However, the etiology of OA remains poorly understood, and diagnosis of early disease is difficult due to the lack of specific identifiers. Recent literature suggests that a series of inflammatory processes may be involved in initiating and propagating OA. We hypothesized that products of neutrophils and macrophages, namely myeloperoxidase (MPO), a specific enzyme responsible for the production of both highly reactive hypochlorous acid (HOCl) and chlorine gas (Cl2) and chlorinated peptides, may be present in the synovial fluid of patients with OA. We examined the synovial fluid from 30 patients to identify and profile the presence of MPO. We divided the samples into three groups using radiographic and clinical assessment: (1) control, patients with acute knee injury with no history of OA and no radiographic evidence of OA; (2) early OA, patients with a mild OA based on radiographs; and (3) late OA, patients with a longstanding history of OA and with radiographic evidence of complete joint loss. Patients with early OA demonstrated significantly elevated levels of MPO. We also demonstrated the presence of HOCl and Cl2 modified proteins (Cl-peptides) in early OA synovial fluid samples by liquid chromatography and mass spectrometry. Patients in the control and advanced OA groups demonstrated little elevation in MPO levels and Cl-peptides were undetectable. These results indicate that MPO and Cl-peptides may serve as diagnostic markers for the detection of early OA. 2007 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 25:1128,1135, 2007 [source]