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Progression Of Type 1 Diabetes

On Type 1 Diabetes Mellitus Pathogenesis

On Type 1 Diabetes Mellitus Pathogenesis

Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, Aghia Sophia Childrens Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece Correspondence should be addressed to C Kanaka-Gantenbein: chriskan{at}med.uoa.gr Type 1 diabetes mellitus (T1DM) results from the autoimmune destruction of cells of the endocrine pancreas. Pathogenesis of T1DM is different from that of type 2 diabetes mellitus, where both insulin resistance and reduced secretion of insulin by the cells play a synergistic role. We will present genetic, environmental and immunologic factors that destroy cells of the endocrine pancreas and lead to insulin deficiency. The process of autoimmune destruction takes place in genetically susceptible individuals under the triggering effect of one or more environmental factors and usually progresses over a period of many months to years, during which period patients are asymptomatic and euglycemic, but positive for relevant autoantibodies. Symptomatic hyperglycemia and frank diabetes occur after a long latency period, which reflects the large percentage of cells that need to be destroyed before overt diabetes become evident. Type 1 diabetes mellitus (T1DM) represents only around 10% of the diabetes cases worldwide, but occurs with increasing incidence much earlier in life. T1DM results from the autoimmune destruction of cells of the endocrine pancreas. A small percentage of affected patients (<10%) are classified as type 1B, with no evidence of autoimmunity and the pathogenesis in these cases is considered idiopathic ( 1 , 2 ). The aim of this comprehensive review is to present updated information on the pathogenesis of T1DM. We will present genetic, environmental and immunologic factors ( Table 1 ) that Continue reading >>

Type 1 Diabetes Cohort Studies

Type 1 Diabetes Cohort Studies

Type 1 diabetes is one of the most common chronic disease in childhood and adolescence and its incidence is increasing worlwide. The development of type 1 diabetes is preceded by autoantibodies against pancreatic islet beta-cell antigens. Progression rate to diabetes after the development of islet autoantibodies is highly variable ranging from few months to years. However the aetiology of type 1 diabetes is still unknown. In the light of the rising incidence of type 1 diabetes a main research area of the Institute of Diabetes Research is to determine the natural history of type 1 diabetes and identify genetic and environmental determinants of islet autoimmunity and progression from islet autoimmunity to diabetes. Therefore we have initiated several Birth Cohort Studies (BABYDIAB, BABYDIET, TEDDY) since 1989 with a prospective intensive follow-up from birth of children with an increased risk (family history and/or genetic susceptibility), a Puberty Cohort Study with a prospective follow-up of children with an increased risk from age 6 to 18 years (TeenDiab), and a Bavarian diabetes incidence cohort of children and adolescents aged 0-20 years (DiMelli). The Munich Diabetes Bioresource collects biomaterial to investigate immunological and genetic factors in the pathogenesis of type 1 diabetes. Further information about the Type 1 Diabetes Cohorts Studies: The BABYDIAB study is the first prospective cohort study that examines the natural history of islet autoimmunity in 1650 children of patients with type 1 diabetes since 1989. BABYDIAB aimed to determine when islet autoantibodies first appear, which genetic and environmental factors influence their development, and what islet autoantibody characteristics were most associated with progression to type 1 diabetes. Blood samp Continue reading >>

Immunotherapy Shows Promise In Treatment Of Type 1 Diabetes

Immunotherapy Shows Promise In Treatment Of Type 1 Diabetes

Around 1.25 million Americans are living with type 1 diabetes and 40,000 new cases are detected each year. In this condition body’s own immune system attacks and damages the insulin-producing β-cells inside the pancreas leading to impaired glucose metabolism in the body. There is no other treatment for this condition than regular painful insulin injections to maintain the normal insulin levels in the body. Type 1 diabetes is currently considered to be incurable. In a landmark study, researchers compared immunotherapy based treatment for type 1 diabetes with placebo and showed that the novel immune treatment can stop the progression of type 1 diabetes. The immune therapy was also deemed safe among subjects. The study was published in the journal Science Translational Medicine. Mohammad Alhadj Ali and colleagues for this study included 27 people who were within 100 days of being diagnosed with type 1 diabetes and randomly divided them into two groups - to receive injections of either placebo or immunotherapy at two or four week intervals for six months. The new immune therapy they have developed is made to distract the T cells of the immune system that normally destroy the beta cells of the pancreas. It works by mimicking a portion of proinsulin peptide. Thus the immune cells attack this imposter and leave the insulin secreted intact. The injected drug also trains the T cells to recognize them as harmless so that they do not attack the beta cells that make proinsulin in the body. Therapy showed no toxic side effects and the progression of beta cell destruction was prevented to a great extent with this therapy not only during the trial but also six months beyond that. All eight subjects who received the placebo injection needed to increase their insulin doses over the y Continue reading >>

The Interplay Of Autoimmunity And Insulin Resistance In Type 1 Diabetes

The Interplay Of Autoimmunity And Insulin Resistance In Type 1 Diabetes

Specialty: Pediatrics, Endocrinology, Immunology Institution: Section of Endocrinology, Department of Pediatrics, University of Colorado Denver and Children's Hospital Colorado Address: Aurora, Colorado, 80045, United States Author: Marian Rewers Specialty: Endocrinology, Pediatrics, Immunology Institution: Department of Pediatrics, University of Colorado School of Medicine Address: Aurora, Colorado, 80045, United States Institution: Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine Address: Aurora, Colorado, 80045, United States Author: Melanie Cree Green Specialty: Endocrinology, Pediatrics, Immunology Institution: Department of Pediatrics, University of Colorado School of Medicine Address: Aurora, Colorado, 80045, United States Institution: Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine Address: Aurora, Colorado, 80045, United States Abstract: Type 1 diabetes (T1D) is a common chronic disease characterized by selective autoimmune destruction of the pancreatic islet beta cells and subsequent dependence on exogenous insulin. Certain alleles including the high-risk HLA genotype, HLA-DR3-DQ2/DR4-DQ8, place individuals at increased risk of developing T1D. Autoantibodies to beta cell antigens are used in the diagnosis of T1D, and studies have shown that they can be used to predict risk of developing T1D in first degree relatives of probands. The annual global incidence of T1D is increasing by 3-5% per year. Many environmental factors have been implicated in the rising incidence of T1D. Proponents of the accelerator hypothesis argue that T1D and type 2 diabetes (T2D) are the same disorder of insulin resistance, although with different genetic backgrounds. While insulin resistance is a recognized ha Continue reading >>

Is It Possible To Prevent Or Delay Type 1 Diabetes?

Is It Possible To Prevent Or Delay Type 1 Diabetes?

A partnership between JDRF and Janssen Pharmaceuticals seeks ways to intercept the disease before it progresses. What if there was a way to determine exactly who would develop type 1 diabetes (T1D) and doctors could intervene to prevent it altogether or at least delay the onset by years? JDRF, a leading research advocacy organization, and the Disease Interception Accelerator (DIA) group of Janssen Pharmaceuticals announced a joint venture earlier this year to take on this challenge.1 The goal is to identify the root cause of T1D and intercept its progression to disease before symptoms arise. There have been many questions about the actual cause of T1D. Work in recent years suggests there is a window of opportunity to stop or delay the disease before the onset of clinical symptoms of the disease.2,3 The autoimmune response directed against beta cells is suggested to be secondary to tissue damage and unrelated to disease pathogenesis.4 The presence of antibodies against the islets of Langerhans that were detected in the serum of patients diagnosed with T1D, but not in healthy individuals, led to the suggestion of the autoimmune etiology of T1D.4 Although T1D has been referred to by many names, such as juvenile diabetes or insulin-dependent diabetes, the treatment has always been the same: insulin. T1D is a pancreatic beta cell specific disease that results in absolute insulin deficiency.4,5 Data from the United Kingdom suggest life expectancy of adults with T1D is reduced by up to 13 years.6,7 The symptoms of T1D are similar to type 2 diabetes, including frequent urination and feeling thirsty, hungry, or tired. Additionally, with T1D, there is the possibility of sudden weight loss, nausea and vomiting from the build-up of ketones in the body, and diabetic ketoacidosis.8 A Continue reading >>

Trial Aims To 'stall' Type 1 Diabetes

Trial Aims To 'stall' Type 1 Diabetes

These are external links and will open in a new window Media playback is unsupported on your device Media captionType 1 diabetes trials give hope for "a more normal life", as Fergus Walsh reports A trial has begun in London of an immunotherapy treatment aimed at halting the progression of type 1 diabetes. Twenty-four volunteers are being recruited for the study in the Biomedical Research Centre at Guy's hospital. In type 1 diabetes the immune system destroys the cells that make insulin, the hormone needed to control blood sugar levels. The hope is the treatment will re-train or reset the immune system. All the patients being recruited have been recently diagnosed with type 1 and so still have some remaining beta cells - which are found in the pancreas and are responsible for making insulin. Prof Mark Peakman, King's College London, who is leading the trial, said: "If we get in with this therapy early enough we may be able to protect the beta cells that remain in those patients so that they continue to make some of their own insulin which would give them better control of blood glucose and mean their risk of future complications of diabetes is reduced." Natalie Worrall from Kent, aged 20, was the first volunteer to receive the MultiPepT1De injection. Natalie, who was diagnosed with type 1 diabetes in December 2014 and needs to inject insulin four times a day in order to keep her blood glucose levels stable, said: "I'm hoping the injections will slow down the progression of my diabetes so that I can live a more normal life." Another trial participant, Aleix Rowlandson, aged 18, from Lancashire, was diagnosed with type 1 in September 2015. She said: "It was a big shock when I found out I had type 1. I was keen to volunteer for something that may help find a cure at some p Continue reading >>

The Metabolic Progression To Type 1 Diabetes As Indicated By Serial Oral Glucose Tolerance Testing In The Diabetes Prevention Trialtype 1

The Metabolic Progression To Type 1 Diabetes As Indicated By Serial Oral Glucose Tolerance Testing In The Diabetes Prevention Trialtype 1

The Metabolic Progression to Type 1 Diabetes as Indicated by Serial Oral Glucose Tolerance Testing in the Diabetes Prevention TrialType 1 Jay M. Sosenko ,1 Jay S. Skyler ,1 Kevan C. Herold ,2 Jerry P. Palmer ,3 and the Type 1 Diabetes TrialNet and Diabetes Prevention TrialType 1 Study Groups 3VA Puget Sound Health Care System, Division of Endocrinology, Metabolism, and Nutrition, University of Washington, Seattle, Washington 1Division of Endocrinology, University of Miami Miller School of Medicine, Miami, Florida 2Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 3VA Puget Sound Health Care System, Division of Endocrinology, Metabolism, and Nutrition, University of Washington, Seattle, Washington Corresponding author: Jay M. Sosenko, [email protected] . Received 2011 Nov 28; Accepted 2012 Mar 13. Copyright 2012 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See for details. This article has been cited by other articles in PMC. Type 1 diabetes (T1D) is often first recognized when signs and symptoms occur, yet the pathogenetic development of T1D usually begins years before that. Pancreatic autoantibodies commonly become elevated long before diagnosis ( 1 ). Although data indicate that the first-phase insulin response (FPIR) is also abnormal well before diagnosis ( 2 5 ), the development and progression of metabolic abnormalities had not been well characterized until the recent performance of T1D prevention trials ( 6 8 ). The unique designs of these trials provided the opportunity to perform longitudinal studies that have yielded new insights into metabolic changes that occur during the progression t Continue reading >>

Identifying Stages Of Type 1 Diabetes Could Help With Intervention

Identifying Stages Of Type 1 Diabetes Could Help With Intervention

Type 1 diabetes onset is sudden and unexpected. The disease is typically diagnosed during a trip to the emergency room for treatment of dangerously high blood sugars. By then, beta cells have been almost completely destroyed by the immune system. The American Diabetes Association (ADA) and the JDRF want to be able to detect type 1 diabetes earlier in its progression, before the immune system can damage the insulin-secreting cells, and hopefully intervene to prevent the development of the damaging symptoms of type 1 diabetes. “The overall goal is to try to develop approaches that can preserve residual beta cell function, but that means we have to identify risk for type 1 diabetes before substantial amounts of beta cells have been irreversibly destroyed by the immune system. If this earlier stage can be identified with certainty, there can be interventions earlier in the process when there are greater amounts of functioning beta cells to preserve, rather than at the current stage of diagnosis when the overwhelming majority have been destroyed or damaged”, says Lori Laffel, M.D., M.P.H., Chief, Pediatric, Adolescent, and Young Adult Section at Joslin Diabetes Center. The ADA and the JDRF recently released a suggested three-stage classification system for diagnosing type 1 diabetes and clarifying risk. Stage 1 indicates the presence of some autoimmunity. Stage 2 happens when the autoimmunity starts to affect blood sugar levels. Stage 3 is the state at which most people are currently diagnosed, involving symptoms such as excessive thirst, hunger and urination. Investigators hope to use this staging system as a research roadmap, to help investigators better plan intervention strategies. Catching the disease at an early stage requires screening, before individuals start sh Continue reading >>

Diabetes Update: The Untold Story Of Disease Progression

Diabetes Update: The Untold Story Of Disease Progression

CE credit is no longer available for this article. Originally posted March 2001 Pick up the paper. Turn on the radio. Diabetes is rapidly becoming a national epidemic. An estimated 18 million Americans have diabetes—and that number is growing, particularly among children. Certain ethnic groups, such as African-Americans, Hispanics, and Native Americans, have the highest incidence. Among those groups, one in four over the age of 45 will most likely develop diabetes. The Centers for Disease Control and Prevention (CDC) reports that between 1990 and 1998, the incidence of diabetes rose by 70% among people ages 30 - 39; by 40% among those 40 - 49; and by 31% among those 50 - 59. What may be even more disturbing is the percentage of people who don't even know that they have diabetes: About 33% of the population with Type 1 diabetes and up to 55% of people with Type 2 go undiagnosed. Many patients are hyperglycemic for up to six years before finding out they have diabetes. The toll diabetes takes is staggering. It is the leading cause of new cases of adult blindness, end-stage renal disease, and nontraumatic lower extremity amputations. And patients with diabetes have an incidence of cardiovascular morbidity and mortality four times that of non-diabetics. In fact, 65% of patients with Type 2 diabetes will die of a cardiovascular complication. The cost is enormous: $138 billion annually. The average per capita medical expenditure is $10,000 per diabetic patient, vs. $2,700 for the non-diabetic individual. The good news is that complications of diabetes can be limited and its progression slowed with strict control of blood sugar and new treatment protocols. New drugs provide more therapeutic options. Insulin sensitizers, insulin secretagogues, medications that alter the diges Continue reading >>

Type 1 Diabetes: Disease Stratification

Type 1 Diabetes: Disease Stratification

Type 1 diabetes, a disorder characterized by immune-mediated loss of functional pancreatic beta cells, is a disease continuum with specific presymptomatic stages with defined risk of progression to symptomatic disease. Prognostic biomarkers have been developed for disease staging and for stratification of subjects that address the heterogeneity in rate of disease progression. Using biomarkers for stratification of subjects at different stages of type 1 diabetes will enable smaller and shorter intervention clinical trials with greater effect size. Addressing the heterogeneity of the disease will allow precision medicine-based approaches to prevention and interception of presymptomatic stages of disease and treatment and cure of symptomatic disease. 2017 The Author(s) Published by S. Karger AG, Basel Type 1 diabetes (T1D) is a chronic, immune-mediated disease associated with destruction of the insulin-producing beta cells of the islets of the pancreas [ 1 ]. Approximately 40-50% of the risk of disease arises from genetics with the remaining risk arising from poorly defined environmental etiologies. The class I and II human leukocyte antigen (HLA) genes contribute about half of the genetic risk of disease with about 40-50 non-HLA genes accounting for the remainder of genetic risk [ 2 , 3 , 4 ]. The most prominent associated HLA genes are HLA class II haplotypes DRB1*0301-DQB1*0201 (DR3-DQ2) and DRB1*0401-DQB1*0302 (DR4-DQ8) with the highest risk occurring in the heterozygous DR3/4 genotype. Non-HLA genes include INS, CTLA4, PTPN22, and IL2RA in addition to multiple non-HLA SNPs that have been mapped to DNA regulatory sequences of immune cells [ 4 , 5 ]. Several non-HLA susceptibility genes are expressed in human islets, and cytokines can alter their expression in the isle Continue reading >>

Type 1 Diabetes

Type 1 Diabetes

Overview Diabetes is a lifelong condition that causes a person's blood sugar (glucose) level to become too high. The hormone insulin, produced by the pancreas, is responsible for controlling the amount of glucose in the blood. There are two main types of diabetes: type 1 – where the pancreas doesn't produce any insulin type 2 – where the pancreas doesn't produce enough insulin or the body's cells don't react to insulin These pages are about type 1 diabetes. Other types of diabetes are covered separately (read about type 2 diabetes, and gestational diabetes, which affects some women during pregnancy). Symptoms of diabetes Typical symptoms of type 1 diabetes are: feeling very thirsty passing urine more often than usual, particularly at night feeling very tired weight loss and loss of muscle bulk The symptoms of type 1 diabetes usually develop very quickly in young people (over a few days or weeks). In adults, the symptoms often take longer to develop (a few months). Read more about the symptoms of type 1 diabetes. These symptoms occur because the lack of insulin means that glucose stays in the blood and isn’t used as fuel for energy. Your body tries to reduce blood glucose levels by getting rid of the excess glucose in your urine. It's very important for diabetes to be diagnosed as soon as possible, because it will get progressively worse if left untreated. Find your local GP service Read about how type 1 diabetes is diagnosed. Causes of type 1 diabetes Type 1 diabetes is an autoimmune condition, which means your immune system attacks healthy body tissue by mistake. In this case, it attacks the cells in your pancreas. Your damaged pancreas is then unable to produce insulin. So, glucose cannot be moved out of your bloodstream and into your cells. Type 1 diabetes is o Continue reading >>

Gad Antibodies

Gad Antibodies

Discovery of GADA Antibodies to unknown antigens found in the islets were originally measured by islet cell cytoplasmic antibody (ICA) staining[1]. Over time the specific autoantibodies contributing to ICA were characterised, including GADA, which were originally identified through immunoprecipitation of a 64kDa protein from 35S methionine labelled rat islets by sera from patients with type 1 diabetes. Autoantibodies to GAD are detected in up to 80% of patients and in the majority of sera from individuals who went on to develop the disease [2]. The identity of this 64kDa protein was established through the critical analysis of patients with a rare disorder, stiff person syndrome. These individuals have antibodies that recognised both GABA-secreting neurones and islet cells. The major autoantigen in these patients had already been identified as GAD by the 1980s. Subsequently, Baekkeskov and colleagues were able to show in 1990 that the 64kDa protein, important in type 1 diabetes, was also GAD [3]. Function of GAD The enzyme glutamate decarboxylase (GAD), with its cofactor, pyridoxal 5’phosphate (PLP), catalyses the α-decarboxylation of L-glutamic acid to synthesise the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in neurons and in the pancreas. GABA regulates the function of β cells via paracrine and autocrine signalling [4]. There are two distinct isoforms of GAD: GAD67 and GAD65, encoded by genes on chromosomes 2q31 and 10p11, respectively. The GAD65 sequence is 76% homologous and 85% similar to that of GAD67 through the last 12 exons (residues 174-585). GAD67 is soluble, and mainly present in the cell body of neurons. GAD65, however, is more hydrophobic and is reversibly anchored to synaptic vesicle membranes of neurons and microvesicles in β-cells. Continue reading >>

Late Stage Complications Of Diabetes And Insulin Resistance

Late Stage Complications Of Diabetes And Insulin Resistance

1Department of Microbiology, Chaitanya Postgraduate College, Kakatiya University, Warangal, India 2Department of Biotechnology, Presidency College, Bangalore University, India *Corresponding Author: Department Of Microbiology, Chaitanya Postgraduate College affiliated to Kakatiya University, Warangal, India E-mail: [email protected] Citation: Soumya D, Srilatha B (2011) Late Stage Complications of Diabetes and Insulin Resistance. J Diabetes Metab 2:167. doi:10.4172/2155-6156.1000167 Copyright: © 2011 Soumya D, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Visit for more related articles at Journal of Diabetes & Metabolism Abstract Diabetes mellitus is considered one of the main threats to human health in the 21st century. Diabetes is a metabolic disorder or a chronic condition where the sugar levels in blood are high. Diabetes is associated with long-term complications that affect almost every part of the body and often leads to blindness, heart and blood vessel disease, stroke, kidney failure, amputations, and nerve damage. Also it is associated with significantly accelerated rates of several debilitating microvascular complications such as nephropathy, retinopathy, and neuropathy, and macrovascular complications such as atherosclerosis and stroke. In the present article it has been discussed about the resistance of insulin and its consequences in diabetic patients. Insulin resistance results in various disorders. Metabolic syndrome is predicted to become a major public health problem in many developed, as well as developing countries. Keywords Diabetes; Complications Continue reading >>

Type 1 Diabetes: What Is It?

Type 1 Diabetes: What Is It?

Diabetes is a disease that affects how the body uses glucose , the main type of sugar in the blood. Our bodies break down the foods we eat into glucose and other nutrients we need, which are then absorbed into the bloodstream from the gastrointestinal tract. The glucose level in the blood rises after a meal and triggers the pancreas to make the hormone insulin and release it into the bloodstream. But in people with diabetes, the body either can't make or can't respond to insulin properly. Insulin works like a key that opens the doors to cells and lets the glucose in. Without insulin, glucose can't get into the cells (the doors are "locked" and there is no key) and so it stays in the bloodstream. As a result, the level of sugar in the blood remains higher than normal. High blood sugar levels are a problem because they can cause a number of health problems. The two types of diabetes are type 1 and type 2. Both make blood sugar levels higher than normal but they do so in different ways. In type 1 diabetes, the pancreas loses its ability to make insulin because the body's  immune system attacks and destroys the cells that produce insulin. No one knows exactly why this happens, but scientists think it has something to do with genes. But just getting the genes for diabetes isn't usually enough. A person probably would then have to be exposed to something else — like a virus — to get type 1 diabetes. In type 2 diabetes , the pancreas still makes insulin but the body doesn't respond to it normally. Glucose is less able to enter the cells and do its job of supplying energy (a problem called insulin resistance ). This raises the blood sugar level, so the pancreas works hard to make even more insulin. Eventually, this strain can make the pancreas unable to produce enough ins Continue reading >>

Type 1 Diabetes: Causes And Symptoms

Type 1 Diabetes: Causes And Symptoms

While type 2 diabetes is often preventable, type 1 diabetes mellitus is not.1 Type 1 diabetes is an autoimmune disease in which the immune system destroys cells in the pancreas. Typically, the disease first appears in childhood or early adulthood. Type 1 diabetes used to be known as juvenile-onset diabetes or insulin-dependent diabetes mellitus (IDDM), but the disease can have an onset at any age.2 Type 1 diabetes makes up around 5% of all cases of diabetes.3,4 What is type 1 diabetes? In type 1 diabetes, the pancreas is unable to produce any insulin, the hormone that controls blood sugar levels.2,3 Insulin production becomes inadequate for the control of blood glucose levels due to the gradual destruction of beta cells in the pancreas. This destruction progresses without notice over time until the mass of these cells decreases to the extent that the amount of insulin produced is insufficient.2 Type 1 diabetes typically appears in childhood or adolescence, but its onset is also possible in adulthood.2 When it develops later in life, type 1 diabetes can be mistaken initially for type 2 diabetes. Correctly diagnosed, it is known as latent autoimmune diabetes of adulthood.2 Causes of type 1 diabetes The gradual destruction of beta cells in the pancreas that eventually results in the onset of type 1 diabetes is the result of autoimmune destruction. The immune system turning against the body's own cells is possibly triggered by an environmental factor exposed to people who have a genetic susceptibility.2 Although the mechanisms of type 1 diabetes etiology are unclear, they are thought to involve the interaction of multiple factors:2 Susceptibility genes - some of which are carried by over 90% of patients with type 1 diabetes. Some populations - Scandinavians and Sardinians, Continue reading >>

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