| Current
Molecular Medicine
ISSN: 1566-5240
Current Molecular Medicine
Volume 8, Number 4, June 2008
Contents
Stress-Induced Deleterious Consequences
in the Gastrointestinal Tract
Guest Editors: Juan C. Leza and Luis Menchén
Editorial Pp. 244-246
The Role of Stress in the Development and Clinical Course
of Inflammatory Bowel Disease: Epidemiological Evidence
Pp. 247-252
Robert G. Maunder and Susan Levenstein
[Abstract]
Epidemiology and Clinical Presentation of Stress-Related
Peptic Damage and Chronic Peptic Ulcer PP. 253-257
Rok Seon Choung and Nicholas J. Talley
[Abstract]
Neuropharmacology of Stress-Induced Mucosal Inflammation:
Implications for Inflammatory Bowel Disease and Irritable
Bowel Syndrome Pp. 258-273
Javier Santos, Carmen Alonso, María Vicario, Laura
Ramos, Beatriz Lobo and J-Ramón Malagelada
[Abstract]
Pathophysiological Mechanisms of Stress-Induced
Intestinal Damage Pp. 274-281
Mélanie G. Gareau, Manuel A. Silva and Mary H.
Perdue
[Abstract]
The Role of Microbiota and Probiotics in Stress-Induced
Gastrointestinal Damage Pp. 282-298
Femke Lutgendorff, Louis M.A. Akkermans and Johan D. Söderholm
[Abstract]
The Effects of Physical and Psychological Stress
on the Gastrointestinal Tract: Lessons from Animal Models
Pp. 299-312
Javier R. Caso, Juan C. Leza and Luis Menchén
[Abstract]
General Articles
Demystifying MST Family Kinases in Cell Death
Pp. 313-318
Maria K. Lehtinen and Azad Bonni
[Abstract]
SnoN in TGF-β
Signaling and Cancer Biology Pp. 319-328
Isabelle Pot and Shirin Bonni
[Abstract]
Abstracts
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Editorial
During the second half of the nineteenth and the
first decades of the twentieth century the separation of medical
and psychiatric disorders started to be reconsidered by a
number of physicians and scientists, leaded by Ivan Pavlov
and Walter Cannon that inherited the legacy of Hippocrates
and Galen who, more than two thousand years ago support the
notion that psychosomatic disorders were abnormal physical
reactions to stressful emotions or situations. Soon after,
Hans Selye defined the physiological responses to stressors
and adapted the term stress from physics and engineering to
introduce it in the medical vocabulary: “in the biological
sense stress is the interaction between damage and defense,
just as in physics tension or pressure represents the interplay
between a force and the resistance offered to it”, [1].
Selye described a uniform array of sequential, adaptive responses
– termed the “General Adaptation Syndrome”
– that, through the years, have been universally accepted
as direct consequences of stress exposure: enlargement of
the adrenal glands, atrophy of immune organs such as thymus,
spleen and lymph nodes, and gastrointestinal ulcers [2, 3].
Eighty years later, the definition of stress remains to be
subject of debate. In biological systems, the classical definition
is any condition that seriously perturbs the physiological/psychological
homeostasis of an organism. Indeed, biological stress occurs
every day to organisms in their relation with other organisms
and also with themselves, provoking a double-faced response:
it can be an adaptive mechanism, allowing the organism to
survive or fight to the stressful experience, but stress have
also a negative impact on the individual, mainly after very
intense, long lasting stressful stimuli. Several decades after
the seminal works cited above, McEwen extended the term of
homeostasis to explain that these mechanisms of stability
are continuously changing and called it allostasis [4]. The
price the organisms pay to maintain (or try to maintain) the
stability is called allostatic load, many times clear diseases.
The development of possible permanent changes depends on factors
such as chronicity, controllability, predictability and habituation,
in part because they are influencing the way an organism can
reduce the impact of stressors (coping strategies). The current
terminology distinguishes between the stimulus (stressful
stimulus or stressor), the state generated in the organism
(stress) and the response to the situation (stress response)
[5].
Nowadays physical and psychological stresses are widely accepted
as triggers and / or modifiers of the clinical course of a
variety of gastrointestinal diseases such as functional gastrointestinal
disorders, peptic ulcers, and inflammatory bowel diseases
[6]. It has been shown that patients with functional gastrointestinal
disorders, gastroduodenal ulcers, and relapsing IBD are more
frequently exposed to stressful stimuli [7]. On the other
hand, stress is involved in the subjective perception of gastrointestinal
symptoms – which is often a challenge for the specialist
– by patients [8], and psychological factors could be
related with the high rate of placebo responses observed in
IBD and IBS clinical trials. But although the relationship
is often recognized both by patients and physicians, obvious
methodological pitfalls of clinical studies make the demonstration
of a casual nexus difficult. During the last years, growing
evidence from experimental studies supports the ability of
psychosocial stress to induce a wide variety of disturbances
on the gastrointestinal tract such as gastric erosions and
ulcers, increased gastrointestinal motility, altered ion secretion,
increased intestinal permeability and enteric neurons dysfunction,
to increase the severity of experimental colitis, and even
to reactivate a quiescent colitis [9].
In this volume of Current Molecular Medicine, several
scientists from some of the most productive groups worldwide
in this topic write theirs reflections on different aspects
of the effects of stress on the gastrointestinal function.
Throughout these pages the possibility that consequences of
stress provoke or predispose to disease, and the molecular
and cellular basis of gut damage will be reviewed.
Maunder and Levenstein, from Toronto and Rome, systematically
review the published epidemiological evidence about the role
of stress in the development and clinical course of IBD. Interestingly,
whereas evidence of a contribution of stress to the onset
of the disease is very weak, longitudinal studies on stress
or depression and IBD disease course (based on inflammatory
parameters) showed a significant relationship between UC and
stress and CD and depression. Although possible therapeutic
benefits of psychological interventions are limited by methodological
weaknesses in these studies, both psychological and pharmacological
interventions may be taken into account in IBD patients.
Choung and Talley, from Rochester and Jacksonville, present
also epidemiological data on stress-related peptic damage.
The syndrome of stress-related mucosal damage of the gastrointestinal
tract was first described in 1971 by Lucas et al.
[10] who termed this “stress-related erosive syndrome”.
Interestingly, admission in an intensive care unit lead to
acute mucosal damage (seen by endoscopy) in 60 -100 % of patients,
a fact that underline the relevan-ce of physical stressors
in the development of gastric erosions and ulcers. However,
epidemiological data on the effects of stress on chronic peptic
damage has not been accurately described, and any association
is controversial. The proportion of chronic peptic ulcers
that are Helicobacter pylori negative appears to
be between 5% and 20%, so it seems possible to suggest that
stress or other psychological factors may play a role here.
Furthermore, stress could act also as a coadjuvant factor
in the development of gastric and duodenal ulcers in Helicobacter
pylori-infected individuals. However, due to study limitations
and the existence of multiple confounding variables in the
data acquisition, at present there is no definitive study
establishing a causal relationship between psychological stress
and the development of chronic peptic ulcer disease. It seems
more likely that concomitant psychological stress may influence
at least symptom reporting by patients.
Santos, Alonso, Vicario, Ramos, Lobo and Malagelada, from
Barcelona, review the neuro-immuno-endocrine circuitry of
stress-related mucosal inflammation in the gut, outlining
that besides inflammatory bowel diseases, irri-table bowel
syndrome patients could be also affected by mucosal inflammation
that is involved in the pathophysiology of the disorder. They
artificially separate the components of this network in three
major subdivisions: 1) The brain/adrenal circuitry, which
stands mainly for the limbic-hypothalamic-pituitary-adrenal
(HPA) axis, 2) The interconnecting circuitry, which is referred
as all the structures and molecules that somehow intermediate
between the brain and the periphery and whose major component
is the autonomic nervous system, in particular, the sympathetic-adrenomedullary
system and 3) The stress-inflammatory peripheral circuitry,
composed by the enteric nervous system and the endocrine-immune-epithelial-endothelial-flora
interface. The whole system provides the anatomical and physiological
basis for the stress-induced gastrointestinal dysfunction
and inflammation. Indeed, psychological stress seems to exert
a pivotal role in the modulation of visceral sensitivity,
motility and mucosal inflammation. Furthermore, the authors
review current and potential pharmacological tools acting
at different subdivisions of the circuitry and directed to
the prevention and treatment of stress-related gastrointestinal
disorders.
Gareau, Silva and Perdue, from Toronto and Hamilton, review
the pathophysiological mechanisms of stress-induced intestinal
damage, focusing specially on changes in epithelial permeability
in the small and large bowel induced by stress and the consequences
of developing a defective barrier. The authors point out that
prolonged exposure to stress induces low-grade mucosal inflammation,
leads to ultrastructural epithelial abnormalities and alters
bacterial-host interactions including bacterial translocation.
This functional damage has been implicated in the development
of intestinal inflammation and hyperalgesia. These authors
point out also CRF as a main mediator of the effects of stress
on the gut, via peripheral mechanisms involving dysregulated
enteric cholinergic nerves, mast cells and improper bacterial
colonization. Finally they outline the importance of early
life stress in the development of anxiety and depression,
as well as the evidence of its potential relevance in the
development of subsequent abnormal colonic responses to noxious
stimuli derived from animal studies.
Lutgendorff, Akkermans and Söderholm, from Linköping
and Utrecht, write an interesting paper on the role of microbiota
and probiotics in stress-induced gastointestinal damage. In
normal conditions, commensal microbes and their hosts benefit
from a symbiotic relationship. Stress does, however, reduce
the number of Lactobacilli on the gut; while on the
contrary, it can induce increased growth, epithelial adherence
and mucosal uptake of gram-negative pathogens, such as E.
coli and Pseudomonas. Söderholm and colleagues
discuss about the use of probi-otics in these conditions:
probiotics are “live microorganisms which, when administered
in adequate amounts, con-fer a health benefit on the host”,
and mainly represented by Lactic Acid Bacteria. In this vein,
probiotics can coun-teract stress-induced changes in intestinal
barrier function, visceral sensitivity and gut motility. Mechanisms
of ac-tion include competition with pathogens for essential
nutrients, induction of epithelial heat-shock proteins, restoring
of tight junction protein structure, up-regulation of mucin
genes, secretion of defensins, and regulation of the NFκB
signalling pathway. In addition, the reduction of intestinal
pain perception was shown to be mediated via cannabi-noid
receptors. All these effects are strain specific and mediated
by direct bacterial-host cell interaction and/or via
soluble factors. These findings provide a rationale for treating
with probiotics patients with stress-related intestinal disorders,
although we still are far from being able to choose the precise
combination of strains or bacterial components for each clinical
setting.
Finally, Caso, Leza and Menchén, from Madrid, review
the use of animal models in the study of the basic mechanisms
responsible of the stress consequences on gut. Models in mice,
rats, guinea pigs, rabbits, pigs, dogs and primates have used
to this. Those characterized by rodent’s exposure of
an unavoidable, physical stress are the most extensively used:
immobilization, exposure to extreme temperatures, fasting,
immersion or electric shocks, among others. Use of these experimental
settings is basic to understand the role of cellular effectors
(mast cells, lymphocytes, dendritic cells, neutrophils and
epithelial cells) and molecular mechanisms of stress induced
changes in the gut (i.e. CRF, TRH, glucocorticoids, acetylcholine,
substance P, angiotensin, endothelin, cytokines and other
mediators such as nitric oxide and prostaglandins). These
models have been used also to describe some of the adaptive
changes elicited by stress in the gut acting by counterbalancing
inflammatory status (peroxisome proliferator-activated receptor
gamma -PPAR γ-
up-regulation and activation by its endogenous agonist 15-deoxyprostaglandin
J2.
Stress scientists are special people among scientist community.
They are always crossing the line between physiology and pathology,
trying to understand a really broad and unspecific physiological
response, which can convert in pathological under certain
conditions such as intensity, time and coping ability of the
organism. We hope the present special volume will contribute
to the knowledge of how gastrointestinal system faces stress
and how it can be affected itself by stress. Obviously, much
more research is needed until specific pharmacological tools
are available to diminish the negative effects of stress on
gut function.
REFERENCES
[1] Selye, H. (1950) Br. Med. J., 1,
1383-92.
[2] Selye, H. (1936) Nature, 138,
32.
[3] Selye, H. (1937) Endocrinology, 21,
169-188.
[4] McEwen, B.S. (2000) Brain Res., 886,
172.
[5] Armario, A. (2006) CNS Neurol. Disord. Drug Targets,
5, 485-501.
[6] Levenstein, S. (1998) Br. Med. J., 316,
538-41.
[7] Cobb, S. and Rose, R.M. (1973) JAMA, 224:
489-92.
[8] Dickhaus, B., Mayer, E.A., Firooz, N., Stains, J., Conde,
F., Olivas, T.I., Fass, R., Chang, L., Mayer, M. and Naliboff,
B.D. (2003) Am. J. Gastroenterol., 98,
135-43.
[9] Patel, S.M., Stason, W.B., Legedza, A., Ock, S.M., Kaptchuk,
T.J., Conboy, L., Canenguez, K., Park, J.K., Kelly, E., Jacobson,
E., Kerr, C.E. and Lembo, A.J. (2005) Neurogastroenterol.
Motil., 17, 332-40.
[10] Lucas, C.E., Sugawa, C., Riddle, J., Rector, F., Rosenberg,
B. and Walt, A.J. (1971) Arch. Surg., 102,
266-273.
Juan C. Leza
Departamento de Farmacología
Facultad de Medicina
Universidad Complutense
28040 Madrid
Spain
E-mail:
jcleza@med.ucm.es
Luis Menchén
Sección de Gastroenterología
Servicio de Aparato Digestivo
Hospital General Universitario “Gregorio Marañón”
28007 Madrid
Spain
E-mail: lamenchen.hgugm@salud.madrid.org
[Back to top]
The Role of Stress in the Development and Clinical Course
of Inflammatory Bowel Disease: Epidemiological Evidence
Robert G. Maunder and Susan Levenstein
Background: It is unclear whether psychological stress
contributes to the inflammatory process in the inflammatory
bowel diseases (IBD), ulcerative colitis (UC) and Crohn’s
disease (CD). This review assesses the epidemiological evidence
regarding a causal link between stress and gut inflammation
in IBD.
Methods: A Medline search identified prospective
studies of the effects of stress on subsequent disease activity
and randomized controlled studies of the effects of psychological
interventions on disease course in IBD. Controlled retrospective
studies were included in the review of aspects of the stress-inflammatory
relationship for which few prospective studies are available
(e.g. the link between stress and disease onset). Studies
were assessed qualitatively.
Results: Among 9 longitudinal studies of stress or
depression and disease course, a significant stress-inflammation
relationship has been found when UC and CD are studied independently
(4 of 4 studies positive) but studies of mixed samples of
CD and UC have mostly had negative results (1 of 5 studies
positive). Evidence of a contribution of stress to disease
onset is very weak. The results of 5 studies of psychological
interventions in IBD have been negative or modestly supportive
of benefit. Confidence in therapeutic benefits of psychological
interventions results is limited by methodological weaknesses
in these studies.
Discussion: There is consistent evidence for a contribution
of psychological factors to IBD disease course, especially
stress in UC and depressive symptoms in CD. More rigorous
tests of psychological interventions in IBD are needed.
[Back to top]
Epidemiology and Clinical Presentation of Stress-Related Peptic
Damage and Chronic Peptic Ulcer
Rok Seon Choung and Nicholas J. Talley
Stress is often considered a risk factor for upper gastrointestinal
tract disease, as any acute threat to homeostasis evokes an
adaptive or allostatic response. Various types of stress may
play a role in the onset and modulation of acute or chronic
peptic ulcer disease. When upper endoscopy is employed, stress-related
acute mucosal damage is found to develop shortly after admission
to an intensive care unit in 60 to 100 percent of patients.
However, the epidemiology of chronic peptic damage has not
been accurately described by type of stressor, and any association
is controversial. The incidence of chronic peptic ulcer disease
is falling; the proportion of chronic peptic ulcers that are
Helicobacter pylori negative appears to be between
5% and 20%, and some have suggested that stress or other psychological
factors may play a role here. Therefore, our objective is
to provide an overview of the epidemiology and clinical presentation
of stress-related peptic damage, in order to shed insights
into the current understanding of the pathophysiology and
treatment.
[Back to top]
Neuropharmacology of Stress-Induced Mucosal Inflammation:
Implications for Inflammatory Bowel Disease and Irritable
Bowel Syndrome
Javier Santos, Carmen Alonso, María Vicario, Laura
Ramos, Beatriz Lobo and J-Ramón Malagelada
Inflammatory bowel disease (IBD) and the irritable bowel
syndrome (IBS) are common causes of medical consultation and
the most frequent diagnosis raised by gastroenterologists.
Recent years have witnessed considerable advances in the understanding
of the mechanisms involved in the initiation and perpetuation
of these chronic and recurrent disorders. However, particularly
in IBS, the success of the “bench-to the-bedside medicine”
has been rather poor since many affected individuals still
experience significant bother and negative impact in their
quality of life despite growing investigative and sanitary
costs.
Besides IBD, several subgroups of IBS patients have been lately
identified as carriers of mucosal inflammation throughout
the gut. Although multifactorial, life stress has emerged
as a critical factor for mucosal inflammation in these conditions.
Due to the clinical and biological heterogeneity of IBD and
IBS patients, the simplistic hypothesis of a stress-related
stepwise progression of gut inflammation may be useful to
gain operative knowledge and render better and specific diagnostic
markers and improved therapeutic options. Therefore, in this
review, we have consciously admitted the possibility of linear
evolution of gut inflammation, from the mucosa to the serosa,
and assumed a bidirectional progression, from physiological
to pathological inflammation. Thus, we have outlined the stress
neurocircuitry implicated in the regulation of gut inflammation
and the participating pathways (mechanisms, receptors and
molecules) and provided with both, evidence and a theoretical-based
approach to present and potential drugs that, alone or in
combination, might help to prevent, control or regress the
stress-induced inflammatory process at different stages.
[Back to top]
Pathophysiological Mechanisms of Stress-Induced Intestinal
Damage
Mélanie G. Gareau, Manuel A. Silva and Mary H.
Perdue
Stress has been shown to have both central and peripheral
effects, promoting psychological illness (such as anxiety
and depression), as well influencing peripheral disease in
the intestine. Stress in humans can exacerbate symptoms of
irritable bowel syndrome (IBS) and inflammatory bowel disease
(IBD), lowering visceral pain thresholds and decreasing mucosal
barrier function. Studies in rodents have revealed that both
acute and chronic exposure to stressors can lead to pathophysiology
of the small and large intestine, including altered ion secretion
and increased epithelial permeability (by both transcellular
and paracellular pathways). Prolonged exposure to stress can
induce low-grade inflammation, cause ultrastructural epithelial
abnormalities, and alter bacterial-host interactions allowing
greater microbial translocation. In this review, we discuss
the stress response and the effects of both acute and chronic
stress to induce pathophysiological damage to the gut. We
present the potential pathways involved, and the proposed
mechanisms of action mediating the effects. Furthermore, we
explore the impact of early life stress on colonic physiology
in neonatal rodents and the implications for gut dysfunction
in adulthood.
[Back to top]
The Role of Microbiota and Probiotics in Stress-Induced Gastrointestinal
Damage
Femke Lutgendorff, Louis M.A. Akkermans and Johan D. Söderholm
Stress has a major impact on gut physiology and may affect
the clinical course of gastro-intestinal diseases. In this
review, we focus on the interaction between commensal gut
microbiota and intestinal mucosa during stress and discuss
the possibilities to counteract the deleterious effects of
stress with probiotics.
Normally, commensal microbes and their hosts benefit from
a symbiotic relationship. Stress does, however, reduce the
number of Lactobacilli, while on the contrary, an
increased growth, epithelial adherence and mucosal uptake
of gram-negative pathogens, e.g. E. coli and Pseudomonas,
are seen. Moreover, intestinal bacteria have the ability to
sense a stressed host and up-regulate their virulence factors
when opportunity knocks.
Probiotics are “live microorganisms which, when administered
in adequate amounts, confer a health benefit on the host”,
and mainly represented by Lactic Acid Bacteria. Probiotics
can counteract stress-induced changes in intestinal barrier
function, visceral sensitivity and gut motility. These effects
are strain specific and mediated by direct bacterial-host
cell interaction and/or via soluble factors. Mechanisms
of action include competition with pathogens for essential
nutrients, induction of epithelial heat-shock proteins, restoring
of tight junction protein structure, up-regulation of mucin
genes, secretion of defensins, and regulation of the NFκB
signalling pathway. In addition, the reduction of intestinal
pain perception was shown to be mediated via cannabinoid
receptors.
Based on the studies reviewed here there is clearly a rationale
for probiotic treatment in patients with stress-related intestinal
disorders. We are however far from being able to choose the
precise combination of strains or bacterial components for
each clinical setting.
[Back to top]
The Effects of Physical and Psychological Stress on the Gastrointestinal
Tract: Lessons from Animal Models
Javier R. Caso, Juan C. Leza and Luis Menchén
Physical and psychological stresses are widely accepted
as triggers and / or modifiers of the clinical course of diverse
gastrointestinal disorders such as peptic ulcer, irritable
bowel syndrome or inflammatory bowel disease. Growing experimental
evidence from a variety of models such as immobilization,
thermal injury or early maternal deprivation in laboratory
animals uniformly supports the ability of stress to induce
the development of gastric ulcers, altered gastrointestinal
motility and ion secretion, and increased intestinal permeability
leading to the passage of antigens to the lamina propria
and bacterial translocation. Stress can also synergize with
other pathogenic factors such as Helicobacter pylori,
non-steroidal anti-inflammatory drugs or colitis-inducing
chemicals to produce gastrointestinal disease. The brain-gut
axis provides the anatomical basis through emotions and environmental
influences modulate the gastrointestinal function through
the regulation of gastrointestinal immune system and mucosal
inflammation; in this sense, mucosal mast cells – at
cellular level – and corticotropin releasing factor
(CRF) – at molecular level – seem to play a crucial
role. On the other hand, an array of adaptive responses have
been evolved in order to maintain the homeostasis and to ensure
the survival of the individual. In the gut mucosa anti-inflammatory
pathways counteract the deleterious effect of the stressful
stimuli on the gastrointestinal homeostasis. In the present
review we discuss the several experimental approaches used
to mimic human stressful events or chronic stress in laboratory
animals, the evidence of stress-induced gastrointestinal inflammation
and dysfunction derived from them, and the involved cellular
and molecular mechanisms that are being discovered during
the last years.
[Back to top]
Demystifying MST Family Kinases in Cell Death
Maria K. Lehtinen and Azad Bonni
The MST family of protein kinases plays a critical role
in the regulation of cell death in diverse organisms including
mammals. The intracellular signaling pathways that regulate
MST-driven cell death in mammalian cells are the subject of
intense investigation. Stress stimuli including oxidative
stress and DNA damaging agents trigger the activity of MST
in cells. Although the mechanisms by which oxidative stress
and DNA damage trigger MST activation remain to be identified,
MST activity can be regulated by caspase-induced cleavage
as well as interactions with other proteins in cells. Once
activated upon oxidative stress, MST induces cell death via
phosphorylation and activation of the transcription factor
FOXO3 or the histone protein H2B. This review focuses on the
currently known upstream activating mechanisms for MST, and
explores the downstream signaling pathways that mediate MST’s
principal function in cell death. Elucidation of MST functions
and their regulatory mechanisms in cell death have important
implications for our understanding of cellular homeostasis
as well as the pathogenesis of diverse diseases.
[Back to top]
SnoN in TGF-β
Signaling and Cancer Biology
Isabelle Pot and Shirin Bonni
The Transforming Growth Factor (TGF)-β-Smad
signaling pathway regulates diverse biological processes essential
for normal development and homeostasis. The Smad-interacting
transcriptional modulator SnoN and its related homologs have
emerged as important modulators of TGF-β
signaling and responses. SnoN forms a physical complex with
the TGF-β-regulated
Smad2/Smad3 and co-Smad4 proteins and either represses or
stimulates TGF-β-induced
Smad-dependent transcription in a cell- and promoter-specific
manner. In addition, the TGF-β-activated
Smads recruit several ubiquitin ligases to SnoN and thereby
promote the ubiquitination and consequent degradation of SnoN.
Additional modifications of SnoN, including sumoylation, may
contribute to the regulation of SnoN function and its role
in TGF-β
signaling. Collectively, these studies suggest that SnoN function
is intimately linked to the TGF-β-Smad
pathway in cellular signaling. Although the mechanisms by
which SnoN modulates signaling in the TGF-β-Smad
pathway are beginning to be characterized, the full range
of SnoN functions and underlying mechanisms in normal development
and disease processes remains to be elucidated.
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