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Hopkins
T h e n e w s l e tt er
FALL 2008
o f th e J ohns H op k ins D e partm e nt o f P s y chiatr y and B e ha v iora l S ci e nc e s
V olu me 5 , N u mber 1
TRANSLATIONS
Deficit Schizophrenia: A First Daisy in the Chain
O
f those who go
through life pressed
under the thumb
of schizophrenia, a smaller
group is nearly flattened by
it. They’re patients suffering deficit schizophrenia.
It’s an add-on, really, to the
disease’s usual disordered
thinking, explains psychiatrist Nicola Cascella. People
with “deficit” lack drive.
Their emotional range is narrow; any sense of purpose
that budded in their teens
has withered. “Ask a patient
what brings the greatest joy
in life,” Cascella says, “and ‘I
went for a walk this morning’ is what I’ll hear.”
Psychiatry sees deficit—it
affects some 20 percent of
schizophrenia patients—
mostly as a difference of
degree within the disorder’s
spectrum of symptoms. But
specialist Cascella thinks
more might be at work. For
one thing, a decade of his
and others’ study consistently
turned up telltale differences
from the more common illness. And now, work out this
fall by a mostly Hopkins team
including Cascella suggests
that deficit may have its own
biology.
Besides the distinct symptoms, the epidemiology stands
out, he says: People with common schizophrenia are typically born in the spring, most
in March. But deficit patients’
birthdays fall in June or July.
They tend to be medicationresistant. These patients are
notorious for being hard to
treat.
The reason may be tied
to genetics. Four years ago,
Cascella had his attention
piqued by PCM1, a gene
A Psychosis Gene?
It may spark the
behavior no matter
what the disease.
PAGE 2
Nicola Cascella seriously believes biology’s behind the deficit disease.
he’d come across during
a Christmas holiday computer escape. Up popped
a Hopkins study about an
obscure genetic disorder,
Bardet-Biedel syndrome, that
linked the ailment to PCM1.
Bardet-Biedel brings obesity
and kidney damage. But,
Cascella knew, patients also
risk schizophrenia; it’s twice
as common as in healthy
folk.
Curious, Cascella sought
PCM1’s particulars in an
online database. The gene’s
address was on chromosome
8, at spot 22 on its short arm.
More clicks brought up a
1998 mammoth Hopkins
study that had linked a mystery gene at 8p22 to schizophrenia. Excited, Cascella
confided in colleague Akira
Sawa, who directs molecular
psychiatry.
It took two years, but the
two assembled a team that
showed disrupting PCM1
in lab mice significantly
flaws their brain development before birth (column,
right); the flaws mimic those
brought about by a known
schizophrenia gene Sawa has
long researched. The implication? There’s a common
mechanism for some forms
of the disease. PCM1, then, has the
makings of a new schizophrenia gene. But was there proof
in people? A tie to deficit
schizophrenia?
Fortunately, Hopkins
psychogeneticist Ann Pulver
had preserved blood samples
from her earlier mammoth
schizophrenia gene hunt.
“Ann saw the promise of our
search,” says Cascella, and
soon they’d analyzed DNA
from 32 volunteers with a
strong family history of the
disease. “When one family
surfaced with a PCM1 mutation, and when we saw that
only family members with
schizophrenia had it, that
finding was just fantastic,”
Cascella grins.
But there’s one more
wrinkle. Last year, a British
group tied abnormal PCM1
to a loss of brain volume,
specifically in the orbitofrontal
cortex. “We’re well aware
of that area,” Cascella says,
“because people with lesions
there get an apathy that looks
a lot like deficit schizophrenia. We know it’s speculation, but it’s tantalizing to
think that flawed PCM1
might be a deficit schizophrenia gene.”
Of course repeat and
expanded studies are in
order. But the beauty of the
work is that it sketches a
possible outline for one sort
of schizophrenia, from gene
to cell to brain to person.
That’s just the sort of daisy
chain that psychiatrists pray
for, the sort that inspires
therapy. n
For info: 410-502-2643 or
[email protected]
To Sleep, Perchance
to Diagnose
When Trauma
is Trauma
Could dreamland
errors reveal illness?
An Iraqi team’s visit opens
eyes on both sides.
PAGE 3
PAGE 4
Guilt By
Centrosome
Centrosomes are a vague memory for
most of us, a shaky freshman-biology recollection of cell parts having to do with
mitosis and waving cilia, perhaps. Yet if
that’s the case, an update is in order:
Not only do centrosomes ready a cell’s
internal scaffolding to carry out movement and transport, but now it seems
they’ve a tie to psychiatric disease.
This fall, in lab mouse studies, a
team led by Psychiatry’s Akira Sawa,
and including Nicola Cascella and colleague Nicholas Katsanis painstakingly
clarified a key centrosomal pathway and
showed its likely relation to one form of
schizophrenia.
Normally, the new work suggests,
proteins made by three centrosomal
genes—abbreviated DISC1, BBS and
PCM1—interact early in some as yet
unknown way in embryonic cells. The
cells then migrate properly to the developing cerebral cortex.
Mutations that warp the proteins,
however, appear to cause a characteristic
sort of havoc. And it’s the team’s additional achievement that they saw some of
that havoc as an early stage of one type
of schizophrenia.
One of the mutated genes, Disrupted
In Schizophrenia (DISC1), was already
linked with psychiatric disease in a
Scottish family—hence the name. In
2006, Sawa’s lab showed that developing
mice whose brains are shortchanged of
normal DISC1 mimic schizophrenia. (His
group later proved DISC1 acts at the
centrosome.)
The second mutant gene on its own
causes Bardet-Biedl syndrome—a genetic
eye and kidney disease that also can bring
abnormal behavior, says Katsanis, who’s
published widely on its biology. And this
new study led the researchers to believe
that mutation in the third gene, PCM1,
may be tied more subtly to schizophrenia
(article, left, on deficit disease).
“Serendipity brought us together
from the corners of the campus,” says
Katsanis, “and allowed us to see the
links between these three proteins, centrosomes and schizophrenia.” n
A Psychosis Gene?
M
r. B, who suffered from bipolar disorder
(BP) for 30 years, had unusual thoughts
and behaviors, but unusual in a typical
way. When, for example, he’d stopped treatment
and slipped into mania, Mr. B hallucinated that
a neighbor wanted to harm him. Troubled by
this, he attached an aluminum foil antenna to
his radio to project the neighbor’s voice and so
warn his family.
Ms. C, who also had lived long with bipolar illness, had “incredible insight,” she said, during a
manic period that coincided with the start of the war
in Iraq. She felt certain she could bring world peace
because the baby she would soon deliver would mark
the second coming of Christ. *
While both patients were no strangers to psychosis, there’s a difference in the way their thinking goes
amiss. In investigating that, psychiatrist Fernando
Goes and colleagues have clarified the biology of
psychosis. Also, they’ve gained insight on one form
of bipolar disorder and are closer to confirm a gene
for the risk of it—all steps toward better therapy.
Mr. B has mood-incongruent psychosis, meaning,
Goes explains, “that the delusions suffered apparently lack ties to the person’s abnormal mood.” Mrs.
C’s mood-congruent thoughts, however, follow more
reasonably from her overactive mood.
“Bipolar disorder is more complex than we’d
thought,” says Goes. “We now see it as more of a
syndrome covering a number of diseases. And that
complexity is probably why we’ve been stumped in
mapping the genes.” Today’s approach, however,
uses those differences. Researchers try to isolate subgroups of BP patients marked by some characteristic:
Some, for example,
have the classic euphoria of mania, while others have more irritable
or “mixed” mania.
Only around half of
bipolar patients experience psychosis. And,
to narrow it further,
such psychosis is mood
incongruent in only a
third of them.
“Narrowing bipolar disorder clinically
should let us narrow
it down genetically,”
Goes explains.
In studying bipolar
psychosis, the Hopkins
team turned to their
records of hundreds
This subgroup of bipolar patients with psychosis may help us pinpoint the gene, says Goes.
of study volunteers
with the disorder—coded
by number and not by
underlies the disordered thinking—one on chromoname—who’d given detailed personal and family
some 13. Earlier Hopkins studies linked that site
histories and blood samples. As part of a government
with both schizophrenia and psychotic bipolar disproject to get a large enough group to be trustwororder. “The fact that there’s an overlap,” Goes says,
thy, those data from 708 families were analyzed and
“tempts us to say there’s a psychosis gene, one that
pooled with others from nine academic centers.
brings a distinct character to illness, one we could
The results? Patients with mood-incongruent BD
target in therapy.” n
have a more severe illness. They’re hospitalized, for
*We’ve altered both patient stories to protect identity.
example, or turn more often to addictive drugs. And
the disorder clearly runs in families.
For information: 443-287-6382
Even more interesting is the possibility that a gene
Drug Dependency: A New Sort of Thinking Cap
Mintzer’s work adds to a national wave of study on how
addiction clouds thinking.
Anesthesiologists know how useful a
well-timed benzodiazepine can be: It
chases away patients’ presurgery fears
and brings on a blessed amnesia for
what goes on in the OR. And many
psychiatrists trust a short course of
the pills to dim memory enough after
a traumatic event to keep acute anxiety from sliding into PTSD.
“But,” says Miriam Mintzer,
“that very effect—or other ways that
drugs can alter thought processes—
may get in the way of therapy for
people who abuse them.” So Mintzer,
a cognitive neuroscientist, has joined
a move to increase awareness of the
scope of cognitive changes that drugs
with abuse potential can bring, subtle
as well as obvious.
Being impulsive, for example, is a
common behavior tied to long-term
drug abuse, Mintzer says, “and, presumably, it makes it more difficult
to stop. The question is: Could we
target it as part of treatment?”
Patients quickly learn what they
need to do in the outside world to
resist temptation, she explains, but
they don’t do it, especially in an environment booby-trapped with pill bottles or other cues. “Training them to
recognize and inhibit their automatic
response could make a difference,”
says Mintzer, who cites studies of successfully schooled impulsive children.
Support for such potential help,
though, lies in the lab. While years
of researching what makes people
dependent on a substance are finally
bearing fruit, knowing the fine cognitive effects—the changes in attention, memory, decision-making abilities—of opioids, marijuana, cocaine
and amphetamines, for example, has
lagged behind. Even work on otherwise well-studied alcohol and benzodiazepines lacks detail that might help
fine-tune therapy.
Much of Mintzer’s work has
focused on the “benzos,” teasing out
cognitive effects of that drug family
in healthy volunteers. Her research
sparks interest in light of collected
observations of chronic benzodiazepine abusers. Both have problems
in encoding new information. “The
drug’s use doesn’t impair your ability
to retrieve memories of past events
(episodic memory),” she says, “but
to lay down new ones.” Added clout
has come from a PET scan study with
Hopkins radiologist colleagues con-
firming that brain areas specific for
memory-encoding are indeed sluggish.
What might that mean for
patients who describe memories for
events as “a fog” or “a blur?” Oftenused tactics like cognitive behavioral
therapy, which rely on remembering
flawed ways of thinking and “encoding” better ones, may need adapting
for drug abusers, Mintzer says.
Recently, she’s turned to cognitive science’s newest baby, metacognition—an awareness of the state of
one’s own thinking. “It’s a particular
problem with the benzodiazepines,”
she says. “After just a single dose,
people often have no idea how much
their memory and performance
is off.” Again, Mintzer is laying a
research base with studies on healthy
volunteers.
Improved metacognition could literally save lives: “If you know you’re
impaired, you might not get in your
car,” she says. “Also, heightened
metacognition is important generally in psychiatric disorders. It helps
patients get well.” n
For more information, call:
410-550-0529.
To Sleep, Perchance to Diagnose
Team sees new friend to psychiatry in REM sleep.
W
hen Ebenezer Scrooge tried to explain
away his ghostly visitors at night as “a bit
of undigested cheese,” his idea wasn’t so
far removed from one 20th century explanation of
dreaming. Harvard’s Hobson and McCarley held that
the dreams we experience are a byproduct of biology—
not of digestion, of course, but rather the result of
twitchings of the brainstem that provoke an intriguing
response from the brain’s cortex as it tries to make sense
of the random input.
But now, a new study by Psychiatry neuroscientist/
psychiatrist Charles Hong and a mostly-Hopkins team
offers evidence that may advance the field in what they
and the earlier researchers think is a truer direction. The
scientists are setting a platform for what may become
a more purposeful biological rationale for dreams. The
work suggests, for example, that the waking conscious
mind and the dreaming one have far more in common
than anyone suspected.
As exciting, says Hong, are the practical implications:
“We believe our techniques could become a natural
probe while people are asleep, a new way to simultaneously examine major brain systems—including those that
go awry in psychiatric disease. This approach may clarify
broadly what happens in patients with schizophrenia,
depression or Alzheimer’s disease,” he explains, “or, one
day, signal brain changes before symptoms appear.”
Basically—and this understates the difficulty—Hong’s
team videotaped the rapid eye movements of healthy volunteers who spent the night asleep in an exquisitely sensitive functional MRI scanner. They then synchronized the
results to get a real-time snapshot of active brain areas.
It wasn’t a stretch to expect that
regions for eye movement would light
up. And because Hong and earlier
colleagues had revealed that, in REM
sleep, eyes apparently track what they
“see” in dreams, the Hopkins team
also anticipated activity in some cortical areas for sight. That was indeed
the case.
Sleep studies could awaken a new field of psychiatric research, Hong says.
Yet there was more. Unexpected
brain sites for hearing, smell, touch
serotonin-secreting neural network has lowered activity
and balance are turned on when rapid
in healthy dreaming subjects’ brains. Having a window
eye movements occur in sleep, they found, as well as
into the workings of serotonin, a molecule closely tied
motor areas that control body movements. They’re
to mood and to mood disorder therapy, could be a
likely the same areas active in awake, fully conscious
great benefit, he says.
people looking at and perceiving something.
The plan, Hong explains, would be to compare
“So, because so much is shared, we believe that
healthy people at sleep with those touched by psychiatconsciousness in waking life and REM sleep dreaming
ric disorders or even with their apparently healthy famare continuous,” says colleague James Harris (Q&A
below). It’s just that the nature of consciousness differs
ily members. “An advantage is that they’re all asleep, all
somewhat in each: “During waking consciousness you’re having rapid eye movements, probably scanning their
seeing things in the real world. In dream consciousness, dreams. So you can carry out accurate studies in uncoyou’re also looking at images, but, it appears, they’re cre- operative schizophrenia patients, in infants, or those
ated internally by your brain,” Harris explains.
with Parkinsonian tremors, which abate during sleep.”
Now for the practical: Hong says many of the brain
Much work lies ahead, Harris adds, “but the potential
regions shown active under fMRI function poorly in psy- has us excited.”
chiatric disease. Both language areas and the basal nucleThe research team included scientists at Kennedy
us, for example, are profoundly affected in Alzheimer’s
Krieger Institute’s F.M. Kirby Research Center. An
disease—areas apparently active in eye-movement sleep.
account is published online in November’s Human
Other REM-active regions—for sensory processing, for
Brain Mapping. n
example—go awry in schizophrenia.
For info: e-mail Charles Hong at [email protected]
Additionally, Hong’s team found that a dense
INSIGHTS: JAMES C. Harris
All You’ve Got to Do Is Dream
You’re really enthused
about this new study, yes?
Absolutely! We think you’ll be
able to study the integrity of
brain circuits while someone’s
asleep.
But, more, since I teach
about Carl Jung’s views, I’m
pleased we’ve found evidence
to support his thoughts on the
continuity of consciousness in
dreaming. The research suggests more strongly than before
that what happens in sleep is
important in emotional adaptation, in making us better able
to carry out life’s tasks.
How?
It’s a lot like that Bergman film
Wild Strawberries that I like
to use to illustrate the human
process. The main character
dreams of his own death and,
in the course of a day, is sharply
reminded—by events and during dreams and daytime rever-
ies—of the important
phases of his life. He
reflects on them, on
their value to himself
and by the movie’s
end, has become a
more integrated person; he’s found new
meaning in relationships that he hadn’t
before. Why? Because
throughout the film,
he holds a dialogue
between his dreams—
his inner self—and
his everyday waking
consciousness. It’s
this back-and-forth
that’s important.
Elaborate, please.
There’s a hypothesis that
imagery from emotional events
of the day surfaces in your
REM sleep. When that’s
“matched” with something
already present in your emo-
And the study’s exciting
because...
photo by Zuhair Kareem
A former head of Child
Psychiatry at Hopkins, James
C. Harris holds deep interests
in sleep, neuropsychiatry and
emotional development. He
co-founded a pediatric sleep
disorders clinic in the early
1980s, for example, and is
a specialist in autism and
intellectual disability—once
called mental retardation—
championing whatever
improves life for young
patients dealt such a hand.
His textbook, Developmental
Neuropsychiatry, effectively
established that specialty.
And for some 30 years, he’s
taught Psychiatry’s course
that describes theories of how
the human psyche comes to
mature throughout a lifetime.
Here we get Harris’
perspective on the work
(above) that ties the
waking and sleeping brain in
new ways.
tional memory banks and then
re-experienced in REM sleep,
the result is a biological modulating of your emotional life.
It smooths the harsh edges, so
to speak, helps you come to
terms with your life. You’re
ready to adapt to a new day.
It suggests that this process, where
there is continuity between waking and REM sleep consciousness,
is meaningful and real. We may
be able to show, at some point, or
begin to quantify how sleep’s most
valuable quality—restoring us by
balancing our emotional life—
works. Also, it may lead to early
detection of depression, Alzheimer’s disease or schizophrenia—all
sleep-disrupting illnesses that affect
our emotional life, memory and
cognitive balance. And finally...
Yes?
This, to me, might begin to help
us understand the neurophysiology
that underlies psychotherapy. Is
the alternation between narrating
and reflecting that’s so basic to psychotherapy mirrored in the continuity of waking and dreaming?
That’s what I’d like to find out. n
When Trauma Is Trauma
Baghdad or Baltimore – kids show similar anxiety from life’s daily blows.
It might be walking by the
body of a dead friend on the
way to school, day after day,
that pushes an Iraqi child
into posttraumatic stress
disorder. (Fear of hidden
bombs keeps officials from
picking up bodies.) It could
be knowing that terrorists
kidnapped your brother and
that after months, your parents can’t raise the ransom.
Or perhaps it’s the constant
atmosphere of fear that
grinds at mental health as
surely as the grit that now
pervades war-torn Iraq.
Last summer, hearing
what Iraqi children experience raised the consciousness
of Hopkins community psychiatry clinicians involved
in an unusual exchange. As
part of a U.S.-Iraq program
—one sponsored by our
federal Substance Abuse
and Mental Health Services
Administration—Hopkins
mentored Iraqi professionals
who aim to reverse trauma’s
effects. “Thousands of children in that country don’t
meet normal developmental
milestones because of what
they’ve suffered psychologically,” says psychiatrist Anita
Everett. Everett directs the Bayview
campus’ Community
Psychiatry Program (CPP)
and has been part of an international network of clinicians
who, since 2005, have offered
medical education and assistance in reviving Iraq’s mental health system. Recently,
she and colleagues held a
Hopkins seminar about their
experiences.
For three weeks, an Iraqi
psychiatrist, two psychologists and a pediatrician studied community psychiatry
in Baltimore and visited
“marker” schools—both
those where neighborhood
“It was such an honor to be with the Iraqis,” says Paige Johnston,
L.C.P.C., here with psychologist Fatima Hasim Asied.
Hopkins
This issue of Hopkins Brain Wise is
published by Johns Hopkins Medicine
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the Department of Psychiatry and
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contact Jessica Lunken,
Director of Development
Department of Psychiatry
100 North Charles Street, Suite 410
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this newsletter, please e-mail
[email protected]
SAVE THE DATE!
This year’s 23rd Annual Mood
Disorders Symposium has Innovative
Treatments as its focus. Renowned
psycho-neurologist Helen S.
Mayberg, whose work sparked the
Deep Brain Stimulation now being
eyed for depression is featured.
Tuesday, April 28, 2009 at Hopkins’
Turner Auditorium.
Call 443-502-9634 for information.
J. Raymond DePaulo, Jr., M.D.
Chief of Psychiatry
Patrick Gilbert, Director of
Editorial Services
Marjorie Centofanti, Editor/Writer
Dalal Haldeman, Vice President,
Marketing and Communications
David Dilworth, Designer
Keith Weller, Photography
Editorial Office
901 South Bond Street, Suite 550
Baltimore, MD 21231
© The Johns Hopkins University 2008
violence or family indifference affects many students
and those that stand as
models of support. “We
were the right choice for the
visit because CPP has mental
health care projects embedded in 14 Baltimore city
schools,” says Kim Hauser,
embraced the idea of
training teachers to recognize PTSD and to use
basic therapeutic techniques.
Perversely, many of the
teachers suffer anxiety disorders as well. “The whole
country is hypervigilant,”
the Iraqis told Johnston.
As for lessons learned?
Seeing the differences in the
“All of Iraq is
hypervigilant.” Baltimore schools was likely
useful. “Our teachers are at
a different starting point,”
the projects’ manager.
says Everett. “They’ve been
Schools were a focal
educated to flag children at
point because Iraq’s efforts
risk. Also, help for students
to help traumatized children here has two layers—the
are schools-based. The stig- school counselors oriented
ma of mental illness in that toward learning-disabilities
country is huge, Hauser and and CPP’s added-on layer
colleague Paige Johnston
that helps kids who need
explained, but parents
treatment. In Iraq, teachers
find no shame in visiting a
must do a little of both.
child’s school.
“It’s hard to sort them
Traditionally, care for
out,” Everett adds. “The
children with anxiety disor- kids who can’t focus, who’re
ders has been the domain
distracted—do they have
of grandmothers or other
underlying ADHD or are
older women in the closethey just reacting to trauma?”
knit, stigma-wary families.
Mentoring the team,
For that and other reahowever, wasn’t all onesons, “you’ll find no child
way. “The Iraqis did find
psychiatrists in Iraq,” says
negatives here,” Hauser
Johnston. Also, medicines
says, “specifically the lack of
are less in use. Ritalin, for
family involvement. They
example, was banned after
were appalled at one visit
Saddam Hussein dosed
to a group home. Where
soldiers with it to get them was the family?” Both sides
back to battle.
came to realize the common
That’s why, in a country points of childhood trauwhere roughly half of the
ma—whether it comes from
population is under the
war and dictators or from
age of 18, officials in Iraq’s addicted parents and neighhealth and education minborhood violence—and that
istries see childhood trauma effective ways of treating it
as an emergency. They
know no borders. n
Hailey Dart: She’s increasing awareness of
teenage mood disorders while fighting stigma.
Films Could Turn Night to Day
Roddy Dart had just celebrated his 22nd birthday
early in 1997. A “much adored, strong-minded
young man and great fun besides,” his mother says,
Dart was a gifted writer at his young age. He’d just
begun to resume life as a college student after a
hospitalization confirmed bipolar disorder and the
idea of coping with the illness was sinking in.
A freak fall, however, ended Roddy’s life. It
also started a search by Hailey Dart, his mother,
with backing from family and friends, to make a
fitting memorial. Several projects caught her eye.
But it was reading An Unquiet Mind—Kay Jamison’s
description of being on the cusp of life and wresting
life from bipolar disorder—that helped Dart decide.
She contacted Jamison and others at Hopkins
who, in turn, described the huge void in young
adults’ awareness of mood disorders. Could Dart
perhaps fund a film that would get out the message?
Something to show that these illnesses are both
common and treatable?
In 1998, Day for Night: Recognizing Teenage
Depression opened to quick praise. The documentary followed seven teenagers diagnosed with and
successfully treated for mood disorders. It was
accessible and, importantly, as color- and classblind as the illnesses themselves, with the young
patients racially varied and from diverse households. “It’s been a wonderful film, fabulous, even,
in what it’s accomplished,” says Sallie Mink, with
the Adolescent Depression Awareness Program
(ADAP), a Hopkins-based effort to educate that age
group. Shown to more than 12,000 kids so far, as
well as parents and teachers, it’s still a mainstay.
But Dart, who runs the Rodwell Dart Memorial
Foundation from its base in Aspen, Colo., has done
more for the Hopkins cause. She’s funded two
more films—each needed to help ADAP extend its
reach nationwide. One, a training film, shows ADAP
director Karen Swartz in action with the program’s
students. And another is meant to educate their
parents. “We want to be proactive,” says Swartz.
“We want to offer hope. And Hailey’s commitment
to sophisticated, much-needed media has been critical to our spreading this message.” n
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