G.
Larralde,
J.
Vivas,
J.
A.
Urbina,
Acta
Cient.
Venez.
39,140
(1988).
18.
Statistical
analysis
of
the
survival
curves,
by
use
of
both
the
log
rank
(Mantel-Cox)
and
Peto-Peto-Wil-
coxon
tests,
indicated
a
significant
(P
<
0.0001)
dif-
ference
between
the
control
(untreated)
animals
and
all
those
that
received
the
drug
treatments,
as
well
as
between
those
that
received
D0870
at
-15
mg/kg
per
day
e.o.d.
and
the
group
treated
with
ketocon-
azole
at
30
mg/kg
per
day
daily.
Survival
analysis
was
carried
out
on
the
StatView
program,
version
4.5,
run
on
a
Power
Macintosh
7100/66
computer.
19.
We
carried
out
hemocultures
by
inoculating
2
ml
of
liver
infusion
medium
with
0.4
ml
of
blood
obtained
from
experimental
mice
by
cardiac
puncture;
micro-
scopic
examination
of
the
cultures
for
the
presence
of
proliferative
epimastigote
forms
was
done
weekly
for
4
weeks.
Surviving
animals
were
killed,
and
organs
(spleen,
liver,
heart,
and
bone
marrow)
were
minced
individually
in
1
ml
of
sterile,
phosphate-buffered
sa-
line
with
10
mM
D-glucose;
0.4
ml
of
the
suspension
was
inoculated
in
juvenile
animals
(15
to
20
g).
Hemoi-
noculation
(50
RI
of
blood
diluted
to
100
,ul
with
sterile,
phosphate-buffered
saline)
was
done
subcutaneous-
ly
in
10-
to
12-day-old
mice.
Xenodiagnosis
was
done
with
10
second-stage
Rodnius
prolixus
nymphs
per
mouse;
after
2
weeks,
the
feces
were
analyzed
for
T.
cruzi
metacyclic
forms,
and
the
exam
was
repeated
weekly
thereafter
for
1
month.
The
presence
of
circu-
lating
T.
cruzi
antibodies
was
detected
by
immuno-
precipitation
of
1251-labeled
total
epimastigote
surface
antigen
antigens
with
experimental
sera
in
the
pres-
ence
of
protein
A,
followed
by
analysis
of
the
precipi-
tate
by
SDS-polyacrylamide
gel
electrophoresis.
20.
C.
Britto,
M.
A.
Cardoso,
P.
Wincker,
C.
M.
Morel,
Mem.
Inst.
Oswaldo
Cruz
Rio
J.
88,
171
(1993);
P.
Winckeret
a/.,Am.
J.
Trop.
Med.
Hyg.
51,
771
(1994).
The
T.
cruzi-specific
primers
used
in
the
tests
were
5'-AAATAATGTACGGG(T/G)GAGATGCATGA-3'
and
5'-GGTTCGATTGGGGTTGGTGTAATATA-3'.
21.
Statistical
analysis
of
the
survival
curves,
by
use
of
both
the
log
rank
(Mantel-Cox)
and
Peto-Peto-Wil-
coxon
tests,
indicated
no
significant
differences
be-
tween
the
control
(untreated)
animals
and
those
that
received
ketoconazole
at
30
mg/kg
per
day
daily
or
D0870
at
10
mg/kg
per
day
e.o.d.,
whereas
there
were
significant
differences
between
these
groups
and
those
receiving
D0870
at
10
mg/kg
per
day
daily
(P
=
0.05)
or
.15
mg/kg/day
e.o.d.
(P
=
0.005).
22.
S.
De
Wit,
E.
O'Doherty,
R.
P.
Smith,
R.
Yates,
N.
Clumeck,
Intersci.
Congr.
Antimicrob.
Agents
Che-
mother.
Abstracts
35,
F97
(1995).
23.
This
work
was
supported
by
the
UN
Development
Programme-World
Bank-World
Health
Organization
Programme
for
Research
and
Training
in
Tropical
Diseases
(grant
930161)
and
the
National
Research
Council
of
Venezuela
(Consejo
Nacional
de
Investi-
gaciones
Cientificas
y
Tbcnicas,
grant
RP-IV-
1
10034).
We
acknowledge
technical
assistance
by
R.
Lira
and
G.
Visbal.
We
dedicate
this
paper
to
the
memory
of
Jose
Witremundo
Torrealba.
8
April
1996;
accepted
12
June
1996
Auditory
Neurophysiologic
Responses
and
Discrimination
Deficits
in
Children
with
Learning
Problems
Nina
Kraus,*
Therese
J.
McGee,
Thomas
D.
Carrell,
Steven
G.
Zecker,
Trent
G.
Nicol,
Dawn
B.
Koch
Children
with
learning
problems
often
cannot
discriminate
rapid
acoustic
changes
that
occur
in
speech.
In
this
study
of
normal
children
and
children
with
learning
problems,
impaired
behavioral
discrimination
of
a
rapid
speech
change
(Vda/versus/ga/)
was
cor-
related
with
diminished
magnitude
of
an
electrophysiologic
measure
that
is
not
depen-
dent
on
attention
or
a
voluntary
response.
The
ability
of
children
with
learning
problems
to
discriminate
another
rapid
speech
change
(/ba/versus/wa/)
also
was
reflected
in
the
neurophysiology.
These
results
indicate that
some
children's
discrimination
deficits
originate
in
the
auditory
pathway
before
conscious
perception
and
have
implications
for
differential
diagnosis
and
targeted
therapeutic
strategies
for
children
with
learning
dis-
abilities
and
attention
disorders.
Learning
and
attention
problems
occur
in
many
children,
often
concurrently
(1).
These
disorders
frequently
involve
an
in-
ability
to
process
complex
auditory
infor-
mation
that
occurs,
for
example,
in
speech.
In
fact,
a
large
subset
of
children
with
such
disorders
cannot
process
com-
plex
auditory
signals,
even
at
the
most
elemental
level
(2,
3).
A
comprehensive
study
is
under
way
to
examine
the
relation
among
psychophysical
speech
discrimination
abilities,
standardized
measures
of
learning
and
academic
achieve-
ment,
and
neurophysiology
in
a
large
pop-
ulation
of
both
normal
children
and
chil-
N.
Kraus,
Communication
Sciences
and
Disorders,
Northwestern
University;
and
Departments
of
Neurobiol-
ogy
and
Physiology,
and
Otolaryngology,
Northwestern
University,
Evanston,
IL
60208,
USA.
T.
J.
McGee,
S.
G.
Zecker,
T.
G.
Nicol,
D.
B.
Koch,
Communication
Sciences
and
Disorders,
Northwestern
University,
Evanston,
IL
60208,
USA.
T.
D.
Carrell,
Special
Education
and
Communication
Dis-
orders,
University
of
Nebraska,
Lincoln,
NE
68583,
USA.
*To
whom
correspondence
should
be
addressed.
E-mail:
dren
with
learning
problems.
One
aim
is
to
determine
whether
children
with
certain
auditory
processing
problems
have
difficul-
ties
that
originate
from
abnormalities
in
the
neurophysiologic
encoding
of
acoustic
dif-
ferences
in
speech
(which
occurs
after
pe-
ripheral
sensory
encoding
and
before
con-
scious
perception)
or
whether
the
problems
arise
from
some
higher
level
processing
def-
icit
(which
may
involve,
for
example,
lin-
guistic
or
cognitive
abilities)
(4).
Such
in-
formation
would
aid
in
the
diagnosis
and
treatment
of
these
children,
whose
learning
problems
have been
difficult
to
define
or
categorize.
An
important
aspect
of
this
work
is
to
establish
a
neurophysiologic
correlate
of
be-
havioral
discrimination.
Fortunately,
there
is
a
neurophysiologic
response
that
occurs
in
response
to
small
(as
well
as
large)
acous-
tic
changes
in
both
simple
and
complex
stimuli
(5).
This
response,
termed
the
mis-
match
negativity
(MMN),
provides
an
in-
dex
of
the
neurophysiologic
representation
of
acoustic
contrasts
and
thus
provides
a
tool
for
exploring
the
processing
of
acoustic
differences
that
underlie
speech
perception.
The
MMN
originates
in
the
auditory
thalamocortical
pathway
(6,
7)
and
demon-
strates
learning-associated
plasticity
(8).
It
is
elicited
by
a
physically
deviant
stimulus
oc-
curring
in
a
series
of
homogeneous
stimuli.
The
response
can
be
elicited
in
a
passive
paradigm
in
which
attention
or
behavioral
responses
are
not
required
(9).
It
has
been
obtained
during
sleep
in
infants
and
adults
and
during
wakefulness,
sleep,
and
barbitu-
rate
anesthesia
in
animal
models
(10).
From
a
developmental
standpoint,
the
MMN
is
robust
in
children
and
appears
to
be
mature
by
school
age
(11,
12).
Thus,
the
MMN
reflects
with
considerable
precision
the
dis-
crimination
of acoustic
change
and
can
be
used
to
determine
which
aspects
of
the
acoustic
signal
are
differentiated
neurophysi-
ologically
and,
ultimately,
which
neuronal
pathways
are
impaired
(7,
13).
In
this
experiment,
behavioral
discrimi-
nation
abilities
and
MMN
responses
were
evaluated
in
a
group
of
normal
children
(n
=
90)
and
in
a
group
of
children
with
learning
problems
(n
=
91).
The
normal
group
consisted
of
children
ages
6
to
15
years
with
no
history
of
learning
or
atten-
tion
problems
(based
on
a
detailed
parent
questionnaire)
and
scores
within
normal
limits
(including
no
discrepancy
between
ability
and
achievement)
on
a
psychoedu-
cational
test
battery
(14).
The
group
with
learning
problems
consisted
of
children
in
the
same
age
range
who
had
been
diagnosed
clinically
as
having
a
learning
disability
(LD
children),
attention
deficit
disorder
(ADD
children),
or
both;
in
some
cases,
they
had
scores
that
were
not
within
the
normal
limits
on
two
or
more
of
the
tests
in
the
psychoeducational
test
battery
and
a
history
of
learning
or
attention
difficulties
(suspected
LD).
All
children
had
normal
intelligence
(scores
>85
on
the
Brief
Cog-
nitive
Scale)
(14).
The
normal
group
dif-
fered
significantly
from
the
group
with
SCIENCE
*
VOL.
273
*
16
AUGUST
1996
971
on April 30, 2012www.sciencemag.orgDownloaded from
