Download Role of Antidiuretic Hormone in Impaired Urinary

Clinical Science (1980) 58,493-500
Role of antidiuretic hormone in impaired urinary dilution
associated with chronic bile-duct ligation
0. S. B E T T E R , G . A. A I S E N B R E Y , T. BERL, R. J. A N D E R S O N ,
W.A. H A N D E L M A N , S. L. L I N A S , S. J. G U G G E N H E I M A N D R. W.S C H R I E R
Department of Medicine, Universiry of Colorado Medical Center, and Department of Pathology, Veterans Administratton Hospital.
Denver, Colorado, U S A .
(Received 31 July 1979; accepted 2 February 1980)
Summary
1. The effect of chronic bileduct ligation on
systemic and renal haemodynamics and on the
capacity to dilute the urine was studied in conscious rats. Sham-operated rats served as controls.
2. In the rats with bile-duct ligation, the maximal urinary diluting czpacity was impaired, despite
an expanded plasma volume, a normal mean
arterial pressure and cardiac output, and normal
intrarenal determinants of water excretion including distal delivery of fluid and function of the
diluting segment.
3. In contrast, maximal urinary dilution
capacity was intact in rats with congenital central
diabetes insipidus and chronic bile-duct ligation.
4. It is concluded that the defect in urinary
dilution in rats with chronic bile-duct ligation is
dependent on antidiuretic hormone.
Key words: bile duct, haemodynamics, jaundice,
liver, water.
Introduction
Hyponatraemia secondary to an impaired ability of
the kidneys to excrete water may be seen in patients
with hepatic cirrhosis (Papper, 1958). This abnormality has been attributed, at least in part, to
diminished distal delivery of fluid to the diluting site
as a result of excessive proximal tubular reabsorption of sodium chloride (Schedl & Bartter,
Correspondence: Dr 0.s. Better, Department of
Nephrology, Rambam Medical Center, Haifa, Israel.
1961). This conclusion was based on the observation that in patients with cirrhosis manoeuvres
employed to augment distal delivery, such as the
infusion of iso-osmotic mannitol solution, could
correct the defect in renal water excretion (Schedl
& Bartter, 1961). In that study, however,
suppression of endogenous antidiuretic hormone
during the volume expansion produced by mannitol
could have contributed to the improved ability to
excrete water. Studies of the concentrations of
antidiuretic hormone in the blood and urine of
patients with cirrhosis of the liver have given
conflicting results (Chaudhury, Chuttani &
Ramalingswami, 1961; Lee & Kerr, 1963). The
purpose of the present study was to examine the
role of antidiuretic hormone in the impaired urinary
diluting capacity of rats with chronic bileduct
ligation.
Methods
Studies were performed on male SpragueDawley
rats of 150-350 g body weight. They were allowed
free access to Purina Rat Chow and distilled water
until the day of study. Ligation of the common bile
duct was performed under pentobarbital anaesthesia. The abdominal cavity was opened and the
common bile duct was mobilized. Two tight silk
ligatures were placed on the common bile duct at
distances of 6 and 8 mm from the duodenum. The
laparotomy wound was then sutured in layers. The
mortality rate was 15-20% in the 8-10 days after
Operation. Of the rats that SUrviVed the Operation
90% developed biochemical changes in the urine
493
0143-5221/80/060493-08S1.50/I
494
0.S . Better et al.
and blood characteristic of obstructive jaundice.
Post-mortem studies 8-10 days after chronic
bile-duct ligation showed gross dilatation of the
portion of the bile duct proximal to the ligatures.
Rats that failed to show biochemical evidence of
obstructive jaundice were excluded from this study.
In sham-operated rats the bile duct was exposed
and manipulated but not ligated. Sham-operated
and chronically bile-duct-ligated rats were studied
under similar conditions. The Brattleboro rats we
studied came from a breeding colony in this
laboratory and had a daily water intake of at least
80% of body weight, and a morning urinary
osmolality of 200 mosmol/kg or less. The studies in
conscious animals, which required intravenous
administration of fluid, were performed in a
restraining cage after the introduction of venous
and arterial lines under ether anaesthesia.
Analytical methods
Sodium was determined by flame photometry
and inulin by standard methods (Schrier &
Earley, 1970). Osmolality was determined by
cryoscopy with an Advanced Instruments 3L
osmometer. The following measurements were
made on plasma: bilirubin (Malloy & Evelyn,
1937);
glutamate-xaloacetate
transaminase
(Amador & Wacker, 1962); alkaline phosphatase
(McComb & Bower, 1972); total protein
(Kingsley, 1942); albumin (Kaplan & Savory,
1965); cholesterol (AUain, Poon, Chan, Richmond
& Fu, 1974); blood urea nitrogen (Beckman
Instruments,
197 1);
creatinine
(Watkins,
Feldkamp, Thibert & Zak, 1975). Blood volume
was determined by the method described by Thiel,
Wilson, Arce & Oken (1967) and by Flamenbaum,
Kotchen, Nagle & McNeil (1973). Microsphere
techniques were used for haemodynamic studies in
chronically bileduct-ligated and control rats (Hsu,
Kurtz & Waldinger, 1977) with modifications
described by Linas, Berl, Aisenbrey, Better &
Anderson ( 1980).
Glomerular jiltration rate (GFR) and free water
formation in chronically bile-duct-ligated and control rats
The right jugular vein and right carotid artery
were cannulated with polyethylene 50 tubing and
polyethylene 200 tubing was passed into the
urinary bladder. During surgery, 0.5% of the body
weight of iso-osmotic sodium chloride solution
(150 mmol/l) was infused to replace estimated fluid
loss. During a 60 min equilibration period a 4%
solution of inulin in hypo-osmotic sodium chloride
solution (75 mmol/l) was infused at 25 pl/min and
an intravenous water load equivalent to 5% body
weight was given as 2.5% glucose in water. Three
timed urine samples and a midpoint blood sample
(0.6 ml) were obtained. The blood was replaced
with an equal volume of iso-osmotic saline. The
resulting diuresis was then augmented by the
infusion of hypo-osmotic saline at rates of 0.2,0.4
and 0.8 ml/min. At each flow rate, the rat was
allowed to equilibrate for 30-45 min, after which
three timed urine collections and a midpoint blood
sample were obtained. All animals on this intravenous loading maintained urine osmolalities below
160 mosmol/kg during the study. G F R was estimated from the clearance of inulin. Absolute and
fractional osmolar clearance, free water clearance
and sodium clearance were calculated from standard formulae. Distal delivery of sodium was
approximated by the term C,, + C,,,,,and sodium
chloride reabsorption at the diluting site by C,,,,,.
The measurements were made in three groups of
rats: six anaesthetized chronically bile-duct-ligated
rats. five conscious chronically bileduct-ligated
rats, and eleven anaesthetized controls.
Oral water load in conscious rats
An oral water load of 30 ml/kg body weight was
given at 09.00 hours via a gastric tube. This was
done under very light ether anaesthesia. The rats
were placed in metabolic cages in an unrestrained
manner. They usually recovered from the effects of
ether within seconds of their placement in the
cages. Every specimen of voided urine during a
period of 3 h was collected for determination of
urinary osmolality and urine volume voided during
the 3 h of the experiment. The lowest osmolality
was used in the comparison of the groups.
Statistical analysis
Statistical analyses were performed with the
unpaired Student’s t-test. A P value of (0.05 was
taken as statistically significant. Mean results k
SEM are shown.
Results
Effect of chronic bile-duct ligation and shamoperation on body weight, liver function, plasma
sodium and blood urea nitrogen (Table 1 )
The rats lost weight after the bileduct ligation
but 8-10 days after chronic bile-duct ligation their
weight was about equal to the operative weight.
495
Urinary dilution in obstructive jaundice
TABLE1. Liver-function tests in sham-operated rats, chronically bile-duct-ligated Sprague-Dawley rats and
chronically bile-duct-ligatedBrattlehro rats
Mean results f SEM are shown with the ranges in parentheses. N.S., Not significant.
Bilirubin
(mg/l@Qml)
~~~
Plasma
glutamatt
oxaloacetate
transaminasc
(i.U.)
Cholesterol
(mgh00 ml)
Total protein
WI00 ml)
Albumin
W100 ml)
68.6 2.1
437 f 48
48.2 f 2.8
(65-77)
(236-526)
(42-58)
3738 f I749 1058 f 383
93.2 f 11.2
(250-11.260) (300-2320)
(60-125)
2854 f 915
586 f 182 138.4 f 50
(1095-5472)
(198-1242)
(53-319)
P < 0.005.
N.S.
P < 0405
6.0 f 0.05
(5.8-6.1)
N.S
3.9 f 0.5
(3.743)
2.6 f 0.2
( 1 * 7-3.3)
2.4 0.3
(1.4-3.1)
P < 0.001
~
Shamoperated Spraguc-Dawley rats 0.14 f 0.02
(0.1-0.2)
(n = 5)
Chronically bile-duct-ligated
6.1 f 1.6
Spraguc-Dawley rats (n = 6)
(1.0-10.7)
12.3 f 1.5
Chronically bileduct-ligated
diabetes insipidus rats (n = 5)
(7.7-16.7)
Shamoperated Sprague-Dawley
P < 0.01
rats vs bileduct-ligated
Spraguc-Dawley rats
Chronicallybile-duct-ligated
P < 0.02
diabetes insipidus rats vs
chronically bileduct-ligated
diabda insipidus rats
Chronically bileduct-ligated
P < 0.001
diabetes insipidus rats vs
sham-operated Spraguc-Dawley
rats
Alkaline
phosphatase
(i.u.)
~
~~
6.2 0.4
(4.4-6.5)
5.5 f 0.6
(3.6-6.5)
N.S.
N.S.
N.S.
N.S
N.S.
P < 0.005*
NS.
P < 0*005*
NS.
P < 0.05
The Wilcoxon Rank sum test was used to determine this P value, because of the variation in experimental values.
Sham operation, on the other hand, did not
interfere with normal weight-gain pattern at 8-10
days after operation. Ascites formation after
chronic bileduct ligation was seen only very rarely
in the present study.
Histological examinations of the liver were
performed on 16 chronically bile-duct-ligated
Sprague-Dawley rats and on all five chronically
bile-duct-ligated diabetes insipidus rats reported in
the oral water load study. The specimens showed
characteristic changes of obstructive jaundice:
proliferation of bile canaliculi, acute and chronic
inflammatory changes and early fibrosis. The
histopathology of the chronically bileduct-ligated
Sprague-Dawley rat was indistinguishable from
that of the chronically bileduct-ligated diabetes
insipidus rat. Liver from sham-operated rats
appeared normal on histological examination.
Table 1 shows the results of some liver-function
tests in three groups of rats. It can be seen that the
chronically bileduct-ligated (Sprague-Dawley and
diabetes insipidus) rats had statistically significant
increases in plasma bilirubin, cholesterol and
glutamate-oxaloacetate transaminase, and a decreased plasma albumin. The increase in plasma
alkaline phosphatase was not statistically significant. These histopathological and biochemical
changes have been reported previously by others
(Trams & Symeonidis, 1957; Ryan, Than &
Blumgart, 1977).
Mean plasma sodium was 137
SEM 0-6
mmolfi in chronically bile-duct-ligated rats (n = 6)
and 141 f 1.8 mmol/l in sham-operated rats (n =
6), values not significantly different. Plasma blood
urea nitrogen and creatinine were 19-4 f 2.2 and
0.4 f 0.1 mg/dl respectively in chronically
bileduct-ligated rats (n = 8), results not statistically different from those for sham-operated rats,
14.7 4 0.8 and 0.6
0.01 mg/dl (n = 13) for
plasma blood urea nitrogen and creatinine
respectively.
-+
Total plasma and blood volumes
Plasma and blood volumes were measured in five
chronically bile-duct-ligated and four control rats
of comparable weight (195 and 210 g respectively).
The plasma volume of chronically bile-duct-ligated
rats was greater either when expressed in absolute
volumes (10.4 f 0.43 vs 6-93 f 0.31 ml, P <
0.001) or when corrected for body weight (5.47 f
0.43 vs 3-56 f 0.25 m1/100 g, P < 0.01). This
increase in plasma volume was associated with a
decrease in packed cell volume in these rats (38.3
k 1.0 vs 44.4 i- 1.4, P < 0.02), and neither the
absolute nor corrected blood volume was different
in the two groups.
0.S. Better et al.
496
TABLE
2. Haemodynamic study in conscious chronically bile-duct-ligatedand sham-operafed rats
Mean results f SEM arc shown. N.S.,Not significant.
Mean
arterial
pressure
(mmHg)
Conscious chronically bdeduct-ligated rats (n = 10)
Conscious sham-operated
rats (n = 9)
P
Cardiac index
(mlmin-' kg-I
body wt.)
Systemic
vax u I ar
resistance
(mmHg ml min-'
kg-l body wt.)
Renal
blood
(mlmin-I 8-l
kidney wt.)
Total renal
vascular
resistance
(mmHg ml min-l
g-I kidney wt.)
flow
99 f 5
289 f 31
0.31 f 0.04
3.1 f 0.5 3.4 f 0.4
41.1 f 10.4
104f3
214 f 19
0.39 f 0.03
5.8 f 0.4 5.9 f 0.2
17.7 f 0.9
N.S.
N.S.
N.S.
Studies on systemic and renal haemodynamics
(Table 2)
Since recent studies in our laboratory have
shown that anaesthesia can profoundly affect
systemic and renal haemodynamics (Linas et al.,
1980), and our preliminary studies revealed that
this effect was particularly marked in chronically
bile-duct-ligated rats, the present studies were
performed in nine conscious sham-operated rats
and in ten conscious chronically bile-duct-ligated
rats. As shown in Table 2, mean arterial pressure,
cardiac index and systemic vascular resistance
were not different in these two groups of animals.
In contrast, the renal blood flow was lower (P <
0.005) and total renal vascular resistance higher (P
< 0.05) in the chronically bile-duct-ligated rats.
Thus, in spite of normal systemic haemodynamics,
the conscious chronically bileduct-ligated rat had a
more than twofold increase in total renal vascular
resistance and a decrease of more than 40% in total
renal blood flow.
GFR in chronical[y bile-duct-ligated and control
animals (Table 3)
Inulin clearance (GFR) under basal conditions
in anaesthetized chronically bileduct-ligated rats
(n = 6) was comparable with that seen in anaesthetized controls (n = 11) (1 1.O f 0.8 vs 9.0 f
1.1 ml min-' kg-I body weight). These values were
also similar to the basal G F R of conscious
chronically bile-duct-ligated rats (n = 5) (8.7 f 0.8
ml min-' kg-' body weight). The increase in G F R
after hypotonic volume expansion was similar in
anaesthetized control rats, and in conscious
chronically bile-duct-ligated rats (1 1.7 f 1.0, 11.O
f 1.3 and 11.0 f 1.0 ml min-I kg-' body weight
respectively).
<0.001
<0.001
<0.05
Studies assessing distal delivery of sodium chloride
and the function of the diluting segment limb
(Table 3; Fig. 1 )
Hypo-osmotic saline infusions were performed in
three groups of animals: (1) control anaesthetized
rats (n = l l ) , (2) chronically bile-duct-ligated
anaesthetized rats (n = 6) and (3) conscious
chronically bile-duct-ligated rats ( n = 5). As can be
seen in Table 3, values obtained at peak hypoosmotic volume expansion such as rate of urine
flow, absolute and fractional C,,,,, and distal
deliveries were comparable in all three groups.
In Fig. 1 the relation between calculated
fractional distal delivery on the abscissa (CNl +
C,,,,,)/GFR is plotted against calculated sodium
chloride reabsorption in the diluting segment limb
on the ordinate (C,,,,,/GRF).
It shows that
calculated sodium chloride reabsorption for given
rates of calculated distal deliveries are comparable
in all three groups studied.
It can be concluded from these experimeiits that
distal delivery of fluid and sodium chloride and
diluting segment function are unchanged in
chronically bile-duct-ligated rats despite the
increased total renal vascular resistance and
diminished total renal blood flow of these animals.
Minimal urinary osmolality aJer an oral water
load in conscious unrestrained rats (Table 4 )
Included in this study are observations in 17
chronically bileduct-ligated Sprague-Dawley rats,
25 sham-operated Sprague-Dawley rats each
studied 'once, and five Brattleboro diabetes insipidus rats each studied twice (once before chronic
bile-duct ligation and then again after chronic
bile-duct ligation). Results of liver-function tests of
six of these 17 chronically bile-duct-ligated
P
Control anaesthetized vs
chronically bile-ductligated anaesthetired rats
P
Chronically bilcductligated anaesthctizcd
rats (n = 6)
Control anaesthetizcd
rats ( n = 11)
Chronically bdcductligated conscious rats
(n = 5)
Chronically bileductligated conscious vs control
anaesthctizcd rats
NS.
N.S.
N.S.
NS.
535 f 54
l l . 0 f 1.0
8.7 f 0.8
N.S.
N.S.
583 f 43
11.0 f: 1.3
9-0 f 1.1
583 f 63
11.7 f 1.0
Maximum
urine flow
@/min)
11 *O ? 0.8
Basal
lnulin clearance
(ml min-' kg-' body wt.)
+ CN,
N.S.
N.S.
N.S.
NS.
538 f 34
244f I8
247 f 26
566 f 58
Od/min)
C,,,
262 f 13
CWI,
@/min)
N.S.
N.S.
11.0 f 2.1
14.6 f 2.5
(%I
100 C,,,AGFR
+ C,J/GFR
(%I
N.S.
N.S.
23.4 f 3.1
32.4 f 8.0
100 (C,,,,
TABLE
3. Free waterformation at thepeak of hypo-osmotic volume expansion in anaesthetized chronically bile-duct-ligatedrats and in control rats
Mean results 2 SEM are shown.
NS.
46.8 f: 3.1
41.6f: 3.0
4' )aN'
(%I
100 C,,A
(cwalct
0'
3
a.
3
C
0.S. Better et al.
498
TABLE4. Minimal urinary osmolality and percentage of water excreted afler
oral water load in conscious sham-operated and bile-duct-ligated rats
Mean results f SEM are shown.
Sham-operated rats ( n = 25)
Spraguc-Dawley bile-duct-ligated rats (n = 17)
Diabetes insipidus chronically bikduct-ligated
rats ( n = 5)
Diabetes insipidus rats before chronic bileduct ligation (n = 5)
P < 0.001
Minimal urinary
osmolality
(mosmol/kd
% o f water load
excreted
127 i: 7
247 f 25.
115 f 14
94 f 3
83 i: 6
171 f 3
6.
127 f 12
126 i: 21
vs sham-operated rats and vs diabetes insipidus chronically bile-duct-ligated
rats.
** P < 0.05 vs sham-operated rats and vs Sprague-Dawley
25J
20
-
::
c! 1 5 -
-2
-"
U
L.
g
10-
e
LI.
5-
0
5
10
15
20
25
Distal sodium delivery
FIO. 1. Relation between calculated distal delivery
(CN, + Cw,tr!ml min-l 100 ml-' GFR) of sodium
chloride (horizontal axis) and calculated sodium
reabsorption (C,,,,, ml min-' 100 ml-' GFR) in the
thick ascending limb (vertical axis) obtained during
intravenous infusion of hypo-osmotic sodium chloride
solution (75 mmolh). 0,Results obtained from six
anaesthetized chronically bile-duct-ligated rats; 0 , results
from 11 anaesthetized control rats. The two broken
curves delineate the range obtained in normal conscious
rats studied in this laboratory by Liaas et al. (1978). It
can be seen that sodium reabsorption at the thick
ascending limb for given rates of distal delivery is
similar in all three groups studied. This suggests normal
distal delivery and ascending limb function in the
chronically bileduct-ligated rats.
Sprague-Dawley rats, five of 25 sham-operated
Sprague-Dawley rats and all five chronically
bile-duct-ligated Brattleboro diabetes insipidus rats
are given in Table 1. Minimal urinary osmolality in
the chronically bile-duct-ligated Sprague-Dawley
bileduct-ligated rats.
rats was higher than in sham-operated SpragueDawley rats (247 f 25 vs 127 f 7 mosmol/kg, P <
0401). Minimal urinary osmolality of chronically
bile-duct-ligated Brattleboro diabetes insipidus rats
was lower than in chronically bile-duct-ligated
Sprague-Dawley rats (115 f 14 vs 247 f 25
mosmol/kg, P < 0.001). Minimal urinary osmolality of the chronically bile-duct-ligated Brattleboro diabetes insipidus rats was comparable before
and after chronic bile-duct ligation.
The percentage of ingested water excreted was
lower in the chronically bile-duct-ligated SpragueDawley rats than in sham-operated SpragueDawley rats. This diminution in urinary volume
after a water load in the chronically bile-ductligated Sprague-Dawley rats approached but did
not quite reach statistical significance (83 f 6 vs
94 f 3%). Interestingly, the percentage water load
excreted in the Brattleboro diabetes insipidus rats
was greater after chronic bileduct ligation than
before chronic bile-duct ligation. This increase,
which suggests augmented distal delivery after
chronic bile-duct ligation, was not, however,
statistically significant.
Discussion
Studies of sodium chloride reabsorption along the
nephron in rats with bile-duct ligation by micropuncture techniques have yielded conflicting results
(Bank & Aynedjian, 1975; Yarger, Schrader &
Boyd, 1976; Allison, Moss, Fraser, Dobbie, Ryan,
Kennedy & Blumgart, 1978). Our results in
conscious rats suggest that proximal tubular
reabsorption of sodium chloride is normal after
bile-duct ligation.
In the present study, renal blood perfusion was
Urinary dilution in obstructive jaundice
decreased in rats with chronic bile-duct ligation
despite normal systemic haemodynamics. Impaired
renal blood flow has been associated with liver
damage in man (Wilkinson, Smith, Clarke, Arroyo,
Richardson, Moodie & Williams, 1977) and several
animal models (Dawson, 1964; Bloom, Bomzon,
RosendorfF& Kew, 1976; Yarger et al., 1976).
The present study shows that liver damage due
to chronic bileduct ligation in the rat is associated
with an impaired capacity to lower urinary osmolality maximally. The defect in urinary dilution
occurred despite adequate systemic circulation and
in the face of normal intrarenal determinants of
water excretion such as distal delivery of fluid and
intact function of the diluting segment. On this
background, the observation that the defect in
urinary dilution occurred only in animals with an
endogenous source of antidiuretic hormone
strongly suggests that this defect is antidiuretic
hormone-dependent.
Our conclusion that the intrarenal dilution
mechanism was intact after chronic bile-duct
ligation is based mainly on the crucial finding of
normal ability to lower urinary osmolality maximally in conscious, unrestrained, non-volumeexpanded rats, with congenital diabetes insipidus
and chronic bileduct ligation.
The validity of the assumption that C,,,,, reflects
sodium chloride transport at the diluting sites
assumes that free water is generated at the thick
ascending limb by sodium chloride reabsorption
and this site is always water impermeable. During
water diuresis the distal tubule and collecting duct
are relatively impermeable to water and the urine
approaches the composition of the tubular fluid
leaving from the thick ascending limb. The usefulness and the limitations of using this methodology for assessing diluting segment function have
been discussed in detail (Seldin & Rector, 1973;
Ish-Shalom, Rapoport, Chaimovitz & Better,
1978).
Hyponatraemia is common in patients with
cirrhosis, but was not seen in our rats. The reason
for this is probably the more severe defect in
urinary dilution in advanced cirrhosis, which may
be due to a conservation of a diminished distal
delivery of fluid and an increased secretion of
antidiuretic hormone. On this background, excessive thirst stimulated by inadequate effective
blood volume would lead to positive water balance
and hyponatraemia. In contrast, our rats with
bile-duct ligation could excrete some hypo-osmotic
urine despite the defect in maximal lowering of
urinary osmolality. This apparently was sufficient
499
to compensate for water ingestion without causing
hyponatraemia.
In summary; our finding suggests that impaired
urinary dilution in conscious rats with chronic
bile-duct ligation is due to a sustained secretion of
antidiuretic hormone. This is compatible with the
finding of lowered osmotic threshold for release of
antidiuretic hormone in patients with cirrhosis
(Earley & Sanders, 1959) and in dogs with chronic
bile-duct ligation (Melman & Robertson, 1977).
Acknowledgments
This work was published in abstract form (Clinical
Research, 1978, 26, 457A) and presented at the
meetings of the American Federation for Clinical
Research, National Meeting, San Francisco,
California, May, 1978. This work was supported
by a grant from the National Institutes of Health.
AM 19928. 0. S. B. is an Established Investigator,
Office of the Chief Scientist, Ministry of Health of
Israel, and was a visiting Professor of Medicine on
sabbatical leave from Rambam Medical Center and
Technion School of Medicine, Haifa, Israel. R. J. A.
is a recipient of a NIH Research Career Development Award. We are grateful to Abby Erickson,
Marilyn Bard, Patricia Arnold and David Hyde for
technical assistance and to Linda Benson for
secretarial assistance.
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