The physiologic basis of the TUR syndrome

JOURNAL

OF SURGICAL

RESEARCH

46,135-141

(1989)

The Physiologic GUY T. BERNSTEIN, Department

M.D.,

Basis of the TUR Syndrome’

KEVIN

R. LOUGHLIN,

of Urology, Brigham and Women’s Hospital, and Harvard Submitted

for publication

To better asses8 the role of hyperammonemia versus hypoosmolarity versus hyponatremia in the TUR syndrome, we developed a rat model. Sprague-Dawley female rats received an intraperitoneal injection (250 cc/ kg body weight) of either 1.5% glycine, 2.0% glycine, 2.0% glycine plus 1.5% mannitol, 3.0% mannitol, 5.0% mannitol, or 2.0% glycine plus 0.25% saline. Arterial blood samples were obtained prior to injection, at 2, 8, 16, and 24 hr and analyzed for osmolarity, sodium, and ammonia. Those animals receiving 2.0% glycine, 2.0% glycine plus 1.5% mannitol, and 5.0% mannitol all died within 24 hr with lethargy, convulsions, and coma. Hyponatremia developed in all animals; death, however, occurred only when the sodium concentration declined to 90-95 meq/dl. Mannitol maintained serum osmolarity but did not prevent coma and death. Including 0.25% saline in the initial injection, or an iv injection of 5.0% saline delayed 8 hr achieved 100% survival. Ammonia concentrations increased 15-fold by 8 hr in groups receiving 2.0% glycine; it rapidly decreased to near normal by 24 hr. Decreasing the rise in ammonia by 50% with iv arginine had no effect on survival. Our results suggest that hyponatremia rather than hyperammonemia or hypoosmolarity accounts for the major morbidity and mortality secondary to the TUR syndrome. o mm Academic Press,

M.D.,

Medical School, Boston, Massachusetts

02115

August 3, 1987

METHODS

For the study, female Sprague-Dawley rats weighing 180-250 g were obtained from Charles River Breeding Laboratory, Inc. (Wilmington, MA). They were housed in the animal facility at Harvard Medical School for a minimum of 1 week prior to the experiment. The animals were maintained on standard rat chow and given water ad lib until the night prior to the study, at which time food was withheld. Water was provided throughout the study period. Each experimental group consisted of five animals, and received an intraperitoneal injection (250 cc/kg body weight) of one of the following solutions: 1.5% glycine (180 mOsm/liter), 2.0% glycine (275 mOsm/liter), 2.0% glycine with 0.25 normal saline (350 mOsm/liter), 2.0% glycine with 1.6% mannitol(350 mOsm/liter), 3.0% mannitol (180 mOsm/liter), or 5.0% mannitol (290 mOsm/liter). Chemicals and their sources include: glycine (Fisher Scientific, Fairlawn, NJ), D-mannitol (Aldrich Chemical Co., Inc., Milwaukee, WI), sodium chloride (Mallinckrodt, Inc., Paris, KY), and L-arginine hydrochloride (Aldrich Chemical Company, Inc., Milwaukee, WI). All solutions were prepared in the laboratory with distilled water and heat sterilized. At the time of the in-

INTRODUCTION

During transurethral resection of the prostate (TURP), large quantities of irrigating fluid can be absorbed through venous sinuses in the periprostatic space into the vascular compartment [13, 23-26, 291. The cardiovascular and central nervous system symptoms that result from this absorption of fluid have been termed the TUR syndrome and include bradycardia, hypertension followed by hypotension, nausea, vomiting, headache, visual disturbances, agitation, confusion, and lethargy. If left untreated, these patients can occasionally progress to seizure, coma, cardiovascular collapse, and, rarely, death [4, 5, 14, 15, 28, 351. It is generally believed that the clinical Urological

M.D.

findings are a result of hypervolemia and dilutional hyponatremia with subsequent cerebral edema and encephalopathy [3, 33, 361. Some have postulated that the concomitant reduction in serum osmolality contributes to this syndrome. Recently, several authors have reported elevations in the ammonia level in patients with encephalopathic changes following transurethral resection of the prostate [17, 31, 321. The hyperammonemia is thought to result from the metabolism of glycine absorbed during surgery. Glycine undergoes oxidative deamination in the liver predominantly, resulting in the formation of glyoxylic acid and ammonia. Elevated plasma ammonia has been shown to occur in encephalopathies associated with certain congenital liver diseases, Reye’s syndrome, and hepatic coma secondary to cirrhotic liver disease [9, 221. To better assess the role of hyperammonemia versus hyponatremia versus hypoosmolality in the TUR syndrome, a rat model was developed in the laboratory.

Inc.

1 Presented at the Annual Meeting of the American sociation, Anaheim, CA, May 1’7-21, 1987.

AND RUBEN F. GITTES,

As-

135 All

oozz-4804/89 $1.50 Copyright 0 1989 by Academic Press, Inc. rights of reproduction in any form reserved.

136

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traperitoneal injection, each rat received 1 unit of vasopressin tannate (Pitressin, Parke-Davis, Morris Plains, NJ) intramuscularly to augment the hyponatremic response. Arterial samples were obtained via aortic puncture and the animals were sacrificed at 2,8,16, and, in those still alive, 24 hr postinjection. Samples were analyzed for osmolality (Advances Wide Range Osmometer 3W2, Advanced Instruments, Inc., Needham Heights, MA), and sent to Bioran Medical Laboratories (Cambridge, MA) for sodium (SMAC) and ammonia (quantitative enzymatic determination, Sigma Diagnostics, St. Louis, MO) concentrations. Animal behavior was assessed at these time points with regard to circling behavior, lethargy, myoclonic jerks or generalized seizure activity, and coma. Ten animals were used as controls, and arterial samples were obtained in the morning following the overnight fast. In a second set of experiments, various therapeutic interventions were attempted in groups of rats injected with some of the above solutions. Animals receiving 2.0% glytine, 2.0% glycine with 0.25 NS, 2.0% glycine with 1.5% mannitol, and 3.0% mannitol were injected intravenously with arginine hydrochloride (2.8 mg/kg body weight) at the onset in order to reduce the rise in ammonia. In groups of animals receiving 2.0% glycine and 2.0% glycine with

of the Intraperitoneal

Injection

on Sodium,

Hours postinjection Control

0

1989

1.5% mannitol, one-half the estimated sodium deficit was replaced with 5% hypertonic saline infused intravenously 8 hr following the intraperitoneal injection. Arterial samples were obtained at the same time points indicated above, and analyzed for osmolality, sodium, and ammonia. The Student t test was used for statistical analysis of all data. RESULTS

Those groups of animals receiving 2.0% glycine, 2.0% glycine with 1.5% mannitol, and 5.0% mannitol all died within 24 hr of the intraperitoneal injection with progressive lethargy, convulsions, and coma. The other groups all survived into the next 24-hr period, although the rats receiving 3.0% mannitol were quite lethargic at 24 hr and most expired by 36 hr. A significant elevation of the ammonia concentration was obtained in all rats receiving glycine infusions, and the increase was proportional to the concentration of glytine in the solution. As shown in Fig. 1, the ammonia concentration increased from a control value of 996.5 f 16.5 rg/liter to a maximum of 15,327.O f 261.0 rg/liter and 6259.3 + 373.5 pg/liter at 8 hr in the 2.0% glycine

TABLE Effect

VOL. 46, NO. 2, FEBRUARY

1

Ammonium,

and Osmolality

Osmolality

at Various

Sodium

Time

Points

Ammonia

312.2 9 14.0

138.2 +

4.6

2 8 16 24

275.0 283.4 288.0 272.0

106.2 99.6 101.0 100.4

+ f k Ik

1.3 2.4 1.7 3.0

4918.5 6259.3 2890.0 2127.5

+ k k +

373.5 218.1 621.0 499.5

2 8 16 24

301.2 + 5.5 303.6 + 3.1 307.0 -t 9.9 a

113.4 * 98.0 + 92.8 f a

2.2 2.9 6.1

7396.5 + 15327.0 k 3823.5 f a

740.5 261.0 163.5

2 8 16 24

310.6 325.0 330.6 316.2

130.0 118.2 116.0 116.0

2.1 9.5 1.9 3.2

8059.0 16565.0 3815.5 1308.0

2 8 16 24

310.6 2 10.3 334.8 -+ 5.8 326.4 f 5.7 D

109.0 * 5.7 91.8 + 5.6 95.4 + 8.5 0

3.0% Mannitol

2 8 16 24

267.6 287.6 313.4 316.6

104.4 94.0 97.2 95.2

5.0% Mannitol

2 8 16 24

293.6 + 1.9 319.6 -c 5.3 331.4 k 10.7 e

1.5% Glycine

2.0% Glycine

2.0% Glycine/O.25

2.0% Glycine/l.5%

NS

mannitol

Note. Values are means + SD. 0 All animals in the group died.

+ + zk zk

5.6 4.0 8.8 7.9

k 2.7 + 3.1 k 6.3 + 18.9

+ 2.7 + 2.8 k 6.1 -t 7.9

f f. f +

57 + f +

4.9 1.1 2.9 3.7

102.2 + 1.3 93.2 f 10.8 89.0 * 4.5 (I

996.5 -t

16.5

f 46.0 k 1135.0 + 106.5 + 17.0

7955.5 + 912.5 12055.0 + 1871.0 3645.5 + 131.5 a 2190.0 2244.0 1614.5 2490.0

+ + f +

213.0 15.0 39.5 330.7

1807.5 k 307.5 3314.5 k 108.5 3161.0 f 31.0 D

BERNSTEIN,

LOUGHLIN,

AND

GITTES:

TUR

137

SYNDROME

J 4 HOURS 1 2

0 0

8 HOURS

I6

POST

L 24

INJECTION

FIG. 1. Serum ammonia concentration at 2, 8, 16, and, in those animals surviving, 24 hr following the intraperitoneal injection of the indicated solution. Elevations in serum ammonia concentration were proportional to the concentration of glycine in the infused solution.

and 1.5% glycine groups, respectively. Those animals receiving 2.0% glycine with either mannitol or saline had a rise in ammonia comparable to that of the 2.0% glycine only group. In all cases, the ammonia elevation was shortlived with a peak at 8 hr, and a rapid return to near normal at 24 hr. The rats treated with nonglycine (mannitol) solutions did demonstrate a slight rise in the ammonia concentration with values in the range of 1614.5-3314.5 rg/ liter. As can be seen in Fig. 2, the serum osmolality was related to the osmolality of the infused solution. The hypoosmolar 1.5% glycine produced a decline in serum osmolality to under 290 mOsm/liter, whereas the isoosmolar 2.0% glycine maintained the serum osmolality within the 300-310 mOsm/liter range. The addition of mannitol or saline to the 2.0% glycine infusion produced a hyperosmolar solution and resulted in a serum osmolality above 310 mOsm/liter. The mannitol-treated animals (Fig. 3)

POST

INJECTION

FIG. 3. Serum osmolality at 2,8,16, and, in those animals surviving, 24 hr following the intraperitoneal injection of 3% mannitol and 5% mannitol.

initially experienced a decline in serum osmolality; however, by 16 hr, the osmolality was 313.4 + 6.1 and 331.4 + 10.7 in the 3.0% and 5.0% mannitol groups, respectively. A possible diuretic effect of mannitol, to explain the latter rise in osmolality, was not measured. Progressive hyponatremia developed in all animals receiving intraperitoneal injections (Fig. 4). As would be expected, the 2.0% glycine with 0.25 NS group had the smallest decline in the sodium concentration reaching a nadir of 116.0 f. 3.2 meq/dl. The most significant fall in serum sodium concentration occurred in those groups in which the animals died by 24 hr, namely, 2.0% glycine, 2.0% glycine with 1.5% mannitol, and 5.0% mannitol. In addition, the rats treated with 3.0% mannitol had a profound decline in the serum sodium by 24 hr. By 16 hr, the sodium had fallen in the above groups of rats into the 89.0-95.4 meq/dl range, whereas the animals receiving 1.5% glycine maintained a serum sodium above 100.4 meq/dl. There was a statistically significant difference in the serum sodium concentration between those animals that survived and those that died (P < 0.05).

A-A m---8

1.5% gly 2% gly

. . . . . . ..*

2% 2%

gly/rK glY/"m

3%

man

A-A o----o ,-.,o

0 0

2

I 16

8 HOURS

POST

1 24

INJECTION

FIG. 2. Serum osmolality at 2,8,16, and, in those animals surviving, 24 hr following the intraperitoneal injection of the indicated solution. Serum osmolality reflected the osmolality of the infused solution.

2

8 HOURS

POST

5 % man

I6

24

INJECTION

FIG. 4. Serum sodium concentration at 2,616, and, in those animals surviving, at 24 hr following the intraperitoneal injection of the indicated solution. A statistically significant difference (P < 0.05) was noted at 16 hr in the sodium concentration between the rats that survived and those that died.

138

JOURNAL

16 14 12 -

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RESEARCH:

VOL. 46, NO. 2, FEBRUARY

\

1 8---m

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\

130 \

--..

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120 \ \ “b

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1989

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OF SURGICAL

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‘.,/&*

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5% NoCl

130 I\

1201

I

2

I

1

8 HOURS POST

\

16

2

INJECTION

FIG. 5.

Serum ammonia concentration at 2, 8, 16, and, in those animals surviving, 24 hr following the intraperitoneal injection of 2% glycine or 2% glycine with 0.25% saline versus similar groups receiving intravenous arginine hydrochloride (2.8 mg/kg body weight) at the onset.

In order to further determine the impact of ammonia production on mortality, arginine hydrochloride was infused intravenously after the initial intraperitoneal injection in rats receiving glycine in any combination. In all groups receiving glycine solutions (Fig. 5), the peak ammonia concentration was reduced by 50%, but this did not alter animal survival. A8 a control, arginine was also infused in a group receiving 3.0% mannitol, and no significant change in the ammonia concentration was produced (Fig. 6). A second therapeutic intervention con-

FIG. 6. Serum ammonia concentration at 2, 8, 16, and, in those animals surviving, 24 hr following the intraperitoneal injection of 3% mannitol versus a similar group receiving intravenous arginine hydrochloride (2.8 mg/kg body weight) at the onset.

I 2

1

I I6

8 HOURS

POST

1I 24

INJECTION

FIG. ‘7. Serum sodium concentration at 2,8,16, and 24 hr following the intraperitoneal injection of 2% glycine or 2% glycine with 1.5% mannitol versus similar groups receiving 5% hypertonic saline at 8 hr in order to replace one-half the calculated sodium deficit.

&ted of replacing one-half the calculated sodium deficit with 5% hypertonic saline at 8 hr postintraperitoneal injection. As shown in Fig. 7, this therapy resulted in a rise in serum sodium and 100% survival at 24 hr in those animals receiving either 2.0% glycine or 2.0% glycine with 1.5% mannitol. DISCUSSION

Since the initial report by Creevy and Webb [6] describing a fatal reaction following transurethral surgery, numerous reports on the TUR syndrome and its pathophysiology have appeared in the literature [4, 5, 13-15, 23-26,28,29,33,35]. The cardiovascular and CNS symptoms were initially explained by the rapid absorption of large amounts of nonelectrolyte, hypoosmolar irrigating fluid through periprostastic venous sinuses with subsequent hypervolemia and dilutional hyponatremia. Although the pathophysiology of the neurologic symptoms associated with hyponatremia has not been completely elucidated, it is thought that subsequent cerebral edema results in seizures, coma, and eventually death. Several recent reports have postulated that hyperammonemia resulting from glycine metabolism may play a role in the TUR syndrome [17,31,32].

BERNSTEIN,

LOUGHLIN,

AND

TABLE Effect

of the Therapeutic

Intervention

on Sodium,

GITTES:

TUR

139

SYNDROME

2

Ammonium,

and Osmolality

at Various

Time Points

Hours postinjection

Osmolality

Sodium

Ammonia

2.0% Glycine/arginine

2 8 16 24

291.0 k 4.8 310.6 + 9.8 327.2 k 16.7 D

107.8 + 2.1 103.2 + 1.7 110.2 f 9.2 0

4602.0 k 284.0 7007.2 + 4477.1 4812.0 -+ 376.0 0

2.0% Glycine/O.25 NS/arginine

2 8 16 24

310.6 f 2.0 322.0 3~ 4.8 312.4 k 13.9 315.0 f 2.2

128.2 f 119.4 + 121.6 + 131.3 +

5.4 4.2 3.4 3.3

3636.5 f 265.5 7042.0 + 528.0 3859.0 5~1576.0 1144.0 + 264.0

2.0% Glycine/l.S% mannitol/arginine

2 8 16 24

312.0 k 2.8 329.0 -t 10.1 329.7 k 2.4 a

111.4 + 1.0 99.2 + 2.3 89.0 k 5.1 0

3295.5 + 416.5 6429.0 2 1015.0 5639.0 + 338.0 a

3.0% Mannitol/arginine

2 8 16 24

271.6 + 2.2 291.2 f 8.0 297.2 f 4.2 b

106.0 f 2.3 95.4 f 5.3 90.8 + 1.7 b

1117.5 + 1553.0 * 2538.0 + b

2.0% Glycine/5% saline

24

285.0 + 17.3

118.2 + 5.2

1087.0 + 254.0

2.0% Glycine/l.5% mannitol/b% saline

24

326.0 f 17.8

115.2 + 4.1

1326.0 + 265.0

56.5 76.0 94.0

Note. values are means + SD. ’ All animals in the group died. bSixty percent of animals in the group died.

Glycine is a nonessential amino acid that is normally present in the circulation, Oxidative deamination of glytine in the liver, and less so in the kidneys, results in the formation of glyoxylic acid and ammonia. Under normal conditions, the activity of the enzyme is thought to be quite low; however, in the presence of glycine, its activity may be significant. A far less important metabolic pathway is the conversion of glycine to serine. In both animals and man, the intravenous infusion of glycine has resulted in increased concentrations of ammonia. Ammonia is normally converted to urea in the liver through the urea cycle. In patients with hepatic failure, congenital or acquired defects in the urea cycle, portocaval shunts, or receiving ammonia infusions, the ammonia cannot be completely metabolized by the liver, and it enters the systemic circulation without being converted to urea [22]. While skeletal muscle may play an important role in detoxifying ammonia by converting it to glutamine, some ammonia may also enter the central nervous system. It has been suggested that the increased brain ammonia concentration is related to the development of encephalopathy. However, not all cases of hepatic coma occur in association with elevated blood ammonia levels [9]. Moreover, several other agents have been shown to exhibit neurotoxic potential. In fact, glycine is an inhibitory neurotransmitter and has been found in various sites in the CNS [30]. Several cases have been reported in which a greater than lo-fold rise in the level of glycine from preoperative results was noted following routine TURP [ 10, 20,301. Some authors have suggested that glycine directly

is responsible for isolated visual disturbances post TURP because of its inhibitory effect on retinal neurons [l, 6, 10, 11, 20, 301. The study was conducted to better assess the factors that may contribute to the TUR syndrome and analyze possible therapeutic interventions. A significant elevation of the ammonia concentration was obtained in all animals receiving glycine and the increase was proportional to the amount of glycine in the solution. Fahey in the 1950s reported elevations in blood ammonia concentrations which were proportional to the rate of glycine administration in both dogs and humans [8,27]. However, Madsen and Madsen failed to demonstrate any significant change in the free whole blood ammonia concentrations in six dogs before and after intravenous infusion of 1.5% glycine [23]. More importantly, in our study, the ammonia elevation was short-lived with a peak at 8 hr, and near normalization by 24 hr. This finding is compatible with the clinical cases which have documented hyperammonemia following TURP. In those cases, the highest elevation was recorded in the immediate postoperative period and returned to normal levels by 24 hr. [17, 31, 321. The ammonia concentration of 996.5 + 16.5 pg/liter in our control rats is comparable to previous reports in the literature which have noted ammonia levels ranging from 400 to 1020 fig/liter [16,18,19,21]. However, all of these studies in the rat model have investigated the effects of a chronic hyperammonemic state. Kyu and Cavanagh reported an elevation in the ammonia concentration to 4000-5000 pg/liter in rats subjected to portocaval shunts

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without observing encephalopathic changes [21]. In a similar model and with a comparable elevation in the ammonia level, Hertz et al. noted mild encephalopathic changes, including a change in posturing and spontaneous motor activities and alterations in the electrocorticographic pattern [16]. Other studies have reported less significant changes in behavior and activity in hyperammonemic rats [ 18,191. Thus, the lack of severe neurologic changes in rats in our study with acute elevations of ammonia to greater than 15,000 pg/liter may not be surprising. A reduction in serum ammonia with intravenously administered arginine hydrochloride has also been reported by Fahey [S]. Arginine given immediately prior to glycine infusion prevented the ammonia rise in fasted subjects. Infusing arginine 45 min following a 60-min glycine infusion was capable of preventing further blood ammonia elevation and induced an early return to normal levels. It is thought that this effect is mediated by the Krebs urea cycle in the liver with arginine acting as a precursor of ornithine [12]. No toxicity was observed with the infusion of arginine in the current study. Arginine given at the time of the initial intraperitoneal injection did reduce the peak ammonia concentration by 50%, but did not change animal survival. Animal survival did not reflect serum osmolality. A variety of hypo-, iso-, and hyperosmolar solutions was infused and the serum osmolality was related to the osmolality of the infusion. Death occurred in animals by 24 hr with serum osmolalities ranging from 307 to 331 mOsm/liter, and animals survived with a serum osmolality as low as 272 mOsm/liter. The addition of mannitol to 2.0% glycine raised the serum osmolality but did not prevent coma and death. The most important parameter in this study was the level of hyponatremia. Hyponatremia developed in all animals but death occurred only when the serum sodium fell below 95 meq/dl. Increasing the sodium concentration by including saline in the initial intraperitoneal injection or by the intravenous injection of 5% hypertonic saline at 8 hr provided 100% survival. As numerous clinical studies have shown, transurethral surgery frequently leads to changes in the serum sodium concentration. However, it is usually a small decline and the patients are rarely symptomatic. In those studies, the cardiovascular and neurologic symptoms that did appear were associated with profound hyponatremia (120 meq/dl). While 5% hypertonic saline was used to correct the hyponatremia, we would not advocate this approach. Several recent reports have linked the rapid correction of severe hyponatremia with a neurologic disorder known as central pontine myelinolysis which may be fatal [2, 341. Brain lesions have been noted in several animal species in the laboratory, and clinically, patients with the demyelination syndrome have had a deterioration in their neurologic status as the hyponatremia was corrected. In addition, the older male population is at risk for congestive heart failure and pul-

VOL. 46, NO. 2, FEBRUARY

1989

monary edema with hypertonic saline therapy. Since the TUR syndrome is a hypervolemic state, diuretic therapy with furosemide should be instituted immediately. Although this study found no correlation between death and hyperammonemia, ammonia may play a role in certain situations. For example, in the patient with liver disease or muscle wasting, the ammonia load may not be completely metabolized by the liver or skeletal muscle, and the neurotoxic manifestations of hyperammonemia may result. Treatment of acute hyperammonemia consists of supportive measures mainly, although arginine hydrochloride may be useful as shown in this study. Nonetheless, in the great majority of cases of TUR syndrome, efforts should be directed at correcting the hyponatremia, and only secondarily should hyperammonemia be considered the causative agent. ACKNOWLEDGMENT This work was supported in part by the Brigham

Surgical Group.

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Gillett, W., Grossman, H. B., and Lee, R. Visual disturbances in TUR reaction. Urology 25: 573, 1965. Goodman, A. G., Goodman, L. S., Rall, T. W., and Murad, F. Tti Pharmacological Basis of Therapeutics, 7th ed., New York: Macmillan, 1985. P. 666. Hagstrom, R. S. Studies on the fluid absorption from the bladder during transurethral prostatic resection. J. Ural. 73: 852, 1955. Harrison, R. H., III, Boren, J. S., and Robinson, J. R. Dilutional hyponatremic shock: Another concept of the transurethral prostatic resection reaction. J. Ural. 75: 95, 1956.

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GITTES:

TUR

141

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