Radioisotope Uptake in Experimental Hydronephrosis

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.Jol-HK.AL OF LR0LoG1

Vol. \J\J,- !\l;xy /'rinied h1 U.S.11

c;opyriglit i:ID HJ68 hy Tlie Willianv-; & \Vilki11s Co,

HADIOISOTOPE l"PTAJ<:E

rx EXPERL\JE_NTAL i::lA>JDOR H. WAX*

From ihc Division of Cro/oyy, Univcr.sily of llochcsler School of Hcclicinc and Dcnlisiry, Uochc.slcr, New York

Ph)·~iological alierati(Jn~ in renal function reculting from urinary trnct obstruction have not, as yet been 1Yell de1ineated. Hmn:ver, with the development ol' mon, 1",,u1,et:u lecbniques, exciting new arlva1tcemm1lc have been made in this field. Careful clearnncr; studies combined with direct renal blor)rl fl
In this paper, we have utilized detectable radioisotope,, &.s 11. rnr,ans or reual functioJL during the obstructive sU:i,tp 125 I-hippurn11, J.1J[.hypaque and ""xP11on have: been used io study functional altc:rntion,.; IJ, the kiducy tlming unilateral hyclronephro~i, in dogs. Ans1Yers have hr,en ,mught 1,
The kidneys of l9 mongrel female 11·ern explantecl to the flanks aud an intenrnl. bladder procedure wa.s pmformecl. 5 After month, clearances were obtaim,d on both kicl-ney5. If the function wa.s normal and stable the animals were used for the Five or thc~e dogs had srna.ll polyvinyl catheters implanted in a renal vein for PAH, creatininc, hippuran s,nd hypaque renal extraction determinatio1t~. Twc, dogs had ]Jolyviuyl tnbing:s implanted into thC' renal artery for estimation of RBF wit,h mxc11011. With the kidneys explanted, the ,cintillatrn· eountcr coulcl be aceuratdy located uver the kidney. Foley cathetern were in~erted into c,ach half of the split bladder for individ1ml clear:J.nl'C studies preoperatively. The aenk prc.s.,me ,;tudiP:i were done as follows: the dogs were anes!heiizeri with nembntal, 0.04 cc per kilogram per weight of 20 per ce!lt para-arninohippuric ctcid 5 llolt., J\l. H., Mauliru, E. L. and Wanic,,. H. E.: A bifid bladder prepiLrn( ion for mental split fnnctio11 reHal st,ndi(,s. J. Surg.

4: 43,. 19G4.

498

WAX

(P AH) and 0.5 cc per kilogram per body weight of 10 per cent creatinine were administered as a priming close. Intravenous infusion of normal saline was started at a rate of 240 cc per hour. Then 6.4 cc 20 per cent P AH and 50 cc 10 per cent creatinine were added to the infusate. One kidney was used as a control. The ureter of the other kidney was isolated close to the bladder and a catheter was passed to the renal pelvis. Control clearances and control isotope studies at O mm. Hg pressure were obtained. The pressure was increased in the renal pelvis by raising the catheter to a predeterrn.ined height. This pressure was maintained for at least 30 minutes before a repeat study was performed. During the middle of the clearance period, blood was obtained from the renal vein and femoral artery for renal extraction studies and from the femoral vein for clearance studies. At the completion of the acute experimental procedure the ureter was divided and doubly ligated. The animal was now followed at intervals with radioisotope studies and renal extractions for up to 4 weeks. The isotopes were measured as follows: the signal was picked up on a scintillation counter which had a 1-inch crystal and a 36 degree collimator which was recessed 4 cm. The signal was passed through a dual window pulse height analyzer which was preset to pick up 131I hypaque and 125I hippuran simultaneously. Each signal was now sent into dual rate-meters and dual recorders for simultaneous isotope studies. At the same time the nuclear pulrntions were transmitted directly to a tape recorder; therefore, the data were permanently stored. This enabled us to read out our data either on a recorder or through a digital analyzer directly from the tape recorder. This digital read-out system enabled us to accurately measure the uptake of 12 5! hippuran and 131 I hypaque. The rate of uptake was arbitrarily determined to be the slope of isotope accumulation between l to 4 minutes after the isotope was initially detected coursinp: through the kidney. · 133Xenon pulsations were likewise stored on tape. The digital read-out was now used to construct a semilog plot of the disappearance of the isotope. r sing a curve fitting· procedure, e Thorburn, G. ~-, Kopald, H. H .., Herd, J. A., Hollenberg, M., 0 Morchoe,. C. C. C. and Barger, A. C.: lntrarenal d1stnbut10n of nutrient blood flow. determmed with krypton 85 in the unanesthet1zed dog. Circ. Res., 13: 290, 1963. 6

cortical blood flow was determined. Clearances and renal extractions of PAR and creatinine were obtained with the use of a technicon auto analyzer. The renal extraction measurements for the isotopes were done in a Nuclear Chicago wellcounter. RESULTS

Comparison of the renal vein extractions of P AH and creatinine to radioisotope hippura;i and hypaque. It has been shown previously that clearances of 125I hippuran are similar to the clearances of PAR and that 131I hypaque is similar to that of creatinine. 7 These studies were performed by continuous infusion methods. In this investigation we were interested in evaluating the uptake of each isotope after a single intravenous injection and relating this to PAR and creatinine uptake. Our method was to compare the renal extraction of each compound. vVe depicted the resu'.ts of the renal vein extraction following eontmuous infusion of the chemicals and com. pared this to the renal vein extraction of the isotopes after a single intravenous injection (fig. 1). The extractions were different due to various levels of pressure created in the renal pelvis. The extraction of 131 I hippuran is about 20 per cent less than that of PAR. However this difference is constant at different extrac~ion levels. 131 I hypaque is quite comparable to the extraction of creatinine and appears to be handled in a similar manner at both normal and elevated pressures. Effect of acute elevation of pressure in the renal pelvis upon the drainage of isotope from the kidney. The e~ect of pressure upon the drainage slope of the h1ppuran renogram was noted (fig. 2). At pressures less than 30 mm. Hg, there was little alteration in the slope of the curve. This can be compared to minimal changes in the renal vein extraction of hippuran at comparable pressures (see table). When pressure is more than 30 mm. Hg, there occur a delay in drainage and a corresponding decrease in renal extraction. The effect of mannitol diuresis is demonstrated in figure 3. Despite a pressure of 50 mm. Hg for 30 minutes, normal drainage ensues. At 75 mm. Hg the urine flow remains above that of the control; however, a marked delay in drainage is recorded. Since the 7 Tanxe, W. N., Maher, F. T. and Hunt, .J.C.: The isotope renog;ram as a test of renal function. Ip:. Dyna~1c c,im1-cal Studies With Radioisotopes. Edited b:y R. M. Kmseley, W. N. Tauxe and KB. Anderson. Oak Ridge, Tennessee: U.S. Atomic Energy Commission, 1964, p. 383.

RADIOISOTOPE UP~'AKE IN EXPERIMENTAL HYDRONEPHROSIS

A

5ol B

/··

80

RENAL VEIN EXTRACTION

%

RENAL VEIN EXTRACTION

"I.

100

I

:f#fi>e

"'"'

60

"'

;::: ~ ~

"''>'. 40

..

20

•:t; 0 0

20

40

80

60

HIPPURAN

100 %

10

20

30

HYPAQUE

I 125

40

sc, %

I 131

F1G. l. .·1, comparison between renal vein extraction of Jz.11 hippunrn 15 mi11utes after a siugle in1 ve11011s injection with extrac1,ion of PAR dnring continuous infusion. JJ, comparison betwee,1 renal vein extraction of WI hypaque 15 minutes after a single in t,ra.venous injection with ext rn.c t,to11 or cre,,tinine during continnons i11fusiou. Extract.ions wore obtained after pressures of O 10 90 mm. Wien, a.pplied to renal pelvis.

THE EFFECT OF PRESSURE ON THE HIPPURAN RENOGRAM B. 30mm Hg.

A. CONTROL

Time 15 Minutes

D. 75mm Hg.

C. 50mm Hg

Time 15 ~inutes

Time 15 Minutes

.Fw. 2. 81 ndies perfonrnecl under conditimrn of normal hydration in dog

500

WAX

Effect of renal pelvic pressure on renal function -------~ Extractions %,

Dog

I I

Pressure

1mm.

I RBF

1

Hg)

.

I

GFR

I

1----------II

Crea-1

PAH Jrippm..an tinine

Hypaque

-----.---------------797 0 j 98.9 21.4 . 69 ,38 21 23 50 )138 1:5.2 38 45 4 26 75 ]134 ,:i.9 11 20 1 2 90 I 78 1. 8 4 11 1 6 798 o mi 22.3 .'i2 62 27 2s 80 /131 20.7 40 49 19 19 50 llfl9 16.7 22 34 13 10 7;"', 68 6 .1 23 27 13 13 800 o 1108 32.7 I 12 10 21 37 30 122 30. 7 61 56 24 :-i.s iiO 4fi.815.9 74 64 30 36 75 4.6 .79 44 45 4 22 806 0 117 31.4 79 47 30 35 30 ]146 39.6 77 49 31 44 1·

~~ 807

0 30 50

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1149

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~~

-~~

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il78 JL'i7 :184 :211 j120

32.9 23.2 19.4 12.4 6.9

66 66 S4 41 38

51 :38 44 21 16

22 17 13 8.4 7.8

4 28 13

4 0

---------

drainage slope is dependent both on urine flow and concentration of isotope reaching the renal pelvis, we analyzed the effect of pressure on the renal extraction of hippuran in 5 dogs (fig. 4). From O to 30 mm. Hg the average decrease in extraction from control value was 17 per cent. From 31 to 50 mm. Hg the extraction fell 30 per cent. From 51 to 90 mm. Hg extraction fell 60 per cent and more than 90 mm. Hg the average decrease in extraction was 81 per cent. Extraction and urine flow are not the only factors involved. In one dog the extraction was almost normal at 50 mm. Hg pressure and urine flow was higher than the control value, yet the slope was markedly delayed. Analysis of the concentration of isotope entering the renal pelvis revealed it to be markedly diminished Thus, the transit time of isotope from the tubules to the pelvis must be considered as another factor leading to alterations in the drainage slope. Comparison of the uptake of hippuran and hypaque with changes in REF, renal extraction and GFR in the acutely obstructed canine kidney. Five dogs were studied. A typical response is seen in figure 5. At 50 mm. Hg pressure RBF

RENOGRAM, PRESSURE ANO URINE FLOW IN ACUTE OBSTRUCTION PRESSURE

PRESSURE

URINE FLOW cc/min

0

50

0.17

0.17

URINE FLOW cc/min EXPERIMENTAL

~~

~

1.9

3.0

0.8

4.0

B MANNITOL DIURESIS

NORMAL HYDRATION V o, ., .,

&

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IO IO I O • •

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50

C

Fm. 3. Following 50 mm

75

0.22

0.15

D H

.

.

-----

1~ri;1~ri~t s{Jf/ results despit/!//!!~11f;:;:,;;:lofjfn:nnarked]y delayed tn , ( ), At 75 mm, ]Jg sl

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.

After 111annjto'd'

ope delayed

desp1te. · ·1 lUJ'es1sI adequate

HADIOISOTOPT!l UPTAKE IN EXPERIMENTAL HYDRONEPHROSIS

was raised 40 per cent, GFR decreased 29 per cent and the renal extraction of hippuran and hypaque decreased slightly. l\/Ieasurement of the slopes of the uptake of hypaque and hippuran revealed no significant change from control slope. RELATIONSHIP BETWEEN RENAL PELVIC PRESSURE AND TUBULAR EXTRACTION OF HI PPURAN

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51-80

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PRESSURE m m /HQ

Fm. 4. Effect of pressure on renal vein extraction of 125 I hippuran,

At 75 mm. Hg pressure the REF continued to be elevated, the GFR was reduced by more than 72 per cent, the extraction of hippura,n 65 per cent and the extraction of hypaque by \.ll per cent. The uptnke slope of hippuran continues to be similar to its control while the uptake of hypa,que is ma,rkedly reduced. At 90 mm. pressure the REF is reduced 20 per cent. puran extraction is reduced 81 per cent and tl.rn GFR is reduced 92 per cent. The slope of Che hippuran uptnke is 52 per cent of normal white the hypaque uptake is JO per cent of normal. fo s,11 clogs studied in this fashion, RBF incrPa.sed with pressures up to 75 mm, Hg: and then de· creased. GFR decrea,sed moderately at 50 mm. Hg and then ma,rkeclly a,t 75 a,nd 90 nun . Ilg;. Extractions of 131 I hypaque and creatinine were moderately decreased at 50 mm. Hg and then rn.arkedly decreased at 75 and 90 mm. Hg. marked decrease in extraction of '"'T and PAH wa,s seen at 50 mm. Hg; \Tith a more marked decrease at 75 and 90 mm. Thb

EFFECT OF URETERAL PRESSURE ON THE HIPPURAN AND HYPAQUE RENOGRAM AND RENAL FUNCTION

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----

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120 80 40

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50mmHg

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60 , '-., 4 0 EI 131 HYPAQUE -----,,. 20..J--------"''

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45

oOl

60

90

105

---·===~ 135 150

MINUTES Frn . .5. Renogram dark line represents 125 I hippunm, light line represents 131 I Tenal vein extraction; C PAH/E PAH represents REF. Pressure maintained for peat studies.

.502

WAX

uptake slopes of hippuran varied little between 0 and 75 imn. Hg and then fell significantly. The uptake slope of hypaque did not vary significantly at pressure less than 50 mm. Hg but then fell progressively after that. Figure 6 shows the effect of pressure in another dog upon the uptake slopes of hippuran and hypaque. Hippuran slopes vary little at pressures from O to 50 mm. Hg while the hypaque slopes progressively decrease with an increase in pressure. We compared changes in the slope of hippuran with changes in RBF and renal extraction at various pressure levels (fig. 7, A and B). The slope of the uptake of hippuran falls more rapidly with pressure than does RBF and inversely less rapidly than the fall in hippuran extraction. Both of these parameters effect the slope of the hippuran uptake. On the other hand, the change in the hypaque slope is directly related to the change in GFR (fig. 7, C). The effect o.f chronic and complete obstruction on renal function in the canine kidney. Nine dogs had their ureters divided and ligated and were followed at various intervals with hippuran and hypaque renograms. Four dogs had catheters chronically implanted in the renal vein and renal extractions were obtained. Two dogs had cathe-

ters chronically implanted in the renal artery and had simultaneous 133xenon clearance studies. One day after ligation the uptake curves of hippuran and hypaque were moderately good. They were usually better than the uptake slopes which occurred at high pressures the previous day but less than the controls. During the next 14 clays the uptakes from both isotopes gradually fell (fig. 8). The hypaque uptake fell more rapidly in the majority of dogs approaching a flat curve in an average of 7 clays. The hippuran uptake maintained a reasonably high level for 10 to 20 clays before assuming a flat type of curve. From the results of our acute studies we have assumed that the hypaque uptake reflected GFR. The hippuran uptake, on the other hand, reflected both RBF and renal tubular extraction. The extraction of hippuran slowly and progressively decreased as the obstruction persisted. To ascertain what was happening to RBF during this obstructed period we injected 133xenon into the renal artery via a chronically implanted catheter. From the disappearance curve we calculated cortical blood flow which remained relatively stable from 1 to 14 days of obstruction (fig. 9). Despite this, the slope of the hippuran uptake fell significantly a~ the obstruction persisted. DISCUSSION

ISOTOPE UPTAKE COMPARED TO RBF RBF cc./min

GFR cc./ min

210 I

32

HIPPURt,;J SLOPES I- 4 rr in

a

HYPAQUE SLOPES I - 4 min.

GFR

We have used 2 methods to evaluate functional changes occurring in acute and chronic obstruction. Our chemical investigations have agreed with several recent reports concerning the effect of acute pressure applied to the renal pelvis. Selkurt has shown that the RBF will at first increase and then slowly fall off at higher or prolonged pressures. 1 He believed the initial increase in RBF was the result of a sudden rise in pelvic pressure reducing transmural pressure in the afferent arterioles and hence producing arteriolar dilatation. On the other hand GFR decreases with increasing pressures but not in a linear fashion. :Malvin has shown that at low pressures there is a gradual reduction in GFR and as the pressure increases and rises above 40 per cent of mean blood pressure, the decrease becomes steeper. 8 He believed that at pressures less than 40 per cent of the mean, vascular reacl-

Fm. 6. Slopes were measured by recordincr radioactivity emitted over kidney between I to 4 8 Malvin, R. L., Kutchai, H. and Ostermann, minutes after first detection of isotope. Uptake _F-: Decreased nephron population resulting from slopes changed as pressure was varied in renal mcreased ureteral pressure. Amer. J. Phvsiol., pelvis, from left to right 0, 30, 50, 70, 90 mm. IIg. 207: 835, 19G4. •

HAJ)]0ISOTOPE UPTAKE JN EXPERIMENTAL HYDRONEPHIWSIS

EFFECT OF ACUTE RENAL PELVIC PRESSURE ON SLOPE OF HIPPURAN UPTAKE AND RENAL BLOOD FLOW

./

'2

9

.

06

EFFECT OF ACUTE RENAL PELVIC PRESSURE ON SLOPE OF HIPPURAN UPTAKE AND RENAL EXTRACTION OF HIPPURAi1

/• I2

. .. .

I0

08

B

0

04

01

,J 2

--02

D4

06 08 RENAL BLOOD FLOW

10

I2

- ---------

1.L

14

TUBULAR EXTRACTION HIPPURi\N

EFFECT OF ACUTE RENAL PELVIC PRESSURE ON SLOPE OF HYPAQUE UPTAKE AND GLOMERULAR FILTRATION RATE

C 1.0

02

0

"

. 0.2

04

06

08

10

GLOMERULAR FILTRATION RATE PRESSURE CONTROL

FrG. 7. A, change in uptake of 1"'I hippuran is compared to change in RBF as prnss1,re 1s raised it>. renal pelvis ,i! increments of 0, :-W, 50, 70 and 90 mm. Hg. FJ, change in uptake slope of 125 I hippuran compared to change in renal vei11 extraction as pressure is raised. in renal pelvis nt increments of 0, :!O, 50, 70 and \)0 mm. Hg. C, change in uptake slope of m1 hypaque is compared to change in CFH. as sure in renal pelvis is raised at increments of 0, :30, 50, 70 a.ncl 90 mm. Hg.

occur which can increase glomerular capillary pre~sure and compensate for increased peh'ic pressures; however, when it is more than 40 per eent, these readjustments can no longer keep pace with the increased pelvic pressure and GFR falls in increasing increments. In this , vrn have introduced isotopes as a means of externally detecting these changes. of the hippuran uptake reveals that it is dependent both on RBF and tubular extraction and appears more close.ly related to the latter. .However, the increased RBF that follows acute obstruction will contribute to a sharply rising hippuran during the early obstructive phase. Only when the extraction is markedly decreased will the hippuran uptake begin to fall. Hypaque uptake on the other hand reflects GFR

in a rather linear fashion. A flat hypaqur, curve indicates minimal GFR. An additional parameter of fundion furnished by the isotopes during obstruction can be tained by visualizing the drainaµ:e segment of Uie hippuran renogram. This is quite sensitive pressure changes under normal states or tion and will be deiayed if the pressure than 30 mm, Hg. However, under intense diuresi.s a normal drainage slope can occur even up to mm. Hg pressure. These factor, can be the dinical situatiou when one i:, tients with low grade obstruction The physiological change., whi~h occur chronic obstruction have not bcEm well documented as those in acute obstrnction. T
504

WAX

kidneys simultaneously in acute experiments on rabbits. 9 He found that REF was reduced 40 per cent, 1 to 17 weeks after unilateral ligation. Murphy and Scott found that total direct RBF was increased immediately after either distal or proximal ureter occlusion and by 24 hours was decreased. 10 This decrease in RBF was progressive thereafter. Schirmer and associates have investigated autoglycolysis in tissue from the renal parenchyma. 4 They found this metabolic response initially increased but became exhausted after 25 days of continued obstruction. Elkin and associates studied the nephrographic effect produced in rabbits with hypaque during obstruction.11 He found that the nephrogram gradually decreased with increasing duration of obstruction in rabbits. However, a moderate nephrogram effect still persisted 5 days after ureteral ligation. Hippuran and hypaque are readily taken up 24 hours after complete ureteral ligation. The renal extraction of both isotopes is high as is the REF. After 14 days the hippuran uptake slowly decreases. As REF remains at reasonable levels, the slow decrease in hippuran uptake is mainly due to a decreasing tubular extraction. Thus, the falling hippuran curve which is seen clinically during the first 2 weeks of chronic obstruction appears to be more related to a decreasing extraction than to decreasing REF. Further studies using xenon clearance should elucidate more clearly the changes in RBF during chronic obstruction. Hypaque uptake appears to be reflecting GFR in the chroni,Jally obstructed kidney. The facts in favor of this are: 1) investigators have shown that in the non-obstructed kidney hypaque accurately measures GFR, 7 2) renal vein extraction of hypaque is similar to that of creatinine at normal and abnormal levels, 3) in the acute experiment the rate of uptake of hypaque changes proportionately with changes in GFR and 4) the rate of hypaque uptake during chronic obstruction does not parallel that of hippuran. Thus, although 9 Idbohrn, H. and Muren, A.: Renal blood flow in experimental hydronephrosis. Acta Physiol. Scand., 38: 200, 1956. 10 Murphy, G. P. and Scott, W. W.: The renal hemodynamic response to acute and chronic ureteral occlusions. J. Urol., 95: 636, 1966. 11 Elkin, M., Boyarsky, S., Martinez, J. and Kaplan, N.: Physiology of ureteral obstruction as determined by roentgenologic studies. Amer. J. Roentgen., 92: 291, 1964.

HIPPURAN AND HYPAQUE UPTAKE DURING CHRONIC COMPLETE OBSTRUCTION EXTRACTION HIPPURAN

HYPAOUE

54

4

DAY

LIGATION

I

18

I '

47

I

I 8

DAY

20

I

LIGATION

2

= 14

DAY

LIGATION

FIG. 8. Example of changes in uptake of iso-

tope during chronic complete obstruction. Solid line represents 125 I hippuran; dotted line represents 131 I hypaque. there may be some tubular excretion of hypaque which would be playing a role in the total hypaque uptake, we do not believe that this is significant. The hypaque curve falls much more rapidly during chronic obstruction than does hippuran but usually does not reach a low level until 7 days. This would indicate a continuing amount of replacement-reabsorption in the totally obstructed canine kidney. Both Taylor and Ullmann12 and Salomon and Lanza13 have shown high rates of GFR occurring in the completely obstructed kidney. However, their observations were only for 4 hours. Since the renal pressure has been found to be from 10 to 25 mm. Hg in 12 Taylor, lVI. G. and Ullmann, E.: Glomerular filtration after obstruction of the ureter. J. Physiol., 157: 38, 1961. 13 Salomon, L. L. and Lanza, F. L.: Glomerular filtration in the rat after ureteral ligation. Amer. J. Physiol., 202: 559, 1962.

RADIOISOTOPE UPTAKE IN EXPERIMEN'l'AL HYDRONEPHHOSIS

305

HIPPURAN UPTAKE DURING CHRONIC COMPLETE OBSTRUCTION

OOG#771

XENON FLOW

-l'c-r===~=~ccc-c:--cc-r---cc cc/Gm/MIN.

DOG# 812

XENON FLOW

--====~====~ cc/Gm/MIN.

Time 15 Minutes

I DAY LIGATION

3 DAY LIGATION

-l-------~+-·.·.. L_:~:.:_.'

t:-~~J___L___ _ _;;,m 2.33

..

§~J''" Time 15 ~inutes

Time 15 Minutes

6 DAY LIGATION

·•'.._:.,.c

I·•

8 DAY LIGATION

§~n+J9~rn >

Time 15 ~linutes

9 DAY UGATION

,

I

'

.

•

I

Time 15 lv'inutes 13 DAY LIGATION

Fm. 9. Change in uptake of 125 I hippuran in 2 dogs during chronic complete obstruction. Xenon dear ance represents cortieal blood flow obtained just prior to serial hippuran studies.

the chronically obstructed canine kidney,4 it would not be unusual for filtration to continue for a much longer period. Studies are neccssar~· to extend these observations and to analyze Yariations in hypaquc up·· take during chronic obstruction uuder different physiological and pathological stresses. CONCLUSJON

An experimental model has been developed to evaluate physiological changes occurring during acute!and ehronic hydronephrnsis. 125I hippuran,

J3JI hypaque and 133xcnon have been used to in vcstigatc the physiological changes during obstruction. 125 I hippnran reflect~ both tubular extraction and RBF, 131 I hypaque reflects GFR and 133xcnoi) reflect., RBF, The changes which occur acute and chronic obstruction arc clcscri bed. Experimental and clinical applications with the use of isotopes in evaluating the obstructed kidney are advanced. Mrs. Holly Pillsbury and l\Irn. Hamilton provided valuable technieal assi~tauc1:..