Gut, 1992,33,580-586

ALIMENTARY TRACT

Site and mechanism of pain perception withoesophageal balloon distension and intravenousedrophonium in patients with oesophageal chest pain

J S de Caestecker, Anne Pryde, R C Heading

AbstractTen healthy volunteers and 13 patients withoesophageal motility disorders whose primarypresenting complaint was chest pain werestudied by distending an intraoesophagealballoon in 1 ml steps to the point of a sensationof discomfort. The net balloon pressure (intra-balloon pressure when inflated within theoesophagus minus the pressure recorded at thesame volume outside the patient) was measuredat each volume increment and the distensionvolume at the perception of discomfort wasnoted. The measurements were repeated afterintravenous injection of edrophonium(80 Ftg/kg) and again after 1.2 mg intravenousatropine. Oesophageal wall compliance wassimilar in patients and controls, and the twogroups showed a similar effect of decreasedcompliance with edrophonium and increasedcompliance after atropine. There were nosignificant differences between patients andcontrols of distending volume at perception ofdiscomfort. Edrophonium, however, resultedin a significant reduction in distension thres-hold for pain (p<0.03) in patients. A similarthough non-significant trend was seen in con-trols. In both controls and patients, distensionvolume for pain production after atropine wassignificantly (p<0.01) higher than after edro-phonium. From these results and otherpublished data, we suggest that the pain recep-tor for noxious stretch and after edrophoniumchallenge is likely to be an 'in series' mechano-receptor located in oesophageal longitudinalmuscle.

Department of Medicine,Royal Infirmary,EdinburghJ S de CaesteckerAnne PrydeR C HeadingCorrespondence to:Dr J S de Caestecker,Department of BiochemicalMedicine, St. George'sHospital and Medical School,Cranmer Terrace, London,SW 17 ORE.

Accepted for publication5 August 1991

Intravenous edrophonium administered duringoesophageal manometry has been advocated as a

useful test to provoke symptoms in patients withangina like chest pain suspected to be of oesopha-geal origin.'3 It has been reported to provokefamiliar chest pain in about a third of suchpatients.34 Some regard the mere occurrence ofsymptoms with the drug as diagnostic ofoesopha-geal pain,' while others require both symptomsand manometric change.4 In healthy individualsas well as patients with oesophageal motilitydisorders, edrophonium causes a short livedincrease in peristaltic amplitude and duration,sometimes in association with non-peristalticcontractions.`

The mechanism of production of pain withedrophonium is unclear: patients who developtheir typical symptoms with the drug have asignificantly greater increase in peristaltic dura-tion (but not amplitude) than those who do not. 'A large overlap exists, however, so that somepatients with large increases in peristaltic dura-tion do not have symptoms whereas othersdevelop symptoms with little manometricchange. Furthermore, provoked chest pain isfrequently continuous over several minutes whileoesophageal pressure waves are only observedintermittently.' A possible reason for this failureto correlate pain and manometric findings is thatpain does not directly result from abnormalmotility but rather from heightened sensoryperception.' This could result in otherwise pain-less 'physiological' stimuli being perceived aspainful. It is possible and likely that the mano-metric changes observed in some patients aremodulated by the sensory receptors, probably byan axon reflex influence on the effector neuronesof the myenteric plexus.'

Balloons have a long history of application tothe study of oesophageal pain.9'-6 The use ofoesophageal balloons has recently beenrevived'7 18 after a long lapse, perhaps resultingfrom the observation that patients with docu-mented ischaemic heart disease could not dif-ferentiate between the pain of their exertionalangina and that induced by oesophageal balloondistension (despite the lack of electrocardio-graphic changes during balloon induced pain)."`These reservations persist,'9 particularly nowthat microvascular angina has emerged as analternative explanation for chest pain in patientswith chest pain but anatomically normal coronaryarteries.20 Nevertheless, oesophageal balloon dis-tension can reproduce pain in 40 to 60% ofpatients with non-cardiac chest pain suspected tobe of oesophageal origin.'710"' There is someevidence that these individuals have increasedoesophageal sensitivity to stretch,' while othershave pointed out that such patients show abnor-malities of the oesophageal peristaltic reflexduring balloon induced pain."The purpose of this investigation was to study

the effects of edrophonium and atropine on theperception of discomfort and oesophageal wallcompliance during oesophageal balloon disten-sion in an attempt to throw some light on themechanisms and site of action of edrophonium

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Site and mechanism ofpain perception with oesophageal balloon distension and intravenous edrophonium in patients with oesophageal chestpain

and balloon distension as provocativemanoeuvres.

Methods

SUBJECTSTen healthy volunteers were recruited (sevenmen and three women, mean age 28 (SD 4.8)years). Three had experienced occasional heart-burn less than once a month; otherwise novolunteer had any oesophageal or gastrointestinalsymptoms.

Thirteen patients agreed to participate (fivemen and three women, mean age 48 (SD 8) years.All had been found to have oesophageal motilitydisorders during previous oesophageal mano-metry and all had had a normal endoscopicexamination of the oesophagus. The manometricdiagnoses were: diffuse oesophageal spasm (six),high amplitude and/or prolonged duraton peris-talsis (six patients - three had also experiencedtheir typical symptoms with provocation testsduring manometry) and vigorous achalasia (one).This latter patient had previously undergoneforceful pneumatic dilatation of the cardia andhad been shown radiologically not to have adilated oesophagus. All patients had originallypresented with chest pain, 10 also complaining ofdysphagia, a further two of odynophagia and twoof heartburn (distinct from their chest pain) inaddition. At the time of the study, 12 of the 13patients were still symptomatic.An Arndorfer ESM3 polyvinyl multilumen

oesophageal manometry catheter connected to alow compliance constant water perfusion pump(Arndorfer Medical Specialties Inc, Greendale,Wisconsin, USA) was adapted by tying a rubberballoon over one of the recording ports so that itwas placed 10 cm above the distal recording port.The balloon was fashioned from a latex rubberfinger cot cut to 3 cm in length.2' The ends weresecured to the polyvinyl tube by winding andtying a silk suture tightly around either end. Theloose ends were trimmed and a silicone glue sealapplied to make the balloon airtight. The balloonchannel was filled with air and connected to anexternal pressure transducer and chart recorder

401

E

E

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35

30

25

20

15

10'

0 5 10 15 20 25Balloon volume (ml)

Figure 1: Volume - diameter relationship for the balloon usedin all the studies. The diameter ofthe balloon at its widest pointwas measured using a micrometer. The individual data pointsare the mean of2 separate benchtop inflations; the meandifference between the 2 measurements at each volumeincrement was 0.4 mm.

(Elcomatic, Neilston, Glasgow) using a threeway tap. This enabled inflation of the balloonwith air in steps of 1 ml, and measurement ofintra-balloon pressure at each step.

Inflations were carried out on the bench in airbefore each patient study, and the balloon waschecked in water for leaks on each occasion. Thesame balloon was used for all experiments inpatients and controls, as preliminary trials in-dicated that different sized balloons or evenballoons of the same size constructed out ofsimilar latex rubber finger cots had differentcompliances. This problem has been noted pre-viously.22 For the balloon used in the studies, therelationship between balloon diameter (measuredwith a micrometer) and volume during benchtopinflations, although not entirely linear, showedno evidence of flattening over the range ofvolumes used during intraoesophageal inflations(Fig 1). Although no in vivo measurements weremade, two studies have indicated that duringinflation in the oesophagus, similar rubberballoons are only slightly deformed.2' 23For patient studies, the deflated balloon and

manometry catheter assembly was passedthrough the nose and positioned so that theballoon lay 9 cm above the respiratory inversionpoint of the lower oesophageal sphincter (identi-fied by a monometric recording channel 1 cmproximal to the distal channel). The balloon wasinflated in 1 ml steps in such a fashion that thepatient did not know when air was being addedto the balloon, until a continuous sensation ofdiscomfort was felt. A short period was allowedto elapse after each step of the inflation for theballoon pressure tracing to stabilise, but theballoon was not deflated between steps. Once astable pressure trace was observed, the minimumintraballoon pressure at each volume step wasmeasured with reference to the basal pressurereading when the balloon had been deflatedwithin the oesophagus.Dry swallows were sensed by a hand on the

patient's throat so that each could be marked onthe chart. The patient was instructed before eachperiod of balloon inflation to report the point atwhich any abnormal chest or back sensationoccurred, and also the point at which this becamedefinitely uncomfortable. No attempt was madeto prompt the patients who were required tovolunteer the information requested. The pointat which definite discomfort was reported wasrecorded on the chart. In the case of patients withproven motility disorders, each was askedwhether the discomfort resembled their spon-taneous symptoms. The balloon was deflatedonce this point had been reached and patientswere asked to describe the location and characterof the symptom that had been provoked.

In each case, the same procedure was repeatedafter intravenous injection of edrophonium(80 rig/kg). In four subjects, an end point ofdiscomfort was not achieved after edrophonium,as the balloon had to be deflated at .he patient'srequest because of intolerable nausea or nasaldiscomfort from aboral balloon traction. Twentyfive to 30 minutes after edrophonium, atropine1.2 mg was administered intravenously and theballoon inflation procedure repeated. In someinstances, more than one inflation procedure

581

Caestecker, Pryde, Heading

L l J

p<0.03 p<0.01

Patients

EdrophoniumAtropine

EdrophoniumBasal Atropine

Figure 2: Mean (SE) intraoesophageal balloon volume at the point ofpain perception incontrols and patients during initial (basal) inflation, after edrophonium and after atropine.Significant differences (by ANOVA) are shown. No significant differences werefound betweenpatients and controls.

was carried out during each stage of the pro-cedure to assess the reproducibility of theresults. The time in minutes taken for eachinflation (mean (SD)) was, for control subjectsand patients respectively, 3.1 (1.2) and 3.1 (1 1)for the basal period, 3.0 (0.9) and 2.7 (1.4) afteredrophonium and 3.1 (1.4) and 3.3 (1.7) afteratropine. In particular, in no subject did theinflation period exceed four minutes 40 secondsafter edrophonium, an important considerationas this drug has a short duration of action.

During each recording, three channels (one at5 cm and one at 10 cm above the balloon and onein the lower oesophageal sphincter) were perfusedwith water from the Arndorfer hydraulic capillaryinfusion pump. A continuous record of oesopha-geal motor activity at these points was obtained.Oesophageal motor activity proximal to theballoon was assessed qualitatively, but no attemptwas made to measure the amplitude or durationof pressure waves, as all swallows were 'dry'.Because the recording channel in the loweroesophageal sphincter tended to slip into thestomach (presumably because of oesophagealshortening known to occur with distension of theoesophageal body),2425 readings from this channelwere not analysed.

After each experiment, the observed intra-balloon pressure at each volume step duringbenchtop inflation was subtracted from the cor-

I

Control subjects

Edrophonium

Patients

Edrophonium

responding value during intraoesophageal dis-tension to obtain a more accurate reflection of thecontribution to the measured balloon pressureresulting from the oesophageal wall. The pressuremeasurements obtained are termed 'net balloonpressure'. According to Laplace's law, tension(T) in the wall of a cylinder is given by therelationship T=pxr, where p=intraluminalpressure and r=the radius of the cylinder. Asoesophageal diameter was not measured, how-ever, the tension could not be calculated, so thepressure measurements are only an indirectreflection of oesophageal mural tension.

STATISTICAL ANALYSISStatistical tests used included analysis ofvariance(either repeated measures or factorial, dependingon whether paired or unpaired samples werebeing compared). Where significant overall dif-ferences were found, Scheffe's test was used as amultiple range test to locate the differences, withan adjustment of the p value for each comparisonto reduce the chance of a type I error. Pearson'sproduct moment correlation coefficient was cal-culated as a measure ofreproducibility. A p valueof <0-05 was taken to indicate a significantresult.

Results

SITE AND NATURE OF DISCOMFORTDiscomfort was experienced by control subjectsretrosternally in six, with radiation to the back(two), abdominal right upper quadrant (two) andthroat (one). Two experienced throat discomfortonly, one back pain alone and one pain in theback and right upper quadrant. The pain wasdescribed as burning by one subject, and by theothers as a 'pressure' or 'ache'.Among the 13 patients, eight experienced

retrosternal discomfort only. In three others, thediscomfort was felt in the back as well asrestrosternally and in the final two, the throatwas the only site of discomfort. Two patientsdescribed the pain as heartburn and five (38%)felt the pain during the initial inflation period(without administered drugs) was the same astheir usual spontaneous symptom. Of these five,three were cases of high amplitude and/or pro-longed duration peristalsis and two had diffuseoesophageal spasm.

Several patients and control subjects com-mented that the discomfort was initially felt atone site but, on subsequent balloon inflations,was also experienced at another site. A minorityof patients and controls noted that the symptomsworsened transiently coincident with peristalticwaves reaching the site of balloon distension.

OESOPHAGEAL MOTOR ACTIVITY DURING BALLOONINFLATIONThis was only analysed qualitatively, as wetswallows were impossible with the oesophagusoccluded by a balloon. Dry swallows were per-mitted, but are known to give variable results interms of patterns of pressure change and ampli-tude or duration of pressure waves.26 27

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Basal Atropine Basal AtropineFigure 3: Mean (SE) net intraoesophageal balloon pressure at the point ofpain perception incontrols and patients during initial (basal) inflation, after edrophonium and after atropine. Nosignificant differences werefound (ANOVA).

1 1 1

1 5

582

Site and mechanism ofpain perception with oesophageal balloon distension and intravenous edrophonium in patients with oesophageal chest pain

In the majority (60 - 80% - the proportionvarying during different phases of the study) ofcontrols, all pressure waves were peristalticduring the balloon inflation, with a few (20-30%)having spontaneous non-propagated wavesoccurring more than once a minute duringballoon inflation. In only one did the non-peristaltic activity occur only during discomfort.Not surprisingly, in less than half (46%) of the

patients was pressure activity only peristaltic, asseven were known to have either diffuseoesophageal spasm or vigorous achalasia. Theproportion with peristaltic activity but no abnor-mal pressure waves increased following edro-phonium to 69%. Although a high proportion(31-46%) of patients exhibited frequent spon-taneous non-peristaltic waves, in only a smallnumber (8-23%) did this abnormality coincidewith the development of symptoms. Even fewercontrols exhibited this feature.Non-swallow related peristaltic waves

proximal to the distending balloon were onlyobserved in 40% of patients and controls, beingreduced or abolished by atropine. The infre-quency of these waves may be attributable to thefact that patients were allowed to swallow at will,resulting in inhibition of this activity. Atropinediminished peristaltic amplitude in all patientsand controls, causing aperistalsis in 23% and40% respectively. A steady rise in baselineproximal intraoesophageal pressure to between 6and 12mm Hg above basal pressure was observedin 10% of controls (but only in one of the 13patients) during balloon inflation, being morefrequently seen (40% of controls) after atropine.This occurred independently of the developmentof symptoms, and represents a phenomenonalready reported by Enzmann and colleagues.28Finally, multipeaked peristaltic waves wereobserved in 31% of patients (but not controls)after edrophonium, always independent ofsymptoms.

RELATIONSHIP OF BALLOON VOLUME ANDPRESSURE TO DISCOMFORTThe balloon distension volumes and pressures atwhich discomfort was first perceived by controlsand patients is shown in Figures 2 and 3. Forpatients and controls considered together, therewas a significant overall difference in volumes atfirst perception of pain by ANOVA (f=2.51;p<002), but not for pressure (f= 1-09; p>0 3).Using Scheffe's multiple range test, mean infla-tion volume at perception of discomfort wassignificantly lower for patients after edro-phonium than after either atropine (p<0-01) orinitial basal inflation period before drugs wereadministered (p<003; Fig 2). A significantreduction was found in controls in balloonvolumes to produce discomfort after edro-phonium compared with balloon distension afteratropine (p<001; Fig 2); although there was atrend for a reduction in distension threshold withedrophonium compared with basal inflation, thiswas not statistically significant in the controls.No significant differences in threshold balloonvolumes at perception of discomfort wereapparent between controls and patients withchest pain. There was a non-significant trend for

lower intraballoon pressures at the perception ofdiscomfort in controls and patients after atropinecompared to basal and post edrophonium periods(Fig 3).The reproducibility of the measurement of

balloon volume and pressure at first perceptionof discomfort was assessed by comparing dupli-cate balloon inflations which were carried out ona total of45 occasions. Reproducible results wereobtained for volume measurement at the firstperception of discomfort (r=0.89; p<0 0001)but less so for pressure (r=0.61; p<0 0001).

EFFECTS OF EDROPHONIUM AND ATROPINE ONOESOPHAGEAL COMPLIANCENet intraoesophageal balloon pressure values areshown in Figures 4 to 6 over the range 1 to 10 mlof air introduced into the balloon. Results forballoon volumes above 10 ml are not given,because the number of control and patientvolunteers became too few for meaningful com-parison.An overall comparison was performed between

six sets of values (three for patients, three forcontrol subjects) at each balloon volume in therange 1 to 10 ml using one way analysis ofvariance. Significant overall differences werefound at 1 and 2 ml (p<0 05). No other signifi-cant differences overall were observed. Theredid not appear to be any consistent reason for thesignificant differences observed at 1 and 2 ml.Because significant differences could not bedetected at other volumes, it seems reasonable toconclude that there were no differences betweenthe patient and control groups with regard tooesophageal compliance resulting from adminis-tration ofthe drugs used. For clarity, the pressurevolume relationship is displayed in Figure 4 forthe basal inflation period only; there is noconsistent difference in oesophageal compliancebetween the two groups.

Further comparisons were made withingroups - that is, for the patients and controlsseparately, using analysis of variance (repeatedmeasures) with Scheffe's multiple range test tolocate significant effects. Although consistentresults were not obtained at low volumes (1 and2 ml) probably because the balloon was notsufficiently distended for the pressure to reflectoesophageal wall tension, and at volumes exceed-

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results in a sustained contraction at the level ofControl subjects2

after edrophonium the balloon24 producing a strong aboral traction15 * Control subjects after atropine force. This is transiently inhibited by swallowinglo * T

but reinforced by the arrival of the primary0 * * b peristaltic wave at the balloon.30 This contraction,

t5 I * I which continues as long as distension is main-

o0* * XI*tained, results in oesophageal shortening below

* S S I I I the balloon, and has been shown in the opossum5 I to be the result of the contraction of musculariso mucosae and the longitudinal muscle of the

muscularis propria.24 The temporal characteris-5 tics of the 'esophageal propulsive force' observedo_ in man by Winship and Zboralske30 and the1 2 3 4 5 6 7 8 9 10 'duration response' observed by Christensen and

Balloon volume (ml) Lund24 make it likely that these represent the5: Intraoesophageal balloon net pressure plotted same phenomenon. This response is abolishedvolume during balloon distension in controls after by anticholinergic drugs.ontum~~~~~~~~~b anndchfterergicodrugsonium and after atropine. In the present study, significant differences

were found in oesophageal compliance afterml (because of small numbers of paired data edrophonium and atropine. From the foregoingags), the overall results for control subjects discussion, a likely cause for changes in oesopha-

patients showed a significantly reduced geal wall compliance measured during ballooniliance in edrophonium treated subjects distension after administration of drugs affectingbared with atropine treatment (Figs 4 and cholinergic pathways is contraction of oesopha-rhere were trends (significant at some geal muscularis mucosae and longitudinalnes but not others) for reduced compliance muscle.24 No differences were found betweenedrophonium and increased compliance patients with motility disorders and controls,atropine compared to basal compliance in however, with respect to oesophageal com-nts and controls (data not shown). pliance. These findings agree with previousproducibility of the compliance measure- observations in the monkey3' and in man.21 32s was assessed by calculating correlation The administration ofedrophonium to patientsicients for paired sets of balloon inflations resulted in a significantly lower balloon volume,the range of volumes for each subject up to but not pressure, at pain perception compared;olume at which discomfort was produced. with both basal and postatropine balloon disten-correlation coefficient varied between 076 sion. A similar significant effect or trend was.97 (p<O0 01) and were highest after atropine observed among controls.owest after edrophonium. This was prob- These findings may be interpreted as indicatingbecause atropine has a long duration of that because administration of a cholinergicn, compared with the brief duration Of blocker reduced oesophageal wall compliance, anofedrophonium, so that repeated measure- critical intraoesophageal pressure (for pain per-s were made when the effect was waning. ception) was reached at a lower distension

volume, with the converse applying afteradministration of an anticholinergic agent. This

uassion is in keeping with the general observation thatluration ofrintraoesophagealballoondisten- changes in gut smooth muscle tension couldas animportant bearingaontheboesophageal modulate changes in pain threshold to disten-r response. Thus, rapid balloon inflation sion.8We were not able to show a clear differencedeflation characteristically produce between patients and controls with respect to

imal stimulation of motor activity both at this effect.above the balloon23 29 with distal inhibition Oesophageal ischaemia consequent on disten-ig inflation while the balloon inflation is sion has been suggested as a mechanism for paintained. Prolonging the period of distension production.33 If so, cholinergic stimulation could

enhance oesophageal wall ischaemia, perhapssimply by allowing a critical oesophageal wallPatients after tension inhibiting blood flow to be reached at an

0o edrophonium T earlier stage of distension. Our findings would be151 Patients after atropine compatible with this hypothesis, but other pre-0 J l liminary studies have failed to find evidence of

35 * * oesophagealischaemia either in patients during30 ~ * episodes of chest pain314 or in a rabbit model2?5 * T h during swallowing before or after intravenous

h r I edrophonium.`1 5T ~~~~~~~~Canany conclusions be reached from these0o V r I observations regarding the mode of action of

5 ] oesophageal balloon distension and intravenous1 2 3 4 6 7 8 9 10 edrophonium when used as provocative agents in

Balloon volume (m)9

patients with non-cardiac chest pain? While our

6nopeBalloon nuetpressureploresults apply only to patients who have been!6: Intraoesophageal balloon net pressure plotted fon tohv .oiiydsrdr uigospat volume during balloon distension in patients after found to have motlity disorders during oesopha-onium and after atropine. geal manometry (and so may not necessarily be

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Site and mechanism ofpain perception with oesophageal balloon distension and intravenous edrophonium in patients with oesophageal chest pain 585

extrapolated to all patients with non-cardiacchest pain), we believe that some conclusionsmay be drawn.With regard to balloon distension, motility

changes proximal to the balloon did not show anyconsistent relationship with pain perception.Other work suggests that a proportion of suchindividuals developing their symptoms duringballoon distension have abnormalities distal tothe balloon. 13 Whether such abnormal distalactivity is the cause of pain or (as seems morelikely) a marker of an abnormal oesophagus is atpresent not clear.We could not show abnormally low thresholds

to stretch in our patients, but our sample size wassmall and highly selected. A reduced thresholdhas been reported by Richter and colleagues inpatients with chest pain,2' but they studied largernumbers of patients who differed from ours inthat although all had non-cardiac chest pain,only a minority had manometric abnormalities.In addition, there are methodological differencesin the techniques of balloon inflation, althoughwe do not believe these are likely to haveinfluenced the results. In agreement with thefindings of this group, we did not observe anydifference in oesophageal compliance betweenour patients and healthy controls. Furthermore,we did not find any differences between patientsand controls in oesophageal wall complianceresulting from cholinergic or anticholinergicdrug administration.Our results are consistent with the hypothesis

that stretch sensitive mechanoreceptors locatedin longitudinally oriented muscle are involved inthe perception ofpain induced by balloon disten-sion. It has recently been shown that mechano-receptors with the electrophysiological charac-teristics of nociceptors appear to be located 'inseries' with oesophageal longitudinal muscle butnot circular muscle.36 Mechanoreceptors in cir-cular muscle layers by contrast do not appear tohave the characteristics of nociceptors,37 res-ponding maximally only to physiologicalchanges in tension that result from peristalticactivity.The observation that edrophonium resulted in

a lowering of the pain threshold to distension andalso in decreased oesophageal wall compliance(which we have argued represents an effect onlongitudinal muscle) prompts the speculationthat pain developing with this drug is sensed bythe same receptors as those responding to balloondistension. If so, it would explain why thereappears not to be a close correlation between themanometric changes which occur after the drugand the appearance of symptoms. Longitudinalmuscle contraction is not directly recorded byconventional manometry, although peristalticduration might be expected to be prolonged bylongitudinal muscle contraction and is the para-meter best correlating with a positive edro-phonium pain response.'7 Why edrophoniumshould cause pain only in individuals with clinicalsymptoms is unclear, unless the neural pathwaysresponsible for pain perception are already 'sen-sitised' in these individuals. Perhaps the noci-ceptors themselves are sensitised in these patientsby quite a different mechanism - for instance inresponse to refluxed gastric acid. There is cer-

tainly good precedent for sensitisation incutaneous mechanonociceptors,38 but visceralpain receptors have been little studied in thisregard. This would seem to be an important areafor future investigation.

This work was presented in part to the British Society ofGastroenterology (Autumn 1990) and has been published as anabstract (Gut 31: Al 165). It has also been used in a dissertationsubmitted by JS de C and accepted by the University ofCambridgefor the degree ofMD.

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