theradial alveolar count ofemery mithal · cisely as described by emery and mithal. in six...

Thorax 1982;37:572-9

The radial alveolar count method of Emery andMithal: a reappraisal 1- Postnatal lung growthTHOMAS P COONEY, WILLIAM M THURLBECK

From the Department ofPathology, University ofBritish Columbia, Vancouver, Canada

ABSTRACr The radial alveolar count method of Emery and Mithal has been re-evaluated on 76normal postnatal lungs. Results of reproducibility assessments suggest that each observer shouldestablish normal control values when beginning with the method, and should subsequently usecontrol cases to maintain strict reproducibility. The use of 10 fields per case was found to beinadequate to obtain satisfactory reproducibility, even for a single observer. Prior inflation of thelungs significantly increased the radial counts, and this factor may help to explain the largediscrepancy between the results of this study and that of Emery and Mithal. The radial countscorrelated well with the chronological age of the child (r = +0*76; p < 0.001).

Alveolarisation of the acinus occurs primarily between birth and 2 years; significant but slowergrowth is seen up to 8 years, after which the results plateau, suggesting that alveolarisation iscomplete. The radial count method appears to provide a relatively simple and reasonably satisfac-tory assessment of alveolar development, as originally proposed by Emery and Mithal.

There is a wide variation in estimations by differentobservers of the number of alveoli in the humanlung at a particular age and of the time at whichalveolar multiplication ceases. These discrepancieshave been attributed to several causes'-differentmethods of preparation of the lungs for analysis;variation in results between different observerswhen the same sections are examined; difficulty inrecognition of alveoli; and the small number of casesfrom which current data have been derived. Addi-tional theoretical limitations are imposed by thealveolar shape constant (a3) and the assumption thatthe characteristic linear dimensions of alveoli arenormally distributed.2 The paucity of casesexamined is due to the difficulties inherent in thecounting technique. Most workers use the method ofWeibel and Gomez.3 This method is both time con-suming and tedious; and results derived from smallnumbers of cases are unsatisfactory as predictiondata because of the large biological variation seen inadults.4

In 1960 Emery and Mithal5 introduced the radialcount method, which assesses the complexity of theterminal respiratory unit (acinus). Measurements in

Address for reprint requests: Dr WM Thurlbeck, Department ofPathology, University of British Columbia Health Sciences CentreHospital, 2211 Wesbrook Mall, Vancouver, BC, V6T 1W5,Canada.

that study were made from a respiratory bronchioleto the edge of the acinus. A respiratory bronchiolewas defined as a bronchiole lined by epithelium inone part of the wall. From the centre of such a bron-chiole a perpendicular was dropped to the edge ofthe acinus (connective tissue septum or pleura), andthe number of alveoli cut by this line was thencounted. Ten such counts were made from each of309 cases and the mean for each case was estimated.Results were expressed as average figures in differ-ent age groups, and an increase in the radial alveolarcount throughout the whole of childhood wasdocumented. By the use of this method of choosingbronchioles adequate reproducibility of results wassaid to have been achieved.Although the information derived by this method

differs from (and is less than) that obtained by con-ventional alveolar counting, the technique has obvi-ous merits. Large numbers of cases may be rapidlyexamined. It is claimed that the method overcomesthe effects of varying degrees of collapse, so thatsections from uninflated lungs may be examined.The method is also independent of tissue shrinkagein the course of processing. Because of these advan-tages the method has been widely applied in assess-ment of the development of the terminal respiratoryunit in such diverse conditions as congenital dia-phragmatic hernia,6-9 anencephaly,79 renalanomalies,7 10 congenital heart disease," severe

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Radial count method of Emery and Mithal-postnatal lungs

rhesus isoimmunisation,'2 polyalveolar lobe withemphysema,'3 kyphoscoliosis,'4 phrenic nerveagenesis,'5 and primary pulmonary hypoplasia.'6Examination of the method both in its original

description and in its subsequent application hasrevealed several problems. Emery and Mithalachieved adequate reproducibility by making theirmeasurements from a respiratory bronchiole; thedegree of reproducibility, however, was notspecified. They observed great variability betweenchildren of the same age. Only 10 counts, however,were made from each case, and this number may notbe adequate in view of the fact that the primarymeasurement may be made in any of three orders ofrespiratory bronchioles: if only 10 counts are made,the random inclusion of even a couple of additionalreadings from a first-order or a third-order respirat-ory bronchiole may drastically alter the radial count,which appears best represented by a mean valuederived from all three respiratory bronchioles. Theuse of only 10 readings per case may also adverselyaffect reproducibility of measurements, for thereasons just outlined. With regard to the examina-tion of collapsed (uninflated) lungs, it is not clearwhether comparable results might be obtained bylooking at inflated lungs. Finally, no attempt wasmade to relate the radial count estimations to con-ventional alveolar counts of even a small group ofcases.

Important inconsistencies are evident in the appli-cation of the method. Of the 11 case reports citedabove, in only three was the method applied pre-cisely as described by Emery and Mithal. In sixinstances the investigators made the measurementsfrom a terminal bronchiole8 16 or counted alveolarsepta rather than alveoli.79 121516 Two reports didnot provide a precise description of the method.' 14Because of the very small spread of results in theseries of Emery and Mithal (2.2 to 9.3) such differ-ences in technique may introduce a significant varia-tion in radial counts. In all but two instances79 theauthors used the data of Emery and Mithal as nor-mal controls. One of these reports, by Reale andEsterly,7 provided a control group of 24 normalinfants of gestational age 32-44 weeks. The meanradial count for that group was 6-2. The mean radialcount for the equivalent group in the series ofEmery and Mithal is about 4. According to the lattercount the cases of Reale and Esterly are normal;using their inbuilt control group the authors felt thatthe lungs they examined were hypoplastic.7The present study is a re-evaluation of the radial

alveolar count method of Emery and Mithal in thelight of the problems raised above. A range of nor-mal values is established and compared with theoriginal data. Both intraobserver and interobserver

reproducibility are scrutinised. The effects ofinflation versus non-inflation on the radial countestimation are examined. Finally, the results arecompared with conventional alveolar counts in thesame cases.

Methods

Lungs from 76 children were examined (48 boys and28 girls), ranging in age from 6 weeks to 17 years.The cases were selected to illustrate normal lunggrowth. Cases of sudden accidental death comprised54% of the group; in the remainder the terminalillness was of short duration (less than two weeks) inchildren previously well. All cases of congenitalanomaly or chronic disease were excluded from thestudy. Fifty-seven of these cases (37 male, 20female) had complete morphometric evaluation,and the results of that examination are available forcomparison with the radial count data (see paper byThurlbeck, pp 564-71).At necropsy the lungs were separated from the

heart and thymus, weighed, and inflated at a con-stant pressure of 25 cm of formalin for at least 24hours. Representative sampling of the mid-sagittalslice of each lung was carried out.'7 Tissue blockswere routinely processed and sections stained withhaematoxylin and eosin.The radial count method was applied strictly

according to the description of Emery and Mithal.5To ensure reproducibility the following additionalcriteria were used: (1) When the respiratory bron-chiole was symmetrical the geometric centre wasused as a starting point (fig 1). When the bronchiolewas irregular the starting point was mid-way be-tween the most proximal part (that is, the wall linedby conducting epithelium) and the first branch point(fig 2). (2) No count was made if the respiratorybronchiole was nearer to the edge of the slide thanto the nearest connective tissue septum. (A closerseptum might have been removed in taking theblock.) (3) All alveoli traversed by the perpendicu-lar were counted. Where the perpendiculartraversed the common wall of adjoining alveoli acount of one was made (the alveolus on the right ofthe perpendicular). (4) When more than 20 alveoliwere noted between respiratory bronchiole and thenearest septum or pleura, the field was discarded onthe assumption that the nearest septum was in aplane other than that of the section.The age and sex of the patient were withheld from

the observers when the counts were made. All suit-able areas in all sections available were counted. Inthe 57 cases that form the core of the study the meannumber of sections examined per case was 10, andthe mean number of fields counted per case was 32.

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Fig 1 Radial count estimation in a symmetrical respiratorybronchiole. The perpendicular is placed from the geometriccentre ofthe bronchiole to the nearest connective tissueseptum (arrow). (Haematoxylin and eosin; originalmagnification x25.)

Testing the hypothesis that 10 counts per case areinadequateTo test the hypothesis that 10 counts per case areinadequate, 25 cases were randomly selected fromthe group. In each case 10 radial counts were madeand a mean value per case obtained (count 1). Thecases were recounted at a later time by the sameobserver (TC), the first 10 suitable fields encoun-tered being used (count 2), and a mean radial countper case was again estimated. On two subsequentseparate occasions (counts 3 and 4) the sameobserver carried out radial counts on all suitablefields in all available sections of the same 25 cases.This resulted in a mean value of 40 suitable fieldsper case. The results from the four separate countswere used to assess intraobserver reproducibilityand to test the hypothesis that 10 counts per case isinadequate.

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Fig 2 Radial count estimation in an irregular respiratorybronchiole. The perpendicular begins at the midpointbetween the conducting epithelium and the first branch point(B), and ends at the nearest connective tissue septum.(Haematoxylin and eosin; original magnification x25.)

Interobserver variatonTo assess interobserver variation 25 cases wereevaluated by two observers. In each case all suitableareas of all available sections were examined.

Testing the hypothesis that inflation affects radialcountTo assess the effect of inflation on radial countexamination, seven additional cases were selected.One lung from each case was inflated and the otherfixed uninflated. Representative sections wereobtained from each lung as described above. .Radialcounts were carried out on all sections and theresults of inflated versus uninflated compared.

Pleural sections versus random sectionsSpecific (non-random) sections which included thepleura were available in 28 cases. Radial counts

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Count 2Fig 3 (a) Intraobserver reproducibility ofradial counts with 10fields per case.counts with a mean of40 fields per case.

were carried out on all sections from these cases and dent's pairedthe radial counts from the specific pleural sections difference bewere compared with those from the random sec- p < 0.02) buttions. (t = 0 17, p

between resulTesting the hypothesis that alveolar multiplication is the Student'scomplete by 8 years below.To investigate the point during growth at which aci-nar alveolar multiplication ceases, lungs from chil- Reproducibiliidren 1-2 years, 6-8, and 11-13 were selected. The Intraobservermean radial count of each age group was estimated although a cland the differences between the means were observer wherexamined statistically. significant di]

Statistical evaluation of the results was by means populations (Fof correlation coefficient (r) and Student's unpaired 3 and 4, howeand paired t test. (0. 18 standari

Results Interobserverdifference be:

The results presented are those relating to radial p < 0.01). Thcount estimations in the 57 cases for which complete (p < 0.001)morphometric data were available. The addition of the mean (0.5results from the 19 cases for which other mor-phometric data were not available did not Radial countcsignificanftly alter the correlation of radial count with A highly signage (r., = +0-77; r,6 = +0.80). the radial cou

(fig 4). The mTen counts per case inadequte 22% higher tCounts of 40 fields per case (counts 3 and 4) pro- two counts pIvided a much closer correlation of results than when but the count10 fields per case were used (figs 3a and 3b). Stu- those of the u

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t test, however, showed a significanttween counts 3 and 4 (t = 2-51,no difference between counts 1 and 2> 0-50). This apparent discrepancy

Ilts of the correlation coefficients ands paired t test is discussed further

tyIt is evident from fig 3b that

lose correlation was obtained by then repeating the readings (r = +0-93) afference was detected between thep < 0.02). The error detected in counts,ver (fig 3b), was only 4% of the mean-d deviation).

There was a highly significanttween the two observers (t = 3-18;e correlation coefficient (r) was +0*72and the error detected was 9% of56 SD).

affected by inflationificant difference was found betweenints from inflated and uninflated lungsiean radial count of inflated lungs wasthan that of the uninflated lungs. Theroduced a high correlation coefficientts of inflated lungs were higher thanininflated in every case.

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Fig 5 Comparison ofradial counts from specific pleuraland random sections.

Pleural sections versus random sectionsRadial counts of specific pleural sections correlatedpoorly (r = +0.60) but significantly (p < 0.001)with those of the random sections from each case(fig 5). The divergence of results was greatest inthose cases in which fewer than five radial countswere possible in the pleural sections available, sup-porting the idea that adequate numbers of fields are

necessary for a reliable mean count for each case.

Cooney, Thurlbeck

Alveolar multiplication completed by 8 yearsFigure 6 depicts the correlation of radial count esti-mations with age (r = +0'76; p < 0X001) in the 57cases examined. The logarithmic curve fit with

1X74 standard deviations is shown. Examination ofmean radial counts at 1-2 years, 6-8 years, and11-13 years showed a statistically significant differ-ence between the means at 1-2 years and 6-8 years(t = 2*303; p < 0.02). There was no significantdifference between the means at 6-8 years and11-13 years (t = 0 949; p < 0.10).

Other correlations examinedThe correlation coefficients of radial count (RC)measurements with age, bone age, body length,body weight, fixed lung volume, and internal surfacearea are set out in the table. The correlation of thenumber of alveoli per unit area (NA), the number ofalveoli per unit volume (NV), and the total numberof alveoli (NAT) with these same parameters in thispopulation is also given for comparison with theradial count correlations (table). The correlationcoefficient of radial count with NAT was +0 59. Theratio NAT/RC was estimated for each case,but correlation of this ratio with age was poor(r = +0.31). The correlation of NAT/RC with agebetween 6 weeks and 2 years was, however, closer (r= +0.43); after 2 years no correlation was found (r= +0.05).No difference was detected between boys and

girls when radial counts for each sex were correlatedwith age. Regression lines were drawn for thegroups and were closely apposed.Twenty native American Indian children were

included in the group (35%). No difference was

detected when correlation of radial count with agewas estimated for Indian and non-Indian subgroups.The regression lines for the groups were almostidentical.

Discussion

Our results lend support to the method of radialalveolar counting proposed by Emery and Mithalboth in regard to method and also as a measure ofthe progressive development of the acinus post-natally.

In the application of the method as many suitableareas as possible should be counted per case. Ten orfewer than 10 areas yield a radial count which isunreliable and difficult to reproduce. If suitableareas are available, 40 counts per case are desirable.As mentioned above, this number of fields isrequired to offset bias due to the considerable dif-ference between counts made from first-order andfrom third-order respiratory bronchioles. If enough

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20 40 60 80 100 120 140 160 180 200 220Chronological age (months)

Fig 6 Correlation ofradial counts withchronological age in normal childrenmore than 1 month ofage. Thelogarithmic curve fit with +1 74 standarddeviation is shown.

Comparison ofcorrelation coeffrients for the different morphometric estimations

Parameters Radial count NA NV NAT

Age r = +0-76 (log) r = -0-74 (exp) r = -0-76 (exp) r = +0-61 (log)Bone age r = +0-78 (log) r = -076 (exp) r = -0-78 (exp) r = +0-61 (log)Body length r = +0-73 (exp) r = -0-76 (exp) r = -0-78 (exp) r = +0-58 (exp)Fixed lung volume r = +0-68 (log) r = -0-78 (exp) r = -0-80 (exp) r = +0-68 (log)Internal surface area r = +0-71 (log) r = -0-65 (exp) r = -0-68 (exp) r = +0-78 (log)Body weight r = +0-74 (log) r = -0-73 (exp) r = -0-75 (exp) r = +0-57 (log)NA - number of alveoli per unit area (Cm2); NV - number of alveoli per unit volume (ml); NAT - total number of alveoli (both lungs,expressed in millions). The best fit is given in each instance.

suitable areas are not found in the available sectionsit is worth cutting deeper in the blocks, as hithertounseen septa may thereby become evident. Emeryand Mithal commented on the difficulty of obtainingadequate numbers of countable fields in some cases.We have examined as many as 14 sections in somecases to obtain 11 suitable areas for counting. Theproblem seems more common in older children, inwhom septa are further apart; but fortunately thisdifficulty is offset in these cases by the ease withwhich a larger number of sections may be obtained.A significant intraobserver error was detected in

assessing reproducibility. For strict reproducibilityeach observer should intermittently use referencecontrol cases. The interobserver error was highlysignificant, so that different observers need to estab-lish normal controls in each instance. This is borneout in the study of Reale and Esterly,' whoexamined uninflated lungs and found the controlmean radial count to be significantly higher than thatof Emery and Mithal, even after due allowance ismade for the fact that the former workers counted

alveolar septa while Emery and Mithal countedalveoli. It seems appropriate that studies of abnor-mal lung growth carried out by the radial countmethod should in each study incorporate a smallseries of normal controls. The essential simplicity ofthe method renders this a feasible procedure.The apparent discrepancy between correlation

coefficients and Student's paired t test in the exami-nation of intraobserver reproducibility (figs 3a and3b) is explicable on the basis of the statistical testused. Use of 40 fields per case was more reproduc-ible (r = + 0.93) than 10 fields per case (r = +0-73).Visual evidence of this is seen in figure 3, with theproximity of the data points to the line of identity.Student's paired t test showed a significant differ-ence between counts 3 and 4 (t = 2-51; p < 0.02)because the observer counted consistently higherduring count 4. No statistical difference was seenbetween counts 1 and 2 (t = 0-17; p > 0.50). Thisoccurred because the correlation between the countswas less strict (r = +0-73), and the results were thusrandomly scattered about the mean.

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present study

Emery and Mithal .

Emery and Mithalcorrected for inflation

2 4 6 8 10 12Years

Fig 7 Radial counts ofthe present study compared withthose ofEmery and Mithal,' with correction ofthe lattercounts for the effects ofinflation before fixation.

Inflation significantly affects the radial countestimation. The range of normal postnatal valuesdocumented here is consistently two to three unitshigher at all ages than the values noted by Emeryand Mithal (fig 7). This may be explained by theobservation of Short that inflation of the lungs byfixative before sectioning may result in a completelydifferent appearance of the lung.t8 Gil and Weibel19have also suggested that alveolar recruitment occurs

on inflation of the lung. The radical difference be-tween our cases and those of Emery and Mithal isconsiderably offset by correcting the latters' resultsfor the effects of inflation by the use of the factor of+22% derived in this study (fig 7).The discrepancy between racaia counts for ran-

dom sections and those for specific pleural sectionsis difficult to evaluate, as in many cases within thelatter group fewer than five areas were counted. Nostatistically significant difference was seen, however.Our results indicate a progressive increase in

complexity (alveolarisation) of the terminalrespiratory unit postnatally (fig 6). The most rapidgrowth occurs between birth and 2 years. Appreci-able but slower growth is seen between 2 and 8 years(p < 0-02). After this the results plateau, suggestingthat alveolarisation of the acinus is reaching comple-tion. The timescale is similar to that documented byDunnill.20 As noted by Emery and Mithal, the radialcount varies considerably among children of thesame age (fig 6).There are theoretical objections to counting

alveoli. The most important number to know is thenumber of alveoli per unit volume. This determinesthe total number of alveoli in the lung, and thenumber of alveoli seen per unit area. The latter isrelated not only to the number of alveoli per unit

volume but also to the alveolar shape constant, thevolume proportion of alveolar air, and the distribu-tion of the characteristic linear dimension of thealveoli. It is possible, perhaps likely, that alveolichange shape and that the distribution of the charac-teristic linear dimension changes during lunggrowth. Thus the number of alveoli per unit areamay not always truly reflect the number of alveoliper unit volume. Since, although linear, the radialcount is a measure of alveoli per unit area, it followsthat it has the same disadvantages as a count ofalveoli per unit area. Changes in the alveolar shapeconstant,21 however, and in the distribution ofcharacteristic linear dimension22 are unlikely to havemajor effects on the relation between number ofalveoli per unit volume and per unit area. In the caseof the radial count this variance would be the squareroot of the change in number of alveoli per unitarea.Comparison of radial count (RC) measurements

with the number of alveoli per unit area (NA) is ofinterest, as these morphometric variables are closelyrelated. As growth proceeds RC rises with increas-ing complexity of the acinus. NA remains the same inthe first two to three years of life (see Thurlbeck,pp 564-71) and decreases thereafter. NA and RCcould be closely related and it might be possible topredict NA from RC if the relationship were closeenough. The correlation of (increasing) RC withage, bone age, body weight, and length parallels thecorrelation of (decreasing) NA with the same growthparameters (table). NA and NV, however, are asclosely related to growth parameters as RC is butthe relation between RC and NA (r = +0.34) andbetween RC and Nv (r = +0.32) is insufficientlyclose to predict NA and NV from RC. In retrospec-tive studies, or where conventional morphometry isnot feasible, it appears that RC may validly be usedas a substitute for NA in assessing the adequacy ofacinar alveolarisation. If both RC and NA are avail-able more precise deductions are possible; if, forexample, NA is found to be normal and RC reducedthen too many units are present per unit area, indi-cating that alveolarisation of the distal bronchiolartree has not proceeded adequately.

Unexpectedly, RC correlated more closely withNAT (r = +0.59) than with NA or Nv. This is appar-ently related to the introduction of another variable,lung volume, in the calculation of NAT. The relation-ship between RC and NAT, however, was stillinsufficiently close to predict NAT from RC. Therelation between RC and NAT is of interest. Theratio of NAT/RC is a factor of the number ofrespiratory bronchiolar units in the lung. This ratiocorrelates poorly with age (r = +0*31, logarithmicregression). The correlation is, however, closer be-

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tween, 6 weeks and 2 years (r = +0-43); but afterthis age there is no correlation (r = +0.05). Thisindicates an increase in respiratory bronchiolar unitsup to the age of 2 years, with no significant changethereafter.The radial alveolar count method of Emery and

Mithal appears a simple and satisfactory method ofassessing lung growth. It should, however, beapplied with attention to the limitations which haveemerged from this study.

We wish to thank Dr JL Paul and Dr FP Glick fortheir assistance with statistical evaluation of thedata. We are also grateful for the special technicalassistance of Joan Mathers and Elizabeth Waszkie-wicz. Cynthia Sturgeon prepared the manuscript.The work was carried out with the aid of grant 6-292from the March of Dimes Foundation and MedicalResearch Council of Canada grant MT-7124.

References

1 Thurlbeck WM. Structure of the lungs. In: WiddicombeJG, ed. International review of physiology. Vol 14.Respiratory physiology II. Baltimore: University ParkPress, 1977:1-36.

2 Holmes C, Thurlbeck WM. Normal lung growth andresponse after pneumonectomy in the rat at variousages. Am Rev Respir Dis 1979;120:1125-36.

3 Weibel ER, Gomez DM. A principle for counting tissuestructure on random sections. J Appl Physiol1962;17:343-8.

4 Angus GE, Thurlbeck WM. Number of alveoli in thehuman lung. J Appl Physiol 1972;32:483-5.

Emery JL, Mithal A. The number of alveoli in the termi-nal respiratory unit of man during late intrauterine lifeand childhood. Arch Dis Child 1960;35:544-7.

6Kitagawa M, Hislop A, Boyden EA, Reid L. Lunghypoplasia in congenital diaphragmatic hernia. Aquantitative study of airway, artery and alveolardevelopment. Br J Surg 1971;58:342-6.

I Reale FR, Esterly JR. Pulmonary hypoplasia: a mor-phometric study of the lungs of infants with diaphrag-matic hernia, anencephaly, and renal malformations.Pediatrics 1973;51:91-6.

8 Areechon W, Reid L. Hypoplasia of lung with congenitaldiaphragmatic hernia. Br Med J 1963;i:230-3.

9 Askenazi SS, Perlman M. Pulmonary hypoplasia: lungweight and alveolar count as criteria of diagnosis. ArchDis Child 1979;54:614-8.

'0 Hislop A, Hey E, Reid L. The lungs in congenital bilat-eral renal agenesis and dysplasia. Arch Dis Child1979;54:32-8.

" Rabinovitch M, Haworth SG, Vance A, et al. Early pul-monary vascular changes in congenital heart diseasestudied in biopsy tissue. Hum Pathol 1980;11,suppl:499-509.

12 Chamberlain D, Hislop A, Hey E, Reid L. Pulmonaryhypoplasia in babies with severe rhesus isiommunisa-tion: a quantitative study. J Pathol 1977;122:43-52.

'3 Hislop A, Reid L. New pathological findings inemphysema of childhood: 1. Polyalveolar lobe withemphysema. Thorax 1970;25:682-90.

14 Berend N, Marlin GE. Arrest of alveolar multiplicationin kyphoscoliosis. Pathology 1979;11:485-91.

15 Goldstein JD, Reid LM. Pulmonary hypoplasia resultingfrom phrenic nerve agenesis and diaphragmatic amyo-plasia. J Pediatr 1980;97:282-7.

16 Swischuk LE, Richardson CJ, Nichols MM, Ingman MJ.Primary pulmonary hypoplasia in the neonate. JPediatr 1979;95:573-7.

17 Langston C, Waszkiewicz E, Thurlbeck WM. A simplemethod for the representative sampling of lungs ofdiverse size. Thorax 1979;34:527-30.

18 Short RHD. Alveolar epithelium in relation to growth ofthe lung. Philos Trans R Soc Lond (Biol Sci)1951;235:35.

9 Gil J, Weibel ER. Morphological study of pressure-volume hysteresis in rat lungs fixed by vascular perfu-sion. Respir Physiol 1972;15:190-213.

20Dunnili MS. Postnatal growth of the lung. Thorax1962;17:329-33.

21 Hansen JE, Ampaya EP. Lung morphometry: a fallacyin the use of the counting principle. J Appl Physiol1974;37:951-4.

22 Weibel ER. Stereological methods. Vol 1. Practicalmethods for biological morphometry. London:Academic Press, 1979.

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