Gut 1996; 39: 299-305

Variability of gastrointestinal transit in healthywomen and men

L P Degen, S F Phillips

AbstractBackground and Aims-Measurementsof gastrointestinal transit are made inclinical and research gastroenterology,yet their intrinsic variability is not wellcharacterised. In particular, an influenceofhormones on transit has been proposedas the basis for gastrointestinal symptomsthat vary with the menstrual cycle. Ouraims were to quantify individual differ-ences in transit during the menstrualcycle in healthy women and to comparethese with the intrinsic variability inhealthy men.Methods-On two occasions, whole guttransit was asssessed scintigraphicallyand colonic transit quantified by radio-opaque markers. Thirty two healthyvolunteers (12 women, 20 men) werestudied, women during the foilicular andluteal phases, men twice within a similarfour week period. Diets and exercise werestandardised prior to and during bothstudies.Results-Colonic transit was significantlyfaster in men, and postlag gastric empty-ing was also more rapid; other indices ofregional transit were not differentbetween the sexes. Total colonic transittime was equally well reflected by thescintigraphic and radio-opaque markermethods. Important intraindividual dif-ferences were noted in both sexes. Thevariances in our samples predicted an 80%chance of detecting (with 95°/0 confidence)a mean effect of menstrual hormones ontransit that was in the same range as theintrinsic variation in men.Conclusions-Colonic transit was fasterin men than in women. Although groupmeans in the two studies were almostidentical, single assessments of transit insubjects sometimes exhibited consider-able variability, implying broad biologicalvariations. Given this intrinsic variability,the influence of menstrual hormones ongastrointestinal transit must be small andofdoubtful clinical significance.(Gut 1996; 39: 299-305)

Keywords: transit, reproducibility, sex differences.

Rates at which food and digestive productstraverse the gastrointestinal tract reflect theintegrated activity of intestinal smooth muscle,are thought to be relevant to certain symp-toms,1-3 and have been quantified by severalmethodologies.1-7 Scintigraphic assessments ofgastric emptying are perhaps best established,and they are now standard in many nuclear

medicine facilities; reports of their repro-ducibility have been published.8-'0 Scinti-graphy has now been applied also to smallbowel and colonic transit235 and the tech-niques have been simplified enough to makeclinical tests for whole gut transit feasible.1 1-3

However, the day to day reproducibility ofsmall bowel and colonic transit have not beenreported, even though these indices arerequired for adequate interpretation of clinicaland experimental studies. Moreover, bowelhabits may vary daily, especially in patientswith functional gastrointestinal disorders. It isimportant, therefore, that the normal biologi-cal variability of gastrointestinal transit bedocumented.

Despite longstanding interest in their influ-ence on bowel habits, the effects of themenstrual hormones on gut function remainquite uncertain. The influences of the sexsteroids on smooth muscle function andmotility in animals is well substantiated,14-18but comparable effects have never been wellsubstantiated in humans. Thus, the results ofearlier studies are in conflict; some propose asignificant influence,'9-24 or no effect,25-30 ofthe menstrual cycle on gastrointestinal transit.On the other hand, gastrointestinal symptomsoften attributed to disorders of motility, havebeen reported to vary with the menstrualcycle.31-33Our non-invasive scintigraphic method2351 1-13

provides a simple, comprehensive, and non-invasive tool by which transit of solid materialthrough the entire, unprepared gastrointestinaltract can be measured. Our aim, therefore, wasto quantify the differences in gastrointestinaltransit in healthy women during the lutealand follicular phases of one menstrual cycleand to compare intraindividual differences ingastrointestinal transit between women andmen.

Methods

EXPERIMENTAL SUBJECTSTwelve healthy women and 20 healthy men,aged between 19 and 45 years, were recruitedby public advertisement. None complained ofgastrointestinal symptoms, or had a history ofgastrointestinal disease or surgery other thanappendicectomy or hemiorrhaphy. Functionalbowel symptoms were specifically excluded byevaluating the Manning criteria.34 Volunteerswith acute symptoms or current use of drugsknown to change gastrointestinal motility, andwomen taking birth control pills or using anintrauterine device within the last six months,were excluded. Persons with a body massindex over 30 kg/M2 were also excluded

Division ofGastroenterology,Mayo Clinic,Rochester, MN, USAS F Phillips

Mayo Foundation,Rochester, MN, USAL P Degen

Correspondence to:Professor S F Phillips,Gastroenterology ResearchUnit, Mayo Clinic, 200 FirstAvenue SW, Rochester,MN 55905, USA.Accepted for publication13 February 1996

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because transit may be altered in clinicallyobese patients.35-37 In addition women musthave had a regular menstrual cycle for the lastsix months, the length needed to be 28±4 daysand there had to be no major symptoms duringthe menstrual cycle. Excluded also were lactat-ing women and those with a pregnancy withinthe last year.

With standardised questions, the smokinghabits as well as the consumption of alcoholand coffee were assessed. After discussion ofthe procedure in detail, written consent wasobtained for a protocol approved previously bythe Institutional Review Board and theRadiation Control Committee ofMayo Clinic.All female volunteers had to have had a nega-tive plasma P human chorionic gonadotrophinpregnancy test no longer than 48 hours beforeeach scintigraphic study.

EXPERIMENTAL PROTOCOLThree days prior to and during the entirestudy, volunteers ingested a weight maintain-ing diet, based on the Harris-Benedict equa-tion,38 with adjustment for daily physicalactivity. Volunteers were asked to avoidunusually intensive physical activity. Mealswere provided by the Mayo General ClinicalResearch Center and their composition wasnormalised to 53% carbohydrate, 17%protein, and 30% fat. Fibre intake was stan-dardised to 15 gram per day, consisting of 60%(9 gram) water insoluble and 40% (6 gram)water soluble fibre.39On each of days 2-4, volunteers ingested

at 9 am a capsule containing 24 radio-opaque markers (SITZMARKSO, LafayettePharmacal, 4200 South Hulen Street, FortWorth, TX 76109). At 9 am on day four, an

abdominal x ray was obtained for assessmentof the distribution of radio-opaque markers.7On day four at 7 am, after fasting since mid-night, the scintigraphic transit study begun andit finished 48 hours later.At the beginning ofeach study period, all par-

ticipants reported their physical activity withinthe last week, corresponding to the HarvardAlumni Activity Survey questionnaire40 andcompleted the self report inventory SCL-90-R4'to reflect their pattern of psychological symp-toms within the past week. Immediately beforethe transit study, a venous blood sample was

draw in women, to measure the concentrationsof progesterone and oestradiol.Women had two studies based on the men-

strual cycle. Day 1 of the cycle was defined as

the first day of menstrual flow. One transitstudy was performed on day 7-10 (=follicularphase) and one on day 21-24 (=luteal phase).At random, seven women had the first studyduring the follicular and five during the lutealphase. Men had the study repeated at equiva-lent times; an initial assessment was followedby the second within 14-17 days.

Study procedureGastric, small bowel, and colonic transit was

measured by the non-invasive scintigraphic

method developed in our laboratory.235 11-13Briefly, polystyrene Amberlite 120-IR-Plusresin pellets (average diameter 1 mm; range0-5-1.8 mm) were labelled in an acid mediumwith 100 ,uCi of "'In C13.42 The efficiency ofthe labelling was >98%, as judged by thin layerchromatography. A capsule filled with approxi-mately 0.5 g pellets and coated with one layerof methacrylate was given to fasting volunteers.As expected, the capsule dissolved in the ileo-caecal region and thereafter marked ileocaecaltransfer and colonic transit of contents.

External radioactive markers were placedover both anterior superior iliac spines to esti-mate the location of the capsule. As soon as theradiolabelled capsule passed into the smallbowel, a breakfast was ingested within fiveminutes. It consisted of two scrambled eggs,one slice of whole wheat bread, and skimmedmilk (35% protein, 52% carbohydrate, 13% fat,219 kcal). The scrambled eggs were mixed andcooked with 1 mCi of 99mTc labelled Amberlite410 resin pellets (average diameter 1 mm) to afirm consistency to provide a solid medium.These pellets had been labelled with 99Tcsodium pertechnetate in a neutral medium.42Four hours after breakfast, a standardised

non-radiolabelled lunch (chicken, potato,butter, tapioca pudding, and water; 535 kcal)and, eight hours after breakfast, a dinner(steak, salad, dessert; 21% protein, 49%carbohydrate, 30% fat; 561 kcal) was con-sumed. During the study volunteers were per-mitted normal physical activity.

Gammacamera imagingGammacamera imaging started immediatelyafter completion of ingestion of the radio-labelled breakfast with a large field of viewgammacamera with a medium energy, parallelhole collimator (GE Starcam, General Electric,Milwaukee, WI). Anterior and posterior imageswere acquired with the subject erect. For the99mTc counts a 140 keV, and for the "'Incounts a 245 keV, energy window (each with±20% window) was utilised. The estimatedwhole body dose equivalent was 130 m Rem.

Images were obtained at the following times(hours) after ingestion of the labelled meal, 0,0 5, 1, 2, 3-5, 8-10, 12, 24, and 48. For eachimage, two minutes of acquisition wereselected. Using variable regions of interest, theradioactivity was quantified in the stomach andascending colon for 99mTc and in four regionsof the colon (ascending, transverse, descend-ing, rectosigmoid) for "'In. The geometricmeans of the counts obtained from anteriorand posterior images were calculated for eachregion and then corrected for radionuclidedecay. The downscatter of "l 'In into the 99mTcwindow was adjusted. For two days, stoolswere collected and the radioactivity for "llIncounts was assessed and corrected for decay.

Colonic transit time measured by radio-opaquemarker methodLocalisation of the radio-opaque markers onthe abdominal film taken 24 hours after

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TABLE I Gastric emptying and small bowel transit. Reproducibility studies in healthywomen (n=12) and men (n=20)

Measurement Sex Mean SEM Median

Gastric lag phase (minutes) Fl 56 7 59F2 56 6 49Ml 55 5 57M2 58 3 58

Gastric half emptying (T /2minutes) Fl 202 26 184

F2 198 22 201Ml 153 9 157M2 163 13 148

Small bowel transit (minutes) Fl 196 22 179F2 210 23 184Ml 181 19 186M2 196 13 190

Fl is the study performed during the follicular and F2 during the luteal phase of the menstrualcycle in women.

ingestion of the last radio-opaque markerrelied on the bony landmarks and gaseousdelineations see on the abdominal x ray.6 7 Ifno clear contours of the bowel were recog-nised, markers located to the right of the verte-bral spinous processes, above a line from thefifth lumbar vertebrae to the pelvic outlet, wereassigned to the right colon. Markers to the leftof the vertebral spinous process and above animaginary line from the fifth lumbar vertebraeto the anterior superior iliac crest were allo-cated to the left colon. Markers inferior to aline from the pelvic brim on the right and thesuperior iliac crest on the left were assigned tothe rectosigmoid and rectum.6 7 However, ifbowel outlines clearly showed a pelvic caecum,an unusual transverse colon or a large sigmoidloop above the fifth lumbar vertebrae, markerswere judged to be in the anatomic segmentbased on the bowel silhouette.

Data analysisGastric emptying by the scintigraphic method

was assessed by the gastric lag time, postlagemptying rate, and the half emptying time(T1/2). The gastric lag time (min) was the timetaken for 10% of the radiolabel to empty fromthe stomach.12 The gastric postlag emptyingrate (0/o/min) was characterised by the slope

1.0 rWomen(n= 12)

0-8 F

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Figure 1: Postlag phase ofgastric emptying, shown as median values (bars), interquartileranges (boxes), and range for men and women. Women were studied in the follicular (F)and luteal (L) phases of the menstrual cycle. Men were studied twice, 14 days apart.Women had slower gastric emptying when evaluated by this index.

estimated from linear regression analysis ofdata from the first point beyond the lag timeuntil the time when 90°/O of the radiolabel hademptied from the stomach.42

Small bowel transit time was assessed by sub-tracting the time for 10% of the radiolabelledbreakfast to empty from the stomach from thetime taken for 10% of the label to enter thecolon. 12 42

Colonic transit was evaluated by the geo-metric centre of counts in the colonic regionsof interest (ROI). The geometric centre wasthe weighted average of the proportions ofcounts in the four ROI of the colon.13 Theregions, designated by numbers 1-4 as weight-ing factors were, respectively, the ascending,transverse, descending, and rectosigmoidcolons. The stool was designated as region 5.The proportion in each region was multipliedby the weighting factor and the sum calculated.A low geometric centre indicated that mostradiolabel was closer to the caecum, whereas ahigh value indicated that the major part of theradiolabel was closer to the stool.

Colonic transit time measured by radio-opaquemarker methodThe total number of all markers for eachcolonic segment was multiplied by a factor of1.0 and designated as the mean colonic transittime for that segment. The mean total colonictransit time was the sum of the calculatedmean segmental transit times.7

Physical activity score, SCL-90-R score, smokinghabits, alcohol, and coffee consumptionAssessments of total energy expenditure,expressed as kilocalories/week,40 and thepsychological symptom scores for primarysymptoms and global indices of distress,4'were rated. Smoking habits were quantified bypack years of actual consumption, alcohol con-sumption by units a week (1 unit beer, wine orhard drink= 10 g alcohol), and coffee by cups aday.

Hormone concentrationsSerum concentrations of progesterone andoestradiol were assessed with enhanced lumi-nescence and radioimmunoassays, respectively.A concentration of progesterone above 2 ng/mlwas regarded as consistent with the lutealphase, values below 0.7 ng/ml with the fol-licular phase.

Statistical analysisGastrointestinal transit data were expressed bybox whisker plots showing the median, theinterquartile, and the total ranges. Normallydistributed values were evaluated statisticallyby paired or unpaired t tests and non-para-metric data by the Wilcoxon's signed rank test.When we compared the radio-opaque andscintigraphic methods, we assessed the correla-tion between both the methods for each studyperiod. Correlations between the results were

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Figure 2: Colonic transit in healthy men and women, expressed as the geometric centre ojcounts at 48 hours, shown as median values (bars), interquartile ranges (boxes), and raifor men and women. Women were studied in the follicular (F) and luteal (L) phases of tmenstrual cycle. Men were studied twice, 14 days apart. Colonic transit was significantlj

Men(n = 20)

1 2W vM: p<0-(

Men(n = 20)

1 2

W vM: p=O.CFigure 3: Total colonic transit as measured by the radio-opaque marker method, in healtmen and women, shown as median values (bars), interquartile ranges (boxes), and randfor men and women. Women were studied in the follicular (F) and luteal (L) phases ofmenstrual cycle. Men were studied twice, 14 days apart. Colonic transit was significantlifaster in men at 24 hours.

* Women (n = 12)o Men (n = 20)

Mean (SEM)

Time (h)Figure 4: Sex differences in colonic transit, expressed as the progression of the geometriccentres ofscintigraphic markers against time. High values for the GC, signifyingfastercolonic transit, became apparent in men after 12 hours (approximately). At that time thGC was approximately 2. 0 indicating that the centre of counts was in the transverse cok

based on linear regression analysis. The influ-ence of covariates on gut transit was evaluatedusing multiple analyses of variance.Significance was declared at a<005.

In women, the indices were compared intraas well as interindividually for the follicular andluteal phase; in men, the first and secondstudies were compared. As the menstrual cyclehad no measurable effect on gastrointestinaltransit, for sex comparisons we used the twovalues for women and the two for men toobtain a single value for each individual.

Intraindividual variability between results ateach level of the gut were not significantlydifferent between sexes and consequently havebeen summarised together.

Results

CHARACTERISTICS OF THE GROUPSnge The mean age in both groups was 29 years

(range, women: 19-44; men: 21-45).Although the body mass index did not differsignificantly between the sexes (mean (SEM)women: 23.97 (0.95); men: 25A48 (0.63),weight and height were significantly different(p<0001). Men were heavier (84 (2) v 68 (3)kg) and taller (182 (2) v 168 (2) cm). Althoughmen ingested slightly more calories, the valueswere not significantly different between sexes,as well as between the two studies (women:study 1: 2845 (420), study 2: 2562 (288)kcal/day, men: 3384 (570) and 3296 (479)kcallday). Smoking, coffee, and alcohol con-sumption were not significantly differentbetween paired studies.Women had their menarche at a mean age of

13 (0.4) years, the mean cycle length was 28(0.7) with a menstrual length of five (0.3) days.The number of pregnancies was one (0 5). Thefluctuation of hormonal concentrationsbetween the follicular and luteal phases was

)01 significant for progesterone and oestradiolthy (p<0.001 and p=0.018, respectively). Pro-ge gesterone measured in the follicular phase wast)he 0.57 (0.07), in the luteal phase 6.07 (1P11)

ng/ml. Oestradiol concentrations were 79.67(11.09) and 137.33 (16.43) pg/ml, respec-tively.

SEX DIFFERENCES

Gastric emptyingThe lag phase for solid meals and the half timesfor gastric emptying were not significantly dif-ferent between sexes (Table I). However, thepostlag gastric emptying rate (Fig 1) wassignificantly faster in men than women(p=0005). No significant change in any of thethree indices of gastric emptying was notedduring the menstrual cycle (Table I, Fig 1).

-J50 Small bowel transit

The index demonstrated no sex differencesand no effect of the menstrual cycle (Table I).

te The variability in women was similar to that inon. men.

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Figure 5: Relations between mean colonic transit time (MCTT) by the radio-opaquemarker method and the geometric centres (radioscintigraphic method) at 24 (A) and 48(B) hours; 64 observations on 32 people.

Colonic transitWhen expressed as the geometric centre (GC)at six and 24 hours (data not shown) and 48hours (Fig 2), colonic transit was stablethroughout the menstrual cycle. Total colonictransit time (Fig 3), measured by the radio-opaque marker method, was also not influencedby the menstrual cycle. However, irrespective ofthe cycle phase in women, colonic transit wassignificantly faster in men (Figs 2 and 3).Mean values of GCs for all available time

points were plotted (Fig 4). Sex differenceswere most pronounced in the later observa-tions, when markers should have reached thedistal colon - that is, at 12 hours and beyond.This difference reached statistical significancewhen the areas under the curves were com-pared (p<0001).

Within individual studies, correlationsbetween the scintigraphic GC at 24 or 48hours and the results with radio-opaque mark-ers were highly significant (p<0001, Fig 5).Using the average value of the two studies foreach individual (data not shown), these corre-lations were also significant (p<0005).

INTRAINDIVIDUAL VARIABILITYIndividual differences between study 1 andstudy 2 for each person were evaluated for each

TABLE II Gastric emptying and small bowel transit. Interindividual variability

Difference between replicate studies

Measurement Sex Mean delta* Median delta Range delta

Gastric lag phase (minutes) F 0 2 60M 3 3 36

Gastric half emptying (TA/minutes) F 3 2 66

M 10 4 183Postlag slope (0/0 per minute) F 0 001 0.004 0.44

M 0039 0-016 0.33Small bowel transit (minutes) F 4 4 36

M 19 6 211

*Delta refers to the difference between studies 1 and 2 for each person.

index of transit. The means and medians ofthese intraindividual differences were not

J significantly different from 0 for the gastric lagphase, postlag emptying slope, and T1/, ofgastric emptying. However, the ranges of theseintraindividual differences were broad. Similarconclusions pertain to small bowel transit(Table II).

j Repeated measurements of colonic transit80 also showed mean results that were very repro-

ducible. When differences between study 1and study 2 for both sexes were combined,median differences of the GCs at six and 24hours were very close to zero and the inter-

_ quartile ranges were also quite narrow (Fig 6).However, outliers were noted and the totalranges of interindividual differences were wide(Fig 7). Radio-opaque marker transit yieldedsimilar comparisons between replicate studies.Figure 7 shows the mean colonic transit timesfor both studies in all subjects.

80

DiscussionEpidemiological findings43 44 suggest thatwomen are more constipated than are men andHeaton et al44 suggested a hormonal cause,especially in women of childbearing age. It isnoteworthy, therefore, that female hormonesinfluence gastrointestinal muscle function inanimals. Contractile activity was inhibited invitro by progesterone45-47 and excited byoestradiolI4 48; moreover, gastrointestinal tran-sit in rodents was influenced by both classes ofhormones.15-18 To extend these findings andquantify the effects in humans, transit timesthrough the gut were estimated with radio-opaque markers49 50 or lactulose H2 breathexcretion.51 The results are inconsistent.Some have indicated no significant differencebetween women and men, whether the mea-surements were those of orocaecal transit52 ormouth to anus transit.53 Others have suggesteda significant prolongation of mean colonictransit in women75457 but were unable todemonstrate changes of transit during themenstrual cycle.56We studied healthy women and men twice

under the same standardised conditions, inparticular we controlled for diet, alcohol, andcoffee consumption, physical activities, andpsychological patterns. None of these factorsexhibited consistent effects. Physical activityand the psychological patterns did not varysignificantly during the menstrual cycle. Bypreselecting healthy, non-obese volunteers,weight and height, although significantly dif-ferent between the sexes did not influencetransit significantly. We confirmed that hor-mone concentrations fluctuated predictablyduring the menstrual cycle, but transit was notsystematically different during the phases ofthe menstrual cycle, even if we excluded fromthe analysis three women who showed the leastchanges in circulating levels of progesteroneduring the luteal phase.

In both sexes, group median (or mean)values were essentially identical for replicatestudies. Closer inspection of the resultsshowed that, though group differences

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Figure 6: Intraindividual differences for colonic transit, expressed as geometric centres at six(A) and 24 (B) hours, for 12 women and 20 men, each ofwhom was studied on twooccasions. The median value for delta (differences between studies 1 and 2) was close tozero, and halfthe subjects (interquartile range in the box) yielded very similar values forreplicate studies. The entire range was wide, as influenced by several outliers.

between replicate tests (for example, medianand interquartile ranges for delta values) weregenerally small, outliers were recorded.Moreover, the intrinsic variability of transit inmen implied that any additional perturbation inwomen (for example, due to the menstrualcycle) would need to be quite large if it were tobe statistically and clinically important. Oursample size provided an 80% statistical power,at a significance level of 0.05, to detect a differ-ence of one standard deviation within a person.Based on this index, the menstrual cycle did notchange gastrointestinal transit. Thus, though aminor effect of the menstrual cycle on transitcannot be excluded, any changes that might befound with larger samples would be smallcompared with intrinsic biological variations.

In both follicular and luteal phases, one ofthree indices of gastric emptying (postlag emp-tying slope) was significantly slower in women.However, two other indices of gastric emptying(T'/2 and lag phase), and small bowel transit,showed no sex differences. Thus, we feel anyeffects of sex on gastric emptying and smallbowel transit are probably not of great biologi-cal significance. The differences between sexesfor colonic transit were more impressive and

Women Men100 100

80 - 80

60 -60-

C 40 -4000

F L 1 2

Figure 7: Mean colonic transit time by the radio-opaque marker method; duplicate studiesin 12 women and 20 men. Women were studied in the follicular (F) and luteal (L) phasesof the menstrual cycle. Men were studied twice, 14 days apart.

consistent with previous studies.7 20 27 55-57The scintigraphic method allowed us to com-pare GCs at various times, Figure 4 suggeststhat the sex difference was most obvious in thelater scans, when the marker had reached thedistal colon.The reproducibility of group results was

impressive. However, in a few persons, intra-individual variabilities were considerable, andthese were seen at all levels of the gut. We feelthese represent the biological variations withina person, which must be kept in mind whenassessing the effects of any intervention, suchas treatment with a drug. The magnitude of theintraindividual variabilities in colonic transitwere similar for the scintigraphic and radio-opaque techniques, suggesting that they reflectphysiological changes in gut function, ratherthan being due to methodological artefacts.Factors that might contribute to this physio-logical variability include diet, physical activity,sex hormones, weight, height, alcohol, andcoffee consumption, as well as psychologicalfactors. We attempted to control for all ofthese, and none was significant.

In summary, we were unable to demonstratein healthy women an effect of the menstrualcycle on gastric emptying, small bowel, andcolonic transit. Thus, physiological effects ofhormones can be disregarded during assess-ments of transit. Although gastrointestinalsymptoms fluctuate during the menstrualcycle, our results imply that these variationsshould not be caused by changes in transit.One of these indices of gastric emptyingshowed a sex difference and slower colonictransit in women was again confirmed.

The study was supported in part by a grant from the SwissNational Science Foundation (LPD) and by grants DK32121and RR00585 from the National Institutes of Health, Bethesda,MD, USA (SFP).

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