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Motility of the Intact Human Colon
Vol. 54. No.2 Printed. in.-U.S. A.
GASTROENTEROLOGY
Copyright © 1968 by The Williams & Wilkins Co.
lUOTJLITY OF THE INTACT HUMAN COLON ALAN A. BLOOM, M.D., PHILIP LOPRESTI, M.D., AND JOHN T. FARRAR, M.D.
Department of Medicine, New York Veterans Administration Hospital, First Avenue and East 24th Street, New York, New York
Studies of motility patterns of the human colon have been limited, with few exceptions,1. :l to the colon distal to the splenic flexure or to the ascending colon through right colostomy stomas, utilizing long tubes with or without balloons, usually inserted by sigmoidoscope. The significance of these studies is limited by unassessed artifactproducing potentials of tube-balloon systems and patient discomfort. With the development of small, ingestible, radio telemanometers3 • 4 patient discomfort is not evident and reflexes, induced by mucosal 5 or intramural6 • 7 stimulation, are minimized. Advantages and limitations of this and other methods for study of motility patterns of the intestinal tract have been reviewed. 8 - n This paper presents observations on pressure patterns of the human colon obtained by telemanometer in normal controls and patients with disorders of the colon. Methods Pressure sensor. The device has been described in connection with studies of other parts of the intestinal tract."" " The telemanometer is composed of two major parts: pressure transducer and oscillator. The former is a nickel bellows which moves a ferrite armature within an encircling solenoid. Altera tions in inductance modify a frequencyReceived June 7, 1967. Accepted October 16, 1967. Address requests for reprints to: Dr. Alan A. Bloom, The Bronx-Lebanon Hospital Center, 1650 Grand Concourse, Bronx, New York 10457. This investigation was supported in part by Grant AM 10364-OIAI from the United States Public Health Service. Dr. Bloom's present address is: The BronxLebanon Hospital Center, 1650 Grand Concourse, Bronx, New York 10457. Dr. Farrar's present address is: Medical College of Virginia, Richmond, Virginia.
modulated signal transmitted by the oscillator. Signals are demodulated by a tuner whose output is recorded permanently. Prior to each study, the capsule, encased in a flaccid latex bag, and tuner are calibrated at 37 C, with a water manometer. Temperature-induced drift does not exceed ±20/0 per degree centigrade. Pressure fluctuations are reproduced faithfully up to 10 cycles per sec. Recording protocols. (A) Subjects swallowed the capsule 6 to 16 hr prior to the study, depending upon an estimate of anticipated transit time. A I-hr recording was obtained in the fasting state. Postcibal recordings were taken in successive 50-min periods, terminated by a lO-min rest period. Subjects were in a recumbent position and were not permitted to sleep. Each study was continued until the capsule passed or came to rest in the lower rectosigmoid. (B) Colonic motility records obtained in conjunction with studies on small intestinal motility were available for study. The recording procedure was similar to protocol A except that radiographic localization data were not available. Only studies which contained information pertinent to this investigation were included. None were analyzed in the manner described below. The number of subjects in each protocol is summarized in table 1. Localization . A colonic locus was indicated when the rate of contraction no longer exceeded 13 per min and continued until passage of the telemanometer. Rates of contraction in excess of 13 per min indicated a small bowel locus. Radiographs were taken between recording periods. Movement of the telemanometer from right to left was determined utili zing osseous and soft tissue landmarks and relationships of colonic gas and fecal rna terial. Analysis of data. Records were viewed as a sequence of discrete pressure events definable in terms of two parameters: amplitude and duration. An interval is an event with a duration 232
grea ter than 2.5 sec and without deviation from base line greater than 2.5 cm of H 2 0. A wave is an event with a positive pressure deviation from base line of at least 2.5 cm of H 20. Several wave forms are discernible and are illustrated in figure l. A simple wave is monophasic and approximately symmetrical. It is preceded and followed by an interval of more than 2.5 sec, and its duration is the time between the point when it leaves the base line and the point when it returns. A complex wave is one in a cluster of two waves or more; each cluster is preceded and followed by an interval of greater than 2.5 sec. Intersections of adjacent limbs of successive waves are more than 2.5 cm of H 2 0 above base line, and duration is the time between successive intersections. A repetitive wave is one occurring in a sequence of two or more; the intersections of successive waves occur at the base line and determine its duration. The activity is the ratio of the sum of durations of all waves during a given period of observation to the total duration of observation .
sum of durations of all waves during time T total time T X 100
Pressure data on oscillographic records were digitized manually and stored on punch cards with a format compatible with input requirements of standard data processing equipment. Frequency distributions of amplitudes and dura tions, classified and tabulated by diag1. Summary of patients and sludie.s in each diagnostic category No. of patients Diagnostic category
Normal.. ... . ..... Ulcerative colitis. Irritable bowel syndrome ....... Constipation. .... Totals . .. " .......
_..
:gE
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ps. A
2gE J~LJc'
cr ~TlOfI.t"'!"'!t"I!'·'~!!I"!!"'!!! !''''~~~~HI!.
I
o
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I 2
I
I
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I 6
TI ME I N MINUTES
FIG. 1. Upper record. Colonic pressure record-
ing from a patient without gastrointestinal complaints. Several wave forms are illustrated: M, simple (monophasic); C, complex wave; R, repetitive wave. Lower record. Colonic pressure recording from a patient with constipation illustrating lack of universal applicability of criteria for wave classification by form. M? appears identical in form with the simple monophasic waves seen in the upper record although superimposed on another wave form (Cn. Strict application of criteria required designation of all peaks (M?, as complex (C).
cn
Activity (%)
TABLE
233
MOTILITY OF INTACT HUMAN COLON
February 1968
Protocol Protocol B A
No. of studies
No. of
studies
analyzed
5
-12 0
11
16 9
10 3
3 2
13 6
10 4
34
17
58
39
16
28
nosis and location, were tested for independence of distribution utilizing X".l4 In this study the null hypothesis was rejected when p < 0.D1. Activity was calculated manually from the pooled data output. Subjects. Volunteers were obtained from the Manhattan Veterans Administration Hospital. Clinical states were defined as follows. Controls: patients with normal bowel histories; 2 of these patients had other disorders of the gastrointestinal tract (cirrhosis, 1 patient; subtotal gastrectomy, 1 patient), but, in view of their negative bowel evaluation, were considered normal. Irritable bowel syndrome: patients with a history of intermittent diarrhea with or without alternating constipation. The stools were characterized as usually loose, with the passage of mucus and the occurrence of cramping abdominal pain and tenesmus. There was no objective evidence of organic disease. All were symptomatic at the time of the study. Ulcerative colitis: patients diagnosed on the basis of a characteristic history, radiographic, and proctosigmoidoscopic findings. All were symptomatic at the time of the study. There were no cases of "right-sided," segmental, or granulomatous colitis. Constipation: patients with a history of passage of
234
BLOOM ET AL . !l:i!!!MII!ll! .
30
eM .
H2 0
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Vol. 54, N o. 2
w.~
~\.I\./,Jv.." . ...,~~_ I
I
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/ , '" I
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8
10
12
14
16
18
20
22
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16
24
TI ME IN MINUTES
FIG. 2. Continuous tracing obtained from patient with ulcerative colitis. Note relative lack of activity. T elemanometer was in hepatic flexure at beginning of record and was passed per rectum 60 min later.
hard stools occurring less frequently than once per day unless laxatives were used. At the time of study the patients were not receiving !axati\'es and were symptomatic. The number of patients in each diagnostic category and recording protocol are summarized in table 1. A total of 41 studies was done on patients in protocol A; two studies were excluded as they showed no colonic activity in 1 subject and only 8 min of colonic activity in the other. Eighteen technically satisfactory studies were available from protocol B.
Results 11[ ov ement of the telemanometer through the colon. Passage of the capsule through
the colon was characterized neither by a smooth, steady progression nor by a single mass movement. Instead, the capsule moved sporadically for varying distances. On occasion, large lengths of colon were traversed : in 2 patients with active ulcerative colitis the capsule was in the hepatic flexure at the beginning of a recording period and passed in the stools 1hr later (fig. 2). The total transit of the telemanometer varied in a wide range. Of 29 patients on whom complete data are available, 21 (72%) passed the capsule between 20 and 48 hr. The shortest (6 hr) and longest (5
days) passages were in patients with ulcerative colitis. In the latter , the telemanometer rested for 4 days proximal to a n arrowed area at the splenic flexure. In 12 patients, recordings were obtained while the telemanometer passed from t erminal ileum into ascending colon (fig. 3) . In none was there a change in the base line pressure. Comparison of the pressure effects on each side of the normal colon. Sixteen studies in 16 controls were analyzed. Amplitudes and durations of 3277 waves were sorted according to their location in the bowel: right side (cecum, ascending colon, hepatic flexure, and right transverse colon) or left side (left transverse colon, splenic flexure, descending colon, and rectosigmoid). Simple waves occuring on the right side of the colon have both higher amplitude (l = 54.5, df = 4, P < 0.001) and longer duration (x 2 = 34.5, dt = 4, P < 0.001). Similarly, amplitudes of complex waves on the right side are greater than on the left (x 2 = 45.5, dt = 6, P < 0.001). However, durations of complex waves on the right are less than on the left (x 2 = 64.5, dt = 12, P < 0.001). The amplitude and duration of repetitive waves were similar on each side of the colon. As indicated in ta-
235
MOTILITY OF INTACT HUMAN COLON
F ebrllary 1968
eM.
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2
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+-________~~w~~~~~.~~~~~~
~~~~~a~__~______
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12
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16 14 TIME IN MINUTES
8
10
18
20
FIG. 3. Ileocolonic transition pattern. Tracing obtained as telemanometer passed from small bowel (minute 0 to 2) to cecum (minute 15+). Vertical arrows indicate respiratory artifacts.
ble 2 the activity was greater on the left side. Comparison of disease states with normal state. Distributions of parameters of all wave forms in normal controls and the several disease states are represented in figure 4 (amplitudes ) and figure 5 (durations). In ulcerative colitis all wave forms have lower amplitudes (x 2 = 90.7, df = 5, P < 0.001) and shorter durations x2 = 38, df 5, P < 0.001) than wave forms from normal controls. Type IV waves 15 • 16 were not seen in ulcerative colitis or in any other clinical state. Patients with irritable bowel syndrome frequently complained of cramping pain but no clear relationship could be observed between the occurrence of pain and any particular wave form. Amplitudes of all wave forms were lower (x 2 = 291.6, df = 5, P < 0.001) and durations shorter (x 2 = 147.2, df = 5, P < 0.001) than controls. Two kinds of pressure waves appeared sufficiently often in the irritable bowel to warrant mention: low amplitude, regular waves occurring approximately 2.5 per min and persisting for 5 to 8 min, seen in 7 patients (fig. 6) ; and waves of approximately eight to 11 per min occurring in sustained bursts of more than 1 min in duration; these may occur without significant elevation of the base line (fig. 7, lower record) or may be superimposed on other wave forms (fig. 7, upper record). In patients with constipation all wave
=
forms have higher amplitudes than controls (x 2 = 171.1, df = 5, P < 0.001) (fig. 4). Durations of all wave forms in constipated patients are shorter (x 2 = 171.3, df 5, P < 0.001) than controls (fig. 5). The activity for each disease state is summarized in table 2.
=
Discussion
The use of a telemanometer to record colonic activity is not without difficulties. At the present level of development only one telemanometer can be used in anyone study. Since identification of propagated waves requires a tandem arrangement of pressure transducers, it was impossible to identify which, if any, of the observed pressure waves were propagated. It is possible, since the capsule is freely movable, that energy developed by propulsive waves may be dissipated in propelling the capsule rather than in expanding its bellows. Also, as the capsule is a pressure-sensitive device, it does not record contractions that may occur without changes in intraluminal pressure,17 although the same is true of open tipped catheters. Another problem is localization of the capsule. In the present study only gross localizations were possible: specifically, differentiation between small and large bowel and differentiation between right and left sides of large bowel. Radiopaque media were not used as they might have given rise to alterations in motility and since they did not offer the likelihood
204
Vol. 54, No.2
WORMSLEY
150
o. CASE1
were associated with lowered sodium concentrations. Bilirubin Content of Duodenal Aspirate
~
100 VOLUME (ml/10 min)
1~
FIG . 14. Comparison of response to Boots and to J orpes-Mutt secretins. Each point represents the bicarbonate concentration and volume during the steady state response to secretin. E ach subject received four dose rates of secretin infusionthe open points representing the Boots secretin and the closed points showing the response to Jorpes-Mutt secretin. Case 1 (N), whose duodenal aspirate was free of bile throughout the test. received 0.5, 1, 2, and 5 units· per kg per hr of Boots secretin and 0.25, 0.5, 1, and 2.5 clinical units7 per kg per hr of Jorpes-Mutt secretin. Case 2 (DU), whose duodenal aspirate was bilestained thro ughout the test, received 0.5, 1, 10, and 25 units· per kg per hr of Boots secretin and 0.25, 0.5, 5, and 12.5 clinical units7 per kg per hr of Jorpes-Mutt secretin. In both subjects, the inerease in dose rate of secretin infusion resulted in increase in volume and decrease in bicarbonate concentration of the duodenal aspirate, in four successive steps from left to right in the figure. The stippled area outlines the relationship shown in figure 3.
Potassium Content of Duodenal Aspirate
The concentration of potassium in duodenal aspirate remained constant, at 3.5 to 4.5 mEq per liter during constant rate infusion of secretin, so that the output of potassium was linearly related to the volume of aspirate. Osmolality of Duodenal Aspirate
The osmolality of the duodenal aspirate reflected the concentration of cations and ranged from 300 to 315 mOsm. Occasional marked decreases, as low as 230 mOsm,
In 5 subjects (1 N , 2 DU, 2 CP) the duodenal aspirate contained no bilirubin at any time during the continuous infusion of secretin. Seven other subjects (2 N, 3 DU, 1 CP, 1 pernicious anemia) produced some samples free of bile pigment. When present, bilirubin concentration was almost constant during the course of the continuous infusion of secretin. The output of bile pigment rose in 8 subjects (3 N, 3 DU, 1 pernicious anemia, 1 abdominal pain) and remained constan t in 15 others (3 N, 4 DU, 2 AP, 2 GS, 2 CP, 1 celiac disease, 1 abdominal pain ) on increasing the dose rate of secretin from 10 to 25 units per kg per hr. There was no constant relationship between the concentration or output of bile pigment and yolume of duodenal aspirate, bicarbonate or chloride concentration, or output. In anyone individual, samples of duodenal juice of equal volume, bicarbonate or chloride concentration could range from colorless to heavily bile-stained. Conversely, followin g a series of colorless samples, the appearance of bile could be associated with a rise in the volume of the sample, decrease in the bicarbonate concentration, and increase in the concentration of chloride. Reproducibility
Infusions were repeated on differen t days in 4 subj ects, two with 10 units pel' kg per hr and two with 25 units pel' kg per hI' secretin. The outputs of bicarbonate in the duplicate tests were 21.5 and 22.3, 20.4 and 18.0, 23.3 and 23.5, and 17.9 and 18.3 mEq in 30 min, respectively. Comparison of Response to Boots and Jorpes-Mutt Secretin
The dose response curves of Boots G and Jorpes-Mutt 7 secretins were very similar (fig. 14), with bicarbonate concentration decreasing as the volume of duodenal aspirate increased in response to increas-
230
Vol. 54, No.2
SHORTER ET AL. TABLE
1. Effect of lymphocytes on colonic epithelial cells in vitro
Incubation systema : colonic cells plus
Viable colonic cells survivingb No. of tests No. (mean ±
Complement only (control) .. . Normal lymphocytes (cont rol ) ...................... . N ormallymphocytes treated with normal horse serum. N ormallymphocyt.es treated with HAHTS .......... . C UC lymphocytes .......... . CUC lymphocytes and normal horse serum .......... . CUC lymphocytes and HAIITS ... ............... . GC lymphocytes ............ . L C lymphocyt.es and normal horse serum. . .......... . GC lymphocytes a nd HAHTS .
SE)
%
P value for difference from con trol
11
68,730 ± 3,600
68.7
11
68,400 ± 4,520
68.4
11
65,400 ± 4,990
65.4
NS
11 6
68,700 ± 4 ,170 38,300 ± 3,950
68.7 38.3
NS <0 .001
6
43,170 ± 3,940
43 .2
<0.001
6
4
75,170 ± 5,050 37,000 ± 4,410
75.2 37.0
NSe <0.001
4 4
43,000 ± 6,360 65,600 ± 7,770
43. 0 65.6
<0.001 NSe
a HARTS, horse anti-human thymus serum; CUC, chronic ulcerat ive colitis; GC, granuloma tous colitis. b Ini t.ial colonic cell population, 1 X 10 5 • e This lack of significant difference from the control values demo ns trates t he effect of HARTS in this in vi tro system.
cells may be responsible in vivo for the initiation or perpetuation of tissue damage, or both, in the colon in ulcerative colitis, then our finding,.; indicate that theoretical consideration might be given to a clinical trial of the effects of heterologous antithymic sera, or the y-globulin fraction , in selected patients with granulomatous or uleerative colitis, in combination with other immunosuppressive agents such as azathioprine an d prednisone. Certainly these heterologous sera are powerful immunosuppressives,5 and the concept of their use clinically is strengthened by the recent study by Starzl and as~ociatesr. who found that the administration of y-globulin derived from horse a nti-human lymphoid serum as an immunosuppressive, in combination with azathioprine and prednisone, to patients receiving allografts of kidneys was not associated with significant toxic effects. Summary
This study reports the cytotoxic effects in vitro of lymphocytes from the peripheral blood of patients with granulomatous or
ulcerative colitis on suspensions of allogeneic colonic epithelial cells after 4 hr of incubation at 37 C. It has shown also that this effect can be inhibited by preliminary incubation of the lymphocytes in the presence of 10% horse anti-human thymus serum but not normal horse serum. Preliminary incubation of the colonic epithelial cells with either serum did not produce any similar inhibitory effect. If the hypothesis is accepted that the cytotoxic effects of lymphocytes on colonic epithelial cells may have a role in the pathogenesis of granulomatous or ulcerative colitis, then it is suggested that a clinical trial of horse anti-human thymus serum, possibly in association with other immunosuppressives, might prove valuable. REFERENCES 1. Perlmann, P., and O. Broberger. 1963. In vitro studies of ulcera tive colitis. II. Cytotoxic action of white blood cells from patients on human fe tal colon cells. J. Exp. Med. 117: 717-733 . 2. Watson, D . W ., A . Quigley, and R . J. Bolt. 1966. Effect of lymphocytes from patients with ulcerative colitis on human adult colon
238
BLOOM ETAL.
or a postcibal pressure gradient which favors aboral propulsion of colonic contents. 26 However, lack of uniformity in protocols, sensing devices, and particularly in methods of analysis probably account for these disparities. Resolution of these difficulties requires: (a) multiple sensing devices that can be accurately localized in two segments or more of the colon, that are minimally inductive of stimulation (or inhibition) of the bowel, and that can be calibrated in terms of absolute pressure; and (b) a technique of analysis that relates absolute pressure, wave duration, and activity and is free of observer error. Certain variations from controls noted in our material and comparison of our findings with those of others deserve further comment. Ulcerative colitis. The pressure effects in ulcerative colitis differ from normal in two ways. The activity is decreased and the waves are shorter in duration and lower in amplitude regardless of wave form. We observed no high amplitude, long duration, bald waves of the type IV variety. Although these waves are infrequent even in ulcerative colitis, the total duration of our observations (in excess of 17 hr in patients with ulcerative colitis) makes it unlikely that we would have failed to record several if they are characteristic of the disease (the difficulties in using a movable sensing system cited previously might apply here as type IV waves are propulsive). Type IV waves have been observed in other diarrheal states 27 and are not specific for ulceratiye colitis. Since they have been detected only with systems utilizing intraluminal tubes (with or without balloons), the possibility must be considered that type IV wa ves are a response of the colon to the presence of relatively fixed and unmoving tubes. We recorded, as have others, long periods of inactivity in ulcerative colitis although we observed comparable periods of inactivity in controls. Irritable bowel syndrome. In this condition, as in ulcerative colitis, we found that wave forms are of lower amplitude and shorter duration than in normal controls. There was no clear relationship between the
Vol. 54, No.2
occurrence of cramps and intraluminal pressure changes as has been previously demonstrated in the small boweP3 in these patients. A striking fe ature of these records was the periodic rhythmicity that involved principally repetitive waves as well as complex and simple waves. The relatively high frequency (eight to 11 per min) waves noted by Ritchie occur in diarrheal states and spastic colonP The 2.5 per min low amplitude simple waves were seen in a series of normal patients studied by means of peranal tubes,28 although in our normal series such repetitive waves were not noted. It is possible that peranal tubes induce this alteration in colonic pressure patterns. Chronic constipation. Records of these patients were characterized by the presence of high pressure simple waves. Similar patterns described by Conne1l 29 were attributed to an outflow obstruction at the rectosigmoid level, induced by high frequency waves (five per min or greater) in the pelvic colon. We did not observe this fast wave activity in constipated patients. The relationship of the preponderance of high pressure waves in the colons of these patients to their constipation is not clear. Summary and Conclusions 1. Fifty-eight intraluminal pressure studies of the colon were performed by means of a telemanometer in 51 patients. 2. Movement of the telemanometer through the colon was intermittent rather than continuous ; it was passed in the stool within 48 hr after ingestion in the majority (72%) of instances. 3. Intraluminal colonic waves are not classifiable into types I or II on the basis of duration or amplitude or both. 4. The colon in ulcerative colitis and irritable bowel syndrome has decreased activity with wave forms that are lower ill amplitude and shorter in duration than in controls. Two types of colonic pressure waves are seen in irritable bowel syndrome: low amplitude waves occurring at the rate of 2.5 per min for bursts of 5 to 8 min; and waves occurring at the rate of eight to 11 per min for bursts of 1 min or more. 5. The colon of patients with constipa-
MOTILITY OF INTACT HUMAN COLON
February 1968
tion has the same or slightly greater activity as controls; the amplitudes of all wav~s are greater in constipated patients than III controls. 6. The presence of a gradient which would account for right to left movement of colonic contents was suggested by the observation of wave forms with higher amplitudes (simple and complex waves) and du~ ations (simple waves only) than theIr counterparts in the left colon. Longer durations of complex waves on the left and the greater activity on the left are not consistent with but do not exclude, the concept of a right to left physiological gradient. REFERENCES
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12.
13.
14. 15.
1. Fink, S. 1951. The intraluminal pressures in
the intact human intestine. Gastroenterology 36: 661-671.
2. Fink, S., and G. Friedman. 1960. The differential effects of drugs on the proximal and distal colon. Amer. J. Med. 28: 534540. 3. Farrar, J. T., V. K. Zworykin, and J. Baum. 1957. Pressure sensitive telemetering capsule for the study of gastrointestinal motility. Science 126: 975-976. 4. Mackay, R. S., and B. Jacobson. 1957. Endoradiosonde. Nature (London) 179: 12391240. 5. Bulbring, E., R. C. Y. Lin, and G. Schofield. 1958. An investigation of the peristaltic reflex in relation to anatomic observations. Quart. J. Exp. Physiol. 43: 26-37. 6. Hukuhara, T., and T. Miyake. 1959. The intrinsic reflexes in the colon. Jap. J. Physiol. 9: 49-55. i. Hukuhara, T., S. Nakayama, and R. Namba. 1960. Locality of receptors concerned with the intertino-intestinal extrinsic and intestinal muscular intrinsic reflexes. Jap. J. Phvsiol. 10: 414-419. 8. Quigiey, J. P., and D. A. Brody. 1952. A physiologic and clinical consideration of the pressures developed in the digestive tract. Amer. J. Med. 13: 73-81. 9. Farrar, J. T., and M. Davidson. 1960. Measurement of gastrointestinal motility in man, pp. 200-221. In H. D. Bruner [ed.], Methods in medical research, Vol. 8. YearBook Publishers, Inc., Chicago. 10. Hightower, N. C., Jr. 1960. Motility of the alimentarv canal in man, pp. 3-61. In J. A. Rider and H. C. Moeller [eds.], Disturb-
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25. Misiewicz, J. J., A. M. Connell, and F. A. Pontes. 1966. Comparison of the effects of meals and prostigmine on the proximal and distal colon in patients with and without diarrhea. Gut 7: 46&-473. 26. Wangel, A. G., and D. J. Deller. 1965. Intestinal motility in man. III. Mechanisms of constipation and diarrhea with particular reference to the irritable colon syndrome. Gastroenterology 48: 69-84. 27. Davidson, M ., M. H . Sleisenger, T. P. Almy,
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and S. Z. Levine. 1956. Studies of distal colonic motility in children. II. Propulsive activity in diarrheal states. Pediatrics 17: 820-832. 28. Connell, A. M. 1961. The motility of the pelvic
colon. I. Motility in normals and in patients with asymptomatic duodenal ulcer. Gut 2: 175-186.
29. Connell, A. M. 1962. The motility of the pelvic colon. II. Paradoxical motility in diarrhea and constipation. Gut 3: 342-348.
GASTROENTEROLOGY
Copyright © 1968 by The Williams & Wilkins Co.
lUOTJLITY OF THE INTACT HUMAN COLON ALAN A. BLOOM, M.D., PHILIP LOPRESTI, M.D., AND JOHN T. FARRAR, M.D.
Department of Medicine, New York Veterans Administration Hospital, First Avenue and East 24th Street, New York, New York
Studies of motility patterns of the human colon have been limited, with few exceptions,1. :l to the colon distal to the splenic flexure or to the ascending colon through right colostomy stomas, utilizing long tubes with or without balloons, usually inserted by sigmoidoscope. The significance of these studies is limited by unassessed artifactproducing potentials of tube-balloon systems and patient discomfort. With the development of small, ingestible, radio telemanometers3 • 4 patient discomfort is not evident and reflexes, induced by mucosal 5 or intramural6 • 7 stimulation, are minimized. Advantages and limitations of this and other methods for study of motility patterns of the intestinal tract have been reviewed. 8 - n This paper presents observations on pressure patterns of the human colon obtained by telemanometer in normal controls and patients with disorders of the colon. Methods Pressure sensor. The device has been described in connection with studies of other parts of the intestinal tract."" " The telemanometer is composed of two major parts: pressure transducer and oscillator. The former is a nickel bellows which moves a ferrite armature within an encircling solenoid. Altera tions in inductance modify a frequencyReceived June 7, 1967. Accepted October 16, 1967. Address requests for reprints to: Dr. Alan A. Bloom, The Bronx-Lebanon Hospital Center, 1650 Grand Concourse, Bronx, New York 10457. This investigation was supported in part by Grant AM 10364-OIAI from the United States Public Health Service. Dr. Bloom's present address is: The BronxLebanon Hospital Center, 1650 Grand Concourse, Bronx, New York 10457. Dr. Farrar's present address is: Medical College of Virginia, Richmond, Virginia.
modulated signal transmitted by the oscillator. Signals are demodulated by a tuner whose output is recorded permanently. Prior to each study, the capsule, encased in a flaccid latex bag, and tuner are calibrated at 37 C, with a water manometer. Temperature-induced drift does not exceed ±20/0 per degree centigrade. Pressure fluctuations are reproduced faithfully up to 10 cycles per sec. Recording protocols. (A) Subjects swallowed the capsule 6 to 16 hr prior to the study, depending upon an estimate of anticipated transit time. A I-hr recording was obtained in the fasting state. Postcibal recordings were taken in successive 50-min periods, terminated by a lO-min rest period. Subjects were in a recumbent position and were not permitted to sleep. Each study was continued until the capsule passed or came to rest in the lower rectosigmoid. (B) Colonic motility records obtained in conjunction with studies on small intestinal motility were available for study. The recording procedure was similar to protocol A except that radiographic localization data were not available. Only studies which contained information pertinent to this investigation were included. None were analyzed in the manner described below. The number of subjects in each protocol is summarized in table 1. Localization . A colonic locus was indicated when the rate of contraction no longer exceeded 13 per min and continued until passage of the telemanometer. Rates of contraction in excess of 13 per min indicated a small bowel locus. Radiographs were taken between recording periods. Movement of the telemanometer from right to left was determined utili zing osseous and soft tissue landmarks and relationships of colonic gas and fecal rna terial. Analysis of data. Records were viewed as a sequence of discrete pressure events definable in terms of two parameters: amplitude and duration. An interval is an event with a duration 232
grea ter than 2.5 sec and without deviation from base line greater than 2.5 cm of H 2 0. A wave is an event with a positive pressure deviation from base line of at least 2.5 cm of H 20. Several wave forms are discernible and are illustrated in figure l. A simple wave is monophasic and approximately symmetrical. It is preceded and followed by an interval of more than 2.5 sec, and its duration is the time between the point when it leaves the base line and the point when it returns. A complex wave is one in a cluster of two waves or more; each cluster is preceded and followed by an interval of greater than 2.5 sec. Intersections of adjacent limbs of successive waves are more than 2.5 cm of H 2 0 above base line, and duration is the time between successive intersections. A repetitive wave is one occurring in a sequence of two or more; the intersections of successive waves occur at the base line and determine its duration. The activity is the ratio of the sum of durations of all waves during a given period of observation to the total duration of observation .
sum of durations of all waves during time T total time T X 100
Pressure data on oscillographic records were digitized manually and stored on punch cards with a format compatible with input requirements of standard data processing equipment. Frequency distributions of amplitudes and dura tions, classified and tabulated by diag1. Summary of patients and sludie.s in each diagnostic category No. of patients Diagnostic category
Normal.. ... . ..... Ulcerative colitis. Irritable bowel syndrome ....... Constipation. .... Totals . .. " .......
_..
:gE
A;' ·,
ps. A
2gE J~LJc'
cr ~TlOfI.t"'!"'!t"I!'·'~!!I"!!"'!!! !''''~~~~HI!.
I
o
I
I 2
I
I
4
I
I 6
TI ME I N MINUTES
FIG. 1. Upper record. Colonic pressure record-
ing from a patient without gastrointestinal complaints. Several wave forms are illustrated: M, simple (monophasic); C, complex wave; R, repetitive wave. Lower record. Colonic pressure recording from a patient with constipation illustrating lack of universal applicability of criteria for wave classification by form. M? appears identical in form with the simple monophasic waves seen in the upper record although superimposed on another wave form (Cn. Strict application of criteria required designation of all peaks (M?, as complex (C).
cn
Activity (%)
TABLE
233
MOTILITY OF INTACT HUMAN COLON
February 1968
Protocol Protocol B A
No. of studies
No. of
studies
analyzed
5
-12 0
11
16 9
10 3
3 2
13 6
10 4
34
17
58
39
16
28
nosis and location, were tested for independence of distribution utilizing X".l4 In this study the null hypothesis was rejected when p < 0.D1. Activity was calculated manually from the pooled data output. Subjects. Volunteers were obtained from the Manhattan Veterans Administration Hospital. Clinical states were defined as follows. Controls: patients with normal bowel histories; 2 of these patients had other disorders of the gastrointestinal tract (cirrhosis, 1 patient; subtotal gastrectomy, 1 patient), but, in view of their negative bowel evaluation, were considered normal. Irritable bowel syndrome: patients with a history of intermittent diarrhea with or without alternating constipation. The stools were characterized as usually loose, with the passage of mucus and the occurrence of cramping abdominal pain and tenesmus. There was no objective evidence of organic disease. All were symptomatic at the time of the study. Ulcerative colitis: patients diagnosed on the basis of a characteristic history, radiographic, and proctosigmoidoscopic findings. All were symptomatic at the time of the study. There were no cases of "right-sided," segmental, or granulomatous colitis. Constipation: patients with a history of passage of
234
BLOOM ET AL . !l:i!!!MII!ll! .
30
eM .
H2 0
°E
Vol. 54, N o. 2
w.~
~\.I\./,Jv.." . ...,~~_ I
I
°
I
I
4
2
I
6
I
8
,)
/ , '" I
I
I
I
8
10
12
14
16
18
20
22
I
16
24
TI ME IN MINUTES
FIG. 2. Continuous tracing obtained from patient with ulcerative colitis. Note relative lack of activity. T elemanometer was in hepatic flexure at beginning of record and was passed per rectum 60 min later.
hard stools occurring less frequently than once per day unless laxatives were used. At the time of study the patients were not receiving !axati\'es and were symptomatic. The number of patients in each diagnostic category and recording protocol are summarized in table 1. A total of 41 studies was done on patients in protocol A; two studies were excluded as they showed no colonic activity in 1 subject and only 8 min of colonic activity in the other. Eighteen technically satisfactory studies were available from protocol B.
Results 11[ ov ement of the telemanometer through the colon. Passage of the capsule through
the colon was characterized neither by a smooth, steady progression nor by a single mass movement. Instead, the capsule moved sporadically for varying distances. On occasion, large lengths of colon were traversed : in 2 patients with active ulcerative colitis the capsule was in the hepatic flexure at the beginning of a recording period and passed in the stools 1hr later (fig. 2). The total transit of the telemanometer varied in a wide range. Of 29 patients on whom complete data are available, 21 (72%) passed the capsule between 20 and 48 hr. The shortest (6 hr) and longest (5
days) passages were in patients with ulcerative colitis. In the latter , the telemanometer rested for 4 days proximal to a n arrowed area at the splenic flexure. In 12 patients, recordings were obtained while the telemanometer passed from t erminal ileum into ascending colon (fig. 3) . In none was there a change in the base line pressure. Comparison of the pressure effects on each side of the normal colon. Sixteen studies in 16 controls were analyzed. Amplitudes and durations of 3277 waves were sorted according to their location in the bowel: right side (cecum, ascending colon, hepatic flexure, and right transverse colon) or left side (left transverse colon, splenic flexure, descending colon, and rectosigmoid). Simple waves occuring on the right side of the colon have both higher amplitude (l = 54.5, df = 4, P < 0.001) and longer duration (x 2 = 34.5, dt = 4, P < 0.001). Similarly, amplitudes of complex waves on the right side are greater than on the left (x 2 = 45.5, dt = 6, P < 0.001). However, durations of complex waves on the right are less than on the left (x 2 = 64.5, dt = 12, P < 0.001). The amplitude and duration of repetitive waves were similar on each side of the colon. As indicated in ta-
235
MOTILITY OF INTACT HUMAN COLON
F ebrllary 1968
eM.
40~ 20
2
0
H 0
+-________~~w~~~~~.~~~~~~
~~~~~a~__~______
I
_.-J-'____i.I/i.L_ __
" - -_ _..............." " ' , ,..... _ ¥O'... ___.....
I
o
10
-
I
SMAU.9OWn
2
I
12
4
6
16 14 TIME IN MINUTES
8
10
18
20
FIG. 3. Ileocolonic transition pattern. Tracing obtained as telemanometer passed from small bowel (minute 0 to 2) to cecum (minute 15+). Vertical arrows indicate respiratory artifacts.
ble 2 the activity was greater on the left side. Comparison of disease states with normal state. Distributions of parameters of all wave forms in normal controls and the several disease states are represented in figure 4 (amplitudes ) and figure 5 (durations). In ulcerative colitis all wave forms have lower amplitudes (x 2 = 90.7, df = 5, P < 0.001) and shorter durations x2 = 38, df 5, P < 0.001) than wave forms from normal controls. Type IV waves 15 • 16 were not seen in ulcerative colitis or in any other clinical state. Patients with irritable bowel syndrome frequently complained of cramping pain but no clear relationship could be observed between the occurrence of pain and any particular wave form. Amplitudes of all wave forms were lower (x 2 = 291.6, df = 5, P < 0.001) and durations shorter (x 2 = 147.2, df = 5, P < 0.001) than controls. Two kinds of pressure waves appeared sufficiently often in the irritable bowel to warrant mention: low amplitude, regular waves occurring approximately 2.5 per min and persisting for 5 to 8 min, seen in 7 patients (fig. 6) ; and waves of approximately eight to 11 per min occurring in sustained bursts of more than 1 min in duration; these may occur without significant elevation of the base line (fig. 7, lower record) or may be superimposed on other wave forms (fig. 7, upper record). In patients with constipation all wave
=
forms have higher amplitudes than controls (x 2 = 171.1, df = 5, P < 0.001) (fig. 4). Durations of all wave forms in constipated patients are shorter (x 2 = 171.3, df 5, P < 0.001) than controls (fig. 5). The activity for each disease state is summarized in table 2.
=
Discussion
The use of a telemanometer to record colonic activity is not without difficulties. At the present level of development only one telemanometer can be used in anyone study. Since identification of propagated waves requires a tandem arrangement of pressure transducers, it was impossible to identify which, if any, of the observed pressure waves were propagated. It is possible, since the capsule is freely movable, that energy developed by propulsive waves may be dissipated in propelling the capsule rather than in expanding its bellows. Also, as the capsule is a pressure-sensitive device, it does not record contractions that may occur without changes in intraluminal pressure,17 although the same is true of open tipped catheters. Another problem is localization of the capsule. In the present study only gross localizations were possible: specifically, differentiation between small and large bowel and differentiation between right and left sides of large bowel. Radiopaque media were not used as they might have given rise to alterations in motility and since they did not offer the likelihood
204
Vol. 54, No.2
WORMSLEY
150
o. CASE1
were associated with lowered sodium concentrations. Bilirubin Content of Duodenal Aspirate
~
100 VOLUME (ml/10 min)
1~
FIG . 14. Comparison of response to Boots and to J orpes-Mutt secretins. Each point represents the bicarbonate concentration and volume during the steady state response to secretin. E ach subject received four dose rates of secretin infusionthe open points representing the Boots secretin and the closed points showing the response to Jorpes-Mutt secretin. Case 1 (N), whose duodenal aspirate was free of bile throughout the test. received 0.5, 1, 2, and 5 units· per kg per hr of Boots secretin and 0.25, 0.5, 1, and 2.5 clinical units7 per kg per hr of Jorpes-Mutt secretin. Case 2 (DU), whose duodenal aspirate was bilestained thro ughout the test, received 0.5, 1, 10, and 25 units· per kg per hr of Boots secretin and 0.25, 0.5, 5, and 12.5 clinical units7 per kg per hr of Jorpes-Mutt secretin. In both subjects, the inerease in dose rate of secretin infusion resulted in increase in volume and decrease in bicarbonate concentration of the duodenal aspirate, in four successive steps from left to right in the figure. The stippled area outlines the relationship shown in figure 3.
Potassium Content of Duodenal Aspirate
The concentration of potassium in duodenal aspirate remained constant, at 3.5 to 4.5 mEq per liter during constant rate infusion of secretin, so that the output of potassium was linearly related to the volume of aspirate. Osmolality of Duodenal Aspirate
The osmolality of the duodenal aspirate reflected the concentration of cations and ranged from 300 to 315 mOsm. Occasional marked decreases, as low as 230 mOsm,
In 5 subjects (1 N , 2 DU, 2 CP) the duodenal aspirate contained no bilirubin at any time during the continuous infusion of secretin. Seven other subjects (2 N, 3 DU, 1 CP, 1 pernicious anemia) produced some samples free of bile pigment. When present, bilirubin concentration was almost constant during the course of the continuous infusion of secretin. The output of bile pigment rose in 8 subjects (3 N, 3 DU, 1 pernicious anemia, 1 abdominal pain) and remained constan t in 15 others (3 N, 4 DU, 2 AP, 2 GS, 2 CP, 1 celiac disease, 1 abdominal pain ) on increasing the dose rate of secretin from 10 to 25 units per kg per hr. There was no constant relationship between the concentration or output of bile pigment and yolume of duodenal aspirate, bicarbonate or chloride concentration, or output. In anyone individual, samples of duodenal juice of equal volume, bicarbonate or chloride concentration could range from colorless to heavily bile-stained. Conversely, followin g a series of colorless samples, the appearance of bile could be associated with a rise in the volume of the sample, decrease in the bicarbonate concentration, and increase in the concentration of chloride. Reproducibility
Infusions were repeated on differen t days in 4 subj ects, two with 10 units pel' kg per hr and two with 25 units pel' kg per hI' secretin. The outputs of bicarbonate in the duplicate tests were 21.5 and 22.3, 20.4 and 18.0, 23.3 and 23.5, and 17.9 and 18.3 mEq in 30 min, respectively. Comparison of Response to Boots and Jorpes-Mutt Secretin
The dose response curves of Boots G and Jorpes-Mutt 7 secretins were very similar (fig. 14), with bicarbonate concentration decreasing as the volume of duodenal aspirate increased in response to increas-
230
Vol. 54, No.2
SHORTER ET AL. TABLE
1. Effect of lymphocytes on colonic epithelial cells in vitro
Incubation systema : colonic cells plus
Viable colonic cells survivingb No. of tests No. (mean ±
Complement only (control) .. . Normal lymphocytes (cont rol ) ...................... . N ormallymphocytes treated with normal horse serum. N ormallymphocyt.es treated with HAHTS .......... . C UC lymphocytes .......... . CUC lymphocytes and normal horse serum .......... . CUC lymphocytes and HAIITS ... ............... . GC lymphocytes ............ . L C lymphocyt.es and normal horse serum. . .......... . GC lymphocytes a nd HAHTS .
SE)
%
P value for difference from con trol
11
68,730 ± 3,600
68.7
11
68,400 ± 4,520
68.4
11
65,400 ± 4,990
65.4
NS
11 6
68,700 ± 4 ,170 38,300 ± 3,950
68.7 38.3
NS <0 .001
6
43,170 ± 3,940
43 .2
<0.001
6
4
75,170 ± 5,050 37,000 ± 4,410
75.2 37.0
NSe <0.001
4 4
43,000 ± 6,360 65,600 ± 7,770
43. 0 65.6
<0.001 NSe
a HARTS, horse anti-human thymus serum; CUC, chronic ulcerat ive colitis; GC, granuloma tous colitis. b Ini t.ial colonic cell population, 1 X 10 5 • e This lack of significant difference from the control values demo ns trates t he effect of HARTS in this in vi tro system.
cells may be responsible in vivo for the initiation or perpetuation of tissue damage, or both, in the colon in ulcerative colitis, then our finding,.; indicate that theoretical consideration might be given to a clinical trial of the effects of heterologous antithymic sera, or the y-globulin fraction , in selected patients with granulomatous or uleerative colitis, in combination with other immunosuppressive agents such as azathioprine an d prednisone. Certainly these heterologous sera are powerful immunosuppressives,5 and the concept of their use clinically is strengthened by the recent study by Starzl and as~ociatesr. who found that the administration of y-globulin derived from horse a nti-human lymphoid serum as an immunosuppressive, in combination with azathioprine and prednisone, to patients receiving allografts of kidneys was not associated with significant toxic effects. Summary
This study reports the cytotoxic effects in vitro of lymphocytes from the peripheral blood of patients with granulomatous or
ulcerative colitis on suspensions of allogeneic colonic epithelial cells after 4 hr of incubation at 37 C. It has shown also that this effect can be inhibited by preliminary incubation of the lymphocytes in the presence of 10% horse anti-human thymus serum but not normal horse serum. Preliminary incubation of the colonic epithelial cells with either serum did not produce any similar inhibitory effect. If the hypothesis is accepted that the cytotoxic effects of lymphocytes on colonic epithelial cells may have a role in the pathogenesis of granulomatous or ulcerative colitis, then it is suggested that a clinical trial of horse anti-human thymus serum, possibly in association with other immunosuppressives, might prove valuable. REFERENCES 1. Perlmann, P., and O. Broberger. 1963. In vitro studies of ulcera tive colitis. II. Cytotoxic action of white blood cells from patients on human fe tal colon cells. J. Exp. Med. 117: 717-733 . 2. Watson, D . W ., A . Quigley, and R . J. Bolt. 1966. Effect of lymphocytes from patients with ulcerative colitis on human adult colon
238
BLOOM ETAL.
or a postcibal pressure gradient which favors aboral propulsion of colonic contents. 26 However, lack of uniformity in protocols, sensing devices, and particularly in methods of analysis probably account for these disparities. Resolution of these difficulties requires: (a) multiple sensing devices that can be accurately localized in two segments or more of the colon, that are minimally inductive of stimulation (or inhibition) of the bowel, and that can be calibrated in terms of absolute pressure; and (b) a technique of analysis that relates absolute pressure, wave duration, and activity and is free of observer error. Certain variations from controls noted in our material and comparison of our findings with those of others deserve further comment. Ulcerative colitis. The pressure effects in ulcerative colitis differ from normal in two ways. The activity is decreased and the waves are shorter in duration and lower in amplitude regardless of wave form. We observed no high amplitude, long duration, bald waves of the type IV variety. Although these waves are infrequent even in ulcerative colitis, the total duration of our observations (in excess of 17 hr in patients with ulcerative colitis) makes it unlikely that we would have failed to record several if they are characteristic of the disease (the difficulties in using a movable sensing system cited previously might apply here as type IV waves are propulsive). Type IV waves have been observed in other diarrheal states 27 and are not specific for ulceratiye colitis. Since they have been detected only with systems utilizing intraluminal tubes (with or without balloons), the possibility must be considered that type IV wa ves are a response of the colon to the presence of relatively fixed and unmoving tubes. We recorded, as have others, long periods of inactivity in ulcerative colitis although we observed comparable periods of inactivity in controls. Irritable bowel syndrome. In this condition, as in ulcerative colitis, we found that wave forms are of lower amplitude and shorter duration than in normal controls. There was no clear relationship between the
Vol. 54, No.2
occurrence of cramps and intraluminal pressure changes as has been previously demonstrated in the small boweP3 in these patients. A striking fe ature of these records was the periodic rhythmicity that involved principally repetitive waves as well as complex and simple waves. The relatively high frequency (eight to 11 per min) waves noted by Ritchie occur in diarrheal states and spastic colonP The 2.5 per min low amplitude simple waves were seen in a series of normal patients studied by means of peranal tubes,28 although in our normal series such repetitive waves were not noted. It is possible that peranal tubes induce this alteration in colonic pressure patterns. Chronic constipation. Records of these patients were characterized by the presence of high pressure simple waves. Similar patterns described by Conne1l 29 were attributed to an outflow obstruction at the rectosigmoid level, induced by high frequency waves (five per min or greater) in the pelvic colon. We did not observe this fast wave activity in constipated patients. The relationship of the preponderance of high pressure waves in the colons of these patients to their constipation is not clear. Summary and Conclusions 1. Fifty-eight intraluminal pressure studies of the colon were performed by means of a telemanometer in 51 patients. 2. Movement of the telemanometer through the colon was intermittent rather than continuous ; it was passed in the stool within 48 hr after ingestion in the majority (72%) of instances. 3. Intraluminal colonic waves are not classifiable into types I or II on the basis of duration or amplitude or both. 4. The colon in ulcerative colitis and irritable bowel syndrome has decreased activity with wave forms that are lower ill amplitude and shorter in duration than in controls. Two types of colonic pressure waves are seen in irritable bowel syndrome: low amplitude waves occurring at the rate of 2.5 per min for bursts of 5 to 8 min; and waves occurring at the rate of eight to 11 per min for bursts of 1 min or more. 5. The colon of patients with constipa-
MOTILITY OF INTACT HUMAN COLON
February 1968
tion has the same or slightly greater activity as controls; the amplitudes of all wav~s are greater in constipated patients than III controls. 6. The presence of a gradient which would account for right to left movement of colonic contents was suggested by the observation of wave forms with higher amplitudes (simple and complex waves) and du~ ations (simple waves only) than theIr counterparts in the left colon. Longer durations of complex waves on the left and the greater activity on the left are not consistent with but do not exclude, the concept of a right to left physiological gradient. REFERENCES
11.
12.
13.
14. 15.
1. Fink, S. 1951. The intraluminal pressures in
the intact human intestine. Gastroenterology 36: 661-671.
2. Fink, S., and G. Friedman. 1960. The differential effects of drugs on the proximal and distal colon. Amer. J. Med. 28: 534540. 3. Farrar, J. T., V. K. Zworykin, and J. Baum. 1957. Pressure sensitive telemetering capsule for the study of gastrointestinal motility. Science 126: 975-976. 4. Mackay, R. S., and B. Jacobson. 1957. Endoradiosonde. Nature (London) 179: 12391240. 5. Bulbring, E., R. C. Y. Lin, and G. Schofield. 1958. An investigation of the peristaltic reflex in relation to anatomic observations. Quart. J. Exp. Physiol. 43: 26-37. 6. Hukuhara, T., and T. Miyake. 1959. The intrinsic reflexes in the colon. Jap. J. Physiol. 9: 49-55. i. Hukuhara, T., S. Nakayama, and R. Namba. 1960. Locality of receptors concerned with the intertino-intestinal extrinsic and intestinal muscular intrinsic reflexes. Jap. J. Phvsiol. 10: 414-419. 8. Quigiey, J. P., and D. A. Brody. 1952. A physiologic and clinical consideration of the pressures developed in the digestive tract. Amer. J. Med. 13: 73-81. 9. Farrar, J. T., and M. Davidson. 1960. Measurement of gastrointestinal motility in man, pp. 200-221. In H. D. Bruner [ed.], Methods in medical research, Vol. 8. YearBook Publishers, Inc., Chicago. 10. Hightower, N. C., Jr. 1960. Motility of the alimentarv canal in man, pp. 3-61. In J. A. Rider and H. C. Moeller [eds.], Disturb-
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25. Misiewicz, J. J., A. M. Connell, and F. A. Pontes. 1966. Comparison of the effects of meals and prostigmine on the proximal and distal colon in patients with and without diarrhea. Gut 7: 46&-473. 26. Wangel, A. G., and D. J. Deller. 1965. Intestinal motility in man. III. Mechanisms of constipation and diarrhea with particular reference to the irritable colon syndrome. Gastroenterology 48: 69-84. 27. Davidson, M ., M. H . Sleisenger, T. P. Almy,
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and S. Z. Levine. 1956. Studies of distal colonic motility in children. II. Propulsive activity in diarrheal states. Pediatrics 17: 820-832. 28. Connell, A. M. 1961. The motility of the pelvic
colon. I. Motility in normals and in patients with asymptomatic duodenal ulcer. Gut 2: 175-186.
29. Connell, A. M. 1962. The motility of the pelvic colon. II. Paradoxical motility in diarrhea and constipation. Gut 3: 342-348.