1181
COLONIC FUNCTION IN PATIENTS WITH DIVERTICULAR DISEASE M. A. EASTWOOD W. G. BRYDON
A. N. SMITH
J. PRITCHARD
Wolfson Laboratories, Gastrointestinal Unit, Departments of Medicine and Clinical Surgery, University of Edinburgh, and
after charring with nitric acid), and p.E.G.5 and estimated in fifty patients. In forty-one patients colonic motility was tested. Colonic motility was studied with open-ended tubes by means of which both basal measurements and response to food were measured in the distal colon and rectum. Measurements were taken 5, 15, and 25 cm from the anal verge. The amplitude and frequency of the waves were calculated to give the motility index.7
toAnalyzer’
Cr 203were
Department of Clinical Chemistry, Western General Hospital,
Results
Edinburgh
The mean stool weight was 98 g/24 h (range 20-190 g/24 h. The transintestinal transit-times ranged from 24 to 190 h (mean 53 h). In the thirty subjects who took P.E.G./Cr203 capsules, the P.E.G./chromium ratio ranged from 0 - 2 to 1-7 (mean of 0-83). Faecal-fat excretion var-
Diverticular disease is thought to be associated with prolonged intestinal transit-time, a reduced stool weight, and increased intracolonic pressure. Sixty patients with diverticular disease did not regularly show these features. Variation in colonic function was considerable in these patients and was similar to that in the general population from which the patients were recruited. Constipation may be a complication of diverticular disease and not necessarily part of
Summary
its ætiology.
Introduction THE management of diverticular disease has changed radically. The rationale for the introduction of dietary fibre into the treatment regimen is based on observations that diverticular disease is characterised by a low stool weight, prolonged intestinal transit-time, and raised intracolonic pressure, all of which are thought to be the result of a reduced intake of dietary fibre. However, since it is not known whether these changes are always present, we investigated colonic function in sixty patients with diverticular disease. Patients and Methods
Sixty patients with diverticular disease were investigated, but not all in the same detail. All the patients had been at home on their usual diet and were investigated as outpatients after consenting to inclusion in the study. The mean age was 60 years, range 32-84 years. Diagnosis was based on a barium-enema examination preceded by sigmoidoscopy and a clinical examination. Symptoms included constipation, diarrhoea, and pain. In some the disease was asymptomatic and diagnosis was the result of a chance finding. Sixty patients recorded their transintestinal transit-time by means of bariumimpregnated markers;2 such markers not only give a crude estimate of transit-time but indicate the accuracy of stool collection. Thirty patients took polyethylene glycol/chromium sesquioxide (P.E.G./Cr203) capsules to demonstrate gastrointestinal streaming.3 The stool was collected and stored at —20°C, pooled, and freeze dried. Faecal wet weight, bile acids,4 fat, electrolytes, sodium, potassium, calcium, and magnesium (’Au-
index of ticular disease.
Motility
rectosigmoid region
in 41
patients with
diver-
ied from 1 to 19 mmol/24 h (mean 8.0 mmol/24 h). Fxcal bile-acid excretion ranged from 0.11 to 1.4 mmol/24 h (mean 0.5mmol/24 h). The mean basal motility index in forty-one patients was 800 and the post-food motility index was 2200 (range 400-6800) (see
accompanying figure). Discussion
patients had been on any kind of treatthey were studied, and they may be regarded as being typical of patients coming to an outpatient department. Our results raise some doubts about the overall importance of the "features" of diverticular disease-i.e., low stool weight, prolonged transit-time, and raised intraluminal pressure-which were formerly thought to be characteristic of this disease. The stool weight and transit-time in our patients with untreated None of these
ment Hussein, M A M , Flynn, D. M., Green, N., Hussein, S., Hoffbrand, A. V. Lancet, 1976, ii, 1278. 5. Propper, R D., Cooper, B., Rufo, R. R., Neinhuis, A. W , Anderson, W. F., Bunn, H. F, Rosenthal, A., Nathan, D. G. New EnglJ Med. 1977, 297,
4.
418. 6.
Hussein,
M. A
M., Flynn, D. M., Green, N., Hoffbrand, A. V. Lancet, 1977,
i,977. 7
Pippard, M. J., Callender, S. T., Weatherall, D. J Clin. Sci. molec. Med. 1978, 54, 99. 8. Zettner, A., Mansbach, L. Am. J. clin. Path. 1965, 44, 517. 9. Wapnick, A. A., Lynch, S. R., Charlton, R. W., Seftel, H. C., Bothwell, T. H Br J. Hæmat. 1969, 17, 563 10 Pippard, M J., Callender, S. T. Unpublished. 11. Ciba Pharmaceutical Company. Clin. Pharmac. Ther. 1969, 10, 595. 12 Cumming, R L. C., Millar, J. A., Smith, J. A., Goldberg, A. Br. J. Hæmat. 1969, 17, 257.
before
diverticular disease were in the same range as those in a normal population-80 g/24 h (range 20-280 g) and 72 h (range 24-168 h), respectively--derived from the same part of Edinburgh and aged 16-80 (unpublished). The motility index in the diverticular-disease patients
1182
also varied widely. In our patients the range of results for stool weight, transit-time, and colonic motility index was considerable. Thus, patients said to have had the hallmarks of diverticular disease-i.e., low stool weight, prolonged transit-time, and an increased motility index,
correctly be said to have represented those with special features such as chronic colonic obstruction or constipation. It seems that only a proportion of patients have diverticular disease attributable to a motility disturbance. The pressure change and the transit disturbance may only become prominent at a certain stage in the disease process, such as when there is a degree of obstruction present. Some more subtle change in colonic function or in the strength or integrity of the wall of the may
more
bowel may have been present in the earlier stages of the disease.
Preliminary
Communications
EXTENSIVE PROLONGATION OF RABBIT KIDNEY ALLOGRAFT SURVIVAL AFTER SHORT-TERM CYCLOSPORIN-A TREATMENT ANTHONY C. ALLISON J. GREEN Divisions of Comparative Medicine and Cell Pathology, M.R.C. COLIN
Clinical Research Centre, Northwick Park, Harrow, Middlesex
The fungal metabolite cyclosporin A has been administered daily at 25 mg/kg to nephrectomised rabbit recipients of a single renal allograft. After only 4 weeks of daily administration, rejection was prevented for long periods without the need for other immunosuppressive therapy. Renal function has been excellent in all cases, rejection episodes have not been encountered except in a small percentage of animals, and the surviving recipients are still in excellent health 3—6 months after transplantation. The possibility that clones of responding lymphocytes might be selectively killed by this agent was suggested from earlier experiments and prompted this study. If toxicity is not encountered in man cyclosporin A may prove valuable in preventing rejection of organ and bone-marrow allografts and might be useful in treating some leukæmias
Summary
This work was done during the tenure of a grant SHERT 491 and with the assistance of Reckitt and Colman, Duphar Laboratories, and the Incorporated National Association of British and Irish Millers. Miss Elizabeth Drummond gave invaluable help with the recording of the motility data.
Requests
for
INTRODUCTION
CYCLOSPORIN A, a fungal metabolite with potent antilymphocytic activity,! has been evaluated as an immunosuppressive agent in animals. It inhibits humoral immunity by reducing plaque-forming cells and haemagglutination titres in mice,2 and suppresses cellmediated immunity to skin allografts, graft-versus-host disease, and experimental allergic encephalomyelitis in rodents. The agent proved highly active in treating chronic inflammatory reactions but exerted only weak myelotoxicity. It was later suggested that cyclosporin A acted selectively on T cells since it failed to suppress antibody synthesis to lipopolysaccharide antigens in
nude mice; bone-marrow cell counts and stem-cell numbers in mice treated with high doses demonstrated its selectivity for lymphocytes and confirmed its low cytotoxicity for hxmopoietic tissues.3 These properties have prompted studies in organ allograft models, and potent immunosuppressive activity in
Western General
to
M.A.E., Wolfson
Hospital, Edinburgh
EH4 2XU.
REFERENCES
Painter, N. S. Diverticular Disease of the Colon. London, 1975. Hinton, J. M., Leonard-Jones, J. E., Young, A. C. Gut, 1969, 10, 842. Findlay, J. M., Mitchell, W. D., Eastwood, M. A., Anderson, A. J. B., Smith, A. N. ibid. 1974, 15, 207. 4. Evrard, E., Janssen, G. J. Lipid Res. 1968, 9, 226. 5. Malawer, S. J., Powell, D. W. Gastroenterology, 1976, 53, 250. 6. Bolin, D. W., King, P., Kolsterman, E. W. Science, 1952, 116, 634. 7. Attisha, R. P., Smith, A. N. Br. J. Surg. 1969, 56, 891. 1. 2. 3.
heart, pig heart, and dog kidney allografts have been reported in brief4-6 rat
We have found that cyclosporin A is toxic for human lymphoblasts of both T and B cell origin but not for7 resting lymphocytes or cells of myeloid or other origins.’ This finding suggested that cyclosporin A might in vivo be able to eliminate clones of lymphocytes responding to a specific antigenic challenge (e.g., allogeneic cells) while leaving intact clones of lymphocytes later able to respond to other challenges such as virus infections. This in turn suggested that short periods of administration might be sufficient to prolong graft survival indefinitely, thus avoiding the problems of continuous therapy with steroids. We have done experiments with short periods of daily cyclosporin A in recipients of rabbit kidney allografts followed by withdrawal of all therapy. MATERIALS AND METHODS
Animals rabbits of either sex weighing 3.0-4-0 kg were donors. Both kidneys were removed, and one was allografted into each of two New Zealand White rabbits by end-toend anastomosis.8 The recipient’s contralateral kidney was removed at the same time. In every experiment the anxsthesia (fentanyl-fluanisone induction, nitrous-oxide/oxygen maintenance), fluid replacement, and postoperative supportive therapy were identical.
Sandy Lop
used
as
Assessment of
of lymphoid origin.
reprints should be addressed
Gastrointestinal Laboratories,
Function
Post-graft renal function was assessed by observation of kidney colour and urine production; by blood-urea (urease an index of renal function obtained by integrating the blood-urea with respect to time over the first 14 days (normal values 6-5±3-3mg/dl days in unoperated rabbits and 8-2±4-2 mg/dl days in rabbits autografted with fresh, unstored kidneys); by serum-creatinine (alkaline-picrate method), normal values being 1-2±0-2 mg/dl for unoperated rabbits with a mean peak of 2-0±0.8 mg/dl in rabbits autografted with fresh, unstored kidneys; by clinical appearance, including weight and food and water intake; and by macroscopic and microscopic appearance of kidneys at necropsy (hasmatoxylin and eosin and periodic-acid/Schiff). The day of operation was taken as day 0. The time of rejection was taken as that day in which the rabbit first showed symptoms of uraemia and was killed. Blood-samples were taken for full haematological investigation, and axillary and popliteal lymph-nodes were examined at necropsy.
method); by
Treatment
Cyclosporin A (Sandoz Ltd., Basle) was dissolved in olive oil at a
concentration of 50
mg/ml
and remained in solution
so
COLONIC FUNCTION IN PATIENTS WITH DIVERTICULAR DISEASE M. A. EASTWOOD W. G. BRYDON
A. N. SMITH
J. PRITCHARD
Wolfson Laboratories, Gastrointestinal Unit, Departments of Medicine and Clinical Surgery, University of Edinburgh, and
after charring with nitric acid), and p.E.G.5 and estimated in fifty patients. In forty-one patients colonic motility was tested. Colonic motility was studied with open-ended tubes by means of which both basal measurements and response to food were measured in the distal colon and rectum. Measurements were taken 5, 15, and 25 cm from the anal verge. The amplitude and frequency of the waves were calculated to give the motility index.7
toAnalyzer’
Cr 203were
Department of Clinical Chemistry, Western General Hospital,
Results
Edinburgh
The mean stool weight was 98 g/24 h (range 20-190 g/24 h. The transintestinal transit-times ranged from 24 to 190 h (mean 53 h). In the thirty subjects who took P.E.G./Cr203 capsules, the P.E.G./chromium ratio ranged from 0 - 2 to 1-7 (mean of 0-83). Faecal-fat excretion var-
Diverticular disease is thought to be associated with prolonged intestinal transit-time, a reduced stool weight, and increased intracolonic pressure. Sixty patients with diverticular disease did not regularly show these features. Variation in colonic function was considerable in these patients and was similar to that in the general population from which the patients were recruited. Constipation may be a complication of diverticular disease and not necessarily part of
Summary
its ætiology.
Introduction THE management of diverticular disease has changed radically. The rationale for the introduction of dietary fibre into the treatment regimen is based on observations that diverticular disease is characterised by a low stool weight, prolonged intestinal transit-time, and raised intracolonic pressure, all of which are thought to be the result of a reduced intake of dietary fibre. However, since it is not known whether these changes are always present, we investigated colonic function in sixty patients with diverticular disease. Patients and Methods
Sixty patients with diverticular disease were investigated, but not all in the same detail. All the patients had been at home on their usual diet and were investigated as outpatients after consenting to inclusion in the study. The mean age was 60 years, range 32-84 years. Diagnosis was based on a barium-enema examination preceded by sigmoidoscopy and a clinical examination. Symptoms included constipation, diarrhoea, and pain. In some the disease was asymptomatic and diagnosis was the result of a chance finding. Sixty patients recorded their transintestinal transit-time by means of bariumimpregnated markers;2 such markers not only give a crude estimate of transit-time but indicate the accuracy of stool collection. Thirty patients took polyethylene glycol/chromium sesquioxide (P.E.G./Cr203) capsules to demonstrate gastrointestinal streaming.3 The stool was collected and stored at —20°C, pooled, and freeze dried. Faecal wet weight, bile acids,4 fat, electrolytes, sodium, potassium, calcium, and magnesium (’Au-
index of ticular disease.
Motility
rectosigmoid region
in 41
patients with
diver-
ied from 1 to 19 mmol/24 h (mean 8.0 mmol/24 h). Fxcal bile-acid excretion ranged from 0.11 to 1.4 mmol/24 h (mean 0.5mmol/24 h). The mean basal motility index in forty-one patients was 800 and the post-food motility index was 2200 (range 400-6800) (see
accompanying figure). Discussion
patients had been on any kind of treatthey were studied, and they may be regarded as being typical of patients coming to an outpatient department. Our results raise some doubts about the overall importance of the "features" of diverticular disease-i.e., low stool weight, prolonged transit-time, and raised intraluminal pressure-which were formerly thought to be characteristic of this disease. The stool weight and transit-time in our patients with untreated None of these
ment Hussein, M A M , Flynn, D. M., Green, N., Hussein, S., Hoffbrand, A. V. Lancet, 1976, ii, 1278. 5. Propper, R D., Cooper, B., Rufo, R. R., Neinhuis, A. W , Anderson, W. F., Bunn, H. F, Rosenthal, A., Nathan, D. G. New EnglJ Med. 1977, 297,
4.
418. 6.
Hussein,
M. A
M., Flynn, D. M., Green, N., Hoffbrand, A. V. Lancet, 1977,
i,977. 7
Pippard, M. J., Callender, S. T., Weatherall, D. J Clin. Sci. molec. Med. 1978, 54, 99. 8. Zettner, A., Mansbach, L. Am. J. clin. Path. 1965, 44, 517. 9. Wapnick, A. A., Lynch, S. R., Charlton, R. W., Seftel, H. C., Bothwell, T. H Br J. Hæmat. 1969, 17, 563 10 Pippard, M J., Callender, S. T. Unpublished. 11. Ciba Pharmaceutical Company. Clin. Pharmac. Ther. 1969, 10, 595. 12 Cumming, R L. C., Millar, J. A., Smith, J. A., Goldberg, A. Br. J. Hæmat. 1969, 17, 257.
before
diverticular disease were in the same range as those in a normal population-80 g/24 h (range 20-280 g) and 72 h (range 24-168 h), respectively--derived from the same part of Edinburgh and aged 16-80 (unpublished). The motility index in the diverticular-disease patients
1182
also varied widely. In our patients the range of results for stool weight, transit-time, and colonic motility index was considerable. Thus, patients said to have had the hallmarks of diverticular disease-i.e., low stool weight, prolonged transit-time, and an increased motility index,
correctly be said to have represented those with special features such as chronic colonic obstruction or constipation. It seems that only a proportion of patients have diverticular disease attributable to a motility disturbance. The pressure change and the transit disturbance may only become prominent at a certain stage in the disease process, such as when there is a degree of obstruction present. Some more subtle change in colonic function or in the strength or integrity of the wall of the may
more
bowel may have been present in the earlier stages of the disease.
Preliminary
Communications
EXTENSIVE PROLONGATION OF RABBIT KIDNEY ALLOGRAFT SURVIVAL AFTER SHORT-TERM CYCLOSPORIN-A TREATMENT ANTHONY C. ALLISON J. GREEN Divisions of Comparative Medicine and Cell Pathology, M.R.C. COLIN
Clinical Research Centre, Northwick Park, Harrow, Middlesex
The fungal metabolite cyclosporin A has been administered daily at 25 mg/kg to nephrectomised rabbit recipients of a single renal allograft. After only 4 weeks of daily administration, rejection was prevented for long periods without the need for other immunosuppressive therapy. Renal function has been excellent in all cases, rejection episodes have not been encountered except in a small percentage of animals, and the surviving recipients are still in excellent health 3—6 months after transplantation. The possibility that clones of responding lymphocytes might be selectively killed by this agent was suggested from earlier experiments and prompted this study. If toxicity is not encountered in man cyclosporin A may prove valuable in preventing rejection of organ and bone-marrow allografts and might be useful in treating some leukæmias
Summary
This work was done during the tenure of a grant SHERT 491 and with the assistance of Reckitt and Colman, Duphar Laboratories, and the Incorporated National Association of British and Irish Millers. Miss Elizabeth Drummond gave invaluable help with the recording of the motility data.
Requests
for
INTRODUCTION
CYCLOSPORIN A, a fungal metabolite with potent antilymphocytic activity,! has been evaluated as an immunosuppressive agent in animals. It inhibits humoral immunity by reducing plaque-forming cells and haemagglutination titres in mice,2 and suppresses cellmediated immunity to skin allografts, graft-versus-host disease, and experimental allergic encephalomyelitis in rodents. The agent proved highly active in treating chronic inflammatory reactions but exerted only weak myelotoxicity. It was later suggested that cyclosporin A acted selectively on T cells since it failed to suppress antibody synthesis to lipopolysaccharide antigens in
nude mice; bone-marrow cell counts and stem-cell numbers in mice treated with high doses demonstrated its selectivity for lymphocytes and confirmed its low cytotoxicity for hxmopoietic tissues.3 These properties have prompted studies in organ allograft models, and potent immunosuppressive activity in
Western General
to
M.A.E., Wolfson
Hospital, Edinburgh
EH4 2XU.
REFERENCES
Painter, N. S. Diverticular Disease of the Colon. London, 1975. Hinton, J. M., Leonard-Jones, J. E., Young, A. C. Gut, 1969, 10, 842. Findlay, J. M., Mitchell, W. D., Eastwood, M. A., Anderson, A. J. B., Smith, A. N. ibid. 1974, 15, 207. 4. Evrard, E., Janssen, G. J. Lipid Res. 1968, 9, 226. 5. Malawer, S. J., Powell, D. W. Gastroenterology, 1976, 53, 250. 6. Bolin, D. W., King, P., Kolsterman, E. W. Science, 1952, 116, 634. 7. Attisha, R. P., Smith, A. N. Br. J. Surg. 1969, 56, 891. 1. 2. 3.
heart, pig heart, and dog kidney allografts have been reported in brief4-6 rat
We have found that cyclosporin A is toxic for human lymphoblasts of both T and B cell origin but not for7 resting lymphocytes or cells of myeloid or other origins.’ This finding suggested that cyclosporin A might in vivo be able to eliminate clones of lymphocytes responding to a specific antigenic challenge (e.g., allogeneic cells) while leaving intact clones of lymphocytes later able to respond to other challenges such as virus infections. This in turn suggested that short periods of administration might be sufficient to prolong graft survival indefinitely, thus avoiding the problems of continuous therapy with steroids. We have done experiments with short periods of daily cyclosporin A in recipients of rabbit kidney allografts followed by withdrawal of all therapy. MATERIALS AND METHODS
Animals rabbits of either sex weighing 3.0-4-0 kg were donors. Both kidneys were removed, and one was allografted into each of two New Zealand White rabbits by end-toend anastomosis.8 The recipient’s contralateral kidney was removed at the same time. In every experiment the anxsthesia (fentanyl-fluanisone induction, nitrous-oxide/oxygen maintenance), fluid replacement, and postoperative supportive therapy were identical.
Sandy Lop
used
as
Assessment of
of lymphoid origin.
reprints should be addressed
Gastrointestinal Laboratories,
Function
Post-graft renal function was assessed by observation of kidney colour and urine production; by blood-urea (urease an index of renal function obtained by integrating the blood-urea with respect to time over the first 14 days (normal values 6-5±3-3mg/dl days in unoperated rabbits and 8-2±4-2 mg/dl days in rabbits autografted with fresh, unstored kidneys); by serum-creatinine (alkaline-picrate method), normal values being 1-2±0-2 mg/dl for unoperated rabbits with a mean peak of 2-0±0.8 mg/dl in rabbits autografted with fresh, unstored kidneys; by clinical appearance, including weight and food and water intake; and by macroscopic and microscopic appearance of kidneys at necropsy (hasmatoxylin and eosin and periodic-acid/Schiff). The day of operation was taken as day 0. The time of rejection was taken as that day in which the rabbit first showed symptoms of uraemia and was killed. Blood-samples were taken for full haematological investigation, and axillary and popliteal lymph-nodes were examined at necropsy.
method); by
Treatment
Cyclosporin A (Sandoz Ltd., Basle) was dissolved in olive oil at a
concentration of 50
mg/ml
and remained in solution
so
