- Email: [email protected]
TRAINING IN GASTROENTEROLOGY
107
angiography at Graduate Hospital in the study of 85 bleeding patients, with successful definition of the source of bleeding in 42. These have included patients with bleeding from varices, Mallory-Weiss lesions, peptic ulcers, and vascular anomalies of the bowel. We have also had success in controlling massive gastrointestinal haemorrhage by slowly infusing vasopressin into the superior mesenteric artery through the catheter used for selective arteriography. This procedure has been of great value in controlling variceal bleeding, as well as arterial bleeding in patients with ulcers or Mallory-Weiss tears at the cardio-oesophageal junction. When necessary the infusions of vasopressin have been maintained over many days, with satisfactory control of bleeding and without adverse reactions. This method of management was reported by us at the 1970 meeting of the American Gastroenterological Association. Angiographic procedures for the investigation and control of gastrointestinal bleeding require specialised equipment and trained personnel, and are of value chiefly if the studies can be carried out while bleeding is in progress. Experiences such as our own, however, show that progress is being made in the management of a difficult problem. It is to be hoped that, as angiography becomes increasingly available, the value of this technique in the treatment of gastrointestinal haemorrhase will be more generallv recosnised. STANLEY BAUM Graduate Hospital, MOREYE NUSBAUM University of Pennsylvania, HENRY J. TUMEN. Philadelphia, Pennsylvania.
Caecal colonoscopy by end-to-end
Association); these are similar to the Olympus colonoscope developed by Niwa.8 Both of these instruments give equally good views of the colon, and allow biopsy specimens to
FIBREOPTIC COLONOSCOPY SIR,-We have read with interest the article by Mr. Dean and Dr. Shearman about a new fibreoptic colonoscope1 and the subsequent correspondence with Dr. Overholt.2,3 Our combined experience includes about 450 cases of endto-end intubation used for various colonic investigations of which 190 were total colonoscopies,4,5and about 150 cases of retrograde colonic intubation6 for purposes of biopsy or fibreoptic colonoscopy. The insertion of the colonoscope into the csecum guided by end-to-end intubation is shown in the accompanying figure. In some cases a narrower colonoscope was introduced through a colon tubepreviously placed in the csecum by retrograde intubation. Total colonoscopy without radiological control is the ultimate aim; but at present this is usually only possible after preliminary end-to-end intubation, which prolongs the procedure and is therefore reserved for patients in whom retrograde colonoscopy has failed. We agree with Dr. Overholt that patients should have sedation, and we use barbiturates and pethidine, supplemented, if necessary, by intravenousValium’ (diazepam). We do not advise general anxsthesia. There have been no cases of perforation in our combined series of 600 patients. Routine addition of ’Pro-Banthine ’ (propantheline bromide) to the premedication may produce an atonic, easily distended colon which permits overinsufflation with air, particularly if a mechanical air-pump is used. We feel that the inherent tone of the colon helps the operator guide the fibrescope, and should only be abolished (by intravenous ’Antrenyl’ [oxyphenonium bromide]) when spasm prevents further insertion. We are at present using colonoscopes made by American Cystoscope Makers Incorporated (agents Medical Supply Dean, A. C. B., Shearman, D. J. C. Lancet, 1970, i, 550. Overholt, B. F. ibid. p. 998. Dean, A. C. B., Shearman, D. J. C. ibid. p. 1108. Provenzale, L., Camerada, P., Revignas, A. Rass. med. Sarda, 1966 69, 149. 5. Provenzale, L., Revignas, A. Gastroint. Endosc. 1969, 16, 11. 6. Fox, J. A., Kreel, L. Gut, 1967, 8, 77. 7. Fox, J. A. Br. med. J. 1969, iii, 50.
1. 2. 3. 4.
technique.
be taken under direct vision. At present
we
recommend
retrograde colonoscopy for investigation of the descending and sigmoid colon; it is unlikely to be successful in the transverse and ascending colon. We are carrying out further research into methods which, we hope, will make radiological control less necessary and enable total colonoscopy to be achieved routinely without end-to-end intubation. General Hospital, Edgware, Middlesex.
Edgware
Department of Surgery, University of Catania, Italy.
J. A. FOX. L. PROVENZALE A. REVIGNAS.
TRAINING IN GASTROENTEROLOGY SIR,-Your comments9 on the schedule of training in gastroenterology recently published by the Royal College of Physicians of London appear to overlook the importance of this publication. You are indeed correct in saying that gastroenterology does not appear in the Ministry’s list of specialties. By accepting this memorandum, one of the Royal Colleges has accepted the principle that gastroenterology should now be accorded recognition as a
specialty. Gastroenterology is a rapidly advancing area of knowledge with many new diagnostic techniques and treatments which require special experience. There is a trend towards some concentration of clinical work in this subject, since this enables accuracy of diagnosis to be increased, the length of stay in hospital shortened, and mortality reduced, particularly in serious crises such as may occur in ulcerative colitis and alimentary bleeding. To this end, posts have been advertised in recent years for consultant physicians with a special interest in gastroenterology. Besides the training of such physicians, there is also a need for a limited number of small units where clinicians and research-workers can work full-time in this field, relating their work closely to the basic sciences and study8. Niwa, H., Utsumi, Y., Nakamura, T., Yoshida, A., Yoshitoshi, Y., Fujino, M., Kaneko, E., Kasumi, A., Matsumoto, M. Gastroent. Endosc., Tokyo, 1969, 11, 163. 9. Lancet, 1970, i, 1377.
108
ing problems in depth. Such small units, which combine advanced diagnostic techniques and research, and which are centres for specialist training, should become a recognised part of the hospital service. Gastroenterology has been a late starter among the subspecialties, but with new and rapidly developing understanding of the mechanisms underlying disease of the gastrointestinal tract it is now attracting many of the best men and women. It is unreasonable to compare the situation with pathology, which is far advanced in its facilities for specialised training. The Royal College of Physicians deserves credit for its foresight in looking ahead for the needs of gastroenterology in this country. FRANCIS AVERY JONES St. Mark’s Hospital,
younger
experiments,
one can
A more complete report of this work is in preparation. I thank Mr. A. R. Mason for his assistance with the kinetic work. I am grateful to Reckitt & Colman Ltd., and the Medical Research Council, for financing this work.
University Department Biochemistry,
of
EILEEN N. RAMSDEN.
Hull HU6 7RX.
J. E. LENNARD-JONES.
London E.C.1.
CYCLIC A.M.P. IN DEPRESSION AND MANIA SIR,-The correlation between the concentration of adenosine-3’, 5’-phosphate (cyclic A.M.P.) in the urine of patients and the clinical status of depression or mania is questioned by Dr. Berg and Dr. Glinsman,l who point out that the lack of physical activity in hospital patients may result in a low urinary cyclic-A. M.P. concentration. This leads them to question the conclusions which Dr. Abdulla and Dr. Hamadahdraw from their studies of the cyclicA.M.P. level in mental illness: these workers attribute depression and mania to a decrease or increase in the level of cyclic A.M.P. in the body. I should like to cite other evidence that the level of cyclic A.M.P. is directly linked to depression and mania. I have done in-vitro experiments on the enzymic hydrolysis of cyclic A.M.P., using the enzyme 3’, 5’-cyclic nucleotide phosphodiesterase extracted from ox heart. All the EFFECT OF ANTIDEPRESSANTS ON
From the results of these in-vitro
explain the action of antidepressants in vivo: by inhibiting 3’, 5’-cyclic nucleotide phosphodiesterase, the antidepressants increase the concentration of cyclic A.M.P. in the body and can therefore raise the low level of cyclic A.M.P. in depressive patients up to the normal level.
3’, 5’-CYCLIC
PHOSPHODIESTERASE
NUCLEOTIDE
* ACTIVITY
ORAL CONTRACEPTIVES AND VASCULAR ANOMALIES SIR,-Women taking oral contraceptives may develop vascular abnormalities, and possibly these play a part in the thromboembolic reactions associated with the Pill.
Telangiectasias
and
associated with
spider angiomas may appear(also pregnancy), and hereditary hasmorrhagic
may, at times, be made worse.2 There is no that other vascular abnormalities are evidence strong induced, but it is our impression that acquired port-wine angiomas are commoner in women taking oral contraceptives. This is a very rare lesion 3; unlike the common angioma, the port-wine spot has mature blood-vessels, does not subside spontaneously, and is resistant to therapy. At the Laser Medical Laboratory of the Children’s Hospital Research Foundation, Cincinnati, we have, in the past seven years, seen 130 patients with port-wine lesions.4 8 of them had acquired lesions; and of these only 1 was a man. Of the 7 women, 3 had never taken oral-contraceptive pills. Their clinical details are shown below.
telangiectasias
Age 51
Site of lesion Lower leg
21
Arm
48
Lower
leg
Clinical details Oral premarin therapy 3 years; no thromboembolism Lesion developed after pregnancy and has persisted; no thromboembolism Lesion developed after 7th pregnancy and has persisted; capillary fragility, but no thromboembolism
The remaining 4 women had taken oral-contraceptive pills for periods of 1-3 years. One had multiple spider-type angiomas, and one had had thrombophlebitis in the leg before the appearance of the port-wine spot on that leg. The details of these patients are shown below. Time on pill Site of lesion Clinical details Age Rate of hydrolysis of cyclic A.M.P. in absence of inhibitor (a) at pH 8-5=0-113 mmole/1./min., (b) at pH 7-0=0-083 mmole/1./min. Cyclic A.M.P. concentration =0-001 M; antidepressant concentration =0-001 M; 37°C; tris buffer 0-1M.
antidepressant drugs I have tried have shown considerable inhibition of phosphodiesterase activity. The results are shown in the accompanying table. The results in the table were obtained by measuring the rate of enzymic hydrolysis of cyclic A.M.P., first alone and secondly with added antidepressant. The kinetic method used was that of Butcher and Sutherland.3 The reaction was started by injecting 4 ml. of enzyme preparation (containing 1-8 enzyme units) into 16 ml. of a solution of cyclic A.M.P. in tris buffer at 37°C. Samples of 2 ml. were withdrawn at 5-minute intervals and the reaction was quenched by boiling for 2 minutes. The extent of reaction was measured by converting the adenosine 5’-phosphate formed by enzymic hydrolysis of cyclic A.M.P. to adenosine and inorganic phosphate, and then estimating the phosphate spectrophotometrically after conversion to ammonium phosphomolybdate by the method of Fiske and Subba Row.4 1. 2. 3. 4.
Berg, G. Abdulla, Butcher, Fiske, C.
R., Glinsmann, W. H. Lancet, 1970, i, 834. H., Hamadah, K. ibid. p. 378. W., Sutherland, E. W. J. biol. Chem. 1962, 237, 1244. H., Subba Row, Y. ibid. 1925, 66, 375.
Y. R.
Upper back
44 31 28
2 yr. 1 yr. 3 yr.
Hand
Leg
Thrombophlebitis left leg. Biopsy showed typicalport-wine-spot
24
1 yr.
Chin
No thrombosis
No thrombosis No thrombosis
structures
There is, as yet, no evidence that these acquired vascular abnormalities predispose to thrombosis.5 However, patients with these accessible vascular malformations could well be useful test models in the investigation of thromboembolic mechanisms; for example, the capillary reactions in these lesions could be compared with those in the conjunctivx and nail-beds of normal controls, pregnant women, and patients on oestrogens. The responses to controlled trauma could also be assessed in line with changes in coagulation factors. Such studies might indicate whether the vascular 1. 2. 3. 4. 5.
Ortiz, Y. Derm. ib. lat. am. 1969, 4, 1. Rowley, P. F., Kurnick, J., Cheville, R. Lancet, 1970, i. 474. Goldman, L., Richfield, D. F. Acta derm. vener. 1966, 46, 177. Solomon, H., Goldman, L., Henderson, B. J. invest. Derm. 1968, 50, 141. Johnson, S. A. in Physiology of Hæmostasis and Thrombosis (edited by S. A. Johnson and W. H. Seegers). Springfield, Illinois, 1967.
angiography at Graduate Hospital in the study of 85 bleeding patients, with successful definition of the source of bleeding in 42. These have included patients with bleeding from varices, Mallory-Weiss lesions, peptic ulcers, and vascular anomalies of the bowel. We have also had success in controlling massive gastrointestinal haemorrhage by slowly infusing vasopressin into the superior mesenteric artery through the catheter used for selective arteriography. This procedure has been of great value in controlling variceal bleeding, as well as arterial bleeding in patients with ulcers or Mallory-Weiss tears at the cardio-oesophageal junction. When necessary the infusions of vasopressin have been maintained over many days, with satisfactory control of bleeding and without adverse reactions. This method of management was reported by us at the 1970 meeting of the American Gastroenterological Association. Angiographic procedures for the investigation and control of gastrointestinal bleeding require specialised equipment and trained personnel, and are of value chiefly if the studies can be carried out while bleeding is in progress. Experiences such as our own, however, show that progress is being made in the management of a difficult problem. It is to be hoped that, as angiography becomes increasingly available, the value of this technique in the treatment of gastrointestinal haemorrhase will be more generallv recosnised. STANLEY BAUM Graduate Hospital, MOREYE NUSBAUM University of Pennsylvania, HENRY J. TUMEN. Philadelphia, Pennsylvania.
Caecal colonoscopy by end-to-end
Association); these are similar to the Olympus colonoscope developed by Niwa.8 Both of these instruments give equally good views of the colon, and allow biopsy specimens to
FIBREOPTIC COLONOSCOPY SIR,-We have read with interest the article by Mr. Dean and Dr. Shearman about a new fibreoptic colonoscope1 and the subsequent correspondence with Dr. Overholt.2,3 Our combined experience includes about 450 cases of endto-end intubation used for various colonic investigations of which 190 were total colonoscopies,4,5and about 150 cases of retrograde colonic intubation6 for purposes of biopsy or fibreoptic colonoscopy. The insertion of the colonoscope into the csecum guided by end-to-end intubation is shown in the accompanying figure. In some cases a narrower colonoscope was introduced through a colon tubepreviously placed in the csecum by retrograde intubation. Total colonoscopy without radiological control is the ultimate aim; but at present this is usually only possible after preliminary end-to-end intubation, which prolongs the procedure and is therefore reserved for patients in whom retrograde colonoscopy has failed. We agree with Dr. Overholt that patients should have sedation, and we use barbiturates and pethidine, supplemented, if necessary, by intravenousValium’ (diazepam). We do not advise general anxsthesia. There have been no cases of perforation in our combined series of 600 patients. Routine addition of ’Pro-Banthine ’ (propantheline bromide) to the premedication may produce an atonic, easily distended colon which permits overinsufflation with air, particularly if a mechanical air-pump is used. We feel that the inherent tone of the colon helps the operator guide the fibrescope, and should only be abolished (by intravenous ’Antrenyl’ [oxyphenonium bromide]) when spasm prevents further insertion. We are at present using colonoscopes made by American Cystoscope Makers Incorporated (agents Medical Supply Dean, A. C. B., Shearman, D. J. C. Lancet, 1970, i, 550. Overholt, B. F. ibid. p. 998. Dean, A. C. B., Shearman, D. J. C. ibid. p. 1108. Provenzale, L., Camerada, P., Revignas, A. Rass. med. Sarda, 1966 69, 149. 5. Provenzale, L., Revignas, A. Gastroint. Endosc. 1969, 16, 11. 6. Fox, J. A., Kreel, L. Gut, 1967, 8, 77. 7. Fox, J. A. Br. med. J. 1969, iii, 50.
1. 2. 3. 4.
technique.
be taken under direct vision. At present
we
recommend
retrograde colonoscopy for investigation of the descending and sigmoid colon; it is unlikely to be successful in the transverse and ascending colon. We are carrying out further research into methods which, we hope, will make radiological control less necessary and enable total colonoscopy to be achieved routinely without end-to-end intubation. General Hospital, Edgware, Middlesex.
Edgware
Department of Surgery, University of Catania, Italy.
J. A. FOX. L. PROVENZALE A. REVIGNAS.
TRAINING IN GASTROENTEROLOGY SIR,-Your comments9 on the schedule of training in gastroenterology recently published by the Royal College of Physicians of London appear to overlook the importance of this publication. You are indeed correct in saying that gastroenterology does not appear in the Ministry’s list of specialties. By accepting this memorandum, one of the Royal Colleges has accepted the principle that gastroenterology should now be accorded recognition as a
specialty. Gastroenterology is a rapidly advancing area of knowledge with many new diagnostic techniques and treatments which require special experience. There is a trend towards some concentration of clinical work in this subject, since this enables accuracy of diagnosis to be increased, the length of stay in hospital shortened, and mortality reduced, particularly in serious crises such as may occur in ulcerative colitis and alimentary bleeding. To this end, posts have been advertised in recent years for consultant physicians with a special interest in gastroenterology. Besides the training of such physicians, there is also a need for a limited number of small units where clinicians and research-workers can work full-time in this field, relating their work closely to the basic sciences and study8. Niwa, H., Utsumi, Y., Nakamura, T., Yoshida, A., Yoshitoshi, Y., Fujino, M., Kaneko, E., Kasumi, A., Matsumoto, M. Gastroent. Endosc., Tokyo, 1969, 11, 163. 9. Lancet, 1970, i, 1377.
108
ing problems in depth. Such small units, which combine advanced diagnostic techniques and research, and which are centres for specialist training, should become a recognised part of the hospital service. Gastroenterology has been a late starter among the subspecialties, but with new and rapidly developing understanding of the mechanisms underlying disease of the gastrointestinal tract it is now attracting many of the best men and women. It is unreasonable to compare the situation with pathology, which is far advanced in its facilities for specialised training. The Royal College of Physicians deserves credit for its foresight in looking ahead for the needs of gastroenterology in this country. FRANCIS AVERY JONES St. Mark’s Hospital,
younger
experiments,
one can
A more complete report of this work is in preparation. I thank Mr. A. R. Mason for his assistance with the kinetic work. I am grateful to Reckitt & Colman Ltd., and the Medical Research Council, for financing this work.
University Department Biochemistry,
of
EILEEN N. RAMSDEN.
Hull HU6 7RX.
J. E. LENNARD-JONES.
London E.C.1.
CYCLIC A.M.P. IN DEPRESSION AND MANIA SIR,-The correlation between the concentration of adenosine-3’, 5’-phosphate (cyclic A.M.P.) in the urine of patients and the clinical status of depression or mania is questioned by Dr. Berg and Dr. Glinsman,l who point out that the lack of physical activity in hospital patients may result in a low urinary cyclic-A. M.P. concentration. This leads them to question the conclusions which Dr. Abdulla and Dr. Hamadahdraw from their studies of the cyclicA.M.P. level in mental illness: these workers attribute depression and mania to a decrease or increase in the level of cyclic A.M.P. in the body. I should like to cite other evidence that the level of cyclic A.M.P. is directly linked to depression and mania. I have done in-vitro experiments on the enzymic hydrolysis of cyclic A.M.P., using the enzyme 3’, 5’-cyclic nucleotide phosphodiesterase extracted from ox heart. All the EFFECT OF ANTIDEPRESSANTS ON
From the results of these in-vitro
explain the action of antidepressants in vivo: by inhibiting 3’, 5’-cyclic nucleotide phosphodiesterase, the antidepressants increase the concentration of cyclic A.M.P. in the body and can therefore raise the low level of cyclic A.M.P. in depressive patients up to the normal level.
3’, 5’-CYCLIC
PHOSPHODIESTERASE
NUCLEOTIDE
* ACTIVITY
ORAL CONTRACEPTIVES AND VASCULAR ANOMALIES SIR,-Women taking oral contraceptives may develop vascular abnormalities, and possibly these play a part in the thromboembolic reactions associated with the Pill.
Telangiectasias
and
associated with
spider angiomas may appear(also pregnancy), and hereditary hasmorrhagic
may, at times, be made worse.2 There is no that other vascular abnormalities are evidence strong induced, but it is our impression that acquired port-wine angiomas are commoner in women taking oral contraceptives. This is a very rare lesion 3; unlike the common angioma, the port-wine spot has mature blood-vessels, does not subside spontaneously, and is resistant to therapy. At the Laser Medical Laboratory of the Children’s Hospital Research Foundation, Cincinnati, we have, in the past seven years, seen 130 patients with port-wine lesions.4 8 of them had acquired lesions; and of these only 1 was a man. Of the 7 women, 3 had never taken oral-contraceptive pills. Their clinical details are shown below.
telangiectasias
Age 51
Site of lesion Lower leg
21
Arm
48
Lower
leg
Clinical details Oral premarin therapy 3 years; no thromboembolism Lesion developed after pregnancy and has persisted; no thromboembolism Lesion developed after 7th pregnancy and has persisted; capillary fragility, but no thromboembolism
The remaining 4 women had taken oral-contraceptive pills for periods of 1-3 years. One had multiple spider-type angiomas, and one had had thrombophlebitis in the leg before the appearance of the port-wine spot on that leg. The details of these patients are shown below. Time on pill Site of lesion Clinical details Age Rate of hydrolysis of cyclic A.M.P. in absence of inhibitor (a) at pH 8-5=0-113 mmole/1./min., (b) at pH 7-0=0-083 mmole/1./min. Cyclic A.M.P. concentration =0-001 M; antidepressant concentration =0-001 M; 37°C; tris buffer 0-1M.
antidepressant drugs I have tried have shown considerable inhibition of phosphodiesterase activity. The results are shown in the accompanying table. The results in the table were obtained by measuring the rate of enzymic hydrolysis of cyclic A.M.P., first alone and secondly with added antidepressant. The kinetic method used was that of Butcher and Sutherland.3 The reaction was started by injecting 4 ml. of enzyme preparation (containing 1-8 enzyme units) into 16 ml. of a solution of cyclic A.M.P. in tris buffer at 37°C. Samples of 2 ml. were withdrawn at 5-minute intervals and the reaction was quenched by boiling for 2 minutes. The extent of reaction was measured by converting the adenosine 5’-phosphate formed by enzymic hydrolysis of cyclic A.M.P. to adenosine and inorganic phosphate, and then estimating the phosphate spectrophotometrically after conversion to ammonium phosphomolybdate by the method of Fiske and Subba Row.4 1. 2. 3. 4.
Berg, G. Abdulla, Butcher, Fiske, C.
R., Glinsmann, W. H. Lancet, 1970, i, 834. H., Hamadah, K. ibid. p. 378. W., Sutherland, E. W. J. biol. Chem. 1962, 237, 1244. H., Subba Row, Y. ibid. 1925, 66, 375.
Y. R.
Upper back
44 31 28
2 yr. 1 yr. 3 yr.
Hand
Leg
Thrombophlebitis left leg. Biopsy showed typicalport-wine-spot
24
1 yr.
Chin
No thrombosis
No thrombosis No thrombosis
structures
There is, as yet, no evidence that these acquired vascular abnormalities predispose to thrombosis.5 However, patients with these accessible vascular malformations could well be useful test models in the investigation of thromboembolic mechanisms; for example, the capillary reactions in these lesions could be compared with those in the conjunctivx and nail-beds of normal controls, pregnant women, and patients on oestrogens. The responses to controlled trauma could also be assessed in line with changes in coagulation factors. Such studies might indicate whether the vascular 1. 2. 3. 4. 5.
Ortiz, Y. Derm. ib. lat. am. 1969, 4, 1. Rowley, P. F., Kurnick, J., Cheville, R. Lancet, 1970, i. 474. Goldman, L., Richfield, D. F. Acta derm. vener. 1966, 46, 177. Solomon, H., Goldman, L., Henderson, B. J. invest. Derm. 1968, 50, 141. Johnson, S. A. in Physiology of Hæmostasis and Thrombosis (edited by S. A. Johnson and W. H. Seegers). Springfield, Illinois, 1967.