359
smoke. Stillbirth, early neonatal death, and preterm and term low birthweight showed significant associations with this factor: Outcome Stillbirth
Early neonatal birth Prcterm LBW Term LBW
No 465 160 644 673
Odds ratios (and 95% 162 (1 30-2 02)
Cl)
1-46 (1-04-2 05) 149 (1 23-1-81) 1 23 (1 02-1 50)
The odds ratio for stillbirth remained significant (OR 1 ’45, CI 1 00-2’H) after adjusting for other important factors; the odds
ratios for other outcomes were no longer significant after multivariate adjustment. These findings suggest the possibility of an adverse pregnancy outcome associated with exposure to biomass smoke. 30-40% of the cases and controls were exposed to such smoke in our study which makes this factor as prevalent as tobacco smoking is in developed countries. Given the high prevalence of such exposure and its potential for adversely affecting pregnancy outcome, we strongly feel that more research should be directed at the effects of biomass smoke and at strategies to reduce such exposure in developing countries. Division of Prevention Research, National Institute of Child Health and Human Development, Bethesda, Maryland 20892, USA
Departments of Otolaryngology, Pulmonary Medicine, and Medical Technology, Orebro Medical Centre Hospital, S-701 85 Orebro, Sweden
Koning HW. Smith KR, Last JM Biomass fuel combustion and health Bull WHO 1985, 63: 11-26. 2 Kleinman JC, Mitchell B, Pierre JR, Madans JH, Land GH, Schramm WF The effect of maternal smoking on fetal and infant mortality. Am J Epidemiol 1988; 127: 274-82 3. Rubm DH, Krasilnikoff PA, Leventhal JM, Weile B, Berget A. Effect of passive smoking on birth weight Lancet 1986; ii: 415-17. 4 Chen BH, Hong CJ, Panday MR, Smith KR. Indoor air pollution in developing counties Wld Health Stat Quart 1990, 43: 127-38 5 Kramer MS Determinants of low birth weight methodological assessment and meta-analysis Bull WHO 1987, 65: 773-37 6 Longo LD The biological effects of carbon monoxide on the pregnant woman, fetus, and newborn infant Am J Obstet Gynecol 1977, 129: 69-103 7 Behera D, Dash S, Malik SK Blood carboxyhaemoglobin levels following acute exposure to smoke of biomass fuel. Indian J Med Res 1988; 88: 522-24 8 Mavalankar DV, Trivedi CR, Gray RH Levels and risk factors for permatal mortality in Ahmedabad, India Bull WHO (in press
Transthoracic endoscopic photodynamic treatment of malignant mesothelioma SIR,-There is no cure for malignant mesothelioma of the pleura, palliation, including pleurectomy and cytotoxic drugs, is
and
ineffective’
and often reduces the quality of life. Photodynamic therapy (PDT) has been used for treatment of malignant tumours with encouraging results,"* especially superficial bladder cancer. There are similarities between cancer of the bladder and mesothelioma of the pleura in that both, at least initially, grow superficially in the wall of a cavity. We treated a 64-year-old man with malignant mesothelioma of the pleura with PDT in January, 1990. The patient, who had previously been healthy, consulted a doctor for extreme tiredness and shortness of breath. Chest radiography revealed an effusion filling a third of the right pleural cavity. At thoracoscopy several polypoid tumours were found on the parietal pleura, and biopsy diagnosis was malignant mesothelioma of the epithelial type. The concentration of hyaluronic acid in the pleural exudate was significantly increased. A model of the right pleural cavity, made from a computerised tomographic (CT) scan, was used to determine the light distribution from fibre-tips in different positions. The patient was given 2-0 mg/kg ’Photofrin II’ and 48 h later thoracoscopy was repeated. The entire surface of the cavity was exposed to 20 J /cm2 of red light (628 nm) from a gold vapour laser. The procedure took 6 h and was done under epidural anaesthesia. The light dose was measured with a fibreoptic probe inserted through a separate puncture through the thoracic wall. The patient was very tired and in a poor general condition for the next 2 days. His serum creatinine rose temporarily and the sedimentation rate increased to 100 mm/h. The serum C-reactive protein became very high. He was given cloxacillin sodium as prophylaxis against infection. A CT scan 14 days after treatment
LENNART LOFGREN MATZ LARSSON LARS THANING STIG HALLGREN
A, Falkson G, Goedhals L, et al. Malignant pleural mesothelioma. a disease unaffected by current therapeutic maneuvers. J Clin Oncol 1988, 6: 527-35. 2. Marcus SL Photodynamic therapy of human cancer: clinical status, potential and needs. In: Gome CJ, ed Future directions and applications m photodynamic therapy (SPIE Inst Adv Optic Technol vol 156) Washington, DC: SPIE Optical Engineering Press, 1990. 3-56 1 Alberts
Trial of inhaled salbutamol for
DILEEP V. MAVALANKAR
1 De
usually
indicated a striking reduction in pleural tumours. To reduce the risk of metastasis in the two puncture channels through the thoracic wall, superficial electron radiation was given over the right thoracic flank 4 weeks after the PDT. No other radiotherapy has been given. The patient has been followed up with CT scans every third month. So far (10 months after the treatment) no sign of progression has been seen; all laboratory values are normal and the patient is symptom free and in good general condition.
proctalgia
fugax SIR,-A few years ago I reported in your correspondence columns that several patients, including a child, attained relief from the pain of proctalgia fugax by the inhalation of salbutamol.’ The efficacy of this treatment has been tested by a double-blind controlled trial. Thirty-one patients with the clinical diagnosis of proctalgia fugax, based on history and the exclusion of rectal pathology, were admitted to the trial. Active salbutamol and matching placebo metered dose inhalers were supplied in pairs by Glaxo, Australia. The patients were asked to use each inhaler, identified only by "A" or "B", for two attacks and to report the response.
Compliance was poor and only fifteen patients completed the protocol. Six found the active drug consistently effective and the placebo ineffective. Five, including two medical practitioners, reported the reverse. Of the others, two gave a mixed inconsistent response, one found both placebo and salbutamol effective, and one found both ineffective. This trial affords no statistical support for the efficacy of inhaled salbutamol in the treatment of proctalgia fugax, but it identifies a small cohort of patients who claim symptomatic relief. 116 Everton Street, Hamilton 2303, New South Wales, Australia
1
Wright JE
J. E. WRIGHT
Inhaled salbutamol for proctalgia
fugax. Lancet 1985, ii:
659-60.
Concerns about BST SIR,-Mr Sibbison’s (Dec 15,
p
1498)
comment on
bovine
somatotropin (BST) is a farrago of misinformation and selective reporting. Having followed the rBST saga for several years with respect to the nutritional safety of milk I would add to some of Sibbison’s statements. To suggest that the risk to man is far from clear is nonsense. Not only does Juskevich and Guyer’sl report, to which Sibbison alludes, provide the background to the US Food and Drug Administration’s statement that the use of rbGH [rBST] in dairy cattle presents no increased health risk to consumers, but Sibbison also cites only the negative comments of campaigners against genetic engineering. Earlier,yAL4 published a special communication2confirming the safety of rBST, and, in an accompanying editorialGrossman concluded "it is both inappropriate and wrong for special interest groups to play on the health and safety fears of the public to further their own ends. If the issue is economic, let it be clearly stated as such and leave genetic engineering out of the controversy". Sibbison also cites negative comment by David Kronfeld at a National Instiiu.ss of Health meeting without mentioning that at
360
that meeting the conclusions of an expert panel chaired by Melvin Grumbach, professor of paediatrics at the University of California, were that "the evidence clearly indicates that overall composition and nutritional quality of milk and meat from rBST treated cows is equal to that from untreated cows". The panel added that rBST does not seem to affect appreciably the general health of dairy cows. With respect to human safety, both the German and the British regulatory authorities have, like the FDA, published statements approving the release of meat and milk from animals in trials of bovine rBST for consumption by the general public. There may be an economic debate about the use of BST but it is malicious of those against its use on economic grounds to raise spurious health and safety concerns. My local supermarket provides "organic" milk at a 30% premium over regular milk which might come in part from herds in continuing trials with rBST. If those who pay the premium can afford it and do so in the belief that the cows who produce it live exclusively in mediaeval meadows, unexposed to agrochemicals of any sort, then I applaud their choice and their freedom to make it, but I suspect that many who pay 45p per pint can ill afford it and do so only to provide for their children milk that they have been deceived into believing is safer. 20 Wimpole Street, London W1 M 7AD, UK
available from the 1-8 T wiggler magnet at the Stanford Synchrotron Radiation Laboratory.2 A new synchrotron medical research beam line has been constructed at Brookhaven National Laboratory’s Synchrotron Light Source.3 The beamline accepts X-rays produced by a superconducting wiggler magnet designed to operate at 5-2 T. The protocol for this study was approved by the hospital committee on human research. Informed consent was obtained from each patient. A right-atrial power injection of 36 ml of X-ray contrast material (’Angiovist 370’; Berlex) was delivered through a no 7 NIH catheter (USCI) at 15 ml/s. The electron beam current was 203 mA, the X-ray ring energy was 2-5 GeV, and the wiggler field strength was 4-0 T. The radiation exposure was 0 40 rad per frame and the total radiation exposure was less than 5 rad. In the first two patients, we have visualised substantial portions of the right and the left anterior descending coronary arteries (figure). With further refinements in operating parameters and X-ray optics, this beamline is expected to provide sufficient X-ray intensity to prove useful in the evaluation of medical therapies directed at coronary artery atherosclerosis.
ALEXANDER MACNAIR
Juskevich JC, Guyer CG. Bovine growth hormone, human food safety evaluation. Science 1990; 249: 875-84. 2. Daughaday WH, Barbano DM. Bovine somatotropin supplementation of dairy cows. is the milk safe? JAMA 1990; 264: 1003-05 3. Grossman CJ. Genetic engineering and the use of bovine somatotropin. JAMA 1990; 1.
264: 1028
National Synchrotron Light Source, Brookhaven National Laboratory, Upton, NY
JOHN MORRISON Department of Medicine, North Shore University HospitalCornell University Medical College, Manhasset, NY 11030, USA
Venous
synchrotron
coronary
angiography
SiR,—To image the coronary arteries after the venous injection of an iodine-containing contrast agent, a much greater sensitivity to iodine is needed than for selective arterial injection because of the 20-30-fold dilution of the contrast agent by blood. One way to achieve this sensitivity is to use a pair of monochromatic X-ray beams from a synchrotron. From a conventional X-ray tube insufficient monochromatic X-ray intensity is available for acquiring accurate image data quickly enough to avoid blurring due to the rapid motion of the coronary arteries. Because X-ray intensity is more than 10’ times higher for synchrotron radiation wiggler magnet sources than for conventional X-ray tubes, synchrotron radiation is ideally suited to energy subtraction venous coronary angiography. Since 1979, work has been in progress at Stanford University on developing synchrotron radiation angiography. However, the quality of the images created has been limited by the X-ray intensity
Right coronary artery images from
a
62-year-old
man
WILLIAM THOMLINSON NICHOLAS GMUR DEAN CHAPMAN RICHARD GARRETT NANCY LAZARZ PETER REISER VELLORE PADMANABHAN LAWRENCE ONG STEPHEN GREEN
Lawrence
Berkeley Laboratory, Berkeley, California
ALBERT THOMPSON
University of Tennessee, Memphis
HERBERT ZEMAN
Department of Physics, Stanford University
ROBERT HOFSTADTER
Stanford
Synchrotron
Radiation
Laboratory
GEORGE BROWN
JOHN GIACOMINI Department of Medicine, Stanford University School of Medicine
HELEN GORDON EDWARD RUBENSTEIN
J, Ong L, Siskind E, Srinivasan M, Frost M, Padmanabhan V, Reiser P Venous coronary angiography. Lancet 1984, ii: 753. 2 Rubenstein E, Hofstadter R, Zeman HD, et al. Transvenous coronary angiography in humans using synchrotron radiation. Proc Natl Acad Sci (USA) 1986, 83: 9724-28 3. Thomlinson W, Chapman D, Gmur N, Lazarz N The superconducting wiggler beamport at the National Synchrotron Light Source. Nucl Inst Meth Phys Res 1. Morrison
who had had
1988, A266.
an
inferior wall myocardialinfarction in 1987.
Coronary angiography revealed as severe stenosis (A) in mid -portion of the artery (arrow) Percutaneous angioplasty was successfuI (B) and the patient has remained symptom-free since that time The transvenous synchrotron radiation coronary angiogram (C), done 3 8 years later, demonstrates a patent right coronary artery with no recurrence
of the lesion
’
smoke. Stillbirth, early neonatal death, and preterm and term low birthweight showed significant associations with this factor: Outcome Stillbirth
Early neonatal birth Prcterm LBW Term LBW
No 465 160 644 673
Odds ratios (and 95% 162 (1 30-2 02)
Cl)
1-46 (1-04-2 05) 149 (1 23-1-81) 1 23 (1 02-1 50)
The odds ratio for stillbirth remained significant (OR 1 ’45, CI 1 00-2’H) after adjusting for other important factors; the odds
ratios for other outcomes were no longer significant after multivariate adjustment. These findings suggest the possibility of an adverse pregnancy outcome associated with exposure to biomass smoke. 30-40% of the cases and controls were exposed to such smoke in our study which makes this factor as prevalent as tobacco smoking is in developed countries. Given the high prevalence of such exposure and its potential for adversely affecting pregnancy outcome, we strongly feel that more research should be directed at the effects of biomass smoke and at strategies to reduce such exposure in developing countries. Division of Prevention Research, National Institute of Child Health and Human Development, Bethesda, Maryland 20892, USA
Departments of Otolaryngology, Pulmonary Medicine, and Medical Technology, Orebro Medical Centre Hospital, S-701 85 Orebro, Sweden
Koning HW. Smith KR, Last JM Biomass fuel combustion and health Bull WHO 1985, 63: 11-26. 2 Kleinman JC, Mitchell B, Pierre JR, Madans JH, Land GH, Schramm WF The effect of maternal smoking on fetal and infant mortality. Am J Epidemiol 1988; 127: 274-82 3. Rubm DH, Krasilnikoff PA, Leventhal JM, Weile B, Berget A. Effect of passive smoking on birth weight Lancet 1986; ii: 415-17. 4 Chen BH, Hong CJ, Panday MR, Smith KR. Indoor air pollution in developing counties Wld Health Stat Quart 1990, 43: 127-38 5 Kramer MS Determinants of low birth weight methodological assessment and meta-analysis Bull WHO 1987, 65: 773-37 6 Longo LD The biological effects of carbon monoxide on the pregnant woman, fetus, and newborn infant Am J Obstet Gynecol 1977, 129: 69-103 7 Behera D, Dash S, Malik SK Blood carboxyhaemoglobin levels following acute exposure to smoke of biomass fuel. Indian J Med Res 1988; 88: 522-24 8 Mavalankar DV, Trivedi CR, Gray RH Levels and risk factors for permatal mortality in Ahmedabad, India Bull WHO (in press
Transthoracic endoscopic photodynamic treatment of malignant mesothelioma SIR,-There is no cure for malignant mesothelioma of the pleura, palliation, including pleurectomy and cytotoxic drugs, is
and
ineffective’
and often reduces the quality of life. Photodynamic therapy (PDT) has been used for treatment of malignant tumours with encouraging results,"* especially superficial bladder cancer. There are similarities between cancer of the bladder and mesothelioma of the pleura in that both, at least initially, grow superficially in the wall of a cavity. We treated a 64-year-old man with malignant mesothelioma of the pleura with PDT in January, 1990. The patient, who had previously been healthy, consulted a doctor for extreme tiredness and shortness of breath. Chest radiography revealed an effusion filling a third of the right pleural cavity. At thoracoscopy several polypoid tumours were found on the parietal pleura, and biopsy diagnosis was malignant mesothelioma of the epithelial type. The concentration of hyaluronic acid in the pleural exudate was significantly increased. A model of the right pleural cavity, made from a computerised tomographic (CT) scan, was used to determine the light distribution from fibre-tips in different positions. The patient was given 2-0 mg/kg ’Photofrin II’ and 48 h later thoracoscopy was repeated. The entire surface of the cavity was exposed to 20 J /cm2 of red light (628 nm) from a gold vapour laser. The procedure took 6 h and was done under epidural anaesthesia. The light dose was measured with a fibreoptic probe inserted through a separate puncture through the thoracic wall. The patient was very tired and in a poor general condition for the next 2 days. His serum creatinine rose temporarily and the sedimentation rate increased to 100 mm/h. The serum C-reactive protein became very high. He was given cloxacillin sodium as prophylaxis against infection. A CT scan 14 days after treatment
LENNART LOFGREN MATZ LARSSON LARS THANING STIG HALLGREN
A, Falkson G, Goedhals L, et al. Malignant pleural mesothelioma. a disease unaffected by current therapeutic maneuvers. J Clin Oncol 1988, 6: 527-35. 2. Marcus SL Photodynamic therapy of human cancer: clinical status, potential and needs. In: Gome CJ, ed Future directions and applications m photodynamic therapy (SPIE Inst Adv Optic Technol vol 156) Washington, DC: SPIE Optical Engineering Press, 1990. 3-56 1 Alberts
Trial of inhaled salbutamol for
DILEEP V. MAVALANKAR
1 De
usually
indicated a striking reduction in pleural tumours. To reduce the risk of metastasis in the two puncture channels through the thoracic wall, superficial electron radiation was given over the right thoracic flank 4 weeks after the PDT. No other radiotherapy has been given. The patient has been followed up with CT scans every third month. So far (10 months after the treatment) no sign of progression has been seen; all laboratory values are normal and the patient is symptom free and in good general condition.
proctalgia
fugax SIR,-A few years ago I reported in your correspondence columns that several patients, including a child, attained relief from the pain of proctalgia fugax by the inhalation of salbutamol.’ The efficacy of this treatment has been tested by a double-blind controlled trial. Thirty-one patients with the clinical diagnosis of proctalgia fugax, based on history and the exclusion of rectal pathology, were admitted to the trial. Active salbutamol and matching placebo metered dose inhalers were supplied in pairs by Glaxo, Australia. The patients were asked to use each inhaler, identified only by "A" or "B", for two attacks and to report the response.
Compliance was poor and only fifteen patients completed the protocol. Six found the active drug consistently effective and the placebo ineffective. Five, including two medical practitioners, reported the reverse. Of the others, two gave a mixed inconsistent response, one found both placebo and salbutamol effective, and one found both ineffective. This trial affords no statistical support for the efficacy of inhaled salbutamol in the treatment of proctalgia fugax, but it identifies a small cohort of patients who claim symptomatic relief. 116 Everton Street, Hamilton 2303, New South Wales, Australia
1
Wright JE
J. E. WRIGHT
Inhaled salbutamol for proctalgia
fugax. Lancet 1985, ii:
659-60.
Concerns about BST SIR,-Mr Sibbison’s (Dec 15,
p
1498)
comment on
bovine
somatotropin (BST) is a farrago of misinformation and selective reporting. Having followed the rBST saga for several years with respect to the nutritional safety of milk I would add to some of Sibbison’s statements. To suggest that the risk to man is far from clear is nonsense. Not only does Juskevich and Guyer’sl report, to which Sibbison alludes, provide the background to the US Food and Drug Administration’s statement that the use of rbGH [rBST] in dairy cattle presents no increased health risk to consumers, but Sibbison also cites only the negative comments of campaigners against genetic engineering. Earlier,yAL4 published a special communication2confirming the safety of rBST, and, in an accompanying editorialGrossman concluded "it is both inappropriate and wrong for special interest groups to play on the health and safety fears of the public to further their own ends. If the issue is economic, let it be clearly stated as such and leave genetic engineering out of the controversy". Sibbison also cites negative comment by David Kronfeld at a National Instiiu.ss of Health meeting without mentioning that at
360
that meeting the conclusions of an expert panel chaired by Melvin Grumbach, professor of paediatrics at the University of California, were that "the evidence clearly indicates that overall composition and nutritional quality of milk and meat from rBST treated cows is equal to that from untreated cows". The panel added that rBST does not seem to affect appreciably the general health of dairy cows. With respect to human safety, both the German and the British regulatory authorities have, like the FDA, published statements approving the release of meat and milk from animals in trials of bovine rBST for consumption by the general public. There may be an economic debate about the use of BST but it is malicious of those against its use on economic grounds to raise spurious health and safety concerns. My local supermarket provides "organic" milk at a 30% premium over regular milk which might come in part from herds in continuing trials with rBST. If those who pay the premium can afford it and do so in the belief that the cows who produce it live exclusively in mediaeval meadows, unexposed to agrochemicals of any sort, then I applaud their choice and their freedom to make it, but I suspect that many who pay 45p per pint can ill afford it and do so only to provide for their children milk that they have been deceived into believing is safer. 20 Wimpole Street, London W1 M 7AD, UK
available from the 1-8 T wiggler magnet at the Stanford Synchrotron Radiation Laboratory.2 A new synchrotron medical research beam line has been constructed at Brookhaven National Laboratory’s Synchrotron Light Source.3 The beamline accepts X-rays produced by a superconducting wiggler magnet designed to operate at 5-2 T. The protocol for this study was approved by the hospital committee on human research. Informed consent was obtained from each patient. A right-atrial power injection of 36 ml of X-ray contrast material (’Angiovist 370’; Berlex) was delivered through a no 7 NIH catheter (USCI) at 15 ml/s. The electron beam current was 203 mA, the X-ray ring energy was 2-5 GeV, and the wiggler field strength was 4-0 T. The radiation exposure was 0 40 rad per frame and the total radiation exposure was less than 5 rad. In the first two patients, we have visualised substantial portions of the right and the left anterior descending coronary arteries (figure). With further refinements in operating parameters and X-ray optics, this beamline is expected to provide sufficient X-ray intensity to prove useful in the evaluation of medical therapies directed at coronary artery atherosclerosis.
ALEXANDER MACNAIR
Juskevich JC, Guyer CG. Bovine growth hormone, human food safety evaluation. Science 1990; 249: 875-84. 2. Daughaday WH, Barbano DM. Bovine somatotropin supplementation of dairy cows. is the milk safe? JAMA 1990; 264: 1003-05 3. Grossman CJ. Genetic engineering and the use of bovine somatotropin. JAMA 1990; 1.
264: 1028
National Synchrotron Light Source, Brookhaven National Laboratory, Upton, NY
JOHN MORRISON Department of Medicine, North Shore University HospitalCornell University Medical College, Manhasset, NY 11030, USA
Venous
synchrotron
coronary
angiography
SiR,—To image the coronary arteries after the venous injection of an iodine-containing contrast agent, a much greater sensitivity to iodine is needed than for selective arterial injection because of the 20-30-fold dilution of the contrast agent by blood. One way to achieve this sensitivity is to use a pair of monochromatic X-ray beams from a synchrotron. From a conventional X-ray tube insufficient monochromatic X-ray intensity is available for acquiring accurate image data quickly enough to avoid blurring due to the rapid motion of the coronary arteries. Because X-ray intensity is more than 10’ times higher for synchrotron radiation wiggler magnet sources than for conventional X-ray tubes, synchrotron radiation is ideally suited to energy subtraction venous coronary angiography. Since 1979, work has been in progress at Stanford University on developing synchrotron radiation angiography. However, the quality of the images created has been limited by the X-ray intensity
Right coronary artery images from
a
62-year-old
man
WILLIAM THOMLINSON NICHOLAS GMUR DEAN CHAPMAN RICHARD GARRETT NANCY LAZARZ PETER REISER VELLORE PADMANABHAN LAWRENCE ONG STEPHEN GREEN
Lawrence
Berkeley Laboratory, Berkeley, California
ALBERT THOMPSON
University of Tennessee, Memphis
HERBERT ZEMAN
Department of Physics, Stanford University
ROBERT HOFSTADTER
Stanford
Synchrotron
Radiation
Laboratory
GEORGE BROWN
JOHN GIACOMINI Department of Medicine, Stanford University School of Medicine
HELEN GORDON EDWARD RUBENSTEIN
J, Ong L, Siskind E, Srinivasan M, Frost M, Padmanabhan V, Reiser P Venous coronary angiography. Lancet 1984, ii: 753. 2 Rubenstein E, Hofstadter R, Zeman HD, et al. Transvenous coronary angiography in humans using synchrotron radiation. Proc Natl Acad Sci (USA) 1986, 83: 9724-28 3. Thomlinson W, Chapman D, Gmur N, Lazarz N The superconducting wiggler beamport at the National Synchrotron Light Source. Nucl Inst Meth Phys Res 1. Morrison
who had had
1988, A266.
an
inferior wall myocardialinfarction in 1987.
Coronary angiography revealed as severe stenosis (A) in mid -portion of the artery (arrow) Percutaneous angioplasty was successfuI (B) and the patient has remained symptom-free since that time The transvenous synchrotron radiation coronary angiogram (C), done 3 8 years later, demonstrates a patent right coronary artery with no recurrence
of the lesion
’
