- Email: [email protected]
Myocardial contrast echocardiography to assess spontaneous reperfusion during myocardial infarction
THE LANCET
Research letters
“Stops walking when talking” as a predictor of falls in elderly people Lillemor Lundin-Olsson, Lars Nyberg, Yngve Gustafson
It was our clinical experience that some frail elderly patients stop walking when they start a conversation with a walking companion, presumably because walking demands attention and they stop when they are expected to do two things at once. We therefore investigated the usefulness of the sign “stops walking when talking” in predicting falls. 58 residents in sheltered accommodation in Umeå, Sweden, were included. All were able to walk with or without aids and able to follow simple instructions (mean age [SD] 80·1 [6·1] years; 72% women). The most common diagnoses (some had more than one) were dementia (n=26), depression (25), and previous stroke (20). The median score (inter-quartile range) of the Mini-Mental State Examination1 was 21·5 (18–26) and the score of activities of daily living was 17 (14–19) as measured by the Barthel Index.2 Participants were observed by a physiotherapist while they were accompanied from their home to an assessment room, and whether or not they stopped walking when a conversation started was recorded. Furthermore, their ability to walk safely was rated and basic functional mobility was measured.3 The staff registered falls indoors during a followup of 6 months. Neither participants nor staff were aware of the physiotherapist’s observations. 12 people stopped walking when a conversation started and ten of them fell during the 6-month follow-up. 21 people fell at least once. Kaplan-Meier distributions of falls differed significantly between those who stopped walking and those who continued to walk (figure, log-rank test 17·46, p⭐0·001). The positive predictive value of “stops walking when talking” was 83% (10/12) and the negative predictive value was 76% (35/46). The specificity was high (95%; 35/37) but the sensitivity was low (48%; 10/21). Those who stopped walking had a significantly less safe gait (p<0·001), 1·0
Proportion without falls
0·8
0·6
0·4
Stops walking when talking (n=12) Continues walking when talking (n=46)
0·2
0 0
1
2
3
4
Time (months)
Kaplan-Meier curves for falls during 6 months
Vol 349 • March 1, 1997
5
6
performed basic mobility more slowly (p<0·001), and were more dependent in activities of daily living (p=0·008). The observation “stops walking when talking” is simple, fast, costs nothing, and needs no equipment. The positive predictive value is higher than that of previously reported protocols aimed at identifying fall-prone people, with the exception of the complicated Fall Risk Index by Tinetti.4 1
2 3
4
Folstein MF, Folstein SE, McHugh PR. Minimental state: a practical method for grading the cognitive state of the patient for the clinician. J Psychiatr Res 1975; 12: 189–98. Mahoney FI, Barthel DW. Functional evaluation: the Barthel Index. Maryland State Med J 1965; 14: 61–65. Podsiadlo D, Richardson S. The timed “Up & Go”: a test of basic functional mobility for frail elderly persons. J Am Geriatr Soc 1991; 39: 142–48. Tinetti ME, Williams TF, Mayewski R. Fall risk index for elderly patients based on a number of chronic disabilities. Am J Med 1986; 80: 429–34.
Department of Geriatric Medicine, Umeå University, s-90187 Umeå, Sweden (L Lundin-Olsson)
Myocardial contrast echocardiography to assess spontaneous reperfusion during myocardial infarction Dominique Himbert, Patrick Seknadji, Daniel Karila-Cohen, Jean-Michel Juliard, Philippe Gabriel Steg
The Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) trial showed the importance of achieving early and complete reperfusion during acute myocardial infarction. Indeed, accelerated administration of t-PA was associated with the highest rate of complete infarct vessel patency, as defined semiquantitatively by flow grade 3 of the Thrombolysis in Myocardial Infarction (TIMI) scoring system, and with the lowest mortality rate at 30 days.1 However, vessel patency does not equal myocardial perfusion, and even with restoration of TIMI grade 3 flow in the infarct-related artery, reperfusion at the myocardial tissue level fails to occur in more than 20% of patients.2 In this context, accurate assessment of the quality of myocardial perfusion becomes critical, because it may help to identify patients who should, or should not, benefit from additional pharmacological or mechanical therapy. Myocardial contrast echocardiography is a technique in which a sonicated contrast agent containing microbubbles is injected into the coronary arteries during angiography; on two-dimensional echocardiography, injection results in a brisk and homogeneous enhancement of myocardial contrast echogenicity, lasting up to a few minutes
617
THE LANCET
Spontaneous reperfusion of right coronary artery during acute inferior myocardial infarction Upper view: emergency coronary angiogram showing complete patency of right coronary artery with severe residual stenosis (arrow). Lower view: two-chamber apical echographic view of left ventricle immediately after injection in right coronary artery of 3 mL sonicated iox aglate (Hex abrix 320), demonstrating normal myocardial perfusion of inferior wall in form of brisk and homogeneous contrast enhancement (arrows). LA: left atrium; LV: left ventricle.
and allowing clear delineation of the normally perfused myocardium. This reflects an intact microvasculature in the corresponding myocardium. Incomplete perfusion resulting from the presence of an epicardial coronary stenosis or inadequate run-off due to microvascular injury appears as a zone of slow, patchy, or absent contrast enhancement. The standard for comparison is myocardial contrast enhancement in a normally perfused segment of the left ventricle, either after injection in the contralateral artery (for the right coronary artery) or in a homolateral normal coronary branch (left circumflex artery for the left anterior descending, and vice versa). This has previously been validated as the reference technique for evaluation of myocardial perfusion,3 and may be applied in the setting of acute myocardial infarction.
618
A 42-year-old man was admitted with an ongoing acute inferior myocardial infarction. Upon arrival in the emergency room, iterative ventricular fibrillations occurred, requiring several electrical countershocks, and prolonged cardiopulmonary resuscitation. When stable sinus rhythm was restored, intravenous thrombolysis was judged too hazardous because of the resuscitation manoeuvres and immediate coronary angiography and primary angioplasty was planned. During transport to the catheterisation laboratory, chest pain progressively vanished, and the electrocardiogram showed a decrease in the amplitude of ST segment elevation observed in inferior leads. Emergency coronary angiography showed a normal left coronary artery, with no collateral circulation towards the right coronary artery. The latter was widely patent (TIMI grade 3 flow), but severely diseased, with a highly stenotic and thrombotic lesion (figure, upper view). At this stage, several therapeutic options were possible: immediate balloon angioplasty, as was originally intended; or treatment with an antagonist of GPIIb-IIIA receptor and delayed angioplasty; or conventional medical therapy with heparin and aspirin. Myocardial contrast echocardiography was carried out immediately after completion of coronary angiography, with a 2·5 MHz transducer fitted on a dedicated echocardiographic system (Hewlett-Packard Sonos 1500). Sonication was obtained before each injection by introducing the tip of a sonicator horn (model VC50, Bioblock) in 20 mL ioxaglate during around 1 min. One injection of sonicated ioxaglate was used for each echographic view. Recording of each view started 10 s before contrast injection and continued with a constant gain setting until disappearance of contrast enhancement. Myocardial contrast echocardiography showed a rapid, intense, and homogeneous opacification of the entire hypokinetic inferior left ventricular wall after injection of 3 mL sonicated ioxaglate in the right coronary artery, thus demonstrating complete reperfusion of the myocardium at risk due to the spontaneous recanalisation of the right coronary artery (figure, lower view). Therefore, no adjunctive intervention was required and the patient was kept on antithrombotic therapy. Elective angioplasty of the right coronary artery was successfully performed 6 days later, and the patient was discharged without complication. In the case of a culprit lesion in the proximal right coronary artery, any abnormality defined as either slowed, heterogeneous, or incomplete myocardial contrast enhancement would qualify as abnormal perfusion. Persistence of a flow-limiting stenosis may encourage immediate angioplasty and reevaluation of perfusion subsequently. In the absence of tight residual stenosis, slow flow on angiography in the epicardial artery is the consequence of distal microvascular injury.4 Myocardial contrast echocardiography is an effective tool for assessment of myocardial perfusion during acute myocardial infarction. As illustrated here, it may have immediate therapeutic implications for triaging patients to reperfusion therapy or conventional medical treatment. It also has prognostic significance, since the presence of noreflow on myocardial contrast echocardiography is associated with left ventricular dysfunction at follow-up.3,5 The impending development of new peripherally injectable contrast media will further extend the scope of applications of myocardial contrast echocardiography. 1
2
The GUSTO Investigators, An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993; 329: 673–82. Lincoff AM, Topol EJ. Illusion of reperfusion. Does anyone achieve optimal reperfusion during acute myocardial infarction? Circulation 1993; 88: 1361–74.
Vol 349 • March 1, 1997
THE LANCET 3
4
5
Ito H, Tomooka T, Sakai N, et al. Lack of myocardial perfusion immediately after successful thrombolysis: a predictor of poor recovery of left ventricular function in anterior myocardial infarction. Circulation 1992; 85: 1699–705. Ragosta M, Camarano G, Kaul S, Powers ER, Sarembock IJ, Gimple LW. Microvascular integrity indicates myocellular viability in patients with recent myocardial infarction: new insights using myocardial contrast echocardiography. Circulation 1994; 89: 1562–69. Ito H, Maryuama A, Iwakura K, et al. Clinical implications of the “no reflow” phenomenon: a predictor of complications and left ventricular remodeling in reperfused anterior wall myocardial infarction. Circulation 1996; 93: 223–28.
1 2
3 4
Hodson ME. Diabetes mellitus and cystic fibrosis. Baillière’s Clinical Endocrinology and Metabolism 1992; 6: 797–805. Lanng S, Thorsteinsson B, Nerup J, Koch C. Diabetes mellitus in cystic fibrosis: effect of insulin therapy on lung function and infections. Acta Pediatr 1994; 83: 849–53. WHO Geneva 1985. Diabetes mellitus. Tech rep ser 727. Cucinotta D, Conti Nabali S, Arrigo T, et al. Beta cell function, peripheral sensitivity to insulin and islet cell autoimmunity in cystic fibrosis patients with normal glucose tolerance. Horm Res 1990; 34: 33–38.
Department of Cystic Fibrosis, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK (B Yung)
Service de Cardiologie, Hôpital Bichat, Paris 75877, France (D Himbert)
Random blood glucose alone in the diagnosis of cystic fibrosis related diabetes Bernard Yung, Michael Kemp, James Hooper, Margaret Hodson
Cystic fibrosis related diabetes (CFRD) is likely to become increasingly common as adult patients with cystic fibrosis survive longer.1 The diagnosis for CFRD is important as its development may be associated with a deterioration in clinical status which can be reversed with prompt treatment.2 Various methods, including random measurement of blood glucose, have been used to diagnose this condition. The diagnosis of non-CFRD may be made if a single random blood glucose estimation is equal or above 11·1 mmol/L, whether the patient has symptoms of hyperglycaemia or not.3 CFRD differs in many aspects from non-CFRD and abnormal glucose and insulin responses to an oral glucose load have been described.4 As part of a study to examine pancreatic β-cell responses after an oral glucose load in patients with cystic fibrosis, seven clinically stable adult patients with cystic fibrosis not known to be diabetic (mean age 25) and seven age and sexmatched controls underwent oral glucose-tolerance tests (OGTTs). Each received 1·75 g/kg body weight of glucose (maximum 75 g). Blood samples were taken at intervals for the measurement of glucose concentrations. All 14 had OGTT-defined normal glucose tolerance, although four of the CF patients had blood glucose values over 11·1 mmol/L at various times (table) in contrast with none in the controls. In practical terms, provided that a large enough glucose load is taken by a patient with cystic fibrosis, such as a large meal or a sugary snack before the random blood glucose is measured, the random blood glucose value may exceed the diabetic range even if they have normal OGTT-defined glucose tolerance. The use of random blood glucose alone is therefore unreliable in the diagnosis of CFRD. A raised random blood glucose should alert clinicians to organise further investigations before a diagnosis of CFRD can be made. We thank Professor Ariel Lant for his helpful comments. Time (min) Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 0 20 30 40 50 60 75 90 120
4·9 11·6 12·8 13·2 13·1 9·3 6·3 5·0 4·1
5·9 12·3 14·0 15·6 14·4 13·2 10·7 9·3 6·1
4·0 6·6 8·3 9·0 9·5 8·9 7·4 6·7 3·8
4·9 9·2 10·7 12·3 13·0 13·6 13·4 11·3 5·9
4·2 8·4 10·6 12·1 13·0 13·4 12·5 8·6 7·3
4·9 7·4 8·2 9·0 8·5 9·4 9·0 8·3 7·6
4·4 8·8 9·3 9·0 9·7 8·5 6·8 5·8 6·5
Blood glucose (mmol/L) after oral glucose-tolerance tests
Vol 349 • March 1, 1997
Reversal of cystic fibrosis phenotype in mice by gene therapy in utero Janet E Larson, Susan L Morrow, Leo Happel, John F Sharp, J Craig Cohen
Current gene therapy trials in human beings are not successful in replacing cystic fibrosis transmembrane receptor (CFTR) protein functions; attempts have been compromised by inflammatory host responses and limited transgene expression. We suggest that successful gene therapy of cystic fibrosis may be done in utero. The transfer of genes into the fetus may bypass the immune response. In a previous study,1 we showed that amniotic fluid provides both an immunotolerant environment as well as a vehicle for transgene delivery. Only small doses of virus were necessary efficiently to target somatic stem cells. The S489X cystic fibrosis knockout mouse strain cftrtm1Unc, mimics the abnormalities of the gastrointestinal tract seen in patients with cystic fibrosis.2 Approximately 5–10% of newborns with cystic fibrosis present with meconium ileus, a form of intestinal obstruction. Without intervention, S489X cftr-mutant (cftr-/-) mice develop intestinal obstruction, resulting in less than 5% survival to adulthood. S489X fetuses were infected with a cftr-containing adenoviral vector, Av1CF2, (Genetic Therapy Inc, Gaithersburg, MD, USA), or a control vector expressing the lacZ reporter gene (Ad5.CMV lacZ) at 16–17 days gestation. A dose of 1⫻108 plaque-forming units was injected into individual amniotic sacs and the fetuses were delivered normally. This procedure mimicked an amniocentesis in the equivalent of a 15–20 week human fetus. Fetuses were examined serially for the presence of the vector by PCR or DNA prepared from lung and gut. Low levels of adenoviral DNA were detectable in fetal gut up to 72 hours after infection but not after birth. 13 of the in-utero cftr-treated, homozygous knockout mice (cftr-/-) that survived the perinatal period reached adulthood (50 days of age), and remain healthy at 250 days. All cftr-/- mice treated with the Ad5.CMVlacZ virus died before 50 days of age. The cftr gene encodes a cAMP-activated chloride channel that is absent in the S489X mouse. We sought confirmation that CFTR protein was not expressed after birth in these mice by testing for the presence of cAMPactivated chloride channels. The chloride channels of jejunum and ileum from 75 day-old, cftr-treated mice were examined by short-circuit current measurements. Intestine from heterozygous mice (cftr+/-) showed the forskolin response expected for cAMP-activated chloride channels encoded by cftr. In contrast, tissue from cftr-treated homozygous knockout animals (cftr-/-) showed no response
619
Research letters
“Stops walking when talking” as a predictor of falls in elderly people Lillemor Lundin-Olsson, Lars Nyberg, Yngve Gustafson
It was our clinical experience that some frail elderly patients stop walking when they start a conversation with a walking companion, presumably because walking demands attention and they stop when they are expected to do two things at once. We therefore investigated the usefulness of the sign “stops walking when talking” in predicting falls. 58 residents in sheltered accommodation in Umeå, Sweden, were included. All were able to walk with or without aids and able to follow simple instructions (mean age [SD] 80·1 [6·1] years; 72% women). The most common diagnoses (some had more than one) were dementia (n=26), depression (25), and previous stroke (20). The median score (inter-quartile range) of the Mini-Mental State Examination1 was 21·5 (18–26) and the score of activities of daily living was 17 (14–19) as measured by the Barthel Index.2 Participants were observed by a physiotherapist while they were accompanied from their home to an assessment room, and whether or not they stopped walking when a conversation started was recorded. Furthermore, their ability to walk safely was rated and basic functional mobility was measured.3 The staff registered falls indoors during a followup of 6 months. Neither participants nor staff were aware of the physiotherapist’s observations. 12 people stopped walking when a conversation started and ten of them fell during the 6-month follow-up. 21 people fell at least once. Kaplan-Meier distributions of falls differed significantly between those who stopped walking and those who continued to walk (figure, log-rank test 17·46, p⭐0·001). The positive predictive value of “stops walking when talking” was 83% (10/12) and the negative predictive value was 76% (35/46). The specificity was high (95%; 35/37) but the sensitivity was low (48%; 10/21). Those who stopped walking had a significantly less safe gait (p<0·001), 1·0
Proportion without falls
0·8
0·6
0·4
Stops walking when talking (n=12) Continues walking when talking (n=46)
0·2
0 0
1
2
3
4
Time (months)
Kaplan-Meier curves for falls during 6 months
Vol 349 • March 1, 1997
5
6
performed basic mobility more slowly (p<0·001), and were more dependent in activities of daily living (p=0·008). The observation “stops walking when talking” is simple, fast, costs nothing, and needs no equipment. The positive predictive value is higher than that of previously reported protocols aimed at identifying fall-prone people, with the exception of the complicated Fall Risk Index by Tinetti.4 1
2 3
4
Folstein MF, Folstein SE, McHugh PR. Minimental state: a practical method for grading the cognitive state of the patient for the clinician. J Psychiatr Res 1975; 12: 189–98. Mahoney FI, Barthel DW. Functional evaluation: the Barthel Index. Maryland State Med J 1965; 14: 61–65. Podsiadlo D, Richardson S. The timed “Up & Go”: a test of basic functional mobility for frail elderly persons. J Am Geriatr Soc 1991; 39: 142–48. Tinetti ME, Williams TF, Mayewski R. Fall risk index for elderly patients based on a number of chronic disabilities. Am J Med 1986; 80: 429–34.
Department of Geriatric Medicine, Umeå University, s-90187 Umeå, Sweden (L Lundin-Olsson)
Myocardial contrast echocardiography to assess spontaneous reperfusion during myocardial infarction Dominique Himbert, Patrick Seknadji, Daniel Karila-Cohen, Jean-Michel Juliard, Philippe Gabriel Steg
The Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) trial showed the importance of achieving early and complete reperfusion during acute myocardial infarction. Indeed, accelerated administration of t-PA was associated with the highest rate of complete infarct vessel patency, as defined semiquantitatively by flow grade 3 of the Thrombolysis in Myocardial Infarction (TIMI) scoring system, and with the lowest mortality rate at 30 days.1 However, vessel patency does not equal myocardial perfusion, and even with restoration of TIMI grade 3 flow in the infarct-related artery, reperfusion at the myocardial tissue level fails to occur in more than 20% of patients.2 In this context, accurate assessment of the quality of myocardial perfusion becomes critical, because it may help to identify patients who should, or should not, benefit from additional pharmacological or mechanical therapy. Myocardial contrast echocardiography is a technique in which a sonicated contrast agent containing microbubbles is injected into the coronary arteries during angiography; on two-dimensional echocardiography, injection results in a brisk and homogeneous enhancement of myocardial contrast echogenicity, lasting up to a few minutes
617
THE LANCET
Spontaneous reperfusion of right coronary artery during acute inferior myocardial infarction Upper view: emergency coronary angiogram showing complete patency of right coronary artery with severe residual stenosis (arrow). Lower view: two-chamber apical echographic view of left ventricle immediately after injection in right coronary artery of 3 mL sonicated iox aglate (Hex abrix 320), demonstrating normal myocardial perfusion of inferior wall in form of brisk and homogeneous contrast enhancement (arrows). LA: left atrium; LV: left ventricle.
and allowing clear delineation of the normally perfused myocardium. This reflects an intact microvasculature in the corresponding myocardium. Incomplete perfusion resulting from the presence of an epicardial coronary stenosis or inadequate run-off due to microvascular injury appears as a zone of slow, patchy, or absent contrast enhancement. The standard for comparison is myocardial contrast enhancement in a normally perfused segment of the left ventricle, either after injection in the contralateral artery (for the right coronary artery) or in a homolateral normal coronary branch (left circumflex artery for the left anterior descending, and vice versa). This has previously been validated as the reference technique for evaluation of myocardial perfusion,3 and may be applied in the setting of acute myocardial infarction.
618
A 42-year-old man was admitted with an ongoing acute inferior myocardial infarction. Upon arrival in the emergency room, iterative ventricular fibrillations occurred, requiring several electrical countershocks, and prolonged cardiopulmonary resuscitation. When stable sinus rhythm was restored, intravenous thrombolysis was judged too hazardous because of the resuscitation manoeuvres and immediate coronary angiography and primary angioplasty was planned. During transport to the catheterisation laboratory, chest pain progressively vanished, and the electrocardiogram showed a decrease in the amplitude of ST segment elevation observed in inferior leads. Emergency coronary angiography showed a normal left coronary artery, with no collateral circulation towards the right coronary artery. The latter was widely patent (TIMI grade 3 flow), but severely diseased, with a highly stenotic and thrombotic lesion (figure, upper view). At this stage, several therapeutic options were possible: immediate balloon angioplasty, as was originally intended; or treatment with an antagonist of GPIIb-IIIA receptor and delayed angioplasty; or conventional medical therapy with heparin and aspirin. Myocardial contrast echocardiography was carried out immediately after completion of coronary angiography, with a 2·5 MHz transducer fitted on a dedicated echocardiographic system (Hewlett-Packard Sonos 1500). Sonication was obtained before each injection by introducing the tip of a sonicator horn (model VC50, Bioblock) in 20 mL ioxaglate during around 1 min. One injection of sonicated ioxaglate was used for each echographic view. Recording of each view started 10 s before contrast injection and continued with a constant gain setting until disappearance of contrast enhancement. Myocardial contrast echocardiography showed a rapid, intense, and homogeneous opacification of the entire hypokinetic inferior left ventricular wall after injection of 3 mL sonicated ioxaglate in the right coronary artery, thus demonstrating complete reperfusion of the myocardium at risk due to the spontaneous recanalisation of the right coronary artery (figure, lower view). Therefore, no adjunctive intervention was required and the patient was kept on antithrombotic therapy. Elective angioplasty of the right coronary artery was successfully performed 6 days later, and the patient was discharged without complication. In the case of a culprit lesion in the proximal right coronary artery, any abnormality defined as either slowed, heterogeneous, or incomplete myocardial contrast enhancement would qualify as abnormal perfusion. Persistence of a flow-limiting stenosis may encourage immediate angioplasty and reevaluation of perfusion subsequently. In the absence of tight residual stenosis, slow flow on angiography in the epicardial artery is the consequence of distal microvascular injury.4 Myocardial contrast echocardiography is an effective tool for assessment of myocardial perfusion during acute myocardial infarction. As illustrated here, it may have immediate therapeutic implications for triaging patients to reperfusion therapy or conventional medical treatment. It also has prognostic significance, since the presence of noreflow on myocardial contrast echocardiography is associated with left ventricular dysfunction at follow-up.3,5 The impending development of new peripherally injectable contrast media will further extend the scope of applications of myocardial contrast echocardiography. 1
2
The GUSTO Investigators, An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993; 329: 673–82. Lincoff AM, Topol EJ. Illusion of reperfusion. Does anyone achieve optimal reperfusion during acute myocardial infarction? Circulation 1993; 88: 1361–74.
Vol 349 • March 1, 1997
THE LANCET 3
4
5
Ito H, Tomooka T, Sakai N, et al. Lack of myocardial perfusion immediately after successful thrombolysis: a predictor of poor recovery of left ventricular function in anterior myocardial infarction. Circulation 1992; 85: 1699–705. Ragosta M, Camarano G, Kaul S, Powers ER, Sarembock IJ, Gimple LW. Microvascular integrity indicates myocellular viability in patients with recent myocardial infarction: new insights using myocardial contrast echocardiography. Circulation 1994; 89: 1562–69. Ito H, Maryuama A, Iwakura K, et al. Clinical implications of the “no reflow” phenomenon: a predictor of complications and left ventricular remodeling in reperfused anterior wall myocardial infarction. Circulation 1996; 93: 223–28.
1 2
3 4
Hodson ME. Diabetes mellitus and cystic fibrosis. Baillière’s Clinical Endocrinology and Metabolism 1992; 6: 797–805. Lanng S, Thorsteinsson B, Nerup J, Koch C. Diabetes mellitus in cystic fibrosis: effect of insulin therapy on lung function and infections. Acta Pediatr 1994; 83: 849–53. WHO Geneva 1985. Diabetes mellitus. Tech rep ser 727. Cucinotta D, Conti Nabali S, Arrigo T, et al. Beta cell function, peripheral sensitivity to insulin and islet cell autoimmunity in cystic fibrosis patients with normal glucose tolerance. Horm Res 1990; 34: 33–38.
Department of Cystic Fibrosis, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK (B Yung)
Service de Cardiologie, Hôpital Bichat, Paris 75877, France (D Himbert)
Random blood glucose alone in the diagnosis of cystic fibrosis related diabetes Bernard Yung, Michael Kemp, James Hooper, Margaret Hodson
Cystic fibrosis related diabetes (CFRD) is likely to become increasingly common as adult patients with cystic fibrosis survive longer.1 The diagnosis for CFRD is important as its development may be associated with a deterioration in clinical status which can be reversed with prompt treatment.2 Various methods, including random measurement of blood glucose, have been used to diagnose this condition. The diagnosis of non-CFRD may be made if a single random blood glucose estimation is equal or above 11·1 mmol/L, whether the patient has symptoms of hyperglycaemia or not.3 CFRD differs in many aspects from non-CFRD and abnormal glucose and insulin responses to an oral glucose load have been described.4 As part of a study to examine pancreatic β-cell responses after an oral glucose load in patients with cystic fibrosis, seven clinically stable adult patients with cystic fibrosis not known to be diabetic (mean age 25) and seven age and sexmatched controls underwent oral glucose-tolerance tests (OGTTs). Each received 1·75 g/kg body weight of glucose (maximum 75 g). Blood samples were taken at intervals for the measurement of glucose concentrations. All 14 had OGTT-defined normal glucose tolerance, although four of the CF patients had blood glucose values over 11·1 mmol/L at various times (table) in contrast with none in the controls. In practical terms, provided that a large enough glucose load is taken by a patient with cystic fibrosis, such as a large meal or a sugary snack before the random blood glucose is measured, the random blood glucose value may exceed the diabetic range even if they have normal OGTT-defined glucose tolerance. The use of random blood glucose alone is therefore unreliable in the diagnosis of CFRD. A raised random blood glucose should alert clinicians to organise further investigations before a diagnosis of CFRD can be made. We thank Professor Ariel Lant for his helpful comments. Time (min) Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 0 20 30 40 50 60 75 90 120
4·9 11·6 12·8 13·2 13·1 9·3 6·3 5·0 4·1
5·9 12·3 14·0 15·6 14·4 13·2 10·7 9·3 6·1
4·0 6·6 8·3 9·0 9·5 8·9 7·4 6·7 3·8
4·9 9·2 10·7 12·3 13·0 13·6 13·4 11·3 5·9
4·2 8·4 10·6 12·1 13·0 13·4 12·5 8·6 7·3
4·9 7·4 8·2 9·0 8·5 9·4 9·0 8·3 7·6
4·4 8·8 9·3 9·0 9·7 8·5 6·8 5·8 6·5
Blood glucose (mmol/L) after oral glucose-tolerance tests
Vol 349 • March 1, 1997
Reversal of cystic fibrosis phenotype in mice by gene therapy in utero Janet E Larson, Susan L Morrow, Leo Happel, John F Sharp, J Craig Cohen
Current gene therapy trials in human beings are not successful in replacing cystic fibrosis transmembrane receptor (CFTR) protein functions; attempts have been compromised by inflammatory host responses and limited transgene expression. We suggest that successful gene therapy of cystic fibrosis may be done in utero. The transfer of genes into the fetus may bypass the immune response. In a previous study,1 we showed that amniotic fluid provides both an immunotolerant environment as well as a vehicle for transgene delivery. Only small doses of virus were necessary efficiently to target somatic stem cells. The S489X cystic fibrosis knockout mouse strain cftrtm1Unc, mimics the abnormalities of the gastrointestinal tract seen in patients with cystic fibrosis.2 Approximately 5–10% of newborns with cystic fibrosis present with meconium ileus, a form of intestinal obstruction. Without intervention, S489X cftr-mutant (cftr-/-) mice develop intestinal obstruction, resulting in less than 5% survival to adulthood. S489X fetuses were infected with a cftr-containing adenoviral vector, Av1CF2, (Genetic Therapy Inc, Gaithersburg, MD, USA), or a control vector expressing the lacZ reporter gene (Ad5.CMV lacZ) at 16–17 days gestation. A dose of 1⫻108 plaque-forming units was injected into individual amniotic sacs and the fetuses were delivered normally. This procedure mimicked an amniocentesis in the equivalent of a 15–20 week human fetus. Fetuses were examined serially for the presence of the vector by PCR or DNA prepared from lung and gut. Low levels of adenoviral DNA were detectable in fetal gut up to 72 hours after infection but not after birth. 13 of the in-utero cftr-treated, homozygous knockout mice (cftr-/-) that survived the perinatal period reached adulthood (50 days of age), and remain healthy at 250 days. All cftr-/- mice treated with the Ad5.CMVlacZ virus died before 50 days of age. The cftr gene encodes a cAMP-activated chloride channel that is absent in the S489X mouse. We sought confirmation that CFTR protein was not expressed after birth in these mice by testing for the presence of cAMPactivated chloride channels. The chloride channels of jejunum and ileum from 75 day-old, cftr-treated mice were examined by short-circuit current measurements. Intestine from heterozygous mice (cftr+/-) showed the forskolin response expected for cAMP-activated chloride channels encoded by cftr. In contrast, tissue from cftr-treated homozygous knockout animals (cftr-/-) showed no response
619