- Email: [email protected]
PERCUTANEOUS EXCIMER LASER CORONARY ANGIOPLASTY
102 NUMBER OF ALLELES (AND FREQUENCIES) AT THE D7S8 LOCUS IN CF FAMILIES WITH OR WITHOUT MECONIUM ILEUS (MI)
In
our
non-CF control families
we
found 25 Fl (0-44) and 32 F2
(0-56)
chromosomes, respectively.
Megaloblastic change in sickle-cell anaemia: Jamaica, 1960-89. Shown as
proportion with megaloblastic change (see text).
to be good; megaloblastic change is and a double-blind trial of folate supplementation failed to indicate significant advantages.1 Folate supplementation is not therefore routine, except in children under the age of 5 years. Following hurricane Gilbert on Sept 12, 1988, our sickle-cell clinic saw an increased number of patients with megaloblastic change. The computer was therefore instructed to identify all episodes in patients of all genotypes of sickle cell disease aged over 5 years in which the mean cell volume (MCV) increased by 10 fl or more associated with a fall in haemoglobin of 1 g/dl or more compared with steady-state values for the same individual. The MCV increase was corrected for fluctuation in reticulocyte level by subtracting the change in reticulocytes x 0-2, based on the observation that reticulocytes have an MCV about 20% greater than normal red cellsThe number of episodes was then divided by the number of patients receiving blood tests in each year (over 1000 annually since 1982) to give a crude incidence rate (figure). The 1988 figure includes the first 8-Lmonths before Gilbert and the 1989 figure includes the 3,1months of 1988 post Gilbert and the first 5 months of 1989. The results suggest a real increase in megaloblastic change (27 affected patients) in the period following Gilbert although lesser increases also occurred in 1978-79 and in 1985-87. Common Jamaican sources of folate are fresh fruit and vegetables, which were scarce and therefore expensive after hurricane Gilbert. Policies on folate supplementation may need review according to changes in social and economic conditions and following natural disasters.
In
Jamaica this appears
uncommon
MRC Laboratories (Jamaica), University of the West Indies,
Mona, Kingston 7, Jamaica
D. R. J. READETT B. E. SERJEANT G. R. SERJEANT
1. Rabb
LM, Grandison Y, Mason K, Hayes RJ, Serjeant BE, Serjeant GR. A tnal of folate supplementation in children with homozygous sickle cell disease. Br J Haematol 1983; 54: 589-94. 2. Killmann S-A. On the size of normal human reticulocytes. Acta Med Scand 1964; 176: 529-33.
GENETIC DIFFERENCES BETWEEN CYSTIC FIBROSIS WITH AND WITHOUT MECONIUM ILEUS
SIR,-Dr Curtis and colleagues (May 13, p 1078) fail to show significant differences in D7S8 frequencies between cystic fibrosis (CF) chromosomes in families with and without meconium ileus. Ourdata’2 showed that the Flallele was more frequently associated with CF chromosomes in families with mecoriium ileus. We have now studied 270 CF chromosomes and our findings are similar to those of Curtis et al (table). Allele frequencies in normal
chromosomes of CF families, as well as in chromosomes of non-CF control families, are similar in both series and in other European series.3,4 If the true difference between Fl frequencies in CF families with and without meconium ileus is about 0-55 versus 0-45, no less than 400 CF chromosomes will have to be tested to secure a significant chi-squared value. Pooling Curtis and colleagues’ and our data gives 452 studied chromosomes and a significant difference (X2 6-04, p = 003; table). Other studies have shown differences in D7S8 marker allele distribution in different clinical situations. Allele 1 was more frequent in patients without pancreatic insufficiencys and in patients from Britanny with a severe form of the diseased Schmidtke and Krawczak7 reported a sex difference in D7S8 marker allele distribution in adult patients. In contrast, in the same studies, no differences were observed with other linked DNA probes, especially KM19. These results at the D7S8 locus suggest a genetic predisposition to a specific clinical expression of CF. =
BRIGITTE SIMON-BOUY
JEAN-LOUIS SERRE INSERM Units 73 and 155, Château de Longchamp, 75016 Paris, France
ETIENNE MORNET AGNÈS TALLANDIER JOËLLE BOUÉ ANDRÉ BOUÉ
E, Simon-Bouy B, Serre JL, et al. Genetic differences between cystic fibrosis with and without meconium ileus. Lancet 1988; i: 376-78. Momet E, Simon-Bouy B, Serre JL, et al. Genetic heterogeneity between two clinical forms of cystic fibrosis evidenced by familial analysis and linked DNA probes. Clin Genet 1988; 33: 53-56. Beaudet A, Bowcock A, Buchwald M, et al. Linkage of cystic fibrosis of two tightly-linked DNA markers: joint report from a collaborative study. AmJ Hum Genet 1986; 39: 681-93. Schmidtke J, Krawczak M, Schwartz M, et al. Linkage relationships and allele associations of the cystic fibrosis locus and four marker loci. Hum Genet 1987; 76: 337-43. Devoto M, Antonelh M, Bellini F, et al. Rarer alleles of DNA RFLPs closely linked to the CF gene are significantly more frequent in Italian CF patients without pancreatic insufficiency. Am J Hum Genet 1988; 3 (suppl): 325 (abstr). Ferec C. Les haplotypes associés au gène de la fibrose kystique (CF). J Genet Hum 1988; 36: 413-24. Schmidtke J, Krawczak M. Sex difference in D7S8 marker allele distribution in adult cystic fibrosis patients. Lancet 1989; i: 393.
1. Momet
2.
3.
4.
5.
6. 7.
PERCUTANEOUS EXCIMER LASER CORONARY ANGIOPLASTY
SIR,-Excimer lasers ablate tissue with precision and minimal thermal effects.1 Fibreoptic transmission and clinical application have been difficult because the nanosecond excimer pulses generate enormous peak powers which tend to destroy fibreoptics.2 We report our first successful experience with excimer laser coronary
angioplasty applied percutaneously. The patient was a 76-year-old man with unstable rest angina. Diagnostic angiography revealed a subtotal proximal right coronary artery stenosis (figure, left). Percutaneous transluminal coronary angioplasty was unsuccessful because of inability to cross the stenosis with a low profile balloon. The patient was referred to us for excimer laser coronary angioplasty.
103
Right coronary artery angiography. Left = before and centre = after excimer laser coronary angioplasty; right = after subsequent balloon
The laser was a 308 nm, xenon chloride, magnetically switched excimer which emitted at 150 mJ per pulse and 20 Hz. The catheter (Advanced Inteventional Systems, Irvine, California) has a 5F shaft and consists of twelve 200 /lffi fibres concentrically placed around a guidewire lumen. Catheter tip energy output was 40 mj/MM2 . The right coronary artery stenosis was crossed with a 0-45 mm floppy tipped guidewire. The laser catheter was positioned under fluoroscopic control at the proximal margin of the stenosis. A total of 412 laser pulses were delivered to the stenosis and the laser catheter crossed the lesion without difficulty. Angiography after excimer laser angioplasty alone revealed a residual stenosis of 40% (figure, centre). To improve the result, balloon angioplasty with a 3-0 mm balloon was done with two inflations at 3 atm (about 300 kPa). Angiography revealed a residual stenosis of 20% (figure, right). The patient tolerated the procedure well and was discharged on the second postoperative day. Follow-up angiography at one month revealed a patent right coronary artery without restenosis. This case demonstrates both the feasibility of this procedure and the ability of excimer laser energy transmitted by a flexible fibreoptic catheter to ablate plaque and recanalise obstructed coronary arteries. A trial is now ongoing.
Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California 90048, USA
FRANK LITVACK WARREN GRUNDFEST NEAL EIGLER DAN TSOI TSVI GOLDENBERG JAMES LAUDENSLAGER JAMES FORRESTER
WS, Litvack IF, Goldenberg T, et al. Pulsed ultraviolet lasers and the potential for safe laser angioplasty. Am J Surg 1985; 150: 220-26. 2. Litvack F, Grundfest WS, Goldenberg T, et al. Pulsed laser angioplasty: wavelength power and energy dependencies relevant to clinical application Lasers Surg Med 1. Grundfest
1988; 8: 60-65.
LONG-TERM EFFECTS OF METHYL ISOCYANATE
SIR,-Idisagree with Dr Andersson’s view (June 3, p 1259) that the focus on hydrogen cyanide (HCN) in my report (April 29, p’952) on the Bhopal disaster is potentially misleading and that a mistaken emphasis on cyanide has underestimated the long-term effects of methyl isocyanate (MIC). Pyrolysis of MIC at temperatures ranging from 427 to 548°C gives rise to HCN, CO, and H2, with smaller amounts of CH4, CO2, NH3, and N,N’dimethylcarbodiimide. This work, by Blake and Ijadi-Maghsoodi,l was published two years before the Bhopal disaster and I do not know why this significant paper has been ignored for such a long time. Indian scientists have shown that even at 350°C, MIC breaks down to form degraded MIC, and that cyanide is one of the products of pyrolysed MIC which is responsible for inhibiting cytochrome oxidase activity in rat brain.2 There is every reason to believe that HCN was a component of the gas that leaked from Union Carbide’s MIC storage tank at
Bhopal. My intention in focusing on HCN, which accounted for some of the early deaths in Bhopal, was to set the record straight. Not all the
angioplasty.
subacute and chronic manifestations of MIC toxicity can be explained by HCN alone. Indeed, the bulk of the work done by Indian scientists during the past 4t years clearly establishes a protracted disturbance in cyanide metabolism since the response to thiosulphate lasts for much longer than can be accounted for by inhalation of HCN. Carbamylation of the N-terminal valine of haemoglobin with MIC in rats and rabbits has been demonstrated in vitro and in vivo by gas chromatography.33 Long-term and multisystem toxicity of MIC is beyond doubt.4-6 An exothermic reaction did take place when the MIC storage tank collapsed to liberate MIC. But by commenting that many deaths occurred soon after the disaster from acute pulmonary oedema resulting from the bums during the highly exothermic reaction of MIC in lung secretions and tissues, surely Andersson is not implying that a second exothermic reaction took place, this time in the lung passages and tissues of victims. Andersson also observes that, acutely, MIC is several times more toxic than HCN. There is no evidence to prove this observation, and the immunological studies of Karol and Kamat’ have yet to be substantiated. Indian researchers are evaluating a great deal of data and are following up several victims of the Bhopal diaster to get a clearer idea of the long-term toxicity of MIC; results should be available soon.
16/5, Doctor’s Lane, New Delhi-110 001, India
BHUPESH MANGLA
PG, Ijadi-Maghsoodi S. Kinetics and mechanism of thermal decomposition of Int J Chem Kinet 1982; 14: 945-52. 2. Bhattacharya BK, Malhotra RC, Chattopadhyay DP. Inhibition of rat brain cytochrome oxidase activity by pyrolysed products of methyl isocyanate. Toxicol Lett 1987; 37: 131-34. 3. Ramachandran PK, Sriramachari S, et al. Gas chromatographic studies on carbamylation of haemoglobin in rats and rabbits. J Chromatogr Biomed Appl 1988; 426 (2): 239-47 4. ICMR. Health effects of the Bhopal gas tragedy. New Delhi: Indian Council of Medical Research, 1986. 5. ICMR. Scientific studies on Bhopal gas victims. Ind J Med Res 1987; 86 (suppl). 6. DRDE. What we did with MIC. Gwalior, India: Defence Research & Development 1. Blake
MIC.
Organisation, 1988. 7. Karol MH, Kamat SR. The antibody response to methyl isocyanate: experimental and clinical findings. Bull Eur Physiopathol Resp 1988; 23: 591-97.
ACUTE IFOSFAMIDE-INDUCED TUBULAR TOXICTTY
SIR,-Dr Newbury-Ecob and colleagues (June 10, p 1328) report of ifosfamide-induced Fanconi syndrome. Other studies1,21,2 indicate that ifosfamide tubular toxicity may be an increasing problem. We report a case in which Fanconi syndrome developed early in the course of ifosfamide and the predominant clinical effects a case
related to bicarbonate loss. An 18-month-old girl presented with
were
an
abdominal
mass
malignant histiocytoma. There was no ureteric obstruction and glomerular filtration rate was 139 ml/min/ 1 -73 m2. Chemotherapy consisted of ifosfamide 3 g/m2 infused over 24 h (days 1-3), mesna 3 g/m2 infused with the ifosfamide with a further 1 ’5 g/m2 on day 4, and vincristine 2 mg/m2 and actinomycin D 0-075 mg/kg on day 1. A second course was given 4 weeks later diagnosed histologically
as a
In
our
non-CF control families
we
found 25 Fl (0-44) and 32 F2
(0-56)
chromosomes, respectively.
Megaloblastic change in sickle-cell anaemia: Jamaica, 1960-89. Shown as
proportion with megaloblastic change (see text).
to be good; megaloblastic change is and a double-blind trial of folate supplementation failed to indicate significant advantages.1 Folate supplementation is not therefore routine, except in children under the age of 5 years. Following hurricane Gilbert on Sept 12, 1988, our sickle-cell clinic saw an increased number of patients with megaloblastic change. The computer was therefore instructed to identify all episodes in patients of all genotypes of sickle cell disease aged over 5 years in which the mean cell volume (MCV) increased by 10 fl or more associated with a fall in haemoglobin of 1 g/dl or more compared with steady-state values for the same individual. The MCV increase was corrected for fluctuation in reticulocyte level by subtracting the change in reticulocytes x 0-2, based on the observation that reticulocytes have an MCV about 20% greater than normal red cellsThe number of episodes was then divided by the number of patients receiving blood tests in each year (over 1000 annually since 1982) to give a crude incidence rate (figure). The 1988 figure includes the first 8-Lmonths before Gilbert and the 1989 figure includes the 3,1months of 1988 post Gilbert and the first 5 months of 1989. The results suggest a real increase in megaloblastic change (27 affected patients) in the period following Gilbert although lesser increases also occurred in 1978-79 and in 1985-87. Common Jamaican sources of folate are fresh fruit and vegetables, which were scarce and therefore expensive after hurricane Gilbert. Policies on folate supplementation may need review according to changes in social and economic conditions and following natural disasters.
In
Jamaica this appears
uncommon
MRC Laboratories (Jamaica), University of the West Indies,
Mona, Kingston 7, Jamaica
D. R. J. READETT B. E. SERJEANT G. R. SERJEANT
1. Rabb
LM, Grandison Y, Mason K, Hayes RJ, Serjeant BE, Serjeant GR. A tnal of folate supplementation in children with homozygous sickle cell disease. Br J Haematol 1983; 54: 589-94. 2. Killmann S-A. On the size of normal human reticulocytes. Acta Med Scand 1964; 176: 529-33.
GENETIC DIFFERENCES BETWEEN CYSTIC FIBROSIS WITH AND WITHOUT MECONIUM ILEUS
SIR,-Dr Curtis and colleagues (May 13, p 1078) fail to show significant differences in D7S8 frequencies between cystic fibrosis (CF) chromosomes in families with and without meconium ileus. Ourdata’2 showed that the Flallele was more frequently associated with CF chromosomes in families with mecoriium ileus. We have now studied 270 CF chromosomes and our findings are similar to those of Curtis et al (table). Allele frequencies in normal
chromosomes of CF families, as well as in chromosomes of non-CF control families, are similar in both series and in other European series.3,4 If the true difference between Fl frequencies in CF families with and without meconium ileus is about 0-55 versus 0-45, no less than 400 CF chromosomes will have to be tested to secure a significant chi-squared value. Pooling Curtis and colleagues’ and our data gives 452 studied chromosomes and a significant difference (X2 6-04, p = 003; table). Other studies have shown differences in D7S8 marker allele distribution in different clinical situations. Allele 1 was more frequent in patients without pancreatic insufficiencys and in patients from Britanny with a severe form of the diseased Schmidtke and Krawczak7 reported a sex difference in D7S8 marker allele distribution in adult patients. In contrast, in the same studies, no differences were observed with other linked DNA probes, especially KM19. These results at the D7S8 locus suggest a genetic predisposition to a specific clinical expression of CF. =
BRIGITTE SIMON-BOUY
JEAN-LOUIS SERRE INSERM Units 73 and 155, Château de Longchamp, 75016 Paris, France
ETIENNE MORNET AGNÈS TALLANDIER JOËLLE BOUÉ ANDRÉ BOUÉ
E, Simon-Bouy B, Serre JL, et al. Genetic differences between cystic fibrosis with and without meconium ileus. Lancet 1988; i: 376-78. Momet E, Simon-Bouy B, Serre JL, et al. Genetic heterogeneity between two clinical forms of cystic fibrosis evidenced by familial analysis and linked DNA probes. Clin Genet 1988; 33: 53-56. Beaudet A, Bowcock A, Buchwald M, et al. Linkage of cystic fibrosis of two tightly-linked DNA markers: joint report from a collaborative study. AmJ Hum Genet 1986; 39: 681-93. Schmidtke J, Krawczak M, Schwartz M, et al. Linkage relationships and allele associations of the cystic fibrosis locus and four marker loci. Hum Genet 1987; 76: 337-43. Devoto M, Antonelh M, Bellini F, et al. Rarer alleles of DNA RFLPs closely linked to the CF gene are significantly more frequent in Italian CF patients without pancreatic insufficiency. Am J Hum Genet 1988; 3 (suppl): 325 (abstr). Ferec C. Les haplotypes associés au gène de la fibrose kystique (CF). J Genet Hum 1988; 36: 413-24. Schmidtke J, Krawczak M. Sex difference in D7S8 marker allele distribution in adult cystic fibrosis patients. Lancet 1989; i: 393.
1. Momet
2.
3.
4.
5.
6. 7.
PERCUTANEOUS EXCIMER LASER CORONARY ANGIOPLASTY
SIR,-Excimer lasers ablate tissue with precision and minimal thermal effects.1 Fibreoptic transmission and clinical application have been difficult because the nanosecond excimer pulses generate enormous peak powers which tend to destroy fibreoptics.2 We report our first successful experience with excimer laser coronary
angioplasty applied percutaneously. The patient was a 76-year-old man with unstable rest angina. Diagnostic angiography revealed a subtotal proximal right coronary artery stenosis (figure, left). Percutaneous transluminal coronary angioplasty was unsuccessful because of inability to cross the stenosis with a low profile balloon. The patient was referred to us for excimer laser coronary angioplasty.
103
Right coronary artery angiography. Left = before and centre = after excimer laser coronary angioplasty; right = after subsequent balloon
The laser was a 308 nm, xenon chloride, magnetically switched excimer which emitted at 150 mJ per pulse and 20 Hz. The catheter (Advanced Inteventional Systems, Irvine, California) has a 5F shaft and consists of twelve 200 /lffi fibres concentrically placed around a guidewire lumen. Catheter tip energy output was 40 mj/MM2 . The right coronary artery stenosis was crossed with a 0-45 mm floppy tipped guidewire. The laser catheter was positioned under fluoroscopic control at the proximal margin of the stenosis. A total of 412 laser pulses were delivered to the stenosis and the laser catheter crossed the lesion without difficulty. Angiography after excimer laser angioplasty alone revealed a residual stenosis of 40% (figure, centre). To improve the result, balloon angioplasty with a 3-0 mm balloon was done with two inflations at 3 atm (about 300 kPa). Angiography revealed a residual stenosis of 20% (figure, right). The patient tolerated the procedure well and was discharged on the second postoperative day. Follow-up angiography at one month revealed a patent right coronary artery without restenosis. This case demonstrates both the feasibility of this procedure and the ability of excimer laser energy transmitted by a flexible fibreoptic catheter to ablate plaque and recanalise obstructed coronary arteries. A trial is now ongoing.
Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California 90048, USA
FRANK LITVACK WARREN GRUNDFEST NEAL EIGLER DAN TSOI TSVI GOLDENBERG JAMES LAUDENSLAGER JAMES FORRESTER
WS, Litvack IF, Goldenberg T, et al. Pulsed ultraviolet lasers and the potential for safe laser angioplasty. Am J Surg 1985; 150: 220-26. 2. Litvack F, Grundfest WS, Goldenberg T, et al. Pulsed laser angioplasty: wavelength power and energy dependencies relevant to clinical application Lasers Surg Med 1. Grundfest
1988; 8: 60-65.
LONG-TERM EFFECTS OF METHYL ISOCYANATE
SIR,-Idisagree with Dr Andersson’s view (June 3, p 1259) that the focus on hydrogen cyanide (HCN) in my report (April 29, p’952) on the Bhopal disaster is potentially misleading and that a mistaken emphasis on cyanide has underestimated the long-term effects of methyl isocyanate (MIC). Pyrolysis of MIC at temperatures ranging from 427 to 548°C gives rise to HCN, CO, and H2, with smaller amounts of CH4, CO2, NH3, and N,N’dimethylcarbodiimide. This work, by Blake and Ijadi-Maghsoodi,l was published two years before the Bhopal disaster and I do not know why this significant paper has been ignored for such a long time. Indian scientists have shown that even at 350°C, MIC breaks down to form degraded MIC, and that cyanide is one of the products of pyrolysed MIC which is responsible for inhibiting cytochrome oxidase activity in rat brain.2 There is every reason to believe that HCN was a component of the gas that leaked from Union Carbide’s MIC storage tank at
Bhopal. My intention in focusing on HCN, which accounted for some of the early deaths in Bhopal, was to set the record straight. Not all the
angioplasty.
subacute and chronic manifestations of MIC toxicity can be explained by HCN alone. Indeed, the bulk of the work done by Indian scientists during the past 4t years clearly establishes a protracted disturbance in cyanide metabolism since the response to thiosulphate lasts for much longer than can be accounted for by inhalation of HCN. Carbamylation of the N-terminal valine of haemoglobin with MIC in rats and rabbits has been demonstrated in vitro and in vivo by gas chromatography.33 Long-term and multisystem toxicity of MIC is beyond doubt.4-6 An exothermic reaction did take place when the MIC storage tank collapsed to liberate MIC. But by commenting that many deaths occurred soon after the disaster from acute pulmonary oedema resulting from the bums during the highly exothermic reaction of MIC in lung secretions and tissues, surely Andersson is not implying that a second exothermic reaction took place, this time in the lung passages and tissues of victims. Andersson also observes that, acutely, MIC is several times more toxic than HCN. There is no evidence to prove this observation, and the immunological studies of Karol and Kamat’ have yet to be substantiated. Indian researchers are evaluating a great deal of data and are following up several victims of the Bhopal diaster to get a clearer idea of the long-term toxicity of MIC; results should be available soon.
16/5, Doctor’s Lane, New Delhi-110 001, India
BHUPESH MANGLA
PG, Ijadi-Maghsoodi S. Kinetics and mechanism of thermal decomposition of Int J Chem Kinet 1982; 14: 945-52. 2. Bhattacharya BK, Malhotra RC, Chattopadhyay DP. Inhibition of rat brain cytochrome oxidase activity by pyrolysed products of methyl isocyanate. Toxicol Lett 1987; 37: 131-34. 3. Ramachandran PK, Sriramachari S, et al. Gas chromatographic studies on carbamylation of haemoglobin in rats and rabbits. J Chromatogr Biomed Appl 1988; 426 (2): 239-47 4. ICMR. Health effects of the Bhopal gas tragedy. New Delhi: Indian Council of Medical Research, 1986. 5. ICMR. Scientific studies on Bhopal gas victims. Ind J Med Res 1987; 86 (suppl). 6. DRDE. What we did with MIC. Gwalior, India: Defence Research & Development 1. Blake
MIC.
Organisation, 1988. 7. Karol MH, Kamat SR. The antibody response to methyl isocyanate: experimental and clinical findings. Bull Eur Physiopathol Resp 1988; 23: 591-97.
ACUTE IFOSFAMIDE-INDUCED TUBULAR TOXICTTY
SIR,-Dr Newbury-Ecob and colleagues (June 10, p 1328) report of ifosfamide-induced Fanconi syndrome. Other studies1,21,2 indicate that ifosfamide tubular toxicity may be an increasing problem. We report a case in which Fanconi syndrome developed early in the course of ifosfamide and the predominant clinical effects a case
related to bicarbonate loss. An 18-month-old girl presented with
were
an
abdominal
mass
malignant histiocytoma. There was no ureteric obstruction and glomerular filtration rate was 139 ml/min/ 1 -73 m2. Chemotherapy consisted of ifosfamide 3 g/m2 infused over 24 h (days 1-3), mesna 3 g/m2 infused with the ifosfamide with a further 1 ’5 g/m2 on day 4, and vincristine 2 mg/m2 and actinomycin D 0-075 mg/kg on day 1. A second course was given 4 weeks later diagnosed histologically
as a