304
prophylaxis.7 Our technique should also be applicable to other protozoan parasites found in blood and to human genetic studies.8 Supported by WHO/UNDP/World Bank special programme and by Overseas Development Administration. F.M.A.E.K. is supported by the British Council and the Sir Halley Stewart Trust and is in receipt of an ORS award. We thank John Frean for help in developing the malaria PCR protocol. PHLS Malaria Reference Laboratory and Department of Medical Parasitology, London School of Hygiene and Tropical Medicine, London W1 E 7HT, UK
D. C. WARHURST F. M. AWAD EL KARIEM M. A. MILES
1. Anon. DNA diagnosis and the polymerase chain reaction. Lancet 1988; i: 1372-73. 2. Wilson CM, Serrano AE, Wasley A, et al. Amplification of a gene related to mammalian mdr genes in drug-resistant Plasmodium falciparum. Science 1989; 244: 1184-86. 3. Foote SJ, Thompson JK, Cowman AF, Kemp DJ. Amplification of the multidrug resistance gene in some chloroquine-resistant isolates of Plasmodium falciparum. Cell 1989; 57: 921-30. 4. Mercier B, Gaucher C, Feugeas O, Mazurier C. Direct PCR from whole blood, without DNA extraction. Nucl Acids Res 1990; 18: 5908. 5. Desjardins RE, Canfield CJ, Haynes JD, Chulay JD. Quantitative assessment of antimalarial activity in vitro by a semi-automated microdilution technique. Antimicrob Ag Chemother 1979; 16: 710-18. 6. Dowling MAC, Shute GT. A comparative study of thick and thin blood films in the diagnosis of scanty malaria parasitaemia. Bull WHO 1966; 34: 249-67. 7. Warhurst DC. Diagnosis of malaria. Lancet 1990; 335: 472. 8. Nelson PV, Carey WF, Moms CP. Gene amplification directly from Guthrie blood spots. Lancet 1990; 336: 1451-52.
and adverse reactions to treatment in Onchocerca volvulus-infected British expatriates treated with ivermectin. We report here our experience in American expatriates. Since 1988, the Centers for Disease Control has monitored the release of ivermectin for the treatment of patients with onchocerciasis in the United States. 27 US citizens have been treated for 0 volvulus infections. 14 patients were male, and the median age was 33. Most were in occupations necessitating long stays in onchocerciasis-endemic areas of West and Central Africa; 9 were field scientists, 8 were Peace Corps volunteers, and 8 were missionaries or their family members. Lengths of stay in these areas ranged from 3 months to 8 years, with a median of 2 years. Onchocerciasis was confirmed in 25 by skin snip, nodulectomy, and/or slit-lamp examination of the ocular anterior chamber. The other two patients had compatible clinical symptoms and exposure history. All were treated as outpatients with a standard oral dose of ivermectin 150 Ixg/kg. 10 patients who had recurrent or persistent symptoms after 6 months or more were re-treated with the same dose; all responded favourably. Adverse reactions were noted at a frequency similar to that recorded in British expatriates except that localised oedema was less common in the Americans and none reported fever. All reactions were mild and transient: Reaction Pruritus Rash
Fatigue Localised oedema Headache Chills
BCG, tuberculosis, and leprosy SIR,-Abel and colleagues1 confirm the results of othersz in their case-control study that showed the protective efficacy of BCG against the non-lepromatous form of leprosy in southern Vietnam. These findings may reflect defective cellular immunity against mycobacteria in lepromatous patients. We have reanalysed our data on risk factors for leprosy3.4 to fmd if there was a negative association between tuberculosis and tuberculoid leprosy. 116 patients with lepromatous leprosy (LL) and 73 patients with tuberculoid leprosy (TT) were studied who were seen as outpatients at the Center for Hansen’s disease in Athens. Only cases with either of the two polar types of leprosy were included. 382 patients of low socioeconomic class, admitted to nearby hospitals for other reasons, acted as a control group. All subjects were of caucasian origin, a unique feature of this study. For patients with LL and TT, 10 (8-6%) and 0 subjects had a history of tuberculosis, respectively (=6-64, p=0-01). The frequency of tuberculosis among control patients was 10%. We conclude that there is a negative correlation between tuberculosis and the TT form of leprosy, which is not found in the LL form. These data support the evidence emerging from efficacy studies of BCG vaccination for leprosy prevention, which suggest that cellular immune responses, probably linked to major histocompatibility complex alleles, are important modifiers of the clinical expression of leprosy. 3,4 University of Athens Medical School, 115 27 Goudi, Athens, Greece
EVANGELIA KAKLAMANI YVONNI KOUMANDAKI KLEA KATSOUYANNI
Department of Epidemiology, Harvard School of Public Health, USA
DIMITRIOS TRICHOPOULOS
1. Abel L, Cua VV, Oberti J, et al. Leprosy and BCG in southern Vietnam. Lancet 1990; i: 1536. 2. Fine PEM. BCG vaccination against tuberculosis and leprosy Br Med Bull 1988; 44: 691-703. 3. Papaioannou DJ, Kaklamani EP, Parissis NG, Koumantaki IG, Karalis DT, Trichopoulos DR. Hepatitis B virus (HBV) serum markers in Greek leprosy patients. Int J Lepr 1986; 54: 245-51. 4. Koumantaki IG, Katsouyanni KM, Kaklamani EP, et al. An investigation of family size and birth order as risk factors in leprosy. Int J Lepr 1987; 55: 463-67.
Expatriates treated with ivermectin we are rapidly gaining experience in the of onchocerciasis in residents of Africa and Latin America, little is known about the effects of this disease or its treatment on visitors to onchocerciasis-endemic regions.1,2 Dr Davidson and colleagues (Oct 20, p 1005) describe initial symptoms
SIR,-Although
treatment
No 6 3 3 3 2 2
Reaction Hives Nausea Dizzmess
Myalgia Groin pain
Limbitis/lens opacities
No 1 1 1 1 1 1
This
experience shows that individuals in certain occupational groups who spend more than 3 months in onchocerciasis-endemic areas are at risk for the disease and should be considered for targeted prevention. Adverse reactions to ivermectin are common in 0 volvulus-infected expatriates but in this series the reactions were not severe and are generally well-tolerated by outpatients. Parasitic Diseases Branch, Division of Parasitic Diseases, and Clinical Medicine Branch, Division of Immunologic, Oncologic, and Hematologic Diseases, Center for Infectious Diseases, Centers for Disease Control, Atlanta, Georgia 30333, USA
RALPH T. BRYAN SUSAN L. STOKES HARRISON C. SPENCER
Pacque M, Munoz B, Greene BM, et al. Safety and compliance with communitybased ivermectin therapy. Lancet 1990; 335: 1377-80 2. Taylor HR, Greene BM. The status of ivermectin in the treatment of human onchocerciasis. Am J Trop Med Hyg 1989; 41: 460-66. 1.
Sudden infant death in Thailand and Alaska S;R,—Dr Wilson (Nov 10, p 1199) questions why sudden infant death syndrome (SIDS) is so uncommon or virtually unknown in south China whereas there is a high frequency in native Indians of Alberta, Canada. The same question could be raised about North Americans of Chinese ancestry, who have a low frequency of SIDS, and Alaska native infants, who have one of the highest rates. In 1990 we visited forensic facilities in Thailand and gathered information about SIDS. In a heavily populated north-west province, a medical examiner who had trained in forensic pathology in the USA could not recall an infant death diagnosed as SIDS during the past several years. In a north-eastern province, a forensic pathologist participating in a government collaborative study on sudden unexplained death in adults (SUDS) could recall only one medical examiner’s case being diagnosed as SIDS. In other provinces the general consensus by medical examiners is that Thai infants are at near zero risk of SIDS. Despite the difficulties of basic sanitation in this developing country, infants may be at less risk for injury in Thailand than those in Western countries. When a Thai mother is occupied with housework, grandparents may attend the infant and provide extra care. In addition, it is culturally unacceptable for Thai (or Chinese) mothers to consume alcohol while nursing or bedsharing with their infants. Fetal alcohol syndrome is not a health problem in Thai or Chinese infants, unlike native North American infants.
305
In our study of SIDS in native Alaskans during the 1980s, we found that in the majority of 30 SIDS cases the carer was a chronic abuser of alcohol and was inebriated on the day that the infant died. We suspect that the high frequency of sudden infant death in the black, Hispanic, native Indian, and Eskimo populations in North America could be attributed in part to unintentional injury caused by a carer who lacks parenting skills. In previous studies by one of us (M. B.) it was concluded that poor judgment by the carer, irrespective of socioeconomic status, was often a contributing factor in sudden infant death.1-3 In the affluent suburban home, a young infant is less likely to be unattended, even for brief intervals, because an older relative or professional carer is usually always available to help the mother. To lower the high post-neonatal mortality rate, we suggest that parents and other carers of infants should be educated about the dangers to infants. Furthermore, the ambitious programme by Inupiat Alaskan Eskimos to promote sobriety and to reaffirm
traditional native values promises to play an increasingly important part in the lowering of the high rate of SIDS in their communities.4,5 MILLARD BASS RITA HASS
1 Plaza Street, Brooklyn, NY 11217, USA
The ability of unlabelled LDL from two patients and a control to compete with 125I-labelled control LDL for uptake by cultured human skin fibroblasts was determined.’ IC50 is the concentration of unlabelled LDL required for a 50% reduction in uptake of control "1-LDL by fibroblasts and results were expressed as IC5. ratio (defective/normal). The absolute value of ICso for control LDL was 10 (2) I1g/ml. The IC50 ratio rose by 50% from 2.8 to 4.2 in patient A and it rose by 30% (10 mg daily) and by 38% (40 mg) in patient B. The binding abnormality of LDL could account for the poor response to simvastatin of patients with familial defective apo-B100. Since the frequency of this defect is about 1 in 500 in the
free-living population6 (similar
in
frequency to heterozygous responders to HMG-CoA
familial hypercholesterolaemia), poor inhibitors may be quite common.
Institute of
Pharmacological Sciences, University of Milan, 20133 Milan, Italy
ALBERTO CORSINI MARIA MAZZOTTI REMO FUMAGALLI ALBERICO L. CATAPANO
G Gaslini Institute, University of Genoa
LUCA ROMANO CESARE ROMANO
1. Bass M. Sudden infant death syndrome. Br Med J 1989; 298: 1267. 2. Bass M, Kravath RE, Glass L. Death-scene investigation in sudden infant death.
Poor response to simvastatin in familial defective apo-B-100 SIR,-Plasma cholesterol levels depend largely upon low-density lipoprotein (LDL) receptors.’ This is best illustrated by familial hypercholesterolaemia in which defective LDL receptor expression triggers an increase in plasma LDL and premature coronary heart disease.2 Most individuals with hypercholesterolaemia, however, possess normal LDL receptors.z In familial defective apo-B-100, a genetic abnormality leads to an aminoacid substitution in the apolipoprotein B-100 that segregates with binding-defective LDL and hypercholesterolaemia .3 ’ Affected individuals so far identified are heterozygous.3-6 Because there is only one copy of apo-B-100 per LDL particle, these heterozygotes have two populations of LDL, one with normal and the other with binding-defective apo-B-100 6 In these patients LDL-cholesterol levels should be relatively unaffected by treatments aimed at up-regulating receptor expression, because of the presence of a large proportion of LDL which does not bind to their receptor.6 Statins, a class of powerful cholesterol-lowering drugs, inhibit cholesterol synthesis, thus increasing cellular LDL-receptor expressionThis approach-though satisfactory in several forms of hypercholesterolaemia, including heterozygous familial hypercholesterolaemia-should therefore not lower plasma LDL cholesterol in familial defective apo-B-100. To test this suggestion two members of a family with familial defective apo-B-100’’-’’ were treated with simvastatin: Patient A (20 mg/day)
Before therapy Plasma LDL HDL 341 298
279 239
49 49
After therapy Plasma LDL HDL
235 201 B (10 mg/day) 203 B (40 mg/day) Patients treated for 4 weeks Patient B received 10 mg/day for 4 followed by 40 mg/day for further 4 weeks ......
300 264 266
54 48 44 weeks,
Total and LDL cholesterol fell by only 12% and 16%, respectively, even at the highest dose; 35-40% reductions are achievable in heterozygous familial hypercholesterolaemia and other primary
hypercholesterolaemias.8,9 That binding-defective
MS, Goldstein JL. A receptor mediated pathway for cholesterol homeostasis. Science 1986; 232: 34-47 2. Brown MS, Goldstein JL. The hyperlipoproteinaemias and other disorders of lipid metabolism. In: Braunwald E, Isselbacher KJ, Petersdorf RG, Wilson JD, Martin JB, Fauci AS, eds. Harrison’s principles of internal medicine. New York: McGraw-Hill, 1987: 1650-61. 3. Innerarity TL, Weisgraber KH, Arnold KS, et al. Familial defective apolipoprotein B-100: low density lipoproteins with abnormal receptor binding. Proc Natl Acad Sci USA 1987; 84: 6919-23. 4. Soria LF, Ludwig EH, Clarke HRG, et al. Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100. Proc Natl Acad Sci USA 1989; 86: 587-91. 5. Corsini A, Fantappiè S, Granata A, et al. Binding-defective low-density lipoprotein in family with hypercholesterolaemia. Lancet 1989; i: 623. 6. Innerarity TL, Mahley RW, Weisgraber KH, et al. Familial defective apolipoprotein B-100: a mutation of apolipoprotein B that causes hypercholesterolaemia. J Lipid 1. Brown
N Engl J Med 1986, 315: 100-05. 3. Bass M. The fallacy of the simultaneous sudden infant death syndrome in twins. Am J Forensic Med Pathol 1989; 10: 200-05. 4. McGann S Elders celebrate Ilitqusiat awards; innovation award honor traditional values. Northwest Arctic NUNA, vol II. Kotzebue, Alaska: Maniilaq Associates, 1990: 1-6. 5. Wilson M. We must stop the deaths of our youths. Tundra Times (Anchorage, Alaska) 1990: 28: 14.
LDL accumulated in plasma after simvastatin treatment was demonstrated by an in-vitro cell binding assay. LDL showed a further decrease in affinity for their receptor.
Res 1990; 31: 1337-49. Fautappiè S, Soria LF, et al. Binding-defective low density lipoproteins in a
7. Corsini A,
family with primary hypercholesterolaemia. In: 30th International Conference on the Biochemistry of Lipid (1989); abstr C14 8. Grundy SM. HMG-CoA reductase inhibitors for a treatment of hypercholesterolemia. N EnglJ Med 1988; 319: 24-33. 9. Stossel TP. A multicentre comparison of lovastatin and cholestyramine therapy for severe primary hypercholesterolemia. JAMA 1988; 260: 359-66.
Not testicular feminisation SiR,—The child described by Dr Goodall (Jan 5, p 33) did not have testicular feminisation, because she had a "normal uterus and bilateral fallopian tubes". In testicular feminisation the testes are normal but the tissues are androgen insensitive. This child had either partial androgen insensitivity or XY gonadal dysgenesis, and the presence of the uterus makes possible a pregnancy by gamete intrafallopian transfer. What a difference that might make to the patient’s outlook on life. Cobbold Laboratories, Middlesex Hospital, London W1N 8AA, UK
** This letter has been shown follows.-ED. L.
C. G. D. BROOK
to
Dr
Goodall, whose reply
SiR,-Professor Brook’s instructive letter has produced a growth spurt in my own conceptual understanding. A better title for my paper would have been "Helping a child to understand her own Y chromosome", and I apologise for my error. Important as correct nomenclature is, the burden of the article, as of the patient, remains
unchanged. Whether she finally attempts adoption of ovum or baby, she has been prepared for this by growing insight and emotional support, which can still be built upon as time goes by. Melton, Burnngton Dnve, Trentham, Stoke-on-Trent ST4 8SP, UK
JANET GOODALL
prophylaxis.7 Our technique should also be applicable to other protozoan parasites found in blood and to human genetic studies.8 Supported by WHO/UNDP/World Bank special programme and by Overseas Development Administration. F.M.A.E.K. is supported by the British Council and the Sir Halley Stewart Trust and is in receipt of an ORS award. We thank John Frean for help in developing the malaria PCR protocol. PHLS Malaria Reference Laboratory and Department of Medical Parasitology, London School of Hygiene and Tropical Medicine, London W1 E 7HT, UK
D. C. WARHURST F. M. AWAD EL KARIEM M. A. MILES
1. Anon. DNA diagnosis and the polymerase chain reaction. Lancet 1988; i: 1372-73. 2. Wilson CM, Serrano AE, Wasley A, et al. Amplification of a gene related to mammalian mdr genes in drug-resistant Plasmodium falciparum. Science 1989; 244: 1184-86. 3. Foote SJ, Thompson JK, Cowman AF, Kemp DJ. Amplification of the multidrug resistance gene in some chloroquine-resistant isolates of Plasmodium falciparum. Cell 1989; 57: 921-30. 4. Mercier B, Gaucher C, Feugeas O, Mazurier C. Direct PCR from whole blood, without DNA extraction. Nucl Acids Res 1990; 18: 5908. 5. Desjardins RE, Canfield CJ, Haynes JD, Chulay JD. Quantitative assessment of antimalarial activity in vitro by a semi-automated microdilution technique. Antimicrob Ag Chemother 1979; 16: 710-18. 6. Dowling MAC, Shute GT. A comparative study of thick and thin blood films in the diagnosis of scanty malaria parasitaemia. Bull WHO 1966; 34: 249-67. 7. Warhurst DC. Diagnosis of malaria. Lancet 1990; 335: 472. 8. Nelson PV, Carey WF, Moms CP. Gene amplification directly from Guthrie blood spots. Lancet 1990; 336: 1451-52.
and adverse reactions to treatment in Onchocerca volvulus-infected British expatriates treated with ivermectin. We report here our experience in American expatriates. Since 1988, the Centers for Disease Control has monitored the release of ivermectin for the treatment of patients with onchocerciasis in the United States. 27 US citizens have been treated for 0 volvulus infections. 14 patients were male, and the median age was 33. Most were in occupations necessitating long stays in onchocerciasis-endemic areas of West and Central Africa; 9 were field scientists, 8 were Peace Corps volunteers, and 8 were missionaries or their family members. Lengths of stay in these areas ranged from 3 months to 8 years, with a median of 2 years. Onchocerciasis was confirmed in 25 by skin snip, nodulectomy, and/or slit-lamp examination of the ocular anterior chamber. The other two patients had compatible clinical symptoms and exposure history. All were treated as outpatients with a standard oral dose of ivermectin 150 Ixg/kg. 10 patients who had recurrent or persistent symptoms after 6 months or more were re-treated with the same dose; all responded favourably. Adverse reactions were noted at a frequency similar to that recorded in British expatriates except that localised oedema was less common in the Americans and none reported fever. All reactions were mild and transient: Reaction Pruritus Rash
Fatigue Localised oedema Headache Chills
BCG, tuberculosis, and leprosy SIR,-Abel and colleagues1 confirm the results of othersz in their case-control study that showed the protective efficacy of BCG against the non-lepromatous form of leprosy in southern Vietnam. These findings may reflect defective cellular immunity against mycobacteria in lepromatous patients. We have reanalysed our data on risk factors for leprosy3.4 to fmd if there was a negative association between tuberculosis and tuberculoid leprosy. 116 patients with lepromatous leprosy (LL) and 73 patients with tuberculoid leprosy (TT) were studied who were seen as outpatients at the Center for Hansen’s disease in Athens. Only cases with either of the two polar types of leprosy were included. 382 patients of low socioeconomic class, admitted to nearby hospitals for other reasons, acted as a control group. All subjects were of caucasian origin, a unique feature of this study. For patients with LL and TT, 10 (8-6%) and 0 subjects had a history of tuberculosis, respectively (=6-64, p=0-01). The frequency of tuberculosis among control patients was 10%. We conclude that there is a negative correlation between tuberculosis and the TT form of leprosy, which is not found in the LL form. These data support the evidence emerging from efficacy studies of BCG vaccination for leprosy prevention, which suggest that cellular immune responses, probably linked to major histocompatibility complex alleles, are important modifiers of the clinical expression of leprosy. 3,4 University of Athens Medical School, 115 27 Goudi, Athens, Greece
EVANGELIA KAKLAMANI YVONNI KOUMANDAKI KLEA KATSOUYANNI
Department of Epidemiology, Harvard School of Public Health, USA
DIMITRIOS TRICHOPOULOS
1. Abel L, Cua VV, Oberti J, et al. Leprosy and BCG in southern Vietnam. Lancet 1990; i: 1536. 2. Fine PEM. BCG vaccination against tuberculosis and leprosy Br Med Bull 1988; 44: 691-703. 3. Papaioannou DJ, Kaklamani EP, Parissis NG, Koumantaki IG, Karalis DT, Trichopoulos DR. Hepatitis B virus (HBV) serum markers in Greek leprosy patients. Int J Lepr 1986; 54: 245-51. 4. Koumantaki IG, Katsouyanni KM, Kaklamani EP, et al. An investigation of family size and birth order as risk factors in leprosy. Int J Lepr 1987; 55: 463-67.
Expatriates treated with ivermectin we are rapidly gaining experience in the of onchocerciasis in residents of Africa and Latin America, little is known about the effects of this disease or its treatment on visitors to onchocerciasis-endemic regions.1,2 Dr Davidson and colleagues (Oct 20, p 1005) describe initial symptoms
SIR,-Although
treatment
No 6 3 3 3 2 2
Reaction Hives Nausea Dizzmess
Myalgia Groin pain
Limbitis/lens opacities
No 1 1 1 1 1 1
This
experience shows that individuals in certain occupational groups who spend more than 3 months in onchocerciasis-endemic areas are at risk for the disease and should be considered for targeted prevention. Adverse reactions to ivermectin are common in 0 volvulus-infected expatriates but in this series the reactions were not severe and are generally well-tolerated by outpatients. Parasitic Diseases Branch, Division of Parasitic Diseases, and Clinical Medicine Branch, Division of Immunologic, Oncologic, and Hematologic Diseases, Center for Infectious Diseases, Centers for Disease Control, Atlanta, Georgia 30333, USA
RALPH T. BRYAN SUSAN L. STOKES HARRISON C. SPENCER
Pacque M, Munoz B, Greene BM, et al. Safety and compliance with communitybased ivermectin therapy. Lancet 1990; 335: 1377-80 2. Taylor HR, Greene BM. The status of ivermectin in the treatment of human onchocerciasis. Am J Trop Med Hyg 1989; 41: 460-66. 1.
Sudden infant death in Thailand and Alaska S;R,—Dr Wilson (Nov 10, p 1199) questions why sudden infant death syndrome (SIDS) is so uncommon or virtually unknown in south China whereas there is a high frequency in native Indians of Alberta, Canada. The same question could be raised about North Americans of Chinese ancestry, who have a low frequency of SIDS, and Alaska native infants, who have one of the highest rates. In 1990 we visited forensic facilities in Thailand and gathered information about SIDS. In a heavily populated north-west province, a medical examiner who had trained in forensic pathology in the USA could not recall an infant death diagnosed as SIDS during the past several years. In a north-eastern province, a forensic pathologist participating in a government collaborative study on sudden unexplained death in adults (SUDS) could recall only one medical examiner’s case being diagnosed as SIDS. In other provinces the general consensus by medical examiners is that Thai infants are at near zero risk of SIDS. Despite the difficulties of basic sanitation in this developing country, infants may be at less risk for injury in Thailand than those in Western countries. When a Thai mother is occupied with housework, grandparents may attend the infant and provide extra care. In addition, it is culturally unacceptable for Thai (or Chinese) mothers to consume alcohol while nursing or bedsharing with their infants. Fetal alcohol syndrome is not a health problem in Thai or Chinese infants, unlike native North American infants.
305
In our study of SIDS in native Alaskans during the 1980s, we found that in the majority of 30 SIDS cases the carer was a chronic abuser of alcohol and was inebriated on the day that the infant died. We suspect that the high frequency of sudden infant death in the black, Hispanic, native Indian, and Eskimo populations in North America could be attributed in part to unintentional injury caused by a carer who lacks parenting skills. In previous studies by one of us (M. B.) it was concluded that poor judgment by the carer, irrespective of socioeconomic status, was often a contributing factor in sudden infant death.1-3 In the affluent suburban home, a young infant is less likely to be unattended, even for brief intervals, because an older relative or professional carer is usually always available to help the mother. To lower the high post-neonatal mortality rate, we suggest that parents and other carers of infants should be educated about the dangers to infants. Furthermore, the ambitious programme by Inupiat Alaskan Eskimos to promote sobriety and to reaffirm
traditional native values promises to play an increasingly important part in the lowering of the high rate of SIDS in their communities.4,5 MILLARD BASS RITA HASS
1 Plaza Street, Brooklyn, NY 11217, USA
The ability of unlabelled LDL from two patients and a control to compete with 125I-labelled control LDL for uptake by cultured human skin fibroblasts was determined.’ IC50 is the concentration of unlabelled LDL required for a 50% reduction in uptake of control "1-LDL by fibroblasts and results were expressed as IC5. ratio (defective/normal). The absolute value of ICso for control LDL was 10 (2) I1g/ml. The IC50 ratio rose by 50% from 2.8 to 4.2 in patient A and it rose by 30% (10 mg daily) and by 38% (40 mg) in patient B. The binding abnormality of LDL could account for the poor response to simvastatin of patients with familial defective apo-B100. Since the frequency of this defect is about 1 in 500 in the
free-living population6 (similar
in
frequency to heterozygous responders to HMG-CoA
familial hypercholesterolaemia), poor inhibitors may be quite common.
Institute of
Pharmacological Sciences, University of Milan, 20133 Milan, Italy
ALBERTO CORSINI MARIA MAZZOTTI REMO FUMAGALLI ALBERICO L. CATAPANO
G Gaslini Institute, University of Genoa
LUCA ROMANO CESARE ROMANO
1. Bass M. Sudden infant death syndrome. Br Med J 1989; 298: 1267. 2. Bass M, Kravath RE, Glass L. Death-scene investigation in sudden infant death.
Poor response to simvastatin in familial defective apo-B-100 SIR,-Plasma cholesterol levels depend largely upon low-density lipoprotein (LDL) receptors.’ This is best illustrated by familial hypercholesterolaemia in which defective LDL receptor expression triggers an increase in plasma LDL and premature coronary heart disease.2 Most individuals with hypercholesterolaemia, however, possess normal LDL receptors.z In familial defective apo-B-100, a genetic abnormality leads to an aminoacid substitution in the apolipoprotein B-100 that segregates with binding-defective LDL and hypercholesterolaemia .3 ’ Affected individuals so far identified are heterozygous.3-6 Because there is only one copy of apo-B-100 per LDL particle, these heterozygotes have two populations of LDL, one with normal and the other with binding-defective apo-B-100 6 In these patients LDL-cholesterol levels should be relatively unaffected by treatments aimed at up-regulating receptor expression, because of the presence of a large proportion of LDL which does not bind to their receptor.6 Statins, a class of powerful cholesterol-lowering drugs, inhibit cholesterol synthesis, thus increasing cellular LDL-receptor expressionThis approach-though satisfactory in several forms of hypercholesterolaemia, including heterozygous familial hypercholesterolaemia-should therefore not lower plasma LDL cholesterol in familial defective apo-B-100. To test this suggestion two members of a family with familial defective apo-B-100’’-’’ were treated with simvastatin: Patient A (20 mg/day)
Before therapy Plasma LDL HDL 341 298
279 239
49 49
After therapy Plasma LDL HDL
235 201 B (10 mg/day) 203 B (40 mg/day) Patients treated for 4 weeks Patient B received 10 mg/day for 4 followed by 40 mg/day for further 4 weeks ......
300 264 266
54 48 44 weeks,
Total and LDL cholesterol fell by only 12% and 16%, respectively, even at the highest dose; 35-40% reductions are achievable in heterozygous familial hypercholesterolaemia and other primary
hypercholesterolaemias.8,9 That binding-defective
MS, Goldstein JL. A receptor mediated pathway for cholesterol homeostasis. Science 1986; 232: 34-47 2. Brown MS, Goldstein JL. The hyperlipoproteinaemias and other disorders of lipid metabolism. In: Braunwald E, Isselbacher KJ, Petersdorf RG, Wilson JD, Martin JB, Fauci AS, eds. Harrison’s principles of internal medicine. New York: McGraw-Hill, 1987: 1650-61. 3. Innerarity TL, Weisgraber KH, Arnold KS, et al. Familial defective apolipoprotein B-100: low density lipoproteins with abnormal receptor binding. Proc Natl Acad Sci USA 1987; 84: 6919-23. 4. Soria LF, Ludwig EH, Clarke HRG, et al. Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100. Proc Natl Acad Sci USA 1989; 86: 587-91. 5. Corsini A, Fantappiè S, Granata A, et al. Binding-defective low-density lipoprotein in family with hypercholesterolaemia. Lancet 1989; i: 623. 6. Innerarity TL, Mahley RW, Weisgraber KH, et al. Familial defective apolipoprotein B-100: a mutation of apolipoprotein B that causes hypercholesterolaemia. J Lipid 1. Brown
N Engl J Med 1986, 315: 100-05. 3. Bass M. The fallacy of the simultaneous sudden infant death syndrome in twins. Am J Forensic Med Pathol 1989; 10: 200-05. 4. McGann S Elders celebrate Ilitqusiat awards; innovation award honor traditional values. Northwest Arctic NUNA, vol II. Kotzebue, Alaska: Maniilaq Associates, 1990: 1-6. 5. Wilson M. We must stop the deaths of our youths. Tundra Times (Anchorage, Alaska) 1990: 28: 14.
LDL accumulated in plasma after simvastatin treatment was demonstrated by an in-vitro cell binding assay. LDL showed a further decrease in affinity for their receptor.
Res 1990; 31: 1337-49. Fautappiè S, Soria LF, et al. Binding-defective low density lipoproteins in a
7. Corsini A,
family with primary hypercholesterolaemia. In: 30th International Conference on the Biochemistry of Lipid (1989); abstr C14 8. Grundy SM. HMG-CoA reductase inhibitors for a treatment of hypercholesterolemia. N EnglJ Med 1988; 319: 24-33. 9. Stossel TP. A multicentre comparison of lovastatin and cholestyramine therapy for severe primary hypercholesterolemia. JAMA 1988; 260: 359-66.
Not testicular feminisation SiR,—The child described by Dr Goodall (Jan 5, p 33) did not have testicular feminisation, because she had a "normal uterus and bilateral fallopian tubes". In testicular feminisation the testes are normal but the tissues are androgen insensitive. This child had either partial androgen insensitivity or XY gonadal dysgenesis, and the presence of the uterus makes possible a pregnancy by gamete intrafallopian transfer. What a difference that might make to the patient’s outlook on life. Cobbold Laboratories, Middlesex Hospital, London W1N 8AA, UK
** This letter has been shown follows.-ED. L.
C. G. D. BROOK
to
Dr
Goodall, whose reply
SiR,-Professor Brook’s instructive letter has produced a growth spurt in my own conceptual understanding. A better title for my paper would have been "Helping a child to understand her own Y chromosome", and I apologise for my error. Important as correct nomenclature is, the burden of the article, as of the patient, remains
unchanged. Whether she finally attempts adoption of ovum or baby, she has been prepared for this by growing insight and emotional support, which can still be built upon as time goes by. Melton, Burnngton Dnve, Trentham, Stoke-on-Trent ST4 8SP, UK
JANET GOODALL
