575
foscamet to his maintenance ganciclovir. He died six months later of pneumonia with no evidence of active CMV disease. Case 2—A 39-year-old HIV-seropositive homosexual man was diagnosed as having bilateral CMV retinitis. He was treated successfully with ganciclovir 10 mg/kg per day for two weeks, which was maintained at 5 mg/kg per day for five consecutive days every week. Sixteen weeks later he was admitted with a six-day history of fever and hepatomegaly. Histological examination of the liver revealed focal areas of hepatocellular necrosis, which were highly suggestive of CMV infection; foscamet was added to his treatment regimen. His fever settled and his hepatomegaly resolved rapidly. Repeat histological examination of the liver showed neither focal necrosis nor evidence suggestive of persistent CMV infection. We support Nelson et al’s suggestion that refractory CMV retinitis may respond to combinaton treatment with ganciclovir and foscamet, and also suggest its use in CMV disease affecting other organs where sole therapy is ineffective. We also wish to emphasise the importance of being alert for other systemic signs of CMV infection despite apparent quiescence of retinal disease. R. J. COKER D. TOMLINSON P. HORNER C. MIGDAL J. R. W. HARRIS
Departments of Genitourinary Medicine and Ophthalmology, Jefferiss Wing, St Mary’s Hospital, London W2 1NY, UK
Sedative and
hypnotic withdrawal states in hospitalised patients
SIR,-Our psychiatric consultation service is located in a university teaching hospital and has encountered a noticeable rise in the cases of delirium among inpatients, which seems to be caused by sedative-hypnotic drug withdrawal. These observations have been made during a period when house staff were being warned against the routine prescription of benzodiazepines for night-time sedation. I will report one case that serves as a typical example. A 68-year-old woman was admitted to hospital for repair of a thoraco-abdominal aneurysm. On her sixth postoperative day, she became acutely agitated in the early evening. Psychiatric consultation revealed disorientation to place and time, extreme motor restlessness, paranoid delusions, and visual hallucinations. Further examination laboratory tests could
patient
was
was
unremarkable and
a
benefit. Review of the case-notes showed that the cardiovascular surgeon had prescribed lorazepam 2 mg for "insomnia secondary to pre-operative anxiety" about 12 weeks before admission. We thought that abrupt cessation had caused an acute benzodiazepine withdrawal. Haloperidol was discontinued and lorazepam 2 mg at bedtime was restarted. This patient’s delirium resolved within 24 h. She later confirmed that she had been taking lorazepam regularly for the 12 weeks before hospital admission. This case is typical of a growing difficulty among our inpatients and, I suspect, is not limited only to our institution. Not only should medical and surgical house staff be more discriminating in their prescription of sedative-hypnotic medications among inpatients, but they must also be vigilant as to the dangers of iatrogenic withdrawal states.1
JAY H. Moss
1. Sellers EM. Alcohol, barbiturate and benzodiazepine withdrawal
management. Can Med Assoc
J 1988; 139:
syndromes: clinical
113-20.
Treatment of anterior tibial artery occlusion SIR,-I was surprised that Dr Bannerjee and colleagues (June 29, 1603) believed that their approach to anterior tibial occlusion was either novel or an important advance. Cannulation of the tibial arteries for selective thrombolysis, augmented, when appropriate, by clot aspiration, has been a standard radiological technique for many years.’ Angiography completed with the type of fluoroscopic equipment available in many operating theatres is often less than satisfactory. There is limited capability for recording investigations
p
prolonged or to require multiple aspirations and long-term thrombolytic therapy. Such procedures have long been the province of the interventional radiologist and should continue to be be
so.
New
England
Deaconess
Hospital,
Boston, Massachusetts 02215, USA 1.
GEORGE G. HARTNELL
Traughber PD, Cook PS, Mieklos TV, Miller FJ. Intraarterial fibrinolytic therapy for popliteal and arterial obstruction: comparison of streptokinase and urokinase. AJR 1987; 149: 453-56.
SiR,—The quality of intra-operative angiograms may be inferior those obtained by conventional means, although failure to visualise vessels in the lower calf in a critically ischaemic limb by conventional angiography is well recognised. However, we use a simple technique of instillation of contrast medium into either the superficial femoral or profunda femoris arteries during in-flow occlusion. On no occasion have we failed to show the lower tibial and plantar arteries during screening. Our equipment (Phillips BV25 image intensifier) provides images of excellent quality, which may be stored on video (Phillips XTV5 HQ medical TV channel). Angiography after embolectomy will show incomplete clearance of thrombus, which requires further embolectomy, in up to 30% of cases.1 We disagree that angiography and thrombolysis are the sole province of the interventional radiologist. Vascular surgeons who undertake such procedures should, like us, work in collaboration with their radiological colleagues. Sadly, radiological support cannot be guaranteed—and, in the UK, its absence has been the main limitation to the widespread use of intra-arterial thrombolysisThat vascular surgeons have adopted procedures that they label as "minimal access" is hardly surprising, but they do so sound in the knowledge that they can proceed to an open operation in the event of failure or complications.
to
review of all
identify what caused the delirium. The given haloperidol 5 mg intramuscularly with little not
Sunnybrook Health Science Centre, Toronto, Ontario M4N 3M5, Canada
and the quality of the fluoroscopic image is frequently poorer than that available in conventional angiography suites. Although fluoroscopy may be a useful adjunct in an emergency if surgical embolectomy is only partly successful, a better result may be expected when selective angiography is completed with proper angiographic equipment and by experienced angiographers. This approach is especially important if the procedure is likely either to
Department of Surgery, Worcester Royal Infirmary, Worcester WR1 5AS, UK
ANJAN K. BANERJEE NICHOLAS HICKEY RICHARD DOWNING
1. Bosma HW, Jorning PJG. Intraoperative arteriography in arterial embolectomy. Eur J Vasc Surg 1990; 4: 469-72. 2. Browse DJ, Barr H, Torrie EPH, Galland RB. Limitations to the widespread usage of low dose intra-arterial thrombolysis. Eur J Vasc Surg 1991; 5: 445-49.
Late-onset
homozygous protein C deficiency
SiR,—The importance of protein C in haemostasis is shown by frequent occurrence of thrombotic disease in those with low plasma concentrations of this factor. Hereditary protein C deficiency is usually but not always transmitted as an autosomal dominant trait; heterozygotes are at risk for thrombophlebitis, deep vein thrombosis (DVT), and pulmonary embolism (PE). Although the homozygous deficiency state was thought to be incompatible with life, several adults are now known to have low plasma protein C
the
concentrations but with much milder symptoms or a later onset of disease.1,2 However formal proof of recessive inheritance requires confirmatory DNA sequencing. We have previously studied a Middle Eastern family with severe type I protein C deficiency and recurrent thrombosis (figure).3 Individuals 11-6,11-7,111-1, and 111-2 (5-14% protein C activity, 5-16% protein C antigen) have had recurrent DVTs and PEs. No symptoms of thrombotic disease are evident in 11-1,11-3, and 11-4 (52-57% activity, 50-73% antigen), or in 11-5 (110% activity, 105% antigen). DNA fragments from 11-7 containing the nine exons and splice junctions of the protein C gene were amplified by the polymerase chain reaction and directly sequenced as described.4 A previously unidentified single nucleotide difference was found when his gene sequence was compared with that of the wild-types (a homozygous
576
C, Tirindelli MC, Mannucci PM, et al. Homozygous protein C deficiency with moderately severe clinical symptoms. Thromb Res 1986; 41: 483-88. 8. Petrini P, Segnestam K, Ekelund H, Egberg N. Homozygous protein C deficiency m two siblings. Ped Hematol Oncol 1990; 7: 165-75. 7 Sharon
Unilateral Pedigree of Middle Eastern family with autosomal recessive protein C deficiency. Shaded and semi-shaded symbols denote individuals shown to be homozygous or heterozygous, respectively, for the Ala 259-->Val substitution by DNA sequencing.
GCA-->GTA transition in exon nine with an alanine to valine substitution at position 259 within the catalytic domain). Other family members were homozygous (11-6, 111-1, and III-2) or heterozygous (11-1, 11-3, and 11-4) for this lesion. 11-5 was indistinguishable from wild-type. The thromboembolic disease and low plasma protein C concentrations in this family seem to be associated with homozygosity for the Ala 259-+Val substitution. The consanguinity of 11-1 and 11-2 is clear from the pedigree; this may also be inferred between individuals 11-3 and 11-4,1-3 and 1-4, and 1-5 and 1-6 since their progeny are homozygous for identicalby-descent alleles. Ala 259 is adjacent to one of the active site residues (Asp 257) of the catalytic triad in a tetrapeptide Asp-Ile-Ala-Leu, which is strictly conserved between the human vitamin-K-dependent factors protein C, prothrombin, and factors VII and IX. Secondary structure predictions indicate that substitution of Ala 259 severely disrupts the alpha-helical conformation of this region. The critical nature of this residue is further suggested by an analogous mutation in the factor IX gene (GCG-+GTG; Ala 271 --+Val)adjacent to the active site residue Asp 269, which results in severe (I% normal factor IX activity) haemophilia B. Our study is the first direct confirmation of homozygous protein C deficiency in adults by DNA sequencing. The recognition of distinct dominant and recessive forms of the disorder is most important for those counselling affected families. Inadequate phenotypic and genotypic analysis could lead to incorrect risk assessment. For those with the Ala 259 mutation, heterozygotes (both confirmed and inferred) are symptom-free despite possessing protein C concentrations characteristic of patients with the dominant form of the disease; homozygotes have a relatively late onset of symptoms. Our observations suggest that a residual amount of protein C activity is probably sufficient to prevent neonatal death but not recurrent venous thrombosis in adult life. Reduced protein C activities and antigen values among homozygotes are consistent with the reduced stability of the mutant protein. However, since the lesion has occurred in a highly conserved region of part of the catalytic triad, this phenotype might also be explained by increased protein C consumption as a result of enhanced zymogen activation. Other cases of late onset and moderately severe homozygous protein C deficiency (below 5-16% activity) have been reported 2,7,8 which may result from homozygosity for similar mis-sense mutations. Molecular genetic analysis will be an important method for diagnosis, assessing clinical outlook, and disease classification.
Unilateral
finger clubbing hemiplegia.
C. B. GRUNDY E. MELISSARI V. LINDO M. F. SCULLY V. V. KAKKAR D. N. COOPER
1. Tuddenham EGD, Tahase T, Thomas AE, et al. Homozygous protein C deficiency with delayed onset of symptoms at 7 to 10 months. Thromb Res 1989; 53: 475-84. 2. Tripodi A, Franchi F, Krachmalnicoff A, Mannucci PM. Asymptomatic homozygous protein C deficiency. Acta Haematol 1990; 83: 152-55. 3. Melissari E, Kakkar VV. Congenital severe protein C deficiency in adults. Br J Haematol 1989; 72: 222-28. 4. Grundy CB, Schulman S, Chisholm M, Kakkar W, Cooper DN. The molecular genetics of thrombophilia: characterisation of three missense mutations in the protein C gene. Hum Genet (m press). 5. Foster DC, Yoshitake S, Davie EW. The nucleotide sequence of the gene for human protein C. Proc Natl Acad Sci USA 1985; 82: 4673-77. 6. Koeberl DO, Bottema CDK, Ketterling RP, Bridge PJ, Lilicrap DP, Sommer SJ. Mutation causing hemophilia B: direct estimate of the underlying rates of spontaneous germ-line transitions, transversions, and deletions in a human gene. Am J Hum Genet 1990; 47: 202-17.
in
a
patient with profound right
other factors may be involved. For instance how would their hypothesis explain the finger clubbing that we have observed in association with ipsilateral dense hemiplegia? Case 1-A 65-year-old man had a stroke at the age of 41. No finger clubbing was present, and no coagulopathy was identified. During a recent admission for a further stroke, unilateral finger clubbing was noted in his right hand, which had remained almost immobile over the previous 24 years. Case 2-An 81-year-old man had a stroke at 61 years of age and was left with a profound right hemiplegia. During the next 20 years, striking finger clubbing developed in his right hand (figure). Although platelet microthrombi do occur in finger clubbing and hypotension together with sludging "would account only for the formation of whole blood thrombi", under certain flow conditions capillaries are not perfused with whole blood.1 Unilateral finger clubbing in dense hemiplegia implies that a local circulatory abnormality, rather than a generalised platelet defect might be the initiating factor in finger clubbing. The association of platelet microthrombi and finger clubbing may be coincidental rather than causal. University College and Middlesex Hospital Medical School, London W1 7PN, UK
SUSANNAH KAHTAN
Edgware General Hospital
NADJI KAHTAN
1. Samson Wright’s
Charter Molecular Genetics Laboratory, Thrombosis Research Institute, London SW3 6LR, UK
finger clubbing
SIR,-Dr Fox and colleagues (Aug 3, p 313) report the association between platelet microthrombi and finger clubbing. They suggest that the formation of these microthrombi, and the subsequent release of platelet-derived growth factor (PDGF), is important in the pathogenesis of this physical sign. Although their theory may be true for some cases of clubbing, there is evidence that
Applied Physiology. Keele CA, Neil E, Joels N, eds. Oxford OUP,
1984: 79.
Medical oncology in the 1990s SIR,-In its short life cancer chemotherapy has not enjoyed an easy acceptance among patients or physicians. A treatment aimed at the selective destruction of rapidly proliferating cells carries a serious risk to normal tissues and imposes a spectre of devastating side-effects. Many patients are not cured, some are harmed more than they are helped, and progress is slow via painstaking trials. Even those specialising in medical oncology have difficulty appreciating the progress that has been made. Dr Braverman (April 13, p 910) presents a pessimistic view. He concludes that "No disseminated neoplasm incurable in 1975 is curable today"; he labels much of the clinical trial effort as "make-work", hardly any current phase II trials are promising, he says, and the cooperative
foscamet to his maintenance ganciclovir. He died six months later of pneumonia with no evidence of active CMV disease. Case 2—A 39-year-old HIV-seropositive homosexual man was diagnosed as having bilateral CMV retinitis. He was treated successfully with ganciclovir 10 mg/kg per day for two weeks, which was maintained at 5 mg/kg per day for five consecutive days every week. Sixteen weeks later he was admitted with a six-day history of fever and hepatomegaly. Histological examination of the liver revealed focal areas of hepatocellular necrosis, which were highly suggestive of CMV infection; foscamet was added to his treatment regimen. His fever settled and his hepatomegaly resolved rapidly. Repeat histological examination of the liver showed neither focal necrosis nor evidence suggestive of persistent CMV infection. We support Nelson et al’s suggestion that refractory CMV retinitis may respond to combinaton treatment with ganciclovir and foscamet, and also suggest its use in CMV disease affecting other organs where sole therapy is ineffective. We also wish to emphasise the importance of being alert for other systemic signs of CMV infection despite apparent quiescence of retinal disease. R. J. COKER D. TOMLINSON P. HORNER C. MIGDAL J. R. W. HARRIS
Departments of Genitourinary Medicine and Ophthalmology, Jefferiss Wing, St Mary’s Hospital, London W2 1NY, UK
Sedative and
hypnotic withdrawal states in hospitalised patients
SIR,-Our psychiatric consultation service is located in a university teaching hospital and has encountered a noticeable rise in the cases of delirium among inpatients, which seems to be caused by sedative-hypnotic drug withdrawal. These observations have been made during a period when house staff were being warned against the routine prescription of benzodiazepines for night-time sedation. I will report one case that serves as a typical example. A 68-year-old woman was admitted to hospital for repair of a thoraco-abdominal aneurysm. On her sixth postoperative day, she became acutely agitated in the early evening. Psychiatric consultation revealed disorientation to place and time, extreme motor restlessness, paranoid delusions, and visual hallucinations. Further examination laboratory tests could
patient
was
was
unremarkable and
a
benefit. Review of the case-notes showed that the cardiovascular surgeon had prescribed lorazepam 2 mg for "insomnia secondary to pre-operative anxiety" about 12 weeks before admission. We thought that abrupt cessation had caused an acute benzodiazepine withdrawal. Haloperidol was discontinued and lorazepam 2 mg at bedtime was restarted. This patient’s delirium resolved within 24 h. She later confirmed that she had been taking lorazepam regularly for the 12 weeks before hospital admission. This case is typical of a growing difficulty among our inpatients and, I suspect, is not limited only to our institution. Not only should medical and surgical house staff be more discriminating in their prescription of sedative-hypnotic medications among inpatients, but they must also be vigilant as to the dangers of iatrogenic withdrawal states.1
JAY H. Moss
1. Sellers EM. Alcohol, barbiturate and benzodiazepine withdrawal
management. Can Med Assoc
J 1988; 139:
syndromes: clinical
113-20.
Treatment of anterior tibial artery occlusion SIR,-I was surprised that Dr Bannerjee and colleagues (June 29, 1603) believed that their approach to anterior tibial occlusion was either novel or an important advance. Cannulation of the tibial arteries for selective thrombolysis, augmented, when appropriate, by clot aspiration, has been a standard radiological technique for many years.’ Angiography completed with the type of fluoroscopic equipment available in many operating theatres is often less than satisfactory. There is limited capability for recording investigations
p
prolonged or to require multiple aspirations and long-term thrombolytic therapy. Such procedures have long been the province of the interventional radiologist and should continue to be be
so.
New
England
Deaconess
Hospital,
Boston, Massachusetts 02215, USA 1.
GEORGE G. HARTNELL
Traughber PD, Cook PS, Mieklos TV, Miller FJ. Intraarterial fibrinolytic therapy for popliteal and arterial obstruction: comparison of streptokinase and urokinase. AJR 1987; 149: 453-56.
SiR,—The quality of intra-operative angiograms may be inferior those obtained by conventional means, although failure to visualise vessels in the lower calf in a critically ischaemic limb by conventional angiography is well recognised. However, we use a simple technique of instillation of contrast medium into either the superficial femoral or profunda femoris arteries during in-flow occlusion. On no occasion have we failed to show the lower tibial and plantar arteries during screening. Our equipment (Phillips BV25 image intensifier) provides images of excellent quality, which may be stored on video (Phillips XTV5 HQ medical TV channel). Angiography after embolectomy will show incomplete clearance of thrombus, which requires further embolectomy, in up to 30% of cases.1 We disagree that angiography and thrombolysis are the sole province of the interventional radiologist. Vascular surgeons who undertake such procedures should, like us, work in collaboration with their radiological colleagues. Sadly, radiological support cannot be guaranteed—and, in the UK, its absence has been the main limitation to the widespread use of intra-arterial thrombolysisThat vascular surgeons have adopted procedures that they label as "minimal access" is hardly surprising, but they do so sound in the knowledge that they can proceed to an open operation in the event of failure or complications.
to
review of all
identify what caused the delirium. The given haloperidol 5 mg intramuscularly with little not
Sunnybrook Health Science Centre, Toronto, Ontario M4N 3M5, Canada
and the quality of the fluoroscopic image is frequently poorer than that available in conventional angiography suites. Although fluoroscopy may be a useful adjunct in an emergency if surgical embolectomy is only partly successful, a better result may be expected when selective angiography is completed with proper angiographic equipment and by experienced angiographers. This approach is especially important if the procedure is likely either to
Department of Surgery, Worcester Royal Infirmary, Worcester WR1 5AS, UK
ANJAN K. BANERJEE NICHOLAS HICKEY RICHARD DOWNING
1. Bosma HW, Jorning PJG. Intraoperative arteriography in arterial embolectomy. Eur J Vasc Surg 1990; 4: 469-72. 2. Browse DJ, Barr H, Torrie EPH, Galland RB. Limitations to the widespread usage of low dose intra-arterial thrombolysis. Eur J Vasc Surg 1991; 5: 445-49.
Late-onset
homozygous protein C deficiency
SiR,—The importance of protein C in haemostasis is shown by frequent occurrence of thrombotic disease in those with low plasma concentrations of this factor. Hereditary protein C deficiency is usually but not always transmitted as an autosomal dominant trait; heterozygotes are at risk for thrombophlebitis, deep vein thrombosis (DVT), and pulmonary embolism (PE). Although the homozygous deficiency state was thought to be incompatible with life, several adults are now known to have low plasma protein C
the
concentrations but with much milder symptoms or a later onset of disease.1,2 However formal proof of recessive inheritance requires confirmatory DNA sequencing. We have previously studied a Middle Eastern family with severe type I protein C deficiency and recurrent thrombosis (figure).3 Individuals 11-6,11-7,111-1, and 111-2 (5-14% protein C activity, 5-16% protein C antigen) have had recurrent DVTs and PEs. No symptoms of thrombotic disease are evident in 11-1,11-3, and 11-4 (52-57% activity, 50-73% antigen), or in 11-5 (110% activity, 105% antigen). DNA fragments from 11-7 containing the nine exons and splice junctions of the protein C gene were amplified by the polymerase chain reaction and directly sequenced as described.4 A previously unidentified single nucleotide difference was found when his gene sequence was compared with that of the wild-types (a homozygous
576
C, Tirindelli MC, Mannucci PM, et al. Homozygous protein C deficiency with moderately severe clinical symptoms. Thromb Res 1986; 41: 483-88. 8. Petrini P, Segnestam K, Ekelund H, Egberg N. Homozygous protein C deficiency m two siblings. Ped Hematol Oncol 1990; 7: 165-75. 7 Sharon
Unilateral Pedigree of Middle Eastern family with autosomal recessive protein C deficiency. Shaded and semi-shaded symbols denote individuals shown to be homozygous or heterozygous, respectively, for the Ala 259-->Val substitution by DNA sequencing.
GCA-->GTA transition in exon nine with an alanine to valine substitution at position 259 within the catalytic domain). Other family members were homozygous (11-6, 111-1, and III-2) or heterozygous (11-1, 11-3, and 11-4) for this lesion. 11-5 was indistinguishable from wild-type. The thromboembolic disease and low plasma protein C concentrations in this family seem to be associated with homozygosity for the Ala 259-+Val substitution. The consanguinity of 11-1 and 11-2 is clear from the pedigree; this may also be inferred between individuals 11-3 and 11-4,1-3 and 1-4, and 1-5 and 1-6 since their progeny are homozygous for identicalby-descent alleles. Ala 259 is adjacent to one of the active site residues (Asp 257) of the catalytic triad in a tetrapeptide Asp-Ile-Ala-Leu, which is strictly conserved between the human vitamin-K-dependent factors protein C, prothrombin, and factors VII and IX. Secondary structure predictions indicate that substitution of Ala 259 severely disrupts the alpha-helical conformation of this region. The critical nature of this residue is further suggested by an analogous mutation in the factor IX gene (GCG-+GTG; Ala 271 --+Val)adjacent to the active site residue Asp 269, which results in severe (I% normal factor IX activity) haemophilia B. Our study is the first direct confirmation of homozygous protein C deficiency in adults by DNA sequencing. The recognition of distinct dominant and recessive forms of the disorder is most important for those counselling affected families. Inadequate phenotypic and genotypic analysis could lead to incorrect risk assessment. For those with the Ala 259 mutation, heterozygotes (both confirmed and inferred) are symptom-free despite possessing protein C concentrations characteristic of patients with the dominant form of the disease; homozygotes have a relatively late onset of symptoms. Our observations suggest that a residual amount of protein C activity is probably sufficient to prevent neonatal death but not recurrent venous thrombosis in adult life. Reduced protein C activities and antigen values among homozygotes are consistent with the reduced stability of the mutant protein. However, since the lesion has occurred in a highly conserved region of part of the catalytic triad, this phenotype might also be explained by increased protein C consumption as a result of enhanced zymogen activation. Other cases of late onset and moderately severe homozygous protein C deficiency (below 5-16% activity) have been reported 2,7,8 which may result from homozygosity for similar mis-sense mutations. Molecular genetic analysis will be an important method for diagnosis, assessing clinical outlook, and disease classification.
Unilateral
finger clubbing hemiplegia.
C. B. GRUNDY E. MELISSARI V. LINDO M. F. SCULLY V. V. KAKKAR D. N. COOPER
1. Tuddenham EGD, Tahase T, Thomas AE, et al. Homozygous protein C deficiency with delayed onset of symptoms at 7 to 10 months. Thromb Res 1989; 53: 475-84. 2. Tripodi A, Franchi F, Krachmalnicoff A, Mannucci PM. Asymptomatic homozygous protein C deficiency. Acta Haematol 1990; 83: 152-55. 3. Melissari E, Kakkar VV. Congenital severe protein C deficiency in adults. Br J Haematol 1989; 72: 222-28. 4. Grundy CB, Schulman S, Chisholm M, Kakkar W, Cooper DN. The molecular genetics of thrombophilia: characterisation of three missense mutations in the protein C gene. Hum Genet (m press). 5. Foster DC, Yoshitake S, Davie EW. The nucleotide sequence of the gene for human protein C. Proc Natl Acad Sci USA 1985; 82: 4673-77. 6. Koeberl DO, Bottema CDK, Ketterling RP, Bridge PJ, Lilicrap DP, Sommer SJ. Mutation causing hemophilia B: direct estimate of the underlying rates of spontaneous germ-line transitions, transversions, and deletions in a human gene. Am J Hum Genet 1990; 47: 202-17.
in
a
patient with profound right
other factors may be involved. For instance how would their hypothesis explain the finger clubbing that we have observed in association with ipsilateral dense hemiplegia? Case 1-A 65-year-old man had a stroke at the age of 41. No finger clubbing was present, and no coagulopathy was identified. During a recent admission for a further stroke, unilateral finger clubbing was noted in his right hand, which had remained almost immobile over the previous 24 years. Case 2-An 81-year-old man had a stroke at 61 years of age and was left with a profound right hemiplegia. During the next 20 years, striking finger clubbing developed in his right hand (figure). Although platelet microthrombi do occur in finger clubbing and hypotension together with sludging "would account only for the formation of whole blood thrombi", under certain flow conditions capillaries are not perfused with whole blood.1 Unilateral finger clubbing in dense hemiplegia implies that a local circulatory abnormality, rather than a generalised platelet defect might be the initiating factor in finger clubbing. The association of platelet microthrombi and finger clubbing may be coincidental rather than causal. University College and Middlesex Hospital Medical School, London W1 7PN, UK
SUSANNAH KAHTAN
Edgware General Hospital
NADJI KAHTAN
1. Samson Wright’s
Charter Molecular Genetics Laboratory, Thrombosis Research Institute, London SW3 6LR, UK
finger clubbing
SIR,-Dr Fox and colleagues (Aug 3, p 313) report the association between platelet microthrombi and finger clubbing. They suggest that the formation of these microthrombi, and the subsequent release of platelet-derived growth factor (PDGF), is important in the pathogenesis of this physical sign. Although their theory may be true for some cases of clubbing, there is evidence that
Applied Physiology. Keele CA, Neil E, Joels N, eds. Oxford OUP,
1984: 79.
Medical oncology in the 1990s SIR,-In its short life cancer chemotherapy has not enjoyed an easy acceptance among patients or physicians. A treatment aimed at the selective destruction of rapidly proliferating cells carries a serious risk to normal tissues and imposes a spectre of devastating side-effects. Many patients are not cured, some are harmed more than they are helped, and progress is slow via painstaking trials. Even those specialising in medical oncology have difficulty appreciating the progress that has been made. Dr Braverman (April 13, p 910) presents a pessimistic view. He concludes that "No disseminated neoplasm incurable in 1975 is curable today"; he labels much of the clinical trial effort as "make-work", hardly any current phase II trials are promising, he says, and the cooperative
