1001
stabilised.2Thirdly, apparent changes in size can take place because of platelet activation when a resistive-particle counter (eg, Coulter counter) is used (these may be induced in vitro by the addition of ADP and are inhibited by PGE1). Such changes are probably due to the formation of a "flock" effect by platelet pseudopodia. Thomas’ results may well relate to this point, although his findings do not exclude an EDTA effect. We believe that our observation that MPV is a risk factor for recurrent ischaemic heart events is based on platelet size. Our previous work, with citrate/PGEl as an anticoagulant, showed similar increases in MPV at the time of Ml.3 Furthermore, the larger platelets were denser than the smaller ones, containing more granules and mitochondria. (There is a positive linear relation between platelet density and MPV with validated methodology.’) Also, we used EDTA in our study of 1716 men under conditions when platelet swelling would have stabilised. Thomas suggests that small platelets might be selectively retained in the dependent limb. However, this is unlikely because larger platelets are more active and, hence, more likely to be consumed. Certainly in MI the whole platelet volume distribution curve is shifted to the right, compared with controls, without evidence of selective consumption.Thomas rightly says that we offer no data showing that pharmacological manipulation of megakaryocytes might alter outcome after MI. Megakaryocyte biology is in its infancy; only lately have preparative methods been developedand the polyploid nature of megakaryocytes makes long-term culture of the mature cell impossible at this time. Drugs that control platelet production will necessitate much more basic research on the mechanisms determining the differentiation of megakaryocytes. J. F. M. is British Heart Foundation professor of cardiovascular science. Department of Medicine, King’s College School of Medicine, London SE5 9PJ, UK
JOHN F. MARTIN
Blood Pressure Unit, St George’s Hospital, London SW17
PHILIP M. W. BATH
Medical Research Council,
Epidemiology Unit, Llandough Hospital,
MICHAEL L. BURR
Penarth
eds. Platelet heterogeneity: biology and pathology. 1990. 2. Trowbridge EA, Reardon DM, Hutchmson D, Pickering C. The routine measurement of platelet volume. a comparison of light-scattering and apenureimpedence technologies. Clin Phys Physiol Meas 1985; 6: 221-38. 3. Martin JF, Plumb J, Kilbey RS, Kishk YT. Changes m volume and density of platelets in myocardial infarction, Br Med J 1983; 287: 456-59 4. Martin JF, Shaw T, Heggie J, Penington DG. Measurement of the density of human platelets and its relationship to volume. Br J Haematol 1983, 54: 337-52. 5. Trowbridge EA, Martin JF The platelet volume distribution: a signature of the prethrombotic state in coronary heart disease? Thromb Haemostas 1987; 58: 714-17. 6. Gladwin AM, Carrier MJ, Beesley JE, Lelchuk R, Hancok V, Martin JF. Identification of mRNA for PDGF B-chain in human megakaryocytes isolated using a novel immunomagnetic separation method. Br J Haematol 1990, 76: 333-39. 1 Martin JF, London
Trowbridge A, Spnnger-Verlag,
Pyramidal tract signs and Parkinson’s disease SIR,-Professor De Keyser and colleagues’ (Jan 18, p 149) report of two cases of so-called idiopathic hemiparetic parkinsonism raises several issues. One concerns their statement that in Parkinson’s disease the plantar response is flexor. Several studies have opposed this view. In a clinical study Babinski’s sign was present in 33 (45%) of 73 patients who had not had stereotactic surgery. In another study,> this sign was found in 57 (19%) of 295 patients with Parkinson’s disease, and seemed to be a marker of poor outlook in an actuarial study of survival. Selby3 writes that although deep tendon reflexes "are never pathologically increased in Parkinson’s disease, extensor plantar responses ... have been noted by many observers in a small proportion of cases". Indeed, these observations are based on clinical studies-ie, the examination of patients fulfilling clinical criteria for Parkinson’s disease. The reliability of the clinical diagnosis of Parkinson’s disease has lately been challenged.’ However, Bernheimer et aP showed that "pyramidal signs" were present in 6 (15%) of 39 pathologically-proven cases of Parkinson’s disease. Clearly, as Ward and Gibbstated, "prospective
are needed, with information not recording the presence or absence of the cardinal triad of bradykinesia, rigidity and tremor". Present knowledge does not allow the assertion that "pyramidal signs should not be present in idiopathic parkinsonism".
clinicopathological correlations restricted to
Service of Diseases of the Nervous System,
Hôpital Tenon, 75020 Paris, France
GILLES FÉNELON ALAIN GUILLARD
WE, Loewenson RB, Resch JA, Baker AB. Parkinson’s disease: clinical analysis of 100 patients. Neurology 1973; 23: 783-90. Guillard A, Chastang C, Fénelon G Etude à long terme de 416 cas de maladie de Parkinson, facteurs de pronostic et implications thérapeutiques. Rev Neurol
1. Martin 2.
(Paris) 1986; 142: 207-14. 3.
Selby G. Clinical features. In: Stem, ed. Parkinson’s disease. London: Chapman and
Hall, 1990: 333-88. 4. Daniel SE, Lees AJ. Neuropathological features of Alzheimer’s disease in nondemented parkinsonian patients. J Neural Neurosurg Psychiatry 1991; 54: 972-75. 5. Bernheimer H, Birkmayer W, Hornykiewicz O, Jellinger K, Seitelberger F. Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations. J Neurol Sci 1973; 20: 415-55. 6. Ward CD, Gibb WR. Research diagnostic criteria for Parkinson’s disease. In: Streifler MB, Korczyn AD, Melamed E, Youdim MBH, eds. Advances in neurology, vol 53. Parkinson’s disease: anatomy, pathology and therapy. New York: Raven, 1990: 245-49.
Low serum cholesterol and suicide SiR,—Dr Engelberg (March 21, p 727) suggests that the increased rates
of suicide and other violent death observed in cholesterol-
lowering trials’ could be explained by alterations in mood or behaviour arising from a reduced expression of serotonin receptors in brain cell membranes. Such a reduction in receptors, it is argued, could result from a decreased cholesterol content in membranes, brought about by the fall in serum cholesterol. This hypothesis overlooks the basic cellular mechanisms of cholesterol homoeostasis. Cholesterol has an important influence on membrane fluidity and permeability and the activities of integral proteins. Indeed, so important is cholesterol that cells have evolved highly ordered regulatory mechanisms to maintain membrane cholesterol levels in the face of extracellular fluctuations. These include the coordinated regulation of intracellular synthesis of cholesterol and receptormediated uptake of low-density lipoprotein (LDL), the principal cholesterol carrier in the extracellular medium.2.3 Thus a fall in cholesterol supply leads to an increase in LDL receptors displayed at the cell surface (to enhance cholesterol uptake) and stimulation of intracellular cholesterol synthesis. The reductions in serum cholesterol achieved in the clinical trials were in the range 8.5-13.6%1-ie, to concentrations that remain within the normal physiological range for the populations studied, and which are well above those in undeveloped communities. Reductions of this magnitude, which still leave an abundant supply of plasma cholesterol for cellular needs, seem very unlikely to have the capacity to compromise the ability of the LDL receptor and synthetic compensatory mechanisms to protect the brain cell from membrane malfunction. If there really is a relation between small reductions in serum cholesterol and death by suicide, accident, and murder, the explanation must be sought elsewhere. Department of Cardiac Medicine, National Heart and Lung Institute, London SW3 6LY, UK
N. J. SEVERS
1. Muldoon MF, Manuck
SB, Matthews KA. Lowenng cholesterol concentrations and mortality: a quantitative review of primary prevention trials. Br Med J 1990; 301: 309-14.
Mahley RW, Innerarity TL. Lipoprotein receptors and cholesterol homeostasis. Biochim Biophys Acta 1983; 737: 197-222. 3. Goldstein JL, Brown MS, Anderson RGW, Russel DW, Schneider WJ. Receptormediated endocytosis: concepts emerging from the LDL receptor system. Annu
2.
Rev Cell Biol 1985, 1: 1-39.
SIR,-Dr Engelberg proposes a neurophysiological explanation for a link between both low and lowered serum cholesterol and death from suicide and violence. This association is apparent in the review by Muldoon et all of lipid-lowering trials but not in long-term observational studies.2,3 In a meta-analysis of primary prevention trials, where dietary and drug interventions to lower serum cholesterol were considered separately, the pooled odds ratios (treatment vs control) for death by injury were 1 ’20 (95% CI
stabilised.2Thirdly, apparent changes in size can take place because of platelet activation when a resistive-particle counter (eg, Coulter counter) is used (these may be induced in vitro by the addition of ADP and are inhibited by PGE1). Such changes are probably due to the formation of a "flock" effect by platelet pseudopodia. Thomas’ results may well relate to this point, although his findings do not exclude an EDTA effect. We believe that our observation that MPV is a risk factor for recurrent ischaemic heart events is based on platelet size. Our previous work, with citrate/PGEl as an anticoagulant, showed similar increases in MPV at the time of Ml.3 Furthermore, the larger platelets were denser than the smaller ones, containing more granules and mitochondria. (There is a positive linear relation between platelet density and MPV with validated methodology.’) Also, we used EDTA in our study of 1716 men under conditions when platelet swelling would have stabilised. Thomas suggests that small platelets might be selectively retained in the dependent limb. However, this is unlikely because larger platelets are more active and, hence, more likely to be consumed. Certainly in MI the whole platelet volume distribution curve is shifted to the right, compared with controls, without evidence of selective consumption.Thomas rightly says that we offer no data showing that pharmacological manipulation of megakaryocytes might alter outcome after MI. Megakaryocyte biology is in its infancy; only lately have preparative methods been developedand the polyploid nature of megakaryocytes makes long-term culture of the mature cell impossible at this time. Drugs that control platelet production will necessitate much more basic research on the mechanisms determining the differentiation of megakaryocytes. J. F. M. is British Heart Foundation professor of cardiovascular science. Department of Medicine, King’s College School of Medicine, London SE5 9PJ, UK
JOHN F. MARTIN
Blood Pressure Unit, St George’s Hospital, London SW17
PHILIP M. W. BATH
Medical Research Council,
Epidemiology Unit, Llandough Hospital,
MICHAEL L. BURR
Penarth
eds. Platelet heterogeneity: biology and pathology. 1990. 2. Trowbridge EA, Reardon DM, Hutchmson D, Pickering C. The routine measurement of platelet volume. a comparison of light-scattering and apenureimpedence technologies. Clin Phys Physiol Meas 1985; 6: 221-38. 3. Martin JF, Plumb J, Kilbey RS, Kishk YT. Changes m volume and density of platelets in myocardial infarction, Br Med J 1983; 287: 456-59 4. Martin JF, Shaw T, Heggie J, Penington DG. Measurement of the density of human platelets and its relationship to volume. Br J Haematol 1983, 54: 337-52. 5. Trowbridge EA, Martin JF The platelet volume distribution: a signature of the prethrombotic state in coronary heart disease? Thromb Haemostas 1987; 58: 714-17. 6. Gladwin AM, Carrier MJ, Beesley JE, Lelchuk R, Hancok V, Martin JF. Identification of mRNA for PDGF B-chain in human megakaryocytes isolated using a novel immunomagnetic separation method. Br J Haematol 1990, 76: 333-39. 1 Martin JF, London
Trowbridge A, Spnnger-Verlag,
Pyramidal tract signs and Parkinson’s disease SIR,-Professor De Keyser and colleagues’ (Jan 18, p 149) report of two cases of so-called idiopathic hemiparetic parkinsonism raises several issues. One concerns their statement that in Parkinson’s disease the plantar response is flexor. Several studies have opposed this view. In a clinical study Babinski’s sign was present in 33 (45%) of 73 patients who had not had stereotactic surgery. In another study,> this sign was found in 57 (19%) of 295 patients with Parkinson’s disease, and seemed to be a marker of poor outlook in an actuarial study of survival. Selby3 writes that although deep tendon reflexes "are never pathologically increased in Parkinson’s disease, extensor plantar responses ... have been noted by many observers in a small proportion of cases". Indeed, these observations are based on clinical studies-ie, the examination of patients fulfilling clinical criteria for Parkinson’s disease. The reliability of the clinical diagnosis of Parkinson’s disease has lately been challenged.’ However, Bernheimer et aP showed that "pyramidal signs" were present in 6 (15%) of 39 pathologically-proven cases of Parkinson’s disease. Clearly, as Ward and Gibbstated, "prospective
are needed, with information not recording the presence or absence of the cardinal triad of bradykinesia, rigidity and tremor". Present knowledge does not allow the assertion that "pyramidal signs should not be present in idiopathic parkinsonism".
clinicopathological correlations restricted to
Service of Diseases of the Nervous System,
Hôpital Tenon, 75020 Paris, France
GILLES FÉNELON ALAIN GUILLARD
WE, Loewenson RB, Resch JA, Baker AB. Parkinson’s disease: clinical analysis of 100 patients. Neurology 1973; 23: 783-90. Guillard A, Chastang C, Fénelon G Etude à long terme de 416 cas de maladie de Parkinson, facteurs de pronostic et implications thérapeutiques. Rev Neurol
1. Martin 2.
(Paris) 1986; 142: 207-14. 3.
Selby G. Clinical features. In: Stem, ed. Parkinson’s disease. London: Chapman and
Hall, 1990: 333-88. 4. Daniel SE, Lees AJ. Neuropathological features of Alzheimer’s disease in nondemented parkinsonian patients. J Neural Neurosurg Psychiatry 1991; 54: 972-75. 5. Bernheimer H, Birkmayer W, Hornykiewicz O, Jellinger K, Seitelberger F. Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations. J Neurol Sci 1973; 20: 415-55. 6. Ward CD, Gibb WR. Research diagnostic criteria for Parkinson’s disease. In: Streifler MB, Korczyn AD, Melamed E, Youdim MBH, eds. Advances in neurology, vol 53. Parkinson’s disease: anatomy, pathology and therapy. New York: Raven, 1990: 245-49.
Low serum cholesterol and suicide SiR,—Dr Engelberg (March 21, p 727) suggests that the increased rates
of suicide and other violent death observed in cholesterol-
lowering trials’ could be explained by alterations in mood or behaviour arising from a reduced expression of serotonin receptors in brain cell membranes. Such a reduction in receptors, it is argued, could result from a decreased cholesterol content in membranes, brought about by the fall in serum cholesterol. This hypothesis overlooks the basic cellular mechanisms of cholesterol homoeostasis. Cholesterol has an important influence on membrane fluidity and permeability and the activities of integral proteins. Indeed, so important is cholesterol that cells have evolved highly ordered regulatory mechanisms to maintain membrane cholesterol levels in the face of extracellular fluctuations. These include the coordinated regulation of intracellular synthesis of cholesterol and receptormediated uptake of low-density lipoprotein (LDL), the principal cholesterol carrier in the extracellular medium.2.3 Thus a fall in cholesterol supply leads to an increase in LDL receptors displayed at the cell surface (to enhance cholesterol uptake) and stimulation of intracellular cholesterol synthesis. The reductions in serum cholesterol achieved in the clinical trials were in the range 8.5-13.6%1-ie, to concentrations that remain within the normal physiological range for the populations studied, and which are well above those in undeveloped communities. Reductions of this magnitude, which still leave an abundant supply of plasma cholesterol for cellular needs, seem very unlikely to have the capacity to compromise the ability of the LDL receptor and synthetic compensatory mechanisms to protect the brain cell from membrane malfunction. If there really is a relation between small reductions in serum cholesterol and death by suicide, accident, and murder, the explanation must be sought elsewhere. Department of Cardiac Medicine, National Heart and Lung Institute, London SW3 6LY, UK
N. J. SEVERS
1. Muldoon MF, Manuck
SB, Matthews KA. Lowenng cholesterol concentrations and mortality: a quantitative review of primary prevention trials. Br Med J 1990; 301: 309-14.
Mahley RW, Innerarity TL. Lipoprotein receptors and cholesterol homeostasis. Biochim Biophys Acta 1983; 737: 197-222. 3. Goldstein JL, Brown MS, Anderson RGW, Russel DW, Schneider WJ. Receptormediated endocytosis: concepts emerging from the LDL receptor system. Annu
2.
Rev Cell Biol 1985, 1: 1-39.
SIR,-Dr Engelberg proposes a neurophysiological explanation for a link between both low and lowered serum cholesterol and death from suicide and violence. This association is apparent in the review by Muldoon et all of lipid-lowering trials but not in long-term observational studies.2,3 In a meta-analysis of primary prevention trials, where dietary and drug interventions to lower serum cholesterol were considered separately, the pooled odds ratios (treatment vs control) for death by injury were 1 ’20 (95% CI
