208
1. Brenner MB, McLean J, Dialynas DP, et al. Identification of a putative second T-cell receptor. Nature 1986; 322: 145-49. 2. Haas W, Kaufman S, Martinez-A C. The development and function of &g r;&dgr; T cells. Immunology Today 1990; 11: 340-43. 3. Strominger JL. Developmental biology of T cell receptors. Science 1989; 244: 943-50. 4. Viney JL, MacDonald TT, Spencer J. Gamma/delta T cells in gut epithelium. Gut 1990; 31: 841-44. 5. Geisler C, Pallesen G, Platz P, et al. Novel primary thymic defect with T lymphocytes expressing the &g r;&dgr; T cell receptor. J Clin Pathol 1989; 42: 705-11. 6. Parker CM, Groh V, Band H, et al. Evidence for extrathymic changes in the T cell receptor &g r;&dgr; repertoire. J Exp Med 1990; 171: 1597-612. 7. Modlin RL, Pirmez C, Hofman FM, et al. Lymphocytes bearing antigen specific &g r;&dgr; T cell receptors accumulate in human infectious disease lesions. Nature 1989; 339: 544-48. 8. Falini B, Flenghi L, Pileri S, et al. Distribution of T cells bearing different forms of the T cell receptor &g r;&dgr; in normal and pathological human tissues. J Immunol 1989; 143: 2480-88. 9. Ohga S, Yoshikai Y, Takeda Y, Hiromatsu K, Nomoto K. Sequential appearance of gamma/delta and alpha/beta bearing T cells in the peritoneal cavity during an intraperitoneal infection with Listeria monocytogenes. Eur J Immunol 1990; 20: 553-58. 10. Carding SR, Allan W, Kyes S, Heyday A, Bottomley K, Doherty PC. Late dominance of the inflammatory process in murine influenza by &g r;&dgr; T cells. J Exp Med 1990; 172: 1225-32. 11. Balbi B, Moller DR, Kirby M, Holroyd KJ, Crystal RG. Increased numbers of T lymphocytes with &ggr;&dgr;-positive antigen receptors in a subgroup of individuals with pulmonary sarcoidosis. J Clin Invest 1990; 85: 1353-61.
The illusion of
intelligence
"The people have little intelligence, the great no heart if I had to choose I should have no hesitation in choosing the people"— ...
JEAN DE LA BRUYÈRE (1645-1690). is a sensitive matter. Debate this has been dominated by the nature-nurture century controversy-how much of our intelligence is genetically determined? Estimates vary, but somewhere between 50% and 80% seems reasonable for a developed society. Eysenckl described three forms of intelligence: biological (the genetic component); social (development of the genetic framework within an environment); and abilities measured in psychometric (specific psychological tests). However, all this presupposes that intelligence is a real and definable entity. Dr Michael Howe,zwriting in The Psychologist, questions this assumption. He argues that the concept of a general intelligence is "obsolete and counterproductive". He accepts that intelligence exists as a descriptive state--eg, a numerical value obtained from a psychometric test-but rejects the application of the word in an explanatory sense. Howe’s view, that intelligence measures performance but does not exist in its own right, has practical implications. It may be incorrect to assume that a child can learn only up to a measurable limit that is set by his or her degree of general intelligence. Although intelligence may describe an ability, it does not and cannot explain it. Howe cites examples of the way in which general intelligence can be dissociated from ability. Some people who have a remarkable capacity to learn languages or to complete mental arithmetic or calendar-date calculations have below average scores
Intelligence
psychometric tests. Thus, skill is not determined according to some general constraint inherent in an individual, but is unique for each action. Howe in
proposes that mental functions need to be broken
separately measurable units, although he acknowledges that this goal has not yet been achieved. Dr Ted Nettelbeck,3in attempting to demolish Howe’s proposition, fails to answer the central question-how can intelligence be assigned a predictive function when it is little more than a retrospective description of an individual’s ability to complete a given test? Intelligence may be illusory down into
after all. 1.
2.
Eysenck HJ. Speed of information processing, reaction time, and the theory of intelligence. In: Vemon PA, ed. Speed of information processing and intelligence. Norwood: Ablex, 1987: 21-67. Howe MJA. Does intelligence exist? Psychologist 1990; November.
490-93. 3. Nettelbeck T. 494-97.
Intelligence does exist. Psychologist 1990; November:
Exploiting angiogenesis A solid tumour is dependent on the continued growth of new blood vessels (angiogenesis) for its own enlargement-no tumour can grow beyond the size of a pin-head unless it is vascularised. In 1972, Folkman proposed that an antiangiogenic strategy might be a way to control tumour growth. At that time his idea was widely regarded as fanciful and generated unexpected hostility. Folkman noted that no one even asked for a reprint.’ However, the doubters were wrong and some of his critics have now become
competitors.2-8 Antiangiogenesis is no longer a theoretical possibility but a practical reality. Folkman’s pioneering studies on angiogenesis and antiangiogenesis stem from his original observations of 1962; he found that, in perfused organs, tumour cells grew to masses about 1-2 mm in diameter. These tiny tumours were viable. On injection into mice, they became vascularised and their growth was exponential. In 1971, he showed that to overcome the "prevascular stage" tumours produce a diffusible factor, which was named tumour angiogenesis factor (TAF). Folkman’s group have now shown that the intensity of angiogenesis correlates with metastasis in patients with breast carcinoma.9 Over the years the discoveries of Folkman and his colleagues have shed light on diverse areas such as cancer, arthritis, wound healing, and developmental biology. It is clear that formation of new blood vessels is a consequence of many events-for example, endothelial cell migration, proliferation, and synthesis of basement membrane. Mast cells are often seen at the tip of a budding blood vessel. It is reasonable to assume that interference with any of these critical events could deprive a tumour of its vasculature. Another paper from Folkman’s groups which we highlighted last month (Dec 22/29, p 1502), is the result of his ignoring a golden rule in tissue culture9-
209
ie, if a culture dish is contaminated, discard it or else the contaminant may spread to other cultures. When, in a culture dish of endothelial cells, fungal growth was seen to produce a local gradient of unhappy round cells, Folkman’s team in Boston, in collaboration with the Takeda Chemical Company of Japan, isolated the fungus. They purified the active principle, which was identified as fumagillin, an antibiotic used to treat amoebiasis in man. The fumagillin inhibited both proliferation of endothelial cells in vitro and vascularisation in vivo in a standard chicken egg assay. However, in tumour-bearing animals, effective doses were toxic. Their painstaking persistence with this work was ultimately richly rewarded, because they were able to synthesise a very potent analogue,
o-(chloroacetylcarbamoyl) fumagillol (AGM 1470), which was safe and effective in vitro and was found to cause few side-effects in vivo. In vitro, AGM 1470 inhibited the proliferation of endothelial cells but had no effect on tumour cells. Since systemic administration of this compound does not effect a cure, it is therefore envisaged that AGM 1470 would be a valuable adjuvant to conventional methods of cancer treatment. In an unpublished study in mice, Folkman found that administration of this agent significantly reduced the number of metastases. Other workers in this area include Tanaka and her group," who have found that synthetic laminin peptide has no effect on proliferation of endothelial cells but inhibits both their migration and tumour growth in vivo. Kumar has examined the effect of ’Krestin’, a protein-bound polysaccharide obtained from mycelia of Coriolus versicolor. 12,13 When this agent was administered systemically to rats it caused profound inhibition of tumour-induced angiogenesis in a dorsal sac assay. Krestin treatment had no effect on endothelial cell migration or proliferation in a separate study. Kumar and his colleagues (and, independently, at least two other groups) found that cromoglycate-a mast cell stabiliser-significantly inhibited tumour growth in mice.5,14,15 Maragoudakis and co-workers 16 have produced two inhibitors of basement membrane synthesis with pronounced antiangiogenic properties both in vitro and in vivo. Earlier in 1990, recombinant platelet factor 4 was found to inhibit proliferation of blood vessels in the chicken assay, and in-vitro studies suggested that the effect was due to inhibition of endothelial cell
proliferation. 17 1. Folkman J. How is blood vessel growth regulated in normal and neoplastic tissue? G. H. A. Clowes Memorial Award lecture. Cancer Res 1986; 46: 467-73. 2. Blood CH, Zetter BR. Tumour interaction with the vasculatures: angiogenesis and tumour metastasis. Biochem Biophys Acta 1990; 1032: 89-118. 3. Folkman J, Cotran RS. Relation of vascular proliferation to tumour growth. Int Rev Exp Pathol 1976; 16: 207-48. 4. Paweletz N, Kivierim M. Tumor-related angiogenesis. Clin Rev Oncol Hematol 1990; 9: 197-242. 5. Kumar S, Arnold F. Can metastasis be restrained? In: Stoll BA, ed. Breast cancer. Oxford: Blackwell, 1986: 287-99.
6. Pober
JS, Cotran RS. The role of endothelial cells
in
inflammation.
Transplantation 1990; 50: 537-44. 7. Kumar S, West DC, Ager A. Heterogeneity in endothelial cells from large vessels and microvessels. Differentiation 1987; 36: 57-70. 8. Kumar S. Angiogenesis and antiangiogenesis. JNCI 1979; 64: 683-87. 9. Weidner N, Semple JP, Welch WR, et al. Tumor angiogenesis and metastasis—correlation in invasive breast cancer. N Engl J Med 1991; 324: 1-8.
10.
Ingber D, Fujita T, Kishimoto S, et al. Synthetic analogues of fumigillin that inhibit angiogenesis and suppress tumour growth. Nature 1990;
348: 555-57. 11. Sakamoto N, Iwahana M, Tanaka NG, Osada Y. Inhibition of angiogenesis and tumour growth by a synthetic laminin peptide, CDPGYIGSR-NH2. Cancer Res (in press). 12. Kumar S. Modulation of tumour growth by a protein-bound plant polysaccharide.J Clin Res Clin Oncol 1990; 116: 872. 13. Kumar S. Control of tumour growth: endothelial cells as an alternative target. Anticancer Res 1990; 10: 1443-44. 14. Ionov ID. Mast cell-basophil system in tumour growth. Neurofibromatosis
1989; 2: 204-12.
Langer RS, Pless NA, Folkman J. Mast cells and tumour 1976; 18: 703-09. angiogenesis. Int Cancer J 16. Maragoudakis ME, Missirlis E, Karakiulakis G. Basement membrane biosynthesis as a target for developing inhibitors of angiogenesis with antitumour activity. Int J Rad Biol (in press). 17. Maione TE, Gray GS, Petro J, et al. Inhibition of angiogenesis by a recombinant human platelet factor-4 and related peptides. Science 15. Kessler DA,
1990; 247: 77-79.
Intensive
care
for the
elderly
"Last scene of all, ... is second childishness, and mere oblivion, sans teeth, sans eyes, sans taste, sans everything" -SHAKESPEARE; As you like it. ...
Shakespeare did not attach chronological ages to his description of senescence, but the author of the 90th psalm suggested that to prolong life beyond "threescore years and ten" was merely to extend "labour and sorrow". Today these poetic images may find expression in the often unformalised exclusion by clinicians of elderly patients from intensive care. But to what extent does a patient’s chronological age influence outcome from critical illness? This question is addressed in a retrospective review of the records of middle-aged (55-65 years) and elderly (> 75 years) patients admitted to a medical intensive care unit. Using the Apache II score minus age-weighting to correct for severity of illness, and logistic regression to correct for diagnosis and cancer, Wu and his colleagues show that chronological age does not seem to be an independent predictor of surviva1.1 This is an important finding, and one that begs further examination. Their results are supported by another investigation in which Apache scoring was used,2 although not by the originators of the score, who studied prospectively a much larger sample of medical and surgical patients.3 Other studies on this subject have not adopted sufficiently rigorous methods to separate the effects of severity of illness, chronic disease history, and diagnosis from those of age. For future work in this area, several important points should be borne in mind. First, studies should be prospective to avoid the difficulties of absent or poor quality data. Second, a large sample size is required to ensure adequate representation of the main medical and surgical diagnostic groups for
1. Brenner MB, McLean J, Dialynas DP, et al. Identification of a putative second T-cell receptor. Nature 1986; 322: 145-49. 2. Haas W, Kaufman S, Martinez-A C. The development and function of &g r;&dgr; T cells. Immunology Today 1990; 11: 340-43. 3. Strominger JL. Developmental biology of T cell receptors. Science 1989; 244: 943-50. 4. Viney JL, MacDonald TT, Spencer J. Gamma/delta T cells in gut epithelium. Gut 1990; 31: 841-44. 5. Geisler C, Pallesen G, Platz P, et al. Novel primary thymic defect with T lymphocytes expressing the &g r;&dgr; T cell receptor. J Clin Pathol 1989; 42: 705-11. 6. Parker CM, Groh V, Band H, et al. Evidence for extrathymic changes in the T cell receptor &g r;&dgr; repertoire. J Exp Med 1990; 171: 1597-612. 7. Modlin RL, Pirmez C, Hofman FM, et al. Lymphocytes bearing antigen specific &g r;&dgr; T cell receptors accumulate in human infectious disease lesions. Nature 1989; 339: 544-48. 8. Falini B, Flenghi L, Pileri S, et al. Distribution of T cells bearing different forms of the T cell receptor &g r;&dgr; in normal and pathological human tissues. J Immunol 1989; 143: 2480-88. 9. Ohga S, Yoshikai Y, Takeda Y, Hiromatsu K, Nomoto K. Sequential appearance of gamma/delta and alpha/beta bearing T cells in the peritoneal cavity during an intraperitoneal infection with Listeria monocytogenes. Eur J Immunol 1990; 20: 553-58. 10. Carding SR, Allan W, Kyes S, Heyday A, Bottomley K, Doherty PC. Late dominance of the inflammatory process in murine influenza by &g r;&dgr; T cells. J Exp Med 1990; 172: 1225-32. 11. Balbi B, Moller DR, Kirby M, Holroyd KJ, Crystal RG. Increased numbers of T lymphocytes with &ggr;&dgr;-positive antigen receptors in a subgroup of individuals with pulmonary sarcoidosis. J Clin Invest 1990; 85: 1353-61.
The illusion of
intelligence
"The people have little intelligence, the great no heart if I had to choose I should have no hesitation in choosing the people"— ...
JEAN DE LA BRUYÈRE (1645-1690). is a sensitive matter. Debate this has been dominated by the nature-nurture century controversy-how much of our intelligence is genetically determined? Estimates vary, but somewhere between 50% and 80% seems reasonable for a developed society. Eysenckl described three forms of intelligence: biological (the genetic component); social (development of the genetic framework within an environment); and abilities measured in psychometric (specific psychological tests). However, all this presupposes that intelligence is a real and definable entity. Dr Michael Howe,zwriting in The Psychologist, questions this assumption. He argues that the concept of a general intelligence is "obsolete and counterproductive". He accepts that intelligence exists as a descriptive state--eg, a numerical value obtained from a psychometric test-but rejects the application of the word in an explanatory sense. Howe’s view, that intelligence measures performance but does not exist in its own right, has practical implications. It may be incorrect to assume that a child can learn only up to a measurable limit that is set by his or her degree of general intelligence. Although intelligence may describe an ability, it does not and cannot explain it. Howe cites examples of the way in which general intelligence can be dissociated from ability. Some people who have a remarkable capacity to learn languages or to complete mental arithmetic or calendar-date calculations have below average scores
Intelligence
psychometric tests. Thus, skill is not determined according to some general constraint inherent in an individual, but is unique for each action. Howe in
proposes that mental functions need to be broken
separately measurable units, although he acknowledges that this goal has not yet been achieved. Dr Ted Nettelbeck,3in attempting to demolish Howe’s proposition, fails to answer the central question-how can intelligence be assigned a predictive function when it is little more than a retrospective description of an individual’s ability to complete a given test? Intelligence may be illusory down into
after all. 1.
2.
Eysenck HJ. Speed of information processing, reaction time, and the theory of intelligence. In: Vemon PA, ed. Speed of information processing and intelligence. Norwood: Ablex, 1987: 21-67. Howe MJA. Does intelligence exist? Psychologist 1990; November.
490-93. 3. Nettelbeck T. 494-97.
Intelligence does exist. Psychologist 1990; November:
Exploiting angiogenesis A solid tumour is dependent on the continued growth of new blood vessels (angiogenesis) for its own enlargement-no tumour can grow beyond the size of a pin-head unless it is vascularised. In 1972, Folkman proposed that an antiangiogenic strategy might be a way to control tumour growth. At that time his idea was widely regarded as fanciful and generated unexpected hostility. Folkman noted that no one even asked for a reprint.’ However, the doubters were wrong and some of his critics have now become
competitors.2-8 Antiangiogenesis is no longer a theoretical possibility but a practical reality. Folkman’s pioneering studies on angiogenesis and antiangiogenesis stem from his original observations of 1962; he found that, in perfused organs, tumour cells grew to masses about 1-2 mm in diameter. These tiny tumours were viable. On injection into mice, they became vascularised and their growth was exponential. In 1971, he showed that to overcome the "prevascular stage" tumours produce a diffusible factor, which was named tumour angiogenesis factor (TAF). Folkman’s group have now shown that the intensity of angiogenesis correlates with metastasis in patients with breast carcinoma.9 Over the years the discoveries of Folkman and his colleagues have shed light on diverse areas such as cancer, arthritis, wound healing, and developmental biology. It is clear that formation of new blood vessels is a consequence of many events-for example, endothelial cell migration, proliferation, and synthesis of basement membrane. Mast cells are often seen at the tip of a budding blood vessel. It is reasonable to assume that interference with any of these critical events could deprive a tumour of its vasculature. Another paper from Folkman’s groups which we highlighted last month (Dec 22/29, p 1502), is the result of his ignoring a golden rule in tissue culture9-
209
ie, if a culture dish is contaminated, discard it or else the contaminant may spread to other cultures. When, in a culture dish of endothelial cells, fungal growth was seen to produce a local gradient of unhappy round cells, Folkman’s team in Boston, in collaboration with the Takeda Chemical Company of Japan, isolated the fungus. They purified the active principle, which was identified as fumagillin, an antibiotic used to treat amoebiasis in man. The fumagillin inhibited both proliferation of endothelial cells in vitro and vascularisation in vivo in a standard chicken egg assay. However, in tumour-bearing animals, effective doses were toxic. Their painstaking persistence with this work was ultimately richly rewarded, because they were able to synthesise a very potent analogue,
o-(chloroacetylcarbamoyl) fumagillol (AGM 1470), which was safe and effective in vitro and was found to cause few side-effects in vivo. In vitro, AGM 1470 inhibited the proliferation of endothelial cells but had no effect on tumour cells. Since systemic administration of this compound does not effect a cure, it is therefore envisaged that AGM 1470 would be a valuable adjuvant to conventional methods of cancer treatment. In an unpublished study in mice, Folkman found that administration of this agent significantly reduced the number of metastases. Other workers in this area include Tanaka and her group," who have found that synthetic laminin peptide has no effect on proliferation of endothelial cells but inhibits both their migration and tumour growth in vivo. Kumar has examined the effect of ’Krestin’, a protein-bound polysaccharide obtained from mycelia of Coriolus versicolor. 12,13 When this agent was administered systemically to rats it caused profound inhibition of tumour-induced angiogenesis in a dorsal sac assay. Krestin treatment had no effect on endothelial cell migration or proliferation in a separate study. Kumar and his colleagues (and, independently, at least two other groups) found that cromoglycate-a mast cell stabiliser-significantly inhibited tumour growth in mice.5,14,15 Maragoudakis and co-workers 16 have produced two inhibitors of basement membrane synthesis with pronounced antiangiogenic properties both in vitro and in vivo. Earlier in 1990, recombinant platelet factor 4 was found to inhibit proliferation of blood vessels in the chicken assay, and in-vitro studies suggested that the effect was due to inhibition of endothelial cell
proliferation. 17 1. Folkman J. How is blood vessel growth regulated in normal and neoplastic tissue? G. H. A. Clowes Memorial Award lecture. Cancer Res 1986; 46: 467-73. 2. Blood CH, Zetter BR. Tumour interaction with the vasculatures: angiogenesis and tumour metastasis. Biochem Biophys Acta 1990; 1032: 89-118. 3. Folkman J, Cotran RS. Relation of vascular proliferation to tumour growth. Int Rev Exp Pathol 1976; 16: 207-48. 4. Paweletz N, Kivierim M. Tumor-related angiogenesis. Clin Rev Oncol Hematol 1990; 9: 197-242. 5. Kumar S, Arnold F. Can metastasis be restrained? In: Stoll BA, ed. Breast cancer. Oxford: Blackwell, 1986: 287-99.
6. Pober
JS, Cotran RS. The role of endothelial cells
in
inflammation.
Transplantation 1990; 50: 537-44. 7. Kumar S, West DC, Ager A. Heterogeneity in endothelial cells from large vessels and microvessels. Differentiation 1987; 36: 57-70. 8. Kumar S. Angiogenesis and antiangiogenesis. JNCI 1979; 64: 683-87. 9. Weidner N, Semple JP, Welch WR, et al. Tumor angiogenesis and metastasis—correlation in invasive breast cancer. N Engl J Med 1991; 324: 1-8.
10.
Ingber D, Fujita T, Kishimoto S, et al. Synthetic analogues of fumigillin that inhibit angiogenesis and suppress tumour growth. Nature 1990;
348: 555-57. 11. Sakamoto N, Iwahana M, Tanaka NG, Osada Y. Inhibition of angiogenesis and tumour growth by a synthetic laminin peptide, CDPGYIGSR-NH2. Cancer Res (in press). 12. Kumar S. Modulation of tumour growth by a protein-bound plant polysaccharide.J Clin Res Clin Oncol 1990; 116: 872. 13. Kumar S. Control of tumour growth: endothelial cells as an alternative target. Anticancer Res 1990; 10: 1443-44. 14. Ionov ID. Mast cell-basophil system in tumour growth. Neurofibromatosis
1989; 2: 204-12.
Langer RS, Pless NA, Folkman J. Mast cells and tumour 1976; 18: 703-09. angiogenesis. Int Cancer J 16. Maragoudakis ME, Missirlis E, Karakiulakis G. Basement membrane biosynthesis as a target for developing inhibitors of angiogenesis with antitumour activity. Int J Rad Biol (in press). 17. Maione TE, Gray GS, Petro J, et al. Inhibition of angiogenesis by a recombinant human platelet factor-4 and related peptides. Science 15. Kessler DA,
1990; 247: 77-79.
Intensive
care
for the
elderly
"Last scene of all, ... is second childishness, and mere oblivion, sans teeth, sans eyes, sans taste, sans everything" -SHAKESPEARE; As you like it. ...
Shakespeare did not attach chronological ages to his description of senescence, but the author of the 90th psalm suggested that to prolong life beyond "threescore years and ten" was merely to extend "labour and sorrow". Today these poetic images may find expression in the often unformalised exclusion by clinicians of elderly patients from intensive care. But to what extent does a patient’s chronological age influence outcome from critical illness? This question is addressed in a retrospective review of the records of middle-aged (55-65 years) and elderly (> 75 years) patients admitted to a medical intensive care unit. Using the Apache II score minus age-weighting to correct for severity of illness, and logistic regression to correct for diagnosis and cancer, Wu and his colleagues show that chronological age does not seem to be an independent predictor of surviva1.1 This is an important finding, and one that begs further examination. Their results are supported by another investigation in which Apache scoring was used,2 although not by the originators of the score, who studied prospectively a much larger sample of medical and surgical patients.3 Other studies on this subject have not adopted sufficiently rigorous methods to separate the effects of severity of illness, chronic disease history, and diagnosis from those of age. For future work in this area, several important points should be borne in mind. First, studies should be prospective to avoid the difficulties of absent or poor quality data. Second, a large sample size is required to ensure adequate representation of the main medical and surgical diagnostic groups for
