- Email: [email protected]
FIBRINOLYSIS IN OBESITY
1205
of 49Ca. There should be little difficulty in reducing both the irradiation time and the delay before the induced activity is measured. Several shorter measurements of body radioactivity might be preferable to one or two longer ones, and there seems to be no reason why quite accurate measurements of total body-calcium should not be made, using a phantom containing a dummy skeleton of known calcium content as a standard. This would be of considerable value in studies of various bone disorders and of the action of drugs. Body-nitrogen too can probably be estimated by neutron activation, for the annihilation radiation (0-511 meV) associated with the decay of 13N can be measured in the whole-body counter. 24Na, 38 Cl, and 49Ca are all produced by capture of thermal neutrons by the stable isotopes ; whereas I3N is produced by a fast neutron reaction, and the optimum conditions for uniformity of production in the body would be quite different from those used in this study. It would be necessary to allow for contributions from other short-lived positron emitters produced by fast neutron reactions-especially 3smK (halflife 7-7 minutes). This might be practicable if the decay of the activity at 0.51 meV were followed and the component with the 10-minute half-life extracted. Determinations of body-nitrogen could prove valuable in detecting a rise in body-nitrogen in patients with gout. Changes in total body-protein would be reflected in this parameter, thus allowing assessment of muscle wasting and malnutrition. Detection of abnormal deposits of other elements, such as copper, might also be possible. The technique enables certain elements, both in the circulation and in cells, to be labelled rapidly and in situ. Thus studies of ion transfer from tissue to blood may become possible in animals. Improvements in detection and irradiation techniques would enable similar studies to be made in man. If this new technique is to be of clinical value, the total radiation dose to the subject must be as small as possible-certainly no greater than is acceptable in diagnostic radiology. Our two subjects each received about 0-1rad, spread fairly uniformly over the body surface. By comparison the radiation dose resulting from the complete decay of all the induced radioactivity was very small (about 0-05 mrad.). The neutron irradiation gave a whole-body dose to the subject of about 1 rem, assuming a Quality Factor of 10 (I.C.R.P. 1963). The average skin dose received during the barium-meal examinations reported by the Adrian Committee was about 22 rem (Osborn 1963), so there need be no greater reluctance to subjecting a patient to this neutron irradiation than to performing a barium-meal examination.
Summary Neutron-activation analysis has been performed in vivo on man, using radiation doses small enough to be comparable with those used in diagnostic radiology. The induced radioactivity enabled estimates to be made of the total body sodium, chlorine, and calcium in two subjects. For sodium and chlorine, the values obtained differ from those reported in the literature as obtained by standard analytical techniques. Within experimental error, the total body sodium is found to be the same as the exchangeable sodium pool determined by isotope dilution. Future developments of this technique are discussed. We are very grateful for the help given by the operating personnel of the Cockcroft-Walton neutron generator at the Atomic Energy Research Establishment and by Mr. A. Holmes and Mr. L. J. Bunce. We gratefully acknowledge the many helpful discussions with Mr. N. G.
Stewart, Mr. D. H. Peirson, and Mr. J. A. Dennis of A.E.R.E., and with Mr. W. N. Saxby and Mr. E. W. Jones of the Atomic Weapons Research Establishment. Aldermaston, who also carried out preliminary measurements. This work would not have been possible without the help and interest of Dr. R. Spence, director of the Atomic Energy Research Establishment, the Marquess of Normanby, chairman of the board of governors, King’s College Hospital, and Dr. Vernon F. Hall, dean of King’s College Hospital Medical School. REFERENCES I. S., James, A. H., Baden, H., Moore, F. D. (1954) J. clin. Invest. 33, 122. Forbes, G. B., Lewis, A. M. (1956) ibid. 35, 596. Grove, E. L., Scott, C. W. (1957) Progress report: Determination of sodium and potassium in animal tissue by flame photometry. Oak Ridge
Edelman,
National Laboratory, unpublished data, quoted by International Commission on Radiological Protection (1959). Hine, G. J., Jagger, P. I., Burrows, B. A. (1962) in Whole Body Counting. International Atomic Energy Agency, Vienna. Hoffman, J. G., Hempelmann, L. H. (1957) Amer. J. Roentgenol. 77, 144. Hurst, G. S., Ritchie, R. H., Emerson, L. C. (1959) Hlth Phys. 2, 121. International Commission on Radiological Protection (1959) Report of Committee II on Permissible Dose for Internal Radiation. London. (1960) Report of Committee III on Protection Against X-rays up to Energies of 3 MeV and Beta- and Gamma-Rays from Sealed Sources. London. (1963) Report of Committee IV on Protection Against Electromagnetic Radiation Above 3 MeV and Electrons, Neutrons and Protons. London. Miller, H., Munro, D. S., Wilson, G. M. (1957) Lancet, i, 734. Osborn, S. B. (1963) Brit. J. Radiol. 36, 230. Richmond, C. R. (1958) Los Alamos Scientific Laboratory Report LA-2207. Rundo, J. (1958) Proceedings of the 2nd U.N. Conference on Peaceful Uses of Atomic Energy, 23, 101. Smith, J. W. (1962) Phys. Med. Biol. 7, 341. Smith, J. W., Boot, S. J. (1962) ibid. p. 45. Widdowson, E. M., McCance, R. A., Spray, C. M. (1951) Clin. Sci. 10, 113. —
—
FIBRINOLYSIS IN OBESITY D. OGSTON M.B., Ph.D. Aberd., M.R.C.P.E. LECTURER IN MEDICINE
G. M. MCANDREW M.B. Aberd., M.R.C.P.E. LECTURER IN MEDICINE
DEPARTMENT OF
MEDICINE,
UNIVERSITY OF
ABERDEEN,
AND ABERDEEN ROYAL INFIRMARY
OBESITY and fibrinolytic activity are inversely correlated (Goldrick 1961, Shaw and MacNaughton 1963), and Ogston (1962) noted diminished fibrinolysis in overweight patients who had had cardiac infarction. We now report further observations on fibrinolysis in lean and obese persons. Methods and Material
Plasma Fibrinolytic Activity Venous-blood samples were withdrawn with minimal stasis, between 7.30 and 8.30 A.M. The fibrinogen and plasminogen were not always estimated. Euglobulin clot-lysis times were estimated by the method of Nilsson and Olow (1962), and expressed by plotting the values logarithmically against units of fibrinolytic activity (Sherry et al. 1959), 10 units being arbitrarily equated with a lysis-time of 50 minutes. Lysis-times greater than 500 minutes were taken as 1 unit.
Plasma-fibrinogen Fibrinogen was
estimated of Nilsson and Olow (1962).
by
a
modification of the method
Plasma-plasminogen ) Plasminogen levels were estimated by the method of Remmert and Cohen (1949) as modified by Alkjaersig et al. (1959). Assessment of Obesity Height was measured to the nearest 1/4 in. (0-6 cm.), and weight to the nearest 1/4 lb. (0’11 kg.). The ratio of observed to standard weight was calculated according to the weight-forheight standards of Kemsley et al. (1962). This ratio is closely correlated with relative adiposity as estimated by body-density measurements. No age-adjustment was made to the standard weights. The body-weight of the 14 subjects who were grossly obese (ratio over 160) ranged from 191 to 377 lb. (86-6 to 171.0 kg.) with a mean of 250 lb. (113.4 kg.).
1206
subjects are in the normal elevated, some strikingly so. Few of the raised levels could be explained by infection, neoplastic disease, or tissue necrosis.
a
few of the values for the obese
range, many
are
Effect of Diet
Fig. 1-Relationship between fibrinolytic activity and observed/ standard weight ratio.
Subjects The subjects of high observed/standard weight ratio were mainly patients admitted to hospital for weight reduction by diet. Most of those with a ratio under 130 were hospital patients with minor disorders which could not affect fibrinolysis. A few members of the medical staff and students were
also included. The total number of the series
was
41.
Diets Two standard dietary regimens were used. The 140 kcal. diet comprised two oranges daily. The 600 kcal. diet was a standard hospital reducing regimen. 2 patients received the 600 kcal. in the form ofMetercal’.’. Unlimited water was allowed. TABLE I-MEAN FIBRINOLYTIC
VALUES,
IN
SUBJECTS
ACTIVITY, FIBRINOGEN AND PLASMINOGEN
OF DIFFERING
OBSERVED/STANDARD
WEIGHT
RATIO
Exercise The exercise stimulus consisted of 3 minutes’ continuous activity on standard step-up equipment, equivalent to ascending and descending a height of 54 feet (16-5 metres). This period was chosen as the maximum tolerated by the grossly obese subjects. Blood-samples were obtained immediately before and after the exercise, and a third after 30 minutes’ rest.
Fig.
Results 1 shows the inverse relation between
fibrinolysis
and observed/standard weight ratio. The mean fibrinolytic activity of the subjects with a ratio of 88-129 was 4-7 units; that of the moderately obese subjects (observed/standard weight ratio 130-160) was 2-9 units; while for the grossly obese subjects (observed/standard weight ratio over 160) it was 1.3 units. The difference between the mean fibrinolytic activity of the grossly obese subjects and of those with normal physique was highly significant (p < 0-001); while that between the moderately obese and the normal subjects was also significant (p < 001). There was no significant difference between the mean plasminogen-levels of the three groups of subjects classified by weight ratio and, conversely, by fibrinolytic activity; but mean fibrinogen levels were greater .in the grossly obese subjects (p < 0-001), and in the moderately obese subjects (p < 0’01) (see table i). Fig. 2 illustrates the individual fibrinogen values. While
To determine the effect of weight reduction on fibrinolysis in the obese, 4 subjects with high observed/standard weight ratio were investigated before and during a period of dietary restriction sufficient to induce rapid weight loss. 2 who received 140 kcal. per day had substantially increased fibrinolytic activity (3 and 4, table 11). 2 others (weight ratios 205 and 206) were given 600 kcal. diets (metercal); their weight loss was slower than that of the subjects on a 140 kcal. diet, and their fibrinolytic activities remained below 1 unit until the 19th day when they rose to 2.2 and 2.1
units, theirweights having fallen by 16 and 15 lb. (7-3 and 6-8 kg.). A subject with initial weight ratio was observed for 4 months. His weight change and fibrinolytic
activity during this period are illustrated in fig. 3.
Fibrinolysis increased strikingly Fig. 2-Relationship between fibrinogen during rapid and observed/standard weight ratio. weight loss, first on a 140 kcal. diet, and later on one of 600 kcal. As the rate of weight loss declined, fibrinolytic activity began to fall again. After discharge he continued nominally on a diet of 600 kcal., but did not adhere to this exactly. After a period of slow, and latterly of absent, weight loss fibrinolytic activity fell to about the pre-diet level. He remained grossly overweight (weight ratio 190) despite having lost 39 lb. (17-7 kg.). To determine whether diet-induced weight loss produces increased fibrinolysis in those with a lower weight ratio, 2 such subjects were restricted to a diet of 140 kcal. for 3 days (1 and 2, table n). The increased fibrinolysis was of the same magnitude as that for the 2 obese subjects on a similar diet. Thus increased fibrinolysis during weight loss must be due to metabolic factors in both obese and normal persons. The levels of plasminogen and fibrinogen did not fluctuate during weight loss; alternation of these factors, therefore, did not contribute to the observed changes in
fibrinolysis. TABLE II-CHANGE IN FIBRINOLYTIC ACTIVITY INDUCED BY DIET
140 kcal.
1207
Effectof Physical
changes of starvation rather than with the degree of weight reduction. We wonder whether the increased fibrinolysis produced in obese subjects by fasting persists when they have achieved, and are maintaining, their ideal body-weight. In contrast to the similar increase in fibrinolysis in both obese and normal persons during weight loss, the stimulus of exercise produces a smaller response in the obese than in those of normal physique. This suggests that these two stimuli increase fibrinolysis by different mechanisms, and bolic
Exertion
Physical effort creases
infibri-
nolysis (Biggs et al. 1947, Ogston and Fullerton
1961).
that some factor in obese persons interferes with one of these mechanisms. Obesity is statistically associated with an increased incidence of occlusive vascular disease (Dawber et al. 1957). Diminished fibrinolysis in the obese may contribute to this association.
To
determine whether the initially low
fibrinolytic activity of
Summary
obese persons increases with exercise, the
fibrinolytic response to
a
standard exercisee stimulus was compared in 4 obese and 3 normal sub-
Fig. 3-Alterations in body-weight and fibrinolytic activity during dietary restriction in one subject.
Plasma fibrinolysis was diminished in obese subjects, some of whom had hypernbrinogensemia, plasminogen levels were normal. Lean and obese persons showed a similarly increased fibrinolysis during rapid weight loss induced by dietary restriction. Fibrinolysis was enhanced by physical exertion less in the obese than in the lean. We are grateful to Dr. J. M. Stowers and Dr. T. N. Morgan for permission to study patients in their care, and to Prof. H. W. Fullerton for helpful advice.
jects. Table
ill shows that obese subjects, despite the greater work entailed by their exercise, had less increase in fibrinolysis than those of normal physique, and 1 of the obese had no increase at all. After 30 minutes’ rest the fibrinolytic activity of both groups fell towards their preexercise level, but this fall in the obese subjects was less pronounced, both absolutely and relatively, than in those of normal phvsioue. discussion
-
This study has confirmed the finding of Goldrick (1961) and Shaw and MacNaughton (1963) that plasma fibrinolysis is diminished in the obese. Some obese persons also have hypernbrinogensemia. Euglobulin clots formed in a high concentration of fibrinogen are more resistant to lysis, and the diminished fibrinolysis may be partly due to this relationship. However, since some of the obese subjects with normal fibrinogen levels had low fibrinolytic activity, this relationship cannot be the sole explanation. The results also indicate that diminished fibrinolysis is not due to plasminogen deficiency. Dietary restriction sufficient to cause rapid weight loss was found to increase fibrinolysis in both normal and obese persons, but only while the weight loss continued. Hence fibrinolysis is probably associated with the metaTABLE III-EFFECT OF EXERCISE ON FIBRINOLYTIC ACTIVITY IN OBESE AND NORMAL
SUBJECTS
REFERENCES
Alkjaersig, N., Fletcher, A. P., Sherry, S. (1959) J. clin. Invest. 38, 1086. Biggs, R., MacFarlane, R. G., Pilling, J. (1947) Lancet, i, 402. Dawber, T. R., Moore, F. E., Mann, G. V. (1957) Amer. J. publ. Hlth, 47, 4. Goldrick, R. B. (1961) Aust. Ann. Med. 10, 20. Kemsley, W. F. F., Billewicz, W. Z., Thomson, A. M. (1962) Brit. J. prev. soc. Med. 16, 189. Nilsson, I. M., Olow, B. (1962) Acta chir. scand. 123, 247. Ogston, D. (1962) Brit. med. J. i, 1242. Fullerton, H. W. (1961) Lancet, ii, 730. Remmert, L. F., Cohen, P. P. (1949) J. biol. Chem. 181, 431. D. Shaw, A., MacNaughton, D. (1963) Lancet, i, 352. Sherry, S., Lindemeyer, R. I., Fletcher, A. P., Alkjaersig, N. (1959) J. clin. —
Invest. 38, 810.
GENETIC BASIS OF SUSCEPTIBILITY TO VIRAL LEUKÆMOGENESIS F. LILLY
E. A. BOYSE
L. J. OLD
Ph.D. Paris
M.D. Lond.
M.D. California
Sloan-Kettering Institute for Cancer Research and Sloan-Kettering Division, Cornell Medical College, and New York University School of Medicine, New York IN the study of the genetic basis of cancer, a number of
From the
marker genes have been used in attempts to locate within the genome the sites responsible for susceptibility to the development of various tumours. Experimentally a few genes have, in fact, shown a weak influence upon susceptia. bility (reviewed by Law 1954, Heston 1960) of the same order of magnitude as the observation of a weak but significant association in man between the blood-group-A phenotype and susceptibility to carcinoma of the stomach (Aird et al. 1953). In laboratory animals, the only gene known to exert a strong influence upon tumorigenesis is WV (viable dominant spotting). In all mice homozygous for this allele invasive ovarian adenomas develop (Russell and Fekete 1958). These WvWv animals have multiple abnormalities, including macrocytic ansemia, and the development of ovarian tumours is preceded by extensive pathological changes in the ovaries. Similarly, certain human diseases that predispose to malignancy may be determined by single genes (polyposis coli, xeroderma pigmentosum, neurofibromatosis-see Sorsby 1953). Thus, with the possible exception of retinoblastoma, which often has a familial incidence indicating monofactorial deter-
of 49Ca. There should be little difficulty in reducing both the irradiation time and the delay before the induced activity is measured. Several shorter measurements of body radioactivity might be preferable to one or two longer ones, and there seems to be no reason why quite accurate measurements of total body-calcium should not be made, using a phantom containing a dummy skeleton of known calcium content as a standard. This would be of considerable value in studies of various bone disorders and of the action of drugs. Body-nitrogen too can probably be estimated by neutron activation, for the annihilation radiation (0-511 meV) associated with the decay of 13N can be measured in the whole-body counter. 24Na, 38 Cl, and 49Ca are all produced by capture of thermal neutrons by the stable isotopes ; whereas I3N is produced by a fast neutron reaction, and the optimum conditions for uniformity of production in the body would be quite different from those used in this study. It would be necessary to allow for contributions from other short-lived positron emitters produced by fast neutron reactions-especially 3smK (halflife 7-7 minutes). This might be practicable if the decay of the activity at 0.51 meV were followed and the component with the 10-minute half-life extracted. Determinations of body-nitrogen could prove valuable in detecting a rise in body-nitrogen in patients with gout. Changes in total body-protein would be reflected in this parameter, thus allowing assessment of muscle wasting and malnutrition. Detection of abnormal deposits of other elements, such as copper, might also be possible. The technique enables certain elements, both in the circulation and in cells, to be labelled rapidly and in situ. Thus studies of ion transfer from tissue to blood may become possible in animals. Improvements in detection and irradiation techniques would enable similar studies to be made in man. If this new technique is to be of clinical value, the total radiation dose to the subject must be as small as possible-certainly no greater than is acceptable in diagnostic radiology. Our two subjects each received about 0-1rad, spread fairly uniformly over the body surface. By comparison the radiation dose resulting from the complete decay of all the induced radioactivity was very small (about 0-05 mrad.). The neutron irradiation gave a whole-body dose to the subject of about 1 rem, assuming a Quality Factor of 10 (I.C.R.P. 1963). The average skin dose received during the barium-meal examinations reported by the Adrian Committee was about 22 rem (Osborn 1963), so there need be no greater reluctance to subjecting a patient to this neutron irradiation than to performing a barium-meal examination.
Summary Neutron-activation analysis has been performed in vivo on man, using radiation doses small enough to be comparable with those used in diagnostic radiology. The induced radioactivity enabled estimates to be made of the total body sodium, chlorine, and calcium in two subjects. For sodium and chlorine, the values obtained differ from those reported in the literature as obtained by standard analytical techniques. Within experimental error, the total body sodium is found to be the same as the exchangeable sodium pool determined by isotope dilution. Future developments of this technique are discussed. We are very grateful for the help given by the operating personnel of the Cockcroft-Walton neutron generator at the Atomic Energy Research Establishment and by Mr. A. Holmes and Mr. L. J. Bunce. We gratefully acknowledge the many helpful discussions with Mr. N. G.
Stewart, Mr. D. H. Peirson, and Mr. J. A. Dennis of A.E.R.E., and with Mr. W. N. Saxby and Mr. E. W. Jones of the Atomic Weapons Research Establishment. Aldermaston, who also carried out preliminary measurements. This work would not have been possible without the help and interest of Dr. R. Spence, director of the Atomic Energy Research Establishment, the Marquess of Normanby, chairman of the board of governors, King’s College Hospital, and Dr. Vernon F. Hall, dean of King’s College Hospital Medical School. REFERENCES I. S., James, A. H., Baden, H., Moore, F. D. (1954) J. clin. Invest. 33, 122. Forbes, G. B., Lewis, A. M. (1956) ibid. 35, 596. Grove, E. L., Scott, C. W. (1957) Progress report: Determination of sodium and potassium in animal tissue by flame photometry. Oak Ridge
Edelman,
National Laboratory, unpublished data, quoted by International Commission on Radiological Protection (1959). Hine, G. J., Jagger, P. I., Burrows, B. A. (1962) in Whole Body Counting. International Atomic Energy Agency, Vienna. Hoffman, J. G., Hempelmann, L. H. (1957) Amer. J. Roentgenol. 77, 144. Hurst, G. S., Ritchie, R. H., Emerson, L. C. (1959) Hlth Phys. 2, 121. International Commission on Radiological Protection (1959) Report of Committee II on Permissible Dose for Internal Radiation. London. (1960) Report of Committee III on Protection Against X-rays up to Energies of 3 MeV and Beta- and Gamma-Rays from Sealed Sources. London. (1963) Report of Committee IV on Protection Against Electromagnetic Radiation Above 3 MeV and Electrons, Neutrons and Protons. London. Miller, H., Munro, D. S., Wilson, G. M. (1957) Lancet, i, 734. Osborn, S. B. (1963) Brit. J. Radiol. 36, 230. Richmond, C. R. (1958) Los Alamos Scientific Laboratory Report LA-2207. Rundo, J. (1958) Proceedings of the 2nd U.N. Conference on Peaceful Uses of Atomic Energy, 23, 101. Smith, J. W. (1962) Phys. Med. Biol. 7, 341. Smith, J. W., Boot, S. J. (1962) ibid. p. 45. Widdowson, E. M., McCance, R. A., Spray, C. M. (1951) Clin. Sci. 10, 113. —
—
FIBRINOLYSIS IN OBESITY D. OGSTON M.B., Ph.D. Aberd., M.R.C.P.E. LECTURER IN MEDICINE
G. M. MCANDREW M.B. Aberd., M.R.C.P.E. LECTURER IN MEDICINE
DEPARTMENT OF
MEDICINE,
UNIVERSITY OF
ABERDEEN,
AND ABERDEEN ROYAL INFIRMARY
OBESITY and fibrinolytic activity are inversely correlated (Goldrick 1961, Shaw and MacNaughton 1963), and Ogston (1962) noted diminished fibrinolysis in overweight patients who had had cardiac infarction. We now report further observations on fibrinolysis in lean and obese persons. Methods and Material
Plasma Fibrinolytic Activity Venous-blood samples were withdrawn with minimal stasis, between 7.30 and 8.30 A.M. The fibrinogen and plasminogen were not always estimated. Euglobulin clot-lysis times were estimated by the method of Nilsson and Olow (1962), and expressed by plotting the values logarithmically against units of fibrinolytic activity (Sherry et al. 1959), 10 units being arbitrarily equated with a lysis-time of 50 minutes. Lysis-times greater than 500 minutes were taken as 1 unit.
Plasma-fibrinogen Fibrinogen was
estimated of Nilsson and Olow (1962).
by
a
modification of the method
Plasma-plasminogen ) Plasminogen levels were estimated by the method of Remmert and Cohen (1949) as modified by Alkjaersig et al. (1959). Assessment of Obesity Height was measured to the nearest 1/4 in. (0-6 cm.), and weight to the nearest 1/4 lb. (0’11 kg.). The ratio of observed to standard weight was calculated according to the weight-forheight standards of Kemsley et al. (1962). This ratio is closely correlated with relative adiposity as estimated by body-density measurements. No age-adjustment was made to the standard weights. The body-weight of the 14 subjects who were grossly obese (ratio over 160) ranged from 191 to 377 lb. (86-6 to 171.0 kg.) with a mean of 250 lb. (113.4 kg.).
1206
subjects are in the normal elevated, some strikingly so. Few of the raised levels could be explained by infection, neoplastic disease, or tissue necrosis.
a
few of the values for the obese
range, many
are
Effect of Diet
Fig. 1-Relationship between fibrinolytic activity and observed/ standard weight ratio.
Subjects The subjects of high observed/standard weight ratio were mainly patients admitted to hospital for weight reduction by diet. Most of those with a ratio under 130 were hospital patients with minor disorders which could not affect fibrinolysis. A few members of the medical staff and students were
also included. The total number of the series
was
41.
Diets Two standard dietary regimens were used. The 140 kcal. diet comprised two oranges daily. The 600 kcal. diet was a standard hospital reducing regimen. 2 patients received the 600 kcal. in the form ofMetercal’.’. Unlimited water was allowed. TABLE I-MEAN FIBRINOLYTIC
VALUES,
IN
SUBJECTS
ACTIVITY, FIBRINOGEN AND PLASMINOGEN
OF DIFFERING
OBSERVED/STANDARD
WEIGHT
RATIO
Exercise The exercise stimulus consisted of 3 minutes’ continuous activity on standard step-up equipment, equivalent to ascending and descending a height of 54 feet (16-5 metres). This period was chosen as the maximum tolerated by the grossly obese subjects. Blood-samples were obtained immediately before and after the exercise, and a third after 30 minutes’ rest.
Fig.
Results 1 shows the inverse relation between
fibrinolysis
and observed/standard weight ratio. The mean fibrinolytic activity of the subjects with a ratio of 88-129 was 4-7 units; that of the moderately obese subjects (observed/standard weight ratio 130-160) was 2-9 units; while for the grossly obese subjects (observed/standard weight ratio over 160) it was 1.3 units. The difference between the mean fibrinolytic activity of the grossly obese subjects and of those with normal physique was highly significant (p < 0-001); while that between the moderately obese and the normal subjects was also significant (p < 001). There was no significant difference between the mean plasminogen-levels of the three groups of subjects classified by weight ratio and, conversely, by fibrinolytic activity; but mean fibrinogen levels were greater .in the grossly obese subjects (p < 0-001), and in the moderately obese subjects (p < 0’01) (see table i). Fig. 2 illustrates the individual fibrinogen values. While
To determine the effect of weight reduction on fibrinolysis in the obese, 4 subjects with high observed/standard weight ratio were investigated before and during a period of dietary restriction sufficient to induce rapid weight loss. 2 who received 140 kcal. per day had substantially increased fibrinolytic activity (3 and 4, table 11). 2 others (weight ratios 205 and 206) were given 600 kcal. diets (metercal); their weight loss was slower than that of the subjects on a 140 kcal. diet, and their fibrinolytic activities remained below 1 unit until the 19th day when they rose to 2.2 and 2.1
units, theirweights having fallen by 16 and 15 lb. (7-3 and 6-8 kg.). A subject with initial weight ratio was observed for 4 months. His weight change and fibrinolytic
activity during this period are illustrated in fig. 3.
Fibrinolysis increased strikingly Fig. 2-Relationship between fibrinogen during rapid and observed/standard weight ratio. weight loss, first on a 140 kcal. diet, and later on one of 600 kcal. As the rate of weight loss declined, fibrinolytic activity began to fall again. After discharge he continued nominally on a diet of 600 kcal., but did not adhere to this exactly. After a period of slow, and latterly of absent, weight loss fibrinolytic activity fell to about the pre-diet level. He remained grossly overweight (weight ratio 190) despite having lost 39 lb. (17-7 kg.). To determine whether diet-induced weight loss produces increased fibrinolysis in those with a lower weight ratio, 2 such subjects were restricted to a diet of 140 kcal. for 3 days (1 and 2, table n). The increased fibrinolysis was of the same magnitude as that for the 2 obese subjects on a similar diet. Thus increased fibrinolysis during weight loss must be due to metabolic factors in both obese and normal persons. The levels of plasminogen and fibrinogen did not fluctuate during weight loss; alternation of these factors, therefore, did not contribute to the observed changes in
fibrinolysis. TABLE II-CHANGE IN FIBRINOLYTIC ACTIVITY INDUCED BY DIET
140 kcal.
1207
Effectof Physical
changes of starvation rather than with the degree of weight reduction. We wonder whether the increased fibrinolysis produced in obese subjects by fasting persists when they have achieved, and are maintaining, their ideal body-weight. In contrast to the similar increase in fibrinolysis in both obese and normal persons during weight loss, the stimulus of exercise produces a smaller response in the obese than in those of normal physique. This suggests that these two stimuli increase fibrinolysis by different mechanisms, and bolic
Exertion
Physical effort creases
infibri-
nolysis (Biggs et al. 1947, Ogston and Fullerton
1961).
that some factor in obese persons interferes with one of these mechanisms. Obesity is statistically associated with an increased incidence of occlusive vascular disease (Dawber et al. 1957). Diminished fibrinolysis in the obese may contribute to this association.
To
determine whether the initially low
fibrinolytic activity of
Summary
obese persons increases with exercise, the
fibrinolytic response to
a
standard exercisee stimulus was compared in 4 obese and 3 normal sub-
Fig. 3-Alterations in body-weight and fibrinolytic activity during dietary restriction in one subject.
Plasma fibrinolysis was diminished in obese subjects, some of whom had hypernbrinogensemia, plasminogen levels were normal. Lean and obese persons showed a similarly increased fibrinolysis during rapid weight loss induced by dietary restriction. Fibrinolysis was enhanced by physical exertion less in the obese than in the lean. We are grateful to Dr. J. M. Stowers and Dr. T. N. Morgan for permission to study patients in their care, and to Prof. H. W. Fullerton for helpful advice.
jects. Table
ill shows that obese subjects, despite the greater work entailed by their exercise, had less increase in fibrinolysis than those of normal physique, and 1 of the obese had no increase at all. After 30 minutes’ rest the fibrinolytic activity of both groups fell towards their preexercise level, but this fall in the obese subjects was less pronounced, both absolutely and relatively, than in those of normal phvsioue. discussion
-
This study has confirmed the finding of Goldrick (1961) and Shaw and MacNaughton (1963) that plasma fibrinolysis is diminished in the obese. Some obese persons also have hypernbrinogensemia. Euglobulin clots formed in a high concentration of fibrinogen are more resistant to lysis, and the diminished fibrinolysis may be partly due to this relationship. However, since some of the obese subjects with normal fibrinogen levels had low fibrinolytic activity, this relationship cannot be the sole explanation. The results also indicate that diminished fibrinolysis is not due to plasminogen deficiency. Dietary restriction sufficient to cause rapid weight loss was found to increase fibrinolysis in both normal and obese persons, but only while the weight loss continued. Hence fibrinolysis is probably associated with the metaTABLE III-EFFECT OF EXERCISE ON FIBRINOLYTIC ACTIVITY IN OBESE AND NORMAL
SUBJECTS
REFERENCES
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GENETIC BASIS OF SUSCEPTIBILITY TO VIRAL LEUKÆMOGENESIS F. LILLY
E. A. BOYSE
L. J. OLD
Ph.D. Paris
M.D. Lond.
M.D. California
Sloan-Kettering Institute for Cancer Research and Sloan-Kettering Division, Cornell Medical College, and New York University School of Medicine, New York IN the study of the genetic basis of cancer, a number of
From the
marker genes have been used in attempts to locate within the genome the sites responsible for susceptibility to the development of various tumours. Experimentally a few genes have, in fact, shown a weak influence upon susceptia. bility (reviewed by Law 1954, Heston 1960) of the same order of magnitude as the observation of a weak but significant association in man between the blood-group-A phenotype and susceptibility to carcinoma of the stomach (Aird et al. 1953). In laboratory animals, the only gene known to exert a strong influence upon tumorigenesis is WV (viable dominant spotting). In all mice homozygous for this allele invasive ovarian adenomas develop (Russell and Fekete 1958). These WvWv animals have multiple abnormalities, including macrocytic ansemia, and the development of ovarian tumours is preceded by extensive pathological changes in the ovaries. Similarly, certain human diseases that predispose to malignancy may be determined by single genes (polyposis coli, xeroderma pigmentosum, neurofibromatosis-see Sorsby 1953). Thus, with the possible exception of retinoblastoma, which often has a familial incidence indicating monofactorial deter-