176 the normal range has been excluded from the analysis. There was a significant increase in the mean serum-glutamic-oxaloacetic-transaminase (S.G.O.T.), serum-glutamic-pyvruic-transaminase (S.G.P.T.), and serum-creatinine on cimetidine 1 - 6 g daily, but no change on 0-88 g

Hypothesis CONTROLLED STORAGE OF BIOLOGICAL ENERGY: THE ROLE OF PLASMA

daily or on placebo.

LIPOPROTEINS

DISCUSSION

Preliminary results of our double-blind comparison of cimetidine 1 - 6 g daily with placebo have shown a significant increase in ulcer healing in the cimetidine group at six and twelve weeks. This effect is not apparent after only two weeks’ treatment. At present the numbers are small, but combining the

two trials, we obtained healing in 21 out of 32 different patients (66%) at six weeks. This is very similar to the healing-rate observed in the multicentre trial of metiamide,8 in which 24 out of 36 patients (67%) had healed at four weeks. The healingrate in their placebo group (25%) was the same as ours. By contrast with metiamide, bone-marrow toxicity was not observed in any of our 32 patients, nor has it been reported in any patient treated elsewhere with cimetidine.12 The small but significant rise in serumtransaminase levels in our trials is likely to be a real

effect, since it is present for both

s.G.o.T. and S.G.P.T. on cimetidine 1.6 g daily, and is absent in the placebo group. The mean value remained within the normal range. The rise in transaminase levels was not accompanied by any other change in routine liver-function tests, and its clinical significance is quite unclear at present. In contrast to our findings, Haggie et all found S.G.O.T. levels unchanged in an uncontrolled trial of cimetidine 1.6 g daily for six weeks in 18 patients. They reported a small but significant increase in serum-creatinine concentration and we have confirmed this. However, no individual patient exceeded the upper limit of normality and there was no change in the blood-urea concentration. These findings emphasise the need to continue close clinical surveillance in patients taking cimetidine in clinical trials. The effect on S.G.O.T., S.G.P.T., and serum-creatinine levels appears to be dose-related and there was no tendency for these to rise on cimetidine 0.8 g daily. This raises the important question of whether this lower dose of cimetidine will prove to be as effective as 1.6 g daily in achieving duodenal-ulcer healing. Our open pilot study comparing the two doses suggests that they may be equally effective and we are now carrying out further studies, on a double-blind basis, to determine the optimum therapeutic dose of cimetidine. We thank our colleagues for referring patients, the departments of biochemistry and hsematology at this hospital for analysis of many blood-samples, and the pharmacy for dispensing the tablets. Cimetidine was generously provided by the clinical research group, Research Institute, Smith, Kline and French Laboratories, Welwyn Garden City, Herts. Requests for reprints should be addressed to T. C. N., Clinical Research Laboratories, St. George’s Hospital Medical School, Tooting T nmlr,n BB717 DDT

REFERENCES

Mainardi, M., Maxwell, V., Sturdevant, R. A. L., Isenberg, J. I. New Engl. J. Med. 1974, 291, 373. 2. Black, J. W., Duncan, W. A. M., Durant, C. J., Ganellin, C. R., Parsons, M. E. Nature, 1972, 236, 385. 3. Wyllie, J. H., Hesselbo, T., Black, J. W. Lancet, 1972, ii, 1117. 1.

D. G. CRAMP

T. R. TICKNER M. R. WILLS

Department of Chemical Pathology, Royal Free Hospital School of Medicine, Pond Street, London NW3 2QG A scheme is advanced

whereby plasmalipoproteins form an integrated controlled pathway for storage of energy as triglyceride. The importance of insulin within this system is indicated and the consequence of possible errors considered. Changes secondary to organ disease are found to fit within the proposed pathway. Although many refinements remain to be added, this hypothesis seems to form a plausible framework within which lipoprotein abnormality and the underlying condition may be better understood and thereby treated.

Summary

INTRODUCTION

THERE is considerable evidence that self-regulation is the major feature of biological systems and that; for mammalian systems, this self-regulation is achieved by biologically economical means. The concept of such economy requires high efficiency of energy coupling in a utilisable form and the ability to store excess material, which may be gained in times of environmental plenty, for use in times of deprivation. Storage. of materials, however, demands that by their presence they should not upset the constitution of the milieu in térieur. This can only be achieved by two means--either storage as a macromolecule of low chemical activity or storage in a separate pool. In either form the stores could become too large so that ultimately the milieu intérieur itself becomes threatened and overflow mechanisms may be required to protect the individual. Two major energy sources are used by the mammal -carbohydrate and fat. That these two are closely linked is shown not only by their shared metabolic intermediates (e.g., acetyl-CoA) but also in the provision by carbohydrate of precursors for triglyceride synthesis. Even at the gross level evidence for the interconnection may be obtained from the lipid abnormalities accom-

Richardson, C. T., Bailey, B. A., Walsh, J. H., Fordtran, J. S. J. clin. Invest. 1975, 55, 536. 5. Carter, D. C., Forrest, J. A. H., Werner, M., Heading, R. C., Park, J., Shearman, D. J. C. Br. med. J. 1974, iii, 554. 6. Burland, W. L., Duncan, W. A. M., Hesselbo, T., Mills, J. G., Sharpe, P. C., Haggie, S. J., Wyllie, J. H. Br. J. clin. Pharmac. 1975, 2, 481. 7. Pounder, R. E., Williams, J. G., Milton-Thompson, G. J., Misiewicz, J. J. Br. med. J. 1975, ii, 307. 8. Multicentre Trial. Lancet, 1975, ii, 779. 9. Burland, W. L., Sharpe, P. C., Colin-Jones, D. G. Turnbull, P. R. G., Bowskill, P. ibid. p. 1085. 10. Brimblecombe, R. W., Duncan, W. A. M., Durant, G. J., Emmett, J. C., Ganellin, C. R., Parsons, M. E. J. int. med. Res. 1975, 3, 86. 11. Haggle, S. J., Fermont, D. C., Wyllie, J. H. Lancet, 1976, i, 983. 12. Sharpe, P. C. Personal communication. 4.

177 diabetes mellitus and the carbohydrate intolin obesity. The aim of this hypothesis is to consider the role and metabolism of plasma-lipoproteins as part of a controlled energy distribution and storage system within the concept of biological economy and to indicate the possible connection between disease states and anomalies of the system.

This apo-A/apo-C2 complex is the substrate for second protease. Thus H.D.L. is released for possible recycling. In this hypothetical pathway no account has been taken either of the site of metabolism, or of interactions with other paths, including the L.C.A.T. reaction. A pathway, however, of this type exemplifies control by substrate availability, triglyceride being rate-limiting. Apo-B is essential for V.L.D.L. and perhaps chylomicron formation, and it is the apoprotein found in L.D.L. It has been stated rather dogmatically that V.L.D.L. is the sole source of L.D.L.l2 in the plasma, but if this were 4 so then the demonstration by Brown and Goldstein 3 that L.D.L. inhibits intracellular cholesterol synthesis would indicate a quirk of nature rather than metabolic control. However, it is rare-that a system so elaborate as that demonstrated by Brown and Goldstein in fibroblasts, whereby intracellular inhibition of synthesis is linked to destruction of the signal, has no biological role. It seems likely, therefore, that L.D.L. has a true control function in cholesterol synthesis. Chylomicra contain the same apoproteins as V.L.D.L. but considerably more lipid. Since chylomicra are formed at times of energetic plenty it would be economic if transfer to storage could proceed directly with minimum interference as the lipid passes from gut to adipocyte. It could be anticipated that insulin would assist such progress, acting as it does as a post-prandial hormone, and there is some evidence supporting this concept. Desai and Hollenberg5 have demonstrated that, in the adipocyte, insulin, acting in conjunction with glucose, enhanced the activity of lipoprotein lipase and that this process involved enzyme or other protein induction. Furthermore, we have been able to demonstrate that the infusion of artificial chylomicra (’Intralipid’)6 can affect the apparent half-life of insulin in vivo. These findings suggest that not only does insulin enhance lipoprotein lipase activity, but also that these lipid-rich particles can either bind insulin in the circulation or inhibit its degradation.

panying

apo-A).

erance seen

a

LIPOPROTEIN PHYSIOLOGY

The

lipoproteins of major importance are very low density lipoprotein (V.L.D.L.) and chylomicra. The former provide transport for endogenous triglycerides, and therefore carry that triglyceride formed from excess carbohydrate (and protein) in the liver, while the latter are concerned largely with exogenous triglyceride transport.

chiefly two types of apoproteinC2 (apo-C2) and apoprotein B (apo-B). apoprotein Apo-C2 is an activator of the clearing enzyme lipoprotein lipase (L.P.L.; EC 3.1.1.34) while apo-B, in addition to being essential to triglyceride transport, plays a part in the control of cholesterol synthesis. Apo-C occurs in three other forms, two of which (C3 and C4) are very similar. Although the interrelationship awaits clarification, the size of these apoproteins suggests an arrangement reminiscent of other plasma selfregulating systems (such as blood coagulation) and it is possible to imagine a sequence such as that given in fig. 1. Here, an apo-B triglyceride complex becomes V.L.D.L. after addition of the C-peptide (apo-C), providing the substrate for a protease which cleaves the C-peptide so that apo-C2 remains within the v.L.D.L. moiety. This apo-C2 activates L.P.L. to hydrolyse the triglyceride component and yields L.D.L. and apo-C2, which exchanges into high-density lipoprotein (H.D.L.) (mainly V.L.D.L.

contains

CHOLESTEROL TURNOVER

The control of apo-B production and its relationship cholesterol turnover merit consideration. For maxi-’ mum economy both total body and dietary cholesterol should exhibit some effect. However, cholesterol is so ubiquitous that it is improbable that total body cholesterol could produce such control: rather a second, smaller pool must be sought which will reflect the total pool. Only two forms of cholesterol are found in the body. Free cholesterol is quantitatively the greater in tissues, while in the plasma compartment esterified cholesterol is the major fraction. Since the esterified form in plasma may be derived from any tissue source it is to

to postulate that esterification is the prerequisite for entry into a further liver pool, the existence of which has been suggested by the studies of Sodhi and Kudchodkar.7 Acceptance of this as a premise highlights the (possible) importance of L.C.A.T. (lecithin cholesterol acyl transferase, EC 2.1.3.43), the enzyme which is probably normally the sole source of esterified cholesterol in man. L.C.A.T. is activated by H.D.L. (largely apo-A). Although apo Ai and Am have both been implicated in this activation, confusion over nomenclature and over the interrelationships of these apoproteins leaves doubt

tempting

i

pathway for C-peptide metabolism (see text). 1. -IIN indicates pothetical activation.

arrou

178 as to whether or not an activation system similar to that considered earlier for apo-C and lipoprotein lipase is appropriate. It seems clear, however, that whatever role

apo-A apo-A)

may

play

acts as an

in

activation H.D.L. (i.e., carrier for apo-C following

L.C.A.T.

acceptor

or

degradation. Although it appears that apo-A is an activator for L.C.A.T. the biological substrate is in doubt. However, as L.C.A.T. activity can be enhanced by both V.L.D.L. and chylomicra it might be postulated that these triglyceride rich fractions are the preferred substrate forms. Moreover, the substrates for L.C.A.T. have an effect on lipoprotein lipase. Fielding8 has shown that, in vitro, cholesV.L.D.L.

Fig. 2.-Schema depicting control

of metabolic interactions

terol inhibits

lipoprotein lipase-a feature not shared by Scanu,9 on the other hand, found lipoprotein lipase activity to be maximal in the presence of lysolecithin. Thus it would appear that L.c.A.T. activity can enhance the removal of triglyceride from its substrate. This removal is of possible advantage to the individual, for, while increasing the "second cholesterol pool" in the plasma, L.C.A.T. simultaneously promotes L.D.L. access to its receptors. It must be realised, however, that, although L.C.A.T. is essential to provision of the second pool, L.c.A.T. is unlikely to be rate-limiting, for, since it is cholesterol control that is sought, cholesterol itself is likely to be the limiting factor. cholesterol

between

ester.

plasma lipoproteins, apoproteins, and their lipid

moietie

179 of the control pool is only part of the and where control is exerted also How problem. demands attention. Clearly the size of this pool must be reflected ultimately in apo-B production. At the same time unnecessary wastage of L.C.A.T. or its activator (apo-A) would be avoided should production of these proteins also respond to the second pool. There are two possible sites of action-the gut and the liver. Both could respond not only to cholesterol from the second pool (perhaps via the bile) but also to dietary choles-, terol-the former by direct bathing with intestinal content and the latter through the hepatic portal system. Functionally, the two sites are very similar, although evidence from pathological states makes the gut appear the more attractive prospect for apo-B synthesis, and production may occur in both organs.. An integrated system can be postulated in which triglyceride and cholesterol metabolism are interlinked and which provides production of necessary lipid carriers and promotes storage of triglyceride. The system is represented diagramatically in fig. 2. The scheme represents part rather than the whole of the story, for simultaneous changes occur in intracellular metabolism promoting such processes as glycogen synthesis and conversion of carbohydrate to fat and inhibiting inapThe

nature

propriate depot mobilisation. Unfortunately, it is neither ethical nor practical to test much of this hypothesis. However, Nature herself has undertaken a number of experiments on man, and man has not been reluctant to tamper with.his own nature.

L.C.A.T. DEFICIENCY

congenital L.C.A.T. deficiency the main clinical feaproteinuria, normochromic anaemia with a haemolytic component, corneal opacities, and a turbid plasma. Plasma cholesterol, phospholipid, and triglyceride concentrations are elevated and the proportion of esterified cholesterol is low as is also the a-lipoprotein. These latter observations could be predicted, for if L.C.A.T. is removed from our model depicted in fig. 2 the following sequence would result. The second cholesterol pool is depleted. Thus apo-B and apo-A production are decreased-as is biliary cholesterol. Cellular cholesterol production is therefore poorly inhibited and total body cholesterol is increased. The possible relevance of such cellular overproduction in atherogenesis is obvious and, In

tures are

in this respect, the condition is somewhat similar to the L.D.L. receptor deficiency demonstrated by Brown and Goldstein.3 4 Further, since cholesterol is not esterified, lipoprotein lipase activity should be diminished, so that V.L.D.L. and chylomicra will be cleared only slowly. This may also explain the triglyceride-laden L.D.L. found in this congenital deficiency. HYPOLIPOPROTE INAE MIA S

Tangier disease (an-a-lipoproteineemia) is characterised by a symptomless hepatosplenomegaly with hypertrophied lymphoid tissue. The enlargement of these organs is due to their infiltration by lipid-laden histio cytes containing cholesterol ester. The plasma shows the opposite with significantly decreased cholesterol an( phospholipid concentrations, yet there is marked hyper triglyceridaemia. The diagnostic abnormality is the gene

tically determined deficiency in the ot-lipoprotein. Thus, it could be expected that Tangier disease might be similar to (although milder than) L.C.A.T. deficiency. However, in addition transport of any cholesterol ester

formed will be impaired leading perhaps

to the deposits in peripheral tissues. The siting of these deposits make it more likely that the primary site of L.C.A.T. activity is in the periphery rather than in the plasma. A-p-lipoprotein deficiency is a better-documented experiment of Nature. Both V.L.D.L. and L.D.L. are lacking in plasma, chylomicra are not formed, and triglyceride accumulates in the gut. Whether the inability to form chylomicra is solely due to lack of apoprotein (an explanation supporting the contention that apo-B is,of gut origin) or whether there may be a secondary decrease in biliary cholesterol remains unresolved. The absence of p-lipoprotein is associated with serious disease. In childhood the affected individuals show signs of intestinal malabsorption, similar to coeliac disease, which improves with age. As the disease progresses there is development of neurological signs, especially cerebellar ataxia and athetosis. There is a typical blood picture, the acanthocytosis being pathognomonic. The neurological and haematological complications associated with this condition may reflect chronic energy deprivation, seen

perhaps combined with essential-fatty-acid deficiency (this alone being inadequate explanation) but the possible relationship to disordered control and distribution of cholesterol should

be overlooked. Apo-C deficiency does not appear for certain to have been described. However, this might be expected to diminish removal of endogenous triglyceride from the blood. Thus an abnormal "V.L.D.L." lacking apo-C would be formed. The "floating p" lipoprotein associated with Fredrickson type in hyperlipoproteinaemia may well represent triglyceride-rich V.L.D.L., and a similar lipoprotein is found in L.c.A.T. deficiency. not

LIPOPROTEIN LIPASE DEFICIENCY

Of two distinct lipoprotein lipase isoenzymes which have been described, one-that of adipose tissue-appears to be lacking in some cases of Fredrickson type I hyperlipoproteinaemia in which a hyperchylomicronaemia is found. This isoenzyme shows no difference between chylomicra and v.L.D.L. for V-max. The liver isoenzyme, on the other hand, appears to demonstrate greater activity for v.L.D.L., and is present in greater amounts in normal blood. This substrate variability no doubt partly explains the occurrence of chylomicra without concomitant rise in v.L.D.L. Moreover, inducibility of the enzyme by insulin and glucose increases the complexity, for lipoprotein lipase activity could be affected not only by aberrations in the enzyme itself but also by anomalies in the control system. Thus three main errors could affect L.P.L. activity (fig. 3) and the final lipoprotein pattern-emerging will reflect the error site and the isoenzyme involved. In addition lipoprotein overproduction may exacerbate a pre-existing hypertriglyceridaemia-for example, a Fredrickson type I could become a type v by overproduction of V.L.D.L. HYPERCHOLESTEROLAEMIA L.D.L. receptor deficiency has been described by Brown and Goldstein.3 Since this receptor (fig. 2) also

180

secondary L.D.L. production (again through L.C.A.T.) and possibly also increase v.L.D.L. through uptake of fatty acids by the liver. Although in both these situations plasma-cholesterol may be raised, tissue cholesterol will be related to the availability of apo-B for interaction with receptor sites. A high cholesterol diet, on the other hand, is likely to increase apo-B production by direct action. However, although hypercholesterolaemia should result, tissue production will be diminished. Thus, any increase in the tissue cholesterol will be due bution and may well be limited.

to

redistri-

RENAL DISEASE

Organ disease can also result in lipoprotein anomalies. Renal failure is frequently accompanied by endogenous hypertriglyceridsemia (Fredrickson type iv).10 Total triglyceride turnover is increased and therefore endogenous overproduction is implicated.’At the same time relative lipoprotein lipase deficiency may well occur.

This

Fig. 3.-Factors affecting lipoprotein lipase (L.P.L.) activity.

hydrolyses L.D.L. apoprotein, hypercholesterolaemia (Fredrickson type IIA) results. Others have not found the complete absence of cholesterol inhibition demonstrated by these workers and have concluded that cholesterol inhibition is polygenic. In addition, a family has been reported in which abnormal L.D.L. rather than an abnormal receptor appeared to prolong L.D.L. turnover. It is imperative to realise that only in these cases of familial hypercholesterolaemia will plasma-cholesterol mirror sinister increases in cellular cholesterol production. In most other cases high plasma L.D.L. inhibits tissue synthesis of cholesterol. Thus, extreme care should be exercised before instituting therapy which may affect synthesis of this protein. OTHER POSSIBLE PROTEIN DEFICIENCIES

In addition to lipoprotein deletions and those of the pathway enzymes, defective control mechanisms may

exist. Such defects

are more likely to be recognised if leading to overproduction and-for the scheme proposed-are chiefly applicable to apo-A and apo-B production. Apo-A excess could lead to increased L.C.A.T. activity and thereby increase the second cholesterol pool (fig. 2). Thus, apo-B production would be enhanced and a "type II" plasma pattern result. Tissue cholesterol levels, however, should be decreased. Similarly, excess apo-B production should diminish tissue cholesterol in response to raised plasma p-lipoprotein. The combination of diminished production with increased binding makes the effect on total plasma lipids difficult to pre-

dict. DIETARY EFFECTS

More frequently the lipoprotein excesses result from man’s own experiments. Excess dietary carbohydrate leads to increased v.L.D.L. production (a change also seen following insulin). In turn v.L.D.L. excess by providing substrate for L.c.A.T. should increase the cholesterol ester pool and thus L.D.L. induction could result. Similarly sufficient dietary triglyceride could stimulate

primary cause of the endogenous triglyceride overproduction associated with renal failure is probably dietary. Nevertheless, plasma-insulin levels are also increased in this disorder and chronic (although not acute) hyperinsulinaemia is associated with hypertriglyceridaemia. Since the liver is the primary source of this triglyceride and since the portal venous insulin levels are greater than those of peripheral blood it seems unlikely that insulin plays an important role except in association with dietary carbohydrate. It is possible, therefore, that the high plasma-insulin follows rather than causes the high triglyceride. Interconversion of lipoprotein abnormalities may well reflect the relative roles of overproduction, L.C.A.T. subtrate availability, and lipoprotein lipase deficiency. These would result in Fredrickson type IV, nb, and v respectively. LIVER DISEASE

Liver disease is more complex. Underproduction of apoproteins, L.C.A.T., and hepatic lipoprotein lipase may all occur together with alterations in carbohydrate and fat interconversion. Furthermore, obstruction prevents cholesterol reaching the gut from the second (cholesterol ester) pool-hence affecting apo-B production-and allowing formation of the apparent lipid bilayer--called lipoprotein X. It must also be remembered that, although hepatic L.P.L. deficiency has been proposed’2 as the primary cause of the hypertriglyceridaemia seen in liver failure, diminished L.C.A.T. activity would lead to inhibition of peripheral L.P.L. activity-exacerbated by the presence of excess free cholesterol. The final effect of hepatocellular disease is, therefore, unpredictable. DIABETES MELLITUS

No consideration of acquired hyperlipidsemia would be complete without reference to diabetes mellitus. An absolute insulin deficiency (such as is seen in "juvenile" diabetes) should result in diminution of triglyceride clearance and of V.L.D.L. production. Secondary apo-B induction is likely. The late-onset diabetic on the other hand shows insulin "resistance". The proposed interaction of insulin with triglyceride could be responsible for this resistance, and it is possible that the hypertriglyceridaemia of the late-onset diabetic is related to the

181

pathogenesis rather than the progress of the disease. The association between obesity and diabetes mellitus is well known, and in the genetically obese ob-ob mouse obesity precedes the plasma-insulin rise. 13 The combination of increased plasma-insulin and impaired glucose tolerancecan be the result of either increased sequestered (that is ineffective) insulin or loss of activity by the insulin receptors. The loss of insulin receptors demonstrated by Roth 14 could be related, for it is likely that the receptormembrane interaction is a loose lipid-protein association which no doubt could as well apply to the "single-sided" membrane of a lipoprotein surface. Thus "receptor stripping" rather than insulin inhibition of receptor production may promote this change. Whatever the

mechanism

may

the

the true enemy of women. Triglyceride and, to a lesser extent, cholesterols15 are both increased-an effect apparently related to the oestrogenic component. If a single action is sought then the primary change would appear to be in triglyceride metabolism, where cholesterol may be secondarily affected, or in L.C.A.T. activity. Clearly much important information remains as yet untapped in these interesting disorders.

haps

be, the insulin

of shedding appears provide excess energy by the body. Rarer forms of diabetes may also be related to these

insensitivity

to

yet be most constructive in the understanding of lipid disorders and their implications. Most of these conditions await exhaustive study. Studies on the effect of the contraceptive pill are more advanced-and once again this therapy may prove the friend of man, although per-

REFERENCES S

means

interactions. Complete lipoprotein lipase deficiency, for example, might be expected to show not only failure of normal adipocyte production, but also insulin resistance. Furthermore, practical therapeutic use of the association may already be standard treatment. Dietary control of the late-onset diabetic tends to reduce plasmatriglyceride. Such reduction is also one of the actions exhibited by the biguanides and by decreasing "bound" insulin could lead to diminished peripheral resistancethus enhancing glucose uptake. Diabetes mellitus is not the only endocrine disorder in which plasma-lipid changes occur. Several others may

Reviews of Books

Bilheimer, D. W., Eisenberg, S., Levy, R. I. Biochim. biophys. Acta, 1972, 260, 212. 2. Eisenberg, S., Bilheimer, D. W., Levy, R. I., Lindgren, F. T. ibid. 1973, 326, 1.

361. 3. Goldstein, J. L., Brown, M. S. Am. J. Med. 1975, 58, 147. 4. Goldstein, J. L., Brown, M. S. J. biol. Chem. 1974, 249, 5153. 5. Desai, K., Hollenberg, C. H. Israel J. med. Sci. 1975, 11, 540. 6. Tickner, T. R., Cramp, D. G. Unpublished. 7. Sodhi, H. S., Kudchodkar, B. J. Lancet, 1973, ii, 513. 8. Fielding, C. J. Biochim. biophys, Acta, 1970, 218, 221. 9. Chung, J., Scanu, A. M., Reman, R. ibid. 1973, 296, 116. 10. Cramp, D. G., Moorhead, J. F., Wills, M. R. Lancet, 1975, i, 672. 11. Cramp, D. G., Beale, D. J., Moorhead, J. F., Tickner, T. R., Wills, M. R. Clin. Sci. molec. Med. 1976, 50, 8P. 12. Müller, P., Fellin, R., Lambrecht, J., Agostini, B., Wieland, H., Rost, W., Seidel, D. Eur. J. clin. Invest. 1974, 4, 419. 13. Chlouverakis, C., Dade, E. F., Batt, R. A. L. Metabolism, 1970, 19, 687. 14. Soth, A. H., Kahn, C. R., Neville, D. M., Roth, J. J. clin. Invest. 1975, 56, 769. 15. Stokes, T., Wynn, V. Lancet, 1971, ii, 677.

Cardiac Ultrasound Edited

Immunological Tolerance British Medical Bulletin: vol. XXXII, no. 2. Edited by D. W. DRESSER. London: British Council. 1976. Pp. 192. C3 (overseas

;[3.50). A PRACTICAL aim of modern immunology, and one which presents some of its most absorbing problems, is to gain insight into the nature of self-tolerance and transplantation tolerance and their relationship with other forms of immunological unresponsiveness. Initially thought of as a central failure of the immune response based on clonal deletion, the nature of tolerance has lately been undergoing extensive re-examination in the light of new knowledge of lymphocyte subpopulations and new ideas about their separate functions, the interactions between them, and, especially, how tolerance may be an endresult of those cellular and humoral interactions that control and limit immune responses. This issue of the British Medical Bulletin provides a timely and engrossing survey of current arguments and enlightening conclusions in this increasingly complex area. Tolerance is discussed against the different backgrounds to which its different forms are relevant-e.g., transplantation and organ grafts, tumour growth, autoimmunity, and viral and parasitic infections. Blocking by antibody, by antigen, or by antigen-antibody complexes, the action of suppressor T and B cells, and the fascinating control networks which, Jerne has postulated, arise from idiotype specificity, are some mechanisms which here receive as serious consideration as clonal deletion or inactivation, in explanations of transplant acceptance, tumour regression, autoimmunity, hypersensitivity reactions, and parasite defences against the host. Surgeons, physicians, biologists, even immunologists, seeking a balanced and lucid exposition of the direction of modern thoughts on tolerance will find this volume

invaluable.

by RAYMOND GRAMIAK, University of Rochester, N.Y. ton. 1976. Pp. 308. £ 20.65.

M.D., and ROBERT C.

St Louis:

Mosby.

WAAG,

London:

M.D.,

Kimp-

IT was towards the beginning of this century that electrocardiography established itself as an important new technique for the investigation of cardiac function, a position from which it has not been dislodged. Cardiac catheterisation opened a totally new dimension, further supported by radiological techniques that delineated the cardiac chambers and the principal blood-vessels originating from the heart. With this, one might have been content, but from a start only 20 years ago, echocardiography has firmly established itself during the 1970s as a useful non-invasive investigation. Indeed, no cardiac department can now consider itself fully equipped unless it has not only echocardiographic equipment but also physicians and technicians trained in its use and understanding. The specialist journals are full of articles, many original but more derivative, that claim to show specific features that enable one to achieve the ultimate in diagnosis without catheters. Those working in cardiac departments are, alas, only too well aware of how even echocardiography fails, in many cases, to achieve the promise excited

by its foremost protagonists.

Several books have

attempted to describe the technique and to lay down important criteria for the diagnosis of various cardiac disorders, and any author who ventures into this area is clearly treading on shifting sands as knowledge advances. Dr Gramiak and Dr Waag have been more successful than many others in their compilation, which is based on a symposium held in 1974. Time dic-tates, unfortunately, that much of what appears does not carry the thrust of entire novelty, but the authors and editors have provided a solid basis that permits recommendation of this book to the novice. The editors themselves provide a sound fundamental introductory chapter, and subsequent sections deal effectively with recording methods and the identification of the various cardiac structures that can be recognised with