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because there is no other place for them to go. Thosewho are cared for at home impose physical and mentalstrains on their parents and families, but all too oftenthere is no help forthcoming from the social-serviceor medical agencies. It is the plight of the parentsin fact, which is the chief concern of the report.Because, it says, successive Governments have starvedthe mental-health services of essential resources, com-munity care is still synonymous with home care.

For the parents caring for their handicapped childat home, one of the worst worries concerns the future;their great fear is that the child will finally enter amental-subnormality hospital. Yet, at present, hardlyany alternative exists, for the provision of hostels andother community resources is nowhere near adequate,even for existing needs. Moreover, parents often feelthat nothing is done to develop what potential theirchild has. At the end of December, 1968, just overtwo-thirds of the mentally subnormal children under16 living in the community were receiving some sortof training, but less than a third of those over 16.In many areas plans for the provision of additionaltraining centres and hostels have had to be deferredfor lack of money. The standard of training providedin these centres is, in any case, the report adds, oftenvery low. The report also criticises social workersfor failing to maintain contact with the families ofthe mentally handicapped; in general, visits are

made only when a crisis arises. The parents oftenfeel that they have to fight with the local authorities,first of all to find out what help they are entitled to,and second, to obtain it. General practitioners oftenact as little more than referral agents in these cases,and parents have complained that they have greatdifficulty in discovering full details of the nature andextent of their children’s illness. Many familiesbecome socially isolated in these circumstances,without anyone to baby-sit, and no chance of aholiday. It is not surprising that, very often, at thetime of assessment of the mentally handicapped child,the mother is in more urgent need of treatment thanthe child.The need for radical changes in the provision for

Britain’s mentally handicapped is now extremelyurgent. New ways of caring for these people and ofhelping their families are, of course, being put intopractice. For example, a report on an assessmentunit for the mentally handicapped at Stoke Park

Hospital, Bristol, shows that the patient, the parents,and the community all benefit from such a unit.The patient receives a full mental and physical assess-ment, and recommendations are made about the mostsuitable placement. The parents learn the truth abouttheir children and are given advice on how best tohelp them. They are comforted by the knowledgethat the child will have somewhere to go when theycan no longer care for him, and they lose some of theirfear of the hospital by coming into close contact

with it. The unit is in touch with all the local com-munity services, as well as with the hospital. Butprojects like this, however successful in isolation, cango only a small way: no amount of assessment canmake up for the absence of friendly places to whichparents and society may, with a clear conscience,send the patient.

PREVENTION OF GRAFT REJECTION

DURING the past decade immunosuppressive therapyin support of organ transplantation has been based oncorticosteroids and azathioprine. Azathioprine doseshave been remarkably uniform, the maximum tolerateddose being given to each patient. But wide variationshave been reported in basic corticosteroid doseschedules: most workers give moderately high doses atfirst, the speed of dose reduction being variable. Insome early series, 1,2 steroids were withheld until evi-dence of rejection appeared. The use of heterologousantilymphocyte globulin (A.L.G.), thoracic-duct drain-age, and thymectomy encouraged the giving of smallerdoses of corticosteroids, especially in young and stillgrowing patients, so that unwanted effects were

minimised.In a proportion of well-matched donor/recipient

groups, basic immunosuppressive therapy should beadequate to overcome acute rejection, but when stronghistoincompatibility is present, and in certain reci-

pients who, though well-matched, reject the graft, aspecific anti-rejection regimen is necessary. It is

customary to increase the dose of corticosteroids and toadd actinomycin C, while keeping the azathioprinedose at the maximum tolerated level. As for the valueof A.L.G. in rejection, results so far have often beenunconvincing, though those of Sheil et al.3 are morehopeful. Local irradiation is still practised by somecentres. Long-continued high-dosage steroid therapy,either by mouth or intramuscularly, is invariably asso-ciated with severe cushingoid features, delayed healing,a rise in the incidence of infection, avascular bonenecrosis, peptic ulceration, and arrest of growth inthe young.

Intra-arterial infusion of methylprednisolone, hepa-rin, and actinomycin C from the time of transplanta-tion for up to forty-eight hours (and later in rejectionepisodes) produced a significant reduction in earlyrejection reactions and prolonged survival. 4,5 5 Thistechnique has not been exploited as widely as mighthave been expected.On p. 876 Mr. Bell and his colleagues in Glasgow

present the results of their immunosuppressive regi-men in 16 recipients of renal allografts-13 fromcadavers and 3 from sibling live donors. The aim is togive large (1 g.) doses of prednisolone intravenouslyduring the transplant operation, followed by similarintravenous doses during episodes of rejection. Con-ventional dose regimens of oral prednisolone andazathioprine were also in use. By virtue of the shorthalf-life of prednisolone given intravenously, the hopeis to achieve the greatest anti-rejection benefit withoutundesirable effects.

Although all recipients of cadaveric allografts hadperiods of postoperative oliguria, it seemed that noneof the kidneys underwent rejection during the crucialoliguric period. Perhaps the all-too-common acuterejection at seven to ten days had been delayed by the

1. Starzl, T. E., Marchioro, T. L., Waddell, W. R. Surgery Gynec.Obstet. 1963, 117, 385.

2. Hamburger, J., Crosnier, J., Dormont, J. Lancet, 1965, i, 985.3. Sheil, A. G. R., Mears, D., Kelley, G. E., Rogers, J. H., Storey,

B. G., Johnson, J. R., May, J., Charlesworth, J., Kalowski, S.,Stewart, J. H. Lancet, Feb. 20, 1971, p. 359.

4. Kountz, S. L., Cohn, R. in Advances in Transplantation; p. 617,Copenhagen, 1967.

5. Kountz, S. L., Cohn, R. Lancet, 1969, i, 338.

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initial intravenous prednisolone. 13 out of 16 graftssurvived for from four months to twenty-four months;and 15 out of 18 rejection episodes (diagnosed clini-cally and not confirmed by biopsy examination) weresuccessfully reversed. In 3 badly matched cases,

transplantation failed. Mr. Bell and his associates alsorecord that intravenous prednisolone can prolong thefunction of heterotopically transplanted rat hearts,protected initially with antilymphocytic serum.

CONTRACTILE MICROFILAMENTS IN CELLMOVEMENT AND IN EMBRYONIC DEVELOPMENT

CONTRACTILITY is one of the fundamental propertiesof living tissue. Although much information is avail-able about the specialised contractile cells of striatedmuscle, much less is known about the way in whichother cells or parts of cells move. 1 Electron micro-

graphs show fine (50 A) filamentous structures in

many animal and plant cells, and from their dispositionit has been concluded that they represent a contractilesystem. Evidence supporting this interpretation hascome from work with the compound cytochalasin B,which is a fungal extract with a novel macrolidestructure in which a lactone ring is joined to a bicycliclactam. It was first found that application of thismaterial causes several types of cell to become multi-nucleate. 2, 3 The mechanism was elucidated bySchroeder who observed that cytochalasin causes

cleavage furrows in fertilised sea-urchin eggs to dis-appear, although the mitotic spindle continues to

function; hence the two nuclei separate but remainin a single cell. Schroeder found that cytochalasindisperses the contractile ring, a band of microfilamentsjust below the cleavage furrow which appears to

contract and pinch the cell in two.Evidence that cytochalasin reacts rather speci-

fically with contractile microfilament systems in manydifferent cell types has now been presented. Several

processes are reversibly inhibited by cytochalasin,including movement of heart fibroblasts and other

cells, activity of the growth cones of nerve-cell axons,cytoplasmic streaming, and shortening of the plateletconstituent, thrombesthenin, which is concernedin blood-clot retraction. In all these situations,ordered microfilament systems which are present inthe normal cells are dispersed by cytochalasin, butother cellular structures, including the microtubulesof the mitotic spindle, are unaffected. Thus, it isnot surprising that movements in relation to micro-tubular systems (such as spindle contraction andbeating of cilia and flagella) are not influenced bycytochalasin. Some labile microtubular systems, suchas those of the mitotic spindle, are dispersed by col-chicine, but this drug, even in high concentrations,has no demonstrable effect on movements due tomicrofilaments which are sensitive to cytochalasin.Neither agent in the concentrations used has detectableeffects on overall metabolism or protein synthesis.

1. Symp. Soc. exp. Biol. 1968, 22, 1.2. Carter, S. B. Nature, 1967, 213, 261.3. Ridler, M. A. C., Smith, G. F. J. Cell Sci. 1968, 3, 595.4. Schroeder, T. E. Biol. Bull. 1969, 137, 413.5. Wessells, N. K., Spooner, B. S., Ash, J. F., Bradley, M. O.,

Luduenda, M. A., Taylor, E. L., Wrenn, J. T., Yamada, K. M.Science, 1971, 171, 135.

If their effects prove to be as specific as the evidenceso far suggests, colchicine and cytochalasin will beuseful tools in the analysis of the roles of microtubulesand microfilaments in cell structure and movement.

Controlled contraction of microfilament systemsalso seems to play an important part in the morpho-genesis of the embryo. Cloney 6 showed that the rapidshortening (in a few minutes) of tadpole tails duringmetamorphosis is caused by contraction of a micro-filament system in epidermal or notochordal cells.Baker and Schroeder found similar filaments in cellsof the amphibian embryonic medullary plate and

suggested that their contraction at the outer apicalends of the cells causes the flat plate to sink down-wards to form a groove, the precursor of the hollowcanal within the vertebrate central nervous system.The model of Baker and Schroeder, in which themicrofilaments act like a "purse string", may havewide application to organogenesis in vertebrateembryos. Many of the early stages of organ develop-ment involve the orderly invagination or evaginationof cell layers, and carefully timed contraction ofbands of microfilaments which develop where theyare required seems to be an essential step in devel-opment. For example, gastrulation, invagination ofthe flat lens placode to form the lens cap, and formationof the pancreatic diverticulum are all events in which aring of filaments is found at one end of the partici-pating cells, and at that end narrowing takes place.Further instances include the budding of chickoviducts and salivary glands in culture to form dif-ferentiated structures; all these processes are rever-

sibly inhibited by cytochalasin. õ

Analysis of the role of different mechanisms ofcontractility in various situations is an importantcontribution to cell biology and embryogenesis, butit may also have interesting implications in pathologyand pharmacology. There is already evidence thatcontractile microfilament systems are concernedin clot retraction and many types of cell movement,including nerve-cell elongation; such movements

are essential in wound healing. If, as seems possible,contractile microfilaments are also involved in dis-

charge of secretory and other granules from cells, theaction of the microfilaments and what triggers itwould be of great importance in drug action. Butthe prediction that sensitivity to cytochalasin impliesthe presence of some type of contractile micro filamentsystem remains to be tested on systems of medicalinterest.The biochemical basis of microfilament contrac-

tion is not yet established, although calcium-activatedadenosine-triphosphatase systems resembling acto-

myosin have been extracted from many differentcell types, including blood-platelets.8 8 A componentof myosin (heavy meromyosin) can be shown to

bind to actin-like microfilaments beneath the plasmamembrane of cells,9 although these filaments may bedistinct from those responsive to cytochalasin. Much re-mains to be learned about the role of these different typesof microfilament, but the way is open for rapid progress.

6. Cloney, R. A. Z. Zellforsch. 1969, 100, 31.7. Baker, P. C., Schroeder, T. E. Develop. Biol. 1967, 15, 432.8. Bettex-Galland, M., Luscher, E. F. Adv. Protein Chem. 1965, 20, 1.9. Ishikawa, H., Bischoff, R., Holtzer, H. J. Cell Biol. 1969, 43, 312.