444 of the microcirculation by platelets has been produced by disruptive forces which cause the dislocation of endothelial cell junctional complexes. 1Z In animals a single injection of corticotrophin (A.C.T.H.) in gelatin solFREQUENCY OF PRESSURE-SORES FOLLOWING OPERATION

administered four hours before trauma stabilises the junctions and prevents cell separation. Platelet thrombosis does not occur and there is marked reduction in the frequency of pressure-sores.3 This paper describes the prevention of pressure-sores which occur in patients subject to operation, who carry a high risk of pressure-sores.

vent

MATERIALS AND METHODS

The trial was conducted in a double-blind form and stratified. A total of 85men and women over the age of sixty-five were admitted, all of whom gave their informed consent. There was no clinical evidence of pressure-sores at the time of operation. The operations to be undergone were those associated with surgery to the upper shaft of the femur and to the hip joint. As part of the pre-medication procedure, 80 LU. of A.C.T.H. in gelatin solvent (’Acthar’ gel) or a placebo consisting of the gelatin solvent alone was administered intramuscularly four hours before operation. This was done in a random fashion. The statistical significance of the results was determined

using Fischer’s test.

without risk to the patient. It is of especial use in the busy understaffed ward, and in the field or casualty situation. Two factors must be borne in mind. Firstly, that the inhibitory effect is a "once only" phenomenon associated with disruptive damage and does not occur where necrosis is due to pressure alone where there is no endothelial cell separation.5 Secondly, optimum cortisol levels following the injection of A.C.T.H. have to be reached by the time that the endothelial cell separation begins to occur.67 If the drug is given too late, no harm is done but there is no inhibitory effect. Sustained treatment, as in the case of long-term corticosteroid therapy, 8 causes pressure-sores to deteriorate. Total-hip replacement is an elective procedure where the reduction in the frequency of pressure-sores, by the technique described, is statistically significant due to the fact that correct timing is possible. In the case of operations for fractured neck of femur, the results were without precedent in this hospital. There were, however, periods of up to four days where sustained pressure was applied to the sacral tissues and sores due to anoxic necrosis did occur. Correct timing of the administration of A.C.T.H. to prevent disruptive damage was not possible, As there were no complications in the administration of a single injection of 80 l.U. A.C.T.H. in gelatin solvent, we suggest that this should form part of standard premedi cation treatment. grateful to Mr T. G. Thomas for allowing us to study the in his care and to the staff of the Buckland Hospital, Dover, for their invaluable assistance. Also to Armour Pharmaceutical Co. Limited, who supplied the material used in the trials and analysed the statistical significance of the results. We

are

patients

Requests for reprints should be addressed to A.A.B., Nunnery Fields Hospital, Canterbury, Kent CT1 3LP. REFERENCES

RESULTS

be seen from the table that 43 patients received gelatin solvent alone. Of these, 12 developed pressuresores, an overall frequency of 27% which was typical of the orthopaedic wards of this hospital chosen for the trial. Five sores occurred in the 16 patients who received a total-hip replacement (31%) and occurred in the area of skin where a sand-bag had been placed to provide support during the operation. Of 27 patients operated on for fractures of the upper shaft of the femur (nail and plate, Thompson, Austin-Moore, McLaughlin) 7 developed sores (26%), a figure comparable to that reported by Campbell.4 These were of generalised sacrococcygeal It

can

distribution. 42 patients received the active compound (acthar gel). 5 developed sores (12%). Although this figure was without precedent on the orthopaedic wards of this hospital it was not statistically significant using Fischen’s test. Of the 16 patients who had a total-hip replacement none developed sores. This was statistically significant. Of 26 patients who were operated on for fractured neck of femur, 5 developed pressure-sores (19%). Neither in this trial nor in another series was any complication observed in any of the patients who received a single dose of 80 i.u. of A.C.T.H. in gelatin solvent. DISCUSSION

The drug-based prevention of pressure-sores by the use of a single preoperative injection of A.C.T.H. in gelatin solvent has provided a useful cost-effective procedure

1. Barton, A. A., Barton, M. Aust. J. exp. Biol. med. Sci. 1968, 46, 166. 2. Barton, A. A. Bedsore Biomechanics (edited by R. M. Kenedi, J. M. Cowden, and J. T. Scales); London, 1976.

3. Barton, A. A., Barton, M. J. Path. Bact. 1968, 96, 345. 4. Campbell, A. J. Age Ageing, 5, 102. 5. Willms-Kretschmer, K., Majno, G. Am. J. Path. 1969, 54, 327. 6. Glick, I. W., Friedman, M. Thorax, 1969, 24, 415. 7. Barton, A. A., Barton, M. Br. J. Pharmac. 1969, 36, 219. 8. Barton, A. A., Barton, M. Age Ageing, 1973, 2, 55.

Hypothesis RELATION BETWEEN CARP

(MULTIPLE-SCLEROSIS ASSOCIATED) AGENT AND MULTIPLE SCLEROSIS D. H. ADAMS Medical Research Council Demyelinating Diseases Unit, Newcastle General Hospital, Newcastle upon Tyne NE4 6BE

It is suggested that the Carp (multiple sclerosis associated and scrapie associated) agents may be the V-R.N.A. form of slow (D.N.A. viruses which are the ætiological agents of the two dis

Summary

eases.

INTRODUCTION

THERE has

recently been an upsurge of interest in the

transmissible factor found by Carp and co-workers’

I

445

Summary of hypothesis.

multiple sclerosis (M.S.) patients which decreased percentage of polymorphonuclear neutrophils (P.M.N.) in the peripheral blood of inocu-3 lated mice. Although there have been two published 2 and several unpublished failures to repeat their results, an independent confirmation has been reported.4 The assay of this factor has mostly been by P.M.N. depression, and the second group of investigators4 show very clearly how temperamental the methodis. Other procedures such as a decreased growth of PAM cells6 and haemagglutination’ have been equally unsatisfactory. tissues from causes a

It is not known how the transmissible factor, called ILS,A.A.4 (M.s.-associated agent), affects P.M.N. levels, but several steps must be involved, any of which may be

susceptible to interference-leading to either false positive or false negative results. However, the experimental data of the two groups1 4are in impressive accord. The simplest hypothesis would seem to be that the results are valid, and that the difficulties in repeating them derive from the assay system.

.

PARALLELS WITH SCRAPIE AGENT

Perhaps prematurely, the results have been hailed as a major advance in M.S. and have been discussed in terms of whether M.S.A.A. is the aetiological agent.8-10 However, and proceeding on the assumption of the basic validity of the results, it appears to have been generally overlooked that the original observations from Carp’s group, published simultaneously with the M.S. work, showed that the same or a similar factor was also associated with scrapie tissue, obtained either from infected mice or from scrapie sheep, the natural host.’This can hardly fail to be taken into account in any serious attempt to assess the relevance of M.S.A.A. to M.S. Both the scrapie-associated agent (S.A.A.) and M.S.A.A. are daimed to be serially transmissible to mice, and to produce brain titres of around 1014 infective doses/g wet weight or more; to persist for long periods in the brain and (probably at much lower titre) in the sera of the infected host; and to pass 50 nm but not 25 nm filters.

aetiological agent of M.S. either, especially in view of additional evidence that a considerable proportion of East African blood-donors show neutralising activity and this in an area in which M.S. inciagainst M.S.A.A., dence is low/5 Carp et al.’2 have suggested that S.A.A. might be:

the

(1) An adventitious virus associated with, but having no influence on the course of, scrapie disease; (2) a virus latent in mice induced to proliferate during scrapie infection; or (3) more speculatively,

part of a two-particle system in which the defective form (scrapie agent) could replicate and cause disease only in the presence of the complete form (S.A.A.). So far as (1) is concerned, the best analogy is the plasma lactate dehydrogenase (L.D.H.) elevating virus discovered by Riley and co-workers’3 in transplantable mouse tumours, which was soon shown to be an adventitious virus unrelated to tumour growth. It has features in common with S.A.A. and M.S.A.A. in persisting for long periods and reaching very high titres, but principally occurs in the serum of infected animals. Adams and Field found L.D.H.-elevating virus associated with scrapie mice but this was shown to be because the colony itself was infected.14 Mice inoculated with the ME7 scrapie agent kindly provided by Dr A. G. Dickinson which has been reported to contain S.A.A." were free of L.D.H. virus (unpublished). Obviously then S.A.A. is not the L.D.H. agent, and if the facts are as reported 1 4 namely, that M.s. patients, but not normal humans over the range tested, carry M.S.A.A.-then it seems unlikely that either M.S.A.A. or S.A.A. can be adventitious viruses of the L.D.H.-elevating type. Incidentally, although it is stated’ that sera from M.s. patients may contain both M.S.A.A. and M.S.A.A. antibodies, it is not clear whether humans (e.g., M.s. contacts) with M.S.A.A. antibodies still carry infectious M.S.A.A. As already indicated, mice deliberately infected with either M.S.A.A. or S.A.A. retain active virus in their tissues and sera for long periods. It would be of considerable interest to see whether individuals who have been in contact with scrapie carry S.A.A. or S.A.A. antibodies. Possibility (2) would seem to require similar latent viruses to be universally distributed through a wide range of animal species, including man, which seems unlikely. There is really no evidence for or against (3), especially since the suggestion itself is not put very clearly. -

Although parallels have been drawn between the properties of the scrapie agent and of S.A.A.," 12 there can

POSSIBLE ROLE OF VIRUS R.N.A.

be almost no room to doubt that the two are different ’ilruses. The titre of S.A.A. rises much faster in the brain than that of the scrapie agent, reaching a higher titre by several logs, and, as might be expected from the data, sufficiently high dilutions of scrapie-mouse-brain homoKMtes can be prepared to dilute out the scrapie agent, ;u; still transmit S.A.A.12 Although mice so inoculated failed to develop scrapie after a long period, S.A.A. could x senally transmitted from their tissues.12 By extrapothese data suggest that M.S.A.A. is probably not

What then could be the relation between S.A.A. and scrapie and between M.S.A.A. and M.s.? The ability of R.N.A. viruses to assume D.N.A. forms in cell cultures by reverse transcriptase enzymes (probably carried by adventitious leukoviruses) may provide a clue. Visna virus R.N.A. replicates via a D.N.A. intermediate usmg a virion-carried reverse transcriptase, and the proviral D.N.A. integrates with the host cell genome. 16 Zhdanov and Parfanovichl7 also showed that cellular nuclear D.N.A. can integrate genomes of classic infectious

446

viruses, including measles. According to Zhdanov’8 and Simpson and linuma19 common R.N.A. viruses may indeed take up D.N.A. forms in tissue culture, probably by utilising reverse transcriptase systems carried by adventitious leukoviruses, and, further, D.N.A. extracted from such cultures can transmit the original infection. Adams and Be1l2O suggested that subacute sclerosing panencephalitis (S.S.P.E.) arises from a rare co-infection of measles cases with an adventitious reverse-transcriptasecarrying leukovirus followed by transcription of measles virion R.N.A. via m-R.N.A. to a D.N.A. form and the establishment of the D.N.A. as a new infectious entity either as the core of a new slow virus or as a membrane-attached viroid. I suggest that s.A.A. and M.S.A.A. may be R.N.A. viruses related to scrapie and M.S. in the same way-i.e., that they are viruses based on the v-R.M.A. forms of the actual aaiological agents. Although there is as yet little conclusive evidence on the nature of the nucleic-acid core of the scrapie agent itself, theoretical considerations and such practical evidence as there is suggest that the scrapie agent is based on D.N.A.20-22 Adams and Dickinson23 also indicated how the assumption that the aetiological agent of M.S. is a scrapie-like slow virus could account for some of the disease characteristics. This proposition is summarised in the figure. Certainly in scrapie, where the most probable size of the core is between 1 x 105 and 2x 105 daltons, the m-R.M.A. and proteins translated from it must also be small. However, there seems no reason why host macromolecules could not be coopted to build the s.A.A. virion up to the 25+nm size indicated by the filtration data. This must happen in the assembly of the scrapie agent itself since the size, as estimated by filtration data, is in the same range. The experimental data showing that proviral D.N.A. produced by reverse transcription of viral R.N .A. 15 16 could be extracted and used to reinfect new cells with recovery of the original (R.N.A.) virus has already been mentioned. Consequently if the above proposals concerning S.A.A. and M.S.A.A. are correct, it should be possible to passage these viruses with D.N.A. isolated from scrapie or M.S. brain, respectively. If successful, such experiments could provide positive evidence of a viral basis for M.s. However, such work must wait on the establishment of a reliable assay system for M.s.A.A.

miological evidence arising from movement of populations between high and low risk M.S. areas which suggests the involvement of a factor acquired at this age. The hypothesis would also indicate that the relationship between M.s. and scrapie is indeed close, as proposed some years ago, and how, by minor errors of transcription between D.N.A. and R.N.A. forms arising in rare instances, results such as those of Field24 involving the development of scrapie in sheep inoculated with M.s. material might occur. REFERENCES

1.

Carp, R. I., 618.

Licursi,

P.

C., Merz, P. A., Merz, G. S. J. exp. Med. 1972, 136,

2. Brown, P., Gajdusek, D. C. Nature, 1974, 247, 217. 3. McNeil, T. A., Killen, M., Trudgett, A. ibid. 1974, 249, 778.

Koldovsky, U., Koldovsky, P., Henle, G., Henle, W., Ackermann, R, Haase, G. Infect. Immun. 1975, 12, 1355. 5. Henle, G., Koldovsky, U., Koldovsky, R., Henle, W., Ackermann, R., Haase, G. ibid. 1975, 12, 1367. 6. Carp, R. I., Merz, G. S., Licursi, P. C. ibid. 1974, 9, 1011. 7. Warner, H. B., Carp, R. I., Narducci, R. Lancet, 1976, i, 688. 8. Lewin, R. New Sci. March 11, 1976, p. 554. 9. Mims, C. Nature, 1976, 260, 190. 10. Lancet, 1976, i, 459. 11. Licursi, P. C., Merz, P. A., Merz, G. S., Carp, R. I. Infect. Immun. 1972, 6, 370. 12. Carp, R. I., Merz, P. A., Licursi, P. C., Merz, G. S. J. infect. Dis. 1973, 128, 4.

256. 13. Riley, V., Lilly, F., Huerto, E., Bordell, D. Science 1960, 132, 545. 14. Adams, D. H., Field, E. J. J. gen. Virol. 1967, 1, 449. 15. Dickinson, A. G., Taylor, D. M., Fraser, H. Nature, 1974, 248, 510. 16. Haase, A. T., Varmus, H. F. Nature new Biol. 1973, 245, 237. 17. Zhdanov, V. M., Parfanovich, M. I. Arch. ges. Virusforsch. 1974, 45, 215. 18. Zhdanov, V. M. Nature, 1975, 256, 471. 19. Simpson, R. W., Iinuma, M. Proc. natn. Acad. Sci. U.S.A. 1975, 72 3230. 20. Adams, D. H., Bell, T. M. Med. Hypoth. 1976, 2, 55. 21. Adams, D. H. J. Neurochem. 1972, 19, 1869. 22. Adams, D. H. Biochem. Soc. Trans. 1973, 1, 1061. 23. Adams, D. H., Dickinson, J. P. Lancet, 1974, i, 1196. 24. Field, E. J. Int. Rev. exp. Path. 1969, 8, 129.

Methods and Devices USE OF PROGRAMMABLE CALCULATOR TO SOLVE PHYSIOLOGICAL EQUATIONS D. G. Ross

OTHER IMPLICATIONS

The suggestion also carries with it some further possibilities. One of the problems with diseases such as scrapie and M.s. is-how are they transmitted in Nature? It has, for example, proved virtually impossible to transmit scrapie to normal mice by caging then with scrapie-infected mice. Whether s.A.A. (or M.s.A.A.) would be transmitted under these circumstances is not yet known. However, the report that a high proportion of contacts of M.s. patients carry anti-M.s.A.A. antibodies,4 suggests that M.s.A.A. is transmissible without great difficulty. If R.N.A. viruses formed via reverse transcription of slowviral D.N.A. are transmissible by the normal contact routes, the original disease could arise in such individuals after co-infection with an adventitious leukovirus, as suggested for s.s.P.E.14 Such a leukovirus infection in an M.s.A.A.-carrying individual (or vice versa) occurring around the age of puberty might then explain the epide-

H.

J. MANSON

Department of Anœsthesia, Aberdeen Royal Infirmary, Aberdeen THE introduction of miniaturised integrated semiconductor circuitry has permitted the development of small electronic calculators.Cheap calculators are now available which can be programmed with keyed-in steps to perform complex mathematical procedures almost instantaneously. Such machines are well suited for processing data which require the repeated solution of an equation; their small size and portability place no restrictions on the time and place of their use, and programming is relatively simple. Doctors may well find programmable calculators useful in several applications, whether in research or in programming everyday calculations. The cheapest calculator of this type is the ’Sinclair Scientific Programmable’, which is supplied with several programs useful in science and technology but mostly not relevantIe medicine. Instructions for producing new programs are not supplied and it takes some time to elucidate the rules by tna, and error. We have therefore prepared programs for soliiiz

Relation between Carp (multiple-sclerosis associated) agent and multiple sclerosis.

444 of the microcirculation by platelets has been produced by disruptive forces which cause the dislocation of endothelial cell junctional complexes...
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