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flocculation reaction 891017 is still being investigated.The fact that flocculation of chylomicrons is caused bythe serum of these patients may, however, be significantin relation to the production of fat-emboli.The occurrence of demyelination is an effect of leci-

thinase which might be expected, or it may be secondaryto fat-embolism in the central nervous system. It is im-possible to demonstrate free toxin in the blood-stream 14although more remote effects are taking place. This maybe due to the concentration in the blood being too low forthe methods of detection available, and to the subsequentfixation of this toxin in the nervous system with a cumu-lative effect, or alternatively there may be a maskingeffect of the circulating toxin in the blood. We havenot detected any obvious neurological symptoms in ouranimals, but these are difficult to elicit. In our clinicalmaterial some gross changes have been seen, but a moredetailed study of this aspect of the problem is required.

Clostridial fat-embolism is of interest not only becauseit may be important in the pathology of clostridialinfections but also because it may throw some light on themechanism by which fat-embolism can occur in othersurgical conditions. With regard to the origin of thefat in clostridial fat-embolism, there are obviously twopossibilities. The first is the free fat which is liberatedfrom adipose tissue and muscles, and can be seen aslarge globules in in-vitro studies and in the material

. from the site of tissue destruction. The second is fromflocculated chylomicrons and the fatty material set freefrom broken lipoprotein complexes. In our experi-mental studies there seems little doubt that the fat mustbe derived from the site of local destruction, since inthese animals the few chylomicrons present do notflocculate with the toxin, and the lipoprotein complexis resistant to lecithinase. Furthermore, fat-embolismcan -be demonstrated within an hour of injection oftoxin, and the toxin even when acting on suitable humansubstrates will not- produce free fat from the blood com-ponents for at least 12 hours. The precise mechanismby which the fat globules pass into the blood-streamis still under investigation. The origin of the fat inhuman subjects is more difficult to determine, especiallyas some of the cases also have fractures. There is nodoubt however that extensive fat-embolism can occurin the human subject without any fracture being present.Whether or not flocculation of fat particles and thebreakdown of lipoprotein complexes are importantcontributions to the clostridial fat-embolism syndromein man is still to be decided.

Summary .

The effect of Cl. welchii toxin on tissue and fluidsubstrates has been studied in, vitro, in animals, and inhuman subjects, with special reference to the effect oflecithinase on structural lipids.The direct local effects on connective tissue, striated

muscle,adipose tissue, and peripheral nerve are described.The, action of the toxin on red blood-cells, chylomicrons,

and plasma lipoprotein complexes are compared inguineapig and man. A chylomicron flocculation testhas been devised and applied in human cases of clostri-dial infection. -

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Demyelination in the central nervous system can bedemonstrated in vitro, and in experimental and clinicalstudies. Fat-embolism can be produced experimentally by

intramuscular or intraperitoneal injection of Cl. welchiitoxin, and. has also been demonstrated in human post-mortem material. The origin of the fat in the animalexperiments is the site of local tissue destruction.We wish to thank Sir Percival Hartley, FRS, for a supply of

standard antitoxin, Dr. W. E. van Heyningen for providingthe Cl. welchii toxin, Dr. H. J. Rogers for estimating itshyaluronidase content, and Miss M. G. Macfarlane for

assaying the antitoxin titre of a number of sera. We arealso indebted to the Sir Halley Stewart Trust for theirfinancial support.

Since sending this paper to press it has come to our noticethat R. G. Macfarlane and J. D. MacLennan have recentlycome to somewhat similar conclusions as a result of an inde-

pendent investigation. We have had the advantage of dis-cussing this unpublished work personally with Major Mac-Lennan to whom we are much indebted.

References at foot of next column

PROF. FRAZER AND OTHERS : REFERENCES1. Bashford, E. F. (1919) Manual of War Surgery, London.2. Blix, G., Tiselius, A., Svensson, H. (1941) J. biol. Chem. 137, 485.3. Bloor, W. R., Snider, R. H. (1937) Proc. Soc. exp. biol., NY,

36, 215.4. Briggs, A. P. (1922) J. biol. Chem. 53, 13.5. Elkes, J. J., Frazer, A. C. (1943) J. Physiol. 102, 24 P.6. — — (1944) unpublished work.7. Glenny, A. T., Barr, M., Llewellyn-Jones, M., Dalling, T., Ross,

H. E. (1933) J. Path. Bact. 37, 53.8. Gray, S. J. (1940) Arch. intern. Med. 65, 524.9. Hanger, F. M. (1939) J. clin. Invest. 18, 261.

10. Kabat, E. A., Hanger, F. M., Moore, D. M., Landon, M. (1943)Ibid, 22, 563.

11. Kropp, B., Smith, D. G. (1941) War Med. 1, 682.12. McClean, D. (1943) Biochem. J. 37, 169.13. — Hale, C. W. (1941) J. Path. Bact. 35, 159.14. — Rogers, H. J., Williams, B. W. (1943) Lancet, i, 355.15. Macfarlane, M. G., Knight, B. C. J. G. (1941) Biochem. J. 35,

884. 16. Macheboeuf, M. (1937) État des lipides dans la matière vivante,

Paris.17. MacLagan, N. F. (1944) Mature, Lond. 154, 671.18. MRC Report (1919) Reports of Committee upon Anaerobic

Bacteria and Infections. Spec. Rep. Ser. med. Res. Coun.,Lond. No. 39.

19. Nagler, F. P. D. (1939) Brit. J. exp. Path. 20, 473. (1941)J. Path. Bact. 52, 105.

20. Tait, H., King, E. J. (1936) Biochem. J. 30, 285.21. van Heyningen, W. E. (1941) Ibid, 35, 1257.22. West, E. S., Hoagland, C. L., Curtis, G. H. (1934) J. biol. Chem.

104, 627.

FACTORS PROMOTING VENOUS RETURNFROM THE ARM IN MAN

E. BOWERS E. J. M. CAMPBELL

C. H. P. JOHNSTONSTUDENTS IN THE DEPARTMENT OF PHYSIOLOGY, MIDDLESEX

HOSPITAL MEDICAL SCHOOL, LONDON

THE criticism by Roberts (1945) of current views onthe mechanism of the venous return stimulated us tocarry out the following two series of experiments.

ROLE OF MUSCLE PUMPThe first series was performed to determine whether

a combination of valves and contracting muscles (" musclepump ") could produce a rise of venous pressure in theabsence of the vis a tergo ; and to obtain some quantita-tive measure of any such rise in pressure.

Method.—The subject’s arm was supported in the hori.zontal position at heart level. Three blood-pressure cuffswere placed round the arm : (A) a narrow cuff 2 in. wideround the proximal part of the upper arm ; (B) a wide cuff4 in. wide below this ; and (c) a narrow cuff 2 in. wide belowcuff (B), just below the elbow.

Cuff (c) was inflated to 80 mm. Hg pressure, and cuff (B) to90-100 mm. Hg. After ten seconds, allowed for the filling ofveins distal to cuff (c), cuff (A) was rapidly inflated to 210mm. Hg to occlude the arterial inflow. Cuff (B) was thendeflated and removed, leaving, a segment of collapsed veinsbetween cuffs (A) and (c). Thus the arm below cuff (A) waswithout arterial inflow or venous outflow. Cuff (c) dividedthe arm into two segments. Any blood passing from thedistal to the proximal segment must overcome the pressurein cuff (c) and could be demonstrated by the filling of theveins in the collapsed segment between cuffs (c) and (A).

Findings.—When the arm was left in this condition forfive minutes, no changes in the veins were observed, indicatingthat no blood was passing under cuff (c). On clenching andunclenchimg the hand six times, the veins in the collapsedsegment between (c) and (A) filled with blood. Distensionof the’veins proximal to each valve in the distal segment wasalso observed, commencing 5 in. below cuff (c).

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Repeating the experiment with increased pressure in cuff(c), the filling of the veins in the collapsed segment becameless apparent, and at pressures over 100 mm. Hg it could notbe detected.

These experiments showed that a combination ofvalves and contracting muscles (in absence of vis atergo) can raise venous pressure to at least 80 mm. Hg(104 cm. H2O).

ROLE OF VIS A TERGO .

Lewis and Grant (1925) showed that, after conipleteocclusion of the limb vessels, release of the limb circula-tion results in a greatly increased blood-flow throughthe limb, accompanied by dilatation of arterioles andcapillaries (reactive hypersemia). This effect was also

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observed when only the veins were occluded. Dilatationof the small peripheral vessels lowers the frictionalresistance and permits more complete transfer of thearterial pressure to the venous side of the circulation.Our second. series of experiments was performed to

demonstrate this transfer of pressure and ascertain itsorder of magnitude under varying degrees of peripheral

dilatation occurring during reactive hyperaemia.Method.-With the arm hanging vertically downwards, a 2 in.

cuff was placed immediately above the subject’s elbow, inflatedto 80 mm. Hg and left for ten seconds so that the veins shouldfill. It was next inflated to 220 mm. Hg and left at this levelfor varying periods. The pressure was then lowered untilblood flowed into the veins proximal to the cuff. This wasobserved in the following way. During the gradual loweringof the pressure a vein proximal to the cuff was collapsed by" milking " towards the heart and maintaining pressure onits proximal end digitally. When blood entered this veinfrom below the cuff, the vein immediately became distended,indicating that the venous pressure exceeded that in the cuff.

After obtaining an approximate value of the venous pres-sure by this method, subsequent readings were taken afterrapid lowering of the pressure to the neighbourhood of thisfigure. By this means damming-up of blood in the veinsdistal to the cuff was minimised. ,

Findings.—The venous pressure increased with increase inthe duration of arterial occlusion and the intensity of theresulting reactive e hypersemia. The range of occlusiondurations was 3 seconds to 3 minutes. The correspondingvenous pressures were 20-30 and 80-100 mm. Hg.

These results show that venous pressure due whollyto vis a tergo increases with the degree of peripheraldilatation. Under conditions of extreme vasodilatation,unaided vis a tergo may produce a venous pressure of atleast 80 mm. Hg (104 cm. H2O). It is to be noted thatthis value was obtained with the arm hanging verticallydownwards and was therefore being exerted againstgravity. As the cuff was 30 cm. below heart level(sternal angle)’ the effective venous pressure was there-fore 134 cm. H2O (100 mm. Hg). In other words itapproximated closely to arterial blood-pressure.

DISCUSSION

It seems likely therefore that under conditions of restvenous pressure in a limb is to a considerable extentgoverned by the tone of the small peripheral vessels.When this tone is diminished, and the vessels are dilated,arterial pressure is transferred to the venous side morecompletely than when tone is high. The tone of thearterioles is in turn governed by the level of dilatormetabolites, this depending on the degree of circulatorystagnation present.A possible explanation of the control of the venous

return from the extremities at rest thus presents itself.Slowing of blood-flow in the veins results in accumulationof metabolites, which by their direct action dilate thesmall vessels and allow more of the arterial pressure to betransferred to the veins ; the rate of flow in the veinsconsequently increases.In exercise an enormous increase in blood-flow through

a limb (accompanied by vasodilatation) has beendemonstrated by Grant (1938). Our experimentsindicate that two factors are involved in venous returnin exercise : (a) dilatation of peripheral vessels increasesthe vis a tergo, (b) the combination of venous valves andcontracting muscles greatly facilitates the venous return.

SUMMARY

1. Experiments were performed to obtain a quantita-tive estimate of two factors concerned in the mechanismof venous return" ,

2. The " muscle pump " alone can produce a venouspressure of at least 80 mm. Hg (104 cm. H2O).

3. Venous pressure due to vis a tergo varies inverselywith the state of peripheral vascular tone and can pro-duce a venous pressure of at least 80 mm. Hg againstgravity-i.e., 100 mm. Hg or 134- cm. H2O effectivepressure.We should like to thank Prof. Samson Wright for his help

and encouragement in the preparation of this article.

REFERENCES

Grant, R. T. (1938) Clin. Sci. 3, 157.Lewis. T., Grant, R. (1925) Heart, 12, 73.Roberts, Ff. (1945) Lancet, i, 209.

HYPERTHYROIDISMTREATED WITH METHYL THIOURACIL

DUNCAN LEYS, D M OXFD, F R C P

PHYSICIAN, ROYAL NORTHERN INFIRMARY, INVERNESS

THE toxic effects of thiourea and thiouracil are

comparable to those caused by the sulphonamides, whichin large doses have a similar action in causing an iodinedeficiency and subsequent goitre. The incidence andseriousness of these effects with thiourea (Newcomb andDeanes 1944, Welshman 1944, St. Johnston 1944, Haler1944) have caused some apprehension among clinicians,and particularly among surgeons who have broughtthe operation of subtotal thyroidectomy to high perfec-tion, with very low mortality. The proportion of indi-viduals showing these effects with a minimum effectivedose of thiourea for a minimum effective period is prob-ably comparable to the incidence of toxicity in effectivesulphapyridine therapy, and just as less toxic compoundshave replaced sulphapyridine so thiouracil and othercompounds are likely to replace thiourea because of theavoidance of serious toxic effects. One fatal case ofagranulocytosis has been reported with thiouracil(Himsworth 1944). This patient had had long previoustreatment with iodine and appeared resistant to treat-ment with thiouracil, the dose of which was held at1 g. daily for 4 weeks and then increased to 2 g.Another derivative of thiourea, 4-methyl thiouracil,

has much the same action as thiouracil, but is more easilyand safely manufactured. The structural formulae arehere compared with that of thiourea.

The purpose of this paper is to report the use of methylthiouracil in 16 cases of hyperthyroidism.

METHOD AND RESULTS OF ADMINISTRATION

Methyl thiouracil was given in daily doses of 200 mg.,stepped up by 200 mg. every day or every other day tothe effective daily dose. At first this was thought to be1-0 g., but in 3 patients a daily dose of 1-4 g. was usedfor a few days : later, it was thought wiser not to exceeda daily dose of 1-0 g., and in cases now under treatmentthe dose is being limited to 0-8 g. When a satisfactoryrate of gain in weight was attained, a maintenance dosewas substituted, of 200 mg. in the first cases, later of100 or even 50 mg. Phenobarbitone was employedduring the period which invariably occurs between thebeginning of treatment with methyl thiouracil andimprovement in symptoms. All patients had someenlargement of the thyroid gland ; several had adenoma.Duration of symptoms ranged from a few weeks to 2years or more. Ages ranged from 16 to 68 years.The BMR was estimated either by Benedict’s method

or (for lack of technical assistance and in patients withouthypertension) by Reade’s formula under the sameconditions of isolation and fasting. Its determinationis neither more nor less necessary than with other formsof therapy, and will be mainly useful in the differentialdiagnosis of anxiety states without hyperthyroidism,and to confirm or refute impressions of hypothyroidism’consequent on atrophy. Observations on the blood-cholesterol were made routinely and were possibly asinformative as the BMR.

There seems no reason to suppose that the careful useof thiouracil will result in such atrophy as will causeundesirable hypothyroidism, or at least that the riskof hypothyroidism will be any greater than with opera-tion or any less amenable to treatment with- thyroxineif necessary. Astwood (1944) has made some pre-liminary observations on the production of hypo-thyroidism in persons with normal thyroid function bythe employment of daily doses of 400-600 mg. daily andhas found that it requires treatment over several monthsto produce a fall in the BMR.