196

paid on a sessional basis. They are especiallyattracted to this system because it would offer adouble portal to specialism and would leave open thevexed issue of what is the best training for a con-sultant. Clinical assistantships, refresher courses,ward rounds, and clinical meetings are other linksbetween the doctor and the hospital that might wellbe reinforced. Like Mr. SANGSTER SIMMONDS, theScottish committee suggest that, as a two-way traffic,registrars might act as locums or temporary assistantsto the practitioners associated with their hospitals,while the practitioners might begin to take a largershare in undergraduate teaching.The committee readily recognise the general practi-

tioner’s claim to access to radiological departmentsand laboratories, and they think that the futuredevelopment of these services should be related tohis needs as well as to those of the hospital andspecialist services. The Sheffield scheme for medicalcoordination committees, described on another page,is a practical step towards making sure that the

practitioner is not overlooked in planning, whetheron the long or short view. Some of his just demandsmay be hard to meet today, but we can ensure thatthey have consideration, and where necessary priority,tomorrow.

1. Rappaport, H., Raum, M., Horrell, J. B. Amer. J. Path.1951, 27, 407.

2. Friesen, S. R., et al. Surgery, 1948, 24, 134.3. Robb-Smith, A. H. T. Lancet, 1941, i, 135.4. Harman, J. W., Ragaz, F. J. Amer. J. Path. 1950, 26, 551.

Fat-embolismFAT-EMBOLISM in man was first described by

ZENKER in 1862 ; and it is now regarded as a notuncommon cause of death after fractures of longbones. It has also been reported as a sequel ofburns, poisoning, and parturition, and in associationwith fat-necrosis, fatty liver, caisson disease, osteo-myelitis, diabetes mellitus, eclampsia, pancreatitis,and tuberculosis ; but in some of these conditionsmetabolic lipæmia may have been confused withtrue fat-embolism. The clinical manifestations are

essentially pulmonary or cerebral ; but emboli aresometimes found in other organs, including the

kidney and skin, and occasionally they are associatedwith bone-marrow embolism.1 FRIESEN and hisassociates 2 ascribe to this cause the peptic ulcersand erosions sometimes associated with fracturesof long bones.The incidence of pulmonary fat-embolism is

uncertain, because this disorder is so often associatedwith severe shock, which gives rise to similar symptomsand necropsy findings ; the only point of differentia-tion may be the abundant ectopic fat in the lung.Some idea of the incidence is to be had from figuresreported by ROBB-SMITH,3 who found that of 125cases of fatal accident 41 showed evidence of grosspulmonary involvement ; these 41 included 6 wherethere had been no bony injury, and in 29 death wasattributed directly to the embolism. Fat apparentlyacts as an embolus when the globules exceed 8 µin diameter 4 ; and symptoms referable to pulmonaryemboli may then appear in anything from threehours up to eight days. The disease often simulates

bronchopneumonia, but sometimes it manifests itselfless directly—for example, by increasingly profoundanæmia due to widespread bleeding into the alveolar

spaces. LEHMAN and MCNATTIN 5 claimed that if theamount of fat reaching the lungs is of the order of120 ml. or more, emboli will pass through the lungcapillaries and find their way into the systemiccirculation where they will initiate a train of secondarydisturbances. CARREAU and HIGGINS 6 ascribe the

rapid feeble pulse and the drop in blood-pressure toocclusion of the smaller coronary vessels with con-

sequent hyperæmia of the myocardium; whilecerebral embolism probably accounts for the restless-ness, headache, drowsiness, vomiting, and coma whichmay occur—sometimes suddenly after a period ofapparent recovery—in patients who have sustainedserious damage to a long bone. Other and morealarming symptoms may follow involvement of thebrain, including hallucinations, convulsions, spasms,paralysis, hyperthermia, and maniacal outbursts.These outbursts may be confused with alcoholism 7;and in a severely injured person it may be difficultto differentiate fat-embolism from intracranial trauma.The pathogenesis of this disorder is still in some

doubt. CARREAU and HIGGINS, like MILOSLAVICH,8hold that fat-embolism will occur when fat globules,liberated by disintegration of the supporting fibroustissues of the bone-marrow fat or adipose tissue,are sucked into torn veins, and that this process isenhanced by increased pressure from local bleeding.GAUSS 7 in 1916 suggested that the explanation ofthe common association of fat-embolism with fracturesof long bones was that the veins in the locality aresurrounded by a bony wall and so cannot collapse asthey can elsewhere in the body; while MILOSLAVICHascribed its supposed greater incidence in old peopleto the greater fluidity of their marrow fat. TOCANTINS,9however, claimed that the marrow cavity com

municates directly with the venous circulation.SCUDERI10 expressed doubts as to the nature of thefat, for he found that all the bone-marrow fatextracted from a femur was insufficient in itself tocause death. He thought that the lethal substancewas not neutral fat but one of its split products—oleic acid—which was seven times as toxic as neutralfat and was present in lethal quantity. LikewiseJEFFERSON and NECHELES11 hold that fat-embolismper se may not be dangerous unless fatty acids arereleased in or into the circulation. On the otherhand, the transported material has been shown togive the staining reactions for neutral fat.12 ARMINand GRANT13 suggest that gross pulmonary fat-embolism is unlikely to cause obvious symptoms or toaccount wholly or even partly for death. Theyfound that, in order to produce in the rabbit’s lung adegree of disease comparable to that which in man mightbe described post mortem as

"

severe," it was necessaryto inject 0·15 ml. of homologous renal fat per kg. body-weight ; and even this amount caused no evidentdisturbance in the animal. In the rabbit the fataldose of fat, introduced intravenously, was given byWARTHIN14 as 0·5—1 ml. per kg. body-weight, while5. Lehman, E. P., McNattin, R. F. Arch. Surg. 1928, 17, 179.6. Carreau, E. P., Higgins, G. A. Arch. intern. Med. 1951, 88, 692.7. Gauss, H. Ibid, 1916, 18, 76.8. Miloslavich, E. L. Wisconsin med. J. 1930, 29, 139.9. Tocantins, L. M. Amer. J. Physiol. 1943, 139, 265.

10. Scuderi, C. S. Surg. Gynec. Obstet. 1941, 72, 732.11. Jefferson, N. C., Necheles, H. Proc. Soc. exp. Biol., N,Y

1948, 68, 248.12. Denman, F. R., Gragg, L. Arch. Surg. 1948, 57, 325.13. Armin, J., Grant, R. T. Clin. Sci. 1951, 10, 441.14. Warthin, A. S. Int. Clin. 1913, 4, 171.

197

sÏMMmn)sl5 mentioned amounts of the order of 2 ml.per kg. AKMIN and GRANT found, however, that inthe rabbit a degree of fat-embolism which in itselfwas not fatal might become so when the circulationwas disturbed by reason of considerable bleeding ;and that death might be averted by transfusion.HABMAN and RAGAZ noted that with either dehydra-tion or " tourniquet shock " the mortality from

injection of homologous fat into rabbits was signi-ficantly increased, and the manner of death altered-an acute mode of death was converted to a

"

peracutetype of dehydration." FRIESEN et al. found that in

dogs the incidence of gastric erosions was increasedwhen the fracture was accompanied by administrationof histamine. Death by fat-embolism in animalshas been shown, therefore, to be determined not onlyby the quantity and quality of fat entering thecirculation but also by preconditioning. Incidentally,bleeding to death had the effect of raising the averageembolic-fat content in ARMIN and GRANT’S animalsfrom 6-2 to 13-1% of the dried lung-weight-doublethe figure found in clinical cases of fat-embolism.How far, however, it is justifiable to compare theexperimental’disease with traumatic lipeemia in manis questionable. In the rabbit, for instance, about85% of the fat was recoverable from the lung andlittle, if any, was found in the brain and kidney.

Clinically, the diagnosis of fat-embolism is probablyjustified only if there has been an injury causingfracture of a long bone or severe soft-tissue trauma.There are, however, some aids to diagnosis. CARREAUand HIGGINS suggest that the most helpful of theseare radiological examination of the cliest, and,in the later stages, examination of the urine for

floating fat. SCUDERI has also detected fat in blood

by dark-ground illumination, while WIL-,O-N "- recom-mends diagnostic lung-puncture. Both VINES 17 andROBB-SMITH suggested examination of the sputum forfat, which should be sought after the oedema fluidhas been expectorated ; it then lies free and is thus

distinguished from fat contained in histiocytes. At

necropsy it may not be easy to distinguish fat-embolism from metabolic lipaemia and post-mortemchanges; in fact, LEHMAN and McNATTIN state

that the disorder cannot be diagnosed anatomically.With regard to prevention, early immobilisation offractured bones is important ; and in suspected casesoxygen and antibiotics should be administered.How vigorously shock should be combated is perhapsopen to question. To some clinicians it seems thatfat-embolism is sometimes liable to occur in patientswho are not greatly shocked ; and rapid restorationof the blood-pressure may possibly precipitate thiscomplication. Specific measures such as proximalvenous ligation, the application of a tourniquetabove the fracture, and intravenous saponificationof the globules seem to have little value.In itself fat-embolism of the lung is not often fatal,

because the transported fat is usually removed by thebody and the disturbed circulation redressed ; indeedin the lung the infarction is commonly transitory.On the other hand, lodgement in the brain of fatglobules beyond the critical size is likely to threatenlife, by reason of anoxia of vital centres.15. Simmonds, J. P. J. exp. Med. 1918, 27, 539.16. Wilson, J. V. The Pathology of Traumatic Injury. Edinburgh,

1946 ; p. 64.17. Vines, H. W. C. Green’s Manual of Pathology. London, 1949; p. 73.

Sources of Vitamin B12IN 1948 vitamin B12 was isolated from liver by

LESTER SMITH and PARKER in this country and byRICKES and his colleagues in the U.S.A. Both groupsof workers were applying new techniques to the furtherpurification of the anti-pernicious-anæmia principleknown to be present in extracts of liver ; and since theeffective dose of vitamin B12 for a patient withpernicious anæmia in relapse is measured in fractionsof a milligramme, they clearly succeeded very well.Subsequent work has surprisingly shown that vitaminB12 is very widely distributed in Nature ; and the

exploration of alternative sources has taught us agreat deal about the compounds in which it is foundand about the rôle of vitamin B12 in animal metabolism.Vitamin B12 was originally isolated from liver by

two methods. In one paper chromatography was used,while in the other advantage was taken of the factthat the vitamin is a necessary growth factor forcertain lactobacilli ; later, when it was found thateach molecule of vitamin B12 contains an atom ofcobalt, search for cobalt-containing pigments becamea practical method. The microbiological methodfirst suggested that vitamin B12 was present in

unexpected places, and at this point RICKES and hiscolleagues 1 found that material from the mother

liquor in which Streptomyces griseus had been grownhad vitamin-B12 activity. This material has sincebeen shown to be a cobalt-containing pigment withexactly the same properties as liver vitamin B12 ;and nowadays the vitamin is obtained mostly fromthis source. It is a remarkable tribute to moderncommerical chemical technique that though thefermentation liquor contains only about 1 part permillion of vitamin B12, the vitamin can be suppliedso cheaply that a patient with pernicious anæmia canbe maintained in good health for as little as 21/2d.-10d.a week. It was also soon found that vitamin B12 ispresent in significant amounts in the fæces of normalpersons and of pernicious-anæmia patients ; it is

produced by bacteria in the colon, though it is notabsorbed there. It is therefore not surprising tolearn from HOOVER et al.2 that there is a largepotential supply of the vitamin in activated sewagesludge. HAUSMANN and his co-workers 3 in Germany,along with others elsewhere, have shown that cobalt-containing pigments are present in cow-dung, sheep-dung, beef-muscle, and various bacterial cultures.These pigments at first proved inactive when given topatients with pernicious anæmia in relapse and some-times also when tested microbiologically ; but after

digestion with hog-stomach mucosa or with pancreaticenzymes they showed typical B12 activity. HAUSMANNtherefore concluded that the original pigments wereconjugates of vitamin B12 and peptides. In this issueDr. HAUSMANN and Dr. MULLI describe yet anothersource of vitamin B12—the press juice from autoclavedfish. The cobalt-containing pigments from thissource, though microbiologically active, were clinicallyinactive ; but treatment with potassium cyanideconverted them into clinically active pigments, andthe material then showed the typical absorption1. Rickes, E. L., Brink, N. G., Koniuszy, F. R., Wood, T. R.,

Folkers, K. Science, 1948, 107, 396.2. Hoover, S. R., Jasewicz, L. B., Porges, N. Ibid, 1951, 114, 213.3. Hausmann, K. Lancet, 1949, ii, 962. Hausmann, K., Mulli, K.

Proceedings of the Third International Congress of Hæmatology.New York, 1951 ; p. 41.