plugging a persistent ductus

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psychology and sociology should be taught in all medicalschools. It considers that the study of the behaviouralsciences should be as important as anatomy and physio-logy and that psychiatry should rank as a major subjectwith medicine and surgery. In the section on post-graduate education it urges that no doctor should be

encouraged to take up general practice " if he has anyreservations about his aptitude for human relations andhis interest in people ". As part of his vocational train-

ing every general practitioner should hold a 3-monthhouse-appointment in a psychiatric department wherethere is ample opportunity for outpatient work, and theworking party proposes that new types of house-appoint-ment should be created for this purpose. The combined wisdom of these reports should go far to

imprint undergraduate and postgraduate students withwhat the college defines as the hallmark of the generalpractitioner: " An interest in people which transcendsthe diseases from which they suffer, and an understandingof man in relation to his family and society."

CEPHALORIDINE IN CHRONIC BRONCHITIS

MANY exacerbations of chronic bronchitis can betreated satisfactorily with tetracycline or ampicillin, butsome fail to respond; and other patients with this diseasemay be admitted to hospital severely ill and with evidenceof complications such as bronchiectasis or cor pulmonale.Such patients require urgent medical treatment, whichcannot be delayed until sputum cultures have been testedfor bacterial sensitivity. Nor is such information

necessarily of primary therapeutic importance, for

penetration of antibiotics from the bloodstream to theinfected areas may be impaired, some reaching infectedtissues more readily than others. What chemotherapyshould be instituted, therefore, which has a good chanceof success and the least risk of toxicity ?

Intramuscular penicillin and streptomycin are popularand reasonably effective, but many patients are hyper-sensitive to penicillin and there is a risk of ototoxicity withstreptomycin, especially if renal function is poor. Pinesand his colleagues 1 2 have described the results of a com-parison between cephaloridine at different dose levelsand combined penicillin and streptomycin. Cepha-loridine 3 is a bactericidal antibiotic which is effective invitro against nearly all strains of Staphylococcus aureuswhether or not they produce penicillinase; and it has anactivity ’similar to benzylpenicillin against Streptococcuspyogenes and Strep. pneumoníae. It is also effective in vitro

against Haemophilus influenza. It is not well absorbedfrom the alimentary tract and must, therefore, be givenintramuscularly or intravenously. While it has structuralaffinities to the penicillins, the replacement of the5-membered thiazolidine ring of the penicillin moleculeby a 6-membered dihydrothiazine ring seems to confer afreedom from the allergenic activity of penicillin.The patients whom Pines et al. studied had persistently

purulent sputum despite at least two fortnightly coursesof two or more other antibiotics. They were allocatedalternately to treatment with either penicillin (2 megaunitstwice daily for fourteen days with 0-5 g. of streptomycintwice daily for the first seven days) or cephaloridine. At1. Pines, A.. Raafat, H. Post-grad. med. J. 1967, 43, suppl. p. 61.2. Pines, A., Raafat, H., Plucinski, K., Greenfield, J. S. B., Linsell, W. D.

Br. J. Dis. Chest, 1967, 61, 101.3. Barber, M. Prescribers J. 1965, 5, 29.

first, patients had 1 g. of cephaloridine twice daily, but,when it was found to be much inferior to penicillin andstreptomycin, bigger doses were used-up to 2 g. threetimes daily for fourteen days. Patients with a history ofhypersensitivity to pencillin were automatically givencephaloridine, and the next patient entered in the trialwas then allocated to the other group. The effect oftreatment was assessed by changes in character and

quantity of sputum judged independently and by a" blind " clinical assessment. More than 180 patientswere studied in 203 courses of treatment. The resultsindicate that, while 2 g. of cephaloridine daily is inferiorand 4 g. daily is equal to penicillin and streptomycin,6 g. daily is superior. Whereas penicillin and streptomycinrendered the sputum mucoid in only 11 of 32 patients,cephaloridine 6 g. daily was effective in 19 out of 34

patients. In 13 of these 19 patients, sputum was stillmucoid a week later, compared with only 2 of the 11

patients treated with the combination. Although 29

patients given cephaloridine had a history of hyper-sensitivity to penicillin, none reacted to cephaloridine.During treatment with cephaloridine, only 1 patient with-out a history of drug allergy had a skin eruption, whichsubsided with steroid therapy. Cephaloridine 6 g. dailyprovoked a variable and sometimes massive outpouringof renal casts, with occasional mild proteinuria, red andwhite cells in the urine, and aminoaciduria. Theseurinary changes continued until treatment was dis-continued and they then disappeared. Repeated blood-urea estimations were normal. The significance of theserenal findings is uncertain (increased excretion of castsand cells may be induced by such simple agents as mildanalgesic drugs 4). Large doses of cephaloridine produceproximal tubular necrosis in some species of laboratoryanimal 5 ; and kidney damage in man has been reportedwith large doses.6 This antibiotic must therefore be usedwith caution in patients with evidence of renal disease.Though the value of cephaloridine in conditions such

as staphylococcal endocarditis is under review,7 a doseof 6 g. daily seems to have a place in the management ofchronic purulent bronchitis or bronchiectasis, whenother antibiotic therapy has failed or when there is a

history of penicillin hypersensitivity. The need to give itparenterally will limit it largely to hospital use, but thiswill ensure a close watch for untoward reactions.

PLUGGING A PERSISTENT DUCTUS

CARDIAC catheterisation, which has already played abig part in the evolution of modern cardiology, hasentered a new and therapeutic phase with the advent ofatrial septostomy and cardiac pacemaking. Balloon

catheters, first used to create atrial septal defects in thepalliative treatment of transposed great arteries,8 weresoon found to be of value where other congenital mal-formations, such as tricuspid or pulmonary atresia,threatened life in the newborn.9 The dramatic resultsof this simple procedure, carried out immediately afterdiagnostic cardiac catheterisation without a thoracotomyand all that that entails, were so impressive that other4. Prescott, L. F. Lancet, 1965, ii, 91.5. Atkinson, R. M., Currie, J. P., Davis, B., Pratt, D. A. H., Sharpe, H. M.,

Tomich, E. G. Toxic. appl. Pharmac. 1966, 8, 398.6. Hinman, A. R., Wolinsky, E. J. Am. med. Ass. 1967, 200, 724.7. See Br. med. J. 1967, i, 515.8. Rashkind, W. J., Miller, W. M. J. Am. med. ass. 1966, 196, 991.9. Watson, H., Rashkind, W. J. Lancet, 1967, i, 403.

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techniques for operating on the heart without surgerywere certain to follow.The first of these has been reported from Berlin by

Porstmann et all who have successfully occluded apersistent ductus arteriosus with a foam-rubber plugduring cardiac catheterisation in a 17-year-old boy.Their ingenious method is to pass a long catheter up thefemoral artery, through the ductus into the right heart,and back down again into the femoral vein, so that bothends are outside the body. The catheter is then replacedby a steel wire along which the plug is pushed into theductus under fluorscopic control by a second catheter.The plugging and the " postoperative " period passeduneventfully in their first patient, and 6 adults have sincehad similar successful treatment.The German cardiologists rightly say that further

experience is required to determine the ultimate resultsand possible complications of their method. Though theyare at pains to point out that it is not intended to providean alternative to the established surgical treatment ofpersistent ductus arteriosus, they may well turn out tohave done iust that.

ACUTE NECROTISING ENCEPHALITIS

IN 1941 the herpes-simplex virus was first isolated fromhuman brain after a fatal encephalitic illness.l1 Since thenmore than a hundred cases of acute necrotising encephalitishave been recorded, and in about three-quarters of themintranuclear inclusions of Cowdry type A have beenobserved.12-18 In several, a viral pathogenesis has beenconfirmed by brain biopsy, viral collection from fxces orcerebrospinal fluid (C.S.F), and, where the patient hassurvived, estimation of titre in paired sera.Van Bogaert et al.19 drew attention to the characteristic

asymmetrical lesions. The most striking feature isinvolvement of the temporal lobes with softening, alwaysasymmetrical, and numerous haemorrhagic foci. Micro-

scopic examination reveals the features of viral encephalitiswith, in addition, extensive cell necrosis and neurono-

phagia. Large mononuclear cells, lymphocytes, and plasmacells invest the subarachnoid and Virchow-Robin spaces,and the infiltration is most pronounced where necrosis iswidespread. Intense patchy cortical necrosis is usual.The division between necrotic areas and the surroundinginflamed cerebral tissue is well defined, especially in theregion of the insular cortex. The necrosis is total and

randomly distributed, following no laminar pattern.It is now generally assumed that herpes-simplex virus

is the cause of acute necrotising encephalitis-a viewsupported by electron microscopic studies,2O-23 and bythe work of Dr. Harland and his colleagues reported on10. Porstmann, W., Wierny, L., Warnke, H. Germ. med. Mon. 1967, 12,

259.11. Smith, M. G., Lennette, E. H., Reames, H. R. Am. J. Path. 1941,

17, 55.12. Haymaker, W., Smith, M. G., Van Bogaert, L. in Viral Encephalitis

(edited by W. S. Fields). Springfield, Ill., 1958.13. Bennett, D. R., Zurhein, G. M., Roberts, T. S. Archs Neurol. 1962,

6, 96.14. Drachman, D. A., Adams, R. D. ibid. 1962, 7, 45.15. Pierce, N. F., et al. Neurology, Minneap. 1964, 14, 708.16. Carmon, A., et al. J. neurol. Sci. 1965, 2, 328.17. Miller, J. K., Hesser, F., Tompkins, V. N. Ann. intern. Med. 1966, 64,

92.18. Rawls, W. E., Dyck, P. J., Klass, K. W., Green, H. D., Hermann, E. C.

ibid. p. 104.19. Van Bogaert, L., Radermecker, J., Devos, J. Rev. Neurol. 1955, 92, 329.20. Ryden, F. W., et al., Sth med. J. La Grange, 1965, 58, 903.21. Itabashi, H. H., Bass, D. M., McCulloch, J. R. Archs Neurol. 1966,

14, 493.22. Vander Haeghen, J. J. Path. europ. 1966, 1, 29.23. Chou, S. M., Cherry, J. D. Neurology, Minneap. 1967, 17, 575.

p. 581. The Cowdry type A inclusions in herpes-simplex encephalitis have been shown to consist primarilyof a finely granular matrix embedding some bundles offibrillar structures, virus particles, and occasional mem-branous profiles which are not seen in the uninfected glialor neuronal nuclei.24 Chou and Cherry 23 suggest that theintranuclear inclusions in herpes-simplex-infected cells,although morphologically similar to the eosinophilicinclusions in non-viral conditions ’25 26 are related in someway to replication and maturation of virus. When thevirus of herpes simplex is injected intraperitoneally in themouse more virus antigen can be demonstrated in thelimbic system than in other parts of the neuraxis,2’suggesting a selective vulnerability of this region.

Clinically the picture is of confusion and hyperpyrexia of101-105° F (38-40.5° C) developing over two to four days,often together with hemiplegia, neck stiffness, and convul-sive seizures. Acute necrotising encephalitis must bedistinguished from temporal-lobe damage and swelling dueto other causes-in particular cerebral abscess, malignantglioma, acute hxmorrhagic leukoencephalitis, and eventuberculous meningitis. Examination of the c.s.F. in-

variably reveals pleocytosis, mainly mononuclear, with aprotein content of up to 360 mg. per 100 ml. The

electroencephalogram rarely shows pathognomonicchanges, and positive and negative contrast radiographsmay also be misleading in that the swollen temporal lobe,by producing a shift in the midline structures, suggestsa space-occupying lesion. Adams and Jennett 2 describeseven cases. Temporal-lobe biopsy was performed in five,with a correct pathological diagnosis in four. The herpes-simplex virus was conclusively identified in only oneinstance, but the histological changes were distinct enoughfor correct interpretation. Adams and Jennett regardbrain biopsy as the most useful technique in establishingthe diagnosis. The disease carries a very high mortality;of the seven patients described by Adams and Jennett,five died within fourteen days of the onset, one patient livedfor two months after surgical decompression, and onesurvives.

Idoxuridine, applied topically, prevents and cures

experimentally induced herpes-simplex keratitis in therabbit 28 and has been shown to be of value in the treat-ment of superficial herpetic ulcers of the human cornea. 29This drug is thought to act by inhibiting viral D.N.A.-polymerase or by becoming incorporated into viral D.N.A.with resulting faulty transcription of messenger R.N.A. andabnormal enzyme and protein synthesis. 30 The drug istoxic and has produced leucopenia, stomatitis, and alope-cia.31 Two reports of its intravenous administration in

herpes encephalitis have been published 32 33 ; and on

p. 579 a third case is recorded in which improvement andsurvival followed surgical decompression and intravenousidoxuridine. Nevertheless, as Evans et al.32 say, " Theplace of idoxuridine in the chemotherapy of viralencephalitis, with or without corticosteroids, must awaitfurther trial".

24. Robertson, D. M. Am. J. Path. 1964, 45, 835.25. Robertson, D. M., McClean, J. D. Archs Neurol. 1965, 13, 287.26. Yamamoto, T., Otani, S., Shiraki, H. Acta neuropath. 1965, 5, 288.27. Adams, J. H., Jennett, W. B. J. Neurol. Neurosurg. Psychiat. 1967, 30,

248.28. Kaufman, H. E. Proc. Soc. exp. Biol. Med. 1962, 109, 251.29. Leopold, I. H. Ann. N.Y. Acad. Sci. 1965, 130, 181.30. Kaplan, A. J. ibid. p 226.31. Calabresi, P. Cancer Res. 1961, 21, 550.32. Evans, A. J., Gray, O. P., Miller, M. H., Verrier Jones, E. R., Weeks,

R. D., Wells, C. E. C. Br. med. J. 1967, ii, 407.33. Breeden, C. J., Hall, T. C., Tyler, H. R. Ann. intern. Med. 1966, 65,

1050.