951

and an amount sufficient to cause toxic reactions

(particularly those related to -thecal or meningealirritation) ; and the possible significance of the

lymphocyte-count of the cerebrospinal fluid in

prognosis. Streptomycin is clearly of short-termradical benefit in some cases of tuberculous meningitis,though the various factors involved and the bestschedule of administration have yet to be worked out.Much will be expected on these points from the currentMedical Research Council trials.The discovery that tuberculosis can after all be

affected by systemic drugs may lead enthusiasts todisregard the strict criteria for assessing the efficacyof treatment ably set out by HiNSHAW and FELDMAN. 10There are already signs that the improvement notedin a hotch-potch of cases, without untreated controls,will be ascribed to some new drug, without regardto the possibility of spontaneous remission. If this

happens the pre-streptomycin story of faded hopeswill be repeated. It took but a few months of

enterprise to introduce tuberculin and ’Sanocrysin’into treatment on a world scale, but more than adecade of scientific slogging to evict them. With

streptomycin we have the impressive results in

meningitis and miliary tuberculosis to justify the

setting up of a limited public service by the Ministryof Health on the advice of the Medical ResearchCouncil. But the indiscriminate use of the drugin every type of tuberculosis, which commercial

vigour has stimulated in the U.S.A., must be guardedagainst. Apart from risk to the patient of his tuberclebacilli becoming streptomycin-resistant, there is thewider public-health danger of new cases arising inwhich the strain is primarily resistant-for example,in infants infected by mothers treated with strepto-mycin. So the M.R.C. has the unenviable responsi-bility, not only of assessing the value of the antibioticand deciding on the best schemes of dosage in variousforms of tuberculosis, but also of advising howit should be distributed for public use in appro-priate conditions only. While British productionis in the pilot stage the council is unlikely tobe hustled.

Fibrocystic Disease of the PancreasINFANTS who fail to thrive and eventually succumb

from a combination of diarrhoea and respiratoryinfection are sadly familiar in practice. The necropsyusually discloses no convincing cause of death, anddoubt remains as to which of the two main symptomswas primary or whether both were secondary tosome other fundamental disturbance of nutrition. Itnow appears that in at least a considerable proportionof these cases there are widespread pathologicalchanges in the pancreas which interfere with thesecretion of pancreatic juice and thus impair digestion.Other changes in the body may be secondary tomalabsorption of essential foods and vitamins. The

principal necropsy finding in the pancreas is dilata-tion of the acini and ductules from blockage of thelumeri with tenacious inspissated material; and thesurrounding tissue undergoes pressure atrophy andprogressive fibrosis. The condition has been named"

fibrocystic disease of the pancreas," but there is notrue cyst formation, and the fibrous tissue which10. Hinshaw, H. C., Feldman, W. H. Amer. Rev. Tuberc. 1944, 50,

202.

develops is not prominent in early cases and must beconsidered secondary. These changes are present atbirth and are progressive. There is no evidence ofinfection and the islet tissue is intact. The main

pancreatic duct is normal, and the few cases in whichatresia has been reported probably represent a

separate condition with somewhat similar -clinicaleffects. According to HOWARD 1 there is a fairly highfamilial incidence. Chronic suppurative inflammatorychanges in the lungs are constantly found in thoseinfants who survive for more than a few weeks ;these consist of varying degrees of purulent bronchitis,bronchiectasis, or bronchiolectasis. The respiratorypassages are obstructed with tenacious mucoid or

mucopurulent material, and the walls are infiltratedwith inflammatory cells. Fibrosis follows in thosewho survive. Keratinising squamous metaplasia issometimes present in the trachea and bronchi, andoccasionally in other organs. Fatty changes in theliver are a common finding.

Isolated instances of this pancreatic disorder,encountered post mortem, have been reported forsome years ; but its association with symptoms andsigns during life was not appreciated and its frequencywas quite unsuspected until ANDERSEN 2 drew atten-tion’to it in 1938. Her paper was closely followed bythree others,3 each reporting a considerable series ofcases, and there have since been numerous reports.There are several reasons for this delay in identifyingwhat now seems to be a definite clinical and patho-logical entity. In the first place, pathologists did notrecognise the condition because, despite the strikingmicroscopical changes, there is usually little to beseen with the naked eye ; and they had not beenaccustomed to making routine sections of the pancreasin infants or young children who had apparently diedof respiratory disease. However, with increasingawareness and suspicion, the incidence has beenestablished at about 3% of all infants who come tonecropsy 4 ; though in one series 5 the incidence wasas high as 12%. Clinically, the condition was notrecognised because of its similarity to other disorders,particularly respiratory and gastro-intestinal infec-tions in infants and coeliac disease in older children.

Symptoms usually appear soon after birth, and infantsmay die within a few days with intestinal obstructiondue to meconium ileus, which is believed to resultfrom the lack of pancreatic enzymes. In other cases

symptoms do not develop until later in childhood.Manifestations may be divided into three main

groups : gastro-intestinal, respiratory, and nutritional.Digestion is impaired through lack of trypsin, amylase,and lipase ; the stools, which are at first loose,become pale and bulky when solid foods are given.Cough develops early and becomes increasinglytroublesome ; scattered physical -signs may be foundin the chest, but there is no evidence of frank consolida-tion. In infancy, X-ray examination is not likely toshow more than increased hilar shadows and basalmarkings ; but later on, if the child survives, therewill be patchy areas of opacity from consolidation,collapse, and emphysema. The general ’picture1. Howard, P. J. Amer. J. Dis. Child. 1944, 68, 330.2. Andersen, D. H. Ibid, 1938, 56, 344.3. Harper, M. Arch. Dis. Childh. 1938, 13, 45. Thomas, J.,

Schultz, F. W. Amer. J. Dis. Child. 1938, 56, 336. Blackfan,K. D., May, C. D. J. Pediat. 1938, 13, 627.

4. Menten, M. L., Middleton, T. O. Amer. J. Dis. Child. 1944,67, 355.

5. Farber, S. Ibid, 1942, 64, 953.

952

resembles that of any chronic wasting illness with’

secondary bronchopneumonia. In spite of a goodappetite, the infant becomes increasingly under-nourished. Cceliac disease rarely develops before theage of nine months, and the association of chest

’

symptoms with loose stools should suggest pancreaticdisease. The diagnosis can be confirmed by examiningthe pancreatic juice. All the pancreatic enzymes aredeficient, but it is only necessary to estimate thetrypsin, which is not difficult. A duodenal tube is

passed, preferably under X-ray control, and the

power of the juice to digest gelatin is analysed by themethods of ANDERSEN and EARLY. Chemical exami-nation of the stools and other laboratory tests arenot of diagnostic value, for they merely reveal thepresence of malabsorption and malnutrition. The

glucose-tolerance curve is usually normal; nitrogenexcretion is increased ; and changes in the fatcontent of the stools are. similar to those in coeliac

disease, the fat being partially split by a lipase inthe succus entericus but too late for proper absorption.The vitamin-A absorption curve is low, and this wasat one time suggested as a diagnostic finding ; butit may be found in any condition associated with

impaired fat-absorption. The condition resemblescoeliac disease in the wasting, distension, and dimin-ished fat-absorption, but coeliac disease can be distin-guished by the later onset of symptoms, the poorappetite, the lack of constant respiratory infection,and the normal enzyme content of the duodenal juice.The fundamental cause of fibrocystic disease of the

pancreas remains a mystery. At one time it was

suggested that the whole condition might arise fromvitamin-A deficiency, but more probably this defi-

ciency, when present, is a secondary manifestation.Other possibilities are congenital malformations or

inflammation of the pancreas during foetal life.FARBER believes that the basic lesion is a physicallyaltered secretion which obstructs the small ’pan-creatic ducts ; and with this disorder he has foundevidence of similar changes in secretion elsewhere inthe body, especially in the lungs, duodenum, andbiliary tracts. He postulates that this results fromdisturbance of autonomic nervous control, and heclaims to have produced similar lesions experi-mentally in kittens. There is no doubt, from clinicalobservations, that lack of pancreatic juice is responsiblefor the diarrhoea and malnutrition, and these can begreatly improved by treatment. The intake of foodmust not only be sufficient to cover the inevitablelosses through imperfect digestion, but enough to

satisfy the requirements of appetite, energy, and

growth. Full use should be made of modern pre-digested foods ; casein hydrolysates can now beobtained in palatable form, and if given in sufficientquantity will supply all the protein needed. Tothese may be added extra carbohydrate, in the formof glucose, minerals, and vitamins ; and pancreatincan usefully be given with solid foods when these arebegun. Chemotherapy and penicillin have materiallyimproved the outlook as regards the respiratoryinfection ; but suppurative changes in the lungs, oncestarted, are likely to progress, and the pancreatic,lesion itself is irreversible. While the aetiology remainsobscure, therefore, the outlook for these cases is poor.

6. Andersen, D. H., Early, M. V. Ibid, 1942, 63, 891.7. Farber, S. Arch. Path., Chicago, 1944, 37, 238.

Annotations

CHLOROMYCETIN: AN ANTIBIOTIC EFFECTIVE

BY MOUTH

THE latest antibiotic is derived from a streptomycesfound in a sample of soil brought from Caracas,Venezuela.! From filtrates of submerged aerated culturesof this organism a crystalline substance, chloromycetin,has been obtained. This is probably a chemical entity,since it has a definite composition, melting-point, andoptical rotation, and it is unique in containing bothnitrogen and non-ionic chlorine. Unlike penicillin it isstable over a wide range of pH and will withstand boilingfor five hours. Chloromycetin is active in vitro in dilutionsof 1 in 3,000,000 against Brucella abortus, Bact. coli,Friedldnder’s bacillus, Proteus vulgaris, and Staphylococcusaureus, and in much higher concentrations (1 in 80,000)against the tubercle bacillus. Judging by tests on miceit should be possible to get a concentration of 1 in 80,000in human tissues without producing toxic effects. Itsdiscoverers have not yet performed in-vivo tests withchloromycetin in tuberculosis, but screening tests withthe pure material showed a striking chemotherapeuticactivity against Bickettsia prowazeki, using chick embryos,and against a number of other rickettsial agents whentested on embryonated eggs.2 From 24 eggs infected withthe Gilliam strain of R. orientalis and protected by chloro-mycetin 8 live chicks were eventually hatched. - The

chemotherapeutic effect of the drug in mice infectedwith scrub-typhus was equally satisfactory, even when itwas administered as late as ten days after infecting theanimals.These preliminary observations suggest that chloro-

mycetin is well worth a clinical trial in tuberculosis andrickettsial infections. It not only is of low toxicity buthas the great merit of being active when given by mouth,and in rickettsial infections it is effective late in thedisease. At the moment the only promising drug againstthe rickettsias is p-aminobenzoic acid, which is not freefrom toxic effects.

IMMUNISATION AND THE DIPHTHERIA

CARRIER-RATE

DOES mass-immunisation against diphtheria increasethe carrier-rate among immunised children ? In the

opinion of Dr. V. F. Soothill,3 M.o.H. of Norwich, thisquestion has still to be satisfactorily answered. Duringthe spring of 1944, a period of low incidence of diphtheriain Norwich, he made a random selection from theimmunisation records of 100 children of each sex inthe age-groups 2-5, 5-10, and 10-14 years. Care wastaken to choose children. attending well-scattered schoolsor welfare centres, or living in appropriate districts. Ascontrols, a random selection of " comparable " childrenwas made among the non-immunised. Immunisedchildren were further divided into those whose post-Schicktests were known to be negative and those who had notbeen Schick tested. The checked counts of immunisedSchick-immunes were 1333 immunised and 1061 non-immunised. Allowing for the immunised with andwithout negative post-Schick tests, these totals became :immunised 1377, non-immunised 1017. Swabbings fromnose and throat obtained from all children in the lattertwo groups were examined for 0. diphtheria and yielded2 positive results in each group.

Unsatisfied with this statistically insignificant result,Soothill arranged for the experiment to be repeated,using the same groups of children, in the winter of1944-45 when it was thought that 0. diphtheria wasmore abundant. Except that a different school nurse

1. Science, 1947, 106, 417.2. Ibid, p. 418.3. Med. Offr, 1947, 78, 191.