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Progress reportIntestinal protozoa

The pathogenic species ofprotozoa that infect the human gut are now receivinggreater attention from both parasitologists and gastroenterologists. Clinicalawareness of these infections is growing and there have been several diagnosticand therapeutic advances. Progress on the biomedical side has also beenconsiderable and some interesting new techniques have been applied. Thehost-parasite relationship is delicately balanced in these infections and smallchanges in the host's immunological responsiveness may affect the clinicaloutcome.The purpose of this paper is to assemble some of the information in this

field that has been published since 1973, in the hope that further interest will bestimulated. Three previous reviews" 2,3 have covered earlier publications in asimilar way.

Amoebiasis

By way of introduction several more general works should be mentioned. Abook edited by Jeon4 deals with the large free-living amoebae but also coversmany aspects ofgeneral biological interest to the parasitologist. The pathogenicmechanisms and ecology of Entamoeba histolytica and free-living pathogenicsoil amoebae (Naegleria, etc.) are compared in a monograph by Singh5. Anew multi-author book edited by Padilla and Padilla6 covers various aspectsof the parasitology ofE. histolytica and its clinical effects, with special referenceto work in Venezuela.Amoebiasis is of great importance in Mexicp from the point of view of

public health and a great deal of exciting cliniical and laboratory work isbeing done in that country. Anyone seriously contemplating further studiesin this subject must consult the supplements to Archivos de Investigacion(Mexico) where the proceedings of the annual Amoebiasis Seminars, held inMexico City since 1969, have been published. In 1975, an internationalcentenary conference was held in Mexico to celebrate the original discoveryof E. histolytica by Losch. The conference proceedings have been publishedas a book edited by Sepulveda and Diamond7 and Losch's original publicationhas now been reprinted in English8.

PATHOGENESISThe mechanism of host tissue destruction has been further clarified by studiesof the ultrastructure of the rectal tissue from dysentery patients9 and the caecalmucosa of infected guinea-pigs'0"'. Amoebae cause contact-dependent lysisof epithelial cells, and are chemotactic to neutrophils that are themselveskilled on contact. Neutrophil degranulation probably contributes to the localtissue damage that includes endothelial damage leading to thrombosis of

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capillaries and venules in the lamina propria. Using an isotope-labelled cellmonolayer as an in vitro substrate, cell damage was proportional to durationof contact and to the number of amoebae; extracts of amoebae caused nodamage12. The ultrastructure of amoeba-cell contact in this system suggeststhat membrane damage precedes lysis13. Amoebic virulence in vitro can alsobe assayed using guinea-pig leucocytes'4. The fine structure of E. histolyticahas been further elucidated with the elegant freeze-etching technique'5;recent electron micrographs16 have shown paranuclear bodies but no evidenceof trigger lysosomes; it appears that membrane-bound cytolytic enzymes arereleased from dendritic plasmalemmal processes'". Diamond and Mattern'8have reviewed the exciting new work on the viruses of E. histolytica. All theaxenic strains studied carried cytoplasmic icosahedral virus, and some also hada filamentous intranuclear virus or beaded intranuclear virus-like particles.All these agents lyse susceptible amoebic hosts, but the relevance of theseviruses to amoebic virulence is uncertain. Quite different structures, resemblingrhabdo-viruses, have been seen in the electron micrographs of several strainsincluding the low temperature Laredo and also E. invadens' 9.

STRAIN CHARACTERISATIONStrain virulence in man has again been shown to correlate with virulence andinfection rate in the weanling rat caecum20; and there appears to be a correla-tion between strain virulence, ease of cultivation, and growth rate2'. Amoebacultivated without bacteria do not infect the rodent caecum22, but largeinocula of crithidia-associated23 or axenic strains24 will infect and producelesions in the hamster liver. New-born mice or hamsters can be infected withaxenic E. histolytica by direct intracerebral25 or intrahepatic26 infection,and these techniques promise to be useful in chemotherapeutic and straincomparison studies. The ease with which a strain may be axenised appearsto be related to its virulence in the hamster liver, and this may decline rapidlyafter axenisation14. Efficient methods of strain cryopreservation have beendescribed27; at 4°C trophozoites may survive for up to 12 days and cysts forup to nine weeks28. Selective agglutination of pathogenic strains by concan-avalin A has been reported29'30, and deserves further study.

HOST SUSCEPTIBILITYSeveral workers have studied host susceptibility in experimental systems.Protein deficiency predisposes to caecal ulceration31; and carbohydratesupplementation of the protein-deficient diet favours infection but reducestissue invasion. Mice infected with Schistosoma mansoni32 or Trichurismuris33 are more susceptible to amoebic tissue invasion, possibly becauseof local tissue damage or immunosuppression. Hamster livers damagedby the intraportal injection of glass particles or ligation of a lobar branch ofthe portal vein, are more likely to develop amoebic abscesses34. Inbred ratstrains differ in their susceptibility to caecal invasion35.Blood lymphocytes from patients with invasive amoebiasis will undergo

blast transformation in the presence of amoebic antigen38 37. Patients withliver abscess may show a temporary depression of lymphocyte transformationto PHA or amoebic antigen38. There is no definite evidence of protectiveimmunity in man, but protection has been shown in guinea pigs followinginjection of amoebic antigen39. Attempts have been made to detect copro-antibodies in human faeces, and further work is needed in this field40'41.

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Autoantibodies to human colon have been demonstrated in the sera oLamoebic colitis patients using haemagglutination and gel diffusion tech-niques42. A series of 92 fatal cases of fulminant colitis documented fromSenegal43 emphasises the diagnostic and therapeutic aspects of this dangerouscondition. The gross and microscopic pathology of the liver that occurs incolitis patients has been classified and discussed44. Invasive amoebiasis maycomplicate infections with Strongyloides stercoralis with fatal consequences45,and among Malayan aborigines heavy infections with Trichuris trichiuramay be complicated by amoebic dysentery46. Double infections with Shigellaand E. histolytica are reported47 but they are probably under-recognised.The significance of the finding of amoebae in duodenal aspirates48 remainsuncertain.

CLINICAL FEATURESFurther cases of amoeboma have been reported49 and also the unusualcomplication of multiple stricture50. Amoebiasis of the skin and genitaliais being increasingly recognised and is reported from Uganda5' and PapuaNew Guinea52. Homosexual venereal transmission has been documented inone patient53 and perianal gangrene due to amoebiasis has been describedin a diabetic54. Amoebiasis may secondarily infect haemorrhoidectomywounds and produce lesions resembling rectal carcinoma55.

The clinical56 and radiological features5' of abscesses of the left lobe ofthe liver have been described in detail, and also the dangerous complicationof amoebic pericarditis58 59. An important paper by Barbour and Juniper60compares amoebic abscesses of the liver with pyogenic ones. In a study of30 patients61, the pH of amoebic pus ranged between 5-2 and 6'7; thisfinding may be of diagnostic value when an empyema is aspirated. Amoebicliver abscess has been described in a patient with situs inversus62 and alsothe abnormalities in fibrinogen metabolism and fibrinolytic activity in aseries of patients63. Amoebic abscesses may occasionally contain Salmonellaenterididis64 or S. typhi65. Scragg66 has described the diagnosis and manage-ment of hepatic amoebiasis in children, with reference to a series of 350 cases.The often difficult medical and surgical management of pleuropulmonaryamoebiasis has also received attention67.

DIAGNOSTIC METHODSThe diagnostic sensitivity of faecal examinations has beenl discussed togetherwith mathematical methods for the interpretation of epidemiological data68.The variable and irregular cyst excretion patterns of different subjects haveagain been documented 69. Amoebae in stools or cultures may be identified asE. histolytica using immunofluorescence and specific antisera70; they mayalso be recognised in tissue sections by the same method7l, and trypan blueis a useful counter stain72. A stool fixative containing sodium acetate,acetic acid, and formalin (SAF) 73 promises to be of value in clinical practiceas it allows the same preserved specimen to be used for both cyst concentra-tion and premanent staining of cysts and trophozoites. The poor sensitivityof routine histology for the recognition of amoebae is emphasised in aretrospective analysis of 11 patients from Uganda74 and in a detailed clinico-pathological study of eight patients in South Carolina75; fresh wet prepara-tions must always be examined. Skin tests using an axenic strain extract(histolyticin) have been further evaluated76'77'78; some control subjects

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may give a delayed response and it is possible that the test itself induces animmunological response.The most promising new serological developments are counter-current

immunoelectrophoresis79 80, and the enzyme-linked immunosorbent test81;the former is rapid, relatively simple to perform, and almost as sensitive asindirect haemagglutination. Counter-immunoelectrophoresis has also beenapplied to the detection of antigen in amoebic pus82; the technique appearsto be much more sensitive than the detection of amoebae in liver aspirateor biopsy. The relative merits of three serological tests have been reportedby Stamm et al. 83. Liver abscess patients do not give positive serologicaltests for a-fetoprotein84. The relative merits of isotope scans and hepaticarteriography have been discussed85 and the scintigrams of 247 liver abscesspatients are reported from South Africa86. Ultrasound is another usefultechnique and its value has been compared with isotopic scanning8 7. Hypaquegiven for intravenous pyelography may also delineate a liver abscess88.

TREATMENTMetronidazole continues to give good results in both amoebic dysenteryand liver abscess. However, five patients have developed liver abscessone to three months after treatment of amoebic colitis with metronidazole89.Fisher90 has described a patient with liver abscess who developed a second non-contiguous abscess while on metronidazole and refers to eight other treatmentfailures in the literature. Treatment failure and death at 48 days has beenreported after multiple drug therapy for liver abscess9l; another patienthad three episodes of hepatic amoebiasis despite multiple drug therapy92,but this was perhaps due to repeated reinvasion from the gut. Griffin93has pointed out that the best results with metronidazole have been fromcentres where therapeutic aspiration is frequently practised; a comparativetrial of metronidazole with and without aspiration has not been reported.In a trial of 66 patients given either chloroquine 500 mg daily for 10 weeksor metronidazole 750 mg tds for 10 days there were three 'drug failures'and resolution times were very similar94; in another trial metronidazole gavethe same results as chloroquine plus emetine95. Parenteral metronidazoleis now available and will be valuable in cases of amoebic colitis with per-foration or ileus; its use has been documented in one patient96.

Tinidazole, like metronidazole, is a nitroimidazole derivative. Its pharma-cology and use in trichomoniasis, giardiasis, and amoebiasis has beenextensively reviewed9 7. So far it has no documented advantage over metroni-dazole for amoebiasis. The results in amoebic colitis are similar98; Scragg99however, has reported particularly good results in children.The treatment of symptomless infections remains a problem, especially

in the USA where some of the halogenated quinolines have been withdrawnand furamide is not available'00. None of the nitroimidazoles gives particu-larly good parasitological cure rates and side-effects may be troublesome'01.A trial carried out in Washington DC has further demonstrated the effective-ness of furamidel02. Paromomycin is a useful alternative and possibly alsodichloracetamidel03. Powell'04 advocated the use of furamide in all abscesspatients treated with metronidazole.The finding that nitroimidazoles have mutagenic effects on some bac-

teria105,106 and can also induce lymphomas and lung tumours in mice whengiven in large doses'07 has raised some doubts about the wisdom of using

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these drugs for symptomless or mild amoebic infections. It is reassuring thata follow-up of the offspring of 1469 women, treated in pregnancy over a20-year period, has shown no damage108. The clinical use and toxicity ofmetronidazole in man and experimental animals has been reviewed byRoe109; prolonged use of this drug, as in Crohn's disease, may cause chromo-somal abnormalities in circulating lymphocytes110 and occasionally peri-pheral neuropathy"l.

Giardiasis

Giardia lamblia is the most frequently reported gut parasite in the UnitedKingdom"12. Transmission occurs in temperate climates and epidemics"13"'4may occur among campers"5, or when domestic water supplies are con-taminated"16. American visitors to the Soviet Union, especially Leningrad,are frequently infected and their symptomatology has been fully described"1.Wolfe 118 has given a useful account of the clinical features of this infection.

PATHOGENESISPhysiological studies of this protozoon have been held back by the difficultyof in vitro culture but Iyer and Gaitonde"19, and Meyer120 have now de-scribed their methodology. The fine structure of the encysted parasite has beendescribed'1 . Scanning electron microscopy has shown that in mice animpression of the ventral aspect of the trophozoite remains on the microvilliat the site of contact between parasite and epithelial cell'22 23. In humansit has been shown that the microvilli and fuzzy coat are damaged at thesesites123"124. A functional correlation of these observations has been theobservation of reduced levels of brush border enzymes in the jejunal mucosaof patients with giardiasis'2 .Roberts-Thomson et al.'26 fed cysts of G. muris to mice and showed that

reduction in villous crypt ratio was dose dependent. Changes regressed overthe next 25 days, and during this period there was spontaneous loss of theinfection. The weight gain of infected mice was significantly lower thancontrols. The same group of workers studied mixed infections with G. murisand Trichinella spiralis in mice; the intestinal phase of T. spiralis wasassociated with reduced counts of Giardia trophozoites and cysts12 7. Sehgalet al.'28 were able to demonstrate patent infection in albino rats fed cystsof G. lamblia. In athymic nude mice, an increased mortality was found inanimals infected with G. muris and the related flagellate Hexamita129;treatment with anti-protozoal drugs reduced mortality. The inability of theseanimals to control gastrointestinal infections may have contributed to theirwasting disease.

CLINICAL FEATURESIn endemic areas children have been the main group reported to be symp-tomatic and to have malabsorption. Blanco Rabassa et al.'30 documentedmalabsorption in 31 out of 50 infected children. Tewari and Tandon'3'were able to show impaired absorption of fat and d-xylose in Indians ofvarying ages. Wright et al.'32 studied 40 expatriate adult patients, most ofwhom had travelled in India and South East Asia, and found malabsorptionof two or three test substances (fat, xylose, and Vitamin B.2) in 20. Thefinding of impaired Vitamin B,2 absorption has been only occasionally

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documented before'33"134. Brandborg'35 has referred to the difficulties ofinterpreting absorption studies in parasitic disease among patients fromareas where sprue or tropical enteropathy is endemic. However, in the studyby Wright et al.132 there was a relative lack of response to tetracyclinefor four weeks while treatment with metronidazole for three days or mepa-crine for 10 days produced consistent functional and morphological im-provement. Tandon et al.'36 report free bile acids in jejunal aspirate fromtheir patients with malabsorption and an abnormal jejunal microfloracomprising mainly enterobacteria. Similar changes in microflora were foundby Wright et al.'32, who, however, obtained normal 14C glycocholate breathtests in 13 of 14 patients with malabsorption.

IMMUNOLOGICAL ASPECTSEastham et al.137 found an increase in intraepithelial lymphocytes in thejejunal mucosa of two patients. In a more extensive study'38 a significantincrease in these cells was found in patients with impaired absorptioncompared with either infected patients with normal absorption or controls.It is possible that immunologically mediated mechanisms contribute tomucosal damage.

Webster'39 has reviewed the relationship between variable hypogamma-globulinaemia and giardiasis; and Fisher et al.140 have reviewed the radiologi-cal changes on barium follow-through examinations in patients with normaland abnormal immunological status. Other immunodeficiencies, includingselective IgA deficiency, do not appear to be associated with giardiasis'4 ;however, jejunal IgA levels were reduced when 10 symptomatic patients werecompared with 10 controls'42. In tropical countries, giardiasis is common inmarasmic children'43 and it is possible that reduced secretory IgA favoursinfection. In two patients in the USA with chronic alcoholic pancreatitis,mepacrine therapy for coexistent giardiasis rapidly reversed the malab-sorption and oedema144. Among a series of 22 symptomatic infections inSweden, five had coexistent pancreatic disease'45. A preponderance of bloodgroup A has been found in Australian children with giardiasis'46.Human serum antibodies to Giardia have been demonstrated by Ridley

and Ridley'14 . The indirect fluorescent antibody test was positive only inthose patients who had impaired intestinal absorption; cysts were used asantigen'48.

DIAGNOSISMahmoud and Warren'49 have suggested a systematised method for thediagnosis of giardiasis. Confirmation depends upon the demonstration ofcysts or trophozoites in the stool or trophozoites in jejunal aspirates, im-pression smears, or biopsies'50. The Enterotest capsule is an efficient methodof obtaining upper gastrointestinal juice without intubation'51. Cyst excretionis irregular and unpredictable'62, the frequency of positive stool examinationsis not related to the presence or absence of malabsorption'32.

TREATMENTIn the treatment of giardiasis the choice lies between mepacrine, metronida-zole, the other 5-nitroimidazoles, and furazolidine. Wolfe"18 reported a 95 %cure rate with mepacrine (100 mg thrice daily for seven days) and 81 % withfurazolidine. The criterion for cure was the absence of cysts from three

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consecutive stool samples one month after treatment. In another studyG. lamblia was not eradicated from six out of nine patients given mepacrineat this dosage for 10 days132. Using the examination of jejunal aspirate andmucosal impression smears as well as stools, metronidazole in a single dailydose of 2-0 g for three days cured 27 out of 31 patients153, and a secondcourse cured two of the remaining four. Using the same regimen, Greenet a1.154 report that a group of 22 patients were all cured. Trials using tini-dazole have been reviewed97.

Muller and Lindmarkl'5 have shown that metronidazole is reduced insideanaerobic organisms allowing more drug to diffuse passively into the or-ganism, so producing very high intracellular concentrations. The site of actionof the reduced drug upon anaerobic metabolism has not been defined.

Isosporiasis

The two species, Isospora belli, and L hominis, have for many years beenclassed together as the causes of human isosporiasis; a relatively uncommoncondition normally recognised by the presence of infective oocysts or sporo-cysts in the stool. Experimental work has now shown that these parasitesare quite distinct, while L belli has a simple direct transmission cycle in man,L hominis is now regarded as a species of Sarcocysts in which man is thedefinitive host and the cow or pig the obligate intermediate hosts. Thetaxonomic problems raised by recent work on this group of Sporozoa havebeen discussed by Frenkel'66.

Sporocysts of . hominis appear in the human stool nine days or more afterthe ingestion of sarcocyst-infected meat and excretion of sporocysts maypersist for 100 days or more, apparently without producing symptoms.Antibodies have been demonstrated by immunofluorescence, using S.fusiformis in cattle heart as antigen, among volunteers fed raw meat167and German sanatorium patients fed regularly on beefsteak tartare'58;there is no cross-reaction with Toxoplasma antigens'59. The infection isoften overlooked but may be surprisingly common in countries such asHolland, Germany, or Kenya where incompletely cooked meat is commonlyeaten. All stages of the life cycle are not yet described, however developmentin the intermediate hosts is probably similar to that of S. muris in the mouse'60,and development in man is likely to be similar to Sarcocystis spp. in cats161.In Sarcocystis, unlike Isospora, there is no schizogony in the gut cyclewithin the definitive host, which proceeds directly to gametogony. It shouldbe noted that man uncommonly acts as intermediate host for anotherspecies of Sarcocystis-namely, S. lindemanni-a muscle parasite that some-times causes myositis or systemic manifestations'62.

Isospora belli is spread directly by the faeco-oral route and is usuallyreported from the tropics, but it also occurs in mental institutions and acci-dental laboratory infections continue to be reported'63. Repeated schizo-gonic cycles occur within the epithelial cells of the small bowel causingvillous shortening and functional changes; gametes are also formed andsoon after oocysts appear in the stool. Many infections are symptomaticand a prolonged debilitating sprue-like illness may result from this under-recognised condition'64; other clinical features are fever, blood eosinophilia,and stool Charcot-Leyden crystals. Treatment requires further study; however,cotrimoxazole 2 g daily for three weeks was successful in a patient in Israel'66,

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as was a 49-day course of pyrimethamine and sulphonamide in an Americannegro who was originally infected in North Africa in 1944164. Nitrofurantoinis used to treat coccidiosis in domestic animals and deserves further study inman.

Balantidiasis

Pigs appear to be the main reservoir of infection and infection rates mayreach 20% in New Guinea where human contact with pigs is particularlyclose166. Infections in Moslem countries and mental institutions result fromdirect transmissiom or a rodent source167. The fuJly documented outbreakin Micronesia'68 followed a typhoon which contaminated surface -watersupplies with pig faeces; the outbreak was self-limited and multifocal,suggesting that person to person infection was unusual. The rare fatal casesmay show extensive ulcerative enteritis'69. Concurrent Trichuris infectionmay favour tissue invasion'6 . Metronidazole was used successfully to treat20 infections in Venezuela' 70, but it failed to cure three out of four asympto-matic infections in Micronesia'68. Nitrimidazine (Naxogin (R)) cured threesymptomatic cases in Mexico'67, and 12 out of 17 children in Columbia whoreceived 500 mg daily for five days' 71. The ultrastructure of this parasitehas now been described'72.

Other parasites

A rectal biopsy from a 3 year old girl, who presented in Tennessee with afive-day history of severe diarrhoea and vomiting, showed parasites resem-bling Cryptosporidium attached to crypt epithelial cells; they measured 2-4 nmand were demonstrated by toluidine blue staining and by electron micro-scopy 73. The illness was severe but self-limiting; a barium enema had shownspiculated ulceration of the rectosigmoid and descending colon. This parasiteshould be looked for again in similar situations.The amoeboflagellate, Dientamoeba fragilis, was found in 4-2% of the

preserved faecal specimens from 43 029 subjects in Canada' 4. The disputedpathogenicity of this parasite is fully discussed in this paper; suggestivesymptoms are diarrhoea or loose stools, abdominal pain, and anal pruritus.A positive association was found in this survey between D. fragilis andthreadworm (Enterobius vermicularis), thus supporting the hypothesis that theegg of this worm acts as a mechanical vector for the protozoan.

R. KNIGHT1 AND S. G. WRIGHTDepartment of Tropical Medicine

Liverpool School of Tropical MedicineLiverpool

Department of Clinical Tropical MedicineHospital for Tropical Diseases

London'Address for reprint requests: Dr. R. Knight, Liverpool School of Tropical Medicine, PembrokePlace, Liverpool L3 4QA.Received for publication 11 April 1978

References

"Marsden, P. D., and Hoskins, D. W. (1966). Intestinal parasites: a progress report. Gastro-enterology, 51, 701-720.

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Gut, 14, 145-168.4Jeon, K. W. (ed.) (1973). The Biology of Amoeba. Academic Press: London.'Singh, B. N. (1975). Pathogenic and Non-pathogenic Amoebae. Macmillan: London."Padilla y Padilla, C. A., and Padilla, G. M. (ed.) (1974). Amebiasis in Man: Epidemiology,

Therapeutics, Clinical Correlations and Prophylaxis. Charles C. Thomas: Springfield, Illinois.7Sepulveda, B., and Diamond, L. S. (1976). Proceedings of the International Conference on

Amoebiasis, Mexico City, 27-29 October 1975. Instituto Mexicano del Seguro Social: Mexico.'L6sch, F. A. (1975). Massive development of amebas in the large intestine. Translation from

German text, 1875. American Journal of Tropical Medicine and Hygiene, 24, 383-392."Griffin, J. L. (1972). Human amebic dysentery. Electron microscopy of Entamoeba histolytica

contacting, ingesting and digesting inflammatory cells. American Journal of Tropical Medi-cine and Hygiene, 21, 895-906.

"Takeuchi, A., and Phillips, B. P. (1975). Electron microscope studies of experimental Entamoebahistolytica infection in the guinea pig. I. Penetration of the intestinal epithelium by tropho-zoites. American Journal of Tropical Medicine and Hygiene, 24, 34-48.

"Takeuchi, A., and Phillips, B. P. (1976). Electron microscope studies of experimental Enta-moeba histolytica infection in the guinea pig. II. Early cellular and vascular changes ac-companying invasion in the lamina propria Virchows Archiv Abteilung B. Zellpathologie.,20, 1-13.

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'4Bos, H. J., and Van de Griend, R. J. (1977). Virulence and toxicity of axenic Entainoeba histo-lytica. Nature (Lond.), 265, 341-343.

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"Proctor, E. M., and Gregory, M. A. (1972). The ultrastructure of axenically cultivated tropho-zoites ofEntamoeba histolytica with particular reference to an observed variation in structuralpattern. Annals of Tropical Medicine and Parasitology, 66, 335-338.

7Deas, J. E., and Miller, J. H. (1977). Plasmalemmal modifications of Entamoeba histolyticain vivo. Journal ofParasitology, 63, 25-31.

"Diamond, L. S., and Mattern, C. F. T. (1976). Protozoal viruses. Advances in Virus Research,20, 87-112.

"Bird, R. G., and McCaul, T. F. (1976). The rhabdovirus ofEntamoeba histolytica and Entamoebainvadens. Annals of Tropical Medicine and Parasitology, 70, 81-93.

2"De, P. K., Bhatia, V. N., Ray, B. G., and Agarwal, D. S. (1973). Virulence of E. histolyticastrains isolated from cases of amoebiasis in New Delhi, India. Indian Journal of MedicalResearch, 61, 45-50.

2"Latter, V. S. (1972). Correlation between strain virulence and evaluation of growth in mono-xenic culture of Entamoeba histolytica. Transactions of the Royal Society of Tropical Medicineand Hygiene, 66, 13.

22Phillips, B. P., Diamond, L. S., Bartgis, I. L., and Stuppler, S. A. (1972). Results of intraceacalinoculation of germ-free and conventional guinea pigs and germ-free rats with axenicallycultivated Entamoeba histolytica. Journal of Protozoology, 19, 498-499.

23Raether, W. (1971). Intrahepatikale Infektions versuche am Goldhamster mit Entamoebahistolytica-Crithidia-Kulturen mit und ohne Beteiligung von Bakterien. Zeitschrift fidrParasitenkunde, 36, 335-345.

24Diamond, L. S., Phillips, B. P. and Bartgis, I. L. (1973). Virulence of axenically cultivatedE. histolytica. Archivos de Investigacion Medica, 4, Suppl. I, 99-104.

2"Mattern, C. F. T., and Keister, D. B. (1977). Experinmental amebiasis I. Pathogenicity ofaxenically cultured Entamoeba histolytica in the brain of the newborn mouse. AmericanJournal of Tropical Medicine and Hygiene, 26, 393-401.

26Mattern, C. F. T., and Keister, D. B. (1977). Experimental amebiasis II. Hepatic amebiasis inthe newborn hamster. American Journal of Tropical Medicine and Hygiene, 26, 402-411.

27Neal, R. A., Latter, V. S., and Richards, W. H. G. (1974). Survival of Entamoeba and relatedamoebae at low temperature. II. Viability of amoebae and cysts stored in liquid nitrogen.International Journal ofParasitology, 4, 353-360.

2"Neal, R. A. (1974). Survival of Entamnoeba and related amoebae at low temperature. I. Via-bility of Entamoeba cysts at 4'C. International Journal ofParasitology, 4, 227-229.

2"Martinez-Palomo, A., Gonzalez-Robles, A., and De la Torre, M. (1973). Selective agglutinationof pathogenic strains of Entamoeba histolytica induced by con A. Nature New Biology,245, 186-187.

3"Silva, P. P. da, and Martinez-Palomo, A. (1974). Induced redistribution of membrane particles,anionic sites and con A receptors in Entamoeba histolytica. Nature (Lond.), 249, 170-171

"Ross, G. W., and Knight, R. (1973). Dietary factors affecting the pathogenicity of Entamoebahistolytica in rats. Transactions of the Royal Society of Tropical Medicine and Hygiene 67

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