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Page 1: The parasites, predators, places and people I have known: a great adventure

The parasites, predators, places and people I have

known: a great adventure$

Max Murray*

The University of Glasgow Veterinary School, Bearsden Road, Bearsdon, Glasgow G61 1QH, UK

Abstract

I am extremely proud to receive the WAAVP/Pfizer Animal Health award, and particularly so in

Africa, the continent where I have spent a large part of my professional life. In the nearly 40 years

in research I have had the privilege and excitement of being involved with many great parasites,

predators, places and people. In my early days in Kenya I saw all the great wild animal predators,

but soon came to appreciate that the greatest predator of all was disease, particularly parasitic

disease, with the devastating effects of tsetse and ticks and the infections they transmitted, and of

the all-prevailing roundworms. I learned several key lessons while working with research teams to

develop better diagnostics, to improve epidemiological understanding as a basis for rational

treatment and control, and to extend the understanding of disease processes with the view to

developing novel methods of treatment or prevention. The Power of Pathology in diagnosing

diseases, identifying new diseases and as a major tool for pathogenic diseases. The Power of

Pathogenesis in identifying key mechanisms that led to new diagnostic techniques, improved

methods of treatment, and possibly to future vaccines. The Power of Application of what we already

know; while recognising that molecular biology will make a massive contribution to improving

animal and human health, it is important to appreciate that we already have a very powerful

armamentaria to diagnose, treat, control or prevent disease, and when used properly they have been

successful and cost-effective. The Power of Genetic Resistance: the recognition that certain species,

certain breeds, and certain individuals within breeds possess remarkable resistance to certain

parasitic diseases such as trypanosomosis and helminthosis, and that this trait is genetically

correlated with production, opens up a very powerful additional approach to improving animal

health. The Importance of Measurement: I completely endorse the sentiments of Lord Kelvin,

Professor of Natural Philosophy at Glasgow University who stated in 1846: `̀ When you can

measure what you are speaking about, and express it in numbers, you know something about it: but

when you cannot measure it, your knowledge is of a meagre and unsatisfactory kind.'' This applies

Veterinary Parasitology 81 (1999) 149±158

* Tel.: +44-141-339-8855; fax: +44-141-942-7215; e-mail: [email protected]$WAAVP Pfizer Award for Excellence in Research in Veterinary Parasitology , Presented at the 16th WAAVP

conference, held in Sun City, South Africa in August 1997. Plenary papers from this conference have beenpublished in Veterinary Parasitology (vol 71, pp. 67±222).

0304-4017/99/$ ± see front matter # 1999 Elsevier Science B.V. All rights reserved.

PII: S 0 3 0 4 - 4 0 1 7 ( 9 8 ) 0 0 2 4 2 - 8

Page 2: The parasites, predators, places and people I have known: a great adventure

very much to Parasitology. The future is bright. The combination and integration of the new

technologies of Biotechnology, Mathematical Methods and Bioinformatics coupled with advances

in Computer Power will produce new standards in animal and human health in the 21st century.

New methods of predicting, diagnosis, treating, controlling, prognosing and preventing disease will

become available. WAAVP has a major role to play by ensuring that veterinary parasitologists are

provided with the proper training, infrastructure and forum to advance new technologies and that

the veterinary profession plays a leading role in the future direction they take. # 1999 Elsevier

Science B.V. All rights reserved.

1. Introduction

I am greatly honoured to receive the WAAVP/Pfizer award in veterinary parasitology

and to be given the opportunity to wander down memory lane with the parasites,

predators, places and people I have known. In the early 1960s when I was employed at the

Veterinary School at Kabete, Nairobi, Kenya I had the privilege to work with the Kenya

Game Department and others involved with wildlife. At that time, I saw both the beauty

and the savagery of the great wild animal predators of Africa: the lion, leopard, cheetah,

hyena etc., as well as the destruction that the magnificent elephant could invoke on local

agriculture. However, I soon came to appreciate that the greatest predator of all was

disease; for example, the effects of tsetse and ticks and the infections they transmitted,

and the all-prevailing roundworms, were devastating. As a consequence, much of my

professional life has been devoted to the challenge of disease, particularly parasitic

disease. I would now like to share with you some of the experiences I have had and some

of the lessons I have learned since my early days in East Africa. The lessons that taught

me the power of pathology, the power of pathogenesis, the power of application of what

we already know, the power of genetic resistance and the power of measurement.

* The power of pathology

Bill Jarrett stimulated me from the day I first met him in 1960 and still continues to do

so. Bill has been the most exciting and brilliant researcher with whom I worked. He is an

intellectual colossus. Bill showed me the Power of Pathology in Diagnosing Disease,

Identifying New Disease and in Understanding of Pathogenesis.

My first necropsy in Africa in September 1963 was carried out on rare Hunters

Antelope which had been dying in large numbers. It was done on a muram road in the

Tsavo National Park with David and Daphne Sheldrick and Tony Harthoorn. Bill helped

me to confirm that the problem was widespread Muscular Dystrophy in these and other

antelope species (Jarrett et al., 1964). The response to Vitamin E/selenium treatment was

dramatic: no more deaths ± The Power of Pathology.

* The power of pathogenesis

I was again privileged to study the pathogenesis of parasitic disease with

multidisciplinary groups comprising giants in the subject, Bill Jarrett, Ian McIntyre,

George Urquhart, Bill Mulligan, Frank Jennings and of course, Jimmy Armour.

150 M. Murray / Veterinary Parasitology 81 (1999) 149±158

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One of the most productive and enjoyable periods was our investigations into

ostertagiosis in cattle and sheep. This parasite produces a remarkable hyperplastic

gastritis in which the key event is the replacement of the functional differentiated gastric

gland cells, including the acid-secreting parietal cells, by rapidly dividing undiffer-

entiated cells (Murray et al., 1970) with the consequence that,

1. abomasal pH becomes elevated with the result that pepsinogen is not activated to the

proteolytic enzyme pepsin with the consequent failure to initiate digestion. At the

same time, there is a logarithmic increase in bacteria in the abomasum;

2. the tight junctions between the rapidly dividing undifferentiated cells are not properly

formed, allowing protein to leak between cells and resulting in a protein-losing

gastropathy.

An exciting finding was that the new benzimidazole drugs by effectively removing all

parasite stages, rapidly reversed these pathogenic processes (Armour et al., 1967).

Subsequently, with Bill Jarrett and Hugh Miller we studied the pathogenesis of worm

expulsion from the gastrointestinal tract using the model system of Nippostrongylus

brasiliensis in the rat, as well as ostertagiosis in cattle and sheep. It was established that

immediate hypersensitivity reactions with subepithelial mast cell proliferation, discharge

of their vasoactive compounds, and consequently related mucosal hyperpermeability

appeared to play a key role in the exponential expulsion of worms from the

gastrointestinal tract (Murray et al., 1971; Murray, 1972). It was also shown by

histochemistry and electron microscopy that the intra-epithelial globule leukocyte (a cell

frequently found in association with mucosal parasitism) was in fact a sub-epithelial mast

cell that had discharged its vasoactive compounds, and was not, as had previously been

proposed, a Russell body-containing plasma cell (Murray et al., 1968).

Other important lessons learnt were that objective quantified clinical observations

often hold the key to identifying and understanding what the important pathogenic

processes are, and that disease is a kinetic process that can change with time. An

outstanding example of this was the appreciation that anaemia was the key indicator of

disease status and process in bovine African trypanosomosis. Many workers throughout

the ages recognised that anaemia was an important disease factor in bovine African

trypanosomosis, but it was Ian McIntyre who appreciated that it was the key driving force

in the disease process and the key marker in evaluating the status and severity of the

disease in any one particular animal (Morrison et al., 1981). We soon realised that several

factors contributed to the onset and progress of the anaemia and that the relative

importance of these factors changed with time (Murray and Dexter, 1988). Thus while

there was a highly significant correlation between the intensity of parasitaemia and the

severity of anaemia over time, in a one-off examination, an animal could be parasitaemic

but not anaemic; equally, it could be anaemic but not detectably parasitaemic.

More recently with advances in technology we are in a position as never before to

investigate and understand disease processes at the molecular level with the real hope that

such an understanding will lead to improved methods of diagnosing, treating or even

presenting disease. An example of this approach involved Peter Kennedy, the brilliant

Burton Professor of Neurology at Glasgow and Frank Jennings; in these studies we used a

mouse model system developed by Frank to study the neuropathogenesis of African

M. Murray / Veterinary Parasitology 81 (1999) 149±158 151

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trypanosomiasis. This model simulates all phases of human African trypanosomosis

(HAT). We found in both in vivo and in vitro studies that astrocytes stimulated directly by

trypanosomes appear to play a pivotal role in producing the cytokines that initiate and

maintain the severe meningoencephalitis that is the main feature of the disease (Hunter

et al., 1992). Subsequently, it was shown that the polyamine inhibitor eflornithine

appeared to selectively block cytokine production by astrocytes and this drug could be

used to prevent or ameliorate the CNS inflammatory process (Jennings et al., 1997).

Further, it was demonstrated that antagonists of substance P (a neuropeptide) had a

significant effect in alleviating the CNS pathology (Kennedy et al., 1997). Both these

findings could lead to novel treatments of HAT and other cytokine-mediated

inflammatory conditions in man (including HIV encephalitis) and animals.

For the first time, it was found using this mouse model that the highly toxic arsenical

drugs which are given intravenously to treat HAT can be administered topically thereby

avoiding the serious side effects of intravenous usage (Jennings et al., 1996). At the same

time, it was shown that the dose of a topical arsenical drug could be reduced by topical

combination chemotherapy with other trypanocidal drugs. While this work was carried

out in the mouse model system, we believe that it will have major significance for the

treatment of HAT. It is another example of the amazing innovative creativity of Frank

Jennings who has contributed so much to improve chemotherapy in African

trypanosomiasis.

* The power of application of what we already know

Molecular biology is making and will make a massive contribution to future

approaches to improving animal and human health. However, we should not forget that

we already have very powerful tools available and that these tools have been and can be

highly successful if used properly. Of the tools available, possibly the most powerful and

least recognised is the clinician/epidemiologist. This is a lesson I learned from Ian

McIntyre and subsequently John Trail in a number of Animal Health Control programmes

in which we were involved in tsetse-infested Africa. Ian, with his understanding of the

disease in both the individual animal and in the herd, played a key role in the successful

implementation of chemoprophylactic and or therapeutic trypanocidal drug control

programmes in beef ranches (Mkwaja Ranch in Tanzania: (Trail et al., 1985), in dairy

ranches (Kilifi Plantations in Kenya: Murray and Trail, 1986), in advising in village/small

holder situations (Muhaka Villages, Coast Province of Kenya; Maloo et al., 1988) etc.

With accurate diagnosis of animal health problems, strategic use of drugs, effective

analysis of databases, demonstration of cost-effectiveness and involvement of the owners,

highly successful sustainable livestock programmes have been maintained in several

tsetse-infested areas of Africa. For one such programme (Muhaka in Kenya), we were

awarded a British Government DTI Technology Transfer Industry Year Award in 1986 for

the successful implementation of Animal Health Control Programmes in Developing

Countries. This award to Glasgow University Veterinary School was in partnership with

May and Baker Pharmaceuticals (James McAinsh and David Niven), International

Livestock Centre for Africa (ILCA, John Trail), International Laboratory for Research on

152 M. Murray / Veterinary Parasitology 81 (1999) 149±158

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Animal Diseases (ILRAD) and Ministry of Agriculture and Livestock Development of

Kenya (Seif Maloo and Sam Chema).

* The power of genetic resistance

During my African Adventure, it became obvious to me, as it had to many others, that

certain breeds of cattle and small ruminants were able to survive in tsetse-infested areas

where other breeds such as Bos indicus-types and imported exotics rapidly succumbed, if

left untreated. This trait was termed trypanotolerance and has been attributed mainly to

the indigenous taurine breeds of cattle in West and Central Africa, namely, the N'Dama

and the West African Shorthorn. However, while this trait has been recognised for many

years and these animals are the core breeds for livestock and mixed agricultural

development in many areas of West and Central Africa, they still make up only a small

proportion of the cattle breeds of Africa, even in tsetse-infested areas. The main reasons

for this are that because of their smaller stature they were believed to have poor

productive potential, and that their resistance was thought to be acquired only to local

populations of trypanosomes with the result that if moved to a distant location they would

be fully susceptible.

However, standing with Ian McIntyre in a small holding in a tsetse-infested area

of The Gambia looking at N'Dama, as fat as butter, grazing with emaciated Zebu

immediately convinced us that this trait and these animals offered a powerful weapon

in our fight against the tsetse fly. Again driven on by Ian McIntyre and later by the

amazing quantitative talents of John Trail ably assisted by Guy d'Ieteren a

complementary series of field and laboratory studies showed that the trypanotolerant

breeds of cattle had unique characteristics that could be exploited in the development of

livestock production and agriculture in tsetse-infested Africa (Murray et al., 1982, 1991;

Trail et al., 1991).

It was confirmed that trypanotolerance was an innate trait characterised by the capacity

to control parasitaemia and the ability to resist the development of anaemia. Such animals

possessed a superior immune response to variable and non-variable trypanosome

antigens, had a better immunological memory and had a greater capacity to acquire

resistance to the effects of infection. This was confirmed in N'Dama taken from The

Gambia to ILRAD as embryos (Jordt et al., 1986). It was also found that these animals

had significant resistance to ticks, tick-borne infections and helminths.

In a magnum opus involving 18 countries in West and Central Africa, John Trail and

his colleagues at ILCA (ILCA, 1979) computed that trypanotolerant breeds were at least

as productive as Bos indicus breeds in areas of no or low tsetse risk, in areas where the

tsetse risk was higher comparison was not possible because only trypanotolerant breeds

were present in significant numbers. In The Gambia first at MRC Fajara and later at the

International Trypanotolerance Centre, it was demonstrated that the N'Dama if properly

managed and fed, possessed remarkably dual purpose potential in terms of milk and meat,

as well as making excellent oxen.

The main clinical manifestation of the disease, namely, anaemia and the ability to resist

it, and the main parasitological manifestation, namely, parasitaemia and the ability to

control it, were found to be variable within the breed but were repeatable, heritable and

M. Murray / Veterinary Parasitology 81 (1999) 149±158 153

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positively genetically correlated with production. This showed for the first time that,

using these phenotypic criteria, programmes for identification, selection and improve-

ment of the resistance and productive traits, both in trypanotolerant and other breeds are

possible.

More recently workers in Glasgow, in particular Mike Stear, working in collaboration

with Kenya Agricultural Research Institute (KARI) and Roslin Institute (Edinburgh) have

been investigating the question of genetic resistance of small ruminants to helminthosis.

Firstly, the earlier observations of John Preston and Ed Allonby (Preston and Allonby,

1979) of the remarkable resistance of the Red Maasai sheep in Kenya to Haemonchus

contortus were confirmed (Mugambi et al., 1997). This work was extended to British

sheep, particularly Scottish Blackface, and the major helminth parasite of temperate

climates Ostertagia (Telodorsagia) circumcincta. In an outstanding multidisciplinary

series of studies (Stear et al., 1997a, b) involving molecular genetics, quantitative

genetics, immunology, pathology, parasitology, clinical evaluation, animal production

and nutrition and epidemiology, Mike Stear and his group demonstrated: remarkable

within-breed variation in faecal egg output in both field and laboratory studies; using

faecal egg output as a marker for resistance, it was shown that resistance to O.

circumcincta was a heritable trait that was genetically correlated with growth rate. A gene

was identified that strongly affects faecal egg production; it is one of the most powerful

parasitic disease-resistant genes demonstrated to date. The basic mechanism of the

resistance trait would appear to be related to the host's ability to regulate egg production

within the worm; this is significantly correlated to worm length which is strongly

correlated to the quantity and specificity of local IgA production. The immediate

hypersensitivity reaction, discussed earlier, that is associated with worm burden kinetics

in the gastrointestinal tract does not appear to have a role in regulating worm length and

fecundity, but is associated with expulsion of adult worms from the gastrointestinal tract.

At the same time, a strong and significant interaction has also been found between

genetic resistance and nutrition, for example, resistant breeds thrive on diets which are

inadequate for genetically susceptible animals while susceptible breeds show a marked

increase in resistance and productivity following dietary supplementation.

Although much still requires to be done, the knowledge already available makes

selective breeding feasible and this has now been initiated in commercial flocks.

* Importance of measurement

Lord Kelvin who was 22 years old when he was appointed to the Chair of Natural

Philosophy (Physics) at Glasgow University stated in 1846: I often say that when you can

measure what you are speaking about, and express it in numbers, you know something

about it: but when you cannot measure it, your knowledge is of a meagre and

unsatisfactory kind.

This statement, which is possibly even more relevant now than it was then, bearing in

mind the mass of data and information that we have to deal with in all aspects of our

lives, was inculcated in my psyche by Bill Jarrett, John Trail and George Gettinby.

Biological studies, whether in the field or in the laboratory, must be properly measured

and quantified.

154 M. Murray / Veterinary Parasitology 81 (1999) 149±158

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The equation I have evolved during my working life is something like

M1 �M2 � E1

E2� TT � SS

where

M1 medicine and disease research

M2 measurement, quantification

E1 cost-effectiveness (socially acceptable)

E2 environment (socially acceptable)

TT dissemination of knowledge

SS sustainable solutions

* The places where the lessons were learned

Glasgow has played a major influence in my work. I graduated from Glasgow and I am

now proud to be a member of the staff. The university will be 550 years old in 2001; it is

the fourth oldest university in the UK and the 17th oldest in the world. The university is

the heart beat of a city with an incredible academic and industrial heritage. Just 100 years

ago, 80% of all ships afloat were Clyde-built with the launching of 1000 ships per year,

an astonishing three per day. Times have changed but Glasgow still flourishes and as you

know is now a major centre of excellence in Parasitology, an achievement that was

unquestionably stimulated by Jimmy Armour and what Jimmy and I call the big 5, Jarrett,

McIntyre, Urquhart, Mulligan and Jennings, who, by developing the first and as far as I

know still the only commercially produced parasitic vaccine against the bovine lung

worm Dictyocaulus viviparus over 40 years ago, laid the foundation for modern

Parasitology (Jarrett et al., 1960).

My path led to Africa. Africa covers 30 million km2, one-fifth of the world's land

mass. It is a continent dominated and constrained by disease, for example, tsetse flies

infest some 50% of the land available for agricultural development. In 1963 we went to

East Africa, to Kenya, to the Veterinary Faculty at Kabete which Ian McIntyre

transformed virtually overnight to produce the first-ever veterinary graduates of the

University of East Africa, a programme that was supported by the incredible foresight of

the Rockefeller Foundation and John McKelvey Jr. It was at this time the concept of

developing a world class research laboratory located in Africa was created. This

laboratory would bring to bear on tropical disease the best brains in the world. What a

magnificent dream! After many international meetings and politicising held mainly at the

Villa Serbaloni, the magnificent facility owned by the Rockefeller Foundation at

Bellagio, Lake Como, ILRAD was established in Nairobi under the auspices of the

Consultative Group on International Agricultural Research (CGIAR). It is important to

recognise that it was Ian McIntyre, and John McKelvey and John Pino of the Rockefeller

Foundation who were the driving force to create what was arguably the finest Animal

Disease Research Institute in the world. I was the first scientist appointed in 1975 by the

then Director General, Jim Henson. Consequently the same team, Ian McIntyre and John

McKelvey, with the encouragement of Sir Dawda Jawara, the then President of The

M. Murray / Veterinary Parasitology 81 (1999) 149±158 155

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Gambia and a Glasgow Veterinary Graduate, established the International Trypanotoler-

ance Centre (ITC), a laboratory created to develop and exploit the disease resistance trait

by carrying out more applied research in the laboratory, and adaptive research in the

villages and small holdings of the Sene±Gambia which in themselves represented a

unique field laboratory. I was very privileged to be an active member of the group and to

work with many great men, including, Bakary Sanyang, Bakary Touray, Tony Davies and

the irrepressible Jos Mortelmans. This African experience was strengthened by my long

relationship with the World Health Organisation (WHO) and the Special Programme for

Research and Training in Tropical Diseases. There I learnt much about Africa from the

dedicated Peter De Raadt of the WHO who directed a highly successful programme,

Adriel Njogu, the first Director General of the Kenya Trypanosomiasis Research Institute

and one of the world's great gentlemen, and the energetic David Molyneux, currently

Director of the Liverpool School of Tropical Medicine.

* The future

The future is bright. While major achievements have been made in our ability to

diagnose, treat, control and prevent disease, much still needs to be done. There is no

doubt that modern science has the technology to make massive inroads into reducing the

still enormous economic losses caused by disease.

Biotechnology is developing new diagnostics, new vaccines, new therapies and even

designer animals; Biomathematics is now recognised as a very powerful tool that ensures

proper quantification, measurement, analysis and modelling of biological processes;

Bioinformatics, by exploiting medical and other data through the use of the massive

analytical power of computers and the Information Technologies, is providing a totally

new approach to interpretation and decision support by improving our capabilities in

diagnosing, prognosing, predicting and preventing disease, thereby, allowing much more

effective application of treatment and control measures. At the same time, the

miniaturisation of the engineering technologies backed by computerisation means that

a whole new generation of Smart Machines is becoming available; these will provide, not

only results rapidly and reliably in a user-friendly way, but also decision support back up

for understanding what the results mean. The VS2000 being developed at The University

of Glasgow Veterinary School is an example of a forerunner of the Smart Machine. This

instrument is a haematology analyser that is high-tech, low cost and easy to use; it not

only delivers results but helps the clinician to interpret what they mean.

The combination and integration of the developments in Biotechnology, Mathematical

Methods and Bioinformatics coupled with advances in Computer Technology and Smart

Machines will establish new standards in Animal and Human Health in the 21st century.

These are lessons I have learnt from George Gettinby, Colin Johnstone, Roger Clampitt

(of VetTest 8008 fame) and Stuart Reid, the recently appointed Professor of Veterinary

Informatics and Epidemiology. Stuart is a veterinary graduate who has been trained in

molecular biology, statistics and epidemiology. He is one of the first joint professorial

appointments between the Universities of Glasgow and Strathclyde. Our initiative in

veterinary informatics would not have been possible without the remarkable foresight and

156 M. Murray / Veterinary Parasitology 81 (1999) 149±158

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support of Dr. Elisabeth Svendsen of The Donkey Sanctuary, and of Professor Derek

Tavernor, James McAinsh, the late Brigadier John Spurry and Paul Irby of The Home of

Rest for Horses.

It is essential that the veterinary profession embraces these technologies to ensure that

we play a leading role in the future direction that they take.

It is reassuring to see at this conference that the WAAVP is pro-active in all of these

areas.

Acknowledgements

In conclusion, I would like to thank WAAVP/Pfizer Animal Health for this award. I am

extremely proud to be recognised in this way and particularly pleased to receive the

award in Africa, the continent I love and where I have learned so many of my lessons. I

cannot let this occasion go by without recognising the presence and the achievements of

Lord and Lady Soulsby, Lawson and Annette ± we know that beside every great man is an

even greater woman. Lawson has been the Le Patron of WAAVP in particular and of the

Veterinary Profession in general. Lawson encouraged, stimulated and supported me from

the moment we met over 30 years ago, as he has done for so many in the audience. I know

everyone would agree that he is a true Social and Academic Aristocrat.

Finally, and most of all, I would like to recognise the support of my family, particularly

over the last few years, my beautiful wife Christine, my daughters, Katie and Kirsty, and

my son, Max. As James Cagney once said in the wonderful movie `Yankee Doodle

Dandy,' `̀ My mother thanks you, my father thanks you, my family thanks you and I

thank you.'' It has been a `Great Adventure.'

References

Armour, J., Jennings, F.W., Kirkpatrick, K.S., Malczewski, A., Murray, M., Urquhart, G.M., 1967. The use of

thiabenzadole in bovine ostertagiasis: Treatment of experimental type I disease. Vet. Rec. 80, 510±514.

Hunter, C.A., Jennings, F.W., Kennedy, P.G.E., Murray, M., 1992. Astrocyte activation correlates with cytokine

production in the central nervous system of Trypanosoma brucei brucei-infected mice. Lab. Invest. 67,

635±642.

ILCA, 1979. Tyrpanotolerant Livestock in West and Central Africa, Monograph 2, ILCA, Addis Ababa,

Ethiopia.

Jarrett, W.F.H., Jennings, F.W., McIntyre, W.I.M., Mulligan, W., Urquhart, G.M., 1960. Immunological studies

on Dictyocaulus viviparus infection. Immunity produced by the administration of irradiated larvae.

Immunology 3, 145±151.

Jarrett, W.F.H., Jennings, F.W., Murray, M., Harthoorn, A.M., 1964. Muscular dystrophy in wild Hunter's

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Jennings, F.W., Atouguia, J.M., Murray, M., 1996. Topical chemotherapy for experimental murine African CNS-

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feximidazole or MK-436. Tropical Medicine and International Health. 1, 590±598.

Jennings, F.W., Gichuki, C.W., Hunter, C.A., Rodgers, J., Kennedy, P.G.E., Murray, M., Burke, J.M., 1997. The

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