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Hicklin et al4 reported improvement in a third of rheumatoidpatients treated with exclusion dieting, Parke and Hughes5 5the response of one patient to restriction of dairy products,and Williams6 improvement with a restricted diet in a

rheumatoid patient with corn intolerance. In 1982, wecompleted a prospective study (unpublished) of whetherdietary elimination therapy in rheumatoid patients producedobjective improvement. This study showed substantialbenefit with dietary therapy but was uncontrolled. Panush etal,’ investigating the Dong diet (free from additives,preservatives, fruit, red meat, herbs, and dairy produce),found no evidence of overall clinical benefit but thought thatindividual dietary manipulations might be beneficial forselected rheumatoid patients. Denman et al found no linkbetween food intolerance and either juvenile chronic arthritisor adult rheumatoid arthritis but did record transient

synovitis caused by food allergy.8 Patients with definite orclassic rheumatoid arthritis improved during a 1-week waterfast,9 and in a prospective, double-blind study patients withrheumatoid arthritis improved on a diet high in

polyunsaturated fats and low in saturated fats, with a dailysupplement of 1’ 8 g eicosapentaenoic acid, and relapsed onits withdrawal.lo

Our results and those of other studies suggest that dietarymanipulation may give benefit in at least some patients.Variation in response may reflect the heterogeneity of therheumatoid population, with dietary therapy helping only aproportion of patients. It is one thing to describe

improvement with dietary therapy in patients with

rheumatoid arthritis and quite another to explain how it maywork. There are several possible mechanisms which, singlyor in combination, could explain improvement on dietarytherapy in rheumatoid arthritis. It may be due to reduction ingenuine intolerance of foods or perhaps to correction ofabnormalities of absorption of food or bacterial antigens,particularly in patients on non-steroidal anti-inflammatorytherapy." The weight losses during the study may have had abeneficial effect on disease activity.

It is believed that low intake of the polyunsaturated fattyacid linoleic acid may lead to reduced formation of

arachidonic acid and thence of active, omega-6prostaglandins. Dietary manipulation that increases intake ofomega-3 fatty acids may, firstly, reduce by competitiveinhibition the supply of arachidonic acid from which omega-6prostaglandins are produced and, secondly, providealternative substrates to encourage production of less activeomega-3 prostaglandins. Both mechanisms may lead to areduced inflammatory response (R. D. Rice, personal com-munication).

Psychological processes are thought to producepathophysiological changes indistinguishable from genuineimmunological reactions; Pearson describes these as

"pseudo-food allergy" .12 Suggestion is obviously importantand up to 40% of rheumatoid arthritis patients have beendescribed as placebo responders.

Before describing enthusiasm for dietary therapy inrheumatoid arthritis as uncritical and unscientific, one

should remember the recent controversy about theeffectiveness of even second-line drugsl3 and that severalrheumatological drugs have caused anxiety and beenwithdrawn. Increasing numbers of scientific studies suggestthat dietary manipulation may help at least some rheumatoidpatients and perhaps the greatest need now is for more carefuland well-designed research so that preconceptions may be put

aside and any role of diet, as a specific or even as a non-specificadjunctive therapy, may be determined.

We thank Dr J. R. Kirwan, Bone and Joint Research Unit, London Hospital,for advice on study design and Mrs Anne Darby-Dowman for help withstatistical analysis.

Correspondence should be addressed to L. G. D., Department of

Rheumatology, Epsom District Hospital, Dorking Road, Epsom, SurreyKT187EG.

REFERENCES

1 Ropes MW, Bennett GA, Cobb S, Jacox R, Jessar RA. Diagnostic criteria forrheumatoid arthritis, 1958 revision. Ann Rheum Dis 1959; 18: 49-53.

2 Royal College of Physicians and British Nutrition Foundation. Food intolerance andfood aversion. J R Coll Phys Lond 1984; 18: 83-123

3 Skoldstam L, Larsson L, Lindström FD. Effects of fasting and lactovegetarian diet onrheumatoid arthritis. Scand J Rheumatol 1979; 8: 249-55.

4. Hicklin JA, McEwen LM, Morgan JE. The effect of diet in rheumatoid arthritis. ClinAllergy 1980; 10: 463-67

5 Parke AC, Hughes GRV. Rheumatoid arthritis and food: a case study. Br Med J 1981,282: 2027-29.

6 Williams R. Rheumatoid arthritis and food a case study. Br Med J 1981; 283: 5637. Panush RS, Carter RL, Katz P, Kowsari B, Longley S, Finnie S. Diet therapy for

rheumatoid arthritis Arthritis Rheum 1983, 26: 462-718. Denman AM, Mitchell B, Ansell BM. Joint complaints and food allergic disorders Ann

Allergy 1983; 51: 260-63.9. Kroker GP, Stroud RM, Marshall RT, et al. Fasting and rheumatoid arthritis: a

multicenter study. Clin Ecol 1984; 2: 137-44.10 Kremer JM, Michaelek AV, Lininger L, et al. Effects of manipulation of dietary fatty

acids on clinical manifestations of rheumatoid arthritis. Lancet 1985; i. 184-8711 Bjarnson 1, So A, Levi AJ, et al. Intestinal permeability and inflammation in

rheumatoid arthritis: effects of non-steroidal anti-inflammatory drugs. Lancet 1984,ii. 1171-74.

12. Pearson DJ Food allergy, hypersensitivity and intolerance. J R Coll Phys Lond 1985;19:154-62

13 Goddard D, Butler R, eds. Rheumatoid arthritis—a treatment controversy.Proceedings of the meeting held at Stratford upon Avon, March 10, 1984. London:MacMillan, 1984.

LIFE EXTENSION IN HEART DISEASE: ANANIMAL MODEL

WALTER N. TAPP BENJAMIN H. NATELSON

Primate Neuro-behavioral Unit (127A), Veterans AdministrationMedical Center, East Orange, New Jersey; and Department of

Neurosciences, New Jersey Medical School, Newark, New Jersey,USA

Summary In an experimental study to investigate theeffect of constant light on longevity in heart

disease male hamsters with inherited heart disease werehoused in pairs in either constant light or 12 h light and 12 hdark cycles. All hamsters had free access to food and water.Constant light slowed the progress of heart failure, made thehamsters more likely to survive the early stages of failure, andextended their lives. This observation may open new avenuesfor the treatment of human beings with heart disease.

Introduction

HEART disease is a major cause of death and disability, andcurrent treatments rely largely on drugs. This reportdescribes life extension in hamsters with heart disease duringtreatment with constant light (CL). CL has been reported toaffect physiology and health, but it has not been tested in awell-described disease entity. We tested the effects of CL onhamsters with inherited heart disease (CMHs). Heart diseasein hamsters has many similarities with human heart disease,2including a well-described disease progression, cardiacdamage followed by compensatory cardiac hypertrophy anddilatation, congestive heart failure, and early death. 3,4

Methods

In two longevity studies weanling, male CMHs (Bio-Research,Cambridge, Massachusetts) were pair-housed in CL or in cycles of

239

Effect of light exposure on survival and indices of heart failure.

(A) Survival curves showing improved survival of CMHs in LL in experiment 1. The y-axis shows the probability of survival to a particular age. Survivalprobabilities were computed as Kaplan-Meier product limit estimates. N=22 in each group. (B) Survival curves showing improved survival of CL CMHs inexperiment 2. N=26 in CL and 42 in LD. (C) Increased fluid retention and organ weights of hamsters that died in CL in experiment 2. Error bars are SEM.*Difference significant at p<O - 05; **difference significant at p<0 01. (D) Fluid retention and organ weights of CMHs in CL and LD in experiment 3. N = 5 in CLand 6 in LD 12:12. Error bars are SEMs. **Indicates significance at p<0-01 and *** at p<0 005.

12 h light and 12 h dark (LD), with free access to food and water.Average light intensity at the cage floor was 1700 lux during lightand less than 0 - 1 lux during dark. CMH deaths were recorded daily,and signs of heart failure (amount of fluid in pleural and abdominalcavities and high organ weights) were noted at necropsy.In the first experiment, we gave CMHs 0 - 07% saline as drinking

water because we thought added sodium would accelerate heartfailure and shorten the experiment. In the second experiment tap-water was used instead of saline. If life extension in CL were solelydue to living longer while in heart failure, then CL and LD rearedhamsters would show no differences in pathological indices of heartdisease in the early stages of heart failure. This possibility was testedin a third experiment. The experiment was identical to the first twoexcept that CMHs were individually housed and had access torunning wheels. Running was recorded on a computer. At 11months of age, CMHs were decapitated and examined.

Results

CMHs lived significantly longer in CL than in LD (see fig[A]) (p<0-01, log-rank tests). Median lifespan was 12%longer in CL (391 days) than in LD (349 days). Hamsters inLD had a 5007o chance of living 349 days, whereas those in CLhad an 87% chance of living that long.

Interpretation of these results was clouded because CMHsin CL drank almost twice as much saline (15-8 ml/day&plusmn;0’ 69SEM) as CMHs in LD (8 - 02--tO - 27 SEM) (p<0 - 01).Without supplemental sodium, CL had even greater life-

prolonging effects (see fig [B]) (p<0 005, log-rank test). Thedifference in median lifespan increased to 25’4%&mdash;358 daysin LD and 449 days in CL. Again, CMHs in LD had only a50% chance of living 358 days, but in CL they had an 88%chance of living that long. Clearly, saline reduced the salutaryeffects of living in CL.Fluids in the pleural and abdominal cavities and heart,

liver, spleen, and lung weights were significantly higher inCL hamsters than in hamsters in LD (see fig [C]). In heartfailure, fluid retention and organ weight usually increase asthe heart becomes less effective as a pump.3 Thus, in CL,CMHs survived early stages of heart failure that were fatal toCMHs in LD.In experiment three there were significantly more cases of

severe heart failure in CMHs in LD than in CMHs in CL.This suggests that CL slows the progress of heart disease. By11 months CMHs in LD had prominent pleural andabdominal fluid effusions (see fig [D]) (CL-LD differencesignificant at p<0 005). CMHs in CL, however, had pleuraland abdominal fluid levels well below the range found inCMH heart failure; fluid weights in CMHs in LD in

experiment three were not significantly different from fluidweights in CMHs that died in experiment two, but fluidweights in CMHs in CL in experiment three were more thanthree standard errors below the terminal levels in experimenttwo.

240

Discussion

Heart weight was significantly lower in 11-month-oldCMHs in CL than in 11-month-old CMHs in LD. Heartweight reflects hypertrophy and dilatation, which increase asCMH heart disease progresses.4 The increase in heart sizebeyond the biomechanical limits of the heart’s effectivenessas a pump is often the event that precipitates the onset of overtheart failure.3 Therefore, the large difference between heartweights in CL and LD suggests that CL slows the process(es)that lead to heart failure.We can exclude several possible explanations for these

results. Lifespan differences were not due to litter biases.CMHs in CL lived longer than their siblings in LD in everyone of the 14 litters in experiments one and two. Nor were theresults due to the time of year the animals entered the study.In experiment two, litters entered the study at intervals ofabout 3 months but time of entry had no significant effects onoverall lifespan or on the difference between lifespan in CLand LD. Activity differences also seem unlikely to account forthe lifespan effects. Experiment three showed no significantdifferences between total use of running wheels in CL

(7976 - 3 turns/24 h&plusmn;671-8 SEM) and total use of runningwheels in LD (7248 - 8&plusmn;591 - 8).We are currently investigating three explanations. First,

the beneficial effects of CL might depend on a direct

photobiological response to light. Second, they might dependon a photoperiodic response to increased daylength; there is

evidence that changes in daylength may improve somedepressive disorders in human beings.6 Third, life extensionmight be due to changes in circadian rhythms-a well-knowneffect of CL.’ This phenomenon should provide an

important model for understanding how an environmentaltreatment can extend life and reduce disability in seriousdisease.

We thank Dr J. Ottenweller for his keen interest and assistance, J. Cook, D.Creighton, and J. Yavorsky for their contributions to all phases of this work,and the Durotest Corp for providing us with the lamps. This study wassupported by HL26760 and Veterans Administration Medical Research.

Correspondence should be addressed to W. N. T., Department ofNeurosciences, New Jersey Medical School, 88 Ross Street, East Orange, NewJersey 07018, USA.

REFERENCES

1. Finger FW. Effects of atypical illumination schedules. In: Brown FM, Graber RC, eds.Rhythmic aspects of behavior. Hillside, New Jersey: Lawrence Erlbaum Assoc,1982: 345-61.

2. Factor SM, Minase T, Cho S, Dominitz R, Sonnenblick EH. Microvascular spasm mthe cardiomyopathic Syrian hamster: a preventable cause of focal myocardialnecrosis. Circulation 1982; 66: 342-54.

3. Hurst JW. The heart. New York: McGraw-Hill, 1978: 528-608.4. Bajusz EH, Homburger F, Baker JR, Bogdanoff P. Dissociation offactors influencing

myocardial degeneration and generalized cardiocirculatory failure. Ann NY AcadSci 1969; 156: 396-420.

5. Kalbfleisch JD, Prentice RL. The statistical analysis of failure time data. New York:Wiley, 1980.

6. Kripke DF. Therapeutic effects of bright light in depressed patients. Ann NY Acad Sci1985; 453: 270-81.

7. Pittendrigh CS Circadian oscillators in cells and the circadian organization ofmulticellular systems. In: Schmitt FO, Worden FG, eds. The neurosciences thirdstudy program. Cambridge, Massachusetts: MIT Press, 1974: 437-58

Preliminary Communication

EPSTEIN-BARR VIRUS RECEPTORS ON HUMANPHARYNGEAL EPITHELIA

L. S. YOUNG

J. W. SIXBEY*D. CLARK

A. B. RICKINSON

Department of Cancer Studies, University of Birmingham, UK; and*Division of Infectious Diseases, St Jude Children’s Research

Hospital, Memphis, USA

Summary The apparently strict tropism of Epstein-Barr virus (EBV) for B lymphocytes has

been attributed to the existence of a B-lineage-specific surfacemolecule, the C3d receptor, which also functions as a

receptor for EBV. Two monoclonal antibodies againstdifferent determinants on the EBV/C3d receptor of B cellswere shown to react with pharyngeal epithelia in a celldifferentiation-dependent manner. These findings, whichraise the possibility of direct virus entry into a naturallyexposed epithelium, strengthen the evidence in favour of anepithelial reservoir of EBV infection in vivo and identify ameans whereby the virus/epithelium interactions leading tonasopharyngeal carcinoma might be initiated.

INTRODUCTION

MOST attempts to understand the biology of Epstein-Barrvirus (EBV) begin from a common premise, that is theextreme tropism which this agent appears to display forhuman B lymphocytes. Certainly the virus preferentiallyinfects B cells in vitro’ and is associated with three

lymphoproliferative diseases ofB cell origin in vivo-namely,infectious mononucleosis (IM), Burkitt’s lymphoma, andlymphoma of the immunocompromised host.2 It has long

been thought that such tropism reflects the existence of aB-cell-specific surface receptor for the virus, and indeedrecent studies with monoclonal antibodies (MAbs) HB53 andanti-B24 have shown unequivocally that the 140-145kilodalton C3d receptor molecule CR2, expressed on Blymphocytes but not on any other haemopoietic cell, has EBVreceptor function.

5

There exists, at the same time, a growing body of evidencethat links EBV infection to epithelial cells. The very strongassociation between EBV and nasopharyngeal carcinoma(NPC) is already well known2 and more recent studies alsoreport detection of the viral genome in lymphoepitheliomasarising in salivary glands and in the thymus. Moreover, thepresence of EBV in desquamated cells shed from the

oropharyngeal epithelium of IM patients8 suggests that

epithelial cell infection forms part of the natural virus-hostinteraction, even though the means of virus entry into suchcells remains unclear.

Using cultures of human ectocervical epithelium at 2 weekspost-explantation-an in-vitro model system in which smallnumbers of cells seem experimentally infectable withEBV9-we recently identified by electron microscopy about5% of cultured cells (morphologically the least differentiatedpopulation) showing specific binding of the HB5 MAb andspecific adsorption of EBV particles to similar sites on themembrane (Sixbey JW, Davis DS, Young LS, Hutt-FletcherL, Tedder TF, Rickinson AB, unpublished). Furthermore,in frozen sections of fresh ectocervical epithelium, the basaland parabasal cells showed unequivocal reactivity with twoindependent antibodies (HB5 and anti-B2) specific fordifferent epitopes of the C3d/EBV receptor molecule on Bcells. These observations on ectocervix strongly suggestedthat HB5/anti-B2 staining of epithelial cells in tissue sectionswas detecting the expression of a functional EBV receptor.The present report describes the extension of these studies topharyngeal epithelia which may be directly exposed to thevirus during its natural transmission by the oral route.