831

further intervention by angioplasty or surgery3l have yet tobe decided.What impact have coronary care units had? The debate

about their effect on mortality has rumbled on for most ofthe past twenty-five years. Early non-randomised trials

indicated a substantial reduction in mortality,2 but twoprospective randomised studies of low-risk patients showedno benefit from hospital admission,32,33 although the

significance of this finding was hotly debated.34 Studies ofthe epidemiology of heart attacks suggest that coronary caredoes reduce hospital mortality,35 and has had a measurableeffect on the overall reduction in coronary artery deaths incountries like New Zealand8 and the USA.36 However, theintroduction of drugs with proven ability to reduce

mortality and infarct size would seem to sweep aside theconvolutions of the old home-versus-hospital argument,and there is probably little justification now for keeping athome patients for whom reducing the risk of death is anappropriate aim. But the impact of the coronary care unit hasextended well beyond the narrow confines of salvagingpatients from myocardial infarction: intensive treatment ofunstable angina, arrhythmias, and cardiac failure;prehospital care;37 general resuscitation; and, not least,considerable insight into trial design21 have all followed

directly from the stimulus of caring for the heart attackpatient. The coronary care unit is twenty-five (and a bit)years old: it has been a good idea.

INTERCELLULAR ADHESION MOLECULESAND RECURRENT INFECTION

LEUCOCYTE chemotaxis plays an important part in theinflammatory response that helps to prevent or containinfection; one of the first steps in this process is cellularadherence to the vascular endothelium.m3 Studies of the

leucocytes from several children with recurrent infectionsdue to defective chemotaxis have now thrown light on themechanism involved in intercellular adhesion; these

findings are of considerable interest because such adhesionis thought to be an early step in many of the signallingsystems that regulate cell functions.

29. The ISAM Study group. A prospective trial of intravenous streptokmase in acutemyocardial infarction (ISAM): mortality morbidity and infarct size at 21 daysN Engl J Med 1986; 314: 1465-71.

30. McNeill AJ, Shannon JS, Cunningham SR, et al A randomised dose ranging study ofrecombinant tissue plasminogen activator in acute myocardial infarction Br Med J1988; 296: 1768-71

31. O’Neill WW. Impact of different reperfusion modalities on ventricular function aftermyocardial infaction Am J Cardiol 1988; 61: 45G-53G.

32. Mather HG, Morgan DC, Pearson NG, et al. Myocardial infarction: a comparisonbetween home and hospital care for patients. Br Med J 1976 i 925-29.

33 Hill JD, Hampton JR, Mitchell JRA. A randomised trail of home-versus-hospitalmanagement for patients with suspected myocardial infarction. Lancet 1978; i:

837-41.34 Rawless JM, Kenmure ACF The coronary care controversy. Br Med J 1980; 281:

783-86.35. Gillum RF, Folsom A, Luepker RV, et al. Sudden death and acute myocardial

infarction in a metropolitan area, 1970-1980: the Minnesota heart survey. N Engl JMed 1983, 309: 1353-58.

36 Goldman L, Cook EF The decline in ischemic heart disease mortality rates: ananalysis of the comparative effects of medical interventions and changes in lifestyle.Ann Intern Med 1984, 101: 825-36.

37 Geddes JS. Twenty years of prehospital coronary care Br Heart J 1986; 56: 491-951 Keller HU, Hess MW, Cottier H. Physiology of chemotaxis and random motility

Semin Hematol 1975; 12: 472 Hoover RL, Briggs RT, Kamovsky MJ The adhesive interaction between

polymorphonuclear leukocytes and endothelial cells in vitro. Cell 1978, 14: 423-283 Fehr J, Dahmden C. Modulating influence of chemotactic-factor induced

adhesiveness on granulocyte function. J Clin Invest 1979; 64: 8-16

Leucocyte adhesion deficiency (LAD) is a rare inheriteddisorder in which the leucocytes are unable to perform thosefunctions that depend on cell adhesion.4-7 Patients present inchildhood with recurrent or severe bacterial infections,particularly cellulitis, pneumonia, or otitis media. Theinfections are characterised by their progressive nature, withneutrophilia but diminished pus formation. Delayedseparation of the umbilical stump and poor wound healingare other characteristic features of LAD.

Patients with LAD have phagocytes that are unable toadhere to nylon wool or glass beads, and these cells show astriking decrease in the level of a particular glycoprotein(molecular weight 180 kD); the severity of their clinicalinfections seems to correlate with the degree of deficiency ofthis protein. The absence of chemotactic inhibitors in theserum, and the fact that transfused neutrophils from normalsubjects retain their function suggest that the primary defectis in the granulocyte. The mothers and sisters of somepatients have mild symptoms with intermediate levels of theglycoprotein, but the exact mode of inheritance is stilluncertain.s8 The deficient glycoprotein is likely to beidentical with an adhesion molecule called the lymphocyte-function-associated antigen-1 (LFA-1), which is expressedon the leucocyte surface, and LAD is a defect in the genecoding for the common beta chain of this molecule.9-12The role of the LFA-1 family of adhesion molecules has

been studied in vitro by use of monoclonal antibodies thatblock the effect of the LFA-1 protein.13 Such antibodiesinhibit lymphocyte functions that require cell-to-cell con-tact, including mitogen responses and cytotoxic activity.13-19Lymphocytes from patients with LAD display the same

4. Bowen T, Ochs HD, Rosen H, Willis-Carr J, et al Severe recurrent bacterial

infections and lack of granulocyte adherence and chemotaxis Clin Res 1979; 27:82A (abstr).

5. Crowley CA, Cumutte JT, Rosin RE, et al. An inherited abnormality of neutrophiladhesion: its genetic transmission and its association with a missing protein. N EnglJ Med 1980; 302; 1163-68.

6. Beatty PG, Ochs HD, Harlan JM, et al Absence of monoclonal-antibody-definedprotein complex in a boy with abnormal leucocyte function. Lancet 1984; i. 535-37.

7 Fischer A, Seger R, Durandy A, et al. Deficiency of the adhesive protein complexlymphocyte function antigen I, complement receptor type 3, glycoprotem p 150, 95in a girl with recurrent bacterial infection. J Clin Invest 1985, 76: 2385-92.

8. Bowen TJ, Ochs HD, Altman LC, et al. Severe recurrent bacterial infectionsassociated with defective adherence and chemotaxis in two patients with

neutrophils deficient in a cell-associated glycoprotein. J Pediatr 1982; 101: 932-409 Springer TA, Thompson WS, Miller LJ, et al Inherited deficiency of the Mac-1,

LFA-1 p 150,95 glycoprotein family and its molecular basis. J Exp Med 1984; 160:1901-18.

10. Marlin SD, Morton CC, Anderson DC, et al. LFA-1 immunodeficiency disease:definition of the genetic defect and chromosomal mapping of alpha and betasubunits by complementation in hybrid cells. J Exp Med 1986; 164: 855-67.

11 Kishimoto TK, Hollander N, Roberts TM, et al. Heterogeneous mutations in the betasubunit common to the LFA-1, MAC-1 and p 150, 95 glycoprotems causeleukocyte adhesion deficiency Cell 1987; 50: 193-202.

12. Dana N, Clayton LK, Tennen DG, et al Leukocytes from four patients with completeor partial Leu-Cam deficiency contain the common &bgr;-subunit messenger RNA.J Clin Invest 1987; 79: 1010-15

13 Martz E LFA-1 and other accessory molecules functioning in adhesions of T and Blymphocytes. Hum Immumol 1987, 18: 3-37

14. Springer TA, Davignon D, Ho MK, et al LFA-1 and Lyt-2,3, molecules associatedwith T lymphocyte-mediated killing, and Mac-1, an LFA-1 homologue associatedwith complement receptor function Immunol Rev 1982; 68: 111-35.

15. Kohl S, Springer TA, Schmalstieg FC, et al. Defective natural killer cytotoxicity andpolymorphonuclear leukocyte antibody-dependent cellular cytotoxicity in patientswith LFA-1/OKM-1 deficiency. J Immunol 1984, 133: 2972-78.

16. Krensky AM, Mentzer SJ, Clayberger C, et al. Heritable lymphocyte function-associated antigen-1 deficiency: abnormalities of cytotoxicity and proliferationassociated with abnormal expression of LFA-1. J Immunol 1985, 135: 3102-08

17. Anderson DC, Miller LJ, Schmalstieg FC, et al. Contributions of the Mac-1

glycoprotein family to adherence-dependent granulocyte function: structure-

function assessments employing subunit-specific monoclonal annbodies.

J Immunol 1986; 137: 15-27.18. Harlan JM, Killen PD, Senecal FM, et al. The role of neutrophil membrane

glycoprotein GP-150 m neutrophil adherence to endothelium in vitro. Blood 1985;66: 167-78.

19. Tonnesen MG, Anderson DC, Springer TA, et al Mac-1 glycoprotein familymediates adherence of neutrophils to endothelial cells stimulated by chemotactic

peptides. Clin Res 1986, 34: 419a

832

defective reactions in vitro as do normal lymphocytesin the presence of anti-LFA-1 antibodies.19 Neutrophilfunctions inhibited by these antibodies include aggregation,chemotaxis in agar, and adherence to endothelium,"-19 andthe neutrophils from LAD patients again show the samedefects. The clinical features in LAD patients can thereforebe attributed to defective leucocyte adhesion to cellular andextracellular surfaces, the defect involving both neutrophilsand lymphocytes.Once the LFA-1 adhesion molecule had been identified,

it became possible to conduct an ingenious series of

immunological experiments: Epstein-Barr-virus-trans-formed B-lymphoblastoid cell-lines from normal subjectsand LAD patients were used to detect and identify anotherintercellular adhesion molecule called ICAM-1, whichbinds with the LFA-1.- This ligand, ICAM-1, isalso a glycoprotein (molecular weight 90-115 kD) and isfound on the surface of various lymphoid and non-lymphoidtissues Zz ICAM-1 is not constantly present, but it appears atsites of inflammation, and can be induced in vitro onfibroblasts and endothelial cells by inflammatory mediatorssuch as interleukin-1, tumour necrosis factor, and gammainterferon.2223 Its expression can be inhibited by the proteinsynthesis inhibitors cyclohexamide and actinomycin D. 22Monoclonal antibodies to ICAM-1 block its function, andthese antibodies will inhibit leucocyte adhesion to

fibroblasts and endothelial cells, just as the LFA-1antibodies do, except that the antibodies to ICAM-1 act onthe fibroblast or endothelial cell whereas LAF-1 antibodyacts on the leucocyte.212224 ICAM-1 is therefore an

inducible glycoprotein on cell surfaces, which mediatesintercellular adhesion by binding with the LFA-1 molecule;this reaction is probably essential for many immunologicaland inflammatory reactions. This is an excitingdevelopment-modulation of ICAM-1 expression mightoffer the possibility of therapeutic control of manyinflammatory processes.25

HEALTH PROMOTION AT WORK

THE identification and control of hazards in the

workplace remains an important aspect of occupationalhealth practice, but success in this endeavour has been suchthat in affluent countries occupational disease is no longerthe scourge which challenged the pioneers of industrialmedicine. As the burden of occupational disease has

receded, the scope of health promotion at work has beenbroadened to include non-occupational causes of disease-eg, many companies have instituted programmes to combatalcohol and drug abuse, and to modify cardiovascular riskfactors such as hypertension, smoking, and diet.

This development reflects a growing interest in healthy

20 Rothlem R, Springer TA. The requirement for lymphocyte function-associatedantigen 1 in homotypic leukocyte adhesion stimulated by phorbol ester. J Exp Med1986; 163: 1132-49

21 Rothlem R, Dustin ML, Marlin SD. A human intercellular adhesion molecule(ICAM-1) distinct from LFA-1. J Immunol 1986; 137: 1270-74.

22. Dustin ML, Rothlein Bahn AK, et al. Induction by IL-1 and interferon tissue

distribution, biochemistry and function of a natural adherence molecule

(ICAM-I) J Immunol 1986; 137: 243-5423 Pober JS, Lapierre LA, Stolpen AH, et al. Activation of cultured human endothelial

cells by recombinant lymphotoxin comparison with tumor necrosis factor andinterlcukin-1 species J Immunol 1987, 138: 3319-24

24 Marlin SD, Springer TA. Purified intercellular adhesion molecule-1 (ICAM-1) is aligand for lymphocyte function-associated antigen-1 (LFA-1). Cell (m press)

25 Wantzin GL, Ralfkiaer E, Lisby S, Rothlem R. The role of intercellular adhesionmolecules in inflammatory skin reactions Br J Dermatol 1988; 119: 141-45

living in society at large, and especially in the better educatedclasses from which managers are drawn. As a point ofcontact for health promotion, the workplace has much tooffer. The target population is readily accessible and

follow-up is easy. Moreover, there are unique opportunitiesto encourage and reinforce desired changes in personalbehaviour. The menu in the staff canteen can be planned toaccommodate dietary recommendations; part or all of thepremises may be designated a no-smoking area; and facilitiesfor exercise can be provided. The suitability of the

occupational setting for this type of intervention is

emphasised in new guidelines prepared by the WorldHealth Organisation.1One recommendation of the WHO report is that more

research should be done to evaluate methods ofintervention. Health promotion is widely perceived as

reducing the long-term costs of employers, but directevidence of economic benefit is limited. Warner and

colleagues lately reviewed data published up to 1986 on tenareas of health promotion, and concluded that goodinformation on the economics of intervention policies wasavailable in only two areas-smoking cessation and thecontrol of hypertension.2 In some areas data were totallylacking-eg, there had been no attempts to assess thecost-effectiveness of the many and varied programmes forthe prevention of back injury.The paucity of information is due in part to the difficulty

of rigorous evaluation. Some benefits, such as enhancementof a company’s public image and improvements in themorale of a workforce, are hard to quantify. Others, such as areduction in sickness absence and decreased turnover oflabour (and therefore less expenditure on training), areeasier to define; but if intervention is aimed at the preventionof chronic disease, effects on these variables may be apparentonly after lengthy follow-up. Thus many studies haverestricted attention to short-term measures of outcome thatcannot be interpreted directly in economic terms. There isno simple equation by which success in persuadingemployees to give up smoking can be translated into afinancial gain. There may even be hidden costs if, for

example, greater life expectancy increases demands on thepension fund.The ultimate economic goal for the employer is a growth

in overall profits, but many factors contribute to

profitability, and it is hard to disentangle their independenteffects. If a retailer makes more money, is it because of thehealth promotion programme or because sales techniqueshave improved? The standard scientific approach to thisproblem is to conduct a controlled experiment, but there areobstacles to this method. Managers must be persuaded thatthere is logic in withholding an intervention that is perceivedas beneficial from one section of the workforce; unions maybe even harder to convince.

Despite these difficulties, progress can and should bemade. Some philanthropic employers are motivated byinterests other than financial gain, but others are morehard-nosed. If the proponents of health promotion cannotproduce convincing evidence of profitability, there is a

danger that good programmes will be thrown out with thebad when healthy scepticism overtakes initial blindenthusiasm.

1 World Health Organisation. Health promotion for working populations WHO TechRep Ser 1988, no 765.

2. Wamer KE, Wickizer TM, Wolfe RA, Schildroth JE, Samuelson MH Economicimplications of workplace health promotion programs review of the literatureJ Occup Med 1988, 30: 106-12.