1067

18. Jobling TW, Granowska M, Britton KE, et al.

Radioimmunoscintigraphy of ovarian tumors using a new monclonalantibody, SM-3. Gynecol Oncol (in press).

19. Crowther ME, Britton KE, Granowska M, Shepherd JH. Monoclonalantibodies and their usefulness in epithelial ovarian cancer: a review.Br J Obstet Gynaecol 1989; 96: 516-21.

Sleeping giantTen years ago, in a letter to The Lancet, Shapiro and

colleagues1 highlighted the apparent rarity ofobstructive sleep apnoea in Britain by comparisonwith the frequency then being reported from theUSA.1 These researchers, all experienced Britishclinicians, went on to conclude that, in view of thisgeographic distribution, the syndrome might berelated to aspects of lifestyle that were prevalent inAmerican but not in British culture. A decade later it isclear that sleep apnoea was present in the UK all thetime, and that the condition is both more common2and more hazardous3 than was originally supposed.Other sleep disorders, especially the insomnias,remain neglected in Britain, where a complaint ofchronic poor sleep is still likely to attract a responseunstructured by medical education and uninfluencedby developments in clinical sleep research. Theseissues have special implications for the wellbeing ofolder patients, in whom sleep disturbances are mostprevalent—eg, 23-33% of elderly British peopleliving at home have disturbed sleep. 5,6 Only a minorityof these sleep difficulties are related to depressivestates; the remainder seem to be largely or totallysomatic in origin.7,8 Nor is it merely the complaint ofpoor sleep that is age related: sleep-disorderedbreathing,9 periodic movements in sleep ("restlesslegs"),9 and disturbances of circadian function1O mayshow a similar age gradient.

In the USA, the National Institutes of Health lastyear convened a consensus conference on thetreatment of sleep disorders in older people, and aconsensus statement has now been issued. 11

Essentially, the statement is an agenda for convertingpure and applied research into clinical practice andhealth education. With respect to management, the

report presents a refreshingly broad view, in which thestrengths of medical (including surgical and

psychiatric), behavioural, and self-help strategies areacknowledged. However, there is little practical adviceon the implementation of such policies. The mainweakness is the lack of substantial representation fromagencies that provide clinical services for elderlypeople, especially primary care and geriatrics. Thus itis easy to say that general practitioners "givenadditional training" should be capable of managingmost of the sleep problems presenting in old age, butin view of the distribution of the disorders and theneed for a more labour-intensive clinical response,would they ever have the time to do so?

Sleep problems in old age can be met with practical,effective responses that include, but need not bedominated by, hypnotic drugs. An important first stepis to include late-life sleep disorders in the medical

curriculum so that doctors are made aware of theseconditions. It helps to have a health service that isconcerned with the wellbeing of old and very oldpeople, but even then sleep disruption is oftendismissed as a natural accompaniment of the ageingprocess. In the USA such an infrastucture is far from

established,12 so the impetus tends to come from highlevels of clinical and research activity into sleepdisorders. Referral of a patient by a primary carephysician to a "sleep disorder center for evaluation ofnighttime sleep by means of polysomnography"13would almost certainly over-stretch health care

resources in most countries. Insomnia in elderlypeople remains a sleeping giant.

1. Shapiro CM, Catterall JR, Oswald I, Flenley DC. Where are the Britishsleep apnoea patients? Lancet 1981; ii: 523.

2. Crosby J, Warley A, Stradling JR. Sleep hypoxaemia and its correlates in480 men aged 35 to 65 years. Thorax 1989; 44: 353.

3. Stradling JR. Obstructive sleep apnoea and driving. Br Med J 1989; 298:904-05.

4. Mellinger GD, Balter MB, Uhlenhuth EH. Insomnia and its treatment.Arch Gen Psychiatry 1985; 42: 225-32.

5. Morgan K, Dallosso H, Ebrahim S, Arie T, Fentem P. Characteristics ofsubjective insomnia among the elderly living at home. Age Ageing 1988;17: 1-7.

6. Livingston G, Hawkins A, Graham N, Blizard B, Mann A. The GospelOak study: prevalence rates of dementia, depression and activitylimitation among elderly residents in Inner London. Psychol Med 1990;20: 137-46.

7. Ford DE, Kamerow DB. Epidemiological study of sleep disturbancesand psychiatric disturbances. JAMA 1989; 262: 1479-84.

8. Gislason T, Almqvist M. Somatic diseases and sleep complaints. ActaMed Scand 1987; 221: 475-81.

9. Ancoli-Israel S, Kripke D, Mason WJ, Gabriel S, Kaplan D. Sleepapnoea and PMS in a randomly selected elderly population: finalprevalence results. Sleep Res 1986; 15: 101 (abstr).

10. Weitzman ED, Czeisler CA, Coleman RM, et al. Delayed sleep phasesyndrome: a chronobiological disorder with sleep-onset insomnia. ArchGen Psychiatry 1981; 38: 737-46.

11. National Institutes of Health. The treatment of sleep disorders in olderpeople: consensus development conference statement. Bethesda: NIH,1990

12. Besdine RW. The maturing of geriatrics. N Engl J Med 1989; 320:181-82.

13. Print PN, Vitello MV, Raskind MA, Thorpy MJ. Geriatrics: sleepdisorders and aging. N Engl J Med 1990; 323: 520-26.

Granulomas and cytokinesGranuloma was the name originally given to a

chronic inflammatory mass resembling a tumour. Useof the term is now restricted to the histological lesionlargely composed of cells of the monocyte lineage(macrophages, epithelioid cells, and giant cells)together with lymphocytes and eosinophils.Granulomas are found most commonly in infectiousdiseases, especially in tuberculosis, leishmaniasis, andschistosomiasis. Granuloma formation is a host tissue

response to a foreign antigen or immune complex. Inmany conditions--eg, Wegener’s granulomatosis,lymphoma, Crohn’s disease, pulmonary sarcoidosis,and other rarer clinical entitiesl-the exact stimulusremains unknown. Immunodeficiency states may alsobe associated with granuloma formation; granulomasare found in about 10% of cases of

hypogammaglobinaemia and in patients with chronicgranulomatous disease (CGD). In CGD, which isusually inherited as either an X-linked

1068

or an autosomal recessive condition, neutrophilsand monocytes do not develop a respiratory burstafter phagocytosis and the granuloma may representa cellular attempt to eliminate infectious

agents.Studies of the intercellular interactions that lead to

formation and maintenance of granulomas have nowfocused on the role of cytokines. Macrophages areactivated by antigens that cause cytokine generationand release. Interleukin-1 (IL-1), interleukin-2

(IL-2), interferon, and migration inhibition factorhave all been found in granulomas.2,3 Use ofantibodies directed against tumour necrosis factor(TNF) has shown that this cytokine is important inthe development and maintenance of granulomas inresponse to intravenous injection of bacille Calmette-Guerin in mice.4 There is in-vivo evidence that IL-1

may be more important in initiation, and TNF in themaintenance of granulomas. However, observationsin rodents cannot necessarily be extrapolated directlyto man.6The role of cytokines emanating from other cells,

especially T lymphocytes, in granuloma formation isless certain. IL-2, a T-cell cytokine and a helper T-cellattractant, increases the size of granulomas arising inacute Schistosoma mansoni infection, while athymicrodents or animals treated with cyclosporin are usuallyheld to be unable to mount the appropriategranulomatous response to infection.8 Eosinophils area prominent feature of some granulomas such as thoseoccurring in schistosomiasis and some of the

arteritides, but their function is largely unknown.Although interleukin-5 secretion is necessary fortissue eosinophilia, antibody to this cytokine doesnot prevent granuloma formation in response to

S mansoni.9

Cytokines are important in the elimination ofinfections characterised by granuloma formation.

Thus, in Leishmania infection, which elicits a

granulomatous response in man, interferon gammaseems to prime monocytes to respond to the parasiteby releasing TNF and IL-1, which are then active inintracellular killing.1O Interleukin-6 (IL-6) is anotherproduct of monocyte-derived cells and may have animportant antimycobacterial role in tuberculous

granulomas.l1 A prospective controlled trial in whichsubcutaneous interferon gamma was given to patientswith CGD showed that such therapy reduced thefrequency of clinically serious infections.12 There wasno change in neutrophil superoxide production in thisstudy, although striking increases in superoxidegeneration after administration of interferon havebeen reported in CGD13-in monocytes more thangranulocytes.14 Interferon potentiates killing ofintracellular pathogens via an oxygen-independentmechanism, is and it now seems that the generation ofnitric oxide, which also involves TNF, is veryimportant. 16The process of resolution of granulomatous

inflammation after the elimination of a foreign antigen

is virtually unexplored. Some cytokines, especiallyIL-4 and transforming growth factor P, downregulatemonocyte function in other circumstances 17 " and

may act at this stage. However, it may simply be thatremoval of antigen and lack of any stimulus for TNFand IL-1 production prevent further recruitment ofcells and allow programmed cell death and initiation ofthe healing process, which requires these same

cytokines.19 The role of endogenous adrenalcorticosteroids in the disappearance of granulomas isuncertain, although steroids are known to

downregulate production of TNF in vivo2O and ofIL-6 in vitro.21 Moreover, exogenous steroids havebeen used successfully in conditions such as

Wegener’s granulomatosis.1. Friedland JS, Weatherall DJ, Ledingham JGG. A chronic

granulomatous syndrome of unknown origin. Medicine (Baltimore)1990; 69: 325-31.

2. Kobayashi K, Allred C, Cohen S, Yoshida T. Role of interleukin 1 inexperimental pulmonary granuloma in mice. J Immunol 1985; 134:358-64.

3. Murray HW, Stem JJ, Welte K, et al. Experimental visceralleishmaniasis: production of interleukin 2 and interferon-&ggr; tissueimmune reaction and response to treatment with interleukin 2 and

interferon-&ggr;. J Immunol 1987; 138: 2290-97.4. Kindler V, Sappino A, Grau GE, et al. The inducing role of tumor

necrosis factor in the development of bactericidal granulomas duringBCG infection. Cell 1989; 56: 731-40.

5. Chensue SW, Ottemess IG, Higashi GI, et al. Monokine production byhypersensitivity (Schistosoma mansoni egg) and foreign body (Sephadexbead)-type granuloma macrophages: evidence for sequentialproduction of IL-1 and tumor necrosis factor. J Immunol 1989; 142:1281-86.

6. Callard RE, Turner MW. Cytokines and Ig switching: evolutionarydivergence between mice and humans. Immunol Today 1990; 11:200-03.

7. Perrin PJ, Phillips SM. The molecular basis of granuloma formation inschistosomiasis. III. In vivo effects of a T cell-derived suppressor-effector factor and IL-2 on granuloma formation. J Immunol 1989; 143:649-54.

8. Wahl SM, Allen JB, Dougherty S, et al. T lymphocyte-dependentevaluation of bacterial cell wall-induced hepatic granulomas. J Immunol1986; 137: 2199-209.

9. Sher A, Coffman RL, Hieny S, et al. Interleukin 5 is required for theblood and tissue eosinophilia but not granuloma formation induced byinfection with Schistosoma mansoni. Proc Natl Acad Sci USA 1990; 87:61-65.

10. Reiner NE, Ng W, Wilson CB, et al. Modulation of in vitro monocytecytokine responses to Leishmania donovani: interferon &ggr; preventsparasite-induced inhibition of interleukin 1 production and primesmonocytes to respond to Leishmania by producing both tumor necrosisfactor-&agr; and interleukin 1. J Clin Invest 1990; 85: 1914-24.

11. Flesch IEA, Kaufmann SHE. Stimulation of antibacterial macrophageactivities by B-cell stimulatory factor 2 (interleukin-6). Infect Immun1990; 58: 269-71.

12. The International Chronic Granulomatous Disease Cooperative StudyGroup. A controlled trial of interferon gamma to prevent infection inchronic granulomatous disease. N Engl J Med 1991; 324: 509-16.

13. Ezekowitz RAB, Dinauer MC, Jaffe HS, Orkin SH, Newburger PE.Partial correction of the phagocyte defect m patients with X-linkedchronic granulomatous disease by subcutaneous interferon gamma.N Engl J Med 1988; 319: 146-51.

14. Sechler JMG, Malech HL, White CJ, Gallin JI. Recombinant humaninterferon-&ggr; reconstitutes defective phagocytic function in patientswith chronic granulomatous disease of childhood. Proc Natl Acad Sci1988; 85: 4874-78.

15. Murray HW, Rubin BY, Rothermel CD. Killing of intracellularLeishmania donovam by lymphokine-stimulated human mononuclearphagocytes: evidence that interferon-&ggr; is the activating lymphokineJ Clin Invest 1983; 72: 1506-10.

16. Liew FY, Li Y, Millott S. Tumor necrosis factor-&agr; synergizes withIFN-&ggr; in mediating killing of Leishmania major through the inductionof nitric oxide. J Immunol 1990; 145: 4306-10.

17. Essner R, Rhoades K, McBride WH, et al. IL-4 down regulated IL-1 andTNF gene expression in human monocytes. J Immunol 1989; 142:3857-61.

1069

18. Wahl SM, Allen JB, Wong HL, et al. Antagonistic and agonistic effects oftransforming growth factor-&bgr; and IL-1 in rheumatoid arthritis.

J Immunol 1990; 145: 2514—19.19. Kovacs EJ. Fibrogenic cytokines: the role of immune mediators in the

development of scar tissue. Immunol Today 1991; 12: 17-23.20. Remick DG, Strieter RM, Lynch JP, et al. In vivo dynamics of murine

tumor necrosis factor-alpha gene expression: kinetics ofdexamethasone-induced suppression. Lab Invest 1989; 60: 766-71.

21. Waage A, Slupphaug G, Shalaby R. Glucocorticoids inhibit the

production of IL6 from monocytes, endothelial cells, and fibroblasts.Eur J Immunol 1990; 20: 2439-43.

AcetylcysteineThe principal indication for acetylcysteine (N-

acetyl-L-cysteine, NAC), given orally or

intravenously, is to lessen the toxic effects of

paracetamol (acetaminophen) after overdosage. NACis also widely prescribed as a mucolytic (orally or byinhalation), although its efficacy is uncertain, and itsuse has been suggested for other purposes—eg, forreducing plasma lipoprotein (a) concentration. NACand its thiol metabolites, notably L-cysteine andreduced glutathione, may act as antioxidants, as

reducing agents, as chelating agents, and bydisrupting disulphide bonds. Glutathione can alsohelp to repair oxidative damage via the glutathioneperoxidase system. In paracetamol poisoning NACmay act by repleting cytosolic and mitochondrialglutathione in liver and kidney,4 I but other

mechanisms—eg, reduction of oxidised thiols,inhibition of neutrophil accumulation, maintenance ofhydrolysis of arylated protein, or even reduction ordirect reaction with the cytotoxic paracetamolmetabolite-may be important.Another complication in assessment of efficacy is

that NAC can be present in several forms (free, metalchelate, internal disulphide, or mixed disulphide withother thiols including protein thiols) which may beindistinguishable with the assay methods used; inplasma, most of a dose is present as disulphides.Moreover, NAC is extensively metabolised.4 Thus,although absorption is tapid after oral doses of100-600 mg, bioavailability is less than 10%.5,6 Bycontrast, after intravenous administration, 20-30% ofthe dose is excreted unchanged in urine. Since NAC,unlike glutathione, can readily cross cell membranes,intravenous rather than oral NAC may be a better wayto increase intracellular NAC (thiol) concentrationsrapidly. Even so, NAC does not seem to raise plasmaglutathione above normal ;7 tissue glutathione maylikewise be unaffected.How might NAC be used in future and how should

its effects be evaluated? Knowledge of the

pharmacokinetics of NAC, especially awareness of thelow bioavailability after oral dosage, is essential. Thetime course of the condition being treated must beconsidered and clear markers of efficacy are needed.Safety considerations, including dose-related side-effects, are also important. Thus in paracetamolpoisoning, NAC is given at doses of up to 1260 mg/kgover 72 h during the short period when paracetamol-induced hepatorenal toxicity might otherwise occur.

In most patients so treated hepatorenal damage is veryslight as judged by conventional markers of hepaticand renal function. Adverse effects from intravenousNAC at the loading dose advocated initially (150mg/kg over 15 min) included angio-oedema,bronchospasm, flush, hypotension, nausea/vomiting,respiratory distress, and tachycardia. More recentwork suggests that the loading dose, and therefore thefrequency and severity of dose-related side-effects,can be much reduced without loss of efficacy. 8

In clinical toxicology NAC may also be beneficialafter poisoning with agents, such as carbontetrachloride and chloroform, for which toxicity is

predictable and for which reactive compoundscontribute to the development of toxic effects.

However, acute poisoning due to chlorinated

hydrocarbons is rare and assay methods to confirm thediagnosis and to provide a basis for assessing efficacyare not widely available. Of the other possible uses ofNAC, evaluation of its role in preventing delayedneuropsychiatric complications of acute carbonmonoxide poisoning is complicated by imprecisepredictive features.9 In heavy metal poisoning moreeffective chelating agents (dimercaptopropanesulphonate, dimercaptosuccinic acid) are available.Despite early reports,4 NAC has not been used widelyto prevent common side-effects of drugs such asdoxorubicin and ifosphamide.

Assessing the role of NAC in conditions notattributable to a specific poison is even more difficult.In disorders such as chronic obstructive lung diseasepossible metabolic/antioxidant actions are hard todistinguish from mucolytic effects. Thus, despitemuch interest in the effects of NAC on markers ofinflammation in bronchoalveolar lavage fluid fromcigarette smokers,10,11 no clear conclusions have

emerged. Protection against ischaemic/reperfusiondamage,12 treatment of inflammatory joint disease,and prevention of human immunodeficiency virusexpression13 are other areas where the use of NAC hasbeen discussed. One condition in whichadministration of short-term intravenous NAC wouldbe feasible is adult respiratory distress syndrome;preliminary data suggest some benefit.14 To evaluatethe role of NAC in these circumstances, use ofanalogues such as N-acetyl-D-cysteine or N-methyl-L-cysteine could help to differentiate the beneficialeffects of NAC itself from any brought about viaL-cysteine/glutathione.

1. Hogan JC, Lewis MJ, Henderson AH. Chronic administration ofN-acetylcysteine fails to prevent nitrate tolerance in patients with stableangina pectoris. Br J Clin Pharmacol 1990; 30: 573-77.

2. Gavish D, Breslow JL. Lipoprotein (a) reduction by N-acetylcysteine.Lancet 1991; 337: 203-04.

3. Stalenhoef AFH, Kroon AA, Demacker PNM. N-acetylcysteine andlipoprotein. Lancet 1991; 337: 491.

4. Holdiness MR. Clinical pharmacokinetics of N-acetylcysteine. ClinPharmacokinet 1991; 20: 123-34.

5. Borgstrom L, Kagedal B, Paulsen O. Pharmacokinetics of N-

acetylcysteine in man. Eur J Clin Pharmacol 1986; 31: 217-22.6. Olsson B, Johansson M, Gabrielsson J, Bolme P. Pharmacokinetics and

bioavailability of reduced and oxidized N-acetylcysteine. Eur J ClinPharmacol 1988; 34: 77-82.