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high blood-pressure, high cholesterol, or smoking, thestatistics seldom have much impact on the patientbecause of the long time-scale. Indeed the risks maywell be psychologically small when it is made clear that,even with a strong statistical association, only a verysmall proportion will come to grief.3 In this connectionthe type A phenomenon may be important from twopoints of view. Firstly, the magnitude of the type A riskhas been assessed as roughly equivalent to that ofhypertension or smoking.4 Because of the

multiplicatory behaviour of coexisting risk factors, thecombination of risks may be great enough to inspireimmediate fear. Secondly, absence of type A behaviourmay partly explain the survival of some people whohave a multiplicity of conventional risks.

It will not be easy to sort out the correlations between

type A, the established risk factors, and sudden death,myocardial infarction, and angina, but there are nofundamental reasons to prevent a reasonably goodscientific job. There are many patterns of mentalstate which have been thought to predispose to acutecardiovascular disease. Widowhood, retirement, jobloss, and divorce are all fruitful sources for

psychometric analysis. But there are more seriousdifficulties. If the type A hypothesis is correct, thenobviously the links between behaviour and the

pathophysiological processes causing disease must befurther explored. It is in this area of analysis that thereal troubles begin. There is a possibility that a genetictrait might be expressed in dual fashion-for example,there might be a factor common to behaviourdetermination and arterial wall degeneration.Alternatively, adverse biochemical changes might ariseonly during a phase of type A behaviour. FRIEDMAN etal. alluded to this possibility in a report on accountantswho had. higher serum cholesterol when they wereparticularly oppressed by deadlines. In either case weare thrown back to the basic mechanisms ofatherosclerosis, thrombosis, and adrenergic drive, allof which have proved difficult enough without theadded complication of behaviour studies. At a lessfundamental level, we may get some information fromthose individuals who are obliged to undergo severalcoronary arteriograms; a selected group, admittedly,but one in which a higher proportion of type Acharacteristics may be expected. In such research,improved angiographic techniques giving better smallvessel definition are important for the future.

Optimistically we must suppose that practicalmedicine will be the better for such knowledge.Through the eyes of the individual the key question is swhether the quality or length of life can be improved byintervention, whether with advice or with drugs.

3. Rose G. Strategy of prevention: Lessons from cardiovascular disease. Br Med J 1981;282: 1847-51.

4. Rosenman RH, Brand RJ, Sholtz RI, Friedman M. Multivariate prediction of coronaryheart disease during 8· 5 year follow up in Western Collaborative Group Study. AmJ Cardiol 1976; 37: 903-09.

5. Friedman M, Rosenman RH, Carroll V. Changes in serum cholesterol and bloodclotting time in men subjected to cyclic variation of occupational stress. Circulation1958; 17: 852-61

Behaviour modification is a sensitive matter. We maynot wish to mend our ways. We may live and work in anenvironment that has encouraged and rewarded thetype A attitude. Our immediate world may or may notwish to change. A substantial loss of type A behaviourcould mean demotion in status, in job function, in theregard of colleagues and possibly in personal income.None of these prospects is very enticing. But, for ahigh-risk individual, the long-term view may offer littlechoice; and with good personal counselling the pricemay not be too high. Such counselling demands muchskill, and the family doctor may have to make anunusual effort.To what degree can behavioural modification alter

the health and lif expectation of the individual? It is alltoo easy to assume that there is a simple link, and thatmodification of the one will alter the other. Given theneed for scientific demonstration, the most rewardingstatistical circumstances are those in which the highestincidence of test points occurs in the shortest period oftime. Thus, hypertensive smokers with unfavourablelipid profiles should be a first focus. In thesecircumstances remoulding of a patient’s life-style mayprove an ethically defensible activity. In type Aindividuals with risk factors of a lower order ofmagnitude, the prospect of a useful result is small:there is scant chance of collecting enough "events," ina manageable number of people. At present there seemsno good reason to advise lower-risk individuals to mendtheir ways. Indeed, devil’s advocates have been heardto argue that, in some quarters, a small infusion of typeA would be beneficial all round.

To Sleep, Perchance to Breathe.ABNORMALITIES in breathing during sleep have

attracted increased attention with the identification,firstly, of sleep apnoea syndromes, in which breathingstops for over 10 seconds an average of more than tentimes per hour of night-time sleep;2 and, secondly, ofthe much more common disturbances of breathingpattern and arterial oxygenation during sleep in

patients with chronic lung disease.3-6 Two types ofsleep apnoea are distinguished-central apnoea, wherechest wall movement and diaphragmatic contractionscease when airflow stops at the nose and mouth; andobstructive apnoea, where transient upper-airwayobstruction is revealed by persistent chest wall

1 Guilleminault C, Tilian A, Dement WC Sleep apnea syndromes. Annu Rev Med 1976,27: 465-85.

2. Guilleminault C, Dement WC, eds. Sleep apnea syndromes. New York: A. R. Liss.1978.

3. Flick MR, Block A. Continuous in vivo monitoring of arterial oxygenation in chronicobstructive lung disease Ann Intern Med 1977; 86: 725-30

4. Wynne JW, Block AJ, Hemenway J, et al Disordered breathing and oxygendesaturation during sleep in patients with chronic obstructive pulmonary diseaseChest 1978; 73: suppl 301-03.

5. Douglas NJ, Calverley PMA, Leggett RJ, et al Transient hypoxaemia during sleep inchronic bronchitis and emphysema. Lancet 1979; i: 1

6 Fleetham JA, Mezon B, West P, Bradley CA, et al. Chemical control of ventilation andsleep arterial oxygen desaturation in patients with COPD. Am Rev Resp Dis 1980.122: 586-89.

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movement despite absent oronasal flow. Oesophagealmanometry is no longer required to detect

diaphragmatic contraction since recording of chestwall movement along with air flow at nose and mouthcan separate the two patterns. In obstructive sleepapnoea, upper airway occlusion results from failure ofcontraction of either the muscles which dilate the

pharynx during inspiration,s or the muscles whichhold the tongue and jaw forwards.9 The

subatmospheric pressure from continued inspiratorydiaphragmatic contraction then sucks the flaccid

tongue or pharyngeal wall inwards, so that theresistance to airflow increases and ventilation

progressively falls’O until apnoea is complete. Apnoeicepisodes are most frequent in the rapid eye movement(REM) phase of sleep, when intercostal and

diaphragmatic tone is reduced, so that the functionalresidual capacity also falls." Both sleep deprivationand alcohol can increase the frequency and duration ofapnoeic episodes in patients with obstructive apnoea.12 IIt is also important to remember that repeated doses ofnitrazepam (and possibly other benzodiazepines)diminish respiratory drive in patients with CO,retention.B 3

Treatment of obstructive sleep apnoea has variedfrom drugs, such as medroxyprogesterone acetate

(MPA) and protriptyline, to tracheostomy. In fourpatients in whom obstructive sleep apnoea was

associated with a low forced expiratory volume in 1 s(FEVI), arterial hypoxaemia, COZ retention, and corpulmonale (thus apparently "blue and bloated"chronic bronchitis and emphysema), MPA (60-120mg/day) reduced apnoeic episodes and improved day-time sleepiness and peripheral oedema.14 However, infive similar patients with low FEV, and sleep apnoea,but with less severe hypoxaemia by day, MPA had noeffect.14 The drug can increase both hypoxic andhypercapnic ventilatory drives in man, 1 and both thesedrives may be depressed in REM sleep in man.16Hypoxaemia and CO2 retention was also improved byMPA in ten obese patients with alveolar

hypoventilation,17 but the drug did not improve sleepapnoea in another seven obese men, although it raised7 Sharp JT, Druz WS, Foster JR, et al. Use ofthe respiratory magnetometer in diagnosis

and classification of sleep apnoea. Chest 1980; 77: 350-52.8. Guilleminault C, Hill MW, Simmons FB, Dement WC. Obstructive sleep apnoea:

Electromyographic and fibreoptic studies. Exp Neurol 1978; 62: 48-67.9. Remmers JE, DeGroot WJ, Sauerland EK, Anch A. Pathogenesis of upper airway

occlusion during sleep. J Appl Physiol 1978; 44: 931-38.10. Martin RJ, Pennock BE, Orr WC, et al. Respiratory mechanics and timing during sleep

in occlusive sleep apnoea. J Appl Physiol 1980; 48: 432-37.11 Muller NL, Francis PW, Gurwitz D, et al. Mechanism of hemoglobin desaturation

during rapid eye movement sleep in normal subjects and in patients with cysticfibrosis. Am Rev Resp Dis 1980; 121: 463-69.

12. Guilleminault C, Rosekind M. The arousal threshold. Sleep deprivation, sleepfragmentation, and obstructive sleep apnoea syndrome. Bull Eur Physiopathol Resp1981; 17: 341-49.

13. Rudolf M, Geddes VM, Turner JA McM, Saunders KB. Depression of centralrespiratory drive by nitrazepam. Thorax 1978; 33: 97-100.

14 Strohl KP, Hensley MG, Saunders NA, et al Progesterone administration andprogressive apneas. JAMA 1981; 245: 1230-32.

15 Skatrud JB, Dempsey JA, Kaiser DJ. Ventilatory response to medroxyprogesteroneacetate in normal subjects: Time course and mechanism. J Appl Physiol 1978; 44:939-44.

16 Sullivan CE, Berthon-Jones M. Ventilatory and arousal responses to eucapnic hypoxiain sleeping humans. Am Rev Resp Dis 1981; 123: 174.

17. Sutton FD, Zwillich CW, Creagh CE, et al. Progesterone for outpatient treatment ofPickwickian syndrome. Ann Intern Med 1975; 83: 467-79.

their arterial POz when they were awake.’8

Progesterone may have a physiological role in sleep.Episodic minor arterial desaturation, hypopnoea, andapnoea were all much more frequent during 4-5 h ofnocturnal sleep in thirty men (average age 38 years)than in nineteen mostly premenopausal women(average age 29 years).19 However, such episodes weremuch more frequent during sleep in postmenopausalwomen,2o in whom progesterone levels are very low,although MPA (30 mg/day) had only minor effects onthe breathing during sleep in these women.21

Protriptyline (2-5-25 mg/day) significantly reducedepisodes of apnoea in eleven out of fourteen adults inwhom obstructive sleep abnormalities22 were

associated with other metabolic or cardiac disease, butthe drug’s cardiac side-effects seem to limit its value.SULLIVAN et a1.23 have described complete reversal ofobstructive sleep apnoea when air under continuouspositive pressure was applied to the nose in five

patients with severe obstructive sleep apnoea. Thistreatment, which seems to have no side-effects andneeds only simple apparatus, looks like a substantialadvance, since the only real alternative in severe

obstructive apnoea is permanent tracheostomy.24 Infifty patients with life-threatening obstructive sleepapnoea, permanent tracheostomy, opened only at

night, led to relief of daytime sleepiness, reversal ofpersonality changes, and return to a normal workinglife.24 Very careful preoperative assessment andeducation were vital to this success, and almost half the

patients still had minor complications.Transient hypoxaemia during REM sleep is now

known to be common in patients with the "blue andbloated" pattern of chronic bronchitis and

emphysema. 1,1,21 Such patients characteristically haveday-time hypoxaemia, CO2 retention, secondarypolycythaemia, pulmonary hypertension, and cor

pulmonale; but despite widespread misconceptions26this pattern cannot be equated only with chronicbronchitis without emphysema. These hypoxaemicepisodes can be associated with a further rise in

pulmonary arterial pressure, 1,27 and usually arise

during episodic or cyclic hypoventilation, for a truesleep-apnoea syndrome is rare in such patients (at least

18. Orr WC, Imes NK, Martin RJ. Progesterone therapy in obese patients with sleepapnea. Arch Intern Med 1979; 139: 109-11.

19. Block AJ, Boysen PG, Wynne JW, Hunt LA. Sleep apnea, hypopnea and oxygendesaturation in normal subjects; a strong male predominance. N Engl J Med 1979;300: 513-17.

20. Block AJ, Wynne JW, Boysen PG Sleep disordered breathing and nocturnal oxygendesaturation in post-menopausal women. Am J Med 1980; 69: 75-79.

21. Block AJ, Wynne JW, Boysen PG, et al. Menopause, medroxyprogesterone andbreathing during sleep. Am J Med 1981, 70: 506-10.

22. Clarke RW, Schmidt HS, Schaal SF. Sleep apnea: Treatment with protrptyline.Neurology 1979; 29: 1287-92.

23. Sullivan CE, Berthon-Jones M, Issa FG, Eves L. Reversal of obstructive sleep apnoeaby continuous positive airway pressure applied through the nares. Lancet 1981; i:862-65.

24. Guilleminault G, Simmons FB, Motta J, et al. Obstructive sleep apnea syndrome andtracheostomy: Long term follow-up experience. Arch Intern Med 1981; 141:985-88.

25. DeMarco FJ, Wynne JW, Block AJ, et al. Oxygen desaturation during sleep as adeterminant of the ’blue and bloated’ syndrome. Chest 1981; 6: 621-25.

26. Ahmad M, Cressman M, Tomasagfski JF. Central alveolar hypoventilation syndrome.Arch Intern Med 1980; 140: 29-30.

27 Boysen PG, Block AJ, Wynne JW Nocturnal pulmonary hypertension in patients withchronic obstructive pulmonary disease. Chest 1979; 76: 536-42.

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when they first present to a respiratory clinic28).Correction of their nocturnal hypoxaemia maytherefore prevent severe pulmonary hypertension andcor pulmonale, and also improve survival, as shown bythe recent N.I.H.29 and M.R.C.3° controlled trials of

long-term low-dose oxygen in chronic bronchitis andemphysema, in both of which oxygen was given atnight. However, in the N.I.H. trial oxygen givenmainly at night (12 h in the 24 h day) did not prolonglife as much as oxygen for 19-24 h in the 24 h day.

Despite the well-known risk that oxygen therapy mayincrease CO2 retention in these patients during anexacerbation,31 no serious rise in PC02 was seen withlong-term low-flow oxygen (possibly because PC02was not measured during sleep). Such oxygen at night’did cause temporary reversible acidosis in one

moderately hypoxic "blue bloater" in whom the

hypoxic drive to breathing was preserved,32 but thereduction in this drive observable in most such

patients33 may protect them from a rise in PC02.GUILLEMINAULT et a1.34 have cautioned against,nocturnal oxygen therapy in chronic bronchitis, forthey describe doubling in the duration of apnoeicevents in REM sleep with 1’5 or 3 1/min of oxygengiven through nasal prongs in four such patients withday-time somnolence and sleep apnoea, only one beinga "blue bloater". Conversely in eleven patients withmild hypoxaemia (mean P02 66 mm Hg) from chronicobstructive lung disease, but without serious C02retention (mean PC02 44 mm Hg), 2 1/min of oxygenby nasal prongs for half the night increased the timespent asleep, and reduced oxygen desaturation, but hadno effect on episodes of apnoea or hypopnoea, whencompared with the other half of the night withoutoxygen.35 Arterial PC02 was measured in five of thesepatients, but did not rise more during episodes ofdisordered breathing when they breathed oxygen thanin similar episodes when they breathed’air.

Certainty as to the safety of nocturnal oxygen in thesepatients clearly requires more measurements, but therecent trials suggest that the treatment is safe, if theoxygen flow is kept low and provided that the patientsare not in an acute exacerbation of respiratoryacidosis.31 Studies of effective respiratory stimulantsduring sleep in "blue bloaters" are badly needed, with

28. Catterall JR, Douglas NJ, Calverley PMA, et al. Hypoventilation is common, but sleepapnea rare, in transient nocturnal hypoxemia of ’blue and bloated’ bronchitis. AmRev Resp Dis 1981; 123: 113.

29 Nocturnal Oxygen Therapy Trial Group. Continuous or nocturnal oxygen therapy inhypoxemia chronic obstructive lung disease. Ann Intern Med 1980; 93: 391-98.

30. M.R.C. Working Party. Long term domiciliary oxygen therapy in chronic hypoxic corpulmonale complicating chronic bronchitis and emphysema. Lancet 1981; i:

681-86.31. Warren PM, Avery A, Millar JS, Flenley DC. Respiratory failure revisited:

Exacerbations of chronic bronchitis 1960-1968 and 1970-1976. Lancet 1980; i:467-74

32 Leitch AG, Clancy LJ, Leggett RJE, et al Arterial blood gas tensions, hydrogen ion,and electroencephalogram during sleep in patients with chronic ventilatory failure.Thorax 1976; 31: 730-35.

33. Flenley DC, Franklin DH, Millar JS. The hypoxic drive to breathing in chronicbronchitis and emphysema. Clin Sci 1970; 38: 503-18.

34. Guilleminault C, Cummiskey J, Motta J. Chronic obstructive airflow disease and sleepstudies. Am Rev Resp Dis 1980; 122: 397-406.

35. Kearley R, Wynne JW, Block AJ, et al The effect of low flow oxygen on sleepdisordered breathing and oxygen desaturation. Chest 1980; 78: 682-85.

or without added oxygen, for such drugs may wellinterfere with sleep. The new French drug almitrine,which can improve hypoxaemia and C02 retention in"blue bloaters" ,36 clearly merits such a trial in sleep.The effects of drugs on breathing during sleep, sincethey concern two of the more important humanactivities, deserve attention from both drug regulatorybodies and the pharmaceutical industry.

THE LANGERHANS CELL

OF the many subjects which reliably produce heated andinconclusive debate amongst dermatologists, the epidermalLangerhans cell takes the prize. Some new findings, mademore than a hundred years after this dendritic cell wasdiscovered by Paul.Langerhans,’ now bid fair to mitigate itscontentious reputation. The Langerhans cell was originallythought to be either a sensory receptor cell or an effete

melanocyte, and progress in its definition was greatlyimpeded by lack of methods for firm identification of thecells. This deficiency was rectified in 1961 by Birbeck,Breathnach, and Everall2 who described the ultrastructuralfeatures of the Langerhans cell and in particular identified aunique racquet-shaped organelle, the Birbeck granule. TheLangerhans cell also occurs in dermis, mucous membranes,and lymphatic tissue. Its derivation from a bone marrow

mesenchymal cell has now been convincingly demonstratedas a result of transplantation and chimaera studies by Tamakiand Katz.3The disease histiocytosis X, which affects bone, lungs, and

skin, is probably due to proliferation of the Langerhans cell4and the possibility that the Langerhans cell is the target cell inmycosis fungoides is being explored.s The major newdiscoveries, however, centre on the involvement of

Langerhans cells in immunological reactions, especiallyallergic contact dermatitis. Convincing evidence of an

important role in allergic contact dermatitis was first

provided by Silberberg,6 who noted the intimate appositionof Langerhans cells with mononuclear cells in positive patchtest reactions. The appearances of the Langerhans cell wereoften suggestive of increased secretory activity. The nextimportant development was the realisation that Langerhanscells, like mononuclear phagocytes, serve a pivotal role insensitisation, by processing antigens before their presen-tation to immunocompetent lymphocytes. Langerhans cellsbehave as dendritic scavengers of foreign small-molecularmaterial which has trespassed within the epidermis.’ Thisfinding is of especial relevance to allergic contact dermatitis,which usually involves a cutaneous hypersensitivity reactionto simple low-molecular-weight substances. The analogywith mononuclear phagocytes was further strengthened

36. Symposium on gas exchange and ventilation perfusion ratios. Round table, AlmitrineBull Eur Physiopathol Resp 1980; 16: 195p-208p.

1. Langerhans P. Uber die Nerven der menschlichen Haut. Virchows Arch 1868; 44:325-37.

2. Birbeck MS, Breathnach AS, Everall JD. An electron microscopic study of basalmelanocytes and high level clear cells (Langerhans cells) in vitiligo. J InvestDermatol 1961; 37: 51-64.

3. Tamaki K, Katz SI. Ontogeny of Langerhans cells J Invest Dermatol 1980; 75: 12-134. Basset F, Turiaf MJ. Identification par la microscopie electronique de particles de

nature probablement virale dans les lesions granulomateuses d’une histiocytose-Xpulmonaire. CR Acad Sci Paris 1965; 261: 3701-03.

5. Mackie RM. Initial event in mycosis fungoides of the skin is viral infection of epidermalLangerhans cells. Lancet 1981; ii: 283-84.

6. Silberberg I. Apposition of mononuclear cells to Langerhans cells in contact allergicreactions. Acta Dermatovener 1973; 53: 1-12.

7. Shelley WB, Juhlin L. Langerhans cells form a reticuloepithelial trap for externalcontact antigens. Nature 1976; 261: 46-47