THE SECOND BRANCH OF LEARNING MEASUREMENT OF BREATH-HOLDING TIME IN THE ACUTE RESPIRATORY PATIENT

on effects of


GUEST EDITORIAL NEIL DOUGLAS
R.M.S. must change.
Its hitherto cocoon-like existence is fine for the forty or so active members, but the Society fails, even in its chosen role as an academic body, as it attracts by no means all of the best brains in the medical school. The Society must enlarge its sphere of activity and dispel its intro verted and self-satisfied image. There are many who would be happy to see R.M.S. quietly fold up, believing that its ideas lie, along with its roots, in the 18th century. However, I am sure that there is a place for a flourishing, undergraduate medical student society, especially one with the funds of R.M.S. The problem is how to make the R.M.S. flourish.
Many of the current objectives of the Society are pertinent and must be pursued, but others need to be added to make it relevant to medical students as a whole. The Society's annual membership is about 120 and whilst it must be said that this is 50% up on five years ago, why are only one-seventh of Edinburgh's medical students members of R.M.S., and equally important in the present context, why are so many of the more intelligent students spurn ing the Society? Doubtless some of this latter group prefer individualised methods of study interspersed with complete relaxation, but there are many who decry the Elitist attitude which has been propagated by some R.M.S. members. Their criticism is valid, but their resulting action is not.
The most effective way to change a small inde pendent body is from within, but I will grant that even this is not easy in R.M.S. Such is the hier archical structure of the Society that by the time one has got to a position of sufficient influence to try to effect change, one's initial reformatory zeal has long worn off and one has become enmeshed in the R.M.S. way of life. It is important that people with new ideas and the drive to pursue them be encouraged to join and carry them out. This requires not only changes in the Presidential election system but also a more outward looking publicity and in formation system. Further, the organisational struc ture of the Society is such that the President is in no position to effect constructive change, but is entirely shackled by Council. This results in the anomalous position that the junior, but not the senior, members of Council have a sphere of influence in which they can operate entirely un challenged.
One reason for not joining the Society is the £2.00 annual subscription. The Society's activities are so structured that until one parts with £2.00 it is impossible to experience what you are going to get for the money. £2.00 will not deter those adamant that they wish to join, but to the uncon vinced this represents 12 pints of beer or 5 S.N.O. concert tickets, and is not to be parted with lightly. We failed narrowly last year in an attempt to reduce the subscription, but we will try again this year. Indeed I think abolition rather than reduction of the subscription will be necessary, at least by the time we enter our new building in Phase III, as I can see no other way in which all students will feel welcome. Only by encompassing the whole student body can there be any hope of dispelling the clique image which has been built up over so many years.
One of the major deficiencies of this medical school is the absence of a central common-room where students can sit and drink coffee or eat their lunch. I believe that this is one of the main reasons why students find the medical school so amorphous and lacking in any feeling of identity or com munity spirit. Our already disparate medical school is to be increased to 100 students per year, and this will exacerbate the existing depersonalisation which not only prevents full enjoyment of University life, but also acts as a disincentive to students per forming to the maximum of their academic abilities. The University intends to put in a common-room in the new medical library in North George Square, but even when this eventually arrives it will be far too small to serve as the focus for medical student life. Some might say that there can be nothing worse than a totally medical student environment, and I would agree that as diverse a group of friends as possible is necessary, but when one is working it is pleasant to have somewhere to relax in comfort for a few minutes. This is one of the roles that I hope our new building will fulfil.
Our new premises will be in part of Phase III, which is the building now going up beside the Refectory and the Health Centre building. The lay out of this building, with a large lounge area and several smaller working rooms will, I hope, leave the way open for R.M.S. to become more of a medical school coffee lounge and less of a library for a few dedicated workers. At present R.M.S. is seen as a place to work, as a means of getting into Ferrier's lending library and as a place for weekly meetings on various medical topics. We must be seen to broaden our interests, as it will be essential for the Society to be an active and broadly-based student body or our position in the student centre will be rightly open to challenge.
A revamped R.M.S. could easily provide the ser vices which medical student societies in other universities supply. It should become the meetingplace and provide the secretarial facilities for such groups as medic sports teams and year clubs. It should work more closely with the Medical Students' Council, and dispel the mutual mistrust that separ ates the two bodies. They should both be serving the best interests of the medical student body, and they should therefore be in close touch with each other. A larger membership could also help the academic side of the Society. Instead of having one meeting per week which necessarily does not attract all medical students, there could be a number of smaller meetings, perhaps utilising mainly Edinburgh speakers, arranged by various groups within the Society. For example, there could be groups on renal medicine, gastro-enterology, etc., and there could also be paraclinical and preclinical groups. These latter two fields are ones in which the Society fails at present to provide much of interest, as the members, and especially those who are organising such meetings, are predominantly from the senior clinical years. In such a way a planned programme of learning could be devised by groups of students interested in a particular field, and although the attendance at these meetings might be low the benefit derived from them would be relatively large. Such projects would not necessarily be more ex pensive than the present way in which the R.M.S. organises its meetings but, even if it were, I feel that this benefit derived by Edinburgh under graduates would be far greater than that obtained from an elaborate R.M.S. Symposium like "The Immunological Aspects of Cancer", which, although an outstanding success from the prestige point of view, benefited very few Edinburgh medical students and cost £1,500.
I have perhaps painted a rather black picture of the Society, which is in fact flourishing in its own sweet way. Membership has risen this year, and, far more important, attendance has been of a high level. Our own library has grown and is about to be supplemented by a tape-slide library for 24-hour use. By this scheme, members will be able to freely borrow tapes from the extensive Medical Recording Service national tape-slide library for use on R.M.S. equipment. Our Travel Scholarships are thriving and many non-members have benefited from this scheme. R.M.S. is under no moral obligation to allow non-members to benefit from this money, but I am glad that it is sufficiently outgoing to con tinue to do so.
These may be seen as faltering steps on the road to improvement but the Society must change further in order to become the forum for medical student opinion. It must change its organisation, its role, and its image, but I hope that it does not forget that its prime objective is in the academic field. The Society was created as a body for the selfeducation of medical students and this is just as pertinent now as it was in 1737.

I. S. PALIN
"There are two branches of learning -religion and medicine" (Saying attributed to the Prophet Muhammad.) Our society is peculiarly reluctant to acknowledge any debt to its forebears other than those of defin itely western nature. Much is made of the Greek and Roman origins of our ideas and ideals, while the contribution of other, more eastern, societies is usually omitted or glossed over in the course of education and in no case is this better demon strated than in the case of our debt to the once mighty and glittering civilization of the Moslems Centuries of misunderstanding and resulting con flicts, culminating in the savage and bloody military failure that was the Crusades, and the westward surge of the Ottoman Turks who, by the late 17th century had reached as far as Vienna and were only narrowly repulsed, produced a torrent of propag anda from both sides which even now obscures the historical closeness of Christian and Islamic societies and the role of Moslem learning in promot ing the great awakening that was the Renaissance.
It comes as a surprise to many to find that while Europe was sunk into its "dark a ge s" there was a civilization in the Middle East with a stability, culture and level of achievement that the West was not to know till the 18th century. The caliphs in Baghdad, at the height of their power, ruled an empire of which it was said that a virgin with a sack of gold could walk from one border to the other without fear of molestation. Their capital was not only a city of glittering mosques and fountains, of paved and torch lit streets, but a city of universities, free hospitals, and public libraries. Islamic learning was so famed that at least one of the Popes, Sylvester II, attended a Moslem university to complete his education before his elevation to the pontificate. Curiously enough, of the great physicians of this period few were Arabs, though the majority were Moslems. The noted Avicenna (980-1036), and Rhazes (864-C.920) were Persian, while Averroes (Ibn-Rushd), 1126-1198, and Avenzoar (Ibn-Zuhr, 1109-1162) were Moors, and the philosopher and scientist Maimonides (1135-1204), whose medical writings alone would have been sufficient to ensure his immortality, was Jewish by both race and religion.
The basis of Moslem medicine was in the classical teachings to which they fell heir and added. Idn-Sina (known in the West as Avicenna) is probably the best-known of the Moslem physicians, parti-cularly for his painstaking Qanun (Canon) of Medicine, an encyclopeadic work ranging through much of medicine and including an admirably clear description of skin diseases. But it was Rhazes, the impressively-named Abu-Bekr Muhammed Ibn-Zakariyya al-Razi, who was the greatest physician Islam produced, worthy to take his place with such immortals as Galen and Hippocrates in the medical pantheon. Born at Rayy, near Teheran, he estab lished a continent-wide reputation for the scholarly and humanitarian practice of medicine, a profession he took up only in middle life. As head of the hospital in his native town he delegated much of the work to his pupils, and to the pupils of his pupils. New cases were admitted by those latter, who if in difficulty would call in one of Rhazes, immediate pupils, or in particularly perplexing cases the great man himself. Invited to participate in the setting up of a new hospital in Baghdad, he had pieces of meat hung on strings in various parts of the city where land was available and sited the hospital where the meat had shown least signs of decomposition. Needless to say, he became the physician-in-chief of this hospital.
An example of Rhazes' clinical approach is given in his account of one of his own cases of a man with pyelonephritis: "Abdu'llah Ibn-Sawada used to suffer from attacks of mixed fever, sometimes quotidian, sometimes tertian, sometimes quartan, and sometimes recur ring once in six days. These attacks, were preceded by a slight rigor, and micturition was very frequent. I gave it as my opinion that either these accesses of fever would turn into quartan (i.e. would adopt a malarial pattern) or that there was ulceration of the kidneys. Only a short while elapsed ere the patient passed pus in his urine. I thereupon in formed him that these feverish attacks would not recur, and so it was.
" The only thing that prevented me at first from giving it as my definite opinion that the patient was suffering from ulceration of the kidneys was that he had previously suffered from tertian and other mixed types of fever: moreover the patient did not com plain to me that his loins felt like a weight depend ing from him when he stood up, and I neglected to ask him about this. When he passed the pus I administered to him diuretics until the urine became free from pus. That the pus was evacuated quickly indicated a limited ulceration. The other physicians whom he consulted besides myself, did not under stand the case at all, even after the patient had passed pus in his urine." Rhazes' ethical teachings reveal him as a basically tolerant and rational man -perhaps too rational for some, since he regarded the idea of romantic love as something for "Bedouins, Kurds, and such like clodhoppers" , not for thinking and mature people. (In this he was echoed by Avicenna, who classed love as a "cerebral or mental disease" along with somnolence, insomnia, amnesia, mania, hydrophobia and melancholia). He anticipated by many centuries current health education campaigns by describing drunkenness as 'one of the evil dis positions that bring those indulging it to ruin, calamity and all kinds of sickness. This is because the excessive' drinker is imminently liable to apoplexy and asphyxia . . . rupture of the arteries of the brain, and stumbling and falling into crevices and wells; not to mention various fevers, bloody clots, and bilious swellings in the intestines and principal parts, and delirium tremens and palsy, especially if there be a natural weakness of the nerves" .
Rhazes' religious speculations -most of them now lost -' were so unorthodox as to bring upon him the attacks of the Moslem clergy, and the cataracts which blinded him towards the end of his life were attributed to Divine punishment.
A curiously modern-sounding admonition to medical students of this time reads -"And of those things which are incumbent on the student of this Art are that he should constantly attend the hospitals and sick-houses: pay unremitting attention to the conditions and circumstances of their inmates, in company with the most acute pro fessors of medicine: and enquire frequently as to the state of the patients and the symptoms apparent in them, bearing in mind what he has read about these variations and what they indicate of good and evil" .
Nor was the more experimental side of medicine neglected. In the 10th Century Al-Majusi described the pumping action of the heart in some detail, and postulated communicating pores between the arteries and the veins, while the 13th Century Ibn Al-Nafis described the pulmonary circulation and denied the Galenic theory of pores in the cardiac septum permitting the passage of blood. These two Moslems therefore published, some hundreds of years before William Harvey, the theory of blood circulation for which our histories still give the British physician credit! An example of the standard of European medicine in the period we are discussing provides some com parison. A Saracen Emir, at a time of truce with the Crusaders then occupying the Holy Land, sent his personal physician, a Christian Arab named Thabit, to treat some of their sick, at the request of a Crusader lord. On his arrival Thabit found two patients, a man with an abscess in his leg and a consumptive woman, and commenced to treat the form er by polticing, the latter by a suitable diet and herbs. Both began to progress but a Frankish doctor intervened, announced this treatment as use less, and turned to the man to ask him whether he preferred to die with two legs or live with one. Not unnaturally the man preferred the latter, whereupon the abscessed leg was amputated with such vigour that the man died almost at once. The doctor then decided that the woman was possessed of a devil in her head. Her hair was shaved off, her diet of fruit and vegetables was stopped, and she was fed instead on the normal Crusader diet of bread, garlic and oil: as she grew worse the Frank had a deep sign of the cross cut on her head, exposing the bone. Salt was rubbed in, but sepsis and death ensued.
"I returned home" , comments Thabit, 'having learned of their medical practice that which had hitherto been unknown to me" . This is not to say that Islamic medicine was free of the mystico-religious outlook that helped hold back development of the art in Europe. The heretical sect of the Isma'ilis, who gave rise to the notorious secret society of the Assassins, were particularly active in this respect and would arouse the interest of potential converts with such questions as " Why has man seven cervical and twelve thoracic verte brae?" and " Why has each of the fingers three joints but the thumbs only two?" , various answers based on numerology being given. Much was made of the fact that the number of Joints on the two hands was the same as the numbed of permanent teeth, the num ber of days in the lunar month (w hich is used in the M osle m calendar) and the num ber of letters in the A ra b ic alphabet. Nonetheless, the evident erudition of M oselm doctors com pared to their western counterparts w as so great that the more progressive of Christian physicians appreciated what w a s translated from their writings. C h a u c e r's Doctor of Ph ysick ha s no less than six M o sle m s in his list of authorities: "Well know he the old Esculapius, A n d D ioscorides, and else Rufus; Old Hippocras, Hali, and Gallien; Serapion, Rasis, and Avicen; Avarrois, D am asce ne and Constantin; Bernard, and Gatisden, and Gilbertin". Little w onder that Christian rulers w ho were in close com m unication with neighbouring Islam ic states, a s in partitioned Sp a in and in the Crusaderruled Holy Land, used to send to the M o sle m s when they wanted a go o d physician! I have attempted to give a brief outline of the debt our current medical practice ow es to the great doctors of classical Islam, and in conclusion I can not do better than quote from M eyerhof's authorita tive work "T h e Legacy of Isla m " -"L o o k in g back we may say that Islam ic medicine and scien ce reflected the light of the Hellenic sun when its day had fled, and that they shon e like a moon, illuminating the darkest night of the European M iddle A ge s: that som e bright stars lent their own light, and that m oon and stars alike faded at the dawn of a new day -the Renaissance. S in ce they had their share in the direction and introduction of that great movement, it may reasonably be claimed that they are with us yet".

NO TE:
For those who wish to follow up this subject the writings of Edw ard Brow ne are recomm ended, who qualified in medicine, turned to M iddle Eastern studies and went on to becom e Professor of Arabic at Cam bridge.
His scholarly work "Arabian M e d icin e " (C.U.P. 1921) is available from the C e n tral M edical Library. The quotations in this article com e from various so u rce s and are translated either by Brow ne or by A. J. Arberry, the present Pro fessor of A rabic to Cam bridge University.

NATRIURETIC HORMONE HEATHER A. DAVIS
Until about 1957 it w a s generally accepted that the regulation of renal sodium excretion w as depend ent solely upon ch a n ge s in (a) glom erular filtration rate (Factor 1) and (b) the activity of the renin-angiotensin-aldosterone system (Factor 2). coupled with the effect of ch an ge s in intrarenal haem odynam ics and physical factors, such a s hydro static pressure surrounding renal tubules, and plasm a protein osm otic pressure in peritubular capillaries.
S in ce that time, however, evidence h a s gradually been accum ulated to su gg e st that these are not the only factors which are relevant in this context, and the existence of a humoral inhibitor of renal sodium reabsorption has therefore been postulated. This 'third factor' has been given the name of natriuretic hormone, and indications of its presence have been found in two principal situations. T h ese are (a) 'Sod ium e sca p e ' during chronic mineralocorticoid administration (b) Volum e expansion with (i) isotonic saline (ii) blood 'Sodium escape' during chronic mineralocorticoid administration W hen the extracellular fluid volum e w as expanded in healthy hum ans or d o g s by chronic mineralo-corticoid administration, an initial diminution of sodium excretion resulted, followed within a few days by a rise to control levels (2,37). This 'sodium escape phenom enon' w a s attributed a s early a s 1957 to the existence of a circulating natriuretic horm one (37).
The presence of such a horm one w as for som e time disputed a s many potential natriuretic factors have been identified during 'sodium e sca p e ' from chronic mineralocorticoid treatment. Other natrieuretic factors include deceased plasm a renin con centrations, increased glom erular filtration rate and increased renal plasm a flow. Sodiu m escape has, however, been show n to occur in the abse nce of each of these variables, thus indicating that none of them is critical to the escape m echanism (se e 8).
Recently, additional evidence for the existence of a circulating natriuretic horm one has been provided by Buckalew and Lancaster in 1972 (8 ).
They demonstrated the presence of a substance with natriuretic activity in ultrafiltrates of jugular venous plasm a when 'sodium e sca p e ' occurred in d o g s undergoing chronic administration of deoxycorti costerone acetate (D O C A ).

Volume expansion with isotonic saline
There is m uch evidence to su gg e st that when the blood volume of an animal is expanded with isotonic saline, the rise in urinary sodium excretion which occurs is due, in part, to a change in the concentra tion of a circulating hormone other than aldosterone.
The release of such a circulating natriuretic hormone was postulated by de Wardener et al, in 1961 (43). They demonstrated that in dogs receiv ing high concentrations of vasopressin and mineralocorticoid hormones, an intravenous infusion of isotonic saline produced a rise in urinary sodium excretion even when the glomerular filtration rate was deliberately lowered by inflating a balloon in the thoracic aorta. A natriuresis also occurred in denervated and isolated kidneys perfused with blood from volume expanded animals. The tubular reabsorption of sodium must therefore have decreased, and this decrease must have been caused by some mechanism other than a fall in the concentration of aldosterone. Similar experiments and cross-perfusion (19) experiments involving volume expansion with isotonic saline have confirmed these results (see 42).
An interesting experiment was devised by Richet and Hornych (32). They saline-loaded rats, and demonstrated that sodium reabsorption was in hibited both in the renal tubules and in a piece of the in vivo perfused Jejunum in each rat. Aldo sterone pretreatment of the rats had no influence on this phenomenon. Since the two epithelial struc tures, which have common histological and immunological characteristics, were far apart, a natriuretic mechanism extrinsic to the kidney was postulated. They suggested that the natriuresis could have been mediated by a circulating hormone.

Volume expansion with blood
More precise evidence for the existence of a natriuretic hormone has been obtained from experi ments in which the blood volume of animals was expanded with blood that was already in equilibrium with their own blood. Thus, haemodilution which is itself a natriuretic factor was excluded. A natriuresis was obtained using this method of volume expansion not only in whole animals but also in isolated kidneys perfused with blood from volume expanded animals. The volume expanded animals were treated with maximal doses of vasopressin and mineralocorticoid hormone and a natriuresis could be obtained even when the glomerular filtration rate was lowered (3,20,26,39).
An elaborate experiment was performed by Tobian et al. (39) in which an isolated rat kidney was perfused with blood at a constant pressure (Fig.1). The kidney's only connexion with the rat which supplied it with blood was the blood itself. When a quantity of a mixture of two parts blood and one part Ringer's solution was placed into the venous reservoir without expanding the blood volume of the rat, there was no increase in sodium excretion by the isolated kidney (Fig. 1). When the same quantity of the mixture was infused intra venously into the rat and the blood volume ex panded, there was in most instances a large rise in sodium excretion from the isolated kidney. This natriuresis was associated with a rise in renal blood flow and glomerular filtration rate. Since the rise in sodium excretion could not be attributed to haemo dilution, renal nerve stimulation or a rise in arterial blood pressure, it was concluded that its cause must be a change in the concentration of a circul ating substance which simultaneously increased renal blood flow by producing renal vasodilatation.

Further evidence for the existence of a circulating natriuretic hormone
This has been obtained from the detection of natriuretic activity in samples of plasma and urine. These sampes were collected from volume ex panded man and animals, and humans with various clinical conditions. Natriuretic activity has been detected in the following -(1) Plasma from saline-loaded dogs, rats, cats, sheep and cows (7,9,12,31,35) and plasma from dogs whose blood volume was expanded with blood (11, 30).

Assay preparations for the detection of natriuretic activity
Many in vivo and in vitro assay preparations have been developed for the detection of natriuretic activity in samples of plasma or urine. These are summarized below.

in vivo preparations
In most cases (6,22,35,36,41) the plasma and urine samples were concentrated and fractionated (using dialysis and ultrafiltration).
Natriuretic activity was then detected in the samples by inject ing or infusing them into assay rats and observing changes in urine flow and in sodium and potassium excretion from the bladder or ureters. The assay rats used in the different laboratories were under varying conditions of salt and water intake, and the samples were injected intravenously, intra-aortically, subcutaneously or directly into a renal artery.
Natriuretic activity has also been detected in un concentrated plasma or dialysed plasma samples when they were injected directly into a renal tubule of an assay rat with hereditary diabetes insipidus. The rate at which the proximal tubular reabsorption of sodium was inhibited by the samples was deter mined by micropuncture (shrinking-drop technique) and by clearance techniques (31).

In vitro preparations
The transport of sodium, potassium and p-aminohippuric acid (PAH) has been studied in renal tubuls fragments which have been incubated in vitro both in untreated plasma (11) and in con centrated and fractionated urine (10) taken from man and animals before and after blood volume expansion. When incubated in plasma or urine obtained after volume expansion, tubule fragments were less able to maintain a constant gradient of sodium and potassium, or to accumulate PAH than when incubated in control plasma.
Blood from blood volume expanded dogs inhibited the transepithelial transport of sodium by the isolated frog skin (30). Similarly, this preparation was used to detect natriuretic activity in concentrated and fractionated samples of uraemic serum (6).
Concentrated and fractionated plasma samples from saline loaded dogs, or dogs in which 'sodium escape' from chronic mineralocorticoid administration had occurred, inhibited toad bladder sodium transport (9).

Mode of action of natriuretic hormone
When natriuretic activity was detected in samples of plasma and urine using in vivo assay prepara tions, the natriuresis was accompanied by an in creased renal blood flow, a factor which itself pro duces a natriuresis. From these experiments, it was, therefore, impossible to determine whether the postulated natriuretic hormone acted by a direct action on renal tubular sodium transport. The sub sequent use of in vitro assay preparations for the detection of natriuretic hormone showed, however, that the hormone directly inhibited the cellular mechanisms for active sodium transport.
Thus, it is probable that natriuretic hormone acts in vivo both by directly inhibiting tubular sodium transport and by producing renal vasodilatation.

Site of action of natriuretic hormone
Micropuncture techniques .have revealed that the fall in sodium reabsorption with volume expansion takes place in the proximal tubules (14, 31). Proximal tubular sodium reabsorption is also in hibited when the sodium escape' phenomenon develops in more prolonged experiments in which the extra cellular fluid volume has been expanded by the administration of mineralocorticoids (44).
It has been reported that the distal tubule plays no regulatory role in the control of sodium excretion (5,42). However, once proximal tubular sodium reabsorption has been maximally depressed during the administration of a saline load, the rate of sodium excretion can still be increased (13). Thus, the inhibition of sodium reabsorption in the distal segments of the nephron is also important in regul ating sodium excretion during saline loading, and natriuretic hormone may act in these segments (13, 34, 35).

Source of natriuretic hormone
Many ablational experiments have been performed in an attempt to locate the source of the proposed natriuretic hormone. Many of these experiments were misleading as saline administration to animals produces a fall in plasma protein osmotic pressure and usually a rise in arterial blood pressure. Both of these changes evoke a natriuresis even in an isolated kidney perfused by a heart lung preparation. Thus, it is not surprising that the administration of saline to a decapitated dog with the adrenals, liver spleen removed, still produced a natriuresis (25).
Ablational experiments should, therefore, be per formed using animals expanded with whole blood or blood with which their own blood is in equilibrium. Such an experiment, which was described earlier in this article, has been performed by Tobian et al., (39: see Fig 1). They suggested it was unlikely that natriuretic hormone was released from the adrenals or kidneys. Other workers have variously reported that natriuretic hormone could (19) and could not (33) be derived from the kidney. The liver (29, 38) and the brain (1, 12, 27, 37) have also been suggested as the source of the hormone. The origin of natriuretic hormone still remains uncertain.

Nature of natriuretic hormone
As a result of various attempts to detect natriuretic activity in plasma and urine samples, various reports as to the nature and properties of natriuretic hor mone have resulted.
From studies using dialysis and gel filtration, the hormone has been reported to be non-dialysable and to have a molecular weight between 5,000 and 70,000 (35, 36). Other workers reported that the hormone was dialysable and had a molecular weight of less than 1,000 (6, 10, 12, 31). These conflict ing results could readily be obtained if natriuretic hormone was a small molecule which was bound to a larger molecule (e.g. a plasma protein). In addi tion, natriuretic hormone has been variously reported to be a protein (35, 36), a polypeptide (12), to be resistant to boiling (6,12,35,36) and to be stable only in the cold (31).
The natriuretic activity detected in some extracts displayed a delay in onset of up to one hour after injection and the effect lasted for up to three hours (35, 36). Again, these properties could suggest that natriuretic hormone was a small molecule which was slowly released from binding to a larger molecule. Other workers (31) however, found that their natriuretic material was rapid in onset (seconds), with a short duration of action (less than thirty minutes). The hormone, which was effective on intravenous, intra-arterial or direct intratubular in jection, has been reported to act primarily on sodium excretion and rarely to increase urine flow (31, 35, 36) but another report suggested that the hormone was more diuretic than natriuretic (12). The hormone produced an increase in renal blood flow 35, 36) but no change in potassium excretion or glomerular filtration rate. Natriuretic activity has been detected in both arterial and venous blood (31, 35, 36) but some workers were only able to detect the hormone in plasma samples which were concenrated before assay (6, 9, 10, 22, 31, 35, 36) whereas others detected it in blood or unconcen trated plasma (11, 12, 30, 31).
Some of the conflicting properties attributed to natriuretic hormone may result from the presence of contaminants in the plasma and urine extracts. Such contaminants could have been introduced during the concentration and fractionation pro cedures. In addition, bacterial endotoxins in urine samples have been shown to produce a potent natriuresis in assay animals (see Discussion after 36).

Natriuretic hormone and prostaglandins
It has been suggested that a prostaglandin could be a circulating (28) or intrarenal natriuretic hormone (23). Prostaglandins are a group of natur ally occuring 20-carbon fatty acids which contain a cyclopentane ring and are derivatives of prostanoic  (Fig. 2). Five series of naturally occurring prostaglandins have so far been described; namely the A, B, C, E and F series, all of which exhibit structural differences in the ring (Fig.3). The pro staglandins possess a wide variety of pharmaco logical actions (18). Prostaglandins of the A and E series have been shown to produce a natriuresis and diuresis in dogs and rabbits when infused in very low concen trations either intra-aortically or directly into a renal artery (17, 28, 40, Davis, unpublished). Prostag landin A1 produces a natriuresis when infused intraaoretically in concentrations as low as 0.001 and 0.6 nanograms per m illilitre of arterial blood in dogs and rabbits, respectively. Since prostaglandins of the A series (unlike the E series) are not meta bolised by the lungs, they also produce a natriuresis when infused intravenously in similar concentrations, and they could be capable of acting as circulating natriuretic hormones (28).
It has also been proposed that prostaglandins of the A and E series could be intrarenal natriuretic hormones, as prostaglandins A2, E2 and F2a have been identified in the renal medulla of the rabbit, dog and rat (see 23). Lee (23) has suggested that when the extracellular fluid volume is increased, prostaglandins A2 and E2 could be released from the renal medulla to circulate intrarenally (possibly via the vasa rectae or lymph) to the renal cortex where they could stimulate a natriuresis. This theory is supported by the observations that the enzymes responsible for the synthesis of prostag landins exist in the renal medulla, whereas the enzymes responsible for their degradation have been detected in high concentrations in the renal cortex and not the medulla (see 23 . However, it is also possible that during volume expansion, prosta glandin A2 could be released from the renal medulla into the renal venous blood, circulate and then produce a natriuresis by an action in the renal cortex. The natriuresis produced by prostaglandins and by natriuretic hormone is accompanied by vaso dilatation in the renal cortex and an increase in renal blood flow. There is a redistribution of intra renal blood flow from the medulla to the cortex. Glomerular filtration rate remains unchanged or increases slightly (see 23). It is not known whether prostaglandins stimulate a natriuresis in vivo solely by producing vasodilatation in the renal cortex, or whether they also exert a direct action on renal tubular sodium transport (16).
Since natriuretic hormone has been detected in samples of peripheral venous plasma, either a prostaglandin of the A series could have been de tected or there is another circulating natriuretic hormone which either acts directly in the kidney to produce a natriuresis or stimulates the intrarenal release of prostaglandins of the A and E series.
Natriuretic hormone has also been detected in urine samples. Recently, prostaglandins E1, E2 and F2x have been identified in female human urine but no search was made for prostaglandins of the A series (15). Natriuretic activity in urine samples could, therefore, be attributable to the pre sence of prostaglandins of the E and possibly the A series.
Since the circulating concentration of prostag landin A1 or A2 required to produce a natriuresis is very low and these prostaglandins are unstable in blood, no evidence for the release and circulation of these prostaglandins, during blood volume ex pansion, has yet been obtained (Davis, un published).

Clinical implications of natriuretic hormone
Natriuretic hormone has been associated with several clinical conditions, namely uraemia, aldo steronism, and congestive heart failure.

Uraemia
Since a natriuretic humoral substance was de tected in the serum of uraemic patients, it was suggested by Bricker et al., (6,7) that this hormone could serve in a homoeostatic role to in crease the rate of sodium excretion per nephron as the number of nephrons diminished in advancing renal disease. Using experimental animals with nephron reduction, it has previously been shown that the progressive natriuresis per nephron cannot be explained by a decrease in mineralocorticoid hormone activity, a change in glomerular filtration rate per nephron or by such physical factors as a change in cardiac output, mean arterial blood pres sure, peripheral resistance or filtration fraction (see 6). It was also suggested (6) that in advanced renal disease, very high levels of natriuretic hor mone could lead to the inhibition of sodium trans port in extrarenal organs and contribute to the symptoms of the uraemic state.

Aldosteronism
Natriuretic activity was detected in extracts of urine and plasma samples collected, before saline loading, from patients with primary aldosteronism, but no such activity was detected in similar extracts from normal healthy humans (see 36). In addition, higher concentrations of natriuretic activity were detected in plasma and urine samples collected from saline loaded patients with primary aldoster onism than from normal humans (35, see 36). It is possible that in patients with primary aldosteronism, the enhanced basal and stimulated levels of circul ating natriuretic hormone were released in order to offset excessive renal sodium retention produced by increased concentrations of aldosterone. This possibility is supported by the demonstration of a circulating natriuretic hormone in venous plasma taken from dogs during 'sodium escape' from chronic mineralocorticoid treatment (8).

Congestive heart failure
Krück (22) demonstrated that extracts of urine from orally water loaded humans possessed natriur etic activity, whereas similar extracts from water loaded patients with congestive heart failure possessed no such activity. He therefore suggested that an insufficiency or lack of natriuretic hormone in patients with congestive heart failure, could be an explanation for the increased renal tubular sodium reabsorption and development of oedema in cardiac disease.

Summary
A considerable amount of evidence has now been accumulated to support the existence of a circul ating natriuretic hormone. Natriuretic activity has been demonstrated in plasma and urine samples collected during volume expansion with isotonic saline or blood, the administration of a high salt diet, 'sodium escape' during chronic mineralo corticoid administration and in certain clinical con ditions. Under these conditions natriuretic hormone is released in detectable concentrations, but lower amounts of the hormone may be released continu ally, to participate in the regulation of sodium excretion. The chemical nature of the hormone still remains unknown, but a prostaglandin of the A series could be intrarenal natriuretic hormones.

ITEM OF MEDICAL INTEREST
The next day, as Candide was walking out, he met a beggar all covered in sores, his eyes were sunk in his head, the end of his nose eaten off, his mouth drawn to one side, his teeth as black as a coal, snuffling and coughing most violently, and every time he attempted to spit, out dropt a tooth.
(This was none other than Candide's old tutor, who described how he came to this state in these words) "O my dear Candide, you must remember Pacquette, that pretty wench, who waited on our noble baroness; in her arms I tasted the pleasures of paradise, which produced these hell-torments with which you see me devoured. She was infected with the disease, and perhaps is since dead of it; she received this present from a learned cordelier, he was indebted for it to an old countess, who had it of a captain of horse, who had it of a marchioness, who had it of a page, the page had it of a Jesuit who, during his noviate had it from one of the fellow-adventurers of Christopher Columbus.
For my part I shall give it to no-body for I am a dying man." From Voltaire's ''Candide'', published in 1759.

THERAPEUTICS PROBLEM
A man attending an anti-coagulant clinic as an out-patient occasionally has unacceptably short pro thrombin times. He claims to have been taking his tablets with religious regularity. He is rather sur prised when the Doctor asks him what type of cook ing oil his wife uses. Is this a relevant question? Answer on page 14.
Editor's note -A list of references provided by Dr. Davis is available from the Society's office.

The Disease
Infectious m ononucleosis ha s long been an enigm a to epidem iologists. The a bse nce of a re co g n ise d casual agent or a specific diagnostic test ha s thrown confusion on such b asic issu e s a s the definition of the disease. Until very recently the d iag n o sis has had to be based on a triad consist ing of characteristic s ig n s and symptoms, an absolute increase in atypical m ononuclear cells, and a positive heterophile aggultination (Paul Bunnell test) test. Unfortunately each of these criteria is subject to variation in interpretation while the rigid application of the three allow s no margin for the d ia g n o sis of subclinical or atypical disease. Within these limits of diagnosis, work on the epidem iology of the d isea se has produced very few concrete re sults. W hile there is no doubt that infectious m ono nu cleosis ha s a peak incidence in young adults and is relatively uncom m on in childhood and older age groups, the evidence concerning infectivity, incubation period and m ethods of transm ission has been circumstantial and often based on a small num ber of observations. C o n c lu sio n s drawn from su ch work su g g e sts that although the disease occasionally develops in contacts it is not highly contagious, and there rem ains doubt a s to whether epidem ics of the classical disease have ever occurred.
Estim ations of the incubation period range between very wide limits, and although there is som e evidence that the causal agent is trans mitted in saliva (hence the term "k is sin g d ise a se " ) the method of natural transm ission is still unproven.
M any of these problem s of the behaviour of in fectious m ononucleosis could be solved if a specific causal agent could be recognised and during the last six years the accum ulation of evidence implicat ing the E B virus has caused considerable interest am ongst epidemiologists.

The Virus
T h e Epstein-Barr virus w as described in 1964 when it w as found to be present in cells cultured from a Burkitt Lymphoma. Its role in the production of the tumour rem ains an exciting controversial pro blem which cannot be dealt with here. All attempts to propagate the virus in other types of cell lines have so far been unsuccessful, and only human lymphoid haem opoietic ce lls will allow the virus to replicate. Antibody to the viral capsid antigen carried in the cells can be detected by an indirect im m unofluorescence test described by Henle in 1966. Serological surveys using this technique show ed that although antibody to the virus is present in all sera from patients with Burkitt Lymphoma, the antibody is a lso widely distributed in populations throughout the world regardless of the incidence of the tumour. T h us the incidence of E B viral capsid antibody in som e students grou p s in Edinburgh is show n in Table I. Table 1 In c id e n c e o f EBV a n tib o d y i n h e a lth y stu d e n ts P o p u la tio n Age Sex Year se ra withdrawn No. se ra tested * EBV an tib od y +ve.

Table II
In order to explain the universal occurrence and common pattern of age incidence of EB virus anti body, attempts were made to link production of this antibody with common infectious diseases. A chance occurrence in the Henle's laboratory in Philadelphia suggested that the antibody might be produced dur ing the course of infectious mononucleosis. In con junction with workers in Yale who had stored sera from patients with infectious mononucleosis for many years, they were able to demonstrate that sera taken from students before the onset of in fectious mononucleosis were devoid of antibody while sera from the same students taken during the acute phase of the disease all had high titres of antibody to the virus. Furthermore, once developed, antibody to the virus persisted for many years, probably for life.
These findings have been confirmed and extended. Recent reports of the finding of macromolecular EBV antibody in the early stages of infectious mono nucleosis and one report of the isolation of the virus from the throat of an acute case, make the case against EB virus almost watertight. Despite the doubtful ethics of the problem infectious mono nucleosis has been produced on one occasion following injection of virus in a human volunteer.
There remain however many questions to be answered. In particular how is the virus spread?, do healthy carriers exist?, how much, if any, of the heterophile antibody negative disease is caused by EBV?, and what clinical syndromes other than classical infectious mononucleosis can be caused by infection with EBV? The fluorescent antibody test is positive in 80% of normal adults and therefore does not give a specific indication of disease -is the demonstration of EBV IgM antibody helpful in the diagnosis of atypical disease or can other specific tests of current infections be developed?

Edinburgh Student Virus Survey
It was with these unanswered questions in mind that the Edinburgh Student Virus Survey was initiated in October 1971. The survey was brought to the notice of individual students at the time of the matriculation chest x-ray and a sample of venous blood taken from volunteers, who also provided details of previous medical and social history. Sera were tested for antibody to EBV and as a service to female students also to rubella virus. Those students who were without antibody to EBV were requested to attend the Student Health Service again in May, 1972. At the second interview details of any illness occurring in the previous six months were noted and another sample of blood withdrawn for testing. In addition, with the co-operation of the physicians of the Student Health Service serial serum samples have been obtained from students who are unfort unate enough to contract illness which might be infectious mononucleosis.
Female students at Dunfermline College of Physical Education have been taking part in a similar survey started in October, 1970.

Results
Preliminary results of the first year of the survey are shown in Tables III -V. A total of 613 sera were obtained from university student volunteers and 65% were found to possess antibody to EBV. There appears to be a higher seropositivity rate in the female students. After approximate seven months of academic life 18 of those students initially seronegative were found to have produced EBV antibody, giving a conversion rate of 11%. Table V shows that of the 18 students known to have acquired EBV antibody in the seven months following their entry to university, 5 (28% ) had been investigated as possible cases of infectious mono nucleosis, while 7 (39% ) had no symptoms of any kind. Other symptoms, mainly sore throats, were reported by 6. In contrast none of the 144 volunteers who remained seronegative were suspected of hav ing infectious mononucleosis.
A small number of sera from patients in the acute phase of infectious mononucleosis have been in vestigated in this first year. It has been found that by the time the patient presents with symptoms, anti body to EBV measured by the fluorescence method is already present at high titre, and little change can be detected during the course of the illness. Anti body measured by the complement fixation reaction however appears to rise much more slowly and may not become positive until several months after the illness. If this is true then a combination of fluores cence antibody and complement fixing antibody may give a valuable indication of the timing of infection.
It is hoped that this, and many other aspects of the disease will be clarified in the next two years of the survey. The numbers involved at this stage are still small but in October 1972 a further 1,000 stud ents have volunteered to take part. We would like to take this opportunity of thanking all our student volunteers and look forward to providing more details of the results at some future date.

Introduction:
In 1909, Douglas and Haldane (1) demonstrated the relationship of Pa02 and PaC02 to breath-holding time (BHT). Muxworthy (7) described the direct effect of initial lung volume on breath-holding time in 1951.
At the present, it is felt that breath-holding time is determined by, "... the interaction of a number of independent variables which can be classified in two major sets of stimuli: those related to lung volume and those derived from changes in gas tension and pH." (3) Although a considerable body of knowledge has been acquired about breath-holding in a laboratory setting, very little work has been done to date on breath-holding in a clinical setting with respir atory patients. It was the object of the present study to determine the feasibility of measuring BHT's on acutely ill patients in a clinical situation.
Another goal of this investigation was to study the hypothesis that breath-holding times would be longer in chronic bronchitics during periods of exacerba tion than during periods of remission. This was felt to be true because of the decreased sensitivity to arterial C02 manifested by these patients during periods of exacerbation. This was thought to be especially likely if any hypoxic stimulus could be eliminated by an inspiration to total lung capacity of pure 02 prior to breath-holding.
It was also felt that in chronic bronchitics during exacerbation that increased importance of the hypoxic stimulus relative to the hypercapnic stimulus would be reflected in a greater ratio of BHT on air to that on 02 as the patient improved; that is, breathholding times on 02 would be relatively longer during exacerbation when the hypercapnic stimulus was relatively weak.
In addition to chronic bronchitics several other types of respiratory patient were incorporated into the study. These included patients with pneumonia and asthma, and one patient with spontaneous pneumothorax. They were all chosen because they shared the characteristic of an acute illness which would be expected to show a good response to therapy and improvement in pulmonary function.

Methods:
Breath-holding times were measured daily at approximately the same time for each patient. A total of four BHT's was done each time, two follow ing an inspiration to total lung capacity of air, and two following a similar inspiration of pure 02. Patients were instructed to inspire maximally to total lung capacity from an unmarked rubber bag con taining air or 02 and then to exhale to a spontan eously chosen lung volume most comfortable to them (an approximation of functional residual capacity). Timing was begun by an observer at this point and continued to breaking point. Nose clips were kept on throughout the procedure. Breath-holds on air were alternated with those on 02, and the order of gases was changed each day.
Peak expiratory flow rate (PEFR) was also mea sured daily at the same time as the breath-holds on a Wright Peak Expiratory Flow Meter.
Arterial blood gases were drawn on days one, seven, fourteen, a n d /o r day of discharge in patients with abnormal blood gases, and more frequently if the clinical situation warranted. No attempt was made to draw blood at the exact time of breathholding, only during the afternoon of the same day.

Results:
Breath-holding times were obtained on a total of twelve patients. Of these, five had exacerbations of chronic bronchitis, three had bacterial pneumonia, three had acute exacerbations of asthma, and one had spontaneous pneumothorax.
There is an excellent correlation of mean breath holding time after a breath of air to that after a breath of 02 in all patients (Fig. 1). Likewise, as has been demonstrated by other observers (5), mean BHT on 02 was significantly longer than on air in all but one patient (Jon).
No patient with chronic bronchitis showed a decreased breath-holding time on air or oxygen with improvement of clinical status or pulmonary function or length of hospitalization.
The author regrets that an adequate number of blood gas analyses as recommended by the protocol V Fig. 1 MEAN BHT -Air could not be made on all patients for technical and other reasons. In those patients in whom several blood gas analyses were made, no correlation be tween BHT and arterial blood gas concentrations drawn on the same day could be determined.
In three patients with chronic bronchitis who showed significant improvement in mean BHT, two, (Jon) and (M ail), had an increased PaC02 drawn on the same day, and one, (M ur), was unchanged. Two, (Mur) and (Jon), had an increased Pa02 as would be expected, but one had a decreased PaC02 (Mau). Likewise, in six other patients who showed significant improvement in mean BHT no correlation between mean BHT and arterial gas tensions could be determined.

Fig. 2 PEFR (Litres/sec)
Peak expiratory flow rate was normal in three patients (> 4 5 0 1 /m in ). In three patients PEFR was greatly reduced (< 1 5 0 1/m in) and showed no improvement with therapy. The remaining six patients all demonstrated improvement in PEFR with treatment (ranging from 123 to 483% ). In these patients PEFR tended to correlate with changes in MBHT (Fig. 2). In three patients (Dav), (G if), and (Mau), the correlation appears highly significant, the correlation coefficients of PEFR plotted against mean BHT being .94, .79, and .72 respectively. In three other patients the correlation is less good, but still apparent, with r values of .43, .40, and .18 when PEFR is plotted against mean BHT.
No general correlation could be shown between mean BHT and length of hospitalization. In the six patients who demonstrated a correlation be tween PEFR and mean BHT, only one (Ser) showed a good correlation between mean BHT and days of hospitalization and three, (G if), (M ax), and (Jon), showed no correlation between these para meters. Of the other six patients in the study, two did show a correlation of mean BHT with length of hospitalization and four did not.
No correlation could be shown between the ratio of mean BHT on air to that on 02 (mean BHTair/mean BHT-02) and mean BHT. Two patients, (Dru) and (M ur), showed a derease in mean a ir/ mean 02 as the mean BHT increased and one patient (Ess) showed an increase in mean air/mean 02 as mean BHT increased.
There was a failure rate of 19% due to the volun tary withdrawal of three patients from the experi ment. One patient had to be withdrawn because of worsening clinical status.

Discussion :
This study has demonstrated that BHT can be measured in a practical way at the bedside and is of potential usefulness in the clinical setting. It must be recognised that breath holding does require a large degree of patient co-operation and is there fore excluded in the extremely ill, stuporous, or uncoperative patient.
Evidence has been obtained which suggests that there is a correlation of mean BHT on air and 02 to PEFR (and hence to airways conductance) in patients of all types who, (1) have airways obstruction upon admission, and (2) have significant change in airways resistance during therapy. Such a relationship might be explained by the lengthtension inappropriateness hypothesis of Campbell for the etiology of dyspnea (4). More study is needed in this area with a larger number of selected patients.
Breathholding times in chronic bronchitics with elevated PaC02's did not decrease with clinical improvement and no correlation between breathholding times and arterial P02 and PC02 drawn on the same day could be demonstrated. Therefore, the original hypothesis that chronic bronchitics with elevated PaC02 and a decreased sensitivity to arterial PC02 would have longer breath holding times than during periods of remission could not be supported.
Since no correlation of the ratio of BHT's on air to those on oxygen could be shown with either mean BHT or PEFR, it could not be demonstrated that the hyercapnic stimulus to respiration became more im portant relative to the hypoxic stimulus with improve ment in patient respiratory function.
The author is especially indebted to the ideas and help of Dr. G. J. R. McHardy of the pulmonary physiology section of the City Hospital, Edinburgh, and to the Medical Student Council of the University of Edinburgh for making the Edinburgh-lllinois student exchange possible.

Sum m ary:
Breath-holding times were measured daily during an acute phase of illness in twelve patients with different types of respiratory disease. A direct correlation between airways conductance as mea sured by the peak expiratory flow rate (PEFR) and mean breath-holding time w as suggested. No re lationship could be shown between breath-holding time and arterial blood gas concentrations taken on the sam e day.
It w as dem onstrated that breathholding time can be m easured and may be useful in the c lin ic a l situation.