SIR,-The 24 h blood-pressure measurements in patients with hypertension, reported by Dr Millar Craig and others show similar nocturnal falls and morning rises to those reported by Davies, Shaw, and me.’ We found a decreased nocturnal fall of blood-pressure in patients with severe hypertension, especially with grade III or iv fundal changes. We studied patients in hospital, using non-invasive equipment which caused some sleep disturbance but which was operated without 2 an observer present. The report by Millar Craig et al., our studies, and those cited by Sir George Pickering fail to establish clearly which of the changes are the result of sleep and which might reflect endogenous circadian rhythms in factors controlling bloodpressure. Professor Littler and Dr Watson suggest that much of the fall is associated with sleep, and this view was supported by Modlinger et a1.3 I look forward to further analysis of records obtained by the intra-arterial technique, but would suggest that simultaneous body temperature records are taken. Temperature provides a stable "reference" rhythm,4 and would be a useful addition to records of sleep and activity. There are nocturnal changes due to circadian rhythmicity in most cellular and organ functions,5 so we must take care in attributing too important a role in illness to nocturnal changes in blood-pressure alone. Driving a car, public speaking, landing an aeroplane, performing operations, and sexual intercourse are all associated with cardiovascular changes similar to those seen in the early morning, but these activities have not been clearly linked statistically with important pathological events. Nocturnal changes may influence other factors, such as blood clotting, which are just as likely to explain an increase in morning strokes and heart-attacks as is an early-morning increase in blood-pressure. These observations help draw attention to the relevance of biological rhythmicity to medicine and therapeutics, but over-interpretation of changes in a single system and too premature an extrapolation into clinical practice, should be avoided. Nocturnal changes are numerous and presumably act in the general interest of the organism. It is difficult to know if a disturbance of rhythmicity observed in a sick person is a cause, an effect, or a protective response. Progress in elucidating such interactions has been slow, partly because of a lack of research by physicians. It is to be hoped that this study will mark a reactivation of interest by cardiologists, and others, in the relevance of biological rhythmicity to hypertension. Published studies6,? and unpublished observations indicate that some drugs, such as the beta-blocking agent atenolol, do control blood-pressure "around the clock". We have used non-invasive automatic blood-pressure measuring equipment in hospital’°8and selfmeasurement of the blood-pressure at home. Preliminary analysis of a study of the importance of the timing of therapy suggests that taking atenolol once daily in the morning (a time selected arbitrarily rather than after investigation) may be a more satisfactory time than some others if blood-pressure is to be controlled both in the early morning and at other times. Renal


Nottingham City Hospital, Nottingham NG5 1PB


SIR,-In our studies the cannula is inserted between 9 A.M. and 10 A.M., and the patients leave the hospital between 10 and 11 A.M., returning for servicing and topping up of the 1 2. 3.

Shaw, D. B., Knapp, M. S., Davies, D. H Lancet, 1963, i, 797. Follett, D M., Freundlich, H. F., Shaw, D B., Davies, D. H ibid. p 808. Modlinger, R S., Sharif-Zadeh, K., Ertel, N. H., Gutkin, M. J. clin. Endocr Metab 43, 1278. 4. Halberg, F., Carandente, F., Cornelissen, G., Catinas, G. S. Chronobiologia, 5.

1977, 4, suppl 1, p 121. Scheving, L. E., von Mayersbach, H., Pauly, J.

F. Eur



203 6. Woolfson, A. M. J., Knapp, M. S. Br. med. J. 1976, ii, 235. 7. Woolfson, A. M. J., Knapp, M. S. Proc. R. Soc. Med. 1977,

p. 36.

1974, 7,

reservoir between 5 and 7 P.M. Recording continues through the night, and they return for servicing at 9 A.M. and at 5-7 P.M. on the following day. The line is removed at 9 A.M. on the third day. Dr Matthews and Dr Willey are quite correct to point to the effects of anxiety on blood-pressure and heart-rate as a possible factor in distortion of the circadian course, but all our points were 1 h means and the early morning readings were so similar that we feel this is unlikely to be a significant factor. Furthermore, the recordings continue for 48 h and we find that the hourly mean curve on the first and second day coincide reasonably well. This would be unlikely if anxiety were affecting the curves


We make every effort to ensure that the patients are familiar with the procedure before a study is started, and to reassure them by demonstration of full activity after the cannula has been inserted. We never continue with a study if the patient experiences any symptoms such as forearm pain. Northwick Park Hospital and Clinical Research Centre, Harrow, Middlesex HA1 3UJ



SIR,-In discussing the oral treatment of acute gastroenteritis, Dr Bygberg (March 18, p. 611) recommends sucrose as the carbohydrate of choice; he comments on its familiarity and relative cheapness. At this hospital a daily outpatient clinic offers each year oral treatment to over 500 children with acute gastroenteritis and we are concerned to find the most effective and safe method of oral management. A previous study’ here showed sucrose to be as effective as glucose. Sucrose electrolyte mixture has the advantage of a lower osmolality than glucose electrolyte mixture.

We extended this study and examined how accurately mothers made up the feeds we provided during the winter of 1976-77. 73 children under the age of 18 months received our concentrated outpatient electrolyte mixtureto be diluted at home, with five times its volume of boiled water. This solution has been used here for many years with the addition of carbohydrate from a measure provided. In a double-blind manner parents were given sucrose (39) or glucose (34) to add to the carbohydrate electrolyte mixture. At their first follow-up visit while the children received only this mixture we measured the mixture’s osmolality and electrolyte composition. Our community health and nutrition sister questioned 36 mothers selected at random on how they made up these solutions and their infants’ normal feeds; only 2 mothers appeared to sterilise or make up feeds inadequately. Despite this, the ranges of osmolality and electrolyte composition were wide-sucrose solutions were 145-360 mosmol/kg and glucose solutions were 192-600; correct osmolalities were 216 and 315, respectively. Variability did not correlate with the need for admission, in which social factors were important as in previous reviews of our experience.3,4 However, the variance of osmolality was significantly greater in those who were admitted in the glucosetreated group (32%) (p≼0.01, F test), but not in the sucrosetreated group (18%). 1 child received a very hyperosmolar glucose electrolyte solution (600 mosmol/kg). This shows that the risk of producing hyperosmolar feeds is greater when glucose solutions are made up incorrectly. Where outpatient treatment was successful, both groups recovered in the same time (2-6 days, mean 3-6). We confirmed the earlier observation’ that sucrose was at least as effective as P. M., Shepherd, R., Challis, D., Walker-Smith, J. A., Manly, J. Archs. Dis. Childh. 1976, 51, 152. 2. Martindale. The Extra Pharmacopœia, p.1716. London, 1972. 3. Gribbin, M., Walker-Smith, J. A., Wood, C. B. S. Acta pædiat. belg. 1976, 1.



29, 69. Tripp, J. H., Wilmers, M. J., Wharton, B. A. Lancet, 1977, ii, 233.

70, suppl. 5,


glucose. The inaccuracy of feed composition prepared from a concentrated electrolyte solution was great; it bore no relation to mothers’ descriptions of how they diluted the solutions. The risk of a dangerously high level of osmolality was greater for the glucose electrolyte mixture. We now give a diluted electrolyte mixture to which parents only add sucrose. Sucrose electrolyte mixture is effective, of low osmotic load, and is also relatively cheap. It has been shown to be effective in more severely affected children in the developing world.5 We recommend its use in outpatient treatment of acute gastroenteritis in infancy.

the care of patients with haemophilia B. However, since thrombotic and haemorrhagic side-effects are recognised complications these products should not be used in patients who are thrombosis prone or who have D.t.c.. PHILIP M. BLATT Departments of Pathology and Medicine, GILBERT C. WHITE, II and Division of Hematology, JONATHAN C. GOLDSMITH University of North Carolina, HAROLD R. ROBERTS Chapel Hill, North Carolina 27514, U.S.A.


SiR,-Professor Scott and his colleagues, in their survey of the immunology of pre-eclampsia (April 1, p. 704), emphasise the possible importance of a hypoimmune response state. They cite evidence of unusual depression of cell-mediated immunity in women with severe pre-eclampsia, but they seem reluctant to come down on either the post hoc or the propter hoc side of the fence. Recent work from their own group in Leeds is mentioned only briefly but may, in fact, suggest the approach to determining whether there is a non-specific relative anergy or a more specific and restricted anomaly of immune responsiveness. They have demonstrated a protective effect of previous blood-transfusion’ and an abnormally low incidence of lymphocytotoxic HLA alloantibodies in severe pre-eclamptic pregnancies.2 Both of these observations tend to support Jeffcoate’s postulate3 that pre-eclampsia results from a failure of adaption. An important component of that adaptive process may be represented by the formation of alloantibodies to paternal transplantation antigens during normal pregnancy. Indeed the suggestion was made many years age4,1 that there are antibodies with properties of specific immunological enhancement which participate in the maintenance of mammalian viviparity. More effective "blocking" alloantibody production might be expected in women who have been previously sensitised by earlier pregnancies or by blood-transfusion; and hence perhaps they have a lesser incidence of pre-eclampsia. An adaptive process was implicit in the hypothesis of Clarke and Kirby6 that the balanced polymorphism for transplantation antigens is sustained in mammals by a selective system in which antigenic disparity between mother and conceptus is beneficial to fetal development. This hypothesis has been very strongly challenged,’ largely on the basis of experiments in rodents. But mice do not develop pre-eclampsia and mechanisms of fetal tolerance applicable to laboratory animals may be only partly applicable to the long human gestation period. The placental barrier functions poorly towards the end of human pregnancy as is indicated by the mechanisms of rhesus isoimmunisation. Further, the extent of depression of non-specific cell-mediated immunity in normal pregnancy8 is unlikely per se to account for the lack of a significant allograft rejection reaction. An additional fetus-specific tolerance mechanism makes good teleological sense and its inadequacy in immunologically inexperienced primigravidse is feasible as a major factor

Queen Elizabeth Hospital for Children, London E2 8PS



SiR,-Dr Tomkin’s letter (April 29, p. 936) should not be allowed to pass without any comment. Most investigators, who have looked critically at the accuracy of the "stix" methods of blood-glucose measurements, as assessed with a meter, have found good correlation between these measurements and standard laboratory techniques. Studies of visual assessment of colour change with ’Dextrpstix’ have shown that this is open to wide observer variation, and can give no more than a rough estimate of the blood-glucose concentration. Further more, while the cost of autoanalyser blood-sugar estimations may be only 4p, how many patients can carry this instrument around with them and how many hospitals can afford to have a supply of these to loan to the patients? Shrewsbury Hospital, Copthrone South, Shrewsbury



SIR,-Dr Schipper and his colleagues (April 22, p. 854) report the successful treatment of bleeding secondary to disseminated intravascular coagulation (D.I.C.) with antithrombin III. The use of a pure preparation of antithrombin m (now available for clinical trial) for D.i.c. is logical, and the initial results are encouraging. The use of antithrombin in for D.i.c. followed by administration of prothrombin complex concentrates apparently resulted in hsemostasis in the patients described. In certain patients prothrombin complex concentrates can produce either thrombosis or D.i.c., and the risk of using prothrombin complex concentrates in the setting of D.I.C.’ is so significant that we urge discontinuation of clinical use of prothrombin complex concentrates in D.I.C. until the active ingredients in these concentrates are adequately delineated. It is unrealistic to believe that_normal antithrombin in levels will always prevent the known thromboembolic and/or hxmorrhagic side-effects sometimes associated with prothrombin complex concentrates. Indeed four recent cases of thrombosis or D.i.c. have recently occurred in the U.S.A. with the use of these products. Antithrombin 111 was measured in two of these patients at the time of the complications and was normal. The prothrombin complex concentrates have revolutionised 5. 1.

Chatterjee, A., Mahalanabis, D. Jalan, K. N., Maitra, T. K., Agarwa, S. K. ibid. 1977, i, 1333. Cederbaum, A. I., Blatt, P. M., Roberts, H. R. Ann. intern. Med. 1976, 84, 683.


in pre-eclampsia. If partial failure of an adaptive immunological enhancement process is one of the causes of the pre-eclampsia syndrome, it may be reasonable to propose the efficacy of specific immunotherapy in matings where there is not a high degree of consanguinity. Parenteral administration of a suitable preparation of isolated paternal lymphocytes, or more particularly B lymphocytes, should increase the maternal alloantibody reFeeney, J. G., Tovey, L. A. D., Scott, J. S. Lancet, 1977, i, 874. Jenkins, D. M., Need, J. A., Rajah, S. M. Clin. exp. Immun. 1977, 27, 485. 3. Jeffcoate, T. N. A. Proc. R. Soc. Med. 1966, 59, 397. 4. Kaliss, N., Dagg, M. K. Transplantation 1964, 2, 416. 5. Currie, G. A. in Fœtal Autonomy (Ciba Fndn. Symp) (edited by G. E. W. Wolstenholme and M. O’Connor); p.32. London, 1969. 6. Clarke, B. C., Kirby, D. R. S. Nature, 1966, 211, 999. 7. McLaren, A. in Immunobiology of Trophoblast (edited by R. G. Edwards, C. W. S. Howe, and M. H. Johnson). London, 1975. 8. Finn, R., St. Hill, C. A., Govan, A. J., Ralfs, I. G., Gurney, F. J., Denye, V. Br. med. J. 1972, iii, 150. 1. 2.

Sucrose instead of glucose in electrolyte solutions.

The authors conducted a double blind trial to determine how accurately the mothers made up the feeds provided them during the winter of 1976-77 as ora...
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