NEONATAL HYPOGLYCAEMIA

1332 DISTRIBUTION BY SUBSITE OF COLORECTAL CANCER FOUND AT NECROPSY AND (A) RECOGNISED AS UNDERLYING CAUSE OF DEATH OR (B) UNRELATED TO PRIMARY CAUSE OF DEATH (NON-FATAL)

I

Numbers of cases

on

Distribution bv site (%)

I

latent cancers of the right colon were in people older than 70. This

(eg, complete colonoscopy and double contrast X-ray) in old people and by a less aggressive attitude by clinicians. The prevalence of unsuspected colorectal cancer in our series was 9-6per 1000, increasing among men from 3-9 in the age group 40-49 to 15-9 per 1000 in those aged over 80 and among women from 3 7 to 14-3 per 1000, respectively. The prevalences we found are lower than the 20-3 per 1000 reported2 for Hawaiian Japanese over 65 (to 10-2 per 1000 in our series for those aged 60 plus). For those over 40 the prevalence we found is only slightly less than that reported by Berg et aP(12’8 per 1000) in a large series of necropsies in Los Angeles county between 1953 and 1959. Our results are also lower than those reported by Lee3 among Chinese in Singapore (13-1for all over age 14 and 27-6 for those aged 60 plus). Differences in the prevalence of latent cancers found at necropsy probably reflect real differences in the frequency of the lesion among populations as well as differences in the methods of ascertainment of malignant lesions. Institute of Anatomy and Histopathology, University of Tneste, 34125 Trieste, Italy

MAURO DELENDI DANIELA GARDIMAN

Unit of Analytical Epidemiology, International Agency for Research on Cancer, 69372 Lyon, France

ELIO RIBOLI ANNIE J. SASCO

Berg JW, Downing A, Lukes RJ. Prevalence of undiagnosed cancer of the large bowel

found at autopsy Cancer 1970; 25: 1076-80. 2. Stemmermann GN. Unsuspected cancer in elderly Hawaiian Japanese Hum Pathol 1982; 13: 1039-44. 3. Lee YS. Incidental carcinoma of the colorectum at autopsy and its effects on the incidence and future trends of colorectal cancers in Singapore. Cancer 1988; 61: 1059-64. 4. Berrino F, Vigano G, Gatta G, Crosignani P, Pisani P, Macaluso M. In. Muir C, Waterhouse J, Mack T, Powell J, Whelan S, eds. Cancer incidence in five continents: vol V (IARC Sci Publ no 88) Lyon: International Agency for Research on Cancer, 1987: 560-65.

ADRENALINE RESPONSE TO HYPOGLYCAEMIA AND INSULIN SPECIES

Siram baffled that Dr Kerr and his colleagues should believe their one case report (April 15, p 836) to "suggest that adrenaline secretion in response to hypoglycaemia may be affected by the

species of insulin". They give too few details of their investigations of January, 1989, for valid comparison with the two previous studies. Were the initial glucose levels at the start of the studies similar, or were fructosamine levels similar? The glucose threshold at which adrenaline "secretion" is triggered is strongly influenced by metabolic (certainly glycaemic) control, but the published evidence, as well as common sense, indicates a period much less than the six weeks or more for which glycated haemoglobin concentrations give a notion of average glycaemia. Yet their only evidence of "metabolic control" comes from the three haemoglobin Al percentages. In the absence of measurement of insulin antibodies we may that their patient had substantial concentrations of these antibodies, raised by use of bovine ultralente (Novo) in 1985-86, assume

at age:

which estimates are based are shown in parentheses

may be explained by difficulty with extensive diagnostic procedures

1.

Prevalence (Der 1000 necronsies)

(FATAL)

and perhaps reactivated by beef soluble and protamine-like insulins in 1989. Hence, many insulin variables may have been quite different between the two clamp studies-in particular, the free insulin concentrations, the rates of insulin disposal, and the rates of change in both free insulin and, especially, glucose concentrations in the 5 or 10 minutes before the adrenaline determination (plasma adrenaline concentration has a short half-life). Hypoglycaemia is not the only stimulus that increases plasma adrenaline concentration. Anxiety and other emotions may do so, and apparently while there was no increase in pulse rate in August, 1988, despite a six-fold increase in plasma adrenaline, heart rate did change (presumably upwards) in January, 1989. The question of

the symptomatic response to hypoglycaemia is complicated by its tendency to disappear with increasing duration of diagnosed diabetes. What is certain is that upsets in glycaemic control (especially hypoglycaemia) will continue to occur if patients are switched from notably antigenic insulins to those much less so (such as the highly purified porcine and human insulins) without reduction in dose, at least initially-as surprisingly was done by Kerr et al in August, 1986. Difficulties caused by antibody formation can be complicated by alterations in formulation. With as empirical a business as individual glycaemic control, there may be patients who fare better on beef and porcine insulin than on human, and on impure rather than pure insulin preparations. But it would prima facie seem a sound policy to aim to replace defective human insulin secretion by insulin preparations of the same or closely similar structures (and as little contaminated as possible); and thus reduce and retard the generation of insulin antibodies. This would seem especially useful for patients starting treatment with insulin, even if such a policy might not bear much fruit for several years. Adrenaline secretion may vary with the rate and extent of decrease in glycaemia, and with the initial blood-glucose

concentration, but there is nothing in Kerr and colleagues’ report to

give any substantial reason to believe that the species of insulin itself either alters the adrenaline response or is a cause of hypoglycaemic unawareness.

Sheikh Rashid Diabetes Unit, Radcliffe Infirmary, Oxford OX2 6HE

T. D. R. HOCKADAY

NEONATAL HYPOGLYCAEMIA

SIR,-Your editorial (April 22, p 882) suggests that the blood glucose be kept above 2-5 mmol/1 in newborn infants. The results of Koh et al,’ cited in the editorial, are only partly relevant because only five of their patients were newborn (gestational ages not reported) and a neurophysiological effect of a blood glucose as high as5 mmol/1 was found in only one of them. We have studied nine preterm infants who had a blood glucose below 1.7 mmol/lin the first hours of life, and no effect of hypoglycaemia was found in visual evoked potentials in amplitude integrated EelsWe did, however, find an increase in cerebral blood flow at a blood glucose below 17 mmolll, reflecting a compensatory mechanism and, possibly, stress.

1333

Although it may seem likely that milder hypoglycaemia imposes a the preterm baby it remains to be proved that this can be prevented without significant side-effects-notably, overhydration with its associated risks. There may be important differences between transitory hypoglycaemia shortly after birth and longerlasting disturbances in blood glucose regulation in older infants. Specialists in neonatal care have, on the basis of descriptive and retrospective studies, implemented several ill-advised "improvements" on nature;3a call for a properly controlled trial is more appropriate. stress on

Department of Neonataology,

GORM GREISEN OLE PRYDS

Rigshospitalet, 2100 Copenhagen Ø, Denmark

1 Koh THHG, Eyre JA, Aynsley-Green A Neural dysfunction during hypoglycaemia Arch Dis Child 1988; 63: 1386-98. 2 Pryds O, Greisen G, Friis-Hansen B. Compensatory increase of CBF in preterm infants during hypoglycaemia. Acta Paediatr Scand 1988; 77: 632-37 3 Silverman WA. Retrolental fibroplasia: a modem parable New York Grune &

Stratton,

1980

INTERFERON IN LUNGS

SIR,-In her review of the molecular and cellular biology of human interferons (IFNs) Dr Balkwill (May 13, p 1060) mentions briefly the possibility of constitutive production of IFNs. Indeed, there is increasing evidence that IFNs are produced in normal human tissues in the apparent absence of recognised inducers. 1,2 They may serve a physiological role in host defence against viruses and in the regulation of cell proliferation and differentiation.2,3 The alveolar surface of the lung is the largest surface within the body which is constantly exposed to the external environment. Various humoral factors, including immunoglobulins, enzymes, and surfactant components, have been identified in normal alveolar epithelial lining fluid,4 which play a role in antimicrobial defence. However, little is known about IFNs in the normal lower

The main sources of IFN in the lungs need to be elucidated. T-lymphocytes are thought to be the major producers of IFN-y,6 and immunocytochemical studies have demonstrated Tlymphocytes in normal lungs, in the alveolar septa and bronchial mucosal tissue.7 Immunocytochemistry has also shown that alveolar macrophages and other cells in the lungs contain IFN-(x.1 The observation that IFN levels in the lungs are far above those in the serum of healthy volunteers indicates that IFNs are constitutively produced within the lungs. This may contribute to host defence by inducing an antiviral state in the respiratory epithelium8 and enhancing alveolar macrophage antimicrobial function.6 Cell Biology Unit, Department of Cardiothoracic Surgery, National Heart and Lung Institute, London SW3 6LY

1. Khan NUD, Pulford KAF, Farquharson MA, et al. The distribution of immunoreactive interferon-alpha in normal human tissues. Immunology 1989; 66: 201-06. 2. Tovey MG, Streuli M, Gresser I, et al. Interferon messenger RNA is produced constitutively in the organs of normal individuals. Proc Natl Acad Sci USA 1987; 84: 5038-42. 3. Toy JL. The interferons. Clin Exp Immunol 1983; 54: 1-13. 4. Reynolds HY. Bronchoalveolar lavage. In: Murray JF, Nadel JA. Textbook of respiratory medicine. Philadelphia: Saunders, 1988: 597-610. 5. Davis GS, Giancola MSA, Costanza MC, Low RB. Analyses of sequential bronchoalveolar lavage samples from healthy human volunteers Am Rev Respir Dis 1982; 126: 611-16. 6. Murray HW. Interferon-gamma, the activated macrophage, and host defense against microbial challenge. Ann Intern Med 1988; 108: 595-608. 7. Kradin RL, Divertie MB, Colvin RB, Ramirez J, Ryu J, Carpenter HA, Bhan AK. Usual interstitial pneumonitis is a T-cell alveolitis. Clin Immunol Immunopathol 1986; 40: 224-35. 8. Bocci V. Roles of interferon produced in physiological conditions: a speculative review. Immunology 1988; 64: 1-9

PREVENTION OF ACUTE GRAFT-VERSUS-HOST DISEASE BY MONOCLONAL ANTIBODY TO INTERLEUKIN-2 RECEPTOR

respiratory tract. We have measured IFN-a and IFN-y in serum and in fluid obtained by washing the lungs of healthy volunteers using the technique of bronchoalveolar lavage (BAL). We used commercial immunoradiometric assays (Abbot Diagnostics and Centocor, respectively). The monoclonal antibodies used in the IFN-a assay recognise the at and a2 subtypes, which are the most prevalent in constitutively produced IFN-a mixtures.2 As shown in the figure, none of the sera contained detectable IFN-a and most were also negative for IFN-y. In contrast, all the cell-free BAL supernatants contained IFN-a (median 10-63, range 7-31-12-42 U/ml) and IFN-y (median 0-227, range 0-123-0-354 U/ml). Since studies of the sequential dilution of lung lining components due to the BAL procedure (4 x 60 ml fluid introduction volumes) suggest that the measured concentration is less than 7% of the in vivo concentration,s the IFN concentration in the original alveolar epithelial lining fluid must be much higher than the values we recorded.

SiR,—Herve et al reported that monoclonal antibody (MoAb) against interleukin-2 receptor (IL-2R) was effective in established graft-versus-host disease (GVHD) and suggested that the synergy of such an MoAb with cyclosporin should be explored.’ Acute GVHD is induced by activated mature T lymphocytes. Marrow depletion of T cells prevented GVHD, but was associated with graft rejection, incomplete donor chimaeras, and increased risks of relapse.2,3 In mice, the prophylactic use of MoAb against IL-2R MoAB significantly decreased the incidence and severity of GVHD with a success rate intermediate between that attained by T-cell depletion and the rate in untreated controls.4 We have investigated the clinical feasibility of a combination of an anti-IL-2R MoAb with cyclosporin in the prevention of GVHD in 18 recipients of HLA matched bone marrow transplants (BMT). 17 patients had leukaemias and were conditioned by marrow ablative conditioning regimens (cyclophosphamide and total body irradiation or busulphan; 1 had severe aplastic anaemia, and was prepared by cyclophosphamide and thoracoabdominal irradiation). All received standard immunosuppression by short-term methotrexate and cyclosporin. We used the 33 B3MoAb (Immunotech), a rat IgG2 which has been extensively studied in vitro and which is clinically active in preventing kidney graft rejections10 mg was given daily following a progressive pattern to study interference with engraftment: 4 patients received MoAb when the BMT was established (day 15-30), 4 patients were treated before evidence of engraftment (day 10-30), and 10 patients were treated from day 0 to 30. Engraftment was achieved in all cases, within a time range similar that in historical controls. Full donor chimaerism was documented in the marrow of 10 recipients of sex-mismatched BMT. No clinical side-effects were observed during the 410 infusions. No anti-rat immunisation was detected during and one month after the end of the infusions. GVHD did not occur during anti-IL-2R therapy. GVHD was observed after day 35 in 3/8 patients treated for 30 days (all grade 2). With a median follow-up of 8 months (range 3-16), 12/18 patients are in remission. This pilot to

Levels of !FN-a and IFN-y volunteers.

in

serum

and BAL fluid of

healthy

CHRISTIAN PRIOR PATRICIA L. HASLAM