Plasma adrenomedullin in diabetes

THE LANCET 1 2 3 4 5 Silverstein RL, Nachman RL. Cancer and clotting—Trousseau’s warning. N Engl J Med 1992; 327: 1163–64. Nordström M, Lindblad B, Bergqvist D, Kjellstrom TA. Prospective study of the incidence of deep vein thrombosis within a defined urban population. J Intern Med 1992; 232: 155–60. Prandoni P, Lensing AWA, Buller HR, et al. Deep-vein thrombosis and the incidence of subsequent symptomatic cancer. N Engl J Med 1992; 327: 1128–33. Nordstöm M, Lindblad B, Anderson H, Bergqvist D, Kjellstrom T. Deep venous thrombosis and occult malignancy: an epidemiological study. BMJ 1994; 308: 891–94. Cornuz J, Pearson S, Creager M, Cook F, Goldman L. Importance of findings on the initial evaluation for cancer in patients with symptomatic idiopathic deep venous thrombosis. Ann Intern Med 1996; 125: 785–93. Service de Médecine Vasculaire-Hôpital Broussais, 75674 Paris, France (J Emmerich) Plasma adrenomedullin in diabetes Michio Hayashi, Tatsuo Shimosawa, Masa-aki Isaka, Satsuki Yamada, Rie Fujita, Toshiro Fujita The hypotensive peptide, adrenomedullin, was first discovered in adrenal medulla tumours, but the main site of adrenomedullin production in vivo is now thought to be the vasculature.1 Both vascular endothelial cells and smooth muscle cells express adrenomedullin and its receptor,2 so adrenomedullin may control vascular functions via autocrine/paracrine systems. Adrenomedullin also controls various cell functions such as proliferation, differentiation, and migration.3–5 Whether adrenomedullin participates in the pathological process of the vasculature in diabetic patients is unclear. If the local expression of adrenomedullin in the vasculature changes in diabetes, the plasma concentration of adrenomedullin would also be expected to change. We compared the plasma adrenomedullin concentration in poorly Vol 350 • November 15, 1997 20 Plasma adrenomedullin (fmol/mL) had secondary DVT and six cancers were diagnosed among these patients during their hospital stay (1·2%). When thrombosis was idiopathic, the rate of occult cancer was significantly higher (3·9%, p<0·02). Among the 64 patients with bilateral DVT, 41 (64%) had secondary bilateral DVT and two cancers were diagnosed (4·9%). When bilateral DVT was idiopathic, the rate of cancer was significantly higher than when it was not (35%, p<0·001). To our knowledge, this is the first study to establish the increased risk of occult cancer in bilateral DVT. The low rate of bilateral DVT probably explains the lack of data in the published research.2 However, this was a retrospective study with possible bias. We cannot rule out the possibility that clinical examination was more meticulous in patients with bilateral DVT. It is also possible that screening tests were more extensive in patients with bilateral venous thrombosis. However, most cancers are diagnosed by clinical examination, chest radiography, or standard biological screening tests,3–5 which were routinely done in all our patients. Further followup will be required to determine the rate of undiagnosed cancers. The rate of known cancers in our series (13%) and the rate of occult cancers found during the hospital stay (3·2%) were similar to those in other studies. Symptomatic pulmonary embolism was more common in patients with bilateral DVT than in those with unilateral DVT. The bilateral thrombosis can explain an increased risk of PE. The presence of PE and the location of DVT (proximal versus inferior vena cava) were not associated with the risk of occult cancer. Our study shows an increased rate of occult cancers in bilateral DVT (mainly in idiopathic bilateral DVT), with malignant disease in one-third of the patients. These data call for an extensive search for occult cancer in this situation, that concerns less than 10% of patients with DVT. 15 10 5 0 Control Diabetics Plasma adrenomedullin in poorly controlled diabetic patients and healthy volunteers Open circles and bars represent mean and SD, respectively. controlled diabetic patients with that in healthy volunteers. Plasma samples from 13 poorly controlled diabetic patients, without renal failure (serum creatinine 159 µmol/L) and other diseases, whose casual plasma glucose concentrations were higher than 16·6 mmol/L (18·2–73·5 mmol/L, mean 30·1 [14·8] mmol/L, eight males, age 57·1 [11·1]), and 20 healthy volunteers (nine men, age 31·0 [5·9]) were assayed for adrenomedullin concentration with radioimmunoassay. Compared with normal volunteers, plasma adrenomedullin in these hyperglycaemic patients was significantly (p<0·001) increased (figure). None of the patients had renal failure or severe diseases other than diabetes. Thus renal failure, in which plasma adrenomedullin concentration rises, and the critically ill states, in which hypercortisolaemia can be seen, might not be involved in producing raised adrenomedullin in diabetic patients. The patients were older than the normal volunteers, but plasma adrenomedullin does not change with age (unpublished data). The main production site of adrenomedullin in vivo is thought to be the vasculature and adrenomedullin expression in the vasculature rises in response to pathological processes.1 The adrenomedullin mRNA level was increased in the vascular smooth muscle cells cultured in high glucose medium, and in the aorta of experimental diabetic rats (our unpublished data). We believe that the rise in plasma adrenomedullin was due to a hyperglycaemia-induced increase of adrenomedullin expression in the vasculature, which may provide a link between hyperglycaemia and alteraction of vascular function. 1 2 3 4 Sugo S, Minamino N, Shoji H, et al. Production and secretion of adrenomedullin from vascular smooth muscle cells: augmented production by tumor necrosis factor-alpha. Biochem Biophys Res Commun 1994; 203: 719–26. Sugo S, Minamino N, Kangawa K, et al. Endothelial cells actively synthesize and secrete adrenomedullin [published erratum appears in Biochem Biophys Res Commun 1994; 203: 1363]. Biochem Biophys Res Commun 1994; 201: 1160–66. Kano H, Kohno M, Yasunari K, et al. Adrenomedullin as a novel antiproliferative factor of vascular smooth muscle cells. J Hypertens 1996; 14: 209–13. Horio T, Kohno M, Kano H, et al. Adrenomedullin as a novel antimigration factor of vascular smooth muscle cells. Circ Res 1995; 77: 1449 THE LANCET 5 660–64. Miller MJ, Martinez A, Unsworth EJ, et al. Adrenomedullin expression in human tumor cell lines: its potential role as an autocrine growth factor. J Biol Chem 1996; 271: 23345–51. Fourth Department of Internal Medicine, School of Medicine, University of Tokyo, Tokyo 112, Japan (M Hayashi); National Hospital Tokyo Disaster Medical Centre, Department of Internal Medicine, Tokyo; Department of Internal Medicine, University of Tsukuba, Tsukuba City; and Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba salbutamol itself, rather than spontaneous variation in disease activity. It also indicates that bradykinin may more accurately detect increased sensitivity following regular salbutamol than histamine or methacholine, and may therefore facilitate investigation of this phenomenon. 1 2 Varied effects of regular salbutamol on airway responsiveness to inhaled spasmogens 3 4 5 Simon D Crowther, John Morley, John F Costello Drazen JM, Israel E, Boushey HA, et al. Comparison of regularly scheduled with as needed use of albuterol in mild asthma. N Engl J Med 1996; 335: 841–47. Sears MR, Taylor DR, Print CG, Lake DC, et al. Regular inhaled betaagonist treatment in bronchial asthma. Lancet 1990; 336: 1391–96. Perrin-Fayolle M. Salbutamol in the treatment of asthma. Lancet 1995; 346: 1101. Boulton DW, Fawcett JP. Enantioselective disposition of albuterol in man following oral and intravenous administration. Br J Clin Pharmacol 1996; 41: 34–40. Cockcroft DW, McParland CP, Britto SA, et al. Regular inhaled salbutamol and airway responsiveness to allergen. Lancet 1993; 342: 833–38. Like fenoterol, salbutamol reduces the sensitivity of asthmatic airways to acute contractile stimuli, but can increase sensitivity in some subjects following regular administration,1 a finding which has inevitably questioned the use of regular inhalation of ␤2-agonists in asthma.2 Such increased sensitivity is paradoxical, since it cannot be attributed to the R-enantiomer which is a bronchodilator and reduces airway sensitivity. However, it could reflect actions of the S-enantimer, which is not a bronchodilator, which can increase sensitivity of asthmatic airways,3 and which accumulates disproportionately because of stereospecific metabolism.4 Following regular inhalation of racemic salbutamol, only modestly increased sensitivity to methacholine has been observed,2 although more pronounced increased sensitivity was evident when allergen was used.5 The possibility therefore arises that allergic mediators may more readily detect this property of racemic salbutamol than does methacholine. As a prelude to comparison between R-salbutamol and racemic salbutamol in a double-blind, placebo-controlled study, we studied 11 volunteers with mild, well-controlled, asthma. All volunteers were atopic non-smokers; none used salbutamol on a daily basis; five used inhaled steroids (two regularly, three intermittently) and no other medications were used. Airway sensitivity, measured as PC20 to methacholine, histamine, peptidoleukotriene C4 (LTC4), or bradykinin, was determined before, and after, regular salbutamol (200 µg four times per day for 7 days) by metered dose inhaler, or after abstinence from salbutamol for 1 week. Measurements were made at the same time of day in each patient, who gave informed signed consent. The study was approved by King’s College Ethics Committee. 31 paired estimations were completed (table). After regular salbutamol, sensitivity to methacholine, histamine, or LTC4 was usually unchanged, with only two of eight volunteers, one of six, and one of six, respectively, showing increased sensitivity greater than two-fold. For bradykinin, however, there was significant (p<0·02) increased sensitivity, which was greater than two-fold in four of 11 volunteers. After abstinence from salbutamol, sensitivity to bradykinin decreased (geometric means 1·91 mg/mL before, and 2·64 mg/mL after, n=11). This study implies that increased sensitivity to bradykinin following regular use of salbutamol reflects an action of Sackler Institute of Pulmonary Pharmacology, Department of Respiratory Medicine, King’s College Hospital, London SE5 9RS, UK (S D Crowther) Spasmogen Day 0 GM (95% CI) Day 7 GM (95% CI) 2 Methacholine (mg/mL) Histamine (mg/mL) LTC4 (µg/mL) Bradykinin (mg/mL) 1·79 (0·38–8·32) 1·33 (0·27–6·46) 8 5·37 (1·55–18·62) 9·71 (2·82–33·88) 2·38 (1·38–4·17) 3·36 (0·87–13·18) 5·31 (1·55–18·62) 0·87 (0·25–3·02) 6 6 11 Number *Students’ t test. NS=not significant (p>0·05). Geometric mean (GM) sensitivity with 95% CI to inhaled spasmogens before (day 0), and after (day 7), regular inhalation of salbutamol 1450 p* Spontaneous pneumothorax: predictable mini-epidemics? Hans J M Smit, Walter L Devillé, Franz M N H Schramel, Pieter E Postmus It is our impression that patients with newly diagnosed idiopathic spontaneous pneumothorax are admitted in clusters of 2 or 3 days, and that spontaneous pneumothorax is less often diagnosed during other periods of time. We analysed the clinical data of 115 patients who were admitted with a spontaneous pneumothorax, which was considered to be idiopathic, due to the lack of any signs of underlying pulmonary disease. This group of 115 patients forms 28% of all patients with spontaneous pneumothorax admitted to nine hospitals between 1992 and 1993 in the Amsterdam area. The clinical data of this complete group were not available for this study. Based on the clinical impression of pulmonary physicians, but otherwise arbitrarily, we defined a cluster when two patients with spontaneous pneumothorax were admitted within 3 days of each other. With this definition, 73% of spontaneous pneumothorax cases were diagnosed in clusters. We cannot explain this clustering, but our results confirm the clinical impression of many physicians, and support previous studies reporting a relation between external conditions such as atmospheric pressure changes, and the occurrence of spontaneous pneumothorax. 1,2 Perhaps spontaneous pneumothorax is related to bronchiolitis, resulting in areas with trapped air,3 which may be prone to rupture if the atmospheric pressure drops. Or there may be a relation between inflammation and weather conditions, as in asthma.4 In these patients a check valve mechanism may result in alveolar areas with higher pressure than the surrounding parenchyma, leading to spontaneous pneumothorax. We concluded that the occurrence of spontaneous pneumothorax is not a random event. 1 NS NS NS <0·02 3 4 Bense L. Spontaneous pneumothorax related to falls in atmospheric pressure. Eur J Respir Dis 1984; 65: 544–46. Scott GC, Berger R, McKean HE. The role of atmospheric pressure ventilation in the development of spontaneous pneumothorax. Am Rev Respir Dis 1989; 139: 659–62. Schramel FMNH, Postmus PE, Vanderschueren RGJRA. Current aspects of spontaneous pneumothorax. Eur Respir J 1997; 10: 1372–79. Newson R, Strachan D, Archibald E, Emberlin J, Hardaker P, Collier C. Effect of thunderstorms and airborne grass pollen on the incidence of acute asthma in England, 1990–94. Thorax 1997; 52: 680–85. Department of Pulmonary Medicine, Free University Hospital, Amsterdam 1007 MB, Netherlands (H J M Smit) Vol 350 • November 15, 1997