554 2. Purcell RH, Ticehurst JR. Enterically transmitted non-A, non-B hepatitis: epidemiology and clinical characteristics. In: Zuckerman AZ, ed. Viral hepatitis and liver disease. New York: Alan R. Liss, 1988: 131-37. 3. Francis DP, Hadler SC, Prendergast TJ, et al. Occurrence of hepatitis A, B and non-A/non-B m the United States: CDC sentinel country hepatitis study I. Am J Med 1984; 76: 69-74. 4. Khuroo MS. Study of an epidemic of non-A, non-B hepatitis. Possibility of another human hepatitis virus distinct from post-transfusion non-A, non-B type. Am J Med 1980; 80: 818-24. 5. Sreenivasan MA, Sehgal A, Prasad SR, Dhorje SP. A sero-epidemiological study of water-borne epidemic of viral hepatitis in Kolhapur city, India. J Hyg 1984; 93: 113-22. 6. Sreenivasan MA, Arankalle VA, Sehgal A, et al. Non-A, non-B epidemic hepatitis: visualization of virus-like particles in the stool by immune electron microscopy. J Gen Virol 1984; 65: 1005-07. 7. Tandon BN, Joshi YK, Jain SK, et al. An epidemic of non-A, non-B hepatitis in North India. Indian J Med Res 1982; 75: 739-44. 8. Viswanathan R Infectious hepatitis in Delhi (1955-56): a critical study; epidemiology. Indian J Med Res 1957; 45 (suppl): 1-30. 9. Wong DC, Purcell RH, Sreenivasan MA, et al. Epidemic and endemic hepatitis m India: evidence for a non-A, non-B hepatitis virus aetiology. Lancet 1980; ii 876-79. 10. Khuroo MS, Duermeyer W, Zargar SA, et al. Acute sporadic non-A, non-B hepatitis in India. Am J Epidemiol 1983; 118: 360-64. 11. Balayan MS, Andjaparidze AG, Savinskaya SS, et al. Evidence for a virus in non-A, non-B hepatitis transmitted via the fecal-oral route. Intervirology 1983; 20: 23-31. 12. Belabbes EH, Bouguermough A, Bentallah A, et al. Epidemic non-A, non-B viral hepatitis in Algeria: strong evidence for its spreading by water J Med Virol 1985; 16: 275-81. 13. Bradley DW, Andjaparidze AG, Cook EH Jr, et al. Etiologic agent of enterically transmitted non-A, non-B hepatitis. J Gen Virol (in press). 14. Bradley DW, Krawczynski K, Cook EH Jr, et al Enterically transmitted non-A, non-B hepatitis: serial passage of disease in cynomolgus macaques and tamarins and recovery of disease-associated 27 to 34-nm virus like particles. Proc Natl Acad Sci USA 1987; 84: 6277-81 15. Kane MA, Bradley DW, Shrestha SM, et al. Epidemic non-A, non-B hepatitis in Nepal. Recovery of a possible etiologic agent and transmission studies in marmosets. JAMA 1984; 252: 3140-45 16. Pillot J, Sharma MD, Lazizi Y, et al. Immunological characterization of a viral agent involved m epidemic and sporadic non-A, non-B hepatitis. Ann Inst Pasteur Virol 1987; 138: 145-58. 17. Shakhgildyan IV, Khukhlovich PA, Kuzin SN, et al. Epidemiological characteristics of viral non-A, non-B hepatitis with fecal-oral mode of transmission. Vopr Virusol 1986; 31: 175-79. 18. Sjogren M, Redfield R, Innis B, et al Similarly between sporadic and epidemic non-A, non-B hepatitis. Hepatology 1987; 7: 1119 (abstr 387) 19. De Cock KM, Bradley DW, Sandford NL, Govindarajan S, Maynard JE, Redeker AG. Epidemic non-A, non-B hepatitis m patients from Pakistan. Ann Intern Med 1987; 106: 227-30 20. Zairov GK, Stakhanova VM, Listovskaya EK, et al. Electron microscopic investigations in non-A, non-B viral hepatitis with fecal-oral transmission mode. Vopr Virusol 1986; 31: 172-75. 21. Andzhaparidze AG, Balayan MS, Savinov AP, et al. Non-A, non-B hepatitis transmitted by the fecal-oral mode experimentally produced in monkeys. Vopr Virusol 1986; 31: 73-81. 22. Kapikian AZ, Dienstag JL, Purcell RH. Immune electron microscopy as method for the detection, identification, and characterization of agents not cultivable in an in vitro system. In: Rose NR, Friedman H, eds. Manual of clinical immunology. Washington, DC: American Society for Microbiology, 1976: 467-80. 23. Dienstag JL, Feinstone SM, Purcell RH, et al. Experimental infection of chimpanzees with hepatitis A virus. J Infect Dis 1975; 132: 532-45. 24. Ticehurst JR, Feinstone SM, Chestnut T, Tassopoulos NC, Popper H, Purcell RH. Detection of hepatitis A virus by extraction of viral RNA and molecular hybridization. J Clin Microbiol 1987; 25: 1822-29. 25. Ticehurst JR, Racaniello Vr, Baroudy BM, et al. Molecular cloning and characterization of hepatitis A virus cDNA. Proc Natl Acad Sci USA 1983; 80: 5885-89. 26. Racaniello VR, Baltimore D. Molecular cloning of poliovirus cDNA and determination of the complete nucleotide sequence of the viral genome. Proc Natl Acad Sci USA 1981; 78: 4887-91. 27. Almeida JD, Waterson AP. The morphology of virus-antibody interaction. Adv Virus Res 1969; 15: 307-38. 28 Rotbart HA, Levin MJ, Villarreal LP. Use of subgenomic poliovirus DNA hybridization probes to detect the major subgroups of enteroviruses J Clin Microbiol 1984; 20: 1105-08 29. Hyypia T, Maaronen M, Auvinen P, et al. Nucleic acid sequence relationships between enterovirus serotypes. Mol Cell Probes 1987; 1: 169-76. REBOUND INCREASE IN BRONCHIAL RESPONSIVENESS AFTER TREATMENT WITH INHALED TERBUTALINE A. S. VATHENEN B. G. HIGGINS A. J. KNOX J. R. BRITTON A. E. TATTERSFIELD Respiratory Medicine Unit, City Hospital, Nottingham NG5 1PB Summary To investigate whether cessation of regular &bgr;-agonist treatment results in an increase in bronchial responsiveness, two double-blind, randomised crossover studies were done. Subjects with mild asthma were investigated to determine the course of change in bronchial responsiveness, measured as the provocative dose (PD20) of histamine that caused a 20% fall in forced expiratory volume in 1 s after short-term and longer term treatment with an inhaled &bgr;-agonist. In the first study in 8 subjects, 500 and 2000 µg terbutaline thrice in 1 day protected against histamine-induced bronchoconstriction, and the increase in PD20 compared with placebo remained high throughout the day and overnight. In the second study 8 subjects received placebo or terbutaline 750 µg thrice daily for 14 days. The protection afforded by terbutaline against histamine-induced bronchoconstriction on day 14 was less than that on day 1 by 40% in the morning and 82% in the afternoon. On day 15 PD20 was lower after stopping terbutaline than placebo, with a maximum difference of 1·5 (95% CI 0·6-2·5) doubling-doses of histamine 23 h after the end of treatment. Thus treatment with terbutaline for 1 day did not result in any rebound increase in bronchial responsiveness. Treatment for 2 weeks impaired the ability of terbutaline to protect against histamine-induced bronchoconstriction, and was followed by a rebound increase in bronchial responsiveness after cessation of treatment. Introduction AFTER the increase in asthma deaths in the 1960s it was suggested that long-term use of p-agonisis might result in the development of resistance to these drugs.1 Since then, homologous desensitisation of p-receptors has been demonstrated in vitro2 and in circulating white cells ex vivo.2-7 But clinical experience and most prospective studies suggest that the bronchodilator effectiveness of P-agonists is maintained long term.8 Bronchodilatation after a single dose of &bgr;-agonist is associated with increased protection against various non- specific challenges. 9-14 In two uncontrolled studies, however, bronchial responsiveness was increased 12-16 h after cessation of long-term inhaled p-agonist treatment.15,16 Such an increase may leave asthmatic patients more vulnerable to provocative stimuli. In single-dose studies measurements of bronchial responsiveness have been made during the first few hours, before any rebound change would be expected. So it is unclear whether the findings with prolonged treatment15,16 were due to the duration of treatment or to the longer time between the last dose of drug and measurement of bronchial responsiveness. We have studied the course of change in bronchial responsiveness after both short-term and longer term 0-agonist administration in a placebo-controlled study. In the first study we gave low-dose and high-dose inhaled terbutaline for 1 day and measured change in bronchial responsiveness during the day and overnight. Because most patients only take asthma medication during the day any rebound increase in bronchial responsiveness is most likely to occur at night, the time when bronchial responsiveness is increased17-19 and asthma morbidity and mortality are highest.20.21 In the second study we looked at changes during and after 2 weeks’ treatment with inhaled terbutaline.