Background-Patientswith diYcult asthma suVer chronic moderate to severe persistent asthma symptoms despite high doses of inhaled and oral corticosteroid therapy. These patients suVer a high level of treatment and disease related morbidity but little is known about the degree of airway inflammation in these patients. Methods-Fifty two patients were examined to assess levels of exhaled nitric oxide (NO) as a surrogate marker of inflammatory activity in this condition. From this group, 26 patients were defined with severe symptoms and current physiological evidence of reversible airway obstruction requiring high dose inhaled (>2000 µg beclomethasone dipropionate (BDP) equivalent) or oral steroid therapy to maintain disease control. Results-Exhaled NO levels were higher in subjects with diYcult asthma (mean 13.9 ppb, 95% CI 9.3 to 18.5) than in normal controls (7.4 ppb, 95% CI 6.9 to 7.8; p<0.002), but lower than levels in steroid naive mild asthmatics (36.9 ppb, 95% CI 34.6 to 39.3; p<0.001). Prednisolone treated patients had higher exhaled NO levels than patients only requiring inhaled corticosteroids (17.5 ppb, 95% CI 11.1 to 24.0 versus 7.2 ppb, 95% CI 4.6 to 9.8; p = 0.016), suggesting greater disease severity in this group. Non-compliance with prednisolone treatment was observed in 20% of patients but this did not explain the diVerence between the treatment groups. Exhaled NO levels were closely correlated with symptom frequency (p = 0.03) and with rescue agonist use (p<0.002), but they did not correlate with lung function. Conclusions-Exhaled NO may serve as a useful complement to lung function and symptomatology in the assessment of patients with chronic severe asthma, and in the control and rationalisation of steroid therapy in these patients.

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Immunohistological analysis using monoclonal antibodies in conjunction with histochemical techniques has been applied to lung biopsy material from patients with cryptogenic fibrosing alveolitis. Subsets of lymphoid and non-lymphoid cells have been identified in situ. This analysis showed that the inflammatory cells present were predominantly mononuclear. Most of the lymphoid cells were B lymphocytes, organised into follicles with occasional germinal centre formation. IgM was the major class of immunoglobulin expressed. Both T4+ and T8+ lymphocytes were seen diffusely distributed in the interstitium. The T4+ positive cells were also seen within the B lymphoid follicles. Almost all non-lymphoid cells expressed the phenotype of inflammatory macrophages, but a few also expressed a phenotype characteristic of interdigitating cells. These results suggest that a local B lymphoid immune response is occurring in cryptogenic fibrosing alveolitis. The possibility that a cell mediated immune response is also emerging is discussed.Current ideas about the pathogenesis of cryptogenic fibrosing alveolitis owe much to the introduction of bronchoalveolar lavage as a diagnostic and investigative tool in pulmonary medicine (for reviews see refs 1-4) and to studies of animal models of pulmonary fibrosis.5 Although the aetiology is unknown it is generally accepted that chronic alveolar inflammation is the forerunner of the irreversible interstitial fibrosis characteristic of cryptogenic fibrosing alveolitis26 and that the immune system is implicated in the development of this chronic alveolitis.78It is argued that in response to an unknown antigenic stimulus macrophages and T lymphocytes are activated, B lymphocytes proliferate, and plasma cells produce immunoglobulins.2 This results in immune complex formation and deposition along with complement in the pulmonary parenchyma."9The immune complexes activate macrophages to

OBJECTIVEProkineticin 2 (PK2) is a hypothalamic neuropeptide expressed in central nervous system areas known to be involved in food intake. We therefore hypothesized that PK2 plays a role in energy homeostasis.RESEARCH DESIGN AND METHODSWe investigated the effect of nutritional status on hypothalamic PK2 expression and effects of PK2 on the regulation of food intake by intracerebroventricular (ICV) injection of PK2 and anti-PK2 antibody. Subsequently, we investigated the potential mechanism of action by determining sites of neuronal activation after ICV injection of PK2, the hypothalamic site of action of PK2, and interaction between PK2 and other hypothalamic neuropeptides regulating energy homeostasis. To investigate PK2's potential as a therapeutic target, we investigated the effect of chronic administration in lean and obese mice.RESULTSHypothalamic PK2 expression was reduced by fasting. ICV administration of PK2 to rats potently inhibited food intake, whereas anti-PK2 antibody increased food intake, suggesting that PK2 is an anorectic neuropeptide. ICV administration of PK2 increased c-fos expression in proopiomelanocortin neurons of the arcuate nucleus (ARC) of the hypothalamus. In keeping with this, PK2 administration into the ARC reduced food intake and PK2 increased the release of α-melanocyte–stimulating hormone (α-MSH) from ex vivo hypothalamic explants. In addition, ICV coadministration of the α-MSH antagonist agouti-related peptide blocked the anorexigenic effects of PK2. Chronic peripheral administration of PK2 reduced food and body weight in lean and obese mice.CONCLUSIONSThis is the first report showing that PK2 has a role in appetite regulation and its anorectic effect is mediated partly via the melanocortin system.