Background-Chronic inflammatory diseases are associated with an increased production of oxidants. Induction of a stress protein, heme oxygenase (HO) HO-1, is a cytoprotective mechanism against oxidative cellular injury. HO-1 catabolises heme to bilirubin, free iron, and carbon monoxide (CO). Methods-Exhaled CO and sputum bilirubin levels were measured and HO-1 protein expression in airway macrophages was determined by Western blotting in asthmatic patients as levels of oxidants are raised in asthma and may induce HO-1. Results-Exhaled CO was significantly increased in 37 non-steroid treated asthmatic patients compared with 37 healthy subjects (5.8 (95% CI 5.20 to 6.39) ppm vs 2.9 (2.51 to 3.28) ppm; p<0.0001) but was similar to normal in 25 patients who received corticosteroids (3.3 (95% CI 2.92 to 3.67) ppm; p>0.05). In non-treated asthmatic patients more HO-1 protein was expressed in airway macrophages than in normal subjects. Bilirubin levels in induced sputum were also higher than in normal subjects. Inhalation of hemin, a substrate for HO, significantly increased exhaled CO from 3.8 (95% CI 2.80 to 4.87) ppm to 6.7 (95% CI 4.95 to 8.38 CI) ppm (p<0.05) with a concomitant decrease in exhaled nitric oxide levels, suggesting an interaction between the two systems. Conclusions-Increased exhaled CO levels and HO-1 expression may reflect induction of HO-1 which may be inhibited by steroids. Measurement of exhaled CO, an index of HO activity in non-smoking subjects, may therefore be clinically useful in the detection and management of asthma and possibly other chronic inflammatory lung disorders. (Thorax 1998;53:668-672)

Oxidative stress contributes to airway inflammation and exhaled hydrogen peroxide (H2O2) and nitric oxide (NO) are elevated in asthmatic patients. We determined the concentrations of expired H2O2 and NO in 116 asthmatic (72 stable steroid-naive, 30 stable steroid-treated, and 14 severe steroid-treated unstable patients) and in 35 healthy subjects, and studied the relation between exhaled H2O2, NO, FEV1, airway responsiveness, and eosinophils in induced sputum. Both exhaled H2O2 and NO levels were elevated in steroid-naive asthmatic patients compared with normal subjects (0.72 +/- 0.06 versus 0.27 +/- 0.04 microM and 29 +/- 1.9 versus 6.5 +/- 0. 32 ppb, respectively; p < 0.001) and were reduced in stable steroid-treated patients (0.43 +/- 0.08 microM, p < 0.05, and 9.9 +/- 0.97 ppb, p < 0.001). In unstable steroid-treated asthmatics, however, H2O2 levels were increased, but exhaled NO levels were low (0.78 +/- 0.16 microM and 6.7 +/- 1.0 ppb, respectively). There was a correlation between expired H2O2, sputum eosinophils and airway hyperresponsiveness (methacholine PC20). Exhaled NO also correlated with sputum eosinophils, but not with airway hyperresponsiveness. Our findings indicate that measurement of expired H2O2 and NO in asthmatic patients provides complementary data for monitoring of disease activity.

Introduction We compared levels of protein and mRNA expression of three members of the claudin (CLDN) family in malignant breast tumours and benign lesions.

This prospective study was designed to address the incidence and clinical and histologic characteristics of balanitis xerotica obliterans in a large random pediatric population with phimosis. We investigated 1178 boys who presented consecutively with phimosis between 1991 and 2001. All patients who underwent complete circumcision and surgical specimens were typed histologically as early, intermediate, or late forms of this disorder or as nonspecific chronic inflammation. Patients with balanitis xerotica obliterans were controlled at 1, 6, and 12 months postoperatively, then yearly. Balanitis xerotica obliterans was found in 471 of the 1178 patients (40%), with the highest incidence in boys aged 9 to 11 years (76%). Secondary phimosis occurred in 93% of boys with balanitis xerotica obliterans and in 32% of those without the disorder. In six instances of balanitis xerotica obliterans, meatotomy and in one meatoplasty was performed, as well as circumcision. On histologic evaluation, we found 19% had early, 60% intermediate, and 21% late form of balanitis xerotica obliterans. Glanular lesions disappeared completely within 6 months in 229 out of 231 patients. Our data strongly suggest that the true incidence of childhood balanitis xerotica obliterans is higher than previously assumed. Its incidence peaks in the 9 to 11 years age group, in whom secondary phimosis was almost exclusively caused by balanitis xerotica obliterans.

In previous studies we have demonstrated that transforming growth factor (TGF)-␣/c-myc double transgenic mice exhibit an enhanced rate of cell proliferation, accumulate extensive DNA damage, and develop multiple liver tumors between 4 and 8 months of age. To clarify the biochemical events that may be responsible for the genotoxic and carcinogenic effects observed in this transgenic model, several parameters of redox homeostasis in the liver were examined prior to development of hepatic tumors. By 2 months of age, production of reactive oxygen species, determined by the peroxidation-sensitive fluorescent dye, 2,7-dichlorofluorescin diacetate, was significantly elevated in TGF-␣/c-myc transgenic hepatocytes versus either wild type or c-myc single transgenic cells, and occurred in parallel with an increase in lipid peroxidation. Concomitantly with a rise in oxidant levels, antioxidant defenses were decreased, including total glutathione content and the activity of glutathione peroxidase, whereas thioredoxin reductase activity was not changed. However, hepatic tumors which developed in TGF-␣/c-myc mice exhibited an increase in thioredoxin reductase activity and a very low activity of glutathione peroxidase. Furthermore, specific deletions were detected in mtDNA as early as 5 weeks of age in the transgenic mice. These data provide experimental evidence that co-expression of TGF-␣ and c-myc transgenes in mouse liver promotes overproduction of reactive oxygen species and thus creates an oxidative stress environment. This phenomenon may account for the massive DNA damage and acceleration of hepatocarcinogenesis observed in the TGF-␣/c-myc mouse model.