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Interleukin (IL)-18 is a pro-inflammatory cytokine suggested to be involved in the development of pulmonary emphysema and inflammation. Studies involving immunology and cancer have revealed that IL-18 can have synergistic effects with IL-12. We have studied the presence of IL-18 and IL-12 receptors (IL-18R/IL-12R) in the lungs and whether IL-18 and IL-12, alone or in combination, have the ability to initiate the induction of mediators related to the development of emphysema and inflammation. The expression of the IL-18R was abundant in lungs compared to other organs (heart, liver, and spleen), and the IL-12R was also expressed in lung tissue. Mice treated with i.p. injection of recombinant murine IL-18 or IL-12 expressed significantly higher pulmonary mRNA levels of the matrix degrading enzymes metalloproteinase (MMP) 12 and cathepsin S, in addition to interferon-γ, tumor necrosis factor-α, and CXC chemokine ligand 9 (CXCL9) (all P < .05) than controls (received PBS). Treatment with IL-18 and IL-12 in combination showed an even more pronounced induction of these mediators, as well as a significant increase in MMP-9, IL-6, IL-1β, and transforming growth factor-β (P < .05). Furthermore, cellular apoptosis in lung tissue was induced. Immunohistochemical analysis revealed T-cell infiltration in pulmonary vessels following co-stimulation. In summary, IL-18 and IL-12 exert a synergistic effect on the lungs by inducing MMPs, cathepsins S, and pro-inflammatory cytokines, which may promote pulmonary emphysema and inflammation. The synergy between IL-18 and IL-12 involves infiltration of T-cells in the lungs, possibly induced by the T-cell chemoattractant CXCL9.

The antidiabetic agent metformin is regularly discussed as a promising treatment for non-alcoholic fatty liver disease (NAFLD), which is characterized by insulin resistance. However, the evidence for its beneficial effects is limited, and conflicting reports have been published. The purpose of this study was to conduct a randomized, double-blind, placebo-controlled trial to test whether metformin improves liver histology in patients with non-alcoholic fatty liver disease.Forty-eight patients with biopsy-proven NAFLD were randomized to treatment with metformin (n=24) or placebo (n=24) for 6 months. A second liver biopsy was obtained in all subjects who completed the trial (n=44). Data analyses are restricted to this group (per-protocol analyses). The primary outcome was changes in histologically assessed liver steatosis. Secondary outcomes were changes in NAFLD activity (NAS)-score, liver steatosis assessed by computed tomography (CT), liver transaminases, body-weight, metabolic variables and inflammatory markers.No significant differences between treatment with metformin or placebo were observed for changes in liver steatosis, assessed either histologically or by CT, NAS-score, liver transaminases or on markers of insulin resistance or inflammation. In contrast, beneficial effects of metformin were observed on changes in body-weight (p0.001), serum levels of cholesterol (p=0.004), LDL-cholesterol (p0.001), glucose (p=0.032) and on HbA1c (p=0.020).Treatment with metformin for 6 months was no better than placebo in terms of improvement in liver histology in patients with NAFLD. Nevertheless, the use of metformin could still be beneficial in this group as it is associated with a reduction in serum levels of lipids and glucose. (ClinicalTrials.gov number, NCT00303537).

Xylose absorption testing has traditionally involved measurement of serum xylose and/or measurement of excreted xylose in urine. However, by enriching xylose with a 13C- or 14C-isotope, absorption of an oral xylose load will be reflected in the time-dependent pattern of 13CO2 or 14CO2 exhaled in breath. Our objectives were to evaluate the diagnostic properties of 13C-xylose and 14C-xylose breath tests in coeliac disease, and to develop a diagnostic breath test index.We reviewed data from 41 coeliac patients who underwent the 14C-xylose breath test before and after commencement of a gluten-free diet, and 60 coeliac patients who underwent the 13C-xylose breath test, 37 of whom repeated the test after starting a gluten-free diet. Coeliac patients were compared with healthy control subjects.Coeliac patients exhaled significantly less 13CO2 or 14CO2 than healthy controls during the first hour of the test and more isotope-labelled CO2 than control subjects after 3 h. Diagnostic accuracy was optimal with test duration of 210 min combining gas measurements at 30 min and 210 min in a simple fraction. This gas fraction index (30 min/210 min) distinguished between coeliac patients and healthy control subjects with 84-95% sensitivity and 87-94% specificity. After commencement of a gluten-free diet, the gas fraction index increased in most coeliac patients, but remained lower than that in healthy control subjects.13C-xylose- and 14C-xylose breath tests discriminate between coeliac patients and healthy control subjects with high sensitivity and specificity. The stable isotope 13C-xylose breath test has comparable diagnostic accuracy to the radioactive isotope 14C-xylose breath test and should be the preferred alternative to traditional xylose absorption tests.