The reconstructed cellular metabolic network of Mus musculus, based on annotated genomic data, pathway databases, and currently available biochemical and physiological information, is presented. Although incomplete, it represents the first attempt to collect and characterize the metabolic network of a mammalian cell on the basis of genomic data. The reaction network is generic in nature and attempts to capture the carbon, energy, and nitrogen metabolism of the cell. The metabolic reactions were compartmentalized between the cytosol and the mitochondria, including transport reactions between the compartments and the extracellular medium. The reaction list consists of 872 internal metabolites involved in a total of 1220 reactions, whereof 473 relate to known open reading frames. Initial in silico analysis of the reconstructed model is presented.

nists have been characterized largely in terms of their effects on lipids and glucose metabolism, whereas little has been reported about effects on amino acid metabolism. We studied responses to the PPAR␣ agonist WY 14,643 (30 mol⅐ kg Ϫ1 ⅐ day Ϫ1 for 4 wk) in rats fed a saturated fat diet. Plasma and urine were analyzed with proton NMR. Plasma amino acids were measured using HPLC, and hepatic gene expression was assessed with DNA arrays. The high-fat diet elevated plasma levels of insulin and triglycerides (TG), and WY 14,643 treatment ameliorated this insulin resistance and dyslipidemia, lowering plasma insulin and TG levels. In addition, treatment decreased body weight gain, without altering cumulative food intake, and increased liver mass. WY 14,643 increased plasma levels of 12 of 22 amino acids, including glucogenic and some ketogenic amino acids, whereas arginine was significantly decreased. There was no alteration in branched-chain amino acid levels. Compared with the fat-fed control animals, WY 14,643-treated animals had raised plasma urea and ammonia levels as well as raised urine levels of N-methylnicotinamide and dimethylglycine. WY 14,643 induced changes in a number of key genes involved in amino acid metabolism in addition to expected effects on hepatic genes involved in lipid catabolism and ketone body formation. In conclusion, the present results suggest that, in rodents, effects of pharmacological PPAR␣ activation extend beyond control of lipid metabolism to include important effects on whole body amino acid mobilization and hepatic amino acid metabolism.peroxisome proliferator-activated receptor-␣ PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-␣ (PPAR␣) agonists are used clinically to treat dyslipidemia and to reduce the risk of cardiovascular complications (7). The beneficial effects of these agents appear to be most significant in patients with insulin resistance and diabetes (32). It is clear that a major and primary action of PPAR␣ activation is the transcriptional regulation of genes involved in lipid metabolism (36). However, the effects of PPAR␣ activation may not be limited to lipid metabolism, given the established interactions between the major substrate classes (19), e.g., the glucose-fatty acid cycle (29) and the glucose-alanine cycle (10). In terms of glucose metabolism, an important physiological role of PPAR␣ is suggested by the hypoglycemia in response to prolonged fasting developed by mice lacking PPAR␣ (17). Furthermore, treatment of fat-fed rats with the selective PPAR␣ agonist WY 14,643 resulted in increases in whole body and skeletal muscle insulin-stimulated glucose utilization, with the enhancement in muscle insulin sensitivity related to the degree of reduction in local lipid accumulation (39). Surprisingly little has been reported concerning effects of PPAR␣ activation on amino acid metabolism, although work based largely on analysis of mRNA in mouse liver (23) suggests an important influence on the handling of this substrate class.The aim of the present study was to provide...

BACKGROUND & AIMS Distinction of IgG4-associated cholangitis (IAC) from primary sclerosing cholangitis (PSC) or cholangiocarcinoma is challenging. We aimed to assess the performance characteristics of endoscopic retrograde cholangiography (ERC) for the diagnosis of IAC. METHODS Seventeen physicians from centers in USA, Japan, and UK, unaware of other clinical data, reviewed 40 preselected ERCs of patients with IAC (n=20), PSC (n=10), and cholangiocarcinoma (n=10). The performance characteristics of ERC for IAC diagnosis, as well as the kappa statistic for intra- and inter-observer agreement, were calculated. RESULTS The overall specificity, sensitivity, and interobserver agreement for the diagnosis of IAC were 88%, 45%, and 0.18 respectively. Reviewer origin, specialty, or years of experience had no statistically significant effect on reporting success(p>0.05). The overall intraobserver agreement was fair (0.74). The operating characteristics of different ERC features for the diagnosis of IAC were poor. CONCLUSION Despite high specificity of ERC for diagnosing IAC, sensitivity is poor, suggesting that many patients with IAC may be misdiagnosed with PSC or cholangiocarcinoma. Additional diagnostic strategies are likely to be vital in distinguishing these diseases.

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IntroductionIgG4 associated cholangitis (IAC) may have similar radiographic appearances to primary sclerosing cholangitis (PSC) and cholangiocarcinoma (CCA). Making the diagnosis is important as IAC usually responds favourably to steroids (in contrast to PSC) and erroneous treatment for presumed CCA may be avoided. We assessed whether specialists familiar with these diseases could reliably distinguish between them based on endoscopic retrograde cholangiograms (ERC).MethodsERCs (n=104) of patients with a definitive diagnosis of IAC, PSC and CCA from centres in the US, Japan and UK were screened for quality by an experienced endoscopist unaware of clinical diagnoses. A final set of 48 ERCs (20 IAC, 10 PSC, 10 CCA and 8 duplicates) were arranged in random order and presented to 18 reviewers unaware of the diagnosis. Reviewers noted presence or absence of key ERC features and provided their three most probable diagnoses given as per cent confidence (95%, 75%, 50%, 25% and 5%, totalling 100%). We used a ≥75% confidence in the diagnosis of IAC to determine sensitivity and specificity for that condition. The κ statistic for intra- and inter-observer agreement was also calculated.ResultsThe specificity of ERC for detecting IAC was high and did not differ significantly between centres (Abstract 061), but sensitivity was uniformly low. Neither reviewer speciality (endoscopist, radiologist, HPB physician) nor years of experience had any statistically significant effect on reporting success. Although intraobserver agreement was generally very good, interobserver agreement was poor (Abstract 061). Abstract PTU-061AllUSAUKJapann=18n=4n=8n=6Sensitivity for IAC (CI)45% (36 to 54%)51% (25 to 78%)42% (25 to 59%)44% (24 to 64%)Specificity for IAC (CI)88% (83 to 93%)88% (68 to 100%)86% (77 to 95%)90% (82 to 98%)Interobs agreement for IAC (κ)0.18−0.020.180.17 ConclusionHigh specificity for diagnosing IAC using ERC suggests that particular cholangiographic features support the diagnosis. However, poor sensitivity suggests that, based on ERC, many patients with IAC, who might benefit from steroid therapy, may be misdiagnosed with PSC or CCA. Additional diagnostic strategies, including pathological sampling, are likely to be vital in distinguishing these diseases.