Despite its high prevalence and mortality, little is known about the pathogenesis of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Given that familial pulmonary fibrosis (FPF) and RA-ILD frequently share the usual pattern of interstitial pneumonia and common environmental risk factors, we hypothesised that the two diseases might share additional risk factors, including FPF-linked genes. Our aim was to identify coding mutations of FPF-risk genes associated with RA-ILD.We used whole exome sequencing (WES), followed by restricted analysis of a discrete number of FPF-linked genes and performed a burden test to assess the excess number of mutations in RA-ILD patients compared to controls.Among the 101 RA-ILD patients included, 12 (11.9%) had 13 WES-identified heterozygous mutations in the ,, or coding regions The burden test, based on 81 RA-ILD patients and 1010 controls of European ancestry, revealed an excess of ,, or mutations in RA-ILD patients (OR 3.17, 95% CI 1.53-6.12; p=9.45×10). Telomeres were shorter in RA-ILD patients with a , or mutation than in controls (p=2.87×10).Our results support the contribution of FPF-linked genes to RA-ILD susceptibility.

No abstract

Radioiodine therapy of nonthyroid cancers after sodium iodide symporter (NIS) gene delivery has been proposed as a potential application of gene therapy. However, it seems to be precluded by the rapid efflux of taken up iodine from most transduced xenografted tumors. We present an in vivo kinetic study of NIS-related hepatic iodine uptake in an aggressive model of hepatocarcinoma induced by diethylnitrosamine in immunocompetent Wistar rats. We followed the whole-body iodine distribution by repeated imaging of live animals. We constructed a rat NIS (rNIS) adenoviral vector, Ad-CMV-rNIS, using the cytomegalovirus (CMV) as a promoter. Injected in the portal vein in 5 healthy and 25 hepatocarcinoma-bearing rats and liver tumors in 9 hepatocarcinoma-bearing rats, Ad-CMV-rNIS drove expression of a functional NIS protein by hepatocytes and allowed marked (from 20 to 30% of the injected dose) and sustained (>11 days) iodine uptake. This contrasts with the massive iodine efflux found in vitro in human hepatic tumor cell lines. In vivo specific inhibition of NIS by sodium perchlorate led to a rapid iodine efflux from the liver, indicating that the sustained uptake was not attributable to an active retention mechanism but to permanent recycling of the effluent radioiodine via the high hepatic blood flow. Radioiodine therapy after Ad-CMV-rNIS administration achieved a strong inhibition of tumor growth, the complete regression of small nodules, and prolonged survival of hepatocarcinoma-bearing rats. This demonstrates for the first time the efficacy of NIS-based radiotherapy in a relevant preclinical model of nonthyroid human carcinogenesis.

Low-dose terlipressin in fluid-challenged endotoxic rats improved systemic and splanchnic hemodynamics and improved the ileal microcirculation.

No abstract

The noninvasive evaluation of liver fibrosis is a major clinical goal in liver diseases. Our aim was to identify MRI parameters to quantify liver fibrosis in vivo in an animal model of liver fibrosis with slight inflammation. We evaluated serum hyaluronate, liver hydroxyproline, area of liver fibrosis (image analysis), and 1.5-T MRI in 10 sham rats and 24 bile duct ligated rats with different stages of liver fibrosis. Liver signal intensity (SI)/muscle SI ratio and liver relaxation times (rT) were measured on T1 and T2 weighted sequences at different echo (TE) or recovery (RT) times of MRI. Among the 66 MRI parameters tested, the highest correlation with the area of fibrosis was observed for rT2 (r=0.78, P < 0.01). The area of liver fibrosis was independently predicted by five MRI variables (adjusted R (2)=0.78, with R (2)=0.64 for rT2 and rT1). Diagnostic accuracy for liver fibrosis was 100% using two variables: liver/muscle SI ratio on T2 at 30-ms TE and liver/muscle SI ratio on T1 at 50-ms RT. We conclude that in this animal model, fibrosis could be diagnosed with an accuracy of 100% using two MRI parameters. The quantification of liver fibrosis was very accurate either with only one MRI parameter (r=0.78 for rT2) or with five parameters (r=0.90) in this cholestatic model.

Fractal analysis measures the complexity of geometric structures. The aim of this study was to evaluate the feasibility and accuracy of fractal analysis in liver fibrosis. A total of 77 rats were included: 10 sham, 46 with fibrosis secondary to bile duct ligation (BDL), and 21 with fibrosis due to CCl 4 intoxication. Measurements included the fractal dimension of Kolmogorov (D k ), histologic lesions, the area of fibrosis by image analysis, liver hydroxyproline content, messenger RNA fibronectin, serum hyaluronate level, and portal pressure. Fibrotic rats were given placebo, octreotide, or O 2 -vinyl 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (V-PYRRO/NO). Intraobserver agreement of D k was excellent with the intraclass (ic) correlation coefficient r ic ‫؍‬ 0.91 (P < .0001) as well as the interobserver agreement with r ic ‫؍‬ 0.88 (P < .001). D k was correlated with other measurements or markers of fibrosis: the area of fibrosis (r ‫؍‬ 0.75; P < .0001), hydroxyproline content (r ‫؍‬ 0.51; P < .001), serum hyaluronate level (r ‫؍‬ 0.52; P < .001), and portal pressure (r ‫؍‬ 0.52; P < .01). D k was significantly different between the 2 models of fibrosis (P < .0001), unlike the area of fibrosis, and this relationship was independent of other histologic lesions. The significant decrease in fibrosis observed with octreotide or V-PYRRO/NO was similarly reflected by D k or the area of fibrosis. The diagnostic accuracy for the fibrosis model was 97% with the 5 main measurements or markers of fibrosis studied, with D k isolated at the first step by stepwise analysis. In conclusion, fractal analysis is suitable for analyzing liver fibrosis and has excellent reproducibility. This is the only quantitative morphometric method that can discriminate among the models of fibrosis and is sensitive enough to detect pharmacologically induced changes in liver fibrosis. (HEPATOLOGY 2002;36:840-849.)

A resident pharmacist detected various DRPs. Most PIs were accepted. DRPs related to the misuse of the CPOE system appeared potentially dangerous and need particular attention by healthcare professionals. The description of the DRPs is an essential step for implementation of targeted clinical pharmacy services in order to optimize pharmacists' job time.