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Circulating endothelial cells (CEC) represent a restricted peripheral blood (PB) cell subpopulation with high potential diagnostic value in many endothelium-involving diseases. However, whereas the interest in CEC studies has grown, the standardization level of their detection has not. Here, we undertook the task to align CEC phenotypes and counts, by standardizing a novel flow cytometry approach, within a network of six laboratories. CEC were identified as alive/nucleated/CD45negative/CD34bright/CD146positive events and enumerated in 269 healthy PB samples. Standardization was demonstrated by the achievement of low inter-laboratory Coefficients of Variation (CVL), calculated on the basis of Median Fluorescence Intensity values of the most stable antigens that allowed CEC identification and count (CVL of CD34bright on CEC ~ 30%; CVL of CD45 on Lymphocytes ~ 20%). By aggregating data acquired from all sites, CEC numbers in the healthy population were captured (medianfemale = 9.31 CEC/mL; medianmale = 11.55 CEC/mL). CEC count biological variability and method specificity were finally assessed. Results, obtained on a large population of donors, demonstrate that the established procedure might be adopted as standardized method for CEC analysis in clinical and in research settings, providing a CEC physiological baseline range, useful as starting point for their clinical monitoring in endothelial dysfunctions.

Thyroid hormone receptors (TRs) are ligand-dependent transcription factors that mediate most of the effects elicited by the thyroid hormone, 3,5,3 0 -L-triiodothyronine (T3). TRs have been implicated in tumorigenesis, although it is unclear whether they act as oncogenes or tumor suppressors, and at which stage of tumorigenesis their dysregulation occurs. Using the resistant-hepatocyte rat model (R-H model), we found downregulation of TRb1 and TRa1 and their target genes in early preneoplastic lesions and hepatocellular carcinoma (HCCs), suggesting that a hypothyroid status favors the onset and progression of preneoplastic lesions to HCC. Notably, TRb1 and, to a lesser extent, TRa1 down-regulation was observed only in preneoplastic lesions positive for the progenitor cell marker, cytokeratin-19 (Krt-19) and characterized by a higher proliferative activity, compared to the Krt-19 negative ones. TRb1 down-regulation was observed also in the vast majority of the analyzed human HCCs, compared to the matched peritumorous liver or to normal liver. Hyperthyroidism induced by T3 treatment caused up-regulation of TRb1 and of its target genes in 1 preneoplastic rat lesions and was associated with nodule regression. In HCC, TRb1 down-regulation was not the result of hypermethylation of its promoter, but was associated with an increased expression of TRb1-targeting microRNAs ([miR]-27a, -181a, and -204). An inverse correlation between TRb1 and miR-181a was also found in human cirrhotic peritumoral tissue, compared to normal liver. Conclusion: Down-regulation of TRs, especially TRb1, is an early and relevant event in liver cancer development and is species and etiology independent. The results also suggest that a hypothyroid status of preneoplastic lesions may contribute to their progression to HCC and that the reversion of this condition may represent a possible therapeutic goal to interfere with the development of this tumor. (HEPATOLOGY 2015;61:249-259) T he thyroid hormones, 3,5,3 0 -triiodo-L-thyronine (T3) and thyroxine (T4), influence a variety of physiological processes.1,2 Most of the effects of T3 are mediated by thyroid hormone nuclear receptors (TRs), which are members of the steroid/thyroid receptor superfamily of nuclear hormone receptors, acting as transcription factors.

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This study aims to validate a tool, the Bologna healing stifle injury index (BHSII), for the evaluation of the clinical picture and the healing after surgical treatment for cranial cruciate ligament (CCL) rupture. The study included 158 client-owned dogs with CCL rupture and 20 healthy dogs. The BHSII is a questionnaire made up of 34 multiple-choice questions, divided into a part directed to the clinician and a part for the dog's owners. It was applied twice in the healthy dogs in order to test and retest the device. It was evaluated for reliability, validity, and responsiveness to clinical changes involving the dogs treated at the time of surgery, and 1, 3, and 6 months postoperatively. Statistical analyses were performed and the intraclass correlation coefficient test was ≥0.9 and the Cronbach-α was 0.84 suggesting good stability and good internal consistency of the tool. The area under the curve of the receiver operating characteristic curve was >0.9, indicative of the high accuracy of this tool. The clinician survey correlated with the owner questionnaire. In dogs with CCL rupture, the scores of the BHSII increased significantly postoperatively as compared with baseline. In conclusion, this clinical study proved the reliability, validity, and responsiveness of the BHSII. The results achieved from the BHSII provided an instantaneous, collective complete vision of the healing process of the stifle joints treated. It can be considered a valid tool for collecting data and for assessing successful surgical treatment in clinical practice.

A large number of real networks are characterized by two fundamental properties: they are small world and scale-free. A recent paper demonstrated that the structure of many complex networks is also self-similar under a length-scale transformation, and calculated their fractal dimension using the "box counting" method. We studied nine large object-oriented software systems, finding that the graphs associated to these networks are self-similar. We also studied the time evolution of the fractal dimension during system growth, finding a significant correlation between the fractal dimension and object-oriented complexity metrics known to be correlated with software fault-proneness. Thus, in software systems the fractal dimension could be considered as a measure of internal complexity, and consequently of the system quality.( 1 )See Supplementary Information of paper [2].c EDP Sciences Article published by EDP Sciences and available at http://www.edpsciences.org/epl or http://dx.

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