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Sant'Ambrogio di Torino, Italy

Biasi F.,University of Turin | Guina T.,University of Turin | Maina M.,University of Turin | Nano M.,University of Turin | And 6 more authors.
PLoS ONE | Year: 2012

Background: Inflammatory reactions, known to promote tumor growth and invasion, have been found associated with colorectal carcinoma (CRC). Macrophages are the chief component of the inflammatory infiltration that occurs early in the progression from non-invasive to malignant tumor, with a switch from the pro-inflammatory phenotype to the tumor-promoting phenotype. Tumor and stroma are additional sources of inflammation-related molecules. The study aimed to evaluate, during colorectal carcinogenesis from benign to malignant phases: i) the trend of serum levels of IL-8, IL-6, TGFβ1, VEGF and MMPs; ii) the parallel trend of CRP serum levels; iii) derangement of the principal TGFβ1 receptors (TGFβ1RI/RII) in tumor tissues. Methodology/Principal findings: 96 patients with colon adenomas or CRC at different stages of progression, and 17 controls, were recruited. Serum IL-8, IL-6, TGFβ1, VEGF, MMPs and CRP levels were analyzed before endoscopy or surgery. TGFβ1 receptors were evaluated in adenoma biopsies and surgically-removed colorectal adenocarcinomas. Serum levels of IL-8 in adenocarcinoma patients were increased from stage II, when also the enzymatic activity of MMP-9 increased. Of note, the increasing trend of the two serum markers was found significantly correlated. Trend of serum CRP was also very similar to that of IL-8 and MMP-9, but just below statistical significance. TGFβ1 levels were lower at stage III CRC, while IL-6 and VEGF levels had no significant variations. In tissue specimens, TGFβ1 receptors were already absent in about 50% of adenomas, and this percentage of missing receptors markedly increased in CRC stages III and IV. Conclusions: Combined quantification of serum IL-8, MMP-9 and CRP, appears a reliable and advanced index of inflammation-related processes during malignant phase of colorectal carcinogenesis, since these molecules remain within normal range in colorectal adenoma bearing patients, while consistently increase in the blood of CRC patients, even if from stage II only. © 2012 Biasi et al. Source

Sansoe G.,Gradenigo Hospital | Aragno M.,University of Turin | Mastrocola R.,University of Turin | Mengozzi G.,Clinical Biochemistry Laboratory | Parola M.,University of Turin
PLoS ONE | Year: 2016

Background: In human cirrhosis, adrenergic hyperfunction causes proximal tubular fluid retention and contributes to diuretic-resistant ascites, and clonidine, a sympatholytic drug, improves natriuresis in difficult-to-treat ascites. Aim: To compare clonidine (aspecific α2-adrenoceptor agonist) to SSP-002021R (prodrug of guanfacine, specific α2A-receptor agonist), both associated with diuretics, in experimental cirrhotic ascites. Methods and Results: Six groups of 12 rats were studied: controls (G1); controls receiving furosemide and potassium canrenoate (G2); rats with ascitic cirrhosis due to 14-week CCl4 treatment (G3); cirrhotic rats treated (over the 11th-14th CCl4 weeks) with furosemide and canrenoate (G4), furosemide, canrenoate and clonidine (G5), or diuretics and SSP002021R (G6). Three rats of each group had their hormonal status and renal function assessed at the end of 11th, 12th, 13th, and 14th weeks of respective treatments.Cirrhotic rats in G3 and G4 gained weight over the 12th-14th CCl4 weeks. In G4, brief increase in sodium excretion over the 11th-12th weeks preceded worsening of inulin clearance and natriuresis (diuretic resistance). In comparison with G4, the addition of clonidine (G5) or guanfacine (G6) to diuretics improved, respectively, sodium excretion over the 11th-12th CCl4 weeks, or GFR and electrolytes excretion over the 13th-14th CCl4 weeks. Natriuretic responses in G5 and G6 were accompanied by reduced catecholamine serum levels. Conclusions: α2A-receptor agonists restore glomerular filtration rate and natriuresis, and delay diureticresistant ascites in experimental advanced cirrhosis. Clonidine ameliorates diuretic-dependent natriuresis just for a short time. © 2016 Sansoè et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Source

Sharma P.,University of Aberdeen | Boyers D.,University of Aberdeen | Boachie C.,University of Aberdeen | Stewart F.,University of Aberdeen | And 5 more authors.
Health Technology Assessment | Year: 2012

Background: Familial hypercholesterolemia (FH) is an autosomal dominant genetic condition causing a high risk of coronary heart disease. The prevalence of this disease is about 1 in 500 in the UK, affecting about 120,000 people across the whole of the UK. Current guidelines recommend DNA testing, however, these guidelines are poorly implemented, therefore 102,000 or 85% of this group remain undiagnosed. Objectives: To assess the diagnostic accuracy, effect on patient outcomes and costeffectiveness of Elucigene FH20 and LIPOchip for the diagnosis of FH. Data sources: Electronic databases including MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, BIOSIS, Science Citation Index, Conference Proceedings Citation Index - Science and Cochrane Controlled Trials Register were searched until January 2011. Review methods: A systematic review of the literature on diagnostic accuracy was carried out according to standard methods. An economic model was constructed to assess the cost-effectiveness of alternative diagnostic strategies for the confirmation of clinically diagnosed FH in index cases and for the identification and subsequent testing of first-, second- and possibly third-degree biological relatives of the index case. Twelve strategies were evaluated linking diagnostic accuracy to treatment outcomes and hence qualityadjusted life-years (QALYs). Deterministic and probabilistic sensitivity analyses were undertaken to investigate model and parameter uncertainty. Results: Fifteen studies were included for diagnostic accuracy; three reported Elucigene FH20, five reported LIPOchip, four reported low-density lipoprotein cholesterol (LDL-C) tests and three reported an age- and gender-specific LDL-C test against a reference standard of comprehensive genetic analysis (CGA). Sensitivity ranged from 44% to 52% for Elucigene FH20 and from 33.3% to 94.5% for various versions of LIPOchip in detecting FH-causing mutations in patients with a clinical diagnosis of FH. For LIPOchip version 10 (designed to detect 189 UK specific mutations), sensitivity would be 78.5% (based on single-centre data - Progenika, personal communication). For all other Elucigene FH20 or LIPOchip studies (apart from one LIPOchip study), specificity could not be calculated as no false-positive results could be derived from the given data. The LDL-C test was generally reported to be highly sensitive but with low specificity. For age- and gender-specific LDL-C cut-offs for cascade testing, sensitivity ranged from 68% to 96%. One UK-based study reported sensitivity of 91% and specificity of 93%. For the cost-effectiveness review, only one study reporting cost-effectiveness of any one of the comparators for this assessment was identified. Pre-screen strategies such as Elucigene FH20 followed by CGA were not cost-effective and were dominated by the single more comprehensive tests (e.g. CGA). Of the non-dominated strategies, Elucigene FH20, LIPOchip platform (Spain) and CGA were all cost-effective with associated incremental cost-effectiveness ratios (ICERs) relative to LDL-C of dominance (test is less costly and more effective), £871 and £1030 per QALY gained respectively. CGA generates the greatest QALY gain and, although other tests have lower ICERs relative to LDL-C, this is at the expense of QALY loss compared with the CGA test. Probabilistic sensitivity analysis shows that CGA is associated with an almost 100% probability of cost-effectiveness at the conventional value of willingness to pay of £20,000 per QALY gain. Limitations: There was much uncertainty regarding the diagnostic accuracy of the included tests, with wide variation in sensitivity across reported studies. A lack of published information for the most recent version of LIPOchip created additional uncertainty, especially in relation to the chip's ability to detect copy number changes. For the economic modelling, we aimed to choose the best studies for the base-case sensitivity of the tests; however, a number of informed choices based on clinical expert opinion had to be made in the absence of published studies for a number of other parameters in the modelling. This adds some uncertainty to our results, although it is unlikely that these would be sufficient in magnitude to alter our main results and conclusions. Conclusions: As targeted tests designed to detect a limited number of genetic mutations, Elucigene FH20 and LIPOchip cannot detect all cases of FH, in contrast with CGA. CGA is therefore the most effective test in terms of sensitivity and QALY gain, and is also highly cost-effective with an associated ICER of £1030 per QALY gain relative to current practice (LDL-C). Other tests such as Elucigene FH20 and LIPOchip are also cost-effective; however, because of inferior sensitivity compared with CGA, these tests offer cost savings but at the expense of large QALY losses compared with CGA. Further prospective multicentred studies are required to evaluate the diagnostic accuracy of new and emerging tests for FH with the LDL-C test in patients with a clinical diagnosis based on the Simon Broome criteria. Such studies should verify both test-positive and -negative results against a reference standard of CGA and should include a full economic evaluation. Funding: The National Institute for Health Research Health Technology Assessment programme. © Queen's Printer and Controller of HMSO 2012. Source

Castro-Santos P.,Autonomous University of Chile | Laborde C.M.,Clinical Biochemistry Laboratory | Diaz-Pena R.,Autonomous University of Chile | Diaz-Pena R.,Hospital Universitario Central Of Asturias
Clinical and Experimental Rheumatology | Year: 2015

Rheumatoid arthritis (RA) is an autoimmune inflammatory rheumatic disease which affects several organs and tissues, predominantly the synovial joints. Despite major advances, the aetiology of this disease is not completely understood. Although several biomarkers are routinely used in RA management and some of them can be detected even prior to the onset of the clinical disease, there is a high demand for novel biomarkers to further improve the early diagnosis of RA. The '-omics' techniques that have emerged and have been developed in recent years have allowed researchers to improve their knowledge of the aetiopathology of RA. At the same time, advances in screening technologies offer an excellent opportunity to find new biomarkers potentially useful for early diagnosis, stratification of patients, and even prediction of a better response to a specific therapy. This review describes what is known about the methodologies used in the discovery of novel biomarkers in RA, along with the findings of these methodologies, with specific attention to recent advances in the fields of genomics, proteomics and metabolomics. © Clinical and Experimental Rheumatology 2015. Source

Giordano R.,University of Turin | Marzotti S.,University of Perugia | Berardelli R.,University of Turin | Karamouzis I.,University of Turin | And 10 more authors.
Clinical Endocrinology | Year: 2012

Object Although glucocorticoids are essential for health, several studies have shown that glucocorticoids replacement in Addison's disease might be involved in anthropometric and metabolic impairment, with increased cardiovascular risk, namely if conventional doses are used. As the effects of glucocorticoids are mediated by the glucocorticoid receptor, encoded by NR3C1 gene, different polymorphisms in the NR3C1 gene have been linked to altered glucocorticoid sensitivity in general population as well as in patients with obesity or metabolic syndrome. Design We investigated the impact of glucocorticoid receptor gene polymorphisms, including the BclI, N363S and ER22/23EK variants, on anthropometric parameters (BMI and waist circumference), metabolic profile (HOMA, OGTT and serum lipids) and ACTH levels in 50 patients with Addison's disease (34 women and 16 men, age 20-82 year) under glucocorticoids replacement. Results Neither N363S nor ER22/23EK variants were significantly associated with anthropometric, metabolic or hormonal parameters, while patients carrying the homozygous BclI polymorphism GG (n = 4) showed higher (P < 0·05) BMI, waist circumference, HOMA and 2-h glucose levels after OGTT, as well as total cholesterol and triglycerides than those with wild-type genotype CC (n = 28) or heterozygous CG (n = 18). The totality of GG patients was connoted by abdominal adiposity, impaired glucose tolerance/diabetes mellitus or dyslipidaemia, while a lower percentage of CC or CG patients showed some anthropometric and metabolic alterations. Conclusion These results suggest that BclI polymorphism may influence the sensitivity to glucocorticoids in patients with Addison's disease and may contribute, along with other factors, to the increase in central adiposity, impaired glucose metabolism and dyslipidaemia. © 2012 Blackwell Publishing Ltd. Source

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