SerpinB3 as hepatic marker of post-resective shear stress

Post-resective liver failure is a frequent complication of liver surgery and it is due to portal hyperperfusion of the remnant liver and to arterial vasoconstriction, as buffer response of the hepatic artery. In this context, splenectomy allows a reduction of portal flow and increases the survival chance in preclinical models. SerpinB3 is over-expressed in the liver in oxidative stress conditions, as a mechanism of cell defense to provide survival by apoptosis inhibition and cell proliferation. In this study, the expression of SerpinB3 was assessed as predictor of liver damage in in vivo models of major hepatic resection with or without splenectomy. Wistar male rats were divided into 4 groups: group A received 30% hepatic resection, group B > 60% resection, group C > 60% resection with splenectomy and group D sham-operated. Before and after surgery liver function tests, echo Doppler ultrasound and gene expression were assessed. Transaminase values and ammonium were significantly higher in groups that underwent major hepatic resection. Echo Doppler ultrasound showed the highest portal flow and resistance of the hepatic artery in the group with > 60% hepatectomy without splenectomy, while the association of splenectomy determined no increase in portal flow and hepatic artery resistance. Only the group of rats without splenectomy showed higher shear-stress conditions, reflected by higher levels of HO-1, Nox1 and of Serpinb3, the latter associated with an increase of IL-6. In conclusion, splenectomy controls inflammation and oxidative damage, preventing the expression of Serpinb3. Therefore, SerpinB3 can be considered as a marker of post-resective shear stress

Serum Albumin Is Inversely Associated With Portal Vein Thrombosis in Cirrhosis

We analyzed whether serum albumin is independently associated with portal vein thrombosis (PVT) in liver cirrhosis (LC) and if a biologic plausibility exists. This study was divided into three parts. In part 1 (retrospective analysis), 753 consecutive patients with LC with ultrasound-detected PVT were retrospectively analyzed. In part 2, 112 patients with LC and 56 matched controls were entered in the cross-sectional study. In part 3, 5 patients with cirrhosis were entered in the in vivo study and 4 healthy subjects (HSs) were entered in the in vitro study to explore if albumin may affect platelet activation by modulating oxidative stress. In the 753 patients with LC, the prevalence of PVT was 16.7%; logistic analysis showed that only age (odds ratio [OR], 1.024; P = 0.012) and serum albumin (OR, -0.422; P = 0.0001) significantly predicted patients with PVT. Analyzing the 112 patients with LC and controls, soluble clusters of differentiation (CD)40-ligand (P = 0.0238), soluble Nox2-derived peptide (sNox2-dp; P < 0.0001), and urinary excretion of isoprostanes (P = 0.0078) were higher in patients with LC. In LC, albumin was correlated with sCD4OL (Spearman's rank correlation coefficient [r(s)], -0.33; P < 0.001), sNox2-dp (r(s), -0.57; P < 0.0001), and urinary excretion of isoprostanes (r(s), -0.48; P < 0.0001) levels. The in vivo study showed a progressive decrease in platelet aggregation, sNox2-dp, and urinary 8-iso prostaglandin F2 alpha-III formation 2 hours and 3 days after albumin infusion. Finally, platelet aggregation, sNox2-dp, and isoprostane formation significantly decreased in platelets from HSs incubated with scalar concentrations of albumin. Conclusion: Low serum albumin in LC is associated with PVT, suggesting that albumin could be a modulator of the hemostatic system through interference with mechanisms regulating platelet activation

The Glucosamine-derivative NAPA Suppresses MAPK Activation and Restores Collagen Deposition in Human Diploid Fibroblasts Challenged with Environmental Levels of UVB

The Ultraviolet (UV) component of solar radiation is the driving force of life on earth but it can cause photoaging and skin cancer. In this study we investigated the effects of the glucosamine-derivative 2-(N-Acetyl)-L-phenylalanylamido-2-deoxy-β-D-glucose (NAPA) on human primary fibroblasts (FBs) stimulated in vitro with environmental levels of UVB radiation. FBs were irradiated with 0,04 J/cm2 UVB dose, which resulted a mild dosage as shown by the cell viability and ROS production measurement. This environmental UVB dose induced activation of MAP kinase ERK 1/2, the stimulation of c-fos and at lower extent of c-jun, and in turn AP-1-dependent up-regulation of pro-inflammatory factors IL-6 and IL-8 and suppression of Collagen type I expression. On the contrary, 0,04 J/cm2 UVB dose was not able to stimulate metalloprotease production. NAPA treatment was able to suppress the up-regulation of IL-6 and IL-8 via the inhibition of MAP kinase ERK phosphorylation and the following AP-1 activation, and was able to attenuates the Collagen type I down-regulation induced by the UVBs. Taken together our results show that NAPA, considering its dual action on suppression of inflammation and stimulation of Collagen type I production, represents an interesting candidate as a new photoprotective and photorepairing agent

Protein Oxidative Damage in UV-Related Skin Cancer and Dysplastic Lesions Contributes to Neoplastic Promotion and Progression

The ultraviolet (UV) component of solar radiation is the major driving force of skin carcinogenesis. Most of studies on UV carcinogenesis actually focus on DNA damage while their proteome-damaging ability and its contribution to skin carcinogenesis have remained largely underexplored. A redox proteomic analysis of oxidized proteins in solar-induced neoplastic skin lesion and perilesional areas has been conducted showing that the protein oxidative burden mostly concerns a selected number of proteins participating to a defined set of functions, namely: chaperoning and stress response; protein folding/refolding and protein quality control; proteasomal function; DNA damage repair; protein- and vesicle-trafficking; cell architecture, adhesion/extra-cellular matrix (ECM) interaction; proliferation/oncosuppression; apoptosis/survival, all of them ultimately concurring either to structural damage repair or to damage detoxication and stress response. In peri-neoplastic areas the oxidative alterations are conducive to the persistence of genetic alterations, dysfunctional apoptosis surveillance, and a disrupted extracellular environment, thus creating the condition for transformant clones to establish, expand and progress. A comparatively lower burden of oxidative damage is observed in neoplastic areas. Such a finding can reflect an adaptive selection of best fitting clones to the sharply pro-oxidant neoplastic environment. In this context the DNA damage response appears severely perturbed, thus sustaining an increased genomic instability and an accelerated rate of neoplastic evolution. In conclusion UV radiation, in addition to being a cancer-initiating agent, can act, through protein oxidation, as a cancer-promoting agent and as an inducer of genomic instability concurring with the neoplastic progression of established lesions

Hypoalbuminemia and Risk of Portal Vein Thrombosis in Cirrhosis.

Background and Aims Hypoalbuminemia, as defined by serum albumin (SA) levels ≤35 g/L, is associated to venous and arterial thrombosis in general population and in patients at risk of cardiovascular disease. It is unknown if SA ≤35 g/L is also associated to portal vein thrombosis (PVT) in cirrhosis. Methods Cirrhotic patients enrolled in the Portal vein thrombosis Relevance On Liver cirrhosis: Italian Venous thrombotic Events Registry (PRO-LIVER) study (n = 753), were followed-up for 2 years to assess the risk of PVT, that was diagnosed by Doppler ultrasonography. Child-Pugh classes, Model for End-Stage Liver Disease score, presence of hepatocellular carcinoma and laboratory variables including SA, D-dimer, and high-sensitivity C-reactive protein (hs-CRP) were measured at baseline. Results SA ≤35 g/L was detected in 52% of patients. A logistic multivariate regression analysis showed that higher Child-Pugh class, hepatocellular carcinoma and thrombocytopenia were significantly associated to SA ≤35 g/L. In a subgroup of patients where data regarding hs-CRP and D-dimer were available, SA ≤35 g/L was inversely associated with hs-CRP and D-dimer. During the follow-up, a total of 61 patients experienced PVT. A Kaplan Meier survival analysis showed SA ≤35 g/L was associated to increased risk of PVT compared to SA >35 g/L (P = .005). A multivariate Cox proportional hazards regression analysis showed that male sex, lower platelet count, and SA ≤35 g/L remained associated to PVT after adjusting for confounding factors. Conclusion Cirrhotic patients with SA ≤35 g/L are at higher risk of experiencing PVT compared to those with SA >35 g/L and could be considered as potential candidates to anticoagulant prophylaxis for PVT prevention

Erratum to: Portal vein thrombosis relevance on liver cirrhosis: Italian Venous Thrombotic Events Registry (Intern Emerg Med, 10.1007/s11739-016-1416-8)

In the original publication, the second author name was incorrectly published as Roberto Gino Corazza. The correct name should read as \u201cGino Roberto Corazza\u201d. Also, the PRO-LIVER Study Collaborator, Dr. Gabriella Carnevale Maff\ue8 has not been included in the Appendix by mistake. The name of Dr. Carnevale Maffe` should read in the Appendix as follows: Bergamaschi Gaetano, Carnevale Maff\ue8 Gabriella, Masotti Michela, Costanzo Filippo (I\ub0 Clinica Medica, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Italy)

Incidence and Recurrence of Portal Vein Thrombosis in Cirrhotic Patients

Cirrhosis has been long considered a risk factor for bleeding due to the co-existence of the so-called \u2018coagulopathy\u2019. More recently, however, compelling evidences have been provided on the occurrence of thrombotic events in the portal and systemic circulation.3\u20135 Portal vein thrombosis (PVT) is predominantly observed in patients with moderate to severe liver failure with a variable prevalence ranging from 0.6 to 25%. Only fewstudies have provided a longitudinal assessment of the PVT incidence and its sequelae, including recurrence and survival.9\u201314 Due to the variability of PVT incidence and the paucity of data regarding recurrence and survival,15\u201320 we prospectively analysed the incidence and the recurrence of PVT in the population of Portal vein thrombosis Relevance On Liver cirrhosis: ItalianVenous thromboticEventsRegistry (PROLIVER), a multi-centre study,8 which involved 43 enrolling centres in Italy (ClinicalTrials.gov Identifier: NCT01470547)

Platelet Count Does Not Predict Bleeding in Cirrhotic Patients: Results from the PRO-LIVER Study.

OBJECTIVES: Thrombocytopenia is a hallmark for patients with cirrhosis and it is perceived as a risk factor for bleeding events. However, the relationship between platelet count and bleeding is still unclear. METHODS: We investigated the relationship between platelet count and major or clinical relevant nonmajor bleedings during a follow-up of ∼4 years. RESULTS: A total of 280 cirrhotic patients with different degrees of liver disease (67% males; age 64±37 years; 47% Child-Pugh B and C) were followed up for a median of 1,129 (interquartile range: 800-1,498) days yielding 953.12 patient-year of observation. The annual rate of any significant bleeding was 5.45%/year (3.57%/year and 1.89%/year for major and minor bleeding, respectively). Fifty-two (18.6%) patients experienced a major (n=34) or minor (n=18) bleeding event, predominantly from gastrointestinal origin. Platelet counts progressively decreased with the worsening of liver disease and were similar in patients with or without major or minor bleeding: a platelet count ≤50 × 103/μl was detected in 3 (6%) patients with and in 20 (9%) patients without any bleeding event. Conversely, prothrombin time-international normalized ratio was slightly higher in patients with overall or major bleeding. On Cox proportional hazard analysis, only a previous gastrointestinal bleeding (hazard ratio (HR): 1.96; 95% confidence interval: 1.11-3.47; P=0.020) and encephalopathy (HR: 2.05; 95% confidence interval: 1.16-3.62; P=0.013) independently predicted overall bleeding events. CONCLUSIONS: Platelet count does not predict unprovoked major or minor bleeding in cirrhotic patients

Platelet count does not predict bleeding in cirrhotic patients: Results from the PRO-LIVER Study

OBJECTIVES: Thrombocytopenia is a hallmark for patients with cirrhosis and it is perceived as a risk factor for bleeding events. However, the relationship between platelet count and bleeding is still unclear. METHODS: We investigated the relationship between platelet count and major or clinical relevant nonmajor bleedings during a follow-up of \ue2\u88\ubc4 years. RESULTS: A total of 280 cirrhotic patients with different degrees of liver disease (67% males; age 64\uc2\ub137 years; 47% Child\ue2\u80\u93Pugh B and C) were followed up for a median of 1,129 (interquartile range: 800\ue2\u80\u931,498) days yielding 953.12 patient-year of observation. The annual rate of any significant bleeding was 5.45%/year (3.57%/year and 1.89%/year for major and minor bleeding, respectively). Fifty-two (18.6%) patients experienced a major (n=34) or minor (n=18) bleeding event, predominantly from gastrointestinal origin. Platelet counts progressively decreased with the worsening of liver disease and were similar in patients with or without major or minor bleeding: a platelet count \ue2\u89\ua450\uc3\u97103/\uce\ubcl was detected in 3 (6%) patients with and in 20 (9%) patients without any bleeding event. Conversely, prothrombin time-international normalized ratio was slightly higher in patients with overall or major bleeding. On Cox proportional hazard analysis, only a previous gastrointestinal bleeding (hazard ratio (HR): 1.96; 95% confidence interval: 1.11\ue2\u80\u933.47; P=0.020) and encephalopathy (HR: 2.05; 95% confidence interval: 1.16\ue2\u80\u933.62; P=0.013) independently predicted overall bleeding events. CONCLUSIONS: Platelet count does not predict unprovoked major or minor bleeding in cirrhotic patients

Relation between drug therapy-based comorbidity indices, Charlson's comorbidity index, polypharmacy and mortality in three samples of older adults.

Background: Comorbidity indexes were designed in order to measure how the disease burden of a patient is related to different clinical outcomes such as mortality, especially in older and intensively treated people. Charlson's Comorbidity Index (CCI) is the most widely used rating system, based on diagnoses, but when this information is not available therapy-based comorbidity indices (TBCI) are an alternative: among them, Drug Derived Complexity Index (DDCI), Medicines Comorbidity Index (MCI), and Chronic Disease Score (CDS) are available. Aims: This study assessed the predictive power for 1-year mortality of these comorbidity indices and polypharmacy. Methods: Survival analysis and Receiver Operating Characteristic (ROC) analysis were conducted on three Italian cohorts: 2,389 nursing home residents (Korian), 4,765 and 633 older adults admitted acutely to geriatric or internal medicine wards (REPOSI and ELICADHE). Results: Cox's regression indicated that the highest levels of the CCI are associated with an increment of 1-year mortality risk as compared to null score for all the three samples. DDCI and excessive polypharmacy gave similar results but MCI and CDS were not always statistically significant. The predictive power with the ROC curve of each comorbidity index was poor and similar in all settings. Conclusion: On the whole, comorbidity indices did not perform well in our three settings, although the highest level of each index was associated with higher mortality