Liver Angiopoietin-2 Is a Key Predictor of De Novo or Recurrent Hepatocellular Cancer After Hepatitis C Virus Direct-Acting Antivirals.

Recent reports suggested that direct acting antivirals (DAAs) might favor hepatocellular carcinoma (HCC). In study 1, we studied the proangiogenic liver microenvironment in 242 DAA-treated chronic hepatitis C patients with advanced fibrosis. Angiopoietin-2 (ANGPT2) expression was studied in tissue (cirrhotic and/or neoplastic) from recurrent, de novo, nonrecurrent HCC, or patients never developing HCC. Circulating ANGPT2,vascular endothelial growth factor (VEGF), and C-reactive protein (CRP) were also measured. In study 2, we searched for factors associated with de novo HCC in 257 patients with cirrhosis of different etiologies enrolled in a dedicated prospective study. Thorough biochemical, clinical, hemodynamic, endoscopic, elastographic, and echo-Doppler work-up was performed in both studies. In study 1, no patients without cirrhosis developed HCC. Of 183 patients with cirrhosis, 14 of 28 (50.0%) with previous HCC recurred whereas 21 of 155 (13.5%) developed de novo HCC. Patients with recurrent and de novo HCCs had significantly higher liver fibrosis (LF) scores, portal pressure, and systemic inflammation than nonrecurrent HCC or patients never developing HCC. In recurrent/de novo HCC patients, tumor and nontumor ANGPT2 showed an inverse relationship with portal vein velocity (PVv; r = -0.412, P = 0.037 and r = -0.409, P = 0.047 respectively) and a positive relationship with liver stiffness (r = 0.526, P = 0.007; r = 0.525, P = 0.003 respectively). Baseline circulating VEGF and cirrhotic liver ANGPT2 were significantly related (r = 0.414, P = 0.044). VEGF increased during DAAs, remaining stably elevated at 3-month follow-up, when it significantly related with serum ANGPT2 (r = 0.531, P = 0.005). ANGPT2 expression in the primary tumor or in cirrhotic tissue before DAAs was independently related with risk of HCC recurrence (odds ratio [OR], 1.137; 95% confidence interval [CI], 1.044-1.137; P = 0.003) or occurrence (OR, 1.604; 95% CI, 1.080-2.382; P = 0.019). In study 2, DAA treatment (OR, 4.770; 95% CI, 1.395-16.316; P = 0.013) and large varices (OR, 3.857; 95% CI, 1.127-13.203; P = 0.032) were independent predictors of de novo HCC. CONCLUSION: Our study indicates that DAA-mediated increase of VEGF favors HCC recurrence/occurrence in susceptible patients, that is, those with more severe fibrosis and splanchnic collateralization, who already have abnormal activation in liver tissues of neo-angiogenetic pathways, as shown by increased ANGPT2. (Hepatology 2018; 00:000-000).

Deficiência visual x habilidades auditivas: desempenho das habilidades do processamento auditivo central em deficientes visuais / Visual impairment x hearing abilities: performance of the central auditory processing abilities in the visually impaired / Deficiencia visual x habilidades auditivas: rendimiento de las habilidades del procesamiento auditivo central en deficientes visuales

Introdução: Na ausência da visão, o cérebro humano necessita compensar tal deficiência sensorial se ajustando para que outros sentidos venham a equilibrar percepções externas. Objetivo: Comparar o desempenho das habilidades do processamento auditivo central entre um grupo de deficientes visuais e um grupo com visão normal. Métodos: Os participantes foram divididos em dois grupos, sendo o grupo estudo (GE), composto por 13 deficientes visuais, que posteriormente foi subdividido de acordo com o grau e tipo da deficiência; e grupo controle (GC), formado pelo mesmo número de participantes, com visão normal. Ambos os grupos foram submetidos a um questionário sobre seu histórico auditivo, meatoscopia, avaliação auditiva básica, composta por audiometria tonal e vocal e imitanciometria, sendo que os participantes com integridade e acuidade auditiva adequada passaram à realização dos testes para avaliação do processamento auditivo central (SSW, MLD, TDCV, PPS e RGDT). Resultados: Observou-se que, no geral, o GE obteve melhor resultado apenas na orelha esquerda em condição competitiva, no teste SSW. No MLD, houve diferença estatisticamente significante com média geral superior no GE. No TDCV, em atenção livre, a ocorrência de acertos geral foi maior no GC, enquanto que, em escuta direcionada, o GE obteve média geral superior na atenção direita e o GC na atenção esquerda. Nos testes PPS e RGDT, observou-se que o GE mostrou desempenho geral superior. Conclusão: Através dos testes de processamento auditivo central, foi possível comprovar que o GE obteve desempenho mais eficiente nas habilidades auditivas avaliadas.

Introduction: In the absence of vision, the human brain needs to compensate this sensorial disability making adjustments so other senses equilibrate external perceptions. Objective: Compare the performance of the central auditory processing abilities between a group of visually impaired and a group with normal vision. Methods: Participants were divided in: study group (SG), composed by 13 visually impaired, that afterwards were subdivided accordingly with degree and type of the deficiency; and control group (CG), formed by the same number of participants with normal vision. Both were submitted to a questionnaire about their hearing history, meatoscopy, basic hearing assessment, composed by tonal and vocal audiometry, and impedance, being that participants with adequate auditory integrity and acuity passed to the execution of the tests for the central auditory processing assessment (SSW, MLD, DLCVS, PPS, RGDT). Results: It was observed that, in general, the SG obtained better result only in the left ear in competitive condition, in SSW test. In the MLD, there was statistical significant difference with higher overall average in the SG. In the DLCVS, in free attention, the occurrence of the general correct answers was higher in the CG, whereas, in directed attention, SG obtained higher overall average in the right attention and CG in the left attention. In the PPS and RGDT tests, it was observed that SG showed higher overall performance. Conclusion: Throughout the central auditory processing tests, it was possible to prove that the SG obtained more efficient performance in the auditory abilities assessed.

Introducción: En la ausencia de la visión, el cerebro humano necesita compensar tal deficiencia, haciendo ajustes para que otros sentidos vengan a equilibrar las percepciones externas. Objetivo: Comparar el rendimiento de las habilidades del procesamiento auditivo central entre un grupo de deficientes visuales y un grupo con visión normal. Métodos: Los participantes fueron divididos en dos grupos: grupo estudio (GE), compuesto por 13 deficientes visuales, siendo subdividido de acuerdo con el grado y tipo de la deficiencia; y grupo control (GC), formado por el mismo número de participantes con visión normal. Los grupos fueron sometidos a un cuestionario sobre su histórico auditivo, otoscopia, evaluación auditiva básica, compuesta por audiometría tonal y vocal e imitanciometría. Los participantes con integridad y acuidad auditiva normales pasaron a realización de las pruebas para evaluación del procesamiento auditivo central (SSW, MLD, TDCV, PPS y RGDT). Resultados: El GE obtuvo mejor resultado sólo en la oreja izquierda, en condición competitiva, en la prueba SSW. En el MLD hubo diferencia estadísticamente significante con media general superior en el GE. En el TDCV, con atención libre, la ocurrencia general de aciertos fue mayor para el GC, mientras que, en la escucha direccionada, el GE obtuvo media general superior en la atención derecha y el GC en atención izquierda. En las pruebas PPS y RGDT, se observo que el GE mostró resultado general superior. Conclusión: A través de las pruebas del procesamiento auditivo central, se comprobó que el GE obtuvo rendimiento más eficiente en las habilidades auditivas evaluadas.

Premature ovarian senescence and a high miscarriage rate impair fertility in women with HCV.

BACKGROUND & AIMS: Premenopausal women who are HCV positive (HCV+) have failing ovarian function, which is likely to impact their fertility. Thus, we investigated the reproductive history, risk of infertility, and pregnancy outcomes in women of childbearing age who were HCV+. METHODS: Three different groups were studied: (1) Clinical cohort: 100 women who were HCV+ and also had chronic liver disease (CLD), age matched with 50 women who were HBV+ with CLD and with 100 healthy women; all women were consecutively observed in three gastroenterology units in hospitals in Italy; (2) 1,998 women who were HCV+ and enrolled in the Italian Platform for the Study of Viral Hepatitis Therapies (PITER); (3) 6,085 women, who were mono-infected with HCV, and 20,415 women, who were HCV-, from a large de-identified insurance database from the USA. MEASUREMENTS: total fertility rate (TFR) defined as the average number of children that a woman would bear during her lifetime. To define the reproductive stage of each participant, levels of anti-Müllerian hormone (AMH) and 17ß-estradiol were measured. RESULTS: Clinical cohort: women who were either HCV+ or HBV+ had similar CLD severity and age at first pregnancy. Based on a multivariate analysis, women who were HCV+ had a higher risk of miscarriage than those who were HBV+ (odds ratio [OR] 6,905; 95% CI 1.771-26.926). Among women who were HCV+, incidence of miscarriage was correlated with median AMH level (1.0 ng/ml). Achieving a sustained virologic response (SVR) after antiviral treatment reduced the risk of miscarriage (OR 0.255; 95% CI 0.090-0.723). In the PITER-HCV cohort, miscarriage occurred in 42.0% of women (44.6% had multiple miscarriages). TFR for women who were HCV+ and between 15 and 49 years of age was 0.7 vs. 1.37 of Italian population of the same age range. In the US cohort: compared with women who were HCV-, women who were HCV+ positive were significantly more likely to have infertility (OR 2.439; 95% CI 2.130-2.794), premature birth (OR 1.34; 95% CI 1.060-1.690), gestational diabetes (OR 1.24; 95% CI 1.020-1.510), and pre-eclampsia (OR 1.206; 95% CI 0.935-1.556), and were less likely to have a live birth (OR 0.754; 95% CI 0.622-0.913). CONCLUSIONS: Ovarian senescence in women of childbearing age who are HCV+ is associated with a lower chance of live birth, greater risk of infertility, gestational diabetes, pre-eclampsia and miscarriage. Such risks could be positively influenced by successful HCV cure. LAY SUMMARY: Most new cases of HCV infection are among people who inject drugs, many of whom are young women in their childbearing years. Women of reproductive age who are HCV+ display markers of ovarian senescence. This is associated with an increased burden in terms of infertility and adverse pregnancy outcomes, including stillbirth, miscarriage, fewer live births, and gestational diabetes. Early viral suppression with therapy is likely to mitigate these risks.

The in vitro effects of verbascoside on human platelet aggregation.

Preliminary in vitro and animal studies have shown that verbascoside, a phenolic compound, may have several favourable biological activities, including an influence on endothelial function and on platelet aggregation. We sought to evaluate the effects of verbascoside, biotechnologically produced from plant cell cultures, on human platelet aggregation (PA). The blood from 40 aspirin-naïve volunteers with at least one cardiovascular risk factor was preincubated in vitro with verbascoside (1 and 2 mg/dL) and aspirin (100 µM). The blood from 20 patients with a prior diagnosis of coronary heart disease who were chronically assuming aspirin was preincubated in vitro with verbascoside (1 and 2 mg/dL). PA is measured with a light transmission aggregometry and multiplate analyzer. As compared to reference, preincubation with verbascoside resulted in a significant inhibition of adenosine diphosphate (ADP) and arachidonic acid (AA)-induced PA (p < 0.01 for both). Verbascoside 2 mg/dL did not show a stronger effect as compared to verbascoside 1 mg/dL (p = 0.4). As expected, the in vitro addition of aspirin reduced AA induced PA (p < 0.01), but not that induced by ADP (p = 0.5). The addition of verbascoside to the blood of aspirin-treated patients did not improve the values of PA after AA stimulus (p = 0.8), whereas it ensured a stronger inhibition after ADP stimulus (p < 0.01). Verbascoside in vitro affects PA by mildly inhibiting aggregation, triggered both by ADP and AA. These preliminary data, while intriguing, require confirmation in subjects receiving verbascoside orally in order to determine whether these findings are clinically relevant.

Prasugrel versus tirofiban bolus with or without short post-bolus infusion with or without concomitant prasugrel administration in patients with myocardial infarction undergoing coronary stenting: the FABOLUS PRO (Facilitation through Aggrastat By drOpping or shortening Infusion Line in patients with ST-segment elevation myocardial infarction compared to or on top of PRasugrel given at loading dOse) trial.

OBJECTIVES: The authors sought to compare the effect on inhibition of platelet aggregation (IPA) of prasugrel therapy versus tirofiban bolus with or without a post-bolus short drug infusion in ST-segment elevation myocardial infarction (STEMI) patients. BACKGROUND: The degree and rapidity of IPA after prasugrel alone with or without concomitant glycoprotein IIb/IIIa inhibition in STEMI patients is unknown. METHODS: A total of 100 STEMI patients randomly received prasugrel 60 mg versus 25 µg/kg tirofiban bolus with or without post-bolus 2-h infusion of tirofiban, with or without concomitant prasugrel. IPA at light transmission aggregometry was performed throughout 24 h. The primary endpoint was IPA stimulated with 20 µmol/l adenosine diphosphate (ADP) at 30 min. RESULTS: At 30 min, patients in the prasugrel group showed a significantly lower IPA to 20 µmol/l ADP stimulation as compared with tirofiban-treated patients (36 ± 35 vs. 87 ± 31, p < 0.0001). Similarly, patients taking prasugrel showed a suboptimal degree of platelet inhibition for at least 2 h compared with tirofiban patients. Post-bolus tirofiban infusion was necessary to maintain a high level of IPA beyond 1 h after bolus administration if concomitant clopidogrel was given, whereas the bolus-only tirofiban and concomitant prasugrel led to the higher and more consistent IPA levels after both ADP and thrombin receptor-activating peptide stimuli than either therapy alone. CONCLUSIONS: Our study shows that prasugrel administration leads to a suboptimal IPA for at least 2 h in STEMI patients. Yet, prasugrel, given in association with a bolus only of glycoprotein IIb/IIIa inhibitor, obviates the need of post-bolus infusion and almost completely abolishes residual variability of IPA after treatment. (Facilitation through Aggrastat By drOpping or shortening Infusion Line in patients with ST-segment elevation myocardial infarction compared to or on top of PRasugrel given at loading dOse [The FABOLUS PRO trial]; NCT01336348).

Prediction of 1-year clinical outcomes using the SYNTAX score in patients with acute ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: a substudy of the STRATEGY (Single High-Dose Bolus Tirofiban and Sirolimus-Eluting Stent Versus Abciximab and Bare-Metal Stent in Acute Myocardial Infarction) and MULTISTRATEGY (Multicenter Evaluation of Single High-Dose Bolus Tirofiban Versus Abciximab With Sirolimus-Eluting Stent or Bare-Metal Stent in Acute Myocardial Infarction Study) trials.

OBJECTIVES: This study sought to evaluate the impact of SYNTAX score (SXscore), and compare its performance in isolation and combination with the PAMI (The Primary Angioplasty in Myocardial Infarction Study) score, for the prediction of 1-year clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention. BACKGROUND: Patients with STEMI were excluded from the original SYNTAX score (SXscore) algorithm. Therefore, the utility of using the SXscore in this patient group remains undefined. METHODS: SXscore was calculated retrospectively in 807 patients with STEMI enrolled in the randomized STRATEGY (Single High-Dose Bolus Tirofiban and Sirolimus-Eluting Stent Versus Abciximab and Bare-Metal Stent in Acute Myocardial Infarction) and MULTISTRATEGY (Multicenter Evaluation of Single High-Dose Bolus Tirofiban Versus Abciximab With Sirolimus-Eluting Stent or Bare-Metal Stent in Acute Myocardial Infarction Study) clinical trials. Clinical outcomes of all-cause death, reinfarction, and clinically driven target vessel revascularization were subsequently stratified according to SXscore tertiles: SX(LOW) ≤ 9 (n = 311), 9 < SX(MID) ≤ 16 (n = 234), SX(HIGH) >16 (n = 262). RESULTS: At 1-year follow-up, all clinical outcomes including mortality, mortality/reinfarction, major adverse cardiac events (MACE) (a composite of all-cause death, reinfarction and target vessel revascularization), and definite, definite/probable, and any stent thrombosis were all significantly higher in patients in the highest SXscore tertile. SXscore was identified as an independent predictor of mortality, MACE, and stent thrombosis out to 1-year follow-up. The combination SYNTAX-PAMI score led to a net reclassification improvement of 15.7% and 4.6% for mortality and MACE, respectively. The C-statistics for the SXscore, PAMI score, and the combined SYNTAX-PAMI score were 0.65, 0.81, and 0.73 for 1-year mortality, and 0.68, 0.64, and 0.69 for 1-year MACE, respectively. CONCLUSIONS: SXscore does have a role in the risk stratification of patients with STEMI having primary percutaneous coronary intervention; however, this ability can be improved through a combination with clinical variables. (Multicentre 2×2 Factorial Randomised Study Comparing Tirofiban Versus Abciximab and SES Versus BMS in AMI; NCT00229515).

Role of xanthine oxidase activation and reduced glutathione depletion in rhinovirus induction of inflammation in respiratory epithelial cells.

Rhinoviruses are the major cause of the common cold and acute exacerbations of asthma and chronic obstructive pulmonary disease. We previously reported rapid rhinovirus induction of intracellular superoxide anion, resulting in NF-kappaB activation and pro-inflammatory molecule production. The mechanisms of rhinovirus superoxide induction are poorly understood. Here we found that the proteolytic activation of the xanthine dehydrogenase/xanthine oxidase (XD/XO) system was required because pretreatment with serine protease inhibitors abolished rhinovirus-induced superoxide generation in primary bronchial and A549 respiratory epithelial cells. These findings were confirmed by Western blotting analysis and by silencing experiments. Rhinovirus infection induced intracellular depletion of reduced glutathione (GSH) that was abolished by pretreatment with either XO inhibitor oxypurinol or serine protease inhibitors. Increasing intracellular GSH with exogenous H2S or GSH prevented both rhinovirus-mediated intracellular GSH depletion and rhinovirus-induced superoxide production. We propose that rhinovirus infection proteolytically activates XO initiating a pro-inflammatory vicious circle driven by virus-induced depletion of intracellular reducing power. Inhibition of these pathways has therapeutic potential.