Liver Stiffness at the Time of Sustained Virological Response Predicts the Clinical Outcome in People Living With Human Immunodeficiency Virus and Hepatitis C Virus With Advanced Fibrosis Treated With Direct-acting Antivirals.

BACKGROUND: Some people living with hepatitis C virus (HCV) with sustained virological response (SVR) develop hepatic complications. Liver stiffness (LS) predicts clinical outcome in people living with human immunodeficiency virus (HIV) with active HCV coinfection, but information after SVR is lacking. We aimed to analyze the predictive ability of LS at SVR for liver complications in people living with HIV/HCV with advanced fibrosis treated with direct-acting antivirals (DAA). METHODS: In sum, 640 people living with HIV/HCV fulfilling the following criteria were included: (i) Achieved SVR with DAA-including regimen; (ii) LS ≥ 9.5 kPa before therapy; and (iii) LS measurement available at SVR. The primary endpoint was the occurrence of a liver complication-hepatic decompensation or hepatocellular carcinoma (HCC)-or requiring liver transplant after SVR. RESULTS: During a median (Q1-Q3) follow-up of 31.6 (22.7-36.6) months, 19 (3%) patients reached the primary endpoint. In the multivariate analysis, variables (subhazard ratio [SHR] [95% confidence interval]) associated with developing clinical outcomes were: prior hepatic decompensations (3.42 [1.28-9.12]), pretreatment CPT class B or C (62.5 [3.08-1246.42]) and MELD scores (1.37 [1.03-1.82]), CPT class B or C at SVR (10.71 [1.32-87.01]), CD4 cell counts <200/µL at SVR time-point (4.42 [1.49-13.15]), FIB-4 index at SVR (1.39 [1.13-1.70]), and LS at SVR (1.05 [1.02-1.08] for 1 kPa increase). None of the 374 patients with LS <14kPa at SVR time-point developed a liver complication or required hepatic transplant. CONCLUSIONS: LS at the time of SVR after DAA therapy predicts the clinical outcome of people living with HIV/HCV with advanced fibrosis. These results suggest that LS measurement may be helpful to select candidates to be withdrawn from surveillance programs.

Impact of interferon-free regimens on the glomerular filtration rate during treatment of chronic hepatitis C in a real-life cohort.

Little data are available on renal toxicity exerted by direct-acting antivirals (DAAs) in real life. The aim of this study was to assess the impact of direct-acting antivirals against hepatitis C virus infection currently used in Spain and Portugal on the estimated glomerular filtration rate (eGFR) in clinical practise. From an international, prospective multicohort study, patients treated with DAAs for at least 12 weeks and with eGFR ≥30 mL/min per 1.73 m2 at baseline were selected. eGFR was determined using the CKD-EPI formula. A total of 1131 patients were included; 658 (58%) were HIV/HCV-coinfected patients. Among the 901 patients treated for 12 weeks, median (interquartile range) eGFR was 100 (87-107) at baseline vs 97 (85-105) mL/min per 1.73 m2 at week 12 of follow-up (FU12) post-treatment (P < .001). For HIV-coinfected subjects who received tenofovir plus a ritonavir-boosted HIV protease inhibitor (PI/r), baseline vs FU12 eGFR were 104 (86-109) vs 104 (91-110) mL/min per 1.73 m2 (P = .913). Among subjects receiving ombitasvir/paritaprevir with or without dasabuvir, eGFR did not show any significant change. Of 1100 subjects with eGFR >60 mL/min per 1.73 m2 at baseline, 22 (2%) had eGFR <60 mL/min per 1.73 m2 at FU12, but none presented with eGFR <30 mL/min per 1.73 m2 . In conclusion, eGFR slightly declines during therapy with all-oral DAAs and this effect persists up to 12 weeks after stopping treatment in subjects with normal to moderately impaired renal function, regardless of HIV status. Concomitant use of tenofovir plus PI/r does not seem to have an impact on eGFR.

Head and neck cancer. An aetiopathogenetic study of non-endemic lymphoepithelioma.

An aetiopathogenetic analysis of non-endemic nasopharyngeal carcinoma (NPC) in European and Southern American patient groups was performed. Specifically, the study sought to determine the proportion of Epstein-Barr Virus (EBV)-positive tumour cells in NPC patients in two very different populations (Europe and South America) in areas not associated with a high incidence of NPC. Clinical data (age, sex and onset of clinical disease) were also analyzed. A total of 50 NPC samples, 24 from a European hospital (EH) and 26 from two South American hospitals (SAH), were included. Nuclear staining for Epstein-Barr virus-encoded small RNA (EBER) was performed by in situ hybridization (ISH). Latent membrane protein 1 (LMP1) expression was measured by immunohistochemical (IHC) analysis. A higher incidence of NPC was observed in patients > 40 years of age in EH; in SAH, by contrast, the incidence was higher in patients aged ≤ 40 years. Cervical lymph node metastasis was detected in 31 patients (of whom 84.6% were from SAH). A total of 72% of samples were EBERpositive; the incidence of EBER positivity was greater in type 3 NPCs. EBV was detected in a large proportion of epithelial cells in samples from both EH and SAH (75% vs. 69.2%, respectively). An association was found between EBER detection in lymphocytes and patient origin (p = 0.0001). LMP1 expression was detected in 64% of patients. ISH for the detection of EBER is the most sensitive technique for demonstrating EBV in tumour tissue. The incidence of EBV was not significantly greater in either of the study populations, but was significantly higher in patients with type 3 NPC. Definitive histological diagnosis of NPC was reached earlier in EH than in SAH, where metastases were more frequently diagnosed, suggesting that the disease had reached a more advanced stage by the time treatment was started.

Thiolated DAB dendrimer/ZnSe nanoparticles for C-reactive protein recognition in human serum.

A nanocomposite obtained by a thiol DAB-dendrimer (generation 5), coated with fluorescent ZnSe quantum dots, was successfully synthesized for the selective recognition of C-reactive protein. The procedure presented was carried out by a novel, cheap and non-toxic bottom up synthesis. The nanocomposite showed an excitation at 180 nm, with two emission bands at 411 and 465 nm, with a full-width at half-maximum of 336 nm. The Stokes shift was influenced by the presence of coating molecules and the intensity was dependent on pH due to the presence of a charge transfer process. The transmission electron microscopy images demonstrated that the spherical nanoparticles obtained displayed a regular shape of 30 nm size. The fluorescence intensity was markedly quenched by the presence of C-reactive protein, with a dynamic Stern-Volmer constant of 0.036 M(-1). The quenching profile shows that about 51% of the ZnSe QDs are located in the external layer of the thiol dendrimer accessible to the quencher. The precision of the method obtained as relative standard deviation was 3.76% (4 mg L(-1), n=3). This water soluble fluorescent nanocomposite showed a set of favorable properties to be used as a sensor for the C-reactive protein in serum samples, at concentrations of risk levels.

The cadherin-catenin complex in nasopharyngeal carcinoma.

Abnormal Wnt signaling and impaired cell-cell adhesion due to abnormal E-cadherin and ß-catenin function have been implicated in many cancers, but have not been fully explored in nasopharyngeal carcinoma. The aim of this study was to analyze ß-Catenin cellular location and E-cadherin expression levels in nasopharyngeal carcinoma. E-cadherin expression levels were also correlated with clinical data and underlying pathology. ß-Catenin and E-cadherin expression were examined in 18 nasopharyngeal carcinoma and 7 non-tumoral inflammatory pharynx tissues using immunohistochemical methods. Patient clinical data were collected, and histological evaluation was performed by hematoxylin/eosin staining. ß-catenin was detected in membrane and cytoplasm in all cases of nasopharyngeal carcinoma, regardless of histological type; in non-tumoral tissues, however, ß-catenin was observed only in the membrane. As for E-cadherin expression levels, strong staining was observed in most non-tumoral tissues, but staining was only moderate in nasopharyngeal carcinoma tissues. E-cadherin expression was associated with ß-catenin localization, study group, metastatic disease, and patient outcomes. Reduced levels of E-cadherin protein observed in nasopharyngeal carinoma may play an important role in invasion and metastasis. Cytoplasmic ß-catenin in nasopharyngeal carcinoma may impair cell-cell adhesion, promoting invasive behavior and a metastatic tumor phenotype.

Modifying RANKL/OPG mRNA expression in differentiating and growing human primary osteoblasts.

The OPG/RANKL system in primary cultures of human osteoblasts has been studied by different authors. However, very few studies have been performed on gene expression of RANKL and OPG at different stages of maturation on human osteoblast cultures. The effect of 17- beta-estradiol and 1,25dihydroxyvitamin D3 on the OPG/RANKL system is not known during the different states of cellular maturation. In this work we quantified OPG and RANKL protein levels (ELISA) and the mRNA of OPG, RANKL, collagen type I, alkaline phosphatase, and osteocalcin (semi-quantitative RT-PCR) in human osteoblasts. We analyzed these in basal conditions and after incubation with 17- beta-estradiol and 1,25dihydroxyvitamin D3 in the first and second phases. We found that OPG secretion and expression levels increased throughout cellular growth. RANKL proteins were detected only in the first stage, and the expression increased throughout the first phase. Thus, the RANKL/OPG ratio was higher in immature osteoblasts than in mature osteoblasts. The evolution of RANKL gene expression was related to collagen I and alkaline phosphatase, while OPG was related to osteocalcin. We observed no modifications after estradiol and 1,25dihydroxyvitamin D3 treatment. Our results suggest that the OB is a positive stimulator at precocious stages of differentiation on osteoclastogenic modulates.

Profile of patients triply infected with HIV and the hepatitis B and C viruses in the HAART era.

HIV-HCV-HBV-coinfected patients were assessed to characterize the viral interactions in the setting of HIV coinfection and in the HAART era. All positive anti-HCV antibody and HBs antigen-positive HIV-infected patients were identified at five HIV clinics. Antihepatitis delta (HDV) antibody, serum HIV RNA, HCV RNA, and HBV DNA quantification and genotype determinations were performed. Out of 67 patients identified 47 (70%) were receiving anti-HBV therapy. HCV RNA and HBV DNA were detectable in 52.5% and 37% of patients, respectively. All possible patterns were found, regardless of anti-HBV therapy. HDV coinfection was associated with undetectable HCV RNA [RR 9.52 (95% CI 1.85-49.01); p = 0.007]. Independent factors predicting undetectable HBV DNA lacked HBeAg [RR 13.94 (95% CI 3.05-63.72); p = 0.001] and use of anti-HBV therapy [RR 11.42 (95% CI 2.43-53.54); p = 0.002]. Replication and genotypes of HCV or HBV had no impact on the replication of the other virus. In conclusion, in this cohort of triple infection (HBV/HCV/HIV) various viral patterns were identified. Spontaneous HCV clearance was frequent, and it was independently associated with HDV coinfection. In the absence of HBV therapy, HBV most often actively replicates. HBV/HCV replication or genotypes were not related to the replication of the other virus.

[The usefulness of abdominal echography in the diagnosis of extrapulmonary tuberculosis in patients with HIV infection]. / Utilidad de la ecografía abdominal en el diagnóstico de la tuberculosis extrapulmonar en pacientes infectados por el HIV.

BACKGROUND: The aim of the present study was to analyze the diagnostic profitability of echography as an indicator of extrapulmonary tuberculosis in patients with HIV infection. PATIENTS AND METHODS: HIV positive patients presenting fever of long duration were prospectively studied with an active search for specific echographic lesions. Descriptive statistics were performed by variance analysis. The diagnostic profitability of echography was evaluated by the calculation of sensitivity, specificity, positive predictive values (PPV) and negative predictive value (NPV). RESULTS: Criteria of prolonged fever was fulfilled by 116 patients. Thirty-five (30.2%) presented specific echographic alterations: 12 had multiple hyoechoic splenic lesions (34.3%), 11 abdominal adenopathies (31.4%), 9 splenic lesions and adenopathies (25.7%) and 3 showed hepato-splenic involvement and adenopathies (8.6%). The final diagnoses of these patients were: one case of toxoplasmosis, 2 MAI infection, 7 with no definitive diagnosis, and 25 (71.4%) tuberculosis. The mean CD4 lymphocyte count was 46.6 x 10(6)/L in patients with tuberculosis with no echographic findings, with a statistically significant difference of p < 0.05. The appearance of some echographic alterations had a global sensitivity of 37.3%, a specificity of 79.6% a PPV of 0.65 and a NPV of 0.51. The isolated findings of hypoechoic splenic lesions showed a sensitivity of 19.23%, a specificity of 95.12%, a PPV of 0.83 and a NPV of 0.47. CONCLUSIONS: The presence of multiple hypoechoic splenic lesions showed an elevated specificity, being greater than 95%, making this finding, although infrequent, that of greatest diagnostic profitability in the echographic study of tuberculosis. We therefore consider abdominal echography to be of great usefulness in the evaluation of patients with HIV infection and prolonged fever since the presence of these lesions, in the most severely immunosuppressed patients, may strongly suggest the diagnosis of extrapulmonary tuberculosis.

[Non-Hodgkin's lymphomas. I. Clinico-biological features of 307 cases]. / Linfomas no hodgkinianos. I. Características clínico biológicas de 307 casos.

PURPOSE: To assess the clinico-biological features appearing in 307 patients with non-Hodgkin's lymphomas (NHL). PATIENTS AND METHODS: The clinical records of 338 patients diagnosed of NHL between January 1975 and December 1988 were revised in retrospect. All cases with histologic diagnosis of NHL aged over 14 years were included, and classified in accordance with the Working Formulation criteria. The following data were analysed: age, sex, first complaints, time elapsed since onset, histologic type, number of sites involved, bulky disease, anaemia, thrombocytopenia, LDH, stage, type of treatment and initial response, survival, and cause of death. The statistical evaluation was performed by actuarial analysis (Kaplan and Meier) and comparison (log-rank test) of survival. RESULTS: According to the three categories of the malignancies, the NHL were distributed into low-grade (37.8%), intermediate (36.1%) and high-grade (26.9%). The mean age of the series was 56.6 years and the M/F ratio was 1.3. Lymph node enlargement was the commonest finding; 36.4% of the patients had symptoms related with the disease, and 26.7% had bulky disease. Anaemia was present in 37.7% of the cases and thrombocytopenia in 14.3%, with similar distribution among the three grades. High LDH levels were found in 44% of the patients. At diagnosis, 85% of the patients were in advanced stages (III+IV) already. Complete response was attained in 51.1% of the cases, with median survival of 48 months. CONCLUSIONS: The clinico-evolutive data found here are similar to other reports in the literature. In one-half of the patients the cause of the first visit is lymph node enlargement. Complete remission is achieved by one out of two patients, this figure being similar for each of the histologic groups. The Working Formulation is useful in determining the different prognostic groups with respect to survival.

Interleukin-4 inhibits human macrophage activation by tumor necrosis factor, granulocyte-monocyte colony-stimulating factor, and interleukin-3 for antileishmanial activity and oxidative burst capacity.

Interleukin (IL)-4 has been implicated in the pathogenesis of leishmaniasis in a murine model. Experiments were done to examine the effect of IL-4 on cytokine activation of macrophages. Interferon (IFN)-gamma, granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor-alpha (TNF alpha), and IL-3 activate macrophages to inhibit replication of leishmaniae. IL-4 abrogated in a dose- and time-dependent manner the induction of antileishmanial activity by these cytokines. The depression of oxidative burst capacity is one mechanism by which IL-4 inhibits macrophage activation. IL-4 diminished in a dose- and time-dependent manner the TNF alpha enhancement of oxidative capacity. Pretreatment with IL-4 for 48, 24, or 0 h, respectively, inhibited the generation of superoxide induced by TNF alpha by 90%, 60%, and 40%. Furthermore, IL-4 abrogated the enhancement of oxidative capacity by IFN-gamma, GM-CSF, and IL-3. These data suggest that IL-4 is a potent deactivator of macrophage antimicrobial functions and may contribute to the pathogenesis of visceral leishmaniasis.

Tolerance induction and immunological priming initiated by mucosal contacts with protein antigens in inbred strains of mice

We show that mouse strains differ widely in susceptibility to tolerance induction and/or immunization (priming) following contact of protein antigens (ovalbumin, human or bovine gamma globulins) with different mucosal surfaces. 2. When compared to a control group pretreated with saline, mice pretreated by the oral (intragastric) route with antigen became significantly less responsive to subsequent parenteral immunization (i.e., tolerant). This was observed in most, but not all, antigen/strain combinations. 3.Similar, although less prominent changes were induced by pretreatments with antigen by the ocular (conjunctival) route. 4. No significant effects were following pretreatments by the nasal, vaginal, or rectal routes. 5. Genes present in strains selected for multispecific "high" or "low" responsivencess are included among those involved in tolerance induction following mucosal contacts with protein antigens

Genetics of susceptibility to oral tolerance to ovalbumin

Inbred mouse strains vary widely in their susceptibility to the induction of tolerance following oral (intragastric) adminsitation of ovalbumin. Marked differences were found berween strains that form a congenic pair differing at the H-2 complex: C3H/HeJ (H-2K) and C3H.SW(H2b) - which were very susceptible and resitant to tolerance induction, respectively. In comtrast, no significant differences were found betwwwn a/J(H-2a) and A.BY (H-2b) congenics, which were both susceptible, nor among C57BL/10J congenics, which were uniformly resitant to tolerance induction. We conclude that H-2-linked genes determine tolerance susceptibility in conjunction with background genes