Low incidence of hepatitis B virus reactivation and subsequent hepatitis in patients with chronic hepatitis C receiving direct-acting antiviral therapy.

To determine the clinical characteristics of hepatitis B virus (HBV) reactivation in patients undergoing interferon-free antihepatitis C virus (HCV) therapy, we examined HBV DNA in 25 HBV co-infected patients and 765 patients with resolved HBV infection during and after treatment with direct-acting antiviral agents (DAAs). Among those with HCV genotype 1, asunaprevir plus daclatasvir was administered to 160 patients, sofosbuvir (SOF) plus ledipasvir to 438 patients and paritaprevir plus ombitasvir and ritonavir to 25 patients. In total, 167 patients with genotype 2 were treated with SOF plus ribavirin. Three patients with an HBV DNA level ≥2000 IU/mL were treated with entecavir before anti-HCV therapy, without reactivation of HBV. In 3 of 22 (12%) HBV surface antigen (HBsAg)-positive patients with an HBV DNA level <2000 IU/mL, the viral load increased during treatment. However, hepatitis flare did not occur in these patients. There was no significant difference in clinical history between patients with and without HBV reactivation. Among 765 patients with resolved HBV infection, HBV reactivation occurred in 1 (0.1%) patient after initial resolution, whose HBV DNA level spontaneously decreased after DAA therapy. We compared anti-HBs titres at baseline with those at post-DAA therapy in 123 patients without HBsAg. There was no significant difference in anti-HBs levels between the two points (P = .79). In conclusion, HBV reactivation was rare in HBsAg-negative patients treated with DAA therapy. Additionally, hepatitis did not occur in HBV-reactivated patients with a baseline HBV DNA level <2000 IU/mL before DAA therapy.

Atezolizumab plus bevacizumab versus lenvatinib or sorafenib in non-viral unresectable hepatocellular carcinoma: an international propensity score matching analysis.

BACKGROUND: A growing body of evidence suggests that non-viral hepatocellular carcinoma (HCC) might benefit less from immunotherapy. MATERIALS AND METHODS: We carried out a retrospective analysis of prospectively collected data from consecutive patients with non-viral advanced HCC, treated with atezolizumab plus bevacizumab, lenvatinib, or sorafenib, in 36 centers in 4 countries (Italy, Japan, Republic of Korea, and UK). The primary endpoint was overall survival (OS) with atezolizumab plus bevacizumab versus lenvatinib. Secondary endpoints were progression-free survival (PFS) with atezolizumab plus bevacizumab versus lenvatinib, and OS and PFS with atezolizumab plus bevacizumab versus sorafenib. For the primary and secondary endpoints, we carried out the analysis on the whole population first, and then we divided the cohort into two groups: non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) population and non-NAFLD/NASH population. RESULTS: One hundred and ninety patients received atezolizumab plus bevacizumab, 569 patients received lenvatinib, and 210 patients received sorafenib. In the whole population, multivariate analysis showed that treatment with lenvatinib was associated with a longer OS [hazard ratio (HR) 0.65; 95% confidence interval (CI) 0.44-0.95; P = 0.0268] and PFS (HR 0.67; 95% CI 0.51-0.86; P = 0.002) compared to atezolizumab plus bevacizumab. In the NAFLD/NASH population, multivariate analysis confirmed that lenvatinib treatment was associated with a longer OS (HR 0.46; 95% CI 0.26-0.84; P = 0.0110) and PFS (HR 0.55; 95% CI 0.38-0.82; P = 0.031) compared to atezolizumab plus bevacizumab. In the subgroup of non-NAFLD/NASH patients, no difference in OS or PFS was observed between patients treated with lenvatinib and those treated with atezolizumab plus bevacizumab. All these results were confirmed following propensity score matching analysis. By comparing patients receiving atezolizumab plus bevacizumab versus sorafenib, no statistically significant difference in survival was observed. CONCLUSIONS: The present analysis conducted on a large number of advanced non-viral HCC patients showed for the first time that treatment with lenvatinib is associated with a significant survival benefit compared to atezolizumab plus bevacizumab, in particular in patients with NAFLD/NASH-related HCC.

Nonalcoholic steatohepatitis in hepatocarcinoma: new insights about its prognostic role in patients treated with lenvatinib.

BACKGROUND: Hepatocellular carcinoma (HCC) treatment remains a big challenge in the field of oncology. The liver disease (viral or not viral) underlying HCC turned out to be crucial in determining the biologic behavior of the tumor, including its response to treatment. The aim of this analysis was to investigate the role of the etiology of the underlying liver disease in survival outcomes. PATIENTS AND METHODS: We conducted a multicenter retrospective study on a large cohort of patients treated with lenvatinib as first-line therapy for advanced HCC from both Eastern and Western institutions. Univariate and multivariate analyses were performed. RESULTS: Among the 1232 lenvatinib-treated HCC patients, 453 (36.8%) were hepatitis C virus positive, 268 hepatitis B virus positive (21.8%), 236 nonalcoholic steatohepatitis (NASH) correlate (19.2%) and 275 had other etiologies (22.3%). The median progression-free survival (mPFS) was 6.2 months [95% confidence interval (CI) 5.9-6.7 months] and the median overall survival (mOS) was 15.8 months (95% CI 14.9-17.2 months). In the univariate analysis for OS NASH-HCC was associated with longer mOS [22.2 versus 15.1 months; hazard ratio (HR) 0.69; 95% CI 0.56-0.85; P = 0.0006]. In the univariate analysis for PFS NASH-HCC was associated with longer mPFS (7.5 versus 6.5 months; HR 0.84; 95% CI 0.71-0.99; P = 0.0436). The multivariate analysis confirmed NASH-HCC (HR 0.64; 95% CI 0.48-0.86; P = 0.0028) as an independent prognostic factor for OS, along with albumin-bilirubin (ALBI) grade, extrahepatic spread, neutrophil-to-lymphocyte ratio, portal vein thrombosis, Eastern Cooperative Oncology Group (ECOG) performance status and alpha-fetoprotein. An interaction test was performed between sorafenib and lenvatinib cohorts and the results highlighted the positive predictive role of NASH in favor of the lenvatinib arm (P = 0.0047). CONCLUSION: NASH has been identified as an independent prognostic factor in a large cohort of patients with advanced HCC treated with lenvatinib, thereby suggesting the role of the etiology in the selection of patients for tyrosine kinase treatment. If validated, this result could provide new insights useful to improve the management of these patients.

Studies on biologically active halogenated compounds. 1. Synthesis and central nervous system depressant activity of 2-(fluoromethyl)-3-aryl-4(3H)-quinazolinone derivatives.

Some 2-(fluoromethyl) analogues of 2-methyl-3-aryl-4-(3H)-quinazolinones have been synthesized and screened for CNS activities. It was shown that the 2-(fluoromethyl) analogues possess in general more potent CNS depressant activities and less toxicities than their parent compounds. Of particular interest were the 2-(fluoromethyl) analogues (22, 24, and 31) of methaqualone and 6-aminomethaqualone. Compound 24 was more potent in CNS depressant activity and less toxic than methaqualone. Compound 31 exhbited potent central muscle relaxing activity and markedly reduced toxicity as compared with 6-aminomethaqualone.

Double-stranded RNA-induced interferon regulatory factor-1 gene expression in FRTL-5 rat thyroid cells.

Double-stranded RNA (dsRNA) plays a role in the regulation of cell growth and apoptosis as well as in the cellular antiviral responses. However, it remains unknown if dsRNA-activated signaling systems are functional in the thyroid. Here we report the presence of the dsRNA-dependent protein kinase (PKR) in FRTL-5 rat thyroid cells. In poly(I)-poly(C) (pIC)-stimulated cells, activation of nuclear factor-kappa B (NF kappa B) binding was clearly induced. Incubation of FRTL-5 cells with pIC resulted in a marked increase in interferon regulatory factor-1 (IRF-1) mRNA and phosphorylated signal transducer and activator of transcription-1 (STAT1) levels. Addition of pIC to cells led to type I interferon (IFN) gene expression, especially IFN beta, which can induce STAT1 phosphorylation, suggesting that dsRNA indirectly induced STAT1 phosphorylation through expression of type I IFN. Thus, our results suggest that the dsRNA-activated signaling pathway may be involved in the regulation of IFN-inducible genes in the thyroid.

Effects of thyroid hormone on carbonic anhydrase I gene expression in human erythroid cells.

Individuals with hyperthyroidism exhibit concentrations of carbonic anhydrase I (CAI) in red blood cells that reflect the integrated serum thyroid hormone concentration over the preceding few months. Furthermore, triiodothyronine T3, at a physiological free concentration, decreases the CAI concentration in both human erythroleukemic YN-1 cells and burst-forming unit-erythroid (BFU-E)-derived cells. In the present study, the effect of T3 on CAI mRNA levels in various human erythroleukemic cell lines (YN-1, HEL and KU-812) and BFU-E-derived cells was studied. Northern analysis of RNA extracted from erythroid cells revealed a CAI mRNA of 1.5 kilobases. T3 significantly decreased the levels of CAI mRNA in YN-1 and BFU-E-derived cells in a dose-dependent manner. Incubation of T3-stimulated cells with actinomycin D prevented the decrease in CAI mRNA levels. By contrast, T3 had no effect on either the concentrations of CAI or the levels of CAI mRNA in HEL and KU-812 cells. These results suggest that YN-1 and BFU-E-derived cells may be useful models for investigating T3 actions on CAI mRNA in human cells.

Antithyroid drugs inhibit radioiodine-induced increases in thyroid autoantibodies in hyperthyroid Graves' disease.

Methimazole (MMI) has been reported to affect prognosis in hyperthyroid Graves' disease patients treated with radioiodine (131I). In the present study, serum concentrations of thyroxine (T4), triiodothyronine (T3), thyroglobulin (Tg), thyrotropin-binding inhibitory immunoglobulin (TBII), thyroglobulin antibody (TgAb), and thyroid-peroxidase antibody (TPOAb) were measured serially for 1 year in patients with Graves' disease after 131I treatment either given alone (group 1, 41 patients) or followed by an antithyroid drug (group 2, 19 patients). The effect of antithyroid drugs on these parameters was analyzed retrospectively. Mean serum concentrations of T4 and T3 both decreased to normal within 3 months after 131I treatment in both groups. Serum Tg concentrations in group 1 showed significant transient increases (about four times the basal value) 1 month after 131I administration. Titers of TBII, TgAb, and TPOAb in group 1 also increased transiently after 131I treatment, with the maximum increase at 3 months. Antithyroid drugs significantly lessened 131I-induced increases in serum concentrations of Tg and all thyroid autoantibodies tested. One year after 131I treatment, 33 of 41 patients (80%) were euthyroid or hypothyroid in group 1; this was true for only 4 of 19 group II patients (22%). The results indicate that administering antithyroid drugs after 131I treatment reduced 131I-induced damage to the thyroid and reduced therapeutic efficacy of 131I in hyperthyroidism. Drug treatment also inhibited release of Tg and blunted 131I-induced increases in titers of thyroid autoantibodies.

Effects of ion channel blockers on rapid postmortem changes in extracellular dopamine and serotonin levels in the rat nucleus accumbens.

In the present study, we used in vivo brain microdialysis to examine the effects of ion channel blockers tetrodotoxin (TTX), EGTA-free Ca2+ and verapamil on rapid postmortem changes in extracellular levels of dopamine (DA), serotonin (5-HT) and their metabolites dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindoleacetic acid (5-HIAA) in the ACC of freely moving rats. Extracellular ACC DA levels decreased following the perfusion of the three ion channel blockers in freely moving rats, and then, at death by cervical dislocation, maximum respective 220-, 60- and 90-fold increases were observed in the extracellular output of DA in animals treated with EGTA, verapamil and TTX, respectively. Also, ACC 5-HT decreased following perfusion with the three blockers in the freely moving rats, and then maximum increases of 80-, 30- and 45-fold in the extracellular output of 5-HT were observed at death in animals treated with EGTA, verapamil and TTX, respectively, compared to the baseline. Cervical dislocation-induced rapid postmortem changes were inhibited markedly by perfusion with CSF containing the CA2+ entry blocker verapamil. These observations suggested that rapid postmortem changes in ACC DA and 5-HT release were associated with the action of calcium ion channels and/or voltage gated channels in the CNS.

Estimation of left ventricular myocardial elasticity and viscosity by a thick-walled spherical model.

The authors measured the transfer function (TF) of the left ventricle (LV) in an isolated canine preparation. Here TF indicates the ratio of induced vibration in LV to input vibration when an external mechanical oscillation is applied. TF had a single peak the frequency of which changed from 40 Hz to 80 Hz when LV pressure (LVP) increased from 6 mm Hg to 96 mm Hg. A mathematical model was formulated to estimate the viscoelasticity of the spherical shell. This model was constructed of the material points, elastic components which connected all the material points, and viscous components placed in series with elastic components. Theoretical TF can be computed if the viscoelastic values are given. The value of viscoelasticity at which the theoretical TF best fitted the experimental TF was considered to be the viscoelasticity of the model. The validity of this approach was verified using a silicone spherical shell. The estimated myocardial elasticity was 40 kPa when LVP was 6 mm Hg, 160-170 kPa when LVP was 96 mm Hg and was approximately proportional to LVP, whereas viscosity showed small change. The inclination of elasticity was consistent with previous reports. These results proved that myocardial elasticity can be estimated by analysing the transfer function of the left ventricle.

Simulation study on heart failure: effects of contractility on cardiac function.

Using the model proposed by Beyar and Sideman, the effect of maximum isometric active stress at optimal sarcomere length (sigma 0) on left ventricular (LV) function was examined. Comparing the results of calculated LV function with those of reported experiments, sigma 0 was shown to be a potential indicator of myocardial contractility, and the model of Beyar and Sideman successfully predicted LV function with various myocardial contractilities. The LVP compensation curve, which describes the relationship between sigma 0 and maximum LV pressure, was then hypothesized. The combination of the Beyar-Sideman model and the LVP compensation curve enabled the prediction and approximation of the actual process of deterioration in heart failure. These models represent a step towards a fundamentally new concept in the current clinical situation of compensated heart failure and also in evaluating the process of heart failure.

Simulation study on the effect of external vibration on left ventricular function: potential indicator of LV tolerance to the sudden reduction of myocardial contractility.

In a previous study the authors reported that external mechanical vibration applied to the left ventricular (LV) epicardium induces contractility-dependent depression in LV pressure, stroke volume and stroke work. It was suggested that this depression may be caused by the direct effect of external vibration on contractile protein. In another paper in this issue, it is proved that LV function with various myocardial contractilities and the actual process of deterioration in heart failure are well simulated in the model proposed by Beyar and Sideman, after some modifications have been made. In the study reported here it is assumed that an external mechanical vibration induces sudden reduction in myocardial active stress in the model of Beyar and Sideman; in this way the contractility-dependent effect of external vibration on LV function has been simulated. The results of this simulation support the suggestion that external mechanical vibration directly affects contractile protein and reduces LV function, and it is further suggested that the reduction of LV function induced by external vibration reflects the reserve or tolerance capacity of LV to a sudden reduction of myocardial contractility.

Model-based learning for mobile robot navigation from the dynamical systems perspective.

This paper discusses how a behavior-based robot can construct a "symbolic process" that accounts for its deliberative thinking processes using models of the environment. The paper focuses on two essential problems; one is the symbol grounding problem and the other is how the internal symbolic processes can be situated with respect to the behavioral contexts. We investigate these problems by applying a dynamical system's approach to the robot navigation learning problem. Our formulation, based on a forward modeling scheme using recurrent neural learning, shows that the robot is capable of learning grammatical structure hidden in the geometry of the workspace from the local sensory inputs through its navigational experiences. Furthermore, the robot is capable of generating diverse action plans to reach an arbitrary goal using the acquired forward model which incorporates chaotic dynamics. The essential claim is that the internal symbolic process, being embedded in the attractor, is grounded since it is self-organized solely through interaction with the physical world. It is also shown that structural stability arises in the interaction between the neural dynamics and the environmental dynamics, which accounts for the situatedness of the internal symbolic process, The experimental results using a mobile robot, equipped with a local sensor consisting of a laser range finder, verify our claims.

Fibrous band compression of the tibial nerve branch of the sciatic nerve.

Compression of the sciatic nerve, or its branches, by a fibrous band in the thigh region is a rare cause of sciatic neuropathy. A 42-year-old farmer with a 1-year history of right leg dysesthesias in the tibial nerve distribution was found on surgical exploration to have a fibrous band constricting the tibial branch of the sciatic nerve proximal to the popliteal fossa. Sectioning of this probably congenital band provided prompt relief of her symptoms with no recurrence 12 months after surgery.

Effects of ethanol on the levels of brain 6R-L-erythro-5, 6, 7, 8-tetrahydrobiopterin in the inbred strains of mice. DBA/2J, C3H/HeJ and C57BL/6J with different alcohol preferences.

6R-L-erythro-5, 6, 7, 8-tetrahydrobiopterin (6R-BH4) is a coenzyme for tyrosine, tryptophan and phenylalanine hydroxylases, the former two of which are the initial and the rate-limiting enzymes in the biosynthesis of the catecholamines and serotonin, respectively. The present study was designed to determine the changes in concentrations of 6R-BH4 in striatum and midbrain of the inbred strains of mice, DBA/2J, C3H/HeJ and C57BL/6J, with different genetically determined alcohol preferences, following the injection of ethanol (EtOH). The intraperitoneal administration of EtOH (0, 1, 2 and 4 g/kg) significantly and dose-dependently reduced the levels of striatal and midbrain 6R-BH4 in DBA/2J mice with the lowest alcohol preference, and EtOH (4 g/kg, i.p.) reduced the level of striatal 6R-BH4 in C3H/HeJ with medium alcohol preference. Following the administration of EtOH (4 g/kg, i.p.), brain 6R-BH4 levels in C57BL/6J mice with high alcohol preference were lowered compared with the control group, but the difference did not reach statistic significance. EtOH has a tendency to reduce the brain 6R-BH4 levels in mice with lower alcohol preference or higher sensitivity to EtOH. Based on these findings, it was proposed that differences in alcohol drinking behavior in the inbred strains of mice was influenced by brain 6R-BH4.

[Pituitary reserve of growth hormone in adolescent patients with cerebral palsy and mental retardation].

The pituitary reserve of growth hormone (GH) was studied in 11 severely handicapped boys (14 approximately 18 years old) with mental retardation and cerebral palsy (CP); athetotic type 4 cases, and spastic type 7 cases. Serum GH was determined before and after intravenous injection of 1 ng/kg growth hormone releasing factor (GRF) or oral administration of 0.1 mg/m2 clonidine. The athetotic type patients showed low somatomedin C (Sm C) concentrations (0.31 +/- 0.11 U/ml), poor responses to clonidine, and good responses to GRF. The spastic type patients showed subnormal responses to GRF although their Sm C was normal (0.91 +/- 0.43 U/ml). Clinically, the stature was small, and the puberty was delayed in the former. The levels of plasma testosterone were significantly lower than those in the latter. It is concluded that athetotic type CP was associated with hypothalamic GRF deficiency and spastic type CP was associated with reduced pituitary reserve of GH.

[Microdensitometric study of maturation and fragility of the bone in male patients with cerebral palsy--the effect of long-term administration of 1 alpha-hydroxy vitamin D3 and the value of osteocalcin as a marker of bony growth].

1) We studied bony maturation and fragility in 48 male patients (4-28 years old) with cerebral palsy. They were divided into three groups; group A (drug free, mild motor handicapped), 10 cases, group B (anticonvulsants administrated, mild motor handicapped), 20 cases, group C (anticonvulsants administrated, severe motor handicapped) 18 cases. The indicator of bone mineral content (sigma GS/D) and metacarpal index (MCI) were analyzed by microdensitometric method. A positive correlation between age and sigma GS/D was detected in all groups but a positive correlation between age and MCI was found only in the group B. There was little difference in sigma GS/D and MIC between group A and group B, but those of group C were significantly decreased. These results suggest that increase of bone mineral is related with aging but metacarpal growth is variable, and a lack of daily activity has greater adverse effect on bony metabolism than administration of anticonvulsants. 2) The alterative rates of sigma GS/D (delta sigma GS/D/sigma GS/D/year) and MCI (delta MCI/MCI/year) after 1 alpha-hydroxy vitamin D3 (D3) treatment for 3 years or more were examined in 17 patients with bony atrophy, as compared with normal controls. The alterative rates of sigma GS/D and MCI were elevated in younger patients with D3 treatment but those were decreased in adult patients. Treatment with D3 remarkably increased bony growth in children. 3) In 37 patients, osteocalcin (OC) was measured by radioimmunoassay. OC was elevated in younger patients who were treated with D3.(ABSTRACT TRUNCATED AT 250 WORDS)