B.A.R.C.O.S. (Brazilian Argentine Hepatitis C Collaborative Observational Study): Effectiveness and clinical outcomes of HCV treatment with daclatasvir and sofosbuvir with or without ribavirin

Real‐world data evaluating the effectiveness of direct‐acting antivirals (DAAs) in hepatitis C virus (HCV) treatment have been reported from different regions. Our aim was to evaluate the effectiveness and clinical outcomes of daclatasvir (DCV) and sofosbuvir (SOF) ± ribavirin (RBV) in a prospective multicentre cohort study including patients from Argentina and Brazil who received DCV/SOF ± RBV for 12 or 24 weeks from 2015 to 2018. Multivariable logistic regression models were carried out to identify factors associated with failure to achieve sustained virologic response (SVR) as a primary end point, and to death, decompensation, hepatocellular carcinoma (HCC) or liver transplantation (LT) as a composite secondary end point. From a total of 1517 patients treated with DCV/SOF, 906 completed 12 weeks post‐treatment evaluation and were included in the analysis. Overall SVR12 rate was 96.1% (95% CI: 94.6%‐97.2%), and 95% (95% CI: 92.8%‐96.6%) in patients with cirrhosis. LT recipients and presence of cirrhosis were independently associated with failure to achieve SVR. During post‐SVR12 follow‐up, cumulative incidence of the secondary end point was 2.4% (95% CI: 1.5%‐3.6%); two patients died from nonliver‐related causes and two from HCC, five underwent LT, 12 developed HCC and 17 patients developed hepatic decompensation. Independent variables associated with these composite secondary end points were prior to HCV treatment and presence of cirrhosis. In conclusion, although the high pangenotypic effectiveness of DCV/SOF ± RBV was confirmed in our real‐life cohort, patients with compensated and decompensated cirrhosis showed higher risk of non‐SVR and complication appearance during treatment or after achieving SVR.     

Imatinib-induced fatal acute liver failure

Imatinib mesylate is a drug that has been approved for treatment of chronic myeloid leukemia (CML) in blast crisis, accelerated or chronic phase, and also for advanced gastrointestinal stromal tumors. Severe hepatic toxicity and three deaths from hepatic failure have been reported. We report the case of a 51-year-old woman who was admitted to our institution with severe acute hepatitis. She was diagnosed with CML and began treatment with imatinib mesylate at a dose of 400 mg/d. Five months after beginning treatment, she developed severe hepatitis associated with coagulopathy, and was admitted to our institution. She had been consuming acetaminophen 500-1000 mg/d after the onset of symptoms. She had a progressive increase in bilirubin level and a marked decrease of clotting factor Ⅴ. Five days after admission, grade Ⅱ encephalopathy developed and she was referred for liver transplantation. Her clinical condition progressively deteriorated, and 48 h after being referred for transplantation she suffered a cardiac arrest and died. This report adds concern about the possibility of imatinib-mesylate-induced hepatotoxicity and liver failure, particularly in the case of concomitant use with acetaminophen. Liver function tests should be carefully monitored during treatment and, with the appearance of any elevation of liver function tests, treatment should be discontinued.     

New kappa opioid receptor from zebrafish Danio rerio

A cDNA that encodes a kappa opioid receptor like from zebrafish (ZFOR3) has been cloned and characterized. The encoded protein is 377 residues long and presents 70% identity with the mammalian kappa receptors, although less homology is found in the amino- and carboxyl-terminus as well as in the extracellular loops. In situ hybridization studies have revealed that ZFOR3 mRNA is highly expressed in particular brain areas that coincide with the expression of the kappa opioid receptor in other species. When ZFOR3 is stably expressed in HEK293 cells, [(3)H]-diprenorphine binds with high affinity (K(D)=1.05+/-0.26 nM), being this value on the same range as those reported for mammalian kappa opioid receptors. On the other hand, the selective agonist for mammalian kappa receptors U69,593 does not bind to ZFOR3. [(3)H]-diprenorphine binding is readily displaced by the peptidic ligand dynorphin A and by the non-endogenous compounds bremazocine, naloxone and morphine, although with different affinities. Our results demonstrate that ZFOR3 is a unique model to study the kappa opioid receptor functionality.     

Visuo-spatial processing is linked to cortical glutamate dynamics in Parkinson's disease — a 7-T functional magnetic resonance spectroscopy study

Background and purpose

Cognitive decline is a frequent and debilitating non-motor symptom for patients with Parkinson's disease (PD). Metabolic alterations in the occipital cortex during visual processing may serve as a biomarker for cognitive decline in patients with PD.

Methods

Sixteen patients with PD (Unified Parkinson's Disease Rating Scale Part 3, OFF, 38.69 ± 17.25) and 10 age- and sex-matched healthy controls (HC) underwent 7-T functional magnetic resonance spectroscopy (MRS) utilizing a visual checkerboard stimulation. Glutamate metabolite levels during rest versus stimulation were compared. Furthermore, correlates of the functional MRS response with performance in visuo-cognitive tests were investigated.

Results

No differences in static MRS between patients with PD and HC were detected, but a dynamic glutamate response was observed in functional MRS in HC upon visual stimulation, which was blunted in patients with PD (F_1,22 = 7.13, p = 0.014; ${\eta }_{\mathrm{p}}^2$ = 0.245). A diminished glutamate response correlated with poorer performance in the Benton Judgment of Line Orientation test in PD (r = −0.57, p = 0.020).

Conclusions

Our results indicate that functional MRS captures even subtle differences in neural processing linked to the behavioral performance, which would have been missed by conventional, static MRS. Functional MRS thus represents a promising tool for studying molecular alterations at high sensitivity. Its prognostic potential should be evaluated in longitudinal studies, prospectively contributing to earlier diagnosis and individual treatment decisions.     

Atorvastatin shows antitumor effect in hepatocellular carcinoma development by inhibiting angiogenesis via TGF-β1/pERK signaling pathway

Hepatocellular carcinoma (HCC) represents 90% of liver tumors. Statins may reduce HCC incidence. Its antitumor activities may be mediated by disrupting several hepatocarcinogenic pathways. To evaluate in vivo and in vitro the antiproliferative and antiangiogenic action of atorvastatin (AT) in the development of HCC as well as its mechanisms of action. In vivo model: hexachlorobenzene (HCB) was used to promote the development of HCC in Balb/C nude mice. Number of hepatic tumor, liver cell proliferation parameters (proliferating cell nuclear antigen, PCNA), angiogenesis, and VEGF levels were analyzed. In vitro model: Hep-G2 and Ea-hy926 cells were used to evaluate the effect of different doses of AT on HCB induced cell proliferation, migration, and vasculogenesis and to analyze proliferative parameters. In vivo: AT prevented liver growth and tumor development and inhibited PCNA, TGF-β1, and pERK levels increase. AT prevented skin blood vessel formation. In vitro, AT prevented cell proliferation and migration as well as tubular formation in the endothelial cell line by inhibiting the MAPK ERK pathway. We were able to demonstrate the potential AT antiproliferative and antiangiogenic effects in an HCC model and the involvement of TGF-β1 and pERK pathways.     

Neocortical and medial temporal seizures have distinct impacts on brain responsiveness

Focal epileptic seizures are characterized by abnormal neuronal discharges that can spread to other cortical areas and interfere with brain activity, thereby altering the patient's experience and behavior. The origin of these pathological neuronal discharges encompasses various mechanisms that converge toward similar clinical manifestations. Recent studies have suggested that medial temporal lobe (MTL) and neocortical (NC) seizures are often underpinned by two characteristic onset patterns, which, respectively, affect and spare synaptic transmission in cortical slices. However, these synaptic alterations and their effects have never been confirmed or studied in intact human brains. To fill this gap, we here evaluate whether responsiveness of MTL and NC are differentially affected by focal seizures, using a unique data set of cortico-cortical evoked potentials (CCEPs) collected during seizures triggered by single-pulse electrical stimulation (SPES). We find that responsiveness is abruptly reduced by the onset of MTL seizures, despite increased spontaneous activity, whereas it is preserved in the case of NC seizures. The present results provide an extreme example of dissociation between responsiveness and activity and show that brain networks are diversely affected by the onset of MTL and NC seizures, thus extending at the whole brain level the evidence of synaptic alteration found in vitro.