Sativex-induced neurobehavioral effects: causal or concausal? A practical advice!

Nabiximols (Sativex) is an oromucosal spray, containing delta-9 tetrahydrocannabinol (THC) and cannabidiol (CBD), used as treatment for unresponsive spasticity in multiple sclerosis (MS) patients. Sativex is thought to not affect cognition or induce any psychiatric problem at the doses generally used. Nonetheless, it is known that the concomitant use of more than one muscle-relaxant drugs can result in additive neuropsychiatric effects. Herein we describe a case of a woman affected by MS and treated with baclofen and methylprednisolone, who developed important behavioral changes, including suicidal ideation, after 4 weeks of Sativex administration. We are not completely able to state if Sativex alone was responsible for our patient’s psychiatric symptoms, in reason of the concomitant use of the other drugs.In conclusion, physicians should pay more attention when prescribing drugs to MS patients affected by spasticity, including Sativex, since neurobehavioral side effects may emerge especially in predisposed individuals.     

Nuclear fractal dimension in oral squamous cell carcinoma: a novel method for the evaluation of grading,staging, and survival

Fractal dimension (FD) in tissue specimens from patients with oral squamous cell carcinoma (OSCC) was evaluated. FD values in different stages of OSCC, and the correlations with clinicopathological variables and patient survival were investigated. Histological sections from OSCC and control non‐neoplastic mucosa specimens were stained with hematoxylin–eosin for pathological analysis and with Feulgen for nuclear evaluation. FD in OSCC groups vs. controls revealed statistically significant differences (P < 0.001). In addition, a progressive increase of FD from stage I and II lesions and stage III and IV lesions was observed, with statistically significant differences (P = 0.003). Moreover, different degrees of tumor differentiation showed a significant difference in the average nuclear FD values (P = 0.001). A relationship between FD and patients' survival was also detected with lower FD values associated to longer survival time and higher FD values with shorter survival time (P = 0.034). These data showed that FD significantly increased during OSCC progression. Thus, FD could represent a novel prognostic tool for OSCC, as FD values significantly correlated with patient survival. Fractal geometry could give insights into tumor morphology and could become an useful tool for analyzing irregular tumor growth patterns.     

Carotid–Femoral Pulse Wave Velocity Assessed by Ultrasound: A Study with Echotracking Technology

Described here is a new method for determination of carotid–femoral pulse wave velocity (PWV) based on arterial diameter waveform recording by an ultrasound system. The study was carried out on 120 consecutive patients. Carotid–femoral PWV was determined using a tonometric technique (PWVpp, PulsePen, DiaTecne, Milan, Italy) and an echotracking ultrasound system (PWVet, E-Track, Aloka, Tokyo, Japan). The relationship between PWVpp and PWVet was evaluated by linear regression and Bland–Altman analysis. There was excellent agreement between PWVet and PWVpp (Pearson's r = 0.94, 95% confidence interval: 0.91–0.96, p < 0.0001; PWVet = 0.88 × PWVpp + 0.57). The Bland–Altman plot revealed an offset of ?0.33 m/s with limits of agreement from ?2.21 to 1.54 m/s. The coefficients of variation for within-subject repeatability between PWVet and PWVpp had were 5.79% and 8.47%, respectively, without significant differences in the Bland–Altman analysis. The results suggest that echotracking technology can provide a reliable estimate of aortic stiffness comparable to that of the tonometric techniques.     

MRI angiography is superior to helical CT for detection of HCC prior to liver transplantation: an explant correlation

Helical computerized tomography (CT) and magnetic resonance imaging (MRI) are used for staging of hepatocellular carcinoma (HCC) prior to curative treatments but underestimate tumor extension in 30% to 50% of cases when compared with pathologic explants. This study compares a new technology, MRI angiography (MRA), with triphasic helical CT in detection of HCC. Fifty cirrhotic patients, 29 with HCC, undergoing liver transplantation were analyzed. MRA was performed with a 3-D breath-hold fast spoiled gradient-echo sequence by using an effective section thickness of 2 to 2.5 mm. The gold standard was the pathologic examination (liver cut into 5-mm slices). One hundred twenty-seven lesions were identified at the explant: 76 HCC, 13 high-grade dysplastic nodules, 31 macroregenerative nodules, 7 hemangiomas. Diameter of the main HCC nodules was 29 +/- 14 mm and 11 +/- 7 mm for the 47 additional nodules. On a per nodule basis, sensitivity of MRA was superior to CT (58/76 [76%] vs. 43/70 [61%], respectively, P =.001). Sensitivity of MRA for detection of additional nodules decreased with size (>20 mm: 6/6 [100%]; 10-20 mm: 16/19 [84%]; <10 mm: 7/22 [32%]) and was superior to CT for nodules 10 to 20 mm (84% vs. 47%, P =.016). Nonspecific hypervascular nodules >5 mm at MRA were HCC in two thirds of the cases. In conclusion, MRA has a high diagnostic accuracy for HCC > or =10 mm and is more sensitive than triphasic helical CT in nodules sized 10 to 20 mm. MRA is the optimal technique for HCC staging prior to curative therapies.     

The antihypertensive chromogranin a peptide catestatin acts as a novel endocrine/paracrine modulator of cardiac inotropism and lusitropism

Circulating levels of catestatin (Cts; human chromogranin A352-372) decrease in the plasma of patients with essential hypertension. Genetic ablation of the chromogranin A (Chga) gene in mice increases blood pressure and pretreatment of Chga-null mice with Cts prevents blood pressure elevation, indicating a direct role of Cts in preventing hypertension. This notable vasoreactivity prompted us to test the direct cardiovascular effects and mechanisms of action of wild-type (WT) Cts and naturally occurring human variants (G364S-Cts and P370L-Cts) on myocardial and coronary functions. The direct cardiovascular actions of WT-Cts and human variants were determined using the Langendorff-perfused rat heart. WT-Cts dose-dependently increased heart rate and coronary pressure and decreased left ventricular pressure, rate pressure product and both positive and negative LVdP/dt. WT-Cts not only inhibited phospholamban phosphorylation, but also the inotropic and lusitropic effects of WT-Cts were abolished by chemical inhibition of beta2-adrenergic receptors, Gi/o protein, nitric oxide or cGMP, indicating involvement of beta2-adrenergic receptors-Gi/o protein-nitric oxide-cGMP signaling mechanisms. In contrast, G364S-Cts did not affect basal cardiac performance but abolished isoproterenol-induced positive inotropism and lusitropism. P370L-Cts decreased rate pressure product and inhibited only isoproterenol-induced positive inotropism and lusitropism by 70%. Cts also inhibited endothelin-1-induced positive inotropism and coronary constriction. Taken together, the cardioinhibitory influence exerted on basal mechanical performance and the counterregulatory action against beta-adrenergic and endothelin-1 stimulations point to Cts as a novel cardiac modulator, able to protect the heart against excessive sympathochromaffin overactivation, e.g. hypertensive cardiomyopathy.     

Critical preparedness and operational response actions directed for the acute and post-acute COVID-19 pandemic in Brazil: the experience of a nationwide outpatient healthcare group

While the new Coronavirus Disease 2019 (COVID-19) pandemic rapidly spread across the world, South America was reached later in relation to Asia, Europe and the United States of America (USA). Brazil concentrates now the largest number of cases in the continent and, as the disease speedily progressed throughout the country, prompt and challenging operational strategies had to be taken by institutions caring for COVID-19 and non-COVID-19 patients in order to assure optimal workflows, triage, and management. Although hospitals in the USA, Europe and Asia have shared their experience on this subject, little has been discussed about such strategies in South America or by the perspective of outpatient centers, which are paramount in the radiology field. This article shares the guidelines adopted early in the pandemic by a nationwide outpatient healthcare center composed by a network of more than 200 patient service centers and nearly 2,000 radiologists in Brazil, discussing operational and patient management strategies, staff protection, changes adopted in the fellowship program, and the effectiveness of such measures.     

Inhibition of hepatitis C virus translation and subgenomic replication by siRNAs directed against highly conserved HCV sequence and cellular HCV cofactors

BACKGROUND/AIMS: Small interfering RNAs (siRNAs) are an efficient tool to specifically inhibit gene expression by RNA interference. Since hepatitis C virus (HCV) replicates in the cytoplasm of liver cells without integration into the host genome, RNA-directed antiviral strategies are likely to successfully block the HCV replication cycle. Additional benefit might arise from inhibition of cellular cofactors of HCV replication, such as proteasome alpha-subunit 7 (PSMA7) or Hu antigen R (HuR). METHODS: In this study, we investigated direct and cofactor-mediated inhibition of HCV by a panel of DNA-based retroviral vectors expressing siRNAs against highly conserved HCV sequences or the putative HCV cofactors PSMA7 and HuR. Effects were determined in HCV IRES-mediated translation assays and subgenomic HCV replicon cells. RESULTS: PSMA7- and HuR-directed siRNAs successfully inhibited expression of the endogenous genes, and PSMA7 and HuR silencing significantly diminished HCV replicon RNA and NS5B protein levels. HCV-directed siRNAs substantially inhibited HCV IRES-mediated translation and subgenomic HCV replication. Combinations of PSMA7- and HuR-directed siRNAs with HCV-directed siRNAs revealed additive HCV RNA inhibitory effects in monocistronic replicon cells. CONCLUSIONS: A dual approach of direct- and cofactor-mediated inhibition of HCV replication might avoid selection of mutants and thereby become a powerful strategy against HCV.     

Weekly docetaxel versus CMF as adjuvant chemotherapy for elderly breast cancer patients: safety data from the multicentre phase 3 randomised ELDA trial

Within an ongoing multicentre phase 3 randomised trial (ELDA, cancertrials.gov ID: NCT00331097), early breast cancer patients, 65-79 years old, with average to high risk of recurrence, are randomly assigned to receive CMF (cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2, fluorouracil 600 mg/m2, days 1-8) or docetaxel (35 mg/m2 days 1-8-15), every 4 weeks. Here we report an unplanned safety analysis prompted by an amendment introducing creatinine clearance as a tool to adjust methotrexate dose. Before such change, 101 patients with a median age of 70 were randomly assigned CMF (53 patients) or docetaxel (48 patients). At least one grades 3-4 toxic event of any type was reported in 40 (75.5%) and 19 (39.6%) patients with CMF and docetaxel, respectively (p=0.0002). Grades 3-4 hematological events were observed in 37 (69.8%) vs. 4 (8.3%) cases (p<0.0001) and grades 3-4 non-hematological toxicity in 12 (22.6%) vs. 15 (31.2%) patients (p=0.11), with CMF and docetaxel, respectively. A higher incidence of anemia, neutropenia, thrombocytopenia and febrile neutropenia was reported with CMF. Constipation, mucositis, nausea and vomiting were more common with CMF; diarrhoea, abdominal pain, dysgeusia, neuropathy and liver toxicity were more frequent with docetaxel. No significant interaction was found between the occurrence of severe toxicity and baseline variables, including creatinine clearance and geriatric activity scales. In conclusion, weekly docetaxel appears to be less toxic than CMF in terms of hematological toxicity.     

Inflammatory status and endothelial function in asymptomatic and symptomatic peripheral arterial disease

Peripheral arterial disease (PAD) is a predictor of cardiovascular risk. However, it is unknown whether PAD severity influences inflammatory status and endothelial function, which play a major role in atherosclerosis. Accordingly, we measured brachial artery flow-mediated dilation (FMD), and plasma levels of several inflammatory markers in 15 control subjects, and 19 asymptomatic and 19 symptomatic PAD patients. Each symptomatic patient was matched to an asymptomatic patient for age, sex, risk factors, presence of cardiovascular disease, and pharmacological treatments. Asymptomatic patients had similar inflammatory profiles as controls, but lower median FMD (11.7% vs 8.5%, p < 0.01). Compared with asymptomatic patients, symptomatic patients had higher median C-reactive protein (1.5 mg/l vs 6.0 mg/l, p < 0.05) and interleukine-6 (1.5 pg/ml vs 3.5 pg/ml, p < 0.05), and lower FMD (8.5% vs 5.1%, p < 0.01). In the 38 PAD patients, the ankle/brachial pressure index correlated positively with FMD (p < 0.01), and negatively with C-reactive protein (p < 0.05), soluble intercellular adhesion molecule-1 (p < 0.05) and soluble vascular cell adhesion molecule-1 (p < 0.05). Thus, in PAD, endothelial function and inflammatory status are related to the severity of the circulatory impairment. This finding may contribute to the explanation of the increasingly poor prognosis with increased PAD severity.