Bark extract of Bathysa cuspidata attenuates extra-pulmonary acute lung injury induced by paraquat and reduces mortality in rats

This study investigated the effect of the bark extract of Bathysa cuspidata on paraquat (PQ)-induced extra-pulmonary acute lung injury (ALI) and mortality in rats. ALI was induced with a single dose of PQ (30 mg/kg, i.p.), and animals were treated with B. cuspidata extract (200 and 400 mg/kg). Analyses were conducted of survival, cell migration, lung oedema, malondialdehyde, proteins carbonyls, catalase, superoxide dismutase, histopathology and the stereology of lung tissue. Rats exposed to PQ and treated with 200 and 400 mg of the extract presented lower mortality (20% and 30%), compared with PQ alone group (50%). Furthermore, lung oedema, septal thickening, alveolar collapse, haemorrhage, cell migration, malondialdehyde and proteins carbonyl levels decreased, and catalase and superoxide dismutase activity were maintained. These results show that the bark extract of B. cuspidata reduced PQ-induced extra-pulmonary ALI and mortality in rats and suggest that these effects may be associated with the inhibition of oxidative damage.     

No meaningful association between suicidal behavior and the use of IL-17A-neutralizing or IL-17RA-blocking agents

ABSTRACT

Introduction: An emerging class of agents blocking IL-17 signaling represents a very promising therapeutic approach. One of these agents, brodalumab, has been associated with an increased risk of suicide behavior.

Areas covered: This review sought to provide an overview strictly focused on suicide behavior signals related to the use of IL-17 agents. Data collection regarding this peculiar safety aspect was primarily based on: (i) a revision of safety outcomes belonging to phase II and phase III trials; (ii) a systematic search using the Pubmed Medline database; and (iii) collecting recent data issued as posters or communications in eminent international meetings.

Expert opinion: Whilst secukinumab and ixekizumab were not associated with increased signal of suicidal behavior, being recently approved for the treatment of psoriasis by EMA and FDA, brodalumab raised concern because of suicide behavior cases that led to pause momentarily its development program during pre-marketing stage before obtaining the positive recommendation by an FDA advisory panel for its approval. Indeed, a careful re-evaluation of brodalumab safety profile is being performed and no evidence clarified a significant association or a pathogenic mechanism linking brodalumab treatment to the risk of suicidal behavior, suggesting that cases of suicidal behavior accidentally occurred during brodalumab trials.     

Polymorphic variants in exon 8 at the 3' UTR of the HLA-G gene are associated with septic shock in critically ill patients

Introduction

Critically ill patients are characterized as individuals hospitalized in the Intensive Care Unit (ICU) and can evolve to sepsis, septic shock or even death. Among others, genetic factors can influence the outcome of critically ill patients. HLA-G is a non-classical class Ib molecule that has limited protein variability, presenting seven isoforms generated by alternative splicing, and presents immunomodulatory properties. Polymorphisms at the 3''UTR are thought to influence HLA-G gene expression. It was previously observed that increased sHLA-G5 levels were predictive of survival among septic shock patients. We assessed the frequencies of 7 polymorphisms in exon 8 at the 3'' UTR of HLA-G and associated these variants with different clinical outcomes in critically ill patients.

Methods

Exon 8 at the 3'' UTR of the HLA-G gene from 638 critically ill subjects was amplified by PCR and sequenced. Genotypes were identified using FinchTV software v.1.4.0 and the most probable haplotype constitution of each sample was determined by PHASE software v.2.1. Haplotype frequencies, linkage disequilibrium, heterozygosity test and Hardy-Weinberg Equilibrium were estimated using ARLEQUIN software v.3.5.

Results

Among all critically ill patients, an association between carriers of the +2960IN_+3142 G_+3187A haplotype and septic shock (P = 0.047) was observed. Septic patients who carried the +2960IN_+3142G_+3187A haplotype presented an increased risk for septic shock (P = 0.031).

Conclusions

The present study showed, for the first time, an association between polymorphisms in exon 8 at the 3 ''UTR of HLA-G gene and outcomes of critically ill patients. These results may be important for understanding the mechanisms involved in evolution to septic shock in critically ill patients.     

Effect of bark extract of Bathysa cuspidata on hepatic oxidative damage and blood glucose kinetics in rats exposed to paraquat

This study investigated the effect of bark extract of Bathysa cuspidata on hepatic oxidative damage and blood glucose kinetics in rats exposed to paraquat. Wistar rats were exposed to a single dose of paraquat (30 mg/kg, i.p.) and treated with an ethanolic extract of Bathysa cuspidata (200 and 400 mg/kg). Analyses were conducted of liver edema, blood glucose, serum transaminases, alkaline phosphatase, collagen, malondialdehyde, catalase, superoxide dismutase, and histomorphometry. In the animals intoxicated with paraquat and treated with 400 mg/kg of extract, edema, hypertrophy of the nucleus of hepatocytes, serum transaminases, alkaline phosphatase, and malondialdehyde levels decreased significantly (p < .05). Catalase and superoxide dismutase activity, the number of hepatocytes per unit volume, and the glycogen proportion were maintained. The increase followed by progressive reduction of blood glucose observed in paraquat-exposed groups was significantly attenuated in the group treated with 400 mg/kg of extract (p < .05). Phytochemical analysis of the extract revealed the presence of flavonoids, proanthocyanidins, and phenolic compounds. The bark extract of Bathysa cuspidata was able to inhibit large variations in blood glucose and reduce hepatic damage in rats exposed to paraquat. This finding suggests a contribution of the extract in reducing lipid peroxidation and the morphofunctional damage to the liver parenchyma.     

Impaired TrkB receptor signaling contributes to memory impairment in APP/PS1 mice

Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal plasticity, learning, and memory. Levels of BDNF and its main receptor TrkB (TrkB.TK) have been reported to be decreased while the levels of the truncated TrkB (TrkB.T1) are increased in Alzheimer's disease. We show here that incubation with amyloid-β increased TrkB.T1 receptor levels and decreased TrkB.TK levels in primary neurons. In vivo, APPswe/PS1dE9 transgenic mice (APdE9) showed an age-dependent relative increase in cortical but not hippocampal TrkB.T1 receptor levels compared with TrkB.TK. To investigate the role of TrkB isoforms in Alzheimer's disease, we crossed AP mice with mice overexpressing the truncated TrkB.T1 receptor (T1) or the full-length TrkB.TK isoform. Overexpression of TrkB.T1 in APdE9 mice exacerbated their spatial memory impairment while the overexpression of TrkB.TK alleviated it. These data suggest that amyloid-β changes the ratio between TrkB isoforms in favor of the dominant-negative TrkB.T1 isoform both in vitro and in vivo and supports the role of BDNF signaling through TrkB in the pathophysiology and cognitive deficits of Alzheimer's disease.     

The Neuro/PsyGRID calibration experiment: identifying sources of variance and bias in multicenter MRI studies

Calibration experiments precede multicenter trials to identify potential sources of variance and bias. In support of future imaging studies of mental health disorders and their treatment, the Neuro/PsyGRID consortium commissioned a calibration experiment to acquire functional and structural MRI from twelve healthy volunteers attending five centers on two occasions. Measures were derived of task activation from a working memory paradigm, fractal scaling (Hurst exponent) from resting fMRI, and grey matter distributions from T(1) -weighted sequences. At each intracerebral voxel a fixed-effects analysis of variance estimated components of variance corresponding to factors of center, subject, occasion, and within-occasion order, and interactions of center-by-occasion, subject-by-occasion, and center-by-subject, the latter (since there is no intervention) a surrogate of the expected variance of the treatment effect standard error across centers. A rank order test of between-center differences was indicative of crossover or noncrossover subject-by-center interactions. In general, factors of center, subject and error variance constituted >90% of the total variance, whereas occasion, order, and all interactions were generally <5%. Subject was the primary source of variance (70%-80%) for grey-matter, with error variance the dominant component for fMRI-derived measures. Spatially, variance was broadly homogenous with the exception of fractal scaling measures which delineated white matter, related to the flip angle of the EPI sequence. Maps of P values for the associated F-tests were also derived. Rank tests were highly significant indicating the order of measures across centers was preserved. In summary, center effects should be modeled at the voxel-level using existing and long-standing statistical recommendations.     

TTC7B emerges as a novel risk factor for ischemic stroke through the convergence of several genome-wide approaches

We hereby propose a novel approach to the identification of ischemic stroke (IS) susceptibility genes that involves converging data from several unbiased genetic and genomic tools. We tested the association between IS and genes differentially expressed between cases and controls, then determined which data mapped to previously reported linkage peaks and were nominally associated with stroke in published genome-wide association studies. We first performed gene expression profiling in peripheral blood mononuclear cells of 20 IS cases and 20 controls. Sixteen differentially expressed genes mapped to reported whole-genome linkage peaks, including the TTC7B gene, which has been associated with major cardiovascular disease. At the TTC7B locus, 46 tagging polymorphisms were tested for association in 565 Portuguese IS cases and 520 controls. Markers nominally associated in at least one test and defining associated haplotypes were then examined in 570 IS Spanish cases and 390 controls. Several polymorphisms and haplotypes in the intron 5-intron 6 region of TTC7B were also associated with IS risk in the Spanish and combined data sets. Multiple independent lines of evidence therefore support the role of TTC7B in stroke susceptibility, but further work is warranted to identify the exact risk variant and its pathogenic potential.     

A novel integrated mechanomyogram-vocalization access solution

We introduce a novel dual-switch control paradigm based on the simultaneous measurement of frontalis muscle mechanomyography (MMG) and vocalizations (humming) using a single contact microphone attached to the forehead. Vibrations of the face and skull during vocalization are manifested as periodic high-frequency components in the microphone signal recorded at the forehead. The presence of these periodic components is detected by a normalized cross-correlation function, while muscle contractions are detected using a continuous wavelet transform method. The dual-switch provides two independent binary control signals. Eleven participants, including one individual with severe physical disabilities, participated in a cued activation task in which the dual-switch exhibited sensitivities and specificities of 96.8 ± 3% and 98.4 ± 1%, respectively for vocalizations, and 99.7 ± 0.5% and 99.2 ± 0.5%, respectively for muscle contractions. Since skin vibrations due to voiced sounds and muscle contractions have non-overlapping dominant bandwidths, the performance of the MMG switch was not affected by vocalizations. This new integrated MMG-vocalization access solution affords the user two binary switches from a single access site, and may thus augment access alternatives for certain individuals with severe physical disabilities.     

Inflammatory pseudotumor: A diagnostic dilemma

Inflammatory pseudotumor (IP) is a disorder that constitutes a differential diagnosis of a series of clinical conditions due to a large spectrum of manifestations in presentation since it can involve any organ of the human body. Its basic characteristic is the appearance of inflammatory masses whose symptoms depend on their location. We describe two cases of IP that clearly illustrate this diversity of presentation and we review the diagnostic and therapeutic strategies for such a condition.