A randomized,multicenter trial assessing the effects of rapastinel compared to ketamine,alprazolam, and placebo on simulated driving performance

N‐methyl‐D‐aspartate ionotropic glutamatergic receptor (NMDAR) modulators, including rapastinel and ketamine, elicit rapid and sustained antidepressant responses in patients with treatment‐resistant major depressive disorder. This phase I, randomized, multicenter, placebo‐controlled, five‐period, crossover, single‐dose study evaluated simulated driving performance of healthy participants (N = 107) after single doses of rapastinel slow intravenous (i.v.) bolus 900 and 1800 mg, alprazolam oral 0.75 mg (positive control), ketamine i.v. infusion 0.5 mg/kg (clinical comparator), and placebo ~ 45 min before driving. The primary end point was SD of lateral position (SDLP) during the 60‐min 100‐km simulated driving scenario. Additional measures of driving performance, sleepiness, and cognition were also evaluated. To assess effects over time, mean SDLP was calculated for each 10‐min interval of driving. Sensitivity of the assays was confirmed with alprazolam (all placebo comparisons p < 0.02). Rapastinel 900 and 1800 mg did not significantly affect simulated driving performance compared to placebo (both p > 0.5). Both rapastinel doses resulted in significantly less impaired driving compared to alprazolam or ketamine (all p < 0.002); ketamine significantly impaired driving compared to placebo (p = 0.0001). Results for the additional measures were similar to the primary end point. No new safety signals were observed for any study interventions. This first study of rapastinel effects on simulated driving found that rapastinel 900 and 1800 mg did not impair driving performance, but ketamine 0.5 mg/kg resulted in significantly impaired driving performance. Ketamine’s effects on driving were maintained for at least 105 min, indicating that clinicians should be vigilant to prevent or postpone driving in patients after ketamine treatment.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Prior to this current study, the effects of rapastinel, an N‐methyl‐D‐aspartate ionotropic glutamatergic receptor (NMDAR) modulator, on driving performance were unknown. Ketamine, a current treatment for major depressive disorder, also an NMDAR modulator, has previously been shown to impair driving. Its effects have not been investigated in a large placebo‐controlled randomized control trial or over multiple time points following dosing.

• WHAT QUESTION DID THIS STUDY ADDRESS?

What are the effects of rapastinel compared to placebo and ketamine on driving performance and driving‐related measures?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This is the first study investigating the effects of rapastinel on driving performance that showed single doses of rapastinel (900 or 1800 mg) did not impair driving performance or affect driving‐related measures compared to placebo. An i.v. infusion of ketamine 0.5 mg/kg impaired driving and related measures for up to 105 min following dosing when compared to placebo, rapastinel 900 mg, and rapastinel 1800 mg.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Clinicians will become aware of the risk of impaired driving in patients treated with ketamine.     

Surgical management of Ebstein anomaly: impact of the adult congenital heart disease anatomical and physiological classifications

OBJECTIVESOur goal was to evaluate the impact of the adult congenital heart disease anatomical and physiological (ACHD AP) classification system on the surgical management of Ebstein anomaly (EA) in adult patients.METHODSFrom February 2000 through August 2017, data of patients aged at least 16 years, who underwent primary EA surgery, were retrospectively evaluated. The cohort was divided in 2 groups according to their ACHD AP classification: the moderate EA group (IIB, IIC) and the severe EA group (IID). Survival, freedom from reoperation and freedom from occurrence of major adverse advents were estimated.Open in a separate windowRESULTSThere were 33 patients (21 women, 12 men). Eighteen belonged to the moderate group, 15 to the severe group. There were 12 female patients (80%) in the severe group. Patients in the moderate group were younger than those in the severe group (P = 0.02): 32 ± 12 vs 44 ± 15 years old. Thirty tricuspid valve repairs and 3 replacements were performed. Repair was mainly performed in the moderate group (P = 0.02). Overall survival was 90.1 ± 5.4% at 9 months after the operation and did not change in the later follow-up period. It was 100% for patients in the moderate group and 80.0 ± 10.3% in the severe group (P = 0.07), and 75.0 ± 12.5% for female patients of in the severe group compared to 100% for the remaining patients (P = 0.025). Survival free from major adverse events, including reoperation, at 10 years was 60.0 ± 12.6% in the moderate and 38.1% ± 12.9% in the severe group (P = 0.03). No patient in the moderate group evolved to be in the severe group at late follow-up.CONCLUSIONAdult EA patients should undergo surgery earlier when they are still in the moderate ACHD AP classification.     

Therapeutic effect of recombinant vaccinia virus expressing the 60-kd heat-shock protein on adjuvant arthritis

Objective. To analyze the effects of recombinant viruses for 2 heat-shock proteins in the treatment of adjuvant arthritis. Methods. Virus vaccinia recombinant for mycobacterial heat-shock protein 65 (hsp65-VV) and human hsp60 (hsp60-VV) were administered to rats during different stages of adjuvant arthritis. Arthritis score and immunity to the recombinant virus were analyzed. Results. When delivered at the pre-arthritis stage, both constructs ameliorated arthritis; greater protection was observed with hsp60-VV. A specific T cell response to the recombinant proteins was detected. Furthermore, hsp60-VV displayed a clear therapeutic effect on established arthritis. Conclusion. Our results suggest novel avenues of therapeutic intervention in autoimmune arthritis associated with immunity to hsp60.     

Colonic Microbiota Profile Characterization of the Responsiveness to Dietary Fibre Treatment in Hypercholesterolemia

This study aimed to determine how the microbiota profile might be predisposed to a better response in blood lipid profiles due to dietary fibre supplementation. A three-arm intervention study that included three different fibre types (mainly insoluble, soluble, and antioxidant fibre) supplemented (19.2 g/day) during 2 months in individuals with hypercholesterolemia was developed. Changes in faecal microbiota and blood lipid profile after fibre supplementation were determined. In all volunteers, regardless of fibre type, an increase in the abundance of Bifidobacterium was observed, and similarly, an inverse relationship between faecal propionic acid and blood LDL-cholesterol, LDL particle size, and LDL/HDL particle ratio (p-values 0.0067, 0.0002, and 0.0067, respectively) was observed. However, not all volunteers presented an improvement in lipid profile. The non-responders to fibre treatment showed a decrease in microbiota diversity (Shannon and Simpson diversity index p-values of 0.0110 and 0.0255, respectively) after the intervention; where the reduction in short-chain fatty acids (SCFAs) producing bacterial genera such as Clostridium XIVa and Ruminococcus after dietary fibre treatment was the main difference. It was concluded that the non-responsiveness to dietary fibre treatment might be mediated by the lack of ability to maintain a stable SCFA producing bacteria diversity and composition after extra fibre intake.     

Subclinical affective and cognitive fluctuations in Parkinson's disease: a randomized double-blind double-dummy study of Oral vs. Intrajejunal Levodopa

Journal of Neurology - Chronic levodopa treatment in Parkinson’s disease (PD) may promote undesirable motor and non-motor fluctuations. Compared to chronic oral levodopa treatment, continuous...     

The effect of chronic neuroglycopenia on resting state networks in GLUT1 syndrome across the lifespan

Glucose transporter type I deficiency syndrome (GLUT1DS) is an encephalopathic disorder due to a chronic insufficient transport of glucose into the brain. PET studies in GLUT1DS documented a widespread cortico‐thalamic hypometabolism and a signal increase in the basal ganglia, regardless of age and clinical phenotype. Herein, we captured the pattern of functional connectivity of distinct striatal, cortical, and cerebellar regions in GLUT1DS (10 children, eight adults) and in healthy controls (HC, 19 children, 17 adults) during rest. Additionally, we explored for regional connectivity differences in GLUT1 children versus adults and according to the clinical presentation. Compared to HC, GLUT1DS exhibited increase connectivity within the basal ganglia circuitries and between the striatal regions with the frontal cortex and cerebellum. The excessive connectivity was predominant in patients with movement disorders and in children compared to adults, suggesting a correlation with the clinical phenotype and age at fMRI study. Our findings highlight the primary role of the striatum in the GLUT1DS pathophysiology and confirm the dependency of symptoms to the patients' chronological age. Despite the reduced chronic glucose uptake, GLUT1DS exhibit increased connectivity changes in regions highly sensible to glycopenia. Our results may portrait the effect of neuroprotective brain strategy to overcome the chronic poor energy supply during vulnerable ages.     

Platelet Activation Favours NOX2-Mediated Muscle Damage in Elite Athletes: The Role of Cocoa-Derived Polyphenols

Mechanisms of exercise-induced muscle injury with etiopathogenesis and its consequences have been described; however, the impact of different intensities of exercise on the mechanisms of muscular injury development is not well understood. The aim of this study was to exploit the relationship between platelet activation, oxidative stress and muscular injuries induced by physical exercise in elite football players compared to amateur athletes. Oxidant/antioxidant status, platelet activation and markers of muscle damage were evaluated in 23 elite football players and 23 amateur athletes. Compared to amateurs, elite football players showed lower antioxidant capacity and higher oxidative stress paralleled by increased platelet activation and muscle damage markers. Simple linear regression analysis showed that sNOX2-dp and H₂O₂, sCD40L and PDGF-bb were associated with a significant increase in muscle damage biomarkers. In vitro studies also showed that plasma obtained from elite athletes increased oxidative stress and muscle damage in human skeletal muscle myoblasts cell line compared to amateurs’ plasma, an effect blunted by the NOX2 inhibitor or by the cell treatment with cocoa-derived polyphenols. These results indicate that platelet activation increased muscular injuries induced by oxidative stress. Moreover, NOX2 inhibition and polyphenol extracts treatment positively modulates redox status and reduce exercise-induced muscular injury.     

Empathic accuracy and cognition in schizotypal personality disorder

Interpersonal dysfunction contributes to significant disability in the schizophrenia spectrum. Schizotypal Personality Disorder (SPD) is a schizophrenia-related personality demonstrating social cognitive impairment in the absence of frank psychosis. Past research indicates that cognitive dysfunction or schizotypy may account for social cognitive dysfunction in this population. We tested SPD subjects and healthy controls on the Empathic Accuracy (EA) paradigm and the Reading of the Mind in the Eyes Test (RMET), assessing the impact of EA on social support. We also explored whether EA differences could be explained by intelligence, working memory, trait empathy, or attachment avoidance. SPD subjects did not differ from controls in RMET, but demonstrated lower EA during negative valence videos, associated with lower social support. Dynamic, multimodal EA paradigms may be more effective at capturing interpersonal dysfunction than static image tasks such as RMET. Schizotypal severity, trait empathy, and cognitive dysfunction did not account for empathic dysfunction in SPD, although attachment avoidance is related to empathic differences. Empathic dysfunction for negative affect contributes to decreased social support in the schizophrenia spectrum. Future research may shed further light on potential links between attachment avoidance, empathic dysfunction, and social support.     

Translocation mechanisms of chemically functionalised carbon nanotubes across plasma membranes

Understanding the mechanisms responsible for carbon nanotube (CNT) internalisation into live cells is considered critical both from a fundamental point of view and for further engineering of CNT-based delivery systems to intracellular targets. While several studies are focused on the development of such CNT-based delivery systems, attempts to systematically elucidate the cellular uptake mechanisms of CNTs are still rather limited. The aim of the present study is to evaluate the cellular internalisation of chemically functionalised multi-walled carbon nanotubes (f-MWCNTs) in the presence of different well-known cellular uptake inhibitors. Our data reveal how f-MWCNTs are able to translocate across cell membranes of both phagocytic and non-phagocytic cell lines. We have evidenced that at least 30-50% of f-MWCNTs are taken up by cells through an energy-independent mechanism. This characteristic makes nanotubes loaded with therapeutic or diagnostic cargos extremely interesting as the release of active molecules directly into the cytoplasm increase their biological activity and therapeutic efficacy.