Pharmacokinetic and -dynamic studies in elderlies with a potential antihypoxidotic/nootropic drug tenilsetam utilizing pharmaco-EEG and psychometry

In a double-blind, placebo-controlled study, the pharmacokinetic, encephalotropic, and psychotropic properties of a new metabolically active thienyl-piperazine derivative were studied in ten elderly subjects in their sixties by means of quantitative EEG and psychometric analyses. At weekly intervals, they received randomized single oral doses of placebo; 75 mg, 150 mg, and 300 mg tenilsetam (CAS 997); and 3.2 g piracetam as reference drug. Blood sampling EEG recordings, psychometric and psychophysiological tests, as well as the monitoring of blood pressure, heart rate, and side effects were carried out at 0, 2, 4, 6, 8, and 24 hr. Pharmacokinetic investigations showed that CAS 997 was rather well absorbed, as peak concentrations were observed consistently at 2 hr and were clearly dose-dependent. The terminal half-life was between 18 and 22 hr, as compared with 6 hr for the reference drug piracetam, which also exhibited plasma peaks at 2 hr. Computer-assisted spectral analyses of the EEG showed a significant CNS effect of CAS 997 as compared with placebo, characterized by an increase of alpha activity, decrease of delta activity, and fast beta activity, as well as by tendency towards an augmentation of total power and decrease of the centroid and centroid deviation of the total beta activity. Partly similar though less pronounced alterations were exhibited by 3.2 g piracetam. Such changes were described previously by us after several other antihypoxidotics/nootropics and are indicative of improvement in vigilance. Dose/treatment–efficacy calculations demonstrated 75 and 150 mg CAS 997 superior both to placebo and the reference compound but also to the highest given dosis (300 mg CAS 997). Time–efficacy calculations showed two pharrnacodynamic peaks: one in the 4th and another one in the 8th to 24th hour. The time lag between pharmacokinetic and -dynamic changes may be due to the penetration of the drug through the blood brain barrier to a deep compartment receptor as well as to the formation of active metabolites. Psychometric investigations showed only small and inconsistent psychotropic effects after single doses of CAS 997 in elderlies. Evaluation of pulse rate, blood pressure, and side effects showed a good tolerability of both drugs.     

Electrodermal Responses to Auditory Stimuli with Different Significance in Neurological Patients

In 16 neurological patients with different levels of severely disturbed vigilance and 16 healthy subjects electrodermal responses to the name and the name backwards were elicited. In the most severely impaired patients, no differences were found between stimulus conditions. In less severe cases, significantly larger responses to the name were found but only on initial trials. In normal subjects differences persisted throughout 10 presentations of each stimulus. All subject groups demonstrated habituation.     

A new metric for quantifying performance impairment on the psychomotor vigilance test

We have developed a new psychomotor vigilance test (PVT) metric for quantifying the effects of sleep loss on performance impairment. The new metric quantifies performance impairment by estimating the probability density of response times (RTs) in a PVT session, and then considering deviations of the density relative to that of a baseline‐session density. Results from a controlled laboratory study involving 12 healthy adults subjected to 85 h of extended wakefulness, followed by 12 h of recovery sleep, revealed that the group performance variability based on the new metric remained relatively uniform throughout wakefulness. In contrast, the variability of PVT lapses, mean RT, median RT and (to a lesser extent) mean speed showed strong time‐of‐day effects, with the PVT lapse variability changing with time of day depending on the selected threshold. Our analysis suggests that the new metric captures more effectively the homeostatic and circadian process underlying sleep regulation than the other metrics, both directly in terms of larger effect sizes (4–61% larger) and indirectly through improved fits to the two‐process model (9–67% larger coefficient of determination). Although the trend of the mean speed results followed those of the new metric, we found that mean speed yields significantly smaller (～50%) intersubject performance variance than the other metrics. Based on these findings, and that the new metric considers performance changes based on the entire set of responses relative to a baseline, we conclude that it provides a number of potential advantages over the traditional PVT metrics.     

Visual attention and the acquisition of information in human crowds

Pedestrian crowds can form the substrate of important socially contagious behaviors, including propagation of visual attention, violence, opinions, and emotional state. However, relating individual to collective behavior is often difficult, and quantitative studies have largely used laboratory experimentation. We present two studies in which we tracked the motion and head direction of 3,325 pedestrians in natural crowds to quantify the extent, influence, and context dependence of socially transmitted visual attention. In our first study, we instructed stimulus groups of confederates within a crowd to gaze up to a single point atop of a building. Analysis of passersby shows that visual attention spreads unevenly in space and that the probability of pedestrians adopting this behavior increases as a function of stimulus group size before saturating for larger groups. We develop a model that predicts that this gaze response will lead to the transfer of visual attention between crowd members, but it is not sufficiently strong to produce a tipping point or critical mass of gaze-following that has previously been predicted for crowd dynamics. A second experiment, in which passersby were presented with two stimulus confederates performing suspicious/irregular activity, supports the predictions of our model. This experiment reveals that visual interactions between pedestrians occur primarily within a 2-m range and that gaze-copying, although relatively weak, can facilitate response to relevant stimuli. Although the above aspects of gaze-following response are reproduced robustly between experimental setups, the overall tendency to respond to a stimulus is dependent on spatial features, social context, and sex of the passerby.     

Characterization of blood donors with high haemoglobin concentration

The literature contains little on the prevalence and causes of high predonation haemoglobin levels among blood donors. This study aimed to characterize and develop an algorithm to manage would-be donors with polycythaemia. Between November 2009 and November 2011, we offered haematology consultations to blood donors with repeated haemoglobin concentration (Hb) above the WHO limit for polycythaemia vera (PV) (10.2 and 11.5 mm ⁄ 16.5 and 18.5 g/dl for women and men, respectively). Investigation of such donors included Hb, haematocrit, mean cell volume, erythropoietin, ferritin, platelet count and leucocyte count, JAK2 V617F and JAK2 exon12 analysis, as well as other routine measurements. Among 46 such donors, 39 had a history of smoking, which contributes to erythrocytosis. Two had PV, five had severe hypertension, one of them because of renal artery stenosis, and two had diabetes mellitus. Thus, we found a high morbidity among such donors. Of the 36 others, 30 donated again before May 2012, at which time the Hb was significantly lower. We recommend JAK2 V617F and JAK2 exon12 screening and clinical investigation for donors with concurrently high Hb, high haematocrit and iron deficiency. We also recommend that they stop or cut down on smoking to reduce the risk of thrombosis in general. We disqualified 10 of the donors.     

Increasing vigilance on the medical/surgical floor to improve patient safety

AIM: This paper reports a study designed to assess an automated non-invasive, patient vigilance system, the (L)G(1TM) system, for determining heart rate and respiration rate. The study uses collected data to optimize the (L)G(1TM)'s alert management scheme for medical/surgical wards. BACKGROUND: Thousands of patients die unnecessarily each year because of compromised patient safety in hospitals. Economic pressures to reduce hospitalization costs, exacerbated by increasing nursing shortages, have created a need for new approaches to patient vigilance. Advanced technologies may help nurses to provide high-quality care while controlling costs and improving patient safety. METHODS: Heart and respiration waveforms from 287 patients were captured by sensor arrays embedded in the mattress coverlets of their beds. No real-time monitoring was performed. Raw data were processed by proprietary algorithms and compared with data captured by a standard reference device. Alert performance was verified by hand-scoring the signal data and matching it against clinical events observed through a systematic review of each patient's medical record. The data were collected between June 2004 and February 2005. RESULTS: Experimental algorithms for heart rate had an accuracy of -1.47 (sd 1.90) and a precision of 4.60 (sd 2.46). Respiration rate algorithms showed an accuracy of -0.94 (sd 1.26) and a precision of 4.02 (sd 1.17). Algorithms identified 178 true-positive physiological alerts on 15 patients. None of the events was deemed clinically significant at chart review. The combined false-positive alert rate for the algorithms was 0.007 events per hour. CONCLUSION: This study demonstrates the accuracy and precision of the signal processing algorithms in the (L)G(1TM) system. Future work will focus on assessing the system's impact on patient outcomes and its integration into the nursing workflow.     

Staying vigilant during recurrent sleep restriction: dose-response effects of time-in-bed and benefits of daytime napping

Study ObjectivesWe characterized vigilance deterioration with increasing time-on-task (ToT) during recurrent sleep restriction of different extents on simulated weekdays and recovery sleep on weekends, and tested the effectiveness of afternoon napping in ameliorating ToT-related deficits.MethodsIn the Need for Sleep studies, 194 adolescents (age = 15–19 years) underwent two baseline nights of 9-h time-in-bed (TIB), followed by two cycles of weekday manipulation nights and weekend recovery nights (9-h TIB). They were allocated 9 h, 8 h, 6.5 h, or 5 h of TIB for nocturnal sleep on weekdays. Three additional groups with 5 h or 6.5 h TIB were given an afternoon nap opportunity (5 h + 1 h, 5 h + 1.5 h, and 6.5 h + 1.5 h). ToT effects were quantified by performance change from the first 2 min to the last 2 min in a 10-min Psychomotor Vigilance Task administered daily.ResultsThe 9 h and the 8 h groups showed comparable ToT effects that remained at baseline levels throughout the protocol. ToT-related deficits were greater among the 5 h and the 6.5 h groups, increased prominently in the second week of sleep restriction despite partial recuperation during the intervening recovery period and diverged between these two groups from the fifth sleep-restricted night. Daytime napping attenuated ToT effects when nocturnal sleep restriction was severe (i.e. 5-h TIB/night), and held steady at baseline levels for a milder dose of nocturnal sleep restriction when total TIB across 24 h was within the age-specific recommended sleep duration (i.e. 6.5 h + 1.5 h).ConclusionsReducing TIB beyond the recommended duration significantly increases ToT-associated vigilance impairment, particularly during recurrent periods of sleep restriction. Daytime napping is effective in ameliorating such decrement.Clinical Trial Registration{"type":"clinical-trial","attrs":{"text":"NCT02838095","term_id":"NCT02838095"}}NCT02838095, {"type":"clinical-trial","attrs":{"text":"NCT03333512","term_id":"NCT03333512"}}NCT03333512, and {"type":"clinical-trial","attrs":{"text":"NCT04044885","term_id":"NCT04044885"}}NCT04044885.     

From the Cover: Testosterone decreases trust in socially na?ve humans

Trust plays an important role in the formation and maintenance of human social relationships. But trusting others is associated with a cost, given the prevalence of cheaters and deceivers in human society. Recent research has shown that the peptide hormone oxytocin increases trust in humans. However, oxytocin also makes individuals susceptible to betrayal, because under influence of oxytocin, subjects perseverate in giving trust to others they know are untrustworthy. Testosterone, a steroid hormone associated with competition and dominance, is often viewed as an inhibitor of sociality, and may have antagonistic properties with oxytocin. The following experiment tests this possibility in a placebo-controlled, within-subjects design involving the administration of testosterone to 24 female subjects. We show that compared with the placebo, testosterone significantly decreases interpersonal trust, and, as further analyses established, this effect is determined by those who give trust easily. We suggest that testosterone adaptively increases social vigilance in these trusting individuals to better prepare them for competition over status and valued resources. In conclusion, our data provide unique insights into the hormonal regulation of human sociality by showing that testosterone downregulates interpersonal trust in an adaptive manner.     

欧盟2009版《医疗器械安全警戒系统指南》浅析

通过介绍欧盟2009版《医疗器械安全警戒指南》的目标和变更内容,对新版指南约束的对象,安全警戒系统中各方的职责,医疗器械不良事件的报告范围和上报期限等医疗器械制造商最关心的问题进行了分析和阐述。     

Daytime sleepiness, psychomotor performance, waking EEG spectra and evoked potentials in women with severe premenstrual syndrome

We assessed daytime sleepiness using objective and subjective measures in women with severe premenstrual syndrome (PMS) compared with women without significant premenstrual symptoms. Nine women with severe PMS and eight controls (aged 18−40 years) completed a laboratory-based daytime protocol including the maintenance of wakefulness test (MWT), psychomotor vigilance task (PVT), quantitative waking electroencephalogram (EEG), auditory and visual event-related potentials (ERPs), and sleepiness and mood scales during the mid-follicular and late-luteal (premenstrual) phases of the menstrual cycle. In association with increased perceived sleepiness, fatigue and other premenstrual symptoms in the late-luteal phase, women with PMS performed more poorly on the PVT, with increased lapses and slower reaction times ( P  <   0.05), compared with the follicular phase and controls. However, there were no significant group or menstrual phase differences in latency to sleep on the MWT. Waking spectral EEG power and ERP measures also did not differentiate PMS women when symptomatic. Both groups of women displayed increased spectral power in the delta/theta frequencies (2−6 Hz) and fast alpha frequency (11−12 Hz) in the late-luteal phase relative to the follicular phase. Trait-like differences were apparent in that women with PMS had increased beta1 (12−16 Hz) power and smaller P300 amplitude than controls in both menstrual cycle phases. Our findings indicate that women with severe PMS are subjectively sleepy and fatigued, and show psychomotor slowing when symptomatic compared with when they are symptom-free and compared with controls. However, the ability to maintain wakefulness under soporific conditions, spectral properties of waking EEG and cognitive processing do not vary in synchrony with premenstrual symptoms.