Main targets of ibogaine and noribogaine associated with its putative anti-addictive effects: A mechanistic overview.

BACKGROUND: There is a growing interest in studying ibogaine (IBO) as a potential treatment for substance use disorders (SUDs). However, its clinical use has been hindered for mainly two reasons: First, the lack of randomized, controlled studies informing about its safety and efficacy. And second, IBO's mechanisms of action remain obscure. It has been challenging to elucidate a predominant mechanism of action responsible for its anti-addictive effects. OBJECTIVE: To describe the main targets of IBO and its main metabolite, noribogaine (NOR), in relation to their putative anti-addictive effects, reviewing the updated literature available. METHODS: A comprehensive search involving MEDLINE and Google Scholar was undertaken, selecting papers published until July 2022. The inclusion criteria were both theoretical and experimental studies about the pharmacology of IBO. Additional publications were identified in the references of the initial papers. RESULTS: IBO and its main metabolite, NOR, can modulate several targets associated with SUDs. Instead of identifying key targets, the action of IBO should be understood as a complex modulation of multiple receptor systems, leading to potential synergies. The elucidation of IBO's pharmacology could be enhanced through the application of methodologies rooted in the polypharmacology paradigm. Such approaches possess the capability to describe multifaceted patterns within multi-target drugs. CONCLUSION: IBO displays complex effects through multiple targets. The information detailed here should guide future research on both mechanistic and therapeutic studies.

Longitudinal and transcultural assessment of the relationship between hallucinogens, well-being, and post-traumatic growth during the COVID-19 pandemic.

The COVID-19 pandemic has had a devastating impact on the health and wellbeing of the global population. This paper presents the results of a longitudinal transcultural study that was begun at the peak of the pandemic (in April, 2020). An online survey was used to collect data from English-, Spanish-, and Portuguese-speaking participants. The survey collected information about sociodemographics, lifestyle activities, COVID-19-related circumstances, and drug use (with an emphasis on hallucinogenic drugs), as well as involving psychometric questionnaires. Users of hallucinogenic drugs had higher psychological well-being and lower scores on psychopathology scales, both at baseline and during follow-ups. This difference was larger when users were distinguished by frequency of use, as regular users scored higher on psychological well-being and lower on psychopathology scales. Subjects with more psychological distress had lower scores for all scales of post-traumatic growth, but if they were regular hallucinogens users, they had higher scores for post-traumatic growth. When comparing the results between cultural contexts, heterogeneous results were obtained. There were more English-speaking regular users of hallucinogenic drugs. Further research should analyse the potential role of hallucinogens in large-scale catastrophes, with a special focus on post-traumatic growth.

Association between traumatic brain injuries and ketamine infusion side effects following combat injury.

INTRODUCTION: Ketamine is a vital component for acute pain management in emergency trauma care for both civilian and military hospitals. This preliminary analysis examined whether combat-injured US service members sustaining traumatic brain injuries (TBI) experienced increased odds of ketamine side effects compared with those without TBI. METHODS: This preliminary analysis included combat-injured service members, ages ≥18 years with documented pain scores during the 24 hours before and 48 hours after receiving an intravenous ketamine infusion at Walter Reed National Military Medical Center (WRNMMC) between 2007 and 2014. Logistic regression modeling examined the association between TBI and ketamine side effects (eg, hallucinations, nightmares, dysphoria, nausea, decreased oxygen saturation) during hospitalisation. RESULTS: Of the 77 patients, 62% presented with a documented TBI. Side effects were documented for 18.8% of those without TBI and 24.4% of those with TBI. Analyses were unable to find evidence against the null hypothesis with the current sample size, even when adjusting for injury characteristics and preinfusion opioid doses (adjusted OR=0.90 (95% CI 0.26 to 3.34), p=0.87). CONCLUSION: In this small sample of combat-injured service members, we were unable to detect a difference in ketamine-related side effects by documented TBI status. These hypothesis-generating findings support the need for future studies to examine the use of intravenous ketamine infusions for pain management, and subsequent care outcomes in patients who experience polytraumatic trauma inclusive of TBI.

Regime change in the recorder: Using Navier-Stokes modeling to design a better instrument.

Blowing a recorder at a low to moderate blowing speed with the toneholes all closed yields the lowest note in the range of the instrument. As the blowing speed is increased, the tone abruptly changes to the tone an octave higher. This "jump" in the frequency of the dominant spectral component of the tone is referred to as "regime change." Interestingly, in conversations with recorder players, several have mentioned that regime change seems to occur at a significantly lower blowing speed for bass recorders than for instruments that sound an octave or more higher. In this paper we study regime change in the recorder and use Navier-Stokes modeling to confirm and study differences in the behavior of different instruments in the recorder family. We show, using modeling, how the regime change threshold in a model of the bass recorder can be increased by changing the geometry in the vicinity of the labium. These results are then confirmed through experimental studies of real recorders with designs inspired by the modeling results. The insights gained from these results suggest new recorder designs that may produce instruments that in some respects are more playable than current instruments.

Cross-Sectional Associations Between Lifetime Use of Psychedelic Drugs and Psychometric Measures During the COVID-19 Confinement: A Transcultural Study.

Background: One of the main public health strategies adopted at the beginning of the COVID-19 pandemic consisted of implementing strict lockdowns to stop the transmission of the virus. Despite being an effective measure, the confinement and the associated social isolation create a stressful, potentially lengthy situations that has been proven to have several psychological consequences. Given the potential benefits that certain psychedelic drugs have shown for the treatment of psychological disorders, this study aimed to assess the impact of lifetime psychedelic drug use on mental health in relation to the first strict lockdown adopted by various countries (April-July 2020). Methods: Subjects completed an online survey that inquired about sociodemographic factors, activities, and lifestyle factors during confinement, as well as health and mental health related factors. Subjects were asked about their lifetime use of psychedelic drugs (MDMA, ayahuasca, psilocybin-containing mushrooms, LSD, peyote, San Pedro, Bufo alvarius or 5-MeO-DMT, and others), being classified as regular users (more than once per 6 months), occasional users, or non-users. The survey included psychometric tests used to assess psychological distress, peritraumatic stress, social support, psychopathological symptoms, and personality. Linear regressions were performed with psychedelic drug users as the independent variable and psychometric factors as the outcomes, while correcting for age, gender, language, religion, spirituality, and use of non-psychedelic drugs. Results: The study included 2,974 English, Portuguese, and Spanish speakers (497 regular users of psychedelic drugs, 606 occasional users, and 1,968 non-users). On average, respondents were 36 years old and 70% were female. Psychedelic drug users, especially regular ones, reported less psychological distress, less peritraumatic stress, and more social support. Regarding personality measures, psychedelic drug users scored higher on the novelty-seeking and self-transcendence scales, and lower on cooperativeness. Conclusion: Our findings showed that regular users of psychedelic drugs had less psychological stress and some personality differences when compared to occasional users and non-users. This suggests that either the use of psychedelics might be a protective factor itself or people with certain previous traits are more prone to frequently using psychedelic drugs. Future prospective longitudinal research should investigate the underlying processes observed in this study to develop consistent hypotheses.

Combining robotics with enhanced serotonin-driven cortical plasticity improves post-stroke motor recovery.

Despite recent progresses in robotic rehabilitation technologies, their efficacy for post-stroke motor recovery is still limited. Such limitations might stem from the insufficient enhancement of plasticity mechanisms, crucial for functional recovery. Here, we designed a clinically relevant strategy that combines robotic rehabilitation with chemogenetic stimulation of serotonin release to boost plasticity. These two approaches acted synergistically to enhance post-stroke motor performance. Indeed, mice treated with our combined therapy showed substantial functional gains that persisted beyond the treatment period and generalized to non-trained tasks. Motor recovery was associated with a reduction in electrophysiological and neuroanatomical markers of GABAergic neurotransmission, suggesting disinhibition in perilesional areas. To unveil the translational potentialities of our approach, we specifically targeted the serotonin 1A receptor by delivering Buspirone, a clinically approved drug, in stroke mice undergoing robotic rehabilitation. Administration of Buspirone restored motor impairments similarly to what observed with chemogenetic stimulation, showing the immediate translational potential of this combined approach to significantly improve motor recovery after stroke.

Navier-Stokes-based model of the clarinet.

A model of a single reed instrument is studied in which the reed is described as an Euler-Bernoulli beam, and the air flow through the instrument is calculated using the Navier-Stokes equations. The hypothetical instrument resembles a clarinet, but is smaller than a real clarinet to keep the numerical modeling feasible on available supercomputers. This article explores the conditions under which the frequency of the reed oscillations and the emitted sound are determined by the resonant frequency of the bore of the instrument. The effect of the contact between the reed and the player's lips is also studied, and quantitative results for the air density and pressure in the mouthpiece and throughout the instrument bore are also presented.

Serotonergic hallucinogens and recognition of facial emotion expressions: a systematic review of the literature.

BACKGROUND: Recognition of emotions in facial expressions (REFE) is a key aspect of social cognition. Anxiety and mood disorders are associated with deficits in REFE, and anxiolytics and antidepressants reverse these deficits. Recent studies have shown that serotonergic hallucinogens (i.e. ayahuasca, dimethyltryptamine, psilocybin, lysergic acid diethylamide [LSD], and mescaline) have anxiolytic and antidepressant properties, but their effects on REFE are not well understood. The purpose of the study was to conduct a systematic review analyzing the effects of serotonergic hallucinogens on REFE in humans. METHODS: Studies published in the PubMed, PsycINFO, and Web of Science databases until 19 October 2018 which analyzed the effects of serotonergic hallucinogens on REFE in humans were included. RESULTS: Of the 62 studies identified, 8 studies were included. Included studies involved the administration of a single or a few doses of LSD or psilocybin, and most trials were randomized and controlled with placebo. LSD and psilocybin reduced the recognition of negative emotions in most studies and modulated amygdala activity to these stimuli, which was correlated with antidepressive effects in patients. Both drugs were well tolerated. CONCLUSIONS: Serotonergic hallucinogens reduced the recognition of negative emotions by modulating amygdala activity. Despite the small sample sizes, results suggest that serotonergic hallucinogens show promising beneficial effects on deficits in REFE.

Force on the lips of a trumpet player.

When modeling a brass instrument such as the trumpet, an estimate of the pressure at the player's lips is essential, since the resulting force drives the oscillations of the lips which are needed to produce a musical tone. In most work to date, the calculation of the force on the lips has relied on values of the pressure derived from the Bernoulli equation, even though that relation assumes steady flow in contrast to the pulsating flow caused by vibrations of the lips. This paper uses a quantitative application of the Navier-Stokes equations to calculate the flow through a model of vibrating lips attached to a toy model of the trumpet. The results are used to explore when the Bernoulli equation can and cannot be used. The Bernoulli equation is found to fail badly during significant portions of each oscillation cycle of the lips. The reasons for this breakdown are elucidated.

Methylsulfonylmethane and mobilee prevent negative effect of IL-1ß in human chondrocyte cultures via NF-κB signaling pathway.

Nutraceuticals are compounds that serve as nutrition with an easy accessibility and favourable safety profile. Recent studies showed their potential activity on osteoarthritis (OA) inflammation and cartilage metabolism. We investigated the effect of methylsulfonylmethane (MSM) and mobilee in human OA chondrocyte cultures exposed to interleukin (IL)-1ß. OA cartilage was obtained from femoral heads of five patients undergoing total replacement surgery. Chondrocytes were incubated with mobilee (200 and 500 µM) and MSM (2000 and 6000 µM) in presence of IL-1ß (10 ng/mL) and nuclear factor (NF)-κB inhibitor (BAY 11-7082, 1 µM), for 24 and 48 h. Viability and apoptosis were performed by MMT and flow cytometry. The metalloproteinase (MMP)-1,-3,-13 and type II collagen (Col2a1) were analyzed by qRT-PCR and ELISA, and NF-κB activation by immunofluorescence. IL-1ß stimulus determined a significant regulation of survival, apoptotic ratio, as well as of gene expression and serum levels of MMP-1,-3,-13 and Col2a1 in OA chondrocytes compared to baseline. Mobilee and MSM incubation significantly reversed the effect of IL-1ß. IL-1ß significantly induced NF-κB p50 nuclear translocation, which was significantly counteracted by the pre-treatment of OA chodrocytes with the tested compounds. BAY11-7082 significantly modulated MMPs and Col2a1 expression respectively to basal state. Co-treatment of IL-1ß with mobilee, MSM and BAY11-7082 didn't cause changes of MMPs or Col2a1 beyond that caused by each single treatment. We demonstrated that MSM and mobilee have a beneficial effect on OA chondrocytes metabolism, probably due to the modulation of NF-κB pathway, providing a powerful rationale for the use of these substances in OA treatment.

Physical modeling of a conical lip reed instrument.

A model of a brass instrument is described in which the air flow and pressure inside the instrument are computed with the Navier-Stokes equations and the motion of the player's lips are described using the swinging lip model of Adachi and Sato [J. Acoust. Soc. Am. 99, 1200-1209 (1996)]. Using the Navier-Stokes equations to treat the air motion allows the calculation of the spatial variations and time dependences of the pressure and velocity near the lips, which has not been possible with previous modeling approaches. Detailed results for these quantities and for the lip motion are presented, and compared with the results of previous modeling of lip reed instruments and with available experimental results. Shortcomings are found in previous treatments of the aerodynamic force on the lips, and the implications of this result for first-principles modeling of brass instruments are discussed.

Metabolomic analysis of 92 pulmonary embolism patients from a nested case-control study identifies metabolites associated with adverse clinical outcomes.

Essentials Risk-stratification often fails to predict clinical deterioration in pulmonary embolism (PE). First-ever high-throughput metabolomics analysis of risk-stratified PE patients. Changes in circulating metabolites reflect a compromised energy metabolism in PE. Metabolites play a key role in the pathophysiology and risk stratification of PE. SUMMARY: Background Patients with acute pulmonary embolism (PE) exhibit wide variation in clinical presentation and outcomes. Our understanding of the pathophysiologic mechanisms differentiating low-risk and high-risk PE is limited, so current risk-stratification efforts often fail to predict clinical deterioration and are insufficient to guide management. Objectives To improve our understanding of the physiology differentiating low-risk from high-risk PE, we conducted the first-ever high-throughput metabolomics analysis (843 named metabolites) comparing PE patients across risk strata within a nested case-control study. Patients/methods We enrolled 92 patients diagnosed with acute PE and collected plasma within 24 h of PE diagnosis. We used linear regression and pathway analysis to identify metabolites and pathways associated with PE risk-strata. Results When we compared 46 low-risk with 46 intermediate/high-risk PEs, 50 metabolites were significantly different after multiple testing correction. These metabolites were enriched in the following pathways: tricarboxylic acid (TCA) cycle, fatty acid metabolism (acyl carnitine) and purine metabolism, (hypo)xanthine/inosine containing. Additionally, energy, nucleotide and amino acid pathways were downregulated in intermediate/high-risk PE patients. When we compared 28 intermediate-risk with 18 high-risk PE patients, 41 metabolites differed at a nominal P-value level. These metabolites were enriched in fatty acid metabolism (acyl cholines), and hemoglobin and porphyrin metabolism. Conclusion Our results suggest that high-throughput metabolomics can provide insight into the pathophysiology of PE. Specifically, changes in circulating metabolites reflect compromised energy metabolism in intermediate/high-risk PE patients. These findings demonstrate the important role metabolites play in the pathophysiology of PE and highlight metabolomics as a potential tool for risk stratification of PE.

Can balneotherapy modify microRNA expression levels in osteoarthritis? A comparative study in patients with knee osteoarthritis.

The aim of this study was to evaluate the whole-blood levels of miR-155, miR-223, miR-181a, miR-146a, and miR-let-7e in patients with bilateral knee osteoarthritis (OA) after a cycle of mud-bath therapy (MBT). Thirty-two patients with knee OA defined by the ACR criteria were included. Twenty-one patients (MBT group) were daily treated with a combination of local mud-packs at 42 °C and baths in mineral water, at 37 °C for 15 min, for 12 applications over a period of 2 weeks, in addition to standard therapy; 11 patients (control group) continued their conventional treatment alone. Global pain score evaluated by visual analog scale (VAS), WOMAC subscores, and microRNA expression were evaluated at baseline and after 2 weeks. Peripheral whole blood was collected into PAXgene™ Blood RNA tubes, stored at - 80 °C, and total RNA was extracted. The expression of miR-155, miR-223, miR-181a, miR-146a, and miR-let-7e was determined by qRT-PCR. After MBT, we observed a statistically significant improvement of clinical parameters and a significant decrease of miR-155, miR-181a, miR-146a (p < 0.001), and miR-223 (p < 0.01) expression levels. No clinical and biochemical modifications were detected in the control group. No significant variations of miR-let-7e were shown in both groups after 2 weeks. In conclusion, MBT can modify the expression of miR-155, miR-181a, miR-146a, and miR-223, which are upregulated in OA. It could be due to the heat stress and the hydrostatic pressure, since some miRNAs were found to be temperature- and mechano-responsive. Further studies are needed to better explain the mechanism of action of MBT and the role of miRNAs in OA.

Computational study of the piccolo: Evidence for chaotic tones.

Direct numerical solutions of the Navier-Stokes equations have been used to compute tones produced by a model of the piccolo. The behavior depends on the angle at which the air jet is directed at the embouchure hole and the displacement of the jet center from the embouchure edge. Values of the jet angle and displacement are found that produce pure tones with spectra similar to those of real piccolo tones. The behavior of calculated tones as a function of the blowing speed u is studied, and it is found that unsteady behavior can occur depending on the value of u, the jet angle, and the jet displacement. Detailed analysis of these unsteady tones suggests that the model piccolo studied here exhibits chaotic behavior with a positive Lyapunov exponent. The implications for piccolo tones produced with real piccolos by real piccolo players are discussed.

Explaining the Railsback stretch in terms of the inharmonicity of piano tones and sensory dissonance.

The perceptual results of Plomp and Levelt [J. Acoust. Soc. Am. 38, 548-560 (1965)] for the sensory dissonance of a pair of pure tones are used to estimate the dissonance of pairs of piano tones. By using the spectra of tones measured for a real piano, the effect of the inharmonicity of the tones is included. This leads to a prediction for how the tuning of this piano should deviate from an ideal equal tempered scale so as to give the smallest sensory dissonance and hence give the most pleasing tuning. The results agree with the well known "Railsback stretch," the average tuning curve produced by skilled piano technicians. The authors' analysis thus gives a quantitative explanation of the magnitude of the Railsback stretch in terms of the human perception of dissonance.

From microvasculature to fibroblasts: Contribution of anti-endothelial cell antibodies in systemic sclerosis.

Systemic sclerosis (SSc) is an autoimmune disease characterized by skin and internal organ fibrosis, caused by microvascular dysfunction. In recent years, the hypothesis that anti-endothelial cell antibodies (AECA) play a key role in microvascular damage seems to be increasingly convincing. In fact, AECA can induce antibody-dependent cellular apoptosis and stimulate the microvasculature to release pro-inflammatory and pro-fibrotic cytokines. Human-microvascular-endothelial-cells (MVECs) were stimulated with SSc sera (with and without AECA) and with sera from healthy donors. The conditioned MVEC culture media were then added to fibroblast cultures obtained from control skin (CTR), non-affected skin of SSc patients (NA), and affected skin of the same sclerodermic (SSc) patients, respectively. AECA contributed to the MVEC increased release of endothelin-1 (ET-1) in the culture medium and to MVEC apoptosis. Fibroblast (CTR, NA, and SSc) proliferation was increased after treatment with AECA-positive conditioned media, compared to AECA-negative and control conditioned media. Furthermore, both AECA-positive (in major contribution) and AECA-negative conditioned media were responsible for alpha-smooth-muscle-actin (αSMA) over-expression in all fibroblast cultures, compared to control conditioned media. Fibroblast type I collagen synthesis was upregulated by both SSc conditioned media (with and without AECA). Finally, the synthesis of fibroblast transforming-growth-factor-beta (TGF-ß) was statistically higher in AECA-positive conditioned media, compared to AECA-negative and control conditioned media. These findings support the concept that AECA may mediate the crosstalk between endothelial damage and dermal-fibroblast activation in SSc.

Simulation studies of a recorder in three dimensions.

The aeroacoustics of a recorder are explored using a direct numerical simulation based on the Navier-Stokes equations in three dimensions. The qualitative behavior is studied using spatial maps of the air pressure and velocity to give a detailed picture of jet dynamics and vortex shedding near the labium. In certain cases, subtle but perhaps important differences in the motion of the air jet near the edge of the channel as compared to the channel center are observed. These differences may be important when analyzing experimental visualizations of jet motion. The quantitative behavior is studied through analysis of the spectrum of the sound pressure outside the instrument. The effect of chamfers and of changes in the position of the labium relative to the channel on the tonal properties are explored and found to be especially important in the attack portion of the tone. Changes in the spectrum as a result of variations in the blowing speed are also investigated as well as the behavior of the spectrum when the dominant spectral component switches from the fundamental to the second harmonic mode of the resonator tube.