Comparison of Antiplatelet Effects of Phenol Derivatives in Humans

Flavonoids are associated with positive cardiovascular effects. However, due to their low bioavailability, metabolites are likely responsible for these properties. Recently, one of these metabolites, 4-methylcatechol, was described to be a very potent antiplatelet compound. This study aimed to compare its activity with its 22 close derivatives both of natural or synthetic origin in order to elucidate a potential structure–antiplatelet activity relationship. Blood from human volunteers was induced to aggregate by arachidonic acid (AA), collagen or thrombin, and plasma coagulation was also studied. Potential toxicity was tested on human erythrocytes as well as on a cancer cell line. Our results indicated that 17 out of the 22 compounds were very active at a concentration of 40 μM and, importantly, seven of them had an IC50 on AA-triggered aggregation below 3 μM. The effects of the most active compounds were confirmed on collagen-triggered aggregation too. None of the tested compounds was toxic toward erythrocytes at 50 μM and four compounds partly inhibited proliferation of breast cancer cell line at 100 μM but not at 10 μM. Additionally, none of the compounds had a significant effect on blood coagulation or thrombin-triggered aggregation. This study hence reports four phenol derivatives (4-ethylcatechol, 4-fluorocatechol, 2-methoxy-4-ethylphenol and 3-methylcatechol) suitable for future in vivo testing.

The effect of observational learning on the development of central sensitization

Watching other people in pain may affect one’s own experience of pain. It is unknown whether it can also modulate secondary mechanical hypersensitivity. We have addressed this question in two experiments in healthy human volunteers. In experiment 1 we tested, on a large sample (N=83), five videos of a model demonstrating high or low pain during high frequency stimulation (HFS) of the skin, a procedure known to induce secondary mechanical hypersensitivity. The aim was to select the two videos rated with the highest and lowest expected pain and fear (high pain and low pain videos). Morevoer, we have explored the correlation between empathy and fear scores. In experiment 2 (N=44), two groups of participants were randomly allocated to watching either the low or the high pain video, and subsequently underwent HFS. The high pain video group reported increased pain during HFS. The two groups differed in the magnitude of secondary mechanical hypersensitivity after HFS, but the unpleasantness scores for mechanical stimulation after HFS, as well as spread of hyperalgesia were not statistically different. Empathy scores correlated positively with fear reports in experiment 1 but not experiment 2. Unexpectedly, we found higher scores of fear of pain for the high pain video only in experiment 1. In summary, observational learning of a model demonstrating high pain seems to have a stastistically significant but small effect on pinprick hypersensitivity. Its operating mechanisms remain partially elusive.

The Human Dive Reflex During Consecutive Apnoeas in Dry and Immersive Environments: Magnitude and Synchronicity

Introduction: The human dive reflex (HDR), an O2 conserving reflex, is characterised by an interplay of central parasympathetic and peripheral sympathetic reactions, which are presumed to operate independently of each other. The HDR is fully activated during apnoea with facial immersion in water and complete immersion in water is thought to increase the magnitude of HDR during consecutive apnoeas. A comparison of HDR activity between consecutive apnoeas in full-body immersion with consecutive apnoeas in dry conditions has not been fully explored. Also, the interplay between parasympathetic and sympathetic reactions involved in the HDR has not been thoroughly analysed.Methods: 11 human volunteers performed 3 consecutive 60 s apnoeas with facial immersion in dry conditions (FIDC) and 3 consecutive apnoeas with facial immersion in full immersion (FIFI). Heart rate (HR), R-R interval (RRI), finger pulse amplitude (FPA), splenic width (SW) and SpO2 were all measured before, during and after apnoeas. A one-way ANOVA using Dunn’s post hoc test was performed to assess HDR activity, and a Pearson’s correlation test was performed to assess HDR synchronisation between physiological parameters during both conditions.Results: Although HDR activity was not significantly different between both conditions, HR and RRI showed progressively greater changes during FIFI compared with FIDC, while SW and FPA changes were relatively equivalent. During FIDC, significant correlations were found between SW & SpO2 and FPA & SpO2. During FIFI, significant correlations were found between RRI & FPA, SW & FPA, HR & SpO2 and FPA & SpO2.Discussion: While there was no significant difference found between HDR activity during FIDC and FIFI, consecutive apnoeas during FIFI triggered a greater magnitude of cardiac activity. Furthermore, significant correlations between RRI and SW with FPA indicate a crosstalk between parasympathetic tone with splenic contraction and increased peripheral sympathetic outflow during FIFI compared to FIDC. In conclusion, HDR activity during consecutive apnoeas does not differ between FIDC and FIFI. There appears to be however a greater level of synchronicity during apnoeas in FIFI compared to FIDC and that this is most likely due to the physiological effects of immersion, which could induce neural recruitment and increased cross talk of HDR pathways.

Optoaccoustic Tomography – good news for microcirculatory research

Tomographic imaging is a well established technology in preventive medicine and biomedical research, although not without limitations and concerns. Optoacoustic tomography (OAT) is a recent development that bridges optical and sonographic techniques to solve spatial resolution in deep-tissue imaging. In addition to safety advantages, OAT allows multiple wavelength readings for natural thermoelastic chromophores. In this study, we explore Multi Spectral Optoacoustic Tomography (MSOT) capacities to simultaneously acquire three independent chromophores – deoxygenated haemoglobin (Hb), oxygenated haemoglobin (HbO2), and melanin, from healthy human volunteers, with maximal molar extinction of HbO2 at 950 nm, Hb at 750 nm and melanin at 680 nm. Later we demonstrate how image stability during acquisition is fundamental for optimal resolution, precision and consistency of high throughout MSOT data collection. From recorded scans, a workflow is layered for data evaluation. With the MSOT dedicated software results were extracted from 3D image analysis of deep (15 mm3) vessels. The possibilities offered by this new system, specially in vascular pathophysiology, are immense and can be extended beyond current knowledge.

Optoaccoustic Tomography – good news for microcirculatory research

Tomographic imaging is a well established technology in preventive medicine and biomedical research, although not without limitations and concerns. Optoacoustic tomography (OAT) is a recent development that bridges optical and sonographic techniques to solve spatial resolution in deep-tissue imaging. In addition to safety advantages, OAT allows multiple wavelength readings for natural thermoelastic chromophores. In this study, we explore Multi Spectral Optoacoustic Tomography (MSOT) capacities to simultaneously acquire three independent chromophores – deoxygenated haemoglobin (Hb), oxygenated haemoglobin (HbO2), and melanin, from healthy human volunteers, with maximal molar extinction of HbO2 at 950 nm, Hb at 750 nm and melanin at 680 nm. Later we demonstrate how image stability during acquisition is fundamental for optimal resolution, precision and consistency of high throughout MSOT data collection. From recorded scans, a workflow is layered for data evaluation. With the MSOT dedicated software results were extracted from 3D image analysis of deep (15 mm3) vessels. The possibilities offered by this new system, specially in vascular pathophysiology, are immense and can be extended beyond current knowledge.

Risk-Promoting Effects of Reward-Paired Cues in Human Sign- and Goal-Trackers

The incentive sensitization theory of addiction proposes that through repeated associations with addictive rewards, addiction-related stimuli acquire a disproportionately powerful motivational pull on behaviour. Animal research suggests trait-like individual variation in the degree of incentive salience attribution to reward-predictive cues, defined phenotypically as sign-tracking (high) and goal-tracking (low incentive salience attribution). While these phenotypes have been linked to addiction features in rodents, their translational validity has been little studied. Here, we examined whether sign- and goal-tracking in healthy human volunteers modulates the effects of reward-paired cues on cost-benefit decision making. Sign-tracking was measured in a Pavlovian conditioning paradigm as the amount of eye gaze fixation on the reward-predictive cue versus the location of impending reward delivery. In Study 1 (Cherkasova et al, 2018), participants were randomly assigned to perform a two-choice lottery task in which rewards were either accompanied (cued, n=63) or unaccompanied (uncued, n=68) by money images and casino jingles. In Study 2, participants (n=58) performed cued and uncued versions of the task in a within-subjects design. Across both studies, cues promoted riskier choice, and both studies yielded evidence of goal-tracking being associated with greater risk-promoting effects of cues. These findings are at odds with the notion of sign-trackers being preferentially susceptible to the influence of reward cues on behavior and point to the role of mechanisms besides incentive salience in mediating such influences.

Spatial and Temporal Context Jointly Modulate the Sensory Response within the Ventral Visual Stream

Both spatial and temporal context play an important role in visual perception and behavior. Humans can extract statistical regularities from both forms of context to help process the present and to construct expectations about the future. Numerous studies have found reduced neural responses to expected stimuli compared with unexpected stimuli, for both spatial and temporal regularities. However, it is largely unclear whether and how these forms of context interact. In the current fMRI study, 33 human volunteers were exposed to pairs of object stimuli that could be expected or surprising in terms of their spatial and temporal context. We found reliable independent contributions of both spatial and temporal context in modulating the neural response. Specifically, neural responses to stimuli in expected compared with unexpected contexts were suppressed throughout the ventral visual stream. These results suggest that both spatial and temporal context may aid sensory processing in a similar fashion, providing evidence on how different types of context jointly modulate perceptual processing.

Checklist to select contract Research Organization for early phase Bioavailability/Bioequivalence Clinical Studies in Healthy Adult Human Volunteers

Nowadays health agencies of regulated markets are becoming stringent regarding the bio-studies. So clinical/contract research organization (CRO) need to be selected carefully after their detailed assessment. As per requirement of bio-study CRO should be assessed with the study specific checklist of questions before awarding the bio-study. Questions related to various services of study like: Clinic phase, analytical phase, Pharmacokinetic and statistical phase, ethics approval, QA/QC, record handing etc. and related to CRO capabilities are discussed here with their relevance to conclude the abilities of CRO for successful execution of bio-study. Hence, this paper focuses all possible questions which need to be assessed before selection of CRO mainly for Bioavailability/Bioequivalence (BABE) study in healthy adult volunteers. Properly selected CRO will help for smooth execution of study and quality report and subsequently, hassle-free approval of dossier submitted to regulatory agency.

Expression of SARS-CoV-2 Spike Protein Receptor Binding Domain on Recombinant B. subtilis on Spore Surface: A Potential COVID-19 Oral Vaccine Candidate

Various types of vaccines, such as mRNA, adenovirus, and inactivated virus by injection, have been developed to prevent SARS-CoV-2 infection. Although some of them have already been approved under the COVID-19 pandemic, various drawbacks, including severe side effects and the requirement for sub-zero temperature storage, may hinder their applications. Bacillus subtilis (B. subtilis) is generally recognized as a safe and endotoxin-free Gram-positive bacterium that has been extensively employed as a host for the expression of recombinant proteins. Its dormant spores are extraordinarily resistant to the harsh environment in the gastrointestinal tract. This feature makes it an ideal carrier for oral administration in resisting this acidic environment and for release in the intestine. In this study, an engineered B. subtilis spore expressing the SARS-CoV-2 spike protein receptor binding domain (sRBD) on the spore surface was developed. In a pilot test, no adverse health event was observed in either mice or healthy human volunteers after three oral courses of B. subtilis spores. Significant increases in neutralizing antibody against sRBD, in both mice and human volunteers, after oral administration were also found. These findings may enable the further clinical developments of B. subtilis spores as an oral vaccine candidate against COVID-19 in the future.