Follow Your Nose: A Key Clue to Understanding and Treating COVID-19

This paper suggests that ATP release induced by the SARS-CoV-2 virus plays a key role in the genesis of the major symptoms and complications of COVID-19. Infection of specific cells which contain the Angiotensin-Converting Enzyme 2 (ACE2) receptor results in a loss of protection of the Mineralocorticoid Receptor (MR). Local activation by cortisol stimulates the release of ATP initially into the basolateral compartment and then by lysosomal exocytosis from the cell surface. This then acts on adjacent cells. In the nose ATP acts as a nociceptive stimulus which results in anosmia. It is suggested that a similar paracrine mechanism is responsible for the loss of taste. In the lung ATP release from type 2 alveolar cells produces the non-productive cough by acting on purinergic receptors on adjacent neuroepithelial cells and activating, via the vagus, the cough reflex. Infection of endothelial cells results in the exocytosis of WeibelPalade bodies. These contain the Von Willebrand Factor responsible for micro-clotting and angiopoietin-2 which increases vascular permeability and plays a key role in the Acute Respiratory Distress Syndrome. To test this hypothesis this paper reports proof of concept studies in which MR blockade using spironolactone and low dose dexamethasone (SpiDex) was given to PCR-confirmed COVID-19 patients. In 80 patients with moderate to severe respiratory failure 40 were given SpiDex and 40 conventional treatment with high dose dexamethasone (HiDex). There was 1 death in the HiDex group and none in the SpiDex. As judged by clinical, biochemical and radiological parameters there were clear statistically significant benefits of SpiDex in comparison to HiDex. A further 20 outpatients with COVID-19 were given SpiDex. There was no control group and the aim was to demonstrate safety. No adverse effects were noted and no patient became hyperkalaemic. 90% were asymptomatic at 10 days. The very positive results suggest that blockade of the MR can produce major benefit in COVID19 patients. Further larger controlled studies of inpatients and outpatients are required not only for SARS-CoV-2 infection per se but also to determine if this treatment affects the incidence of Long COVID.

Comparison of two injectable anaesthetic techniques on induction and subsequent anaesthesia in pigs

Pig experiments often require anaesthesia, and a rapid stress-free induction is desired. Induction drugs may alter the subsequent anaesthesia. Therefore, the aim of the present study was to compare, in pigs, the effects of two different injectable anaesthetic techniques on the induction and on the physiological variables in a subsequent eight hours of total intravenous anaesthesia (TIVA). Twelve domestic castrates (Swedish Landrace/Yorkshire) 27‒31 kg were used. The pigs were randomly assigned to different induction drug combinations of zolazepam–tiletamine and medetomidine intramuscularly (ZTMe) or midazolam, ketamine intramuscularly and fentanyl intravenously (MiKF). Time from injection to unconsciousness was recorded and the ease of endotracheal intubation assessed. The TIVA infusion rate was adjusted according to the response exhibited from the nociceptive stimulus delivered by mechanically clamping the dewclaw. The time from injection to unconsciousness was briefer and intubation was easier in the ZTMe group. Results from the recorded heart rate, cardiac index and arterial blood pressure variables were satisfactorily preserved and cardiovascular function was maintained in both groups. Shivering was not observed in the ZTMe group, but was observed in four of the pigs in the MiKF group. The requirement of TIVA was lower in the ZTMe group. In conclusion, ZTMe had better results than MiKF in areas such as shorter induction time, better intubation scoring results and less adjustment and amount of TIVA required up to six hours of anaesthesia. The results may have been due to a greater depth of anaesthesia achieved with the ZTMe combination at the dose used.

Observation of Nociceptive Processing: Effect of Intra-Epidermal Electric Stimulus Properties on Detection Probability and Evoked Potentials

Monitoring nociceptive processing is a current challenge due to a lack of objective measures. Recently, we developed a method for simultaneous tracking of psychophysical detection probability and brain evoked potentials in response to intra-epidermal stimulation. An exploratory investigation showed that we could quantify nociceptive system behavior by estimating the effect of stimulus properties on the evoked potential (EP). The goal in this work was to accurately measure nociceptive system behavior using this method in a large group of healthy subjects to identify the locations and latencies of EP components and the effect of single- and double-pulse stimuli with an inter-pulse interval of 10 or 40 ms on these EP components and detection probability. First, we observed the effect of filter settings and channel selection on the EP. Subsequently, we compared statistical models to assess correlation of EP and detection probability with stimulus properties, and quantified the effect of stimulus properties on both outcome measures through linear mixed regression. We observed lateral and central EP components in response to intra-epidermal stimulation. Detection probability and central EP components were positively correlated to the amplitude of each pulse, regardless of the inter-pulse interval, and negatively correlated to the trial number. Both central and lateral EP components also showed strong correlation with detection. These results show that both the observed EP and the detection probability reflect the various steps of processing of a nociceptive stimulus, including peripheral nerve fiber recruitment, central synaptic summation, and habituation to a repeated stimulus.

Influence of Different Doses of Butorphanol in Anesthesia with Sevoflurane in Blue-fronted Parrots (Amazona aestiva)

Background: Parrots frequently require veterinary medical care. To reduce their stress, it is necessary to use chemical restraint or anesthesia. The use of balanced anesthesia techniques such as combinations of inhaled and injectable drugs is recommended. However, there is a shortage of anesthetic and analgesic protocols and data on cardiovascular and respiratory variables in wild birds. The objective of the present study was to evaluate the analgesic, cardiovascular, and respiratory effects and the quality of anesthetic recovery in blue-front parrots (Amazona aestiva) anesthetized with sevoflurane in combination with various doses of butorphanol.Materials, Methods & Results: Twenty-four clinically healthy animals, based on their clinical and hematological results (hematocrit and total plasma protein), were divided into 3 groups: 1- sevofluoran alone (GS); 2- associated with butorphanol at 3 mg/kg (GB3), and 3- 6 mg/kg (GB6) doses administered via the intramuscular (IM) route; digital clamping was used as a nociceptive stimulus. Induction and anesthetic maintenance were performed with sevoflurane at 5 and 2.5 V%, respectively, administered through a calibrated vaporizer and an anesthetic system adequate for the weight of the animals that were kept under spontaneous ventilation. It took 15 min after induction for the expired sevoflurane concentration (EtSevo) to stabilize, after which one intramuscular treatment was applied. The digital clamping was continued as a supramaximal nociceptive stimulus; if it presented a positive response, EtSevo increased by 10%, and when the stimulus decreased by 20%, digital clamping was repeated every 15 min until a positive response to the stimulus was observed. Heart rate (HR) and rhythm, respiratory rate (f), systolic blood pressure (SBP), EtSevo, expired CO2 (EtCO2), and body temperature (T°C) were measured during digital clamping. At the end, anesthetic recovery was evaluated through the extubation times, bipedal positioning, and quality of recovery. Significant statistical differences were observed between the GS and GB6 groups in the variable EtSevo and SBP, with mean ± standard deviation of 2.61 ± 0.48 and 2.17 ± 0.43 V%, and 188 ± 20 and 159 ± 22 mmHg, respectively. The quality of recovery was optimal for all groups, with the mean time ± standard deviation of extubation time of 1.25 ± 0.46, 1.12 ± 0.35, and 1.50 ± 0.92 min, and bipedal positioning of 1.87 ± 1.45, 1.75 ± 0.88, and 2.75 ± 1.28 min for the GS, GB3, and GB6 groups, respectively.Discussion: Balanced anesthesia techniques have demonstrated benefits in veterinary medicine as they reduce cardiovascular and respiratory depression, increase drug potency due to synergism, and require a reduced amount of inhalable anesthetic. The results of this study showed that the combination of sevoflurane and butorphanol at the doses used in the present study reduced the anesthetic concentration necessary for the maintenance of the animals without nociceptive stimulation, respiratory stability, and rapid and quiet anesthetic recovery; it also maintained blood pressure and heart rate within the normal physiological limits. Severe heart rhythm disorders were observed in groups GB3 and GB6, but it is worth mentioning that at the end of anesthesia all animals sinus rhythm. However, the electrocardiographic findings showed that this practice was not considered safe for the species.

GABAA Receptor/STEP61 Signaling Pathway May Be Involved in Emulsified Isoflurane Anesthesia in Rats

(1) Background: Emulsified isoflurane (EISO) is a type of intravenous anesthetic. How emulsified isoflurane works in the brain is still unclear. The aim of this study was to explore whether epigenetic mechanisms affect anesthesia and to evaluate the anesthetic effects of emulsified isoflurane in rats. (2) Methods: Rats were randomly divided into four groups (n = 8/group): The tail vein was injected with normal saline 0.1 mL·kg−1·min−1 for the control (Con) group, with intralipid for the fat emulsion (FE) group, with EISO at 60 mg·kg−1·min−1 for the high-concentration (HD) group, and 45 mg·kg−1·min−1 for the low-concentration (LD) group. The consciousness state, motor function of limbs, and response to nociceptive stimulus were observed after drug administration. (3) Results: Using real-time polymerase chain reaction (PCR) to assess the promoter methylation of ion channel proteins in the cerebral cortex of rats anesthetized by EISO, we demonstrated that the change in the promoters’ methylation of the coding genes for gamma-aminobutyric acid A receptor α1 subunit (GABAAα1), N-methyl-D-aspartate receptor subunit 1 (NMDAR1), and mu opioid receptor 1 (OPRM1) was accompanied by the change in messenger ribonucleic acid (mRNA) and protein expression by these genes. (4) Conclusion: These data suggest that the epigenetic factors’ modulation might offer a novel approach to explore the anesthetic mechanism of EISO.

Acupuncture Induces Reduction in Limbic-Cortical Feedback of a Neuralgia Rat Model: A Dynamic Causal Modeling Study

Background. Neuropathic pain after brachial plexus avulsion remained prevalent and intractable currently. However, the neuroimaging study about neural mechanisms or etiology was limited and blurred. Objective. This study is aimed at investigating the effect of electroacupuncture on effective connectivity and neural response in corticolimbic circuitries during implicit processing of nociceptive stimulus in rats with brachial plexus pain. Methods. An fMRI scan was performed in a total of 16 rats with brachial plexus pain, which was equally distributed into the model group and the electroacupuncture group. The analysis of task-dependent data determined pain-related activation in each group. Based on those results, several regions including AMY, S1, and h were recruited as ROI in dynamic causal modeling (DCM) analysis comparing evidence for different neuronal hypotheses describing the propagation of noxious stimuli in regions of interest and horizontal comparison of effective connections between the model and electroacupuncture groups. Results. In both groups, DCM revealed that noxious stimuli were most likely driven by the somatosensory cortex, with bidirectional propagation with the hypothalamus and amygdala and the interactions in them. Also, the 3-month intervention of acupuncture reduced effective connections of h-S1 and AMY-S1. Conclusions. We showed an evidence that a full connection model within the brain network of brachial plexus pain and electroacupuncture intervention reduces effective connectivity from h and AMY to S1. Our study for the first time explored the relationship of involved brain regions with dynamic causal modeling. It provided novel evidence for the feature of the organization of the cortical-limbic network and the alteration caused by acupuncture.

A New Perspective of Acupuncture: The Interaction among Three Networks Leads to Neutralization

Acupuncture has been used to treat multiple medical conditions, but whether the diverse effects of acupuncture are intrinsically linked and how they might be connected have yet to be determined. More and more researches have shown that acupuncture is a kind of nociceptive stimulus, which can cause inflammatory reaction in the sites of acupuncture and then further activate the nerve-endocrine-immune systems to cause the cascade amplification of the acupuncture effect. This review seeks to provide a comprehensive summary of the existing literature concerning the role of “acupoint-meridian-disease network” in various effects of acupuncture and suggest a novel notion that acupuncture may restore homeostasis under different pathological conditions by regulating this network, resulting in the activation of different reaction cascades in response to pathological injury. We think that acupuncture acts on acupoints, first activating the small network of acupoints (Acupoint Network). The information of acupuncture is amplified by cascade, and the nerve endocrine immune system (NEI) is activated through the large network of meridians (Meridian Network) of the body itself. The nerve-endocrine-immune system (NEI) further outputs the effect information to the target organ through multilevel and multisystems and finally acts on the disease network (Disease Network) to produce acupuncture effect.

Neural indicators of perceptual variability of pain across species

Individuals exhibit considerable and unpredictable variability in painful percepts in response to the same nociceptive stimulus. Previous work has found neural responses that, while not necessarily responsible for the painful percepts themselves, can still correlate well with intensity of pain perception within a given individual. However, there is no reliable neural response reflecting the variability in pain perception across individuals. Here, we use an electrophysiological approach in humans and rodents to demonstrate that brain oscillations in the gamma band [gamma-band event-related synchronization (γ-ERS)] sampled by central electrodes reliably predict pain sensitivity across individuals. We observed a clear dissociation between the large number of neural measures that reflected subjective pain ratings at within-subject level but not across individuals, and γ-ERS, which reliably distinguished subjective ratings within the same individual but also coded pain sensitivity across different individuals. Importantly, the ability of γ-ERS to track pain sensitivity across individuals was selective because it did not track the between-subject reported intensity of nonpainful but equally salient auditory, visual, and nonnociceptive somatosensory stimuli. These results also demonstrate that graded neural activity related to within-subject variability should be minimized to accurately investigate the relationship between nociceptive-evoked neural activities and pain sensitivity across individuals.