Ketamine: Neuroprotective or Neurotoxic?

Ketamine, a non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist, has been employed clinically as an intravenous anesthetic since the 1970s. More recently, ketamine has received attention for its rapid antidepressant effects and is actively being explored as a treatment for a wide range of neuropsychiatric syndromes. In model systems, ketamine appears to display a combination of neurotoxic and neuroprotective properties that are context dependent. At anesthetic doses applied during neurodevelopmental windows, ketamine contributes to inflammation, autophagy, apoptosis, and enhances levels of reactive oxygen species. At the same time, subanesthetic dose ketamine is a powerful activator of multiple parallel neurotrophic signaling cascades with neuroprotective actions that are not always NMDAR-dependent. Here, we summarize results from an array of preclinical studies that highlight a complex landscape of intracellular signaling pathways modulated by ketamine and juxtapose the somewhat contrasting neuroprotective and neurotoxic features of this drug.

The clinically validated viral superinfection therapy (SIT) platform technology could cure early cases of COVID-19 disease

Currently, SARS-CoV-2 infection which is the causative agent for COVID-19 disease is a worldwide pandemic with more than 100 million global cases and more than 2.0 million deaths (as of January, 2021). While several vaccines for prevention of COVID-19 have already been registered by the regulatory authorities, the problem is that the substitution rate of this virus is estimated to be one change per 2 weeks, thus mutations could arise that threaten the efficacy of vaccines. Unfortunately, there is no current evidence from random clinical trials to recommend any specific post-exposure treatment for patients with suspected or confirmed COVID-19 disease. Here we propose an innovative superinfection therapeutic (SIT) strategy, which could complement the development of prophylactic vaccines. SIT is based on clinical observations that unrelated harmless viruses might interact in patients infected with pathogenic virus. During SIT, the patient benefits from superinfection with an apathogenic double-stranded RNA (dsRNA) virus such as the infectious bursal disease virus (IBDV), which is a powerful activator of the interferon-dependent antiviral gene program. An attenuated vaccine strain of IBDV was already successfully administered to resolve acute and persistent infections induced by two completely different viruses, the hepatitis B (DNA) and C (RNA) viruses (HBV/HCV). The safety of orally administered acid-resistant IBDV strain R903/78 reverse engineered viral drug candidate was demonstrated in 10 stage IV cancer patients who exhausted all conventional therapy. Following repeated oral administration of the virus up to 109 infectious units (IU)/ dose, only mild flu-like side effects were reported in some patients. Proof-of-principle efficacy was demonstrated in an early COVID-19 patient who was successfully treated with 3x106 IU of an attenuated IBDV vaccine. A small scale dose-finding Phase I safety study is proposed.

The Clinically Validated Viral Superinfection Therapy (SIT) Platform Technology May Mitigate Severe Cases of COVID-19 Infections

The transmission characteristic of COVID-19 is of similar magnitude to severe acute respiratory syndrome-related coronavirus (SARS-CoV) and the 1918 pandemic influenza. The virus is now in more than 100 countries and on nearly all continents. The World Health Organization (WHO) declared the COVID-19 outbreak a pandemic. There is no current evidence from random clinical trials (RCTs) to recommend any specific anti-COVID-19 treatment for patients with suspected or confirmed COVID-19 infection. In order to mitigate the impact of the COVID-19 outbreak, here we propose an innovative superinfection therapeutic (SIT) strategy, which could complement the development of prophylactic vaccines. SIT is based on clinical observations that unrelated viruses might interact in co-infected patients. During SIT, the patient benefit from superinfection with an apathogenic dsRNA virus such as the infectious bursal disease virus (IBDV), which is a powerful activator of the interferon-dependent antiviral gene program. An attenuated vaccine strain of IBDV was already successfully administered to resolve acute and persistent infections induced by two completely different viruses, the hepatitis B (DNA) and C (RNA) viruses (HBV/HCV). Importantly, the epidemiological efficacy of a similar strategy to SIT had already been successfully tested in large controlled trials. Standard live orally administered enterovirus vaccines that stimulate the production of endogenous interferon of the host mitigated the seasonal outbreaks of influenza and other associated acute respiratory infections in 152,042 individuals without adverse reactions.

The Clinically Validated Viral Superinfection Therapy (SIT) Platform Technology May Mitigate Severe Cases of COVID-19 Infections

The transmission characteristic of COVID-19 is of similar magnitude to severe acute respiratory syndrome-related coronavirus (SARS-CoV) and the 1918 pandemic influenza. The virus is now in 50 countries and on nearly all continents. The World Health Organization (WHO) says to prepare for a pandemic. There is no current evidence from random clinical trials (RCTs) to recommend any specific anti-COVID-19 treatment for patients with suspected or confirmed COVID-19 infection. In order to mitigate the impact of the COVID-19 outbreak, here we propose an innovative superinfection therapeutic (SIT) strategy, which could complement the development of prophylactic vaccines. SIT is based on clinical observations that unrelated viruses might interact in co-infected patients. During SIT, the patient benefit from superinfection with an apathogenic dsRNA virus such as the infectious bursal disease virus (IBDV), which is a powerful activator of the interferon-dependent antiviral gene program. An attenuated vaccine strain of IBDV was already successfully administered to resolve acute and persistent infections induced by two completely different viruses, the hepatitis B (DNA) and C (RNA) viruses (HBV/HCV). Importantly, the epidemiological efficacy of a similar strategy to SIT had already been successfully tested in large controlled trials. Standard live orally administered enterovirus vaccines that stimulate the production of endogenous interferon of the host mitigated the seasonal outbreaks of influenza and other associated acute respiratory infections in 152,042 individuals without adverse reactions.

The Clinically Validated Viral Superinfection Therapy (SIT) Platform Technology May Mitigate Severe Cases of 2019-nCoV Infections

Stochastic simulations of early outbreak trajectories found that the basic reproduction number, R0, of the Wuhan new coronavirus (2019-nCoV) is around 2.2, which indicates the potential for sustained human-to-human transmission. In fact, this transmission characteristic is a similar magnitude to severe acute respiratory syndrome-related coronavirus (SARS-CoV) and the 1918 pandemic influenza. Cases have now spread to at least 4 continents, currently with 43,108 cases and 1,018 lives lost. The World Health Organization (WHO) declared the outbreak a public health emergency of international concern. There is no current evidence from random clinical trials (RCTs) to recommend any specific anti-nCoV treatment for patients with suspected or confirmed 2019-nCoV infection. In order to mitigate the impact of the 2019-nCoV outbreak, here we propose an innovative superinfection therapeutic (SIT) strategy, which could complement the development of prophylactic vaccines. SIT is based on clinical observations that unrelated viruses might interact in co-infected patients. During SIT, the patient benefit from superinfection with an apathogenic dsRNA virus such as the infectious bursal disease virus (IBDV), which is a powerful activator of the interferon-dependent antiviral gene program. An attenuated vaccine strain of IBDV was already successfully administered to resolve acute and persistent infections induced by two completely different viruses, the hepatitis B (DNA) and C (RNA) viruses (HBV/HCV). Importantly, IBDV is also a potential prophylactic vaccine vector drug candidate, since a recombinant IBDV was previously generated that displays exogenous viral peptides from a replication-competent IBDV.

Effects of High-Frequency Proprioceptive Training on Single Stance Stability in Older Adults: Implications for Fall Prevention

Single-limb stance instability is a major risk factor for falls in older adults. Thus, improvement of stance stability could play an important role in fall prevention. This study aimed to determine whether high-frequency proprioceptive training (HPT) could significantly improve single stance stability (SSS) in older adults, by increasing proprioceptive control and optimizing the contribution of vision. Sixty-one subjects (30 men, 31 women) aged 65-85 years were investigated. The subjects were randomly assigned to three intervention groups, i.e., HPT, treadmill, and no intervention, stratifying by gender and proprioceptive control at baseline. Stability tests and HPT, consisting of 12 sessions (6 weeks), were performed with computerized postural stations. Pre-post analysis showed that HPT significantly improved SSS by increasing proprioceptive control (p<0.001) and postural control (p<0.01). The treadmill and no intervention groups did not show any significant change. The results showed that different levels of proprioceptive control may activate, inhibit, or minimize the stabilizing intervention of vision. Given that HPT significantly reduced ankle sprains and low back pain in professional athletes (previous study), we discuss the hypothesis that the risk of falls in older adults and the risk of recurrent injuries in athletes would have a common origin: lack of proprioceptive control consequent to reduced interaction with uneven ground. The findings suggest that HPT may be a powerful activator of refined proprioceptive control, which allows increased SSS, safer interaction with the ground, and mitigation of other risk factors.

Effects of age-dependent membrane transport changes on the homeostasis of senescent human red blood cells

Little is known about age-related changes in red blood cell (RBC) membrane transport and homeostasis. We investigated first whether the known large variation in plasma membrane Ca2+ (PMCA) pump activity was correlated with RBC age. Glycated hemoglobin, Hb A1c, was used as a reliable age marker for normal RBCs. We found an inverse correlation between PMCA strength and Hb A1c content, indicating that PMCA activity declines monotonically with RBC age. The previously described subpopulation of high-Na+, low-density RBCs had the highest Hb A1c levels, suggesting it represents a late homeostatic condition of senescent RBCs. Thus, the normal densification process of RBCs with age must undergo late reversal, requiring a membrane permeability increase with net NaCl gain exceeding KCl loss. Activation of a nonselective cation channel, Pcat, was considered the key link in this density reversal. Investigation of Pcat properties showed that its most powerful activator was increased intracellular Ca2+. Pcat was comparably selective to Na+, K+, choline, and N-methyl-D-glucamine, indicating a fairly large, poorly selective cation permeability pathway. Based on these observations, a working hypothesis is proposed to explain the mechanism of progressive RBC densification with age and of the late reversal to a low-density condition with altered ionic gradients.