Sigma Receptor Ligands Prevent COVID Mortality In Vivo: Implications for Future Therapeutics.

The emergence of lethal coronaviruses follows a periodic pattern which suggests a recurring cycle of outbreaks. It remains uncertain as to when the next lethal coronavirus will emerge, though its eventual emergence appears to be inevitable. New mutations in evolving SARS-CoV-2 variants have provided resistance to current antiviral drugs, monoclonal antibodies, and vaccines, reducing their therapeutic efficacy. This underscores the urgent need to investigate alternative therapeutic approaches. Sigma receptors have been unexpectedly linked to the SARS-CoV-2 life cycle due to the direct antiviral effect of their ligands. Coronavirus-induced cell stress facilitates the formation of an ER-derived complex conducive to its replication. Sigma receptor ligands are believed to prevent the formation of this complex. Repurposing FDA-approved drugs for COVID-19 offers a timely and cost-efficient strategy to find treatments with established safety profiles. Notably, diphenhydramine, a sigma receptor ligand, is thought to counteract the virus by inhibiting the creation of ER-derived replication vesicles. Furthermore, lactoferrin, a well-characterized immunomodulatory protein, has shown antiviral efficacy against SARS-CoV-2 both in laboratory settings and in living organisms. In the present study, we aimed to explore the impact of sigma receptor ligands on SARS-CoV-2-induced mortality in ACE2-transgenic mice. We assessed the effects of an investigational antiviral drug combination comprising a sigma receptor ligand and an immunomodulatory protein. Mice treated with sigma-2 receptor ligands or diphenhydramine and lactoferrin exhibited improved survival rates and rapid rebound in mass following the SARS-CoV-2 challenge compared to mock-treated animals. Clinical translation of these findings may support the discovery of new treatment and research strategies for SARS-CoV-2.

Emerging mutation patterns in SARS-CoV-2 variants.

There is an urgent need to understand the functional effects of mutations in emerging variants of SARS-CoV-2. Variants of concern (alpha, beta, gamma and delta) acquired four patterns of spike glycoprotein mutations that enhance transmissibility and immune evasion: 1) mutations in the N-terminal domain (NTD), 2) mutations in the Receptor Binding Domain (RBD), 3) mutations at interchain contacts of the spike trimer, and 4) furin cleavage site mutations. Most distinguishing mutations among variants of concern are exhibited in the NTD, localized to sites of high structural flexibility. Emerging variants of interest such as mu, lambda and C.1.2 exhibit the same patterns of mutations as variants of concern. There is a strong likelihood that SARS-CoV-2 variants will continue to emerge with mutations in these defined patterns, thus providing a basis for the development of next line antiviral drugs and vaccine candidates.

Motion sickness: an evolutionary and genetic basis for the negative reinforcement model.

It has been theorized that motion sickness evolved as a negative reinforcement system which terminates motion involving postural instability and/or sensory conflict. A hypothetical example is provided by a "thought experiment" whereby protohominids are in a tree looking for food. Selection pressure results when the organisms that have an aversion to motion-producing sensory conflict do not venture out too far on the tree limbs and therefore tend to survive. In order to support an evolutionary model for motion sickness there must be evidence for genetic and/or heritable predisposition. The present study involves a retrospective literature review which reveals abundant evidence for genetic/heritable factors in motion sickness. Examples include genetic polymorphism of the alpha-2-adrenergic receptor, which has been shown to increase susceptibility to motion sickness, examination of family trees revealing heritable motion sickness susceptibility, evidence indicating that Asians are hyper-susceptible to motion sickness, and twin studies, just to mention a few. Thus, the theory of heritable negative reinforcement as a basis for motion sickness is supported by extensive evidence in the medical literature. This theory is compared and contrasted with other theories. Further areas for research are suggested.

CO2 laser-assisted posterior semicircular canal ablation for benign paroxysmal positional vertigo.

OBJECTIVES: The objective of this study was to analyze a new technique, CO2 laser-assisted posterior semicircular canal ablation (LAPSCCA), in the treatment of refractory benign paroxysmal positional vertigo. STUDY DESIGN: Prospective study of patients with disabling BPPV who failed conservative therapy. METHODS: Patients noted to have been treated with at least three Epley maneuvers without success and continuing to have disabling symptoms were enrolled in this study. Patients underwent pre- and post-operative electronystagmography. The surgical technique is modified from Parnes1 and involves plugging each end of the fenestrated posterior semicircular canal with bone grafts and fibrin glue. The CO2 fiberoptic (Omniguide) laser is then used at a setting of 2 watts to incise between the cut ends of the canal to completely section the membranous labyrinth. RESULTS: All six patients had excellent relief of positional vertigo symptoms. CONCLUSIONS: LAPSCCA is an excellent treatment option for patients with intractable BPPV.

Shape-memory stapes prosthesis for otosclerosis surgery.

OBJECTIVES: The aim of this study was to determine the efficacy of a shape-memory alloy, Nitinol, as a component of an improved stapes prosthesis. STUDY DESIGN: Prospective laboratory and clinical study to develop a Nitinol stapes prosthesis. METHODS: Various diameters of Nitinol wire and temperature transition variants were analyzed with regard to ease of deformation, response to heating, and strength. The size and geometry of the closed hook was determined by measurement of 50 incus cadaver bones. Several heat sources for activating the shape memory were evaluated, including electrocautery, lasers, and warm water. Trial surgeries were then performed on human temporal bones in the laboratory. The closure characteristics of the Nitinol loop were studied. Magnetic resonance imaging (MRI) testing at 1.5 Tesla was performed to determine safety during MRI studies. Preliminary human subject trials were then instituted. RESULTS: In all cases, a low heat condition was ample to activate the shape memory characteristics of the hook and return it to a closed position after it had been opened. Laser power was generally set well below the power needed for removing bone. The Nitinol loop closed snugly around the incus with application to the top of the hook with a low temperature laser setting. Almost any heat source was effective. MRI testing at 1.5 Tesla showed no movement of the prosthesis. Preliminary results in human subjects showed excellent air-bone closure. The Nitinol loop holds uniform contact around the incus. CONCLUSIONS: The Nitinol piston greatly simplifies the stapedectomy procedure by taking the need for a hand operated instrument out of the surgeon's hands. Because of the nature of the Nitinol wire, it can never over-crimp. All these characteristics make the prosthesis advantageous for otosclerosis surgery.