As of April 20, 2020, over time, the COVID-19 pandemic has resulted in 157 970 deaths out of 2 319 066 confirmed cases, at a Case Fatality Rate of ~6.8%. With the pandemic rapidly spreading, and health delivery systems being overwhelmed, it is imperative that safe and effective pharmacotherapeutic strategies are rapidly explored to improve survival. In this paper, we use established and emerging evidence to propose a testable hypothesis that, a vicious positive feedback loop of des-Arg(9)bradykinin-and bradykinin-mediated inflammation → injury → inflammation, likely precipitates life threatening respiratory complications in COVID-19. Through our hypothesis, we make the prediction that the FDA-approved molecule, icatibant, might be able to interrupt this feedback loop and, thereby, improve the clinical outcomes. This hypothesis could lead to basic, translational, and clinical studies aimed at reducing COVID-19 morbidity and mortality. K E Y W O R D Sbradykinin, bradykinin receptor, coronavirus, icatibant, inflammation, injury How to cite this article: Roche JA, Roche R. A hypothesized role for dysregulated bradykinin signaling in COVID-19 respiratory complications.

We studied the response of dysferlin-null and control skeletal muscle to large- and small-strain injuries to the ankle dorsiflexors in mice. We measured contractile torque and counted fibers retaining 10-kDa fluorescein dextran, necrotic fibers, macrophages, and fibers with central nuclei and expressing developmental myosin heavy chain to assess contractile function, membrane resealing, necrosis, inflammation, and myogenesis. We also studied recovery after blunting myogenesis with X-irradiation. We report that dysferlin-null myofibers retain 10-kDa dextran for 3 days after large-strain injury but are lost thereafter, following necrosis and inflammation. Recovery of dysferlin-null muscle requires myogenesis, which delays the return of contractile function compared with controls, which recover from large-strain injury by repairing damaged myofibers without significant inflammation, necrosis, or myogenesis. Recovery of control and dysferlin-null muscles from small-strain injury involved inflammation and necrosis followed by myogenesis, all of which were more pronounced in the dysferlin-null muscles, which recovered more slowly. Both control and dysferlin-null muscles also retained 10-kDa dextran for 3 days after small-strain injury. We conclude that dysferlin-null myofibers can survive contraction-induced injury for at least 3 days but are subsequently eliminated by necrosis and inflammation. Myogenesis to replace lost fibers does not appear to be significantly compromised in dysferlin-null mice.

Children with DCD demonstrate impairments in bimanual finger tapping during self-paced tapping and tapping in synchrony to different frequencies. In this study, we investigated the ability of children with DCD to adapt motorically to perceptible or subliminal changes of the auditory stimuli without a change in frequency, and compared their performance to typically developing controls (TDC). Nineteen children with DCD between ages 6-11years (mean age±SD=114±21months) and 17 TDC (mean age±SD=113±21months) participated in this study. Auditory perceptual threshold was established. Children initially tapped bimanually to an antiphase beat and then to either a perceptible change in rhythm or to gradual subliminal changes in rhythm. Children with DCD were able to perceive changes in rhythm similar to TDC. They were also able to adapt to both perceptible and subliminal changes in rhythms similar to their age- and gender- matched TDC. However, these children were significantly more variable compared with TDC in all phasing conditions. The results suggest that the performance impairments in bilateral tapping are not a result of poor conscious or sub-conscious perception of the auditory cue. The increased motor variability may be associated with cerebellar dysfunction but further behavioral and neurophysiological studies are needed.

Electroporation (EP) is used to transfect skeletal muscle fibers in vivo, but its effects on the structure and function of skeletal muscle tissue have not yet been documented in detail. We studied the changes in contractile function and histology after EP and the influence of the individual steps involved to determine the mechanism of recovery, the extent of myofiber damage, and the efficiency of expression of a green fluorescent protein (GFP) transgene in the tibialis anterior (TA) muscle of adult male C57Bl/6J mice. Immediately after EP, contractile torque decreased by ∼80% from pre-EP levels. Within 3 h, torque recovered to ∼50% but stayed low until day 3. Functional recovery progressed slowly and was complete at day 28. In muscles that were depleted of satellite cells by X-irradiation, torque remained low after day 3, suggesting that myogenesis is necessary for complete recovery. In unirradiated muscle, myogenic activity after EP was confirmed by an increase in fibers with central nuclei or developmental myosin. Damage after EP was confirmed by the presence of necrotic myofibers infiltrated by CD68+ macrophages, which persisted in electroporated muscle for 42 days. Expression of GFP was detected at day 3 after EP and peaked on day 7, with ∼25% of fibers transfected. The number of fibers expressing green fluorescent protein (GFP), the distribution of GFP+ fibers, and the intensity of fluorescence in GFP+ fibers were highly variable. After intramuscular injection alone, or application of the electroporating current without injection, torque decreased by ∼20% and ∼70%, respectively, but secondary damage at D3 and later was minimal. We conclude that EP of murine TA muscles produces variable and modest levels of transgene expression, causes myofiber damage due to the interaction of intramuscular injection with the permeabilizing current, and that full recovery requires myogenesis.

Children with Developmental Coordination Disorder (DCD) are more variable in timing their fingers to an external cue. In this study, we investigated the intrinsic coordination properties of self-selected anti-phase finger tapping with and without vision and audition in children with and without DCD and compared their performance to that of adults. Ten children with DCD (Mean age = 7.12 ± 0.3 years), ten age-and sex-matched typically developing (TD) children, and ten adults participated in this study. Participants tapped their fingers in anti-phase at a self-selected speed under four different sensory conditions: (1) with vision and audition, (2) with vision but no audition, (3) with audition but no vision, and (4) without vision and audition. We assessed intertap interval (ITI), variability of ITI, mean relative phasing (RP) between the fingers and the variability in RP. Children with DCD adopted a similar mean frequency, but were less accurate and more variable than the other groups. The different sensory conditions did not affect performance in any of the groups. We conclude that visual and auditory feedback of tapping are not salient information sources for bilateral self-selected tapping and that children with DCD are intrinsically less accurate and more variable in their tapping frequency and coordination.