Purpose of Review The present review discusses the peripheral nervous system (PNS) manifestations associated with coronavirus disease 2019 (COVID-19). Recent Findings Nerve pain and skeletal muscle injury, Guillain-Barré syndrome, cranial polyneuritis, neuromuscular junction disorders, neuro-ophthalmological disorders, neurosensory hearing loss, and dysautonomia have been reported as PNS manifestations in patients with COVID-19. Summary Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19. COVID-19 has shown syndromic complexity. Not only does SARS-CoV-2 affect the central nervous system but also it involves the PNS. The PNS involvement may be due to dysregulation of the immune system attributable to COVID-19. Here we review the broad spectrum of PNS involvement of COVID-19.
Unapposed connexin hemichannels exhibit robust closure in response to membrane hyperpolarization and extracellular calcium. This form of gating, termed "loop gating," is largely responsible for regulating hemichannel opening, thereby preventing cell damage through excessive flux of ions and metabolites. The molecular components and structural rearrangements underlying loop gating remain unknown. Here, using cysteine mutagenesis in Cx50, we demonstrate that residues at the TM1/E1 border undergo movement during loop gating. Replacement of Phe 43 in Cx50 with a cysteine resulted in small or no appreciable membrane currents. Bath application of dithiothreitol or TPEN (N,N,N,N-tetrakis(2-pyridylmethyl) ethylenediamine), reagents that exhibit strong transition metal chelating activity, led to robust currents indicating that the F43C substitution impaired hemichannel function, producing "lock-up" in a closed or poorly functional state due to formation of metal bridges. In support, Cd 2؉ at submicromolar concentrations (50 -100 nM) enhanced lock-up of F43C hemichannels. Moreover, lock-up occurred under conditions that favored closure, indicating that the sulfhydryl groups come close enough to each other or to other residues to coordinate metal ions with high affinity. In addition to F43C, metal binding was also found for G46C, and to a lesser extent, D51C substitutions, positions found to be pore-lining in the open state using the substitutedcysteine accessibility method, but not for A40C and A41C substitutions, which were not found to reside in the open pore. These results indicate that metal ions access the cysteine side chains through the open pore and that closure of the loop gate involves movement of the TM1/E1 region that results in local narrowing of the large aqueous connexin pore.
Purpose of Review Coronavirus disease 2019 (COVID-19) has become a global health crisis of our time. The disease arises from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that binds to angiotensin-converting enzyme 2 (ACE2) receptors on host cells for its internalization. COVID-19 has a wide range of respiratory symptoms from mild to severe and affects several other organs, increasing the complexity of the treatment. There is accumulating evidence to suggest that SARS-CoV-2 can target the nervous system. In this review, we provide an account of the COVID-19 central nervous system (CNS) manifestations. Recent Findings A broad spectrum of the CNS manifestations including headache, impaired consciousness, delirium, loss of smell and taste, encephalitis, seizures, strokes, myelitis, acute disseminated encephalomyelitis, neurogenic respiratory failure, encephalopathy, silent hypoxemia, generalized myoclonus, neuroleptic malignant syndrome and Kawasaki syndrome has been reported in patients with COVID-19. Summary CNS manifestations associated with COVID-19 should be considered in clinical practice. There is a need for modification of current protocols and standing orders to provide better care for COVID-19 patients presenting with neurological symptoms.
Objective:To test ketamine infusion efficacy in the treatment of super-refractory status epilepticus (SRSE), we studied retrospectively SRSE patients who were treated with ketamine. Additionally, we studied the effect of high doses of ketamine on brain physiology as reflected by invasive multimodality monitoring (MMM).Methods:We studied a consecutive series of 68 SRSE patients who were admitted between 2009 and 2018, were treated with ketamine and monitored with scalp EEG. Eleven of these patients underwent MMM at the time of ketamine administration. We compared patients who had seizure cessation after ketamine initiation to those who did not.Results:Mean age was 53+/-18 years old, 46% of patients were female. Seizure burden decreased by at least 50% within 24 hours of starting ketamine in 55 (81%) patients, with complete cessation in 43 (63%). Average dose of ketamine infusion was 2.2+/-1.8 mg/kg/h, with median duration of 2 (1; 4) days. Average dose of midazolam was 1.0+/-0.8 mg/kg/h at the time of ketamine initiation and was started at a median of 0.4 (0.1; 1.0) days before ketamine. Using a generalized linear mixed effect model, ketamine was associated with stable mean arterial pressure (OR 1.39, 95% CI 1.38-1.40), and with decreased in vasopressor requirements over time. We found no effect on intracranial pressure, cerebral blood flow, and cerebral perfusion pressure.Conclusion:Ketamine treatment was associated with a decrease in seizure burden in patients with SRSE. Our data support the notion that high dose ketamine infusions are associated with decreased vasopressor requirements without increased intracranial pressure.Classification of Evidence:This study provides Class IV evidence that ketamine decreases seizures in patients with SRSE.
Background An estimated 10-15% of sudden infant death syndrome (SIDS) may stem from channelopathy-mediated lethal arrhythmias. Loss of the GJA1-encoded gap junction channel protein connexin43 (Cx43) is known to underlie formation of lethal arrhythmias. GJA1 mutations have been associated with cardiac diseases including atrial fibrillation. Therefore, GJA1 is a plausible candidate gene for premature sudden death. Methods and Results GJA1 open reading frame mutational analysis was performed using PCR, DHPLC, and direct DNA sequencing on DNA from 292 SIDS cases. Immunofluorescence and dual whole cell patch-clamp studies were performed to determine functionality of mutant gap junctions. Immunostaining for gap junction proteins was performed on SIDS-associated paraffin-embedded cardiac tissue. Two rare, novel missense mutations, E42K and S272P, were detected in 2 of 292 SIDS cases, a 2-month-old white male and a 3-month-old white female, respectively. Analysis of the E42K victim’s parental DNA demonstrated a de novo mutation. Both mutations involved highly conserved residues and were absent in over 1000 ethnic-matched reference alleles. Immunofluorescence demonstrated no trafficking abnormalities for either mutation and S272P demonstrated wildtype junctional conductance. However, junctional conductance measurements for the E42K mutation demonstrated a loss-of-function not rescued by wildtype. Moreover, the E42K victim cardiac tissue demonstrated a mosaic immunostaining pattern for Cx43 protein. Conclusions This study provides the first molecular and functional evidence implicating a GJA1 mutation as a novel pathogenic substrate for SIDS. E42K-Cx43 demonstrated a trafficking-independent reduction in junctional coupling in vitro as well as demonstrating a mosaic pattern of mutational DNA distribution in deceased cardiac tissue, suggesting a novel mechanism of Cx43-associated sudden death.
Chimeric antigen receptor (CAR)-modified T cells targeting the CD19 antigen are approved to treat relapsed and refractory B-cell malignancies. [1][2][3][4] Despite durable objective responses, most patients experience acute toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). 5 Although many cases of ICANS resolve with supportive measures, high-grade ICANS may result in status epilepticus, lasting neurologic deficits, cerebral edema, 6 and death. 7 Therefore, novel approaches for severe ICANS fill an urgent unmet need to enhance the use of adoptive cellular therapy.15. Diaconu I, Ballard B, Zhang M, et al. Inducible caspase-9 selectively modulates the toxicities of CD19-specific chimeric antigen receptormodified T cells.
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