Retinoid receptor-based signaling plays a role in voltage-dependent inhibition of invertebrate voltage-gated Ca2+ channels.

The retinoic acid receptor (RAR) and retinoid X receptor (RXR) mediate the cellular effects of retinoids (derivatives of vitamin A). Both RAR and RXR signaling events are implicated in hippocampal synaptic plasticity. Furthermore, retinoids can interact with calcium signaling during homeostatic plasticity. We recently provided evidence that retinoids attenuate calcium current (ICa) through neuronal voltage-gated calcium channels (VGCCs). We now examined the possibility that constitutive activity of neuronal RXR and/or RAR alters calcium influx via the VGCCs. We found that in neurons of the mollusk Lymnaea stagnalis, two different RXR antagonists (PA452 and HX531) had independent and opposing effects on ICa that were also time-dependent; whereas the RXR pan-antagonist PA452 enhanced ICa, HX531 reduced ICa Interestingly, this effect of HX531 occurred through voltage-dependent inhibition of VGCCs, a phenomenon known to influence neurotransmitter release from neurons. This inhibition appeared to be independent of G proteins and was largely restricted to Cav2 Ca2+ channels. Of note, an RAR pan-antagonist, LE540, also inhibited ICa but produced G protein-dependent, voltage-dependent inhibition of VGCCs. These findings provide evidence that retinoid receptors interact with G proteins in neurons and suggest mechanisms by which retinoids might affect synaptic calcium signaling.

Pannexin-1 Deficiency Decreases Epileptic Activity in Mice.

OBJECTIVE: Pannexin-1 (Panx1) is suspected of having a critical role in modulating neuronal excitability and acute neurological insults. Herein, we assess the changes in behavioral and electrophysiological markers of excitability associated with Panx1 via three distinct models of epilepsy. Methods Control and Panx1 knockout C57Bl/6 mice of both sexes were monitored for their behavioral and electrographic responses to seizure-generating stimuli in three epilepsy models-(1) systemic injection of pentylenetetrazol, (2) acute electrical kindling of the hippocampus and (3) neocortical slice exposure to 4-aminopyridine. Phase-amplitude cross-frequency coupling was used to assess changes in an epileptogenic state resulting from Panx1 deletion. RESULTS: Seizure activity was suppressed in Panx1 knockouts and by application of Panx1 channel blockers, Brilliant Blue-FCF and probenecid, across all epilepsy models. In response to pentylenetetrazol, WT mice spent a greater proportion of time experiencing severe (stage 6) seizures as compared to Panx1-deficient mice. Following electrical stimulation of the hippocampal CA3 region, Panx1 knockouts had significantly shorter evoked afterdischarges and were resistant to kindling. In response to 4-aminopyridine, neocortical field recordings in slices of Panx1 knockout mice showed reduced instances of electrographic seizure-like events. Cross-frequency coupling analysis of these field potentials highlighted a reduced coupling of excitatory delta-gamma and delta-HF rhythms in the Panx1 knockout. SIGNIFICANCE: These results suggest that Panx1 plays a pivotal role in maintaining neuronal hyperexcitability in epilepsy models and that genetic or pharmacological targeting of Panx1 has anti-convulsant effects.

Divergent neuroendocrine responses to localized and systemic inflammation.

The sympathetic nervous system (SNS) is part of an integrative network that functions to restore homeostasis following injury and infection. The SNS can provide negative feedback control over inflammation through the secretion of catecholamines from postganglionic sympathetic neurons and adrenal chromaffin cells (ACCs). Central autonomic structures receive information regarding the inflammatory status of the body and reflexively modulate SNS activity. However, inflammation and infection can also directly regulate SNS function by peripheral actions on postganglionic cells. The present review discusses how inflammation activates autonomic reflex pathways and compares the effect of localized and systemic inflammation on ACCs and postganglionic sympathetic neurons. Systemic inflammation significantly enhanced catecholamine secretion through an increase in Ca(2+) release from the endoplasmic reticulum. In contrast, acute and chronic GI inflammation reduced voltage-gated Ca(2+) current. Thus it appears that the mechanisms underlying the effects of peripheral and systemic inflammation neuroendocrine function converge on the modulation of intracellular Ca(2+) signaling.

VENOUS STASIS RETINOPATHY SECONDARY TO MYELIN OLIGODENDROCYTE GLYCOPROTEIN ANTIBODY-POSITIVE OPTIC NEURITIS.

PURPOSE: To report a case of a 38-year-old woman with venous stasis retinopathy secondary to myelin oligodendrocyte glycoprotein-IgG optic neuritis. METHODS: Observational case report. RESULTS: We report a unique case of venous stasis retinopathy secondary to myelin oligodendrocyte glycoprotein-IgG optic neuritis with significant optic disc edema, tortuous and dilated retinal venules, and retinal hemorrhages, which resolved promptly with high-dose corticosteroids. The retinal changes were likely secondary to severe inflammation of the optic nerve and optic nerve sheath, which exhibited significant postcontrast enhancement on magnetic resonance imaging. Despite aggressive treatment with high-dose corticosteroids and plasmapheresis, the patient had a significant generalized visual field defect at 6 months. CONCLUSION: Venous stasis retinopathy may be secondary to myelin oligodendrocyte glycoprotein-IgG optic neuritis due to reduced venous outflow from significant optic nerve edema. This may be a poor prognostic factor and a marker for more severe optic nerve inflammation.

Comparison of Barrett Toric Calculations Using Measured and Predicted Posterior Corneal Astigmatism in Cataract Surgery Patients.

Aim: To compare residual astigmatism prediction errors across Barrett toric calculations using predicted posterior corneal astigmatism (PCA) and PCA measured using the IOL Master 700 with total keratometry (IOLM). Methods: A retrospective cohort study was undertaken on patients with corneal astigmatism and no other ocular comorbidities that underwent uneventful refractive femtosecond laser-assisted cataract surgery with toric IOL implantation between May 2019 and November 2019. Toric calculations were performed using the Barrett toric calculator and the following values: predicted PCA with anterior corneal measurements from Pentacam, IOLM standard keratometry (SK), OPD scan, and median measurements from these devices; predicted PCA with IOLM total keratometry (TK); and measured PCA with IOLM SK or IOLM TK. Residual astigmatism prediction error was calculated for each device and method of calculation at postoperative month 1 and 3 using the astigmatism double angle plot tool. Results: A total of 24 eyes, 10 with-the-rule (WTR), 10 against-the-rule (ATR) and 4 oblique astigmatism, from 24 patients were included in this study. PCA ranged from 0.00 to 0.67 D with a mean of 0.24 ± 0.15 D in all eyes. PCA was significantly greater in WTR eyes (0.32 D) compared to ATR eyes (0.16 D; p < 0.05). In ATR eyes, calculations made using IOLM SK and measured PCA had significantly lower total corneal astigmatism and toric IOL cylinder power compared to calculations made using Pentacam and IOLM TK (p < 0.05). No significant difference in mean absolute or centroid residual astigmatism prediction error was observed across devices or calculation methods. The percentage of eyes with absolute astigmatism prediction errors ≤0.5 D was not significantly different across groups. Conclusion: Barrett toric calculations using predicted PCA and PCA measured using IOLM produced comparable residual astigmatism prediction errors. The incorporation of median measurements did not significantly impact calculation accuracy.

Altered adrenal chromaffin cell function during experimental colitis.

The sympathetic nervous system regulates visceral function through the release of catecholamines and cotransmitters from postganglionic sympathetic neurons and adrenal chromaffin cells (ACCs). Previous studies have shown that norepinephrine secretion is decreased during experimental colitis due to the inhibition of voltage-gated Ca(2+) current (I(Ca)) in postganglionic sympathetic neurons. The present study examined whether colonic inflammation causes a similar impairment in depolarization-induced Ca(2+) influx in ACCs using the dextran sulfate sodium (DSS) model of acute colitis in mice. Alterations in ACC function during colitis were assessed using fura 2-acetoxymethyl ester Ca(2+) imaging techniques and perforated patch-clamp electrophysiology. In ACCs isolated from mice with DSS-induced acute colitis, the high-K(+)-stimulated increase in intracellular Ca(2+) concentration ([Ca(2+)](i)) was significantly reduced to 74% of the response of ACCs from control mice. Acute colitis caused a 10-mV hyperpolarization of ACC resting membrane potential, without a significant effect on cellular excitability. Delayed-rectifier K(+) and voltage-gated Na(+) current densities were significantly enhanced in ACCs from mice with DSS-induced acute colitis, with peak current densities of 154 and 144% that of controls, respectively. Importantly, acute colitis significantly inhibited I(Ca) in ACCs between -25 and +20 mV. Peak I(Ca) density in ACCs from mice with DSS-induced acute colitis was 61% that of controls. High-K(+)-induced increases in [Ca(2+)](i) were also reduced in ACCs from mice with 2,4,6-trinitrobenzene sulfonic acid-induced acute colitis and DSS-induced chronic colitis to 68 and 78% of the control responses, respectively. Our results suggest that, during colitis, voltage-dependent Ca(2+) influx is impaired in ACCs. Given the importance of Ca(2+) signaling in exocytosis, these alterations may decrease systemic catecholamine levels, which could play an important role in inflammatory bowel disease. This is the first demonstration of aberrant ACC function during experimental colitis.

Incremental effect of topical and oral moxifloxacin administration with surgical intracameral prophylaxis.

OBJECTIVE: To determine how supplemental perioperative topical or oral moxifloxacin administration impacts anterior chamber (AC) antibiotic concentrations beyond those achieved by intracameral (IC) administration alone for postoperative endophthalmitis (POE) prophylaxis. DESIGN: Mathematical modeling. METHODS: The mathematical model developed by Arshinoff, Modabber, and Felfeli was adapted to calculate all reported data. A literature review of pharmacokinetic data for topical and oral moxifloxacin was used to inform the expansion of the model. RESULTS: Our previously constructed IC model yields a dose of moxifloxacin in the AC sufficient to confer bactericidal coverage against the most common POE pathogen, methicillin-sensitive Staphylococcus aureus (MSSA), for ∼40 hours postoperatively. Topical 0.5% moxifloxacin eye drops alone, administered every 4 or 6 hours, achieve an AC concentration just above or at the mutant prevention concentration (MPC) for MSSA, respectively, whereas 8-hour dosing produces levels generally below the MPC. Combining topical moxifloxacin with IC increases the AC concentration above IC alone only after 20 or more hours and maintains the AC concentration at, or just below, the MPC for MSSA for as long as the drops are continued. Combined perioperative oral moxifloxacin with IC increases AC levels over IC alone only after 16 hours and maintains the AC concentration above the MPC for MSSA for an additional 5 hours, owing to the systemic reservoir. CONCLUSIONS: The addition of topical or oral moxifloxacin supplemental to IC can extend the duration of bactericidal coverage for the most common, but not the most resistant POE-causing pathogens.

Spontaneous Resolution of Dorsal Midbrain Syndrome Caused by a Pineal Cyst.

BACKGROUND: Pineal lesions are common causes of dorsal midbrain syndrome and typically require surgical intervention in symptomatic patients. We describe a unique case of spontaneous resolution of dorsal midbrain syndrome resulting from a pineal gland cyst. CASE DESCRIPTION: A 23-year-old woman developed a supranuclear upgaze palsy, convergence-retraction nystagmus, and light-near dissociation from a pineal gland cyst (1.0 × 1.3 × 1.2 cm) with mild mass effect on the posterior surface of the tectum. Seven days after symptom onset, she had complete, spontaneous resolution of her symptoms, and examination returned to normal. Repeat magnetic resonance imaging demonstrated an unchanged pineal cyst with new T2/fluid attenuated inversion recovery hyperintensity along the mesial surface of the left thalamus. CONCLUSIONS: Dorsal midbrain syndrome resulting from a pineal cyst may spontaneously improve even without a significant change in lesion size. This suggests that observation may be an appropriate initial management strategy.

Homonymous hemi-macular atrophy of the ganglion cell-inner plexiform layer with preserved visual function.

Homonymous hemimacular thinning of the retinal ganglion cell-inner plexiform layer (GCIPL) on optical coherence tomography (OCT) in the absence of significant visual field defects may be identified in the workup of patients with visual complaints, but the causes of this finding remain unknown. We retrospectively reviewed 1425 consecutive patients referred for neuro-ophthalmic assessment who had high quality OCT scans and reliable Humphrey 24-2 SITA-Fast testing. A total of 7 patients, 3 females and 4 males, with a mean age of 39.4 ± 10.5 years that had homonymous thinning of the OCT macular-GCIPL without significant visual field defects were included in the study. Four patients had demyelinating disease and 3 patients had traumatic brain injury. Three patients with demyelinating disease had a documented prior homonymous visual field defect that resolved. The differential diagnosis of homonymous hemimacular thinning of the GCIPL without obvious visual field defects includes previous retrochiasmal demyelination and traumatic brain injury. OCT GCIPL provides a permanent objective way of documenting previous retrochiasmal disease including demyelination and may be helpful in establishing dissemination in time and space in patients being evaluated for multiple sclerosis.

Tumour necrosis factor alpha activates nuclear factor kappaB signalling to reduce N-type voltage-gated Ca2+ current in postganglionic sympathetic neurons.

Inflammation has profound effects on the innervation of affected tissues, including altered neuronal excitability and neurotransmitter release. As Ca(2+) influx through voltage-gated Ca(2+) channels (VGCCs) is a critical determinant of excitation-secretion coupling in nerve terminals, the aim of this study was to characterize the effect of overnight incubation in the inflammatory mediator tumour necrosis factor alpha (TNFalpha; 1 nM) on VGCCs in dissociated neurons from mouse superior mesenteric ganglia (SMG). Voltage-gated Ca(2+) currents (I(Ca)) were measured using the perforated patch clamp technique and the VGCC subtypes present in SMG neurons were estimated based on inhibition by selective VGCC blockers: omega-conotoxin GVIA (300 nM; N-type), nifedipine (10 microM; L-type), and omega-conotoxin MVIIC (300 nM; N-, P/Q-type). We used intracellular Ca(2+) imaging with Fura-2 AM to compare Ca(2+) influx during depolarizations in control and TNFalpha-treated neurons. TNF receptor and VGCC mRNA expression were measured using PCR, and channel alpha subunit (CaV2.2) was localized with immunohistochemistry. Incubation in TNFalpha significantly decreased I(Ca) amplitude and depolarization-induced Ca(2+) influx. The reduction in I(Ca) was limited to omega-conotoxin GVIA-sensitive N-type Ca(2+) channels. Depletion of glial cells by incubation in cytosine arabinoside (5 microM) did not affect I(Ca) inhibition by TNFalpha. Preincubation of neurons with SC-514 (20 microM) or BAY 11-7082 (1 microM), which both inhibit nuclear factor kappaB signalling, prevented the reduction in I(Ca) by TNFalpha. Inhibition of N-type VGCCs following TNFalpha incubation was associated with a decrease in CaV2.2 mRNA and reduced membrane localization of CaV2.2 immunoreactivity. These data suggest that TNFalpha inhibits I(Ca) in SMG neurons and identify a novel role for NF-kappaB in the regulation of neurotransmitter release during inflammatory conditions with elevated circulating TNFalpha, such as Crohn's disease and Guillain-Barré syndrome.