Faculty Bibliography

We describe 4 cases of spinal cord ischemia resulting in paraplegia after peripheral venoarterial extracorporeal membrane oxygenation for cardiogenic shock. This is an uncommon, but possibly underreported, complication with significant irreversible long-term morbidity. While causes are likely multifactorial, it is possible that thrombosis may occur at the level of the mixing cloud due to turbulent flow. Additional studies will be needed to elucidate the true incidence of this complication and investigate whether flow dynamics may potentiate clot formation.

Humans and mice with natural red hair have elevated basal pain thresholds and an increased sensitivity to opioid analgesics. We investigated the mechanisms responsible for higher nociceptive thresholds in red-haired mice resulting from a loss of melanocortin 1 receptor (MC1R) function and found that the increased thresholds are melanocyte dependent but melanin independent. MC1R loss of function decreases melanocytic proopiomelanocortin transcription and systemic melanocyte-stimulating hormone (MSH) levels in the plasma of red-haired (Mc1r^e/e ) mice. Decreased peripheral α-MSH derepresses the central opioid tone mediated by the opioid receptor OPRM1, resulting in increased nociceptive thresholds. We identified MC4R as the MSH-responsive receptor that opposes OPRM1 signaling and the periaqueductal gray area in the brainstem as a central area of opioid/melanocortin antagonism. This work highlights the physiologic role of melanocytic MC1R and circulating melanocortins in the regulation of nociception and provides a mechanistic framework for altered opioid signaling and pain sensitivity in red-haired individuals.

A Correction to this paper has been published: 10.1038/s41593-020-00768-3.

Objective/UNASSIGNED:To test the hypothesis that many patients presenting with congenital insensitivity to pain have lesser known or unidentified mutations not captured by conventional genetic panels, we performed whole-exome sequencing in a cohort of well-characterized patients with a clinical diagnosis of congenital hereditary sensory and autonomic neuropathy with unrevealing conventional genetic testing. Methods/UNASSIGNED:We performed whole-exome sequencing (WES) in 13 patients with congenital impaired or absent sensation to pain and temperature with no identified molecular diagnosis from a conventional genetic panel. Patients underwent a comprehensive phenotypic assessment including autonomic function testing, and neurologic and ophthalmologic examinations. Results/UNASSIGNED:). Conclusions/UNASSIGNED:Our results expand the genetic landscape of congenital sensory and autonomic neuropathies. Further validation of some identified variants should confirm their pathogenicity. WES should be clinically considered to expedite diagnosis, reduce laboratory investigations, and guide enrollment in future gene therapy trials.

OBJECTIVE:We aimed to test the hypothesis that computational features of the first several minutes of EEG recording can be used to estimate the risk for development of acute seizures in comatose critically-ill children. METHODS:In a prospective cohort of 118 comatose children, we computed features of the first five minutes of artifact-free EEG recording (spectral power, inter-regional synchronization and cross-frequency coupling) and tested if these features could help identify the 25 children who went on to develop acute symptomatic seizures during the subsequent 48 hours of cEEG monitoring. RESULTS:Children who developed acute seizures demonstrated higher average spectral power, particularly in the theta frequency range, and distinct patterns of inter-regional connectivity, characterized by greater connectivity at delta and theta frequencies, but weaker connectivity at beta and low gamma frequencies. Subgroup analyses among the 97 children with the same baseline EEG background pattern (generalized slowing) yielded qualitatively and quantitatively similar results. CONCLUSIONS:These computational features could be applied to baseline EEG recordings to identify critically-ill children at high risk for acute symptomatic seizures. SIGNIFICANCE/CONCLUSIONS:If confirmed in independent prospective cohorts, these features would merit incorporation into a decision support system in order to optimize diagnostic and therapeutic management of seizures among comatose children.

Atherosclerosis and obesity share pathological features including inflammation mediated by innate and adaptive immune cells. LXRα plays a central role in the transcription of inflammatory and metabolic genes. LXRα is modulated by phosphorylation at serine 196 (LXRα pS196), however, the consequences of LXRα pS196 in hematopoietic cell precursors in atherosclerosis and obesity have not been investigated. To assess the importance of LXRα phosphorylation, bone marrow from LXRα WT and S196A mice was transplanted into Ldlr^-/- mice, which were fed a western diet prior to evaluation of atherosclerosis and obesity. Plaques from S196A mice showed reduced inflammatory monocyte recruitment, lipid accumulation, and macrophage proliferation. Expression profiling of CD68⁺ and T cells from S196A mouse plaques revealed downregulation of pro-inflammatory genes and in the case of CD68⁺ upregulation of mitochondrial genes characteristic of anti-inflammatory macrophages. Furthermore, S196A mice had lower body weight and less visceral adipose tissue; this was associated with transcriptional reprograming of the adipose tissue macrophages and T cells, and resolution of inflammation resulting in less fat accumulation within adipocytes. Thus, reducing LXRα pS196 in hematopoietic cells attenuates atherosclerosis and obesity by reprogramming the transcriptional activity of LXRα in macrophages and T cells to promote an anti-inflammatory phenotype.

Early life is a sensitive period in which enhanced neural plasticity allows the developing brain to adapt to its environment. This plasticity can also be a risk factor in which maladaptive development can lead to long-lasting behavioral deficits. Here, we test how early-life exposure to the selective-serotonin-reuptake-inhibitor, fluoxetine, affects motivation and dopaminergic signaling in adulthood. We show for the first time that mice exposed to fluoxetine in the early postnatal period exhibit a reduction in effort-related motivation. These mice also show blunted responses to amphetamine and reduced dopaminergic activation in a sucrose reward task.Interestingly, we find that the reduction in motivation can be rescued in the adult by administering bupropion, a dopamine-norepinephrine reuptake inhibitor used as an antidepressant and a smoke cessation aid, but not by fluoxetine. Taken together, our studies highlight the effects of early postnatal exposure of fluoxetine on motivation and demonstrate the involvement of the dopaminergic system in this process.Significance StatementThe developmental period is characterized by enhanced plasticity. During this period, environmental factors have the potential to lead to enduring behavioral changes. Here we show that exposure to the SSRI fluoxetine during a restricted period in early-life leads to a reduction in adult motivation. We further show that this reduction is associated with decreased dopaminergic responsivity. Finally, we show that motivational deficits induced by early-life fluoxetine exposure can be rescued by adult administration of bupropion but not by fluoxetine.