The role of glial-specific Kir4.1 in normal and pathological states of the CNS.

Kir4.1 is an inwardly rectifying K(+) channel expressed exclusively in glial cells in the central nervous system. In glia, Kir4.1 is implicated in several functions including extracellular K(+) homeostasis, maintenance of astrocyte resting membrane potential, cell volume regulation, and facilitation of glutamate uptake. Knockout of Kir4.1 in rodent models leads to severe neurological deficits, including ataxia, seizures, sensorineural deafness, and early postnatal death. Accumulating evidence indicates that Kir4.1 plays an integral role in the central nervous system, prompting many laboratories to study the potential role that Kir4.1 plays in human disease. In this article, we review the growing evidence implicating Kir4.1 in a wide array of neurological disease. Recent literature suggests Kir4.1 dysfunction facilitates neuronal hyperexcitability and may contribute to epilepsy. Genetic screens demonstrate that mutations of KCNJ10, the gene encoding Kir4.1, causes SeSAME/EAST syndrome, which is characterized by early onset seizures, compromised verbal and motor skills, profound cognitive deficits, and salt-wasting. KCNJ10 has also been linked to developmental disorders including autism. Cerebral trauma, ischemia, and inflammation are all associated with decreased astrocytic Kir4.1 current amplitude and astrocytic dysfunction. Additionally, neurodegenerative diseases such as Alzheimer disease and amyotrophic lateral sclerosis demonstrate loss of Kir4.1. This is particularly exciting in the context of Huntington disease, another neurodegenerative disorder in which restoration of Kir4.1 ameliorated motor deficits, decreased medium spiny neuron hyperexcitability, and extended survival in mouse models. Understanding the expression and regulation of Kir4.1 will be critical in determining if this channel can be exploited for therapeutic benefit.

"Ripping Off the Band-Aid": uncovering future health care Professionals' "Fractured Knowledge" about sexual and reproductive health.

Background: Research has shown the role of identity on future health professionals' confidence and competence in addressing the sexual and reproductive health (SRH) needs of their patients. While there has been some work in increasing the sexual health literacy of future providers via various curricular approaches and comprehensive clinical-based training, there are research gaps on how social differences around identity impact future healthcare professionals' knowledge and practices around SRH. Objectives: This article presents research findings on the experiences of US undergraduate students attending a campus that provides training in the health sciences and health professions. Our study aims to understand the perspectives of these students as they pertain to their future career choices in healthcare, with a focus on how their past experiences learning about sex, sexuality, and reproduction impact their current and future professional trajectories. Methods: We present a qualitative analysis from 40 in-depth interviews with U.S. undergraduates. The interview questions were designed in collaboration with undergraduate researchers interested in sexual health education. These student researchers collected all the interview data and worked with senior researchers to analyze some of these data. Results: The themes that emerged from the interviews were around experiences with what students perceived as "fractured" sexual and reproductive health (SRH) knowledge they received as children and adolescents. This knowledge shaped essential aspects of their identity as young adults and future healers. Data indicated unique processes implicated in how past as well as present socialization experiences learning about sex, sexuality, and reproduction positions undergraduates in health professions to see young adulthood as a journey of "catching up" on sexual knowledge but also as an ongoing experience of anticipation and planning influencing their career-building journey. Conclusions: The importance of sexual health literacy among healthcare professionals cannot be overstated, as it is vital in providing patient-centered and non-judgmental sexual and reproductive health (SRH) care and services. To date, there is a shortage of studies looking at the impact of sexual health knowledge on healthcare professionals. More research is needed on educational strategies that could be implemented at the intra-personal level to assist college-aged young adults in healthcare career tracks to "catch up" or "fill in the gaps" in their sexual education journey.

Creating a sustainable action-oriented engagement infrastructure-a UMN-MIDB perspective.

Following the murder of George Floyd on May 25, 2020, Minneapolis represented the epicenter of protests that would reverberate internationally and re-instantiate a reckoning of the systemic and institutional racism that plagues American society. Also in the summer of 2020, and after several years of planning, the University of Minnesota (UMN) launched the Masonic Institute for the Developing Brain (MIDB), an interdisciplinary clinical and community research enterprise designed to create knowledge and engage all members of our community. In what follows, we describe the mission of the MIDB Community Engagement and Education (CEEd) Core and adjacent efforts within the UMN neuroscience and psychology community. Inherent to these efforts is the explicit attempt to de-center the dominant academic voice and affirm knowledge creation is augmented by diverse voices within and outside of traditional academic institutions. We describe several initiatives, including the Neuroscience Opportunities for Discovery and Equity (NODE) network, the NextGen Psych Scholars Program (NPSP), the Young Scientist Program, among others as exemplars of our approach. Developing and fortifying sustainable pathways for authentic community-academic partnerships are of central importance to enhance mutually beneficial scientific discovery. We posit that traditional academic approaches to community engagement to benefit the institution are severely constrained and perpetuate inherently exploitative power dynamics between academic institutions and communities.

Blood-Brain Barrier Dysfunction After Smoke Inhalation Injury, With and Without Skin Burn.

Only a handful of published reports exist today that describe neurological complications following smoke inhalation injury. In this study, we characterize acute pathophysiological changes in the brain of sheep exposed to smoke inhalation, with- and without third-degree skin burn that models the injuries sustained by human victims of fire accidents. Blood-brain barrier integrity and hemorrhage were analyzed throughout the brain using specific histological stains: Hematoxylin & Eosin, Luxol fast blue, Periodic acid-Schiff (PAS), and Martius, Scarlet and Blue (MSB). Our data show that, following smoke inhalation injury, alone and in combination with third-degree skin burn, there was a significant increase in the number of congested and dilated blood vessels in the frontal cortex, basal ganglia, amygdala, hippocampus, pons, cerebellum, and pituitary gland as compared to sham-injured controls. Positive PAS staining confirmed damage to the basement membrane of congested and dilated blood vessels throughout the brain. Severe rupturing of blood vessels, microvascular hemorrhaging and bleeding throughout the brain was also observed in the injured groups. No significant changes in hemodynamics and PaO2 were observed. Our data demonstrate for the first time that acute smoke inhalation alone results in diffuse blood-brain barrier dysfunction and massive bleeding in the brain in the absence of hypoxia and changes in hemodynamics. These findings provide critical information and prompt further mechanistic and interventional studies necessary to develop effective and novel treatments aimed at alleviating CNS dysfunction in patients with smoke and burn injuries.

Modulation of Peroxynitrite Reduces Norepinephrine Requirements in Ovine MRSA Septic Shock.

Vascular hypo-responsiveness to vasopressors during septic shock is a challenging problem. This study is to test the hypothesis that reactive nitrogen species (RNS), such as peroxynitrite, are major contributing factors to vascular hypo-responsiveness in septic shock. We hypothesized that adjunct therapy with peroxynitrite decomposition catalyst (PDC) would reduce norepinephrine requirements in sepsis resuscitation. Fourteen female Merino sheep were subjected to a "two-hit" injury (smoke inhalation and endobronchial instillation of live methicillin-resistant Staphylococcus aureus [1.6-2.5 × 10 CFUs]). The animals were randomly allocated to control: injured, fluid resuscitated, and titrated norepinephrine, n = 7; or PDC: injured, fluid resuscitated, titrated norepinephrine, and treated with PDC, n = 7. One-hour postinjury, an intravenous injection of PDC (0.1 mg/kg) was followed by a continuous infusion (0.04 mg/kg/h). Titration of norepinephrine started at 0.05 mcg/kg/min based on their mean arterial pressure. All animals were mechanically ventilated and monitored in the conscious state for 24 h. The mean arterial pressure was well maintained in the PDC with significantly less norepinephrine requirement from 7 to 23 h after injury compared with control. Total norepinephrine dose, the highest norepinephrine rate, and time on norepinephrine support were also significantly lower in PDC. Modified sheep organ failure assessment scores at 6 to 18 h postinjury were significantly lower in PDC compared with control. PDC improved survival rate at 24 h (71.4% vs. 28.6%). PDC treatment had no adverse effects. In conclusion, the modulation of RNS may be considered an effective adjunct therapy for septic shock, in the case of hypo-responsiveness to norepinephrine.