Analysis of a novel virtual pediatric concussion clinic in a rural setting.

PURPOSE: Children and adolescents who sustain concussion in rural communities are lost to follow-up after initial evaluation more often than their urban counterparts. Thus, this study aims to determine the feasibility and accessibility of a novel virtual pediatric concussion clinic at a rural academic hospital. METHODS: Data regarding patients referred to a virtual concussion clinic at a rural Pediatric Level 2 Trauma Center over a 16-month period was prospectively collected. Patients experiencing concussive symptoms were referred to the pediatric neurosurgery clinical registered nurse and received a phone call following an injury. Referrals to therapy were made based on symptoms reported. RESULTS: Data from 44 patients was collected: 9 did not follow-up in concussion clinic despite leaving a voicemail. Forty-three were referred from the emergency department. The median time from referral placed to completing a virtual follow-up was 4.5 days. Among the referrals, 3 (8.6%) were to pediatric neurology, 10 (28.6%) to occupational therapy (OT), 6 (17.1%) to physical therapy (PT), 4 (11.4%) to speech-language pathology (SLP), and 25 (71.4%) did not receive referrals as their symptoms had abated. Patients followed with pediatric neurology post-injury for an average of 75.9 days, OT for an average of 52.7 days, and PT for an average of 2.3 days. CONCLUSION: This is a feasible model to follow patients and place referrals for additional therapeutic services in a rural community. With 79.5% of patients completing a follow-up, the clinic demonstrates easy accessibility and reliable adherence.

Social isolation alters hypothalamic pituitary adrenal axis activity after chronic variable stress in male C57BL/6 mice.

The chronic variable stress (CVS) paradigm is frequently used to model the changes in hypothalamic pituitary adrenal (HPA) axis function characteristic of many stress-related diseases. However, male C57BL/6 mice are typically resistant to CVS's effects, making it difficult to determine how chronic stress exposure may alter acute HPA function and regulation in these mice. As social support in rodents can profoundly influence physiological and behavioral processes, including the HPA axis, we sought to characterize the effects of CVS exposure on basal and acute stress-induced HPA axis function in pair- and single-housed adult male mice. Despite all subjects exhibiting decreased body weight gain after six weeks of CVS, the corticosterone response to a novel, acute restraint stressor was enhanced by CVS exclusively in single-housed males. CVS also significantly increased arginine vasopressin (AVP) mRNA in the hypothalamic paraventricular nucleus (PVN) in single-housed males only. Moreover, in single-, but not pair-housed mice, CVS attenuated decreases in circulating OT found following acute restraint. Only the effect of CVS to elevate PVN corticotropin releasing hormone (CRH) mRNA levels after an acute stressor was restricted to pair-housed mice. Collectively, our findings suggest that social isolation reveals effects of CVS on the HPA axis in male C57BL/6 mice.

The Hypothalamic-Pituitary-Adrenal Axis: Development, Programming Actions of Hormones, and Maternal-Fetal Interactions.

The hypothalamic-pituitary-adrenal axis is a complex system of neuroendocrine pathways and feedback loops that function to maintain physiological homeostasis. Abnormal development of the hypothalamic-pituitary-adrenal (HPA) axis can further result in long-term alterations in neuropeptide and neurotransmitter synthesis in the central nervous system, as well as glucocorticoid hormone synthesis in the periphery. Together, these changes can potentially lead to a disruption in neuroendocrine, behavioral, autonomic, and metabolic functions in adulthood. In this review, we will discuss the regulation of the HPA axis and its development. We will also examine the maternal-fetal hypothalamic-pituitary-adrenal axis and disruption of the normal fetal environment which becomes a major risk factor for many neurodevelopmental pathologies in adulthood, such as major depressive disorder, anxiety, schizophrenia, and others.

Exportin 1 Inhibition Induces Nerve Growth Factor Receptor Expression to Inhibit the NF-κB Pathway in Preclinical Models of Pediatric High-Grade Glioma.

High-grade glioma (HGG) is the leading cause of cancer-related death among children. Selinexor, an orally bioavailable, reversible inhibitor of the nuclear export protein, exportin 1, is in clinical trials for a range of cancers, including HGG. It inhibits the NF-κB pathway and strongly induces the expression of nerve growth factor receptor (NGFR) in preclinical cancer models. We hypothesized that selinexor inhibits NF-κB via upregulation of NGFR. In HGG cells, sensitivity to selinexor correlated with increased induction of cell surface NGFR expression. Knocking down NGFR in HGG cells increased proliferation, anchorage-independent growth, stemness markers, and levels of transcriptionally available nuclear NF-κB not bound to IκB-α, while decreasing apoptosis and sensitivity to selinexor. Increasing IκB-α levels in NGFR knockdown cells restored sensitivity to selinexor. Overexpression of NGFR using cDNA reduced levels of free nuclear NF-κB, decreased stemness markers, and increased markers of cellular differentiation. In all HGG lines tested, selinexor decreased phosphorylation of NF-κB at serine 536 (a site associated with increased transcription of proliferative and inflammatory genes). Because resistance to selinexor monotherapy occurred in our in vivo model, we screened selinexor with a panel of FDA-approved anticancer agents. Bortezomib, a proteasome inhibitor that inhibits the NF-κB pathway through a different mechanism than selinexor, showed synergy with selinexor against HGG in vitro Our results help elucidate selinexor's mechanism of action and identify NGFR as a potential biomarker of its effect in HGG and in addition suggest a combination therapy strategy for these challenging tumors.

Chronic variable stress alters hypothalamic-pituitary-adrenal axis function in the female mouse.

Chronic stress is often associated with a dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, which can greatly increase risk for a number of stress-related diseases, including neuropsychiatric disorders. Despite a striking sex-bias in the prevalence of many of these disorders, few preclinical studies have examined female subjects. Hence, the present study aimed to explore the effects of chronic stress on the basal and acute stress-induced activity of the HPA axis in the female C57BL/6 mouse. We used a chronic variable stress (CVS) paradigm in these studies, which successfully induces physiological and behavioral changes that are similar to those reported for some patients with mood disorders. Using this model, we found pronounced, time-dependent effects of chronic stress on the HPA axis. CVS-treated females exhibited adrenal hypertrophy, yet their pattern of glucocorticoid secretion in the morning resembled that of controls. CVS-treated and control females had similar morning basal corticosterone (CORT) levels, which were both significantly elevated following a restraint stressor. Although morning basal gene expression of the key HPA-controlling neuropeptides corticotropin releasing hormone (CRH), arginine vasopressin (AVP) and oxytocin (OT) was unaltered within the paraventricular nucleus (PVN) by CVS, CVS altered the PVN OT and AVP mRNA responses to acute restraint. In control females, acute stress decreased AVP, but not OT mRNA; whereas, in CVS females, it decreased OT, but not, AVP mRNA. Unlike the morning pattern of HPA activity, in the evening, CVS-treated females showed increased basal CORT with hypoactive responses of CORT and PVN c-Fos immunoreactivity to restraint stress. Furthermore, CVS elevated evening PVN CRH and OT mRNAs in the PVN, but it did not influence anxiety- or depressive-like behavior after a light/dark box or tail suspension test. Taken together, these findings indicate that CVS is an effective model for HPA axis dysregulation in the female mouse and may be relevant for stress-related diseases.

Chronic Variable Stress Induces Sex-Specific Alterations in Social Behavior and Neuropeptide Expression in the Mouse.

Chronic exposure to stressors impairs the function of multiple organ systems and has been implicated in increased disease risk. In the rodent, the chronic variable stress (CVS) paradigm has successfully modeled several stress-related illnesses. Despite striking disparities between men and women in the prevalence and etiology of disorders associated with chronic stress, most preclinical research examining chronic stressor exposure has focused on male subjects. One potential mediator of the consequences of CVS is oxytocin (OT), a known regulator of stress neurocircuitry and behavior. To ascertain the sex-specific effects of CVS in the C57BL/6 mouse on OT and the structurally similar neuropeptide arginine vasopressin (AVP), the numbers of immunoreactive and mRNA-containing neurons in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) were determined using immunohistochemistry and in situ hybridization, respectively. In addition, the mice underwent a battery of behavioral tests to determine whether CVS affects social behaviors known to be regulated by OT and AVP. Six weeks of CVS increased sociability in the female mouse and decreased PVN OT immunoreactivity (ir) and AVP mRNA. In the male mice, CVS decreased PVN OT mRNA but had no effect on social behavior, AVP, or OT-ir. CVS also increased the soma volume for PVN OT neurons. In contrast, OT and AVP neurons in the SON were unaffected by CVS treatment. These findings demonstrate clear sex differences in the effects of CVS on neuropeptides in the mouse, suggest a pathway through which CVS alters sociability and stress-coping responses in females and reveals a vulnerability to CVS in the C57BL/6 mouse strain.