Corticotropin (ACTH) acts directly on amygdala neurons to down-regulate corticotropin-releasing hormone gene expression.

The hormone corticotropin (ACTH) is employed as therapy for diverse neurological disorders, but the mechanisms for its efficacy remain unknown. ACTH promotes the release of adrenal steroids (glucocorticoids), and most ACTH effects on the central nervous system (CNS) have been attributed to activation of glucocorticoid receptors. However, in several human disorders, ACTH has therapeutic actions that differ qualitatively or quantitatively from those of steroids. This study tested the hypothesis that ACTH directly influences limbic neurons via the recently characterized melanocortin receptors and focused on the effects of ACTH on the expression of corticotropin-releasing hormone (CRH), a neuropeptide involved in neuroimmune functions and in certain developmental seizures. The results demonstrated that ACTH potently reduced CRH expression in amygdala neurons. This down-regulation was not abolished by experimental elimination of steroids or by blocking their receptors and was reproduced by a centrally administered ACTH fragment that does not promote steroid release. Importantly, selective blocking of melanocortin receptors prevented ACTH-induced down-regulation of CRH expression. Taken together, these data indicate that ACTH activates central melanocortin receptors to modulate CRH gene expression in amygdala, supporting the notion that direct, steroid-independent actions of ACTH may account for some of its established clinical effects on the CNS

DEVELOPMENT OF AN ADDITIVELY MANUFACTURED RIGID SPACESUIT COMPONENT FOR LONG DURATION MISSIONS

Gemstone Team SPACELong duration human exploration of Mars will pose demands on spacesuits that current designs are unable to overcome, including the need for in-situ replacement and repair of suit components. Advancements in additive manufacturing (AM) technologies provide capabilities to repair or replace rigid pressure garments on-site and on-need. This thesis focuses on a potential application for in-situ hard suit manufacturing: the integration of AM components into a functional spacesuit arm. Material tests were conducted and top candidates were selected for the joint segment components. AM bearing con figurations were tested under operational loads and seals were incorporated for pressure retention. Selected components were integrated into a hard suit arm, which was compared to the Shuttle-era EMU arm through human tests in a pressurized glove-box. The results indicate that further re finement of hard suits has the potential to match the performance of operational EMU models while reducing the logistical issues with current spacesuits

Left ventricular thrombus found in a patient with ARDS and stress-induced cardiomyopathy requiring veno-arterial ECMO.

Presentation: 68 year-old male with a history of acute leukemia with complete remission after bone marrow transplant 4 months ago, coronary disease s/p LAD stents about 14 years ago with no chronic anti-platelet medication, and repeated episode of DVT despite appropriate anti-coagulation, presented with viral pneumonia (rhinovirus)

MRSA sepsis and acute respiratory distress syndrome during veno-arterial extracorporeal membrane oxygenation (ECMO).

Presentation: A 39 year old female African American presented with respiratory distress two days after ERCP for pancreatitis. The patient quickly deteriorated, required intubation, and developed severe hypotension requiring vasopressors. VA-ECMO was initiated for ARDS and SIRS due to on-going pancreatitis. Pre ECMO ABG: PH 7.01, PaCO2 70, PaO2 70 with FiO2 100% with PEEP 15 Profound hypotension, required 2 pressors Preliminary results of cultures were negative at the time of ECMO placement. Presented 24th Annual ELSO Conference. Philadelphia, PA. Sep 19-21, 2013

Role of Brain Inflammation in Epileptogenesis

Inflammation is known to participate in the mediation of a growing number of acute and chronic neurological disorders. Even so, the involvement of inflammation in the pathogenesis of epilepsy and seizure-induced brain damage has only recently been appreciated. Inflammatory processes, including activation of microglia and astrocytes and production of proinflammatory cytokines and related molecules, have been described in human epilepsy patients as well as in experimental models of epilepsy. For many decades, a functional role for brain inflammation has been implied by the effective use of anti-inflammatory treatments, such as steroids, in treating intractable pediatric epilepsy of diverse causes. Conversely, common pediatric infectious or autoimmune diseases are often accompanied by seizures during the course of illness. In addition, genetic susceptibility to inflammation correlated with an increased risk of epilepsy. Mounting evidence thus supports the hypothesis that inflammation may contribute to epileptogenesis and cause neuronal injury in epilepsy. We provide an overview of the current knowledge that implicates brain inflammation as a common predisposing factor in epilepsy, particularly childhood epilepsy

GABAergic regulation of cerebellar NG2 cell development is altered in perinatal white matter injury.

Diffuse white matter injury (DWMI), a leading cause of neurodevelopmental disabilities in preterm infants, is characterized by reduced oligodendrocyte formation. NG2-expressing oligodendrocyte precursor cells (NG2 cells) are exposed to various extrinsic regulatory signals, including the neurotransmitter GABA. We investigated GABAergic signaling to cerebellar white matter NG2 cells in a mouse model of DWMI (chronic neonatal hypoxia). We found that hypoxia caused a loss of GABAA receptor-mediated synaptic input to NG2 cells, extensive proliferation of these cells and delayed oligodendrocyte maturation, leading to dysmyelination. Treatment of control mice with a GABAA receptor antagonist or deletion of the chloride-accumulating transporter NKCC1 mimicked the effects of hypoxia. Conversely, blockade of GABA catabolism or GABA uptake reduced NG2 cell numbers and increased the formation of mature oligodendrocytes both in control and hypoxic mice. Our results indicate that GABAergic signaling regulates NG2 cell differentiation and proliferation in vivo, and suggest that its perturbation is a key factor in DWMI

Mice lacking doublecortin and doublecortin-like kinase 2 display altered hippocampal neuronal maturation and spontaneous seizures.

Mutations in doublecortin (DCX) are associated with intractable epilepsy in humans, due to a severe disorganization of the neocortex and hippocampus known as classical lissencephaly. However, the basis of the epilepsy in lissencephaly remains unclear. To address potential functional redundancy with murin Dcx, we targeted one of the closest homologues, doublecortin-like kinase 2 (Dclk2). Here, we report that Dcx; Dclk2-null mice display frequent spontaneous seizures that originate in the hippocampus, with most animals dying in the first few months of life. Elevated hippocampal expression of c-fos and loss of somatostatin-positive interneurons were identified, both known to correlate with epilepsy. Dcx and Dclk2 are coexpressed in developing hippocampus, and, in their absence, there is dosage-dependent disrupted hippocampal lamination associated with a cell-autonomous simplification of pyramidal dendritic arborizations leading to reduced inhibitory synaptic tone. These data suggest that hippocampal dysmaturation and insufficient receptive field for inhibitory input may underlie the epilepsy in lissencephaly, and suggest potential therapeutic strategies for controlling epilepsy in these patients