Early Enteral Nutrition in Aeromedically Evacuated Critically Ill/Injured Patients With a Resultant Validation Algorithm for the Theater Validating Flight Surgeon.

INTRODUCTION: Early enteral feeding in critically ill/injured patients promotes gut integrity and immunocompetence and reduces infections and intensive care unit/hospital stays. Aeromedical evacuation (AE) often takes place concurrently. As a result, AE and early enteral feeding should be inseparable. MATERIALS AND METHODS: This retrospective descriptive study employed AE enteral nutrition (EN) data (2007-2019) collected from patients who were U.S. citizens and mechanically ventilated. The dataset was created from the En Route Critical Care, Transportation Command Regulating and Command and Control Evacuation System, and Theater Medical Data Store databases. Comparisons were performed between patients extracted and patients not extracted, patients treated with EN and patients treated without EN, and within the EN group, between AE Fed and AE Withheld. The impact of the nutrition support in the Joint Trauma System Clinical Practice Guidelines (CPG) was assessed using the 'before' and 'after' methodology. RESULTS: An uptick in feeding rates was found after the 2010 CPG, 15% → 17%. With the next two CPG iterations, rates rose significantly, 17% → 48%. Concurrently, AE feeding holds rose significantly, 10% → 24%, later dropping to 17%. In addition, little difference was found between those patients not enterally fed preflight and those enterally fed across collected demographic, mission, and clinical parameters. Likewise, no difference was found between those enterally fed during AE and those withheld. Yet, 83% of the study's patients were not fed, and 18% of those that were fed had feeding withheld for AE. CONCLUSIONS: It appeared that the Clinical Practice Guidelines (CPGs) reinforced the value of feeding, but may well have sensitized to the threat of aspiration. It also appeared that early enteral feeding was underprescribed and AE feeding withholds were overprescribed. Consequently, an algorithm was devised for the Theater Validating Flight Surgeon, bearing in mind relevant preflight/inflight/clinical issues, with prescriptions designed to boost feeding, diminish AE withholding, and minimize complications.

Estrogen receptor ß deficiency impairs BDNF-5-HT2A signaling in the hippocampus of female brain: A possible mechanism for menopausal depression.

Depression currently affects 350 million people worldwide and 19 million Americans each year. Women are 2.5 times more likely to experience major depression than men, with some women appearing to be at a heightened risk during the menopausal transition. Estrogen signaling has been implicated in the pathophysiology of mood disorders including depression; however, the underlying mechanisms are poorly understood. In this study, the role of estrogen receptor (ER) subtypes, ERα and ERß, in the regulation of brain-derived neurotrophic factor (BDNF) and serotonin (5-HT) signaling was investigated; two pathways that have been hypothesized to be interrelated in the etiology of depression. The analyses in ERα-/- and ERß-/- mouse models demonstrated that BDNF was significantly downregulated in ERß-/- but not ERα-/- mice, and the ERß-/--mediated effect was brain-region specific. A 40% reduction in BDNF protein expression was found in the hippocampus of ERß-/- mice; in contrast, the changes in BDNF were at a much smaller magnitude and insignificant in the cortex and hypothalamus. Further analyses in primary hippocampal neurons indicated that ERß agonism significantly enhanced BDNF/TrkB signaling and the downtream cascades involved in synaptic plasticity. Subsequent study in ERß mutant rat models demonstrated that disruption of ERß was associated with a significantly elevated level of 5-HT2A but not 5-HT1A in rat hippocampus, indicating ERß negatively regulates 5-HT2A. Additional analyses in primary neuronal cultures revealed a significant association between BDNF and 5-HT2A pathways, and the data showed that TrkB activation downregulated 5-HT2A whereas activation of 5-HT2A had no effect on BDNF, suggesting that BDNF/TrkB is an upstream regulator of the 5-HT2A pathway. Collectively, these findings implicate that the disruption in estrogen homeostasis during menopause leads to dysregulation of BDNF-5-HT2A signaling and weakened synaptic plasticity, which together predispose the brain to a vulnerable state for depression. Timely intervention with an ERß-targeted modulator could potentially attenuate this susceptibility and reduce the risk or ameliorate the clinical manifestation of this brain disorder.

Human ApoE ɛ2 Promotes Regulatory Mechanisms of Bioenergetic and Synaptic Function in Female Brain: A Focus on V-type H+-ATPase.

Humans possess three major isoforms of the apolipoprotein E (ApoE) gene encoded by three alleles: ApoE ɛ2 (ApoE2), ApoE ɛ3 (ApoE3), and ApoE ɛ4 (ApoE4). It is established that the three ApoE isoforms confer differential susceptibility to Alzheimer's disease (AD); however, an in-depth molecular understanding of the underlying mechanisms is currently unavailable. In this study, we examined the cortical proteome differences among the three ApoE isoforms using 6-month-old female, human ApoE2, ApoE3, and ApoE4 gene-targeted replacement mice and two-dimensional proteomic analyses. The results reveal that the three ApoE brains differ primarily in two areas: cellular bioenergetics and synaptic transmission. Of particular significance, we show for the first time that the three ApoE brains differentially express a key component of the catalytic domain of the V-type H+-ATPase (Atp6v), a proton pump that mediates the concentration of neurotransmitters into synaptic vesicles and thus is crucial in synaptic transmission. Specifically, our data demonstrate that ApoE2 brain exhibits significantly higher levels of the B subunit of Atp6v (Atp6v1B2) when compared to both ApoE3 and ApoE4 brains, with ApoE4 brain exhibiting the lowest expression. Our additional analyses show that Atp6v1B2 is significantly impacted by aging and AD pathology and the data suggest that Atp6v1B2 deficiency could be involved in the progressive loss of synaptic integrity during early development of AD. Collectively, our findings indicate that human ApoE isoforms differentially modulate regulatory mechanisms of bioenergetic and synaptic function in female brain. A more efficient and robust status in both areas-in which Atp6v may play a role-could serve as a potential mechanism contributing to the neuroprotective and cognition-favoring properties associated with the ApoE2 genotype.

Sex differences in metabolic aging of the brain: insights into female susceptibility to Alzheimer's disease.

Despite recent advances in the understanding of clinical aspects of sex differences in Alzheimer's disease (AD), the underlying mechanisms, for instance, how sex modifies AD risk and why the female brain is more susceptible to AD, are not clear. The purpose of this study is to elucidate sex disparities in brain aging profiles focusing on 2 major areas-energy and amyloid metabolism-that are most significantly affected in preclinical development of AD. Total RNA isolated from hippocampal tissues of both female and male 129/C57BL/6 mice at ages of 6, 9, 12, or 15 months were comparatively analyzed by custom-designed Taqman low-density arrays for quantitative real-time polymerase chain reaction detection of a total of 182 genes involved in a broad spectrum of biological processes modulating energy production and amyloid homeostasis. Gene expression profiles revealed substantial differences in the trajectory of aging changes between female and male brains. In female brains, 44.2% of genes were significantly changed from 6 months to 9 months and two-thirds showed downregulation. In contrast, in male brains, only 5.4% of genes were significantly altered at this age transition. Subsequent changes in female brains were at a much smaller magnitude, including 10.9% from 9 months to 12 months and 6.1% from 12 months to 15 months. In male brains, most changes occurred from 12 months to 15 months and the majority were upregulated. Furthermore, gene network analysis revealed that clusterin appeared to serve as a link between the overall decreased bioenergetic metabolism and increased amyloid dyshomeostasis associated with the earliest transition in female brains. Together, results from this study indicate that: (1) female and male brains follow profoundly dissimilar trajectories as they age; (2) female brains undergo age-related changes much earlier than male brains; (3) early changes in female brains signal the onset of a hypometabolic phenotype at risk for AD. These findings provide a mechanistic rationale for female susceptibility to AD and suggest a potential window of opportunity for AD prevention and risk reduction in women.

Estrogen receptor ß in Alzheimer's disease: From mechanisms to therapeutics.

Alzheimer's disease (AD) disproportionally affects women and men. The female susceptibility for AD has been largely associated with the loss of ovarian sex hormones during menopause. This review examines the current understanding of the role of estrogen receptor ß (ERß) in the regulation of neurological health and its implication in the development and intervention of AD. Since its discovery in 1996, research conducted over the last 15-20 years has documented a great deal of evidence indicating that ERß plays a pivotal role in a broad spectrum of brain activities from development to aging. ERß genetic polymorphisms have been associated with cognitive impairment and increased risk for AD predominantly in women. The role of ERß in the intervention of AD has been demonstrated by the alteration of AD pathology in response to treatment with ERß-selective modulators in transgenic models that display pronounced plaque and tangle histopathological presentations as well as learning and memory deficits. Future studies that explore the potential interactions between ERß signaling and the genetic isoforms of human apolipoprotein E (APOE) in brain aging and development of AD-risk phenotype are critically needed. The current trend of lost-in-translation in AD drug development that has primarily been based on early-onset familial AD (FAD) models underscores the urgent need for novel models that recapitulate the etiology of late-onset sporadic AD (SAD), the most common form of AD representing more than 95% of the current human AD population. Combining the use of FAD-related models that generally have excellent face validity with SAD-related models that hold more reliable construct validity would together increase the predictive validity of preclinical findings for successful translation into humans.

Pregnane X receptor modulates the inflammatory response in primary cultures of hepatocytes.

Bacterial sepsis is characterized by a rapid increase in the expression of inflammatory mediators to initiate the acute phase response in liver. Inflammatory mediator release is counterbalanced by the coordinated expression of anti-inflammatory molecules such as interleukin 1 receptor antagonist (IL1-Ra) through time. This study determined whether activation of pregnane X receptor (PXR, NR1I2) alters the lipopolysaccharide (LPS)-inducible gene expression program in primary cultures of hepatocytes (PCHs). Preactivation of PXR for 24 hours in PCHs isolated from wild-type mice suppressed the subsequent LPS-inducible expression of the key inflammatory mediators interleukin 1ß (IL-1ß), interleukin 6 (IL-6), and tumor necrosis factor α (TNFα) but not in PCHs isolated from Pxr-null (PXR-knockout [KO]) mice. Basal expression of key inflammatory cytokines was elevated in PCHs from PXR-KO mice. Stimulation of PCHs from PXR-KO mice with LPS alone produced enhanced levels of IL-1ß when compared with wild-type mice. Experiments performed using PCHs from both humanized-PXR transgenic mice as well as human donors indicate that prolonged activation of PXR produces an increased secretion of IL1-Ra from cells through time. Our data reveal a working model that describes a pivotal role for PXR in both inhibiting as well as in resolving the inflammatory response in hepatocytes. Understanding the molecular details of how PXR is converted from a positive regulator of drug-metabolizing enzymes into a transcriptional suppressor of inflammation in liver will provide new pharmacologic strategies for modulating inflammatory-related diseases in the liver and intestine.