Transient Acute Diplopia as a Rare Side Effect of Hydromorphone: A Case Report.

Diplopia, or double vision, has been listed as a rare adverse effect of intravenous hydromorphone, although there are no case studies or literature documenting this. We detail a case of acute transient diplopia correlated with the use of intraoperative hydromorphone and postoperative hydromorphone patient-controlled analgesia. Although the mechanism for this adverse effect is unknown, there may be risk factors that predispose patients to the potential toxic metabolic effects of hydromorphone. We share the first published case of diplopia as a clinically relevant adverse effect of hydromorphone and propose a potential reason behind this association.

Systemic Immune Bias Delineates Malignant Astrocytoma Survival Cohorts.

Patients with grade III anaplastic astrocytomas (AA) separate into survival cohorts based on the presence or absence of mutations in isocitrate dehydrogenase (IDH). Progression to glioblastoma (GBM), morphologically distinguishable by elevated microvascular proliferation, necrosis, and cell division in tumor tissues, is considerably more rapid in IDH wild-type tumors such that their diagnosis as AA is relatively rare. More often initially presenting as GBM, these contain higher numbers of tumor-associated macrophages (TAMs) than most AA, and GBM patients also have higher levels of circulating M2 monocytes. TAM and M2 monocytes share functional properties inhibitory for antitumor immunity. Yet, although there is a wealth of data implicating TAM in tumor-immune evasion, there has been limited analysis of the impact of the circulating M2 monocytes. In the current study, immune parameters in sera, circulating cells, and tumor tissues from patients with primary gliomas morphologically diagnosed as AA were assessed. Profound differences in serum cytokines, glioma extracellular vesicle cross-reactive Abs, and gene expression by circulating cells identified two distinct patient cohorts. Evidence of type 2-immune bias was most often seen in patients with IDH wild-type AA, whereas a type 1 bias was common in patients with tumors expressing the IDH1R132H mutation. Nevertheless, a patient's immune profile was better correlated with the extent of tumor vascular enhancement on magnetic resonance imaging than IDH mutational status. Regardless of IDH genotype, AA progression appears to be associated with a switch in systemic immune bias from type 1 to type 2 and the loss of tumor vasculature integrity.

Input-output signal processing plasticity of vagal motor neurons in response to cardiac ischemic injury.

Vagal stimulation is emerging as the next frontier in bioelectronic medicine to modulate peripheral organ health and treat disease. The neuronal molecular phenotypes in the dorsal motor nucleus of the vagus (DMV) remain largely unexplored, limiting the potential for harnessing the DMV plasticity for therapeutic interventions. We developed a mesoscale single-cell transcriptomics data from hundreds of DMV neurons under homeostasis and following physiological perturbations. Our results revealed that homeostatic DMV neuronal states can be organized into distinguishable input-output signal processing units. Remote ischemic preconditioning induced a distinctive shift in the neuronal states toward diminishing the role of inhibitory inputs, with concomitant changes in regulatory microRNAs miR-218a and miR-495. Chronic cardiac ischemic injury resulted in a dramatic shift in DMV neuronal states suggestive of enhanced neurosecretory function. We propose a DMV molecular network mechanism that integrates combinatorial neurotransmitter inputs from multiple brain regions and humoral signals to modulate cardiac health.

Investigating the Effects of Brainstem Neuronal Adaptation on Cardiovascular Homeostasis.

Central coordination of cardiovascular function is accomplished, in part, by the baroreceptor reflex, a multi-input multi-output physiological control system that regulates the activity of the parasympathetic and sympathetic nervous systems via interactions among multiple brainstem nuclei. Recent single-cell analyses within the brain revealed that individual neurons within and across brain nuclei exhibit distinct transcriptional states contributing to neuronal function. Such transcriptional heterogeneity complicates the task of understanding how neurons within and across brain nuclei organize and function to process multiple inputs and coordinate cardiovascular functions within the larger context of the baroreceptor reflex. However, prior analysis of brainstem neurons revealed that single-neuron transcriptional heterogeneity reflects an adaptive response to synaptic inputs and that neurons organize into distinct subtypes with respect to synaptic inputs received. Based on these results, we hypothesize that adaptation of neuronal subtypes support robust biological function through graded cellular responses. We test this hypothesis by examining the functional impact of neuronal adaptation on parasympathetic activity within the context of short-term baroreceptor reflex regulation. In this work, we extend existing quantitative closed-loop models of the baroreceptor reflex by incorporating into the model distinct input-driven neuronal subtypes and neuroanatomical groups that modulate parasympathetic activity. We then use this extended model to investigate, via simulation, the functional role of neuronal adaptation under conditions of health and systolic heart failure. Simulation results suggest that parasympathetic activity can be modulated appropriately by the coordination of distinct neuronal subtypes to maintain normal cardiovascular functions under systolic heart failure conditions. Moreover, differing degrees of adaptation of these neuronal subtypes contribute to cardiovascular behaviors corresponding to distinct clinical phenotypes of heart failure, such as exercise intolerance. Further, our results suggest that an imbalance between sympathetic and parasympathetic activity regulating ventricular contractility contributes to exercise intolerance in systolic heart failure patients, and restoring this balance can improve the short-term cardiovascular performance of these patients.

A Comprehensive Integrated Anatomical and Molecular Atlas of Rat Intrinsic Cardiac Nervous System.

We have developed and integrated several technologies including whole-organ imaging and software development to support an initial precise 3D neuroanatomical mapping and molecular phenotyping of the intracardiac nervous system (ICN). While qualitative and gross anatomical descriptions of the anatomy of the ICN have each been pursued, we here bring forth a comprehensive atlas of the entire rat ICN at single-cell resolution. Our work precisely integrates anatomical and molecular data in the 3D digitally reconstructed whole heart with resolution at the micron scale. We now display the full extent and the position of neuronal clusters on the base and posterior left atrium of the rat heart, and the distribution of molecular phenotypes that are defined along the base-to-apex axis, which had not been previously described. The development of these approaches needed for this work has produced method pipelines that provide the means for mapping other organs.

An agent-based model to investigate microbial initiation of Alzheimer's via the olfactory system.

BACKGROUND: Alzheimer's disease (AD) is a degenerative brain disease. A novel agent-based modelling framework was developed in NetLogo 3D to provide fundamental insights into the potential mechanisms by which a microbe (eg. Chlamydia pneumoniae) may play a role in late-onset AD. The objective of our initial model is to simulate one possible spatial and temporal pathway of bacterial propagation via the olfactory system, which may then lead to AD symptoms. The model maps the bacteria infecting cells from the nasal cavity and the olfactory epithelium, through the olfactory bulb and into the olfactory cortex and hippocampus regions of the brain. RESULTS: Based on the set of biological rules, simulated randomized infection by the microbe led to the formation of beta-amyloid (Aß) plaque and neurofibrillary (NF) tangles as well as caused immune responses. Our initial simulations demonstrated that breathing in C. pneumoniae can result in infection propagation and significant buildup of Aß plaque and NF tangles in the olfactory cortex and hippocampus. Our model also indicated how mucosal and neural immunity can play a significant role in the pathway considered. Lower immunities, correlated with elderly individuals, had quicker and more Aß plaque and NF tangle formation counts. In contrast, higher immunities, correlated with younger individuals, demonstrated little to no such formation. CONCLUSION: The modelling framework provides an organized visual representation of how AD progression may occur via the olfactory system to better understand disease pathogenesis. The model confirms current conclusions in available research but can be easily adjusted to match future evidence and be used by researchers for their own individual purposes. The goal of our initial model is to ultimately guide further hypothesis refinement and experimental testing to better understand the dynamic system interactions present in the etiology and pathogenesis of AD.

Conceptualization of a Parasympathetic Endocrine System.

We here propose a parasympathetic endocrine system (PES) comprised of circulating peptides released from secretory cells in the gut, significantly modulated by vagal projections from the dorsal motor nucleus of the vagus (DMV). While most of these gut peptides mediate well-described satiety and digestive effects that increase parasympathetic control of digestion (Lee et al., 1994; Gutzwiller et al., 1999; Klok et al., 2007), they also have actions that are far-reaching and increase parasympathetic signaling broadly throughout the body. The actions beyond satiety that peptides like somatostatin, cholecystokinin, glucagon-like peptide 1, and vasoactive intestinal peptide have been well-examined, but not in a systematic way. Consideration has been given to the idea that these and other gut-derived peptides are part of an endocrine system has been partially considered (Rehfeld, 2012; Drucker, 2016), but that it is coordinated through parasympathetic control and may act to increase the actions of parasympathetic projections has not been formalized before. Here only gut-derived hormones are included although there are potentially other parasympathetically mediated factors released from other sites like lung and liver (Drucker, 2016). The case for the existence of the PES with the DMV as its integrative controller will be made through examination of an anatomical substrate and evidence of physiological control mechanisms as well as direct examples of PES antagonism of sympathetic signaling in mammals, including humans. The implications for this conceptual understanding of a PES reframe diseases like metabolic syndrome and may help underscore the role of the autonomic nervous system in the associated symptoms.

GutLogo: Agent-based modeling framework to investigate spatial and temporal dynamics in the gut microbiome.

Knowledge of the spatial and temporal dynamics of the gut microbiome is essential to understanding the state of human health, as over a hundred diseases have been correlated with changes in microbial populations. Unfortunately, due to the complexity of the microbiome and the limitations of in vivo and in vitro experiments, studying spatial and temporal dynamics of gut bacteria in a biological setting is extremely challenging. Thus, in silico experiments present an excellent alternative for studying such systems. In consideration of these issues, we have developed a user-friendly agent-based model, GutLogo, that captures the spatial and temporal development of four representative bacterial genera populations in the ileum. We demonstrate the utility of this model by simulating population responses to perturbations in flow rate, nutrition, and probiotics. While our model predicts distinct changes in population levels due to these perturbations, most of the simulations suggest that the gut populations will return to their original steady states once the disturbance is removed. We hope that, in the future, the GutLogo model is utilized and customized by interested parties, as GutLogo can serve as a basic modeling framework for simulating a variety of physiological scenarios and can be extended to capture additional complexities of interest.

A simple and accurate rule-based modeling framework for simulation of autocrine/paracrine stimulation of glioblastoma cell motility and proliferation by L1CAM in 2-D culture.

BACKGROUND: Glioblastoma multiforme (GBM) is a devastating brain cancer for which there is no known cure. Its malignancy is due to rapid cell division along with high motility and invasiveness of cells into the brain tissue. Simple 2-dimensional laboratory assays (e.g., a scratch assay) commonly are used to measure the effects of various experimental perturbations, such as treatment with chemical inhibitors. Several mathematical models have been developed to aid the understanding of the motile behavior and proliferation of GBM cells. However, many are mathematically complicated, look at multiple interdependent phenomena, and/or use modeling software not freely available to the research community. These attributes make the adoption of models and simulations of even simple 2-dimensional cell behavior an uncommon practice by cancer cell biologists. RESULTS: Herein, we developed an accurate, yet simple, rule-based modeling framework to describe the in vitro behavior of GBM cells that are stimulated by the L1CAM protein using freely available NetLogo software. In our model L1CAM is released by cells to act through two cell surface receptors and a point of signaling convergence to increase cell motility and proliferation. A simple graphical interface is provided so that changes can be made easily to several parameters controlling cell behavior, and behavior of the cells is viewed both pictorially and with dedicated graphs. We fully describe the hierarchical rule-based modeling framework, show simulation results under several settings, describe the accuracy compared to experimental data, and discuss the potential usefulness for predicting future experimental outcomes and for use as a teaching tool for cell biology students. CONCLUSIONS: It is concluded that this simple modeling framework and its simulations accurately reflect much of the GBM cell motility behavior observed experimentally in vitro in the laboratory. Our framework can be modified easily to suit the needs of investigators interested in other similar intrinsic or extrinsic stimuli that influence cancer or other cell behavior. This modeling framework of a commonly used experimental motility assay (scratch assay) should be useful to both researchers of cell motility and students in a cell biology teaching laboratory.

The role of the gut-brain axis in alcohol use disorders.

Neuroimmune and inflammatory processes have been locally associated with the amygdala in alcohol exposure and withdrawal. We and others have suggested that this inflammation in the amygdala may cause disturbance of neural function observed as anxiety and autonomic distress in withdrawal. Despite the potential importance of the robust neuroinflammatory response, the mechanisms contributing to this response are not well understood. We review literature that suggests the effects of alcohol, and other substances of abuse, cause dysbiosis of the gut microbiome. This peripheral response may modulate neuroprotective vagal afferent signaling that permits and exacerbates a neuroinflammatory response in the amygdala. We will examine the mounting evidence that suggests that (1) gut dysbiosis contributes to neuroinflammation, especially in the context of alcohol exposure and withdrawal, (2) the neuroinflammation in the amygdala involves the microglia and astrocytes and their effect on neural cells, and (3) amygdala neuroinflammation itself contributes directly to withdrawal behavior and symptoms. The contribution of the gut to an anxiogenic response is a promising therapeutic target for patients suffering with withdrawal symptoms given the safe and well-established methods of modulating the gut microbiome.