Neuromodulation of spinal autonomic regulation

The central nervous system is largely responsible for receiving sensory information from the environment and determining motor output. Yet, centrally-derived behavior and sensation depends on the optimal maintenance of the cells, tissues, and organs that feed and support these functions. Most of visceral regulation occurs without conscious oversight, making the spinal cord a key site for integration and control. How the spinal cord modulates output to our organs, or sensory information from them, is poorly understood. The overall aim of this dissertation was to better understand spinal processing of both visceral sensory information to and sympathetic output from the spinal cord. I first established and validated a HB9-GFP transgenic mouse model that unambiguously identified sympathetic preganglionic neurons (SPNs), the spinal output neurons for the sympathetic nervous system. Using this model, I investigated the electrophysiological similarities and diversity of SPNs, and compared their active and passive membrane properties to those in other animal models. My results indicate that while many of the same characteristics are shared, SPNs are a heterogeneous group that can be differentiated based on their electrophysiological properties. Since descending monoaminergic pathways have particularly dense projections to sympathetic regions of the spinal cord, I next examined the modulatory role that the monoamines have on spinal sympathetic output. While each neuromodulator tested had a unique signature of action, serotonin and norepinephrine appeared to increase the excitability of individual SPNs, while dopamine had more mixed actions. Since many autonomic reflexes are integrated by the spinal cord, I also questioned whether these reflexes would be similarly modulated. I therefore developed a novel in vitro spinal cord and sympathetic chain preparation, which allowed for the investigation of visceral afferent-mediated reflexes and their neuromodulation by monoamines. This preparation exposed a dichotomy of action, where sympathetic and somatic motor output is generally enhanced by the monoamines, but reflexes mediated by visceral input are depressed. Utilizing the spinal cord and sympathetic chain preparation, I also investigated how the spinal cord modulates visceral sensory information. One of the most powerful means of selectively inhibiting afferent information from reaching the spinal cord is presynaptic inhibition. I hypothesized that both spinal visceral afferents and descending monoaminergic systems would depress transmission of visceral afferents to the spinal cord. My results demonstrated that activity in spinal visceral afferents can lead to spinally generated presynaptic inhibition, and that in addition to depressing synaptic transmission to the spinal cord, the monoamines also depress the intrinsic circuitry that generates this activity-dependent presynaptic inhibition. Taken together, my results indicate that descending monoaminergic pathways act to limit the amount of visceral sensory information reaching the central nervous system and increase sympathetic output, resulting in an uncoupling of output from visceral sensory input and transitioning to a feed-forward, sympathetically dominant control strategy. This combination offers complex modulatory strategies for descending systems.PhDCommittee Chair: Hochman, Shawn; Committee Member: Nichols, Richard T; Committee Member: Schramm, Lawrence; Committee Member: Shinohara, Minoru; Committee Member: Tansey, Keit

Toward one‐pot olefin/thiophene block copolymers using an in situ ligand exchange

Block copolymers containing both conducting and insulating segments are of interest due to their enhanced electrical properties arising from their increased crystallization. Yet few methods exist for generating these copolymers, because the reaction conditions for synthesizing each block are often incompatible. Herein, efforts toward identifying a one‐pot, living polymerization method for synthesizing block copolymers of 1‐pentene and 3‐hexylthiophene is described. An in situ ligand exchange enables the optimal catalyst to be utilized for synthesizing each block. Even under these conditions, however, only homopolymers are observed. Computational studies modeling the ligand exchange reveal that the added stabilizing ligands likely inhibit propagation of the second block. These results suggest an ancillary ligand‐based “goldilocks” effect wherein catalysts that are stable yet still reactive are required. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019, 57, 1601–1605Combined experimental and computational studies revealed unexpected challenges in applying sequential catalysis for the streamlined synthesis of insulating/conducting block copolymers.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/150553/1/pola29426_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150553/2/pola29426.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150553/3/pola29426-sup-0001-AppendixS1.pd

Postoperative Length of Stay Following Enhanced Recovery After Surgery Protocol Implementation for Scheduled Cesarean Deliveries

Background Cesarean delivery is the most common major surgery worldwide. 1 In 2018, 1.2 million cesarean deliveries occurred in the United States, accounting for nearly 32% of all deliveries.2 Research has shown ERAS benefits include decreased length of stay, improved pain control, and improved patient satisfaction.2,3 Despite its use in numerous surgical specialties, ERAS implementation within obstetrics has been slow.2 The ERAS Society released a three-part guideline specific to cesarean deliveries in 2018 and 2019,4,5,6 yet few studies have assessed the impact of ERAS on cesarean postoperative outcomes.2 An improved perioperative course would be particularly beneficial for mothers undergoing cesarean delivery as they require a quick recovery in order to care for their newborn. The purpose of this retrospective, observational study was to determine how the recovery process following cesarean delivery may be improved by standardizing the perioperative care pathway, with the primary outcome of interest being postoperative length of stay. Methods • Design: Retrospective, observational cohort study at Providence Sacred Heart Medical Center (PSHMC) • This project was approved by the PSHMC Clinical Innovation and Research Council and deemed exempt from human subjects research by Providence Health Care Institutional Review Board. • Human subjects protection: Patient demographic and surgical data from electronic medical records were extracted, deidentified, and encrypted using a REDCap data collection tool • Inclusion Criteria: parturients 18 years of age or older who underwent scheduled cesarean delivery between June 1, 2017 to May 31, 2018 for pre-intervention group and June 1, 2019 to February 29, 2019 for postintervention group. • Exclusion Criteria: urgent or emergent cesarean deliveries, cesarean deliveries occurring in the run-in time period of June 1, 2018 through May 31, 2019, and mothers under the age of 18 years. • Outcome measurement: postoperative length of stay, defined as time of end of surgery to time of discharge • Exposure measurement: defined as post-ERAS protocol implementation following April 1, 2019. • Other variables considered included: age, weeks gestation, BMI, ASA, primary vs repeat cesarean, weeks gestation, and multiparty births. • Statistical analysis: a-prior power analysis, univariate analysis, bivariate analysis, and multivariate analysis Discussion In this retrospective observational study, this facility’s postoperative LOS following cesarean delivery was found to be low, with a median of 52.4 hours. Following ERAS implementation, the median postoperative LOS decreased to 51.2 hours but was not found to be statistically significant in an adjusted model. Cesarean deliveries comprised nearly 29% of all births at this facility, 58.5% of which were scheduled or elective cesarean deliveries. Characteristics of parturients were very similar among the pre- and post-ERAS patient groups; most patients were classified as ASA 2 and a mean age of 31 years. Repeated multivariate analysis using run-in periods of varying lengths and controlling for time consistently showed no significant difference in postoperative LOS between the pre-ERAS and post-ERAS groups. With the postoperative LOS at PSHMC being low prior to protocol implementation, it is likely that other facilities with longer postoperative LOS may see a greater benefit of ERAS implementation. Additional work is still required to further the understanding of ERAS for cesarean deliveries and its impact on postoperative recovery. Future studies of interest includes determining 30-day readmission rates and emergency room visits following discharge. In order to determine the true effect ERAS may have on postoperative length of stay and the recovery process following cesarean delivery, large prospective control trials are needed.https://digitalcommons.psjhealth.org/other_pubs/1110/thumbnail.jp

The cellular and synaptic architecture of the mechanosensory dorsal horn

The deep dorsal horn is a poorly characterized spinal cord region implicated in processing low-threshold mechanoreceptor (LTMR) information. We report an array of mouse genetic tools for defining neuronal components and functions of the dorsal horn LTMR-recipient zone (LTMR-RZ), a role for LTMR-RZ processing in tactile perception, and the basic logic of LTMR-RZ organization. We found an unexpectedly high degree of neuronal diversity in the LTMR-RZ: seven excitatory and four inhibitory subtypes of interneurons exhibiting unique morphological, physiological, and synaptic properties. Remarkably, LTMRs form synapses on between four and 11 LTMR-RZ interneuron subtypes, while each LTMR-RZ interneuron subtype samples inputs from at least one to three LTMR classes, as well as spinal cord interneurons and corticospinal neurons. Thus, the LTMR-RZ is a somatosensory processing region endowed with a neuronal complexity that rivals the retina and functions to pattern the activity of ascending touch pathways that underlie tactile perception

The early career researcher's toolkit:translating tissue engineering, regenerative medicine and cell therapy products

Although the importance of translation for the development of tissue engineering, regenerative medicine and cell-based therapies is widely recognized, the process of translation is less well understood. This is particularly the case among some early career researchers who may not appreciate the intricacies of translational research or make decisions early in development which later hinders effective translation. Based on our own research and experiences as early career researchers involved in tissue engineering and regenerative medicine translation, we discuss common pitfalls associated with translational research, providing practical solutions and important considerations which will aid process and product development. Suggestions range from effective project management, consideration of key manufacturing, clinical and regulatory matters and means of exploiting research for successful commercialization

Serum from COVID-19 patients early in the pandemic shows limited evidence of cross-neutralization against variants of concern

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) results in a variety of clinical symptoms ranging from no or mild to severe disease. Currently, there are multiple postulated mechanisms that may push a moderate to severe disease into a critical state. Human serum contains abundant evidence of the immune status following infection. Cytokines, chemokines, and antibodies can be assayed to determine the extent to which a patient responded to a pathogen. We examined serum and plasma from a cohort of patients infected with SARS-CoV-2 early in the pandemic and compared them to negative-control sera. Cytokine and chemokine concentrations varied depending on the severity of infection, and antibody responses were significantly increased in severe cases compared to mild to moderate infections. Neutralization data revealed that patients with high titers against an early 2020 SARS-CoV-2 isolate had detectable but limited neutralizing antibodies against the emerging SARS-CoV-2 Alpha, Beta and Delta variants. This study highlights the potential of re-infection for recovered COVID-19 patients

Defining a spinal microcircuit that gates myelinated afferent input: implications for tactile allodynia

Chronic pain presents a major unmet clinical problem. The development of more effective treatments is hindered by our limited understanding of the neuronal circuits underlying sensory perception. Here, we show that parvalbumin (PV)-expressing dorsal horn interneurons modulate the passage of sensory information conveyed by low-threshold mechanoreceptors (LTMRs) directly via presynaptic inhibition and also gate the polysynaptic relay of LTMR input to pain circuits by inhibiting lamina II excitatory interneurons whose axons project into lamina I. We show changes in the functional properties of these PV interneurons following peripheral nerve injury and that silencing these cells unmasks a circuit that allows innocuous touch inputs to activate pain circuits by increasing network activity in laminae I–IV. Such changes are likely to result in the development of tactile allodynia and could be targeted for more effective treatment of mechanical pain

Evaluating Cumulative Ecosystem Response to Restoration Projects in the Lower Columbia River and Estuary, 2009

This is the sixth annual report of a seven-year project (2004 through 2010) to evaluate the cumulative effects of habitat restoration actions in the lower Columbia River and estuary (LCRE). The project, called the Cumulative Effects Study, is being conducted for the U.S. Army Corps of Engineers Portland District (USACE) by the Marine Sciences Laboratory of the Pacific Northwest National Laboratory (PNNL), the Pt. Adams Biological Field Station of the National Marine Fisheries Service (NMFS), the Columbia River Estuary Study Taskforce (CREST), and the University of Washington. The goal of the Cumulative Effects Study is to develop a methodology to evaluate the cumulative effects of multiple habitat restoration projects intended to benefit ecosystems supporting juvenile salmonids in the 235-km-long LCRE. Literature review in 2004 revealed no existing methods for such an evaluation and suggested that cumulative effects could be additive or synergistic. From 2005 through 2009, annual field research involved intensive, comparative studies paired by habitat type (tidal swamp versus marsh), trajectory (restoration versus reference site), and restoration action (tidegate replacement vs. culvert replacement vs. dike breach)

Ecology of Juvenile Salmon in Shallow Tidal Freshwater Habitats of the Lower Columbia River, 2007?2010

The TFM study was designed to investigate the ecology and early life history of juvenile salmonids within shallow (<5 m) tidal freshwater habitats of the LCRE. We started collecting field data in June 2007. Since then, monthly sampling has occurred in the vicinity of the Sandy River delta (rkm 192–208) and at other sites and times in lower river reaches of tidal freshwater (rkm 110 to 141). This report provides a comprehensive synthesis of data covering the field period from June 2007 through April 2010

Characterizing Long COVID in Children and Adolescents

ImportanceMost research to understand postacute sequelae of SARS-CoV-2 infection (PASC), or long COVID, has focused on adults, with less known about this complex condition in children. Research is needed to characterize pediatric PASC to enable studies of underlying mechanisms that will guide future treatment.ObjectiveTo identify the most common prolonged symptoms experienced by children (aged 6 to 17 years) after SARS-CoV-2 infection, how these symptoms differ by age (school-age [6-11 years] vs adolescents [12-17 years]), how they cluster into distinct phenotypes, and what symptoms in combination could be used as an empirically derived index to assist researchers to study the likely presence of PASC.Design, setting, and participantsMulticenter longitudinal observational cohort study with participants recruited from more than 60 US health care and community settings between March 2022 and December 2023, including school-age children and adolescents with and without SARS-CoV-2 infection history.ExposureSARS-CoV-2 infection.Main outcomes and measuresPASC and 89 prolonged symptoms across 9 symptom domains.ResultsA total of 898 school-age children (751 with previous SARS-CoV-2 infection [referred to as infected] and 147 without [referred to as uninfected]; mean age, 8.6 years; 49% female; 11% were Black or African American, 34% were Hispanic, Latino, or Spanish, and 60% were White) and 4469 adolescents (3109 infected and 1360 uninfected; mean age, 14.8 years; 48% female; 13% were Black or African American, 21% were Hispanic, Latino, or Spanish, and 73% were White) were included. Median time between first infection and symptom survey was 506 days for school-age children and 556 days for adolescents. In models adjusted for sex and race and ethnicity, 14 symptoms in both school-age children and adolescents were more common in those with SARS-CoV-2 infection history compared with those without infection history, with 4 additional symptoms in school-age children only and 3 in adolescents only. These symptoms affected almost every organ system. Combinations of symptoms most associated with infection history were identified to form a PASC research index for each age group; these indices correlated with poorer overall health and quality of life. The index emphasizes neurocognitive, pain, and gastrointestinal symptoms in school-age children but change or loss in smell or taste, pain, and fatigue/malaise-related symptoms in adolescents. Clustering analyses identified 4 PASC symptom phenotypes in school-age children and 3 in adolescents.Conclusions and relevanceThis study developed research indices for characterizing PASC in children and adolescents. Symptom patterns were similar but distinguishable between the 2 groups, highlighting the importance of characterizing PASC separately for these age ranges