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Immunomodulatory Roles of the Lysosomal Sialidase Neuraminidase 1
Get PDFBackground Sialic acids are key sugar moieties located at the non-reducing terminals of glycan chains on glycoproteins and glycolipids. By virtue of their location, they influence the functions and biochemical properties of the macromolecules they are bound to. Removal of sialic acids in mammalian cells is carried out by four sialidases, which are differentially expressed and localized in distinct subcellular compartments. Neuraminidase 1 (NEU1), the most abundant and ubiquitous of the four sialidases, functions primarily in the acidic environment of the lysosomes, but can hydrolyze substrates at the plasma membrane, at least in certain cell types. The enzyme initiates the sequential degradation of sialo-glycoconjugates by removing their terminal sialic acids. Through this activity, NEU1 modulates the sialic acid contents of its substrates, which affect their turnover rates, folding, ligand interactions, subcellular distribution, and subsequently the cellular pathways they control. Genetic deficiency of NEU1 leads to a pediatric neurodegenerative lysosomal storage disease known as sialidosis. In sialidosis, loss of NEU1 disrupts lysosomal catabolism, leading to accumulation of unprocessed substrates that drive pathogenesis by impinging on basic cellular processes, one of which is calcium-dependent lysosomal exocytosis. NEU1 negatively regulates this process by cleaving the sialic acids of LAMP1, thereby promoting its timely degradation. Since LAMP1 is required for the recruitment to and docking of lysosomes at the plasma membrane, loss of NEU1 results in an increased number of lysosomes preferentially docked at the plasma membrane ready to fuse and release their contents extracellularly. The end result is unrestrained and excessive lysosomal exocytosis from cells of different organs including the nervous system, with deleterious consequences for the integrity of plasma membranes and the extracellular matrix. These data from our laboratory established a paradigm, which we applied to investigate the course of neuropathogenesis in Neu1 KO mice, a faithful model of sialidosis. These mice develop a severe brain pathology sharing many hallmarks with Alzheimer’s disease (AD), including dystrophic neurites, progressive amyloidosis and neuroinflammation, features prominent in the hippocampal region. The amyloidogenic process starts with lysosomal accumulation of the amyloid precursor protein, a natural substrate of Neu1, which remains sialylated in absence of the enzyme and is abnormally cleaved into amyloidogenic peptides that are then released extracellularly via lysosomal exocytosis. These events initiate the formation of amyloid deposits in the Neu1 KO hippocampus and elicit a massive neuroinflammatory response mediated in part by the microglia. These findings have remarkable parallels with AD, where changes in the sialylation status of glycoproteins in both neurons and glia have been shown to correlate with disease stage in patients. In this dissertation we investigate microglia-mediated neuroinflammation and identify an AD- mimicking response occurring in Neu1 KO mice. Purpose We sought to determine the role of Neu1 in microglial functions by ascertaining whether microglia are activated and reacting in Neu1 KO hippocampi, assessing their phagocytic capacity, and investigating whether AAV-induced expression of human NEU1 in Neu1 KO mice would ameliorate microglial-mediated neuroinflammation. Results In the first section of the results, we showed that Neu1 KO microglia are higher in number, larger in size, and more granular when compared to wild-type cells. These features, combined with their amoeboid morphology, characterized Neu1 KO microglia as activated. Genetic analyses of Neu1 KO hippocampal tissue showed an upregulation of pro-inflammatory, myeloid-specific genes mimicking the immunoprofile of AD patients. We went on to demonstrate excessive lysosomal exocytosis in Neu1 KO microglia and established that these cells release increased levels of CCL3 and TNFalpha. Furthermore, we showed that lysosomal exocytosis contributes to the release of these signaling molecules by microglia. In the next section of the results, we established that Neu1 KO microglia have a reduced phagocytic capacity for multiple materials, the most relevant to AD being Abeta-42 oligomers. Through our analyses of microglial phagocytic receptors, we identified CD68 as a substrate of Neu1 and showed that Trem2 homeostasis is altered in Neu1 KO microglia. In these cells, Trem2 is abnormally sequestered into endo-lysosomal vesicles, wherein sialylated Trem2 accumulates in lysosomes, promoting excessive proteolytic cleavage of the protein into soluble Trem2 and Trem2-C-terminal fragment. Moreover, by comparing Neu1 KO and Neu1/Trem2 dKO microglia, we determined that Trem2 signaling in these cells contributes to the production of cytokines and chemokines, diminishes phagocytosis, and influences the levels of CD68 and Lamp1 at the plasma membrane. In the last section, we demonstrated that AAV-mediated replanishment of NEU1 ameliorates microglia-mediated neuroinflammation in Neu1 KO hippocampi. Microglia from AAV-treated hippocampi have reduced size, granularity, and expression of CD68. These cells also have lower levels of Lamp1 at the plasma membrane and secrete less CCL3 and TNFalpha, likely due to reduced lysosomal exocytosis. We determined that Trem2 cleavage is reduced in microglia from AAV-treated hippocampi, and phagocytic capacity is increased in a Trem2-dependent manner, likely due to corrected homeostasis of the receptor. Conclusions From our investigations we can conclude that Neu1 regulates microglial function by modulating lysosomal exocytosis, cytokine and chemokine production, and phagocytic capacity. As a negative regulator of lysosomal exocytosis, Neu1 can effectively reduce the levels of degradative hydrolases and neurotoxic signaling molecules that are released by microglia into the extracellular matrix. Neu1 acts as an antagonist towards the production of pro-inflammatory cytokines and chemokines, further reducing neurotoxic signaling by microglia. Neu1 promotes phagocytosis, enhancing the ability of microglia to clear harmful debris such as Abeta-42 oligomers, preventing subsequent neurodegeneration, and contributing to a neuroprotective microenvironment. Since all these processes occur in most microglia-mediated neuroinflammatory responses, including sialidosis and Alzheimer’s disease, and given that AAV-mediated replenishment of NEU1 effectively diminishes the on-going neuroinflammatory response in Neu1 KO mice, AAV-NEU1 gene therapy represents a possible therapeutic avenue for any neurodegenerative condition that possesses a NEU1-dependent pathogenic component
Nursing Perspectives and Opinions on Early or Delayed Sepsis Treatment: A Mixed Methods Approach
Get PDFPurpose. Each year at least 1.7 million adults in America develop sepsis. Sepsis can lead to life threatening organ dysfunction, severe hypotension, and death when severe sepsis or septic shock is involved. Sepsis is responsible for 50% of acute kidney injury (AKI), which is the most common form of organ dysfunction seen in critical care. Sepsis associated AKI results in loss of, or decreased renal function, is associated with adverse long-term outcomes, and carries a higher mortality rate than non-septic AKI, sepsis without AKI, or septic shock without AKI. Surviving sepsis guidelines suggests a 1-hour window from the time of sepsis diagnosis to initiating critical treatments. Nurses are vital in identifying early signs and symptoms of sepsis. Early sepsis treatment is essential to hinder preventable sepsis deaths. The purpose of this study was to gauge how critical care nurses who work in ED and ICU perceive factors that might affect early or delayed sepsis treatment. Methods. An exploratory sequential mixed methods approach was performed to describe the study findings. Qualitative data was collected and analyzed from 14 nurses, whereby themes were extracted and explained using a phenomenological method. Descriptive statistics were used to analyze the results of a self-completed survey for the quantitative portion of the study. Surveys were given out to and collected from 100 nurses. The quantitative data was utilized to strengthen the themes of the qualitative themes. Results. Themes from the quantitative study corroborated qualitative findings. Study participants ranked poor communication and coordination of care, knowledge deficit regarding appropriate management, and lab delays as the 1st, 2nd, and 3rd greatest cause of delays in sepsis treatment, respectively. Although self-knowledge of sepsis identification was high among participants, sepsis management was more difficult. Conclusion. Sepsis bundles assist nurses in facilitating early sepsis treatment. Edu- cation programs dedicated to ED and ICU nurses are needed. Yearly continuing education programs focusing on sepsis management should be implemented to keep nurses well informed on sepsis identification and management
The Impact of Outcomes on Depression Literacy in School-Age Children Who Received Depression Education
Get PDFPurpose/Background Recognizing mental illness is crucial in adolescence. It is the second leading cause of suicide and death in children 10-19 years of age. Early identification and recognition of signs and symptoms could prevent progressive mental health illness in early childhood and adulthood. We are seeking to answer the PICO question: In adolescents between 10 and 19 years of age who are enrolled in school (P), how does receiving education on depression awareness (I) compared to not receiving education on depression awareness (C) affect depression scores (O)?
Methods This review was conducted on articles about adolescent children. These articles were written within the past ten years and were scientifically researched, peer-reviewed, and published by a professional medical journal in the English language. The research was conducted in a school-based setting throughout the country and abroad. The information was evidence-based and included systematic reviews. In the fall of 2019, we began searching the literature on school-based education programs and the effectiveness of education in identifying signs and symptoms of depression.
Results The review yielded 40 results. Ten articles of high quality were used to support positive findings that school-based programs such as ADAP programs effectively taught signs and symptoms of depression and help-seeking behavior. This program was administered by teachers, nurses, and other school personnel educated before the program\u27s start. The program consists of a 6-week program with education on depression provided. Pre and post-tests were given to show improvement in knowledge of depression. There was an increase in depression scores from 0% pretest to 74.5% post-screening.
Implications for Nursing This scoping review reveals evidence that education on depression awareness improves help-seeking behavior and increases knowledge on signs and symptoms of depression. The ADAP curriculum and other curricula have effectively promoted positive outcomes. However, further research is needed to make these programs available to all students
Sleep Deprivation and Delirium Development in the ICU
Get PDFPurpose/Background Delirium is an acute syndrome characterized by disturbances in cognition occurring in critically ill patients, particularly those over 65 in the intensive care unit (ICU). Numerous risk factors are associated with delirium development, with sleep being a modifiable factor. This review explores existing literature regarding the relationship between sleep deprivation and delirium development while evaluating the effectiveness of a sleep promotion protocol to decrease the incident of delirium in those ICU patients 65 years or older.
Method A literature review of peer-reviewed studies from PubMed and additional search engines was completed. Articles reviewed were published within the last five years, focusing on ICU delirium, sleep deprivation, and the relationship shared between these two factors. Of these articles, eleven reviewed examined the relationship between sleep and delirium development, with several of these articles focusing on the use of sleep promotion protocol to aid in preventing delirium development for patients over 65 in the ICU.
Results A mixture of studies was utilized for this review, including randomized control trials, meta-analysis, and qualitative data. Each article reviewed in the study sample (N=11) demonstrated a relationship between sleep deprivation and delirium development. In addition, six articles proposed a statistical correlation between sleep deprivation and delirium development, while eight articles revealed a reduction in delirium development when utilizing a sleep promotion protocol. Overall, utilizing different levels of evidence supports the effectiveness of implementing a sleep promotion protocol towards decreasing the development of ICU delirium for those patients 65 years or older.
Implications for Nursing Practice The results from this review demonstrated relevant data regarding using a sleep promotion protocol to decrease the incidence of delirium development. Modifications of risk factors such as sleep deprivation are non-invasive, risk-free, and low-cost strategies that are beneficial towards preventing and managing delirium within the ICU setting, primarily when incorporated as part of a multicomponent plan
Reducing 30 Day CHF Readmission Rates: Evaluating Medication Efficacy
Get PDFPurpose/Background Heart failure (HF) is a leading cause of hospital readmissions and lost revenue under the Hospital Readmission Reduction Program (HRRP). Medication management plays a crucial role in controlling HF symptoms leading to hospitalization. This scoping review examines the benefits of angiotensin receptor-neprilysin inhibitors versus beta-blockers in reducing hospital readmissions within 30 days of discharge related to heart failure with reduced ejection fraction (HFrEF) in the United States.
Methods We conducted a literature search from August 2020 to November 2021 on the Google Scholar, PubMed, and CINAHL databases using the key phrases heart failure with reduced ejection, beta-blockers, angiotensin receptor-neprilysin inhibitor, and hospital readmission. Inclusion criteria include peer review, English language, publication within the past five years, free access, and full-text availability. Ultimately, we chose ten articles based on relevance, rigor, and quality.
Results Our review shows that both BBs and ARNIs aid in reducing hospital readmissions as well as mortality in patients with HFrEF. However, ARNIs are typically used later in the progression of HF and are generally part of combination therapy. We were unable to find a single study that directly compared the efficacy of BBs to ARNIs as monotherapies in reducing 30-day hospital readmissions.
Implications for Nursing Practice This scoping review provides insight into the complexity of medication management for HFrEF and its role in reducing hospitalizations. Our review indicates a need for further research into the implementation of ARNIs as monotherapy in the treatment of HF compared to BBs
Effectiveness of Perioperative Ketamine vs. Opioid Analgesia on Extubation Time and Total Perioperative Opioid Requirement
Get PDFPurpose/Background Opioid analgesics are a primary source of pain control in the perioperative patient. However, all opioids decrease ventilatory drive secondary to mu2 receptor agonism in the brainstem. Ventilatory depression delays extubation after mechanical ventilation in post-operative patients, thus increasing the risk of complications such as ventilator-associated pneumonia and barotrauma. Non-opioid analgesics such as ketamine have been considered for use in order to reduce this risk. Ketamine is a noncompetitive N-methyl-D-aspartate receptor-antagonizing sedative that bears analgesic properties while preserving respiratory drive. Research suggests that ketamine provides effective perioperative pain control and decreases postoperative extubation time when given alone or with other non-opioids.
Methods Fifteen peer-reviewed studies published between 2009 and 2020 were chosen for the scoping review. Eligible studies compared the effects of opioid anesthetics versus ketamine anesthesia on extubation time, total perioperative opioid use, and perioperative adverse outcomes. A synthesis table was formulated to compare perioperative ketamine use with reduced postoperative extubation time and perioperative opioid requirements.
Results Of the study sample (N=15), all fifteen articles provide evidence that perioperative ketamine administration results in either decreased post-operative extubation time, reduced perioperative opioid requirements, decreased incidence of perioperative respiratory depression, or a combination of these in comparison to opioid use alone. Three systematic reviews, nine randomized controlled trials, one controlled trial without randomization, and one cohort study were chosen in order to provide credible evidence across all research levels that perioperative ketamine use is beneficial towards reducing time to postoperative extubation.
Implications for Nursing Practice The scoping review provides evidence across multiple research levels suggesting that perioperative ketamine use reduces time to extubation in the postoperative patient. Evidence also suggests that perioperative ketamine use reduces post-operative opioid requirements. This practice may be implemented within surgical settings to reduce the risk of postoperative respiratory complications in surgical patients
Targeting Myeloid Protein Kinase C Signaling to Overcome Immune Suppression and Improve Immunotherapy in Cancer
Get PDFCheckpoint immunotherapy unleashes T cell antitumor potential which has revolutionized cancer treatment showing unprecedented long-term responses. However, most patients do not respond to immunotherapy which often correlates with a dysfunctional or immunosuppressive myeloid compartment. Immunosuppressive myeloid cells comprise Myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) and can suppress T cells via production of immunosuppressive factors. Conversely, efficient cytotoxic T cell priming is dependent on the ability of antigen-presenting cells (APCs), mainly conventional dendritic cells (cDCs) and macrophages, to present or cross-present tumor antigens to T cells. Thus, targeting immunosuppressive myeloid cells while simultaneously enhancing APCs represents a promising strategy that, when combined with immunotherapy, may result in long-lasting protective immunity. In this dissertation, we first investigated the effect of protein kinase C (PKC) agonist PEP005 on MDSC expansion, differentiation, and recruitment to the tumor microenvironment. We found that PKC agonists decreased MDSC expansion from the bone marrow and induced MDSC differentiation to an APC-like phenotype via activation of the p38 mitogen-activated protein kinase (MAPK) pathway. PKC agonists blunted MDSC suppressive activity and enhanced MDSC cross-priming capacity both in vitro and in vivo. Concurrently, PKC agonists favored the expansion of cross-presenting cDC1 at the expense of cDC2 and plasmacytoid DCs (pDC). Lastly, combination of PKC agonism with agonistic CD40 mAb, a form of innate immunotherapy, resulted in a reduction in tumor growth with a significant increase in intratumoral activated CD8+ T cells in a syngeneic breast cancer mouse model. This work proposes a novel promising strategy to simultaneously target MDSCs and promote APC function that may have highly impactful clinical relevance in cancer patients
Comparison of Routine Health Screening Rates Between Two EMR Systems
Get PDFAn EMR, electronic medical record, system refers to the software widely adopted by medical practitioners to reduce the use of hard-copy files, and improve the documentation, storage, and retrieval of patient information. Some EMR systems can generate automatic alerts reminding providers when patients are due for certain preventive services or meet the criteria for various screening measures. Epic, one of the leading EMR systems in use today, contains this additional feature. The screening recommendations built into Epic are derived from a committee of USPSTF, U.S. Preventive Services Task Force, medical experts whose focus is to improve patient health across the nation. In September of 2021, the University of Tennessee-Family Medicine Jackson clinic switched from using the Centricity EMR to Epic EMR. The primary goal of this study was to measure whether there is any quantifiable improvement in USPSTF screening rates after implementing the Epic EMR, which contains the notifications to prevent lapses in patient care.
For each EMR, 100 patients were selected at random including those greater than 44 years of age and less than 65 years of age. This study involved checking whether patients were up-to-date on thirteen potential USPSTF screening measures and recording the data in the SPSS statistical software program. Chi-square analysis comparing the data across both Centricity and Epic, revealed no statistical significance between screening rates. However, when accounting for sex (male vs. female) across both EMRs, women in the study had 16% more drug screening, 3% more tobacco screening, and 18% more statin use in comparison to men. Furthermore, statistical significance was found when comparing race (black vs. white). For example, black patients had 10% more syphilis screening and 33% more STD screening, whereas white patients had 28% more lung cancer screening across both EMR systems.
Although reassuring to find no statistical significance when comparing screening rates across both EMRs, conclusions to explain the results for specific screening measures pertaining to race and sex cannot be drawn based on the data at this time. Future research analyzing external variables such as patient compliance, provider biases, and population risk, may be useful in providing further insight to explain the statistical significance of this data
Effects of dietary ω-3 Polyunsaturated Fatty Acids (n-3 PUFA) in light sensitivity of retinas of mice models to prevent retinal damage
Get PDFLight-induced retinal degeneration (LIRD) causes photoreceptor cell death in albino mice after exposure to high intensity light for a set period of time (6-24 hours). This causes retinal photoreceptor cell death through apoptosis. From several previous studies, Dr. Mandal’s lab concluded that de novo biosynthesis of ceramide mediates photoreceptor cell death in a LIRD model. Previous studies in Dr. Mandal’s lab has shown that mouse models with higher endogenous ω-3 Polyunsaturated Fatty Acids (n-3 PUFA) generates less ceramide upon neuronal injury and prevent neurodegeneration (Mol Neurobio 2021). There are currently not many available effective therapies for retinal degeneration in humans that have inherited diseases leading to blindness. We speculate that higher endogenous n-3 PUFA will prevent retinal degeneration in mouse model of light induced retinal degeneration.
This project aimed to see a significant difference between LD-Control vs LD-PUFA. Results showed that there was a significant difference between NLD-Control vs LD-Control and NLD-PUFA vs LD-PUFA. Similar levels of degeneration of retinal photoreceptors occurred in n-3 PUFA and control. n-3 PUFA has shown inconclusive results for decreasing photoreceptor cell death. Further testing should be done to confirm the significance of the effect of n-3 PUFA in a mouse-model
Utility of AV Nodal Characteristics in Identification of Atrioventricular Nodal Reentrant Tachycardia and Risk of Recurrence
Get PDFBackground: Catheter ablation of the slow atrioventricular (AV) nodal pathway is a safe and effective treatment for atrioventricular nodal reentrant tachycardia (AVNRT). While AVNRT occurs frequently in both children and adults, pediatric patients experience higher rates of AVNRT recurrence.
Objective: The purpose of this study was to characterize changes in AV nodal conduction properties following catheter ablation and correlate these properties with AVNRT recurrence in pediatric patients.
Methods: This was a retrospective review of patients aged(AVRT) at a single tertiary care center between January 01, 2010 and September 01, 2021. Demographics, pre- and post-ablation ECG intervals, and AV nodal conduction properties were compared between AVNRT patients with and without recurrence as well as between patients with AVNRT versus AVRT.
Results: Data from 148 patients were analyzed, of which 73 (49%) were female and mean age was 13 ± 3 years. There were 71 patients with AVNRT, of which 65 (92%) had typical AVNRT and 69 (99%) were ablated with cryothermal energy. Four patients (6%) had AVNRT recurrence within 5 years. Baseline demographics were not different in patients with recurrence compared to those without recurrence. There was no significant difference in post-ablation PR interval (p=0.28), AH interval (p=0.38), Wenckebach cycle length (p=0.94) or effective refractory period (p=0.25) between patients with versus without AVNRT recurrence. Presence of post-ablation AV nodal echo beats did not predict risk of recurrence (p=0.99). The pre-ablation effective refractory period (ERP) was similar in AVNRT and AVRT patients (p=0.8); however, patients with AVNRT had longer post ablation ERP (p
Conclusions: In this pediatric cohort, changes in AV node conduction properties seen at electrophysiology study do not correlate with risk of AVNRT recurrence