Cardiogenic Shock

Cardiogenic shock is a commonly seen problem within intensive care units across the world. Despite significant research into the process, mortality rates remain high. It is a condition that is frequently developed secondary to myocardial infarction (MI) and can lead to significant hemodynamic compromise and death. The purpose of this poster is to provide more in-depth knowledge of cardiogenic shock. The poster highlights the pathophysiology, signs and symptoms, treatment, and the implications for nursing surrounding the condition. No specific studies were addressed in the poster, however, several examples can be found through the references listed

Proposal of a Clinical Practice Guideline for a Non-Pharmacologic Music Listening Complementary Pain Therapy

Background: As many as 65% of post-surgical patients experience moderate to severe pain. Post-surgical pain is associated with a variety of negative physical and psychological consequences for patients. Currently, medical treatments for postoperative pain rely heavily on pharmaceuticals which can cause adverse side effects. Opioid analgesics, most notably, cause hypoventilation, apnea, and in some cases, dependence and addiction. In 2017, in response to state and national opioid prescription reduction programs, The Joint Commission (TJC) began requiring healthcare institutions to provide patients with non-pharmacologic pain treatment modalities. These pain treatment modalities, also known as complementary therapies, include music listening interventions, which have been shown to safely decrease pain in postoperative patients. The analgesic benefits of music have been measured in numerous controlled trials and meta-analyses. Problem: The culmination of over 30 stakeholder reports and direct observations by the project team revealed that a midwestern level-1 trauma medical center has been unable to meet TJC’s requirement to provide postoperative patients with the required non-pharmacologic pain therapies. This inspired a policy search at the healthcare facility of interest which revealed that no policy currently exists that dictates the provision of non-pharmacologic complementary therapy to patients. Purpose: The ultimate purpose of this project is to identify, adapt, and recommend an evidence-based clinical practice guideline for a postoperative music listening intervention to meet TJC’s requirement for the provision of non-pharmacologic pain treatment modalities at the healthcare facility of interest. Project leaders gathered valuable data and developed recommendations for the leadership groups which have the authority to mitigate, monitor, and sustain non-pharmacological modalities such as music listening at the healthcare facility of interest. Methods: The following objectives and methods are framed using the Plan-Do-Check-Act (PDCA) cycle, also known as the Deming cycle. 1) The project team has reviewed and synthesized evidence from the literature, hospital policy, and TJC accreditation requirements for hospitals to aid in the identification of a guideline for non-pharmacologic complementary pain therapy for patients. The planning phase also included a SWOT analysis discussion with stakeholders and personnel directly caring for patients in the PACU. 2) Members of the project team identified and modified an evidence-based clinical practice guideline from current literature incorporating feedback from the SWOT analysis for future proposal to the healthcare facility of interest. 3) The project team then collaborated with and incorporated feedback on proposed clinical practice guideline from preoperative and PACU leadership, nurses, and other stakeholders involved in the care of postoperative patients. 4) Lastly, the project team presented project findings and the modified evidence-based guideline recommendations to key stakeholders. Implications: This scholarly project can serve as a beginning point towards improving post-surgical patient pain and the medical center’s compliance with TJC requirement for healthcare facilities to provide non-pharmacologic pain treatment modalities by recommending an evidence-based clinical practice guideline for a music listening intervention in the PACU. This project is significant because it can assist the healthcare facility of interest in complying with TJC requirements. The findings of the scholarly project can also assist other departments within the healthcare system in implementing non-pharmacological pain therapy, specifically music listening interventions

Exercise Attenuates CTGF Levels, Delaying the Onset of Fibrosis in the Aging Left Ventricle

Aging is associated with a progressive increase in collagen (i.e., fibrosis) in the aging heart. Fibrosis is associated with a stiffening of the heart and a decrease in heart function. Previous data (Kwak, 2008) showed that matrix metalloproteinase (MMP) activity in the aging heart is decreased linked to an elevation TIMP-1 (tissue inhibitor of MMPs-1); while exercise training increased TIMP-1 and reduced MMP expression. Connective tissue growth factor (CTGF) is an upstream inhibitor of TIMP-1 and is implicated in diabetes and heart failure. We hypothesized that exercise would decrease CTGF levels, thus reducing fibrosis in the aged left ventricle. Young (3 months) and old (31 months) male Fischer 344 × Brown Norway F1 hybrid (F344BNF1) rats were used for the study. The rats were randomly assigned to one of the following experimental groups (n=10/group): young sedentary controls (YS), young exercise trained (YE), old sedentary controls (OS), and old exercise trained (OE). Rats walked quickly on a motor-driven treadmill for 45 min/day, 5 days/wk, for 12 wks. Heart levels of CTGF were determined via Immunohistochemistry (IHC). CTGF was expressed more in the old group compared to the young group, as well as the sedentary group compared to the exercise group. Future studies will determine if CTGF is downstream of angiotensin II, TGF-beta, and oxidative stress in regulating MMPs and TIMP-1

The effects of exercise on caspase-independent mitochondrial proteins in regards to age-related apoptosis

Exercise may have protective factors in reducing oxidative stress, mitochondrial dysfunction and mitochondrial caspase-dependent apoptosis with aging. It is presently unclear whether the caspase-independent apoptosis via EndonucleaseG (EndoG) and Apoptosis Inducing Factor (AIF) translocation from the mitochondria to the nucleosome is effected by exercise in aging skeletal muscle. It is understood that in aging skeletal muscle EndoG and AIF do translocate from the mitochondria to the nucleosome. We hypothesize that exercise will attenuate the translocation of EndoG and AIF from the mitochondria to the nucleosome in aging white gastrocnemius muscle. Twenty-four Fischer Brown Norway rats were randomly assigned to four groups, young sedentary, old sedentary, young exercisers and old exercisers. The exercise consisted of treadmill training. The protein expression of EndoG and AIF were analyzed using western blot assays. In the old sedentary group, EndoG increased 86.4 % in the soluble fraction, but there was no change in the young groups. EndoG protein levels in the nucleosome fraction of young exercisers decreased 49 % when compared to young sedentary controls and old sedentary increased by 86.5 % when compared to young sedentary controls. With AIF changes in the soluble fraction were neglible. Protein levels of AIF in the nucleosome fraction increased 64 % in the old sedentary group compared to young sedentary controls. The data indicates that exercise was a protective factor against caspase-independent apoptosis by decreasing the translocation of EndoG and AIF to the nucleosome in aged skeletal muscle

Role of extracellular matrix and microenvironment in regulation of tumor growth and LAR-mediated invasion in glioblastoma

The cellular dispersion and therapeutic control of glioblastoma, the most aggressive type of primary brain cancer, depends critically on the migration patterns after surgery and intracellular responses of the individual cancer cells in response to external biochemical cues in the microenvironment. Recent studies have shown that miR-451 regulates downstream molecules including AMPK/CAB39/MARK and mTOR to determine the balance between rapid proliferation and invasion in response to metabolic stress in the harsh tumor microenvironment. Surgical removal of the main tumor is inevitably followed by recurrence of the tumor due to inaccessibility of dispersed tumor cells in normal brain tissue. In order to address this complex process of cell proliferation and invasion and its response to conventional treatment, we propose a mathematical model that analyzes the intracellular dynamics of the miR-451-AMPK- mTOR-cell cycle signaling pathway within a cell. The model identifies a key mechanism underlying the molecular switches between proliferative phase and migratory phase in response to metabolic stress in response to fluctuating glucose levels. We show how up- or down-regulation of components in these pathways affects the key cellular decision to infiltrate or proliferate in a complex microenvironment in the absence and presence of time delays and stochastic noise. Glycosylated chondroitin sulfate proteoglycans (CSPGs), a major component of the extracellular matrix (ECM) in the brain, contribute to the physical structure of the local brain microenvironment but also induce or inhibit glioma invasion by regulating the dynamics of the CSPG receptor LAR as well as the spatiotemporal activation status of resident astrocytes and tumor-associated microglia. Using a multi-scale mathematical model, we investigate a CSPG-induced switch between invasive and non-invasive tumors through the coordination of ECM-cell adhesion and dynamic changes in stromal cells. We show that the CSPG-rich microenvironment is associated with non-invasive tumor lesions through LAR-CSGAG binding while the absence of glycosylated CSPGs induce the critical glioma invasion. We illustrate how high molecular weight CSPGs can regulate the exodus of local reactive astrocytes from the main tumor lesion, leading to encapsulation of non-invasive tumor and inhibition of tumor invasion. These different CSPG conditions also change the spatial profiles of ramified and activated microglia. The complex distribution of CSPGs in the tumor microenvironment can determine the nonlinear invasion behaviors of glioma cells, which suggests the need for careful therapeutic strategies.<br/

Prediction of clinical outcome in glioblastoma using a biologically relevant nine-microRNA signature

Background Glioblastoma is the most aggressive primary brain tumor, and is associated with a very poor prognosis. In this study we investigated the potential of microRNA expression profiles to predict survival in this challenging disease. Methods MicroRNA and mRNA expression data from glioblastoma (n = 475) and grade II and III glioma (n = 178) were accessed from The Cancer Genome Atlas. LASSO regression models were used to identify a prognostic microRNA signature. Functionally relevant targets of microRNAs were determined using microRNA target prediction, experimental validation and correlation of microRNA and mRNA expression data. Results A 9-microRNA prognostic signature was identified which stratified patients into risk groups strongly associated with survival (p = 2.26e−09), significant in all glioblastoma subtypes except the non-G-CIMP proneural group. The statistical significance of the microRNA signature was higher than MGMT methylation in temozolomide treated tumors. The 9-microRNA risk score was validated in an independent dataset (p = 4.50e−02) and also stratified patients into high- and low-risk groups in lower grade glioma (p = 5.20e−03). The majority of the 9 microRNAs have been previously linked to glioblastoma biology or treatment response. Integration of the expression patterns of predicted microRNA targets revealed a number of relevant microRNA/target pairs, which were validated in cell lines. Conclusions We have identified a novel, biologically relevant microRNA signature that stratifies high- and low-risk patients in glioblastoma. MicroRNA/mRNA interactions identified within the signature point to novel regulatory networks. This is the first study to formulate a survival risk score for glioblastoma which consists of microRNAs associated with glioblastoma biology and/or treatment response, indicating a functionally relevant signatur

First demonstration of hydrophobic membrane contactors for removal of ammonia from condensate wastewater

Hydrophobic membrane contactors represent a promising solution to the problem of recovering ammoniacal nitrogen from wastewater. The process has been shown to work best with wastewater streams that present high ammonia concentrations, low buffering capacities and low total suspended solids. The removal of ammonia from rendering condensate, produced during heat treatment of waste animal tissue, was assessed in this research using a hydrophobic membrane contactor. The main objective was to test the ammonia stripping technology using two types of hydrophobic membrane materials, polypropylene and polytetrafluoroethylene, at pilot scale and carry out process modification for ammonia removal. The results demonstrate that polypropylene membranes are not compatible with the condensate waste as it caused wetting. The polytetrafluoroethylene membranes showed potential and had a longer lifetime than the polypropylene membranes, removing up to 64% of ammonia from the condensate waste. The product formed contained a 30% concentrated ammonium sulphate salt which has a potential application as a fertilizer. This is the first demonstration of hydrophobic membrane contactors for treatment of condensate wastewater

miR451 and AMPK Mutual Antagonism in Glioma Cell Migration and Proliferation: A Mathematical Model

Glioblastoma multiforme (GBM) is the most common and the most aggressive type of brain cancer; the median survival time from the time of diagnosis is approximately one year. GBM is characterized by the hallmarks of rapid proliferation and aggressive invasion. miR-451 is known to play a key role in glioblastoma by modulating the balance of active proliferation and invasion in response to metabolic stress in the microenvironment. The present paper develops a mathematical model of GBM evolution which focuses on the relative balance of growth and invasion. In the present work we represent the miR-451/AMPK pathway by a simple model and show how the effects of glucose on cells need to be “refined” by taking into account the recent history of glucose variations. The simulations show how variations in glucose significantly affect the level of miR-451 and, in turn, cell migration. The model predicts that oscillations in the levels of glucose increase the growth of the primary tumor. The model also suggests that drugs which upregulate miR-451, or block other components of the CAB39/AMPK pathway, will slow down glioma cell migration. The model provides an explanation for the growth-invasion cycling patterns of glioma cells in response to high/low glucose uptake in microenvironment in vitro, and suggests new targets for drugs, associated with miR-451 upregulation

A validated microRNA profile with predictive potential in glioblastoma patients treated with bevacizumab

Purpose: We investigated whether microRNA expression data from glioblastoma could be used to produce a profile that defines a bevacizumab responsive group of patients. Patients and Methods: TCGA microRNA expression data from tumors resected at first diagnosis of glioblastoma in patients treated with bevacizumab at any time during the course of their disease were randomly separated into training (n=50) and test (n=37) groups for model generation. MicroRNA-seq data for 51 patients whose treatment included bevacizumab in the BELOB trial were used as an independent validation cohort. Results: Using penalized regression we identified 8 microRNAs as potential predictors of overall survival in the training set. We dichotomized the response score based on the most prognostic minimum of a density plot of the response scores (log-rank HR=0.16, p=1.2e-5) and validated the profile in the test cohort (one-sided log-rank HR=0.34, p=0.026). Analysis of the profile using all samples in the TCGA glioblastoma dataset, regardless of treatment received, (n=473) showed that the prediction of patient benefit was not significant (HR=0.84, p=0.083) suggesting the profile is specific to bevacizumab. Further independent validation of our microRNA profile in RNA-seq data from patients treated with bevacizumab (alone or in combination with CCNU) at glioblastoma recurrence in the BELOB trial confirmed that our microRNA profile predicted patient benefit from bevacizumab (HR=0.59, p=0.043). Conclusion: We have identified and validated an 8-microRNA profile that predicts overall survival in patients with glioblastoma treated with bevacizumab. This may be useful for identifying patients who are likely to benefit from this agent

USP11 regulates PML stability to control Notch-induced malignancy in brain tumours

The promyelocytic leukaemia (PML) protein controls multiple tumour suppressive functions and is downregulated in diverse types of human cancers through incompletely characterized post-translational mechanisms. Here we identify USP11 as a PML regulator by RNAi screening. USP11 deubiquitinates and stabilizes PML, thereby counteracting the functions of PML ubiquitin ligases RNF4 and the KLHL20–Cul3 (Cullin 3)–Roc1 complex. We find that USP11 is transcriptionally repressed through a Notch/Hey1-dependent mechanism, leading to PML destabilization. In human glioma, Hey1 upregulation correlates with USP11 and PML downregulation and with high-grade malignancy. The Notch/Hey1-induced downregulation of USP11 and PML not only confers multiple malignant characteristics of aggressive glioma, including proliferation, invasiveness and tumour growth in an orthotopic mouse model, but also potentiates self-renewal, tumour-forming capacity and therapeutic resistance of patient-derived glioma-initiating cells. Our study uncovers a PML degradation mechanism through Notch/Hey1-induced repression of the PML deubiquitinase USP11 and suggests an important role for this pathway in brain tumour pathogenesis