bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 266: Screening and Validation of Small Molecule Inhibitors of Serum and Glucocorticoid Regulated Kinase-1 as Novel Therapy for Cardiac Arrhythmia Disorders
Authors: Bezzerides Vassilios J , Simonson Bridget , Shanmugasundaram Kumaran , Phyllis Ottaviano , Lynch Stacey , Hessler Katherine , Milan David , Rigby Alan , Das Saumya , Rosenzweig Anthony 
Published: July 2021

Alterations in sodium flux (INa) play an important role in the pathogenesis of cardiac arrhythmias and may also contribute to the development of cardiomyopathies. Recent data demonstrates a critical role for the serum and glucocorticoid regulated kinase-1 (SGK1) by modulation of INa in the heart, by regulating the voltage-gated sodium channel NaV1.5. To better understand and pharmacologically probe the significance of SGK1 in cardiac dysrhythmias, we have used computer aided drug discovery (CADD) to identify small molecule inhibitors of SGK1.
Expression of a constitutively active form of SGK1 (SGK1-CA) increased INa (1.7 fold, p <0.005) in a stable line of HEK cells expressing NaV1.5. Conversely, expression of a dominant negative form (SGK-DN) decreased NaV1.5 channel activity (2.8 fold, p <0.005). We examined the effects of SGK1 inhibition in a LQT model, by quantifying the ability of SGK1 inhibition to rescue the 2:1 AV block phenotype of the potassium channel zebrafish mutant, breakdance (bkd). Morpholino injection or expression of SGK1-DN significantly rescued the 2:1 AV block phenotype as compared to controls (p < 0.05).
Using CADD partnered with iterative empirical screens we identified several hit chemical scaffolds. Our lead compound inhibits the phosphorylation of the SGK1 target gene, GSK3-β in a dose dependent manner in cardiomyocytes (CMs) expressing SGK1-CA at the lowest effective concentration of 0.5μM. There was no significant inhibition of AKT dependent phosphorylation of GSK3-β up to a concentration of 50μM, demonstrating specificity of the inhibitor for SGK1. Incubation of bkd zebrafish mutants with the inhibitor rescued the 2:1 AV block in a dose dependent manner (60% rescue with 45μM, p < 0.05). Acute application of the inhibitor dramatically inhibited INa with either expression of SGK1-CA (90.8% reduction, p <0.05 ) or with RFP only (77.5% reduction p < 0.005). The half-time of inhibition was 200s with resulting current densities that were not statistically different than those observed with genetic inhibition by expression of SGK1-DN.
We conclude SGK1 activity regulates INa and speculate that structure activity relationship (SAR) derivatives of our lead compound might have a role in treatment of human cardiac arrhythmias.
Abstract 347: Identification and Characterization of a miRNA Cohort Initiated Transitional Program That Controls Cell Cycle Arrest of the Perinatal Heart
Authors: Burgon Patrick G , Weldrick Jonathan J 
Published: July 2021

During fetal and early perinatal development the myocardium undergoes a period of hyperplastic growth, which results in an exponential increase in the number of cardiomyocytes (CM) that will constitute the adult heart. Soon after birth, CMs proceed through a final round of cell division in the absence cytokinesis that results in binucleation of >95% of adult CMs. Fetal heart genes are re-activated with the onset of pathological hypertrophic or dilated cardiomyopathies, yet there is no evidence of CM re-entry into the cell cycle. Despite the importance of this phenomenon, little is known about the molecular basis for the transition from hyperplastic to hypertrophic-based myocardial growth.
Hypothesis: A perinatal heart gene program is necessary for the normal transition from a fetal heart gene program to an adult heart gene program.
To identify the molecular mechanisms and pathways involved in CM differentiation during the perinatal transition, RNA was isolated from E18, and 1, 3, 5, 7, 10 and 35d old mouse hearts. CM gene expression and micro-RNA profiles (n=3 arrays/time point) were determined by oligonucleotide array analysis. The raw array data was normalized by Robust Multi-array analysis. Empirical Bayes estimation of gene-specific variances was performed between each of the time points in order to identify genes that are transiently and significantly changed at days 3 and 5 as compare to E18 and 10d post-birth. The analysis identified 2,799 genes (E18 v 5d) and 3,347 genes (5d v 10d) that were then clustered to determine significant pathway enrichment (p<0.05) with Ingenuity Pathway Analysis.
Our analysis confirmed previous observations of a down regulation of glucose oxidative metabolism (p=0.02) with an up-regulation of fatty acid metabolism (p=0.0001) between E18 and 5d post-birth. Also, 63 cell cycle genes are collectively down regulated (p=4.3x10-4) between 5d and 10d post-birth. We identified 131 genes that are transiently up regulated at 5d compared to E18 and 10d and this transition was proceeded by a specific cohort of miRNAs. The data generated from this study provide new insight into the molecular mechanisms by which CMs regulate and permanently exit from the cell cycle.
Abstract 386: The Role of GAPDH in the Cardio-metabolic Response to Ischemia
Authors: Rhee James , Houstis Nicholas , Asara John , Liu Laura , Jang Cholsoon , Arany Zoltan , Rosenzweig Anthony 
Published: July 2021

Fundamental changes in nutrient metabolism underlie many disease processes, including obesity, diabetes, and cancer. Metabolic derangements are also a hallmark of heart disease, both in the context of failure and ischemia, and likely contributors to its etiology. For example, while the healthy heart favors fats as a fuel, failing hearts will consume more glucose; but it is unclear if this is pathological or protective. It is very likely that manipulation of metabolic pathways can affect, and possibly augment and protect, heart function. Yet no drug therapy exists that targets cardiac metabolism. Staples of ischemic disease management largely focus on anti-platelet, cholesterol-lowering, and beta-adrenergic blocking regimens. Heart failure medicines focus on maladaptive neuro-hormonal responses, a strategy several decades old. Our goal here is to delineate exactly how critical aspects of metabolism are altered in cardiac ischemia, and to identify new targets of pharmacological intervention.
Metabolism largely remains unexplored because of its intricate network of regulation, compounded by the fact that variations in this network will often escape traditional methods of gene expression profiling. But by using high throughput metabolomic and proteomic platforms, we have striking evidence that the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is instrumental in the heart’s response to ischemia. Dynamic, real-time metabolomic flux using heavy carbon isotope labeling points toward a partial shift of glycolytic intermediates toward lipid synthesis during ischemic stress in cardiomyocytes, precisely at the step catalyzed by GAPDH. Expansive phospho-proteomic analyses from Langendorff ex vivo hanging heart experiments show that this shift in metabolism may be triggered by an inhibitory phosphorylation of GAPDH. Our hypothesis that glycolysis is in part rerouted toward triglyceride synthesis is a revolutionary departure from decades-old perceptions of energy management. Modulating GAPDH function, either directly or indirectly via partner proteins, may offer insight into untapped areas of therapy. Our early attempts with chemicals that inhibit GAPDH already show heart cells with improved survival under ischemia.
Abstract 121: Development of Enzyme Replacement Therapy in Mammalian Models of Barth Syndrome
Authors: Dinca Ana , Chien Wei-Ming , Chin Michael 
Published: July 2021

Barth Syndrome (BTHS) is caused by a single gene mutation in the mitochondrial transacylase, tafazzin (TAZ), which results in impaired lipid metabolism leading to dysfunction in highly energetic tissues such as the heart and skeletal muscle. TAZ remodels the signature mitochondrial phospholipid, cardiolipin (CL), which is responsible for providing support to the electron transport chain. BTHS patients suffer from growth deficiencies, cardiomyopathy, hypotonia and neutropenia. Currently, treatment for patients with BTHS is supportive, seeking to ameliorate rather than prevent heart problems, skeletal muscle problems and recurring infections. Protein therapy, on the other hand, might treat and even prevent cardiac, skeletal muscle as well as infection-related morbidities.
We designed a recombinant TAZ protein containing a cell penetrating peptide in its C-terminus, which enables the recombinant TAZ to penetrate cells and then treated TAZ-deficient cells with it. We tested the permeability of the recombinant protein by direct delivery to H9C2 cardiomyoblasts and found that the protein is successfully taken up by the cells. We have generated a CRISPR-mediated TAZ knock out cardiomyoblast cell line and we found that TAZ knock out cells show a decrease in oxygen consumption as compared to the wild type cells; this is consistent with data from BTHS patient-derived cells. We are using this cell line to assess the enzymatic activity of the delivered protein by conducting mitochondrial respiration measurements. We have also acquired a mouse model of BTHS and are testing the recombinant TAZ in vivo. Preliminary data shows an augmentation in oxygen consumption following treatment with TAZ.
These results indicate that the protein is able to reach the mitochondria, where it is enzymatically active and able to enhance respiration. As the protein is able to rescue respiration in cells in which tafazzin was absent, this suggests that our approach should not only be able to prevent onset of symptoms, but also rescue the phenotype in already affected tissues.
Abstract 319: Role of Phosphodiesterases 4B and 4D in cAMP Signal Compartmentation Around Calcium Handling Proteins
Authors: Kraft Axel E , Nikolaev Viacheslav O , Conti Marco 
Published: July 2021

Phosphodiesterase subfamilies 4B and 4D are critically involved in the regulation of cAMP signaling in mammalian cardiomyocytes. Alterations in activity of these enzymes in human hearts have been shown to result in arrhythmia and heart failure. The aim of this project was to systematically investigate specific roles of PDE4B and PDE4D in regulating cAMP dynamics in three distinct subcellular microdomains formed around Ca
2+
handling proteins, such as L-type calcium channels (LTCCs), sarco/endoplasmic reticulum Ca
2+
-ATPase (SERCA) and ryanodine receptors (RyRs), to understand their impact on heart function and disease.

Transgenic mice expressing three different Förster resonance energy transfer (FRET) based cAMP biosensors targeted to caveolin rich plasma membrane, SERCA and RyR microdomains, were crossed with PDE4B and PDE4D knockout mice. Using FRET imaging in ventricular cardiomyocytes freshly isolated from wildtype and knockout mice, direct analysis of the specific effect of both PDE subfamilies in these microdomains could be performed by measuring the kinetics of local cAMP degradation.
Our results indicate that the cAMP kinetics around the LTCC microdomain is critically regulated by PDE4B and PDE4D. So far was it has been known that the isoform that is associated with the RyR microdomain belongs to the PDE4D family, however we found PDE4B to be involved in regulating the cAMP signaling in this microdomain. PDE4D deletion also revealed the critical role of this subfamily for the control of cAMP dynamics in the SERCA microdomain of adult mouse cardiomyocytes. Basal levels of cAMP were elevated when PDE4B was absent from any of the PDE4B-regulated microdomain, whereas no such alterations were detected for PDE4D knockout cells.
These data demonstrate that all three microdomains are differentially regulated by PDEs. Even within one organelle such as sarcoplasmic reticulum, we could show the existence of at least two distinct cAMP microdomains, i.e. around RyR and SERCA which are preferentially controlled by PDE4B and PDE4D, respectively. In the future, we aim to systematically analyze biochemical composition of the three microdomains, their distinct roles in cardiac function and disease as well as ways of their pharmacological modulation.
Sodium Transport in the Toad Bladder
Authors: FRAZIER HOWARD S. 
Published: July 2021

The isolated urinary bladder of the toad transports sodium actively across its epithelial layer and responds to the hormones vasopressin and aldosterone, properties which make it a useful model for the study of certain functions of the renal tubule. Sodium transport in the granular cells of the bladder is thought to involve first an energetically passive but selective entry step at the mucosal surface, the rate of which is increased after vasopressin administration. The second step in transport is considered to be active extrusion of the ion across the serosal boundary of the cell.
Recent evidence concerning the cellular pool of sodium and the site and mode of action of vasopressin suggests that this description is at best incomplete. No equally simple alternative hypothesis for the organization of sodium transport in this system is available at present.
Abstract TP159: Correlation Between Arterial Stiffness And The Severity Of Acute Cerebral Infarction
Authors: LEE YEONG-BAE , Park Joo-Hwan , Kim Eunja , Kim Ki-Tae , Lee Ju Kang , Lee Ju-Hun , San Jung , Koh Seong-Ho 
Published: July 2021

Arterial stiffness is an independent predictor of cardiovascular disease and stroke and can be evaluated by measuring pulse wave velocity(PWV) between 2 sites in the arterial tree, with a higher PWV indicating stiffer arteries. Recent studies have demonstrated that arterial stiffness is associated with intracranial large artery disease and the severity of cerebral small vessel disease. The aim of this study is to clarify whether pulse wave velocity value predict initial severity of acute ischemic stroke.
We enrolled consecutive patients with acute ischemic stroke. Demographic factors, laboratory data, brain imaging, neurological exam and arterial stiffness measured by brachial ankle PWV (baPWV) were evaluated on admission in all subjects. The subtype of acute ischemic stroke was classified according to the TOAST classification. All patients were categorized into two groups based on the initial severity of stroke, indicated by modified Rankin Scale(mRS). Severe group was defined as a mRS ≥ 3 at admission. Unpaired student’s t-test or Mann-whitney U-test were used to compare maximal and meanbaPWV values between two groups.
We enrolled 78 patients. According to the TOAST classification, the etiology of stroke was large artery disease (LAD) in 34 patients, small vessel disease (SVD) in 23 patients, and other subtypes in 12 patients. There were 28 patients with good outcome and 41 patients with poor outcome. The maximal and mean baPWV values were significantly increased in inpatients with high mRS score (2120.17± 527.75, 1999.21 ± 437.46) compared with those with low mRS score (1751.96 ± 363.49, 1723.14 ± 353.02)(p=0.001, p=0.007). In patients with SVD subtype, there was significant difference in maximal and mean baPWVvalues between two groups (p=0.030, p=0.047), whereas there was no significant difference in baPWV in patients with LAD subtype (p=0.141, p=0.172).
The main finding of our study is that arterial stiffness indicated by baPWV is associated with the initial severity of acute ischemic stroke. Because initial stroke severity is strongly associated with functional outcome of stroke, this findings suggest that measurement of baPWV may predict long-term outcome in patients with stroke especially in those with TOAST classification confirmed as SVD.
Abstract TP339: Stroke Severity Scoring: A Bi-variate Analysis of Clinical Outcomes Post Intravenous t-PA as a Guide to Influence Potential Change in Clinical Practice
Authors: Rehman Zia u , Mazer Mark A , Freeman Susan D , Small Cristine W , Butt Abid 
Published: July 2021

Background:
Care of the acute stroke patient in a dedicated stroke unit or ICU has been associated with improved outcomes. Not all post tPA patients require ICU level care, however general practice is admission to the ICU for 24 hours following tPA administration. In a Certified Primary Stroke Center nestled in the buckle of the stroke belt, 800+ patients with a primary diagnosis of stroke are admitted annually. There is a dedicated stroke unit with continuous multichannel telemetry. All post tPA patients are admitted to the medical ICU for the first 24 hours.

Purpose:
Hospitals administering intravenous tPA should continuously evaluate the impact of patient selection, unit placement and overall outcomes to include clinical efficiency, cost effectiveness, quality, safety, complications and deaths. Partnering with critical care physicians to evaluate stroke severity scores is essential for empirical consideration.

Methods:
Data analysis of clinical elements that may predict patient outcomes and serve as a guide to influence change in clinical practice was reviewed.

Bi-variate analysis of stroke severity scores, whereby the first National Institute of Health Stroke Scale (NIHSS), < 15 and > 15

Review of comorbities

Blood pressure control

Complications to include symptomatic bleeding

Discharge disposition

Death

Results:
Clinical outcomes of 171 patients post tPA administration were reviewed over a two year period.

• 80% of patients with NIHSS < 15 were discharged to home or rehab
• 42% of patients with NIHSS > 15 were discharged to home or rehab
• Four deaths occurred in patients with NIHSS < 15. Three deaths unrelated to tPA administration included one cardiac arrest and two respiratory failure. The fourth death, a regional transfer with advanced age, complex comorbities and uncontrolled blood pressure, resulting in a symptomatic bleed.
• 16 deaths occurred in the patients with NIHSS > 15

Conclusions:
Analytical review of outcome data, specifically stroke severity scores, should serve to influence ICU admission criteria and processes. Engagement of board certified neurocritical physicians or intensivists supports empirical evidence for improved utilization of resources and critical care beds using NIHSS < 15 as a reference.
Abstract T P279: Recognizing Depression in the Stroke Patient
Authors: Donnelly Rose M , Burns Jo-Ann 
Published: July 2021

Depression is a frequent sequela of stroke that has been associated with poor recovery and rehabilitation response. Clinical depression may occur within 3 months post stroke and can last for several years if left untreated.
Utilization of a depression screen helps identify patients at risk for post-stroke depression.
It is important to recognize and treat depression symptoms early to improve patient outcomes.
In performing a gap analysis in preparation for our survey for Comprehensive Stroke Center Certification, it became apparent this psychological aspect of patients was not being met. A systemic literature review was performed in search of a depression screening tool that was easy to use and addressed the needs of the patient. The tool chosen is the validated 2-item Patient Health Questionnaire depression module (PHQ-2). This depression screen is also utilized in our rehabilitation center which enhances the communication between our facilities.
After educating all the neuroscience nursing staff and stroke physicians, the tool became part of the patient assessment. The nurse screens each stroke patient on admission to the division or transfer from the intensive care unit. If the patient scores 3 or greater, the physician is notified so appropriate follow-up and treatment can occur. If a patient is unable to be assessed, the physician is notified so other depression assessment measures can be considered.
The utilization of a depression screening tool along with staff education has increased our staff’s awareness of the potential devastating effects depression can have on stroke recovery.
Abstract 15: Preoperative Transdural Collaterals in Moyamoya
Authors: Akagbosu Cynthia , Storey Armide , Robertson Richard , Scott R. Michael , Smith Edward 
Published: July 2021

Introduction:
The prevalence of angiographically evident pre-operative transdural collaterals to the brain in moyamoya is not well documented.

Hypothesis:
We hypothesized that presence of transdural collaterals would be associated with more advanced moyamoya disease at diagnosis, more frequent operative complications and better long-term angiographic results.

Methods:
Single institution case series reviewing all moyamoya patients with 6 vessel arteriograms treated surgically from 2005-2013.

Results:
204 patients (n=121 (59%) F / 83 (41%) M) were diagnosed with moyamoya at 9.5 years of age (range 0.4-35 years). Presentation included ischemia (84% stroke or TIA), headache (36%), incidental (7%), chorea (3%) and hemorrhage (1%).

Radiographically, 154 (75%) had bilateral disease for a total of 358 affected hemispheres, 152 (75%) had radiographic stroke and 190 (93%) had ivy sign on FLAIR MRI, indicating slow flow.
Of the 358 hemispheres, 324 were treated operatively.
On preoperative angiogram, 99 patients (49%) had transdural collaterals in 174 affected hemispheres (54%). Suzuki grades were higher in patients with collaterals (3.4 vs. 3.0, p=0.002). Of a total of 324 treated hemispheres, 84 (26%) had collaterals within the area of the surgical field.
Complications included 12 strokes (3.7% stroke rate per hemisphere), with 5 (42%) directly attributable to interruption of a transdural collateral.
In one-year postoperative arteriograms in 215 hemispheres, while not significant, Matsushima grades trended better in patients with preoperative collaterals, (1.6 vs. 1.8; A=1, B=2, C=3, p=0.09).

Conclusions:
In conclusion, transdural collaterals are present in nearly half of all moyamoya patients. They are more common in advanced disease, are associated with stroke as a perioperative complication and may suggest increased capacity to produce surgical collaterals postoperatively. These data support the utility of preoperative arteriograms.
Abstract T P234: Multiparametric Assessment of Longitudinal Changes in Tissue Microstructure in Normal and Abnormal Brain Tissue in Patients with Small Vessel Disease
Authors: Valdes-Hernandez Maria D , Armitage Paul A , Sakka Eleni , Munoz Maniega Susana , Royle Natalie A , Makin Stephen , Wardlaw Joanna M 
Published: July 2021

Background:
Volume measures of normal brain tissue and white matter hyperintensities (WMH) between two time points gives limited information about the complex dynamics of tissue change. We evaluated two quantitative parameters that characterise the microstructure of normal-appearing white matter (NAWM), deep grey matter (DGM) and WMH on brain images obtained at presentation with minor stroke and at 1 year to investigate the microstructural changes.

Methods:
From 182 brain MRI datasets of patients with minor stroke obtained at baseline and 1 year, we extracted the WMH, DGM and NAWM, and separated WMH into less-intense and intense WMH, using validated semi-automatic methods and validated criteria. We registered the binary structural masks to diffusion space and performed a voxel-wise subtraction of the combined masks at both time points. Then we measured fractional anisotropy (FA) and mean diffusivity (MD)(valuex10
-9
m
2
/s) in each tissue mask at baseline and 1 year.

Results:
WMH volume median increase was 1.4ml (IQR 6.98) mainly due to changes in less-intense WMH: 0.94ml (7.13). WMH that were visible at both time points, ie damage that remained after a year, had the lowest FA=

0.21(0.06) and highest MD=1.05(0.12) at baseline, and were mainly intense WMH at baseline (FA=0.12(0.03), MD=1.55(0.27)). WMH seen only at follow-up, ie that were NAWM at baseline, had the highest FA=0.30(0.06) and lowest MD=0.85 (0.06) at baseline. WMH that were observed only at baseline had intermediate
FA=0.26(0.08) and MD=0.90(0.10). NAWM FA=0.26(0.03), MD=0.78(0.04) and DGM
FA=0.23(0.03), MD=0.79(0.06) did not change between time points.

Conclusions:
WMH at baseline can partially evolve to normal-appearing tissues, remain or precede tissue loss. Differentiation between severe and subtle damage and spatial analysis are necessary to characterise the dynamic of

WMH evolution.