bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 225: Ischemic Cardiomyopathy Perturbs GSK-3β Myofilament Localization and Reduces Function
Authors: Stachowski Marisa J , Papadaki Maria , Martin Jody L , Moravec Christine S , Kirk Jonathan A 
Published: March 2022

In ischemic cardiomyopathy (ICM), regions with ischemic damage are weaker than surrounding tissue, leading to contractile heterogeneity (ischemia-induced dyssynchrony, IID) that worsens function and mortality. IID is distinct from conduction abnormality-induced dyssynchrony that is treated with Cardiac Resynchronization Therapy (CRT). Our previous work found CRT reactivates glycogen synthase kinase 3β (GSK-3β) and restores myofilament function. Pacing an infarct cannot strengthen it, so CRT is ineffective in IID. However, we hypothesized GSK-3β may modulate myofilament function in ICM and could be leveraged to treat IID.
We measured GSK-3β in whole tissue and myofilament-enriched samples from human rejected donor (Control), ICM, and dilated cardiomyopathy (no IID, DCM) LV. GSK-3β was detected in all the myofilament samples, but there was a 71±12% reduction in ICM. In whole tissue, there was very little phospho-Y216 GSK-3β, however it was highly enriched in the myofilament. Immunofluorescence on adult human myocytes showed weak co-localization of total GSK-3β and α-actinin at the z-disc compared to a strong correlation with p-Y216 GSK-3β. Furthermore, co-IP of GSK-3β and the myofilament show total GSK-3β had low-affinity to myofilament proteins, while p-Y216 GSK-3β binds with a high affinity. This led us to hypothesize Y216 phosphorylation modulates GSK-3β binding to the myofilament. To remove the confounding effect of antibodies, we created adenoviral constructs of myc-tagged wild-type, Y216F (unphosporylatable) and Y216E (constitutively phosphorylated) GSK-3β and transfected them into rat neonatal ventricular myocytes (NRVMs). The Y216E construct alone associated with the myofilament in co-IP experiments. We then performed skinned myocyte functional studies on human Control and ICM LV. The ICM myocytes were desensitized to calcium compared to Control and this was restored with exogenous GSK-3β treatment, but had no effect on Control myocytes.
While GSK-3β is a promiscuous kinase in the myocyte, we have identified a specific regulatory mechanism involving Y216 phosphorylation, a site with a largely unknown role, that could allow precise therapeutic intervention to improve contractile function in the ICM heart.
Abstract 387: Weighted Gene Co-Expression Network Analysis Identification and Experimental Validation of Genetic Determinants of Right Ventricular Function
Authors: Rau Christoph , Lee Katie , Chukwuneke Jeffrey , Liu Yanan , Li Qing , Wang Yibin , Tsai Emily J 
Published: March 2022

Right ventricular dysfunction (RVD) portends worse outcomes in chronic heart failure (HF), irrespective of left ventricular function. Despite the significance and prevalence of RVD, its molecular pathobiology is poorly understood. Gene networks can identify and explore complex relationships between genes, gene pathways, and phenotypes. We used weighted gene co-expression network analysis (WGNA) of human heart samples to identify genetic determinants of RV function and validated candidate genes in animal models of RV versus LV dysfunction.
We isolated and sequenced total RNA from explanted left and right ventricles of ischemic cardiomyopathy (ICM) patients (n=10) who underwent cardiac transplantation. Non-failing donor hearts that were declined for transplant were used as controls (n=5). Half the ICM patients had severe RV failure (RVF) based upon hemodynamic indices (mean±SEM) with mean RA 25.8±1.7 mmHg, RA:PCWP ratio 1.05±0.11, and PA pulsatility index 1.6±0.2.

Using direct gene membership comparison and z-score analysis, we found that more than half the modules in RV-specific networks are shared by combined RV-LV gene networks. We used principle component analysis to examine modules that correlated with RVF-related phenotypes. Two modules unique to the RV network identified selenium-binding protein gene
Selenbp1
as a potential driver of RVF. We also identified a strong association between anti-apoptotic gene
Mif
and vesicle fusion gene
Snap47
with RA:PCWP and PA pulsatility indices, suggesting potential important roles of these genes in RVF. Finally, peroxiredoxin 5
PRDX5
and E3 ubiquitin-protein ligase
SHPRH
were associated with protection against RVF. We sought to validate these candidate gene drivers of RV function in mouse models of RV versus LV-specific dysfunction induced by pulmonary artery banding (PAB) and transverse aortic constriction (TAC), respectively.
PRDX5
expression was markedly reduced in RV of PAB versus Sham but unchanged in LV of TAC versus Sham.
Selenbp1
was diminished in both RV of PAB and LV of TAC mice, relative to Sham. Expression of other candidate genes did not vary significantly with PAB or TAC. Our preliminary findings suggest that cardiac
PRDX5
may play an important role in regulating RV function.
18-Hydroxy-Deoxycorticosterone Secretion in Experimental Hypertension in Rats
Authors: RAPP JOHN P. , DAHL LEWIS K. 
Published: March 2022

Adrenal steroidogenesis was studied in vitro and in vivo in rats which have been specifically bred for susceptibility (S strain) or resistance (R strain) to the hypertensive effects of salt. A marked quantitative difference was found between S and R rats in the adrenal biosynthetic pathways which are subsequent to deoxycorticosterone (DOC). There was a twofold difference in the ability to 18-hydroxylate DOC to form 18-hydroxy-deoxycorticosterone (18OH-DOC) with the greater activity in the S rats. This increment in 18-hydroxylation of DOC in S over R rats was offset by an equal decrement in 11β-hydroxylation of DOC to form corticosterone (B) in S compared with R rats. These alterations in metabolic pathways gave rise to characteristic 18OH-DOC/B ratios for S and R animals that were obvious both in vitro and in vivo.
The data suggest, therefore, that in selectively breeding rats on the basis of blood pressure response to salt, a gene (or genes) which affects the 18OH-DOC/B ratio has been segregated in the S and R strains. Although this segregation is in itself good evidence for an effect of 18OH-DOC (or 18OH-DOC/B ratio) on blood pressure in rats, it was also emphasized that there is evidence for more than one gene affecting blood pressure in rats. Thus, the steroid difference described is likely to be controlled by only one of several genes affecting the quantitative character of blood pressure. Comparison of 18OH-DOC/B ratios in S and R strains with other strains of rats showed that the high ratio in S rats was quite common, but that the low ratio in R rats was rather unique. Thus, it seems that the low 18OH-DOC/B ratio of R animals connotes resistance to salt, while the higher ratio in S and unselected strains probably only connotes normal susceptibility to salt. The extreme sensitivity of S rats to salt must therefore be accounted for by other genes.
Abstract 3057: Increased rt-PA Utilization Will Decrease Healthcare Costs in SC
Authors: Kazley Abby S , Simpson Kit , Simpson Annie , Jauch Edward , Adams Robert 
Published: March 2022

Recombinant tissue plasminogen activator (rt-PA) has been approved for acute ischemic stroke (AIS) patients since 1996. An early (1998) paper reported net financial and health benefits from its use, but we are aware of no reports of economic impacts of rt-PA use in todays healthcare system. We used a Markov model to estimate the expected current economic and health benefits of rt-PA use for the state of South Carolina.
We compared expected cost for all stroke hospital admission for patients treated with rt-PA at the current rate (3%) of rt-PA use to the stroke costs if the treatment rate increased to 20% of all stroke admissions. We estimated total stroke costs for a five year time period (2012 through 2016). The Markov model used the original rt-PA trial data for estimation of expected outcomes based on the modified Rankin Scale (mRS) of disability at discharge. Health benefits are measured using quality-adjusted life years (QALYs), and the economic impacts are estimated cost to treat a patient based on cost for SC hospital discharges and other stroke care. Costs are reported in 2010 currency. Inflationary factors and economic discounting is not employed for the budget impacts reported here.Assumptions in the model include the rate of recurrent stroke (.052), rate of symptomatic hemorrhage after rt-PA (6.45%), the inclusion of charge for a two hour specialist fee during initial evaluation, patients discharged to a nursing home remain there until death, subsequent strokes do not receive rt-PA, those discharged from rehabilitation went to a nursing home. Patients were assumed to have a median age of 67 years at the time of the stroke. Cost of rt-PA was $2750 for 100mg. A CDC AIS-specific death rate was assumed.
We predicted a total cost of care for stroke in SC for 2012 through 2016 of $2,531,398,032 if rt-PA use continues at a rate of 3%. However, if the rate increases to 20% we will save $16,615,723 in stroke care cost over 5 years. Thus, given the current cost of AIS and the benefits documented for rt-PA treatment, concerted efforts to increase rt-PA use in SC may be expected to save money for payers in addition to improving quality of life for many stroke survivors.
Abstract 149: Endothelial NADPH Oxidase 4 Worsens Ischemic Stroke by Suppressing eNOS Activity
Authors: Arimura Koichi , Ago Tetsuro , Nishimura Ataru , Kuroda Junya , Sugimori Hiroshi , Kamouchi Masahiro , Sasaki Tomio , Kitazono Takanari 
Published: March 2022

NADPH oxidase (Nox) family proteins are a major source of reactive oxygen species (ROS) and play various important roles in immune systems, arteriosclerosis, angiogenesis and aging. We have previously demonstrated that among the Nox proteins, Nox4 is abundantly expressed and is a major source of ROS in endothelial cells; however, its roles in endothelial cells are not fully understood. In the present study, we investigated the roles of endothelial Nox4 in brain ischemia, using mice with endothelial cell-specific Nox4 overexpression (Tg-EC-Nox4) and cultured human brain microvascular endothelial cells (HMEC) overexpressing Nox4.
Nox4 was abundantly expressed and was significantly upregulated in response to hypoxia at O2 1% (2.0-fold increase, p<0.001) in HMEC. Immunofluorescent double staining demonstrated that in a middle cerebral occlusion model (MCAO) of wild type mice, Nox4 was markedly upregulated in endothelial cells in peri-infarct area. We subjected Tg-EC-Nox4 mice and their littermates to either transient (ischemia 90 min and reperfusion) or permanent MCAO. Triphenyltetrazolium chloride staining demonstrated that infarct volume at 1 day after MCAO was significantly larger in Tg-EC-Nox4 than wild-type mice in both the models (transient MCAO: 151 %, permanent MCAO: 132 %, p<0.05). We overexpressed Nox4 by adenovirus in HMEC. In the endothelial cells overexpressing Nox4, angiopoietin-2 (Ang-2) was drastically upregulated (30-fold increase, p<0.0001) at mRNA levels and the phosphorylation of Akt at Ser-473 (47 %, p<0.01) and endothelial nitric oxide synthase (eNOS) at Ser-1177 (43 %, p<0.01) were significantly attenuated. Treatment with Ang-2 suppressed the phosphorylation of Akt and eNOS induced by angiopoietin-1 in a dose-dependent manner in HMEC. Consistently, Ang-2 mRNA was significantly increased (2.0-fold, p<0.05), and the phosphorylation of Akt (37 %, p<0.05) and eNOS (41 %, p=0.12) were suppressed in the ischemic hemisphere of Tg-EC-Nox4, compared to those of wild-type mice. In conclusion, the overexpression of endothelial Nox4 may increase infarct volume by suppressing eNOS activity through the upregulation of Ang-2 in brain ischemia.
Abstract 211: GAMES (Glyburide Advantage in Malignant Edema and Stroke) Pilot Study
Authors: Sheth Kevin N , Kimberly W. T , Elm Jordan , Yarbrough Karen , O'Connor Sydney , Hammer Maxim , Kane April , Busl Katharina , Cole Terry , Yoo Albert J , Jacobson Sven , Stern Barney 
Published: March 2022

Introduction:
Malignant infarction is characterized by the formation of cerebral edema, and decompressive craniectomy (DC) is the only proven therapy. The NC (Ca-ATP) channel, regulated by the SUR1 receptor, is blocked by the sulfonylurea drug glyburide, which attenuates brain water content in preclinical models of large stroke. A phase I study has been safely completed. We assessed the hypothesis that a pilot study of RP-1127 (Glyburide for Injection) in patients at high risk for malignant infarction was safe and feasible.

Methods:
The objective of this four-center prospective, open label, phase IIa trial was to assess the safety and feasibility of treating severe anterior circulation ischemic stroke patients with RP-1127, whether or not treated with IV rtPA. The study enrolled patients with a baseline MRI DWI lesion between 82 cm3 and 210 cm3, age 18-80 years, and time from symptom onset to drug infusion of ≤ 10 hours. Patients received a RP-1127 bolus followed by continuous infusion for 72 hours.

Results:
Recruitment of 10 patients was completed within 9.6 months. The mean initial DWI lesion volume was 102 ± 23 cm3. There were no serious adverse events related to the drug. The incidence of malignant edema was 20%, compared to 88% in a prospective observational study with DWI ≥82 cm3. Further, 8/10 patients did not require any bolus osmotherapy or DC. The mean increase in ipsilateral hemisphere volume was 50±33 cm3 compared to historical controls of 71.5±27 cm3. The proportion of 30 day mRS ≤ 4 was 90% compared to 23.8% (at 12 months) in control patients from a pooled analysis of DC trials.

Conclusions:
These findings suggest that a Phase II trial for patients at risk of malignant infarction is feasible and will provide important insights into the safety and potential efficacy of RP-1127.
Abstract 212: Estrogen Protects against Aneurysmal Rupture Through Estrogen Receptor-beta in Ovariectomized Mice
Authors: Tada Yoshiteru ,   The Univ of Tokushima, Wada Kosuke , Makino Hiroshi , Liang Elena I , Murakami Shoko , Kudo Mari , Shimada Kenji ,   The Univ of Tokushima, Kitazato Keiko T ,   The Univ of Tokushima, Nagahiro Shinji , Hashimoto Tomoki 
Published: March 2022

Introduction
Epidemiological studies suggest that estrogen has protective effects against the formation and rupture of intracranial aneurysms. Post-menopausal women are at a higher risk for aneurysmal rupture. In our mouse model of intracranial aneurysms, aneurysmal rupture occurs at a high incidence and results in neurological symptoms. We hypothesized that estrogen or stimulation of estrogen receptors (ERs) is protective against aneurysmal rupture in ovariectomized female mice. We also sought to determine the role of ER subtypes on aneurysmal rupture.

Methods
All female mice received bilateral ovariectomy. Intracranial aneurysms were induced using a combination of a single injection of elastase into the cerebrospinal fluid and deoxycorticosterone acetate (DOCA) salt hypertension. Six days after aneurysm induction, we started 2-week treatment with vehicle (n=19), 17β-estradiol (n=17) with (n=14) or without ER antagonist, ERα agonist (n=12), or ERβ agonist (n=15). Nitric oxide synthase (NOS) inhibitor (L-NAME, n=15) was used to determine roles of NOS in ER mediated prevention of aneurysmal rupture. Aneurysmal rupture was detected by neurological symptoms.

Results
17β-estradiol (E2) reduced rupture rates in ovariectomized female mice (P < 0.05). ER antagonist reversed the protective effect of E2 on the aneurysmal rupture (P < 0.05). While ERα agonist did not prevent aneurysmal rupture, ERβ agonist reduced the rupture rate (P < 0.05). Inhibition of NOS by L-NAME abolished the protective effects of ERβ agonist on aneurysmal rupture (P < 0.05) (Figure).

Conclusion
These findings suggest that estrogen protects against aneurysmal rupture through ERβ activation. In addition, the protective effect of estrogen through ERβ is dependent on NOS. ERβ an NOS may be used as therapeutic targets for the prevention of aneurysmal rupture in post-menopausal women
Abstract 213: The Probability of Ischemic Stroke Therapeutic Targets at Extended Time Windows
Authors: Warach Steven , Luby Marie , Davis Lisa A , Merino José G , Hsia Amie W , Jesser Christine , Robertson Henry T , Latour Lawrence L 
Published: March 2022

BACKGROUND.
A contributing factor in the decreased efficacy of thrombolysis over time may be a decrease in the probability of the therapeutic target, but this has not been well studied. Detection of therapeutic targets beyond 4.5 hr is the premise for reperfusion trials at extended time windows. We quantified the relationship of time from onset to the probability of detection of therapeutic targets.

METHODS.
We analyzed a consecutive series of 1103 ischemic stroke patients with NIHSS > 3 and an MRI within 24 hr from last known well. Potential therapeutic targets were occlusion on MRA (ARTERY), M1 or M2 occlusion (MCAO), focal ischemia on perfusion MRI (PERFUSION), and diffusion-perfusion mismatch (MISMATCH). Logistic regression models evaluated hours from onset, NIHSS, age, and sex as predictors of target.

RESULTS.
ARTERY, PERFUSION, and MISMATCH probabilities decreased over time (p < 0.0001) at approximately 1% per hour. More severe strokes increased the probability of detection by about 1% per NIHSS point. Logistic regression model found significant relationships of MISMATCH to hours, NIHSS, MCAO, and the interaction of NIHSS X MCAO (Table). MCAO patients had higher probabilities of MISMATCH, which decreased more rapidly over time (Graph). The probability of MISMATCH can be estimated by the logistic regression model: e.g., MCAO and NIHSS 12 at 9 hr = 78%; MCAO and NIHSS 14 at 20 hr = 47%.

CONCLUSION.
The probability of potential targets of reperfusion therapy declines over the first 24 hours from stroke onset. A substantial proportion of patients have a target beyond the proven time window for thrombolytic therapy, and the proportion can be estimated by the logistic regression model.
Abstract 53: Cerebral Hemodynamic Changes in Patients with Wartime Traumatic Brain Unjury
Authors: Razumovsky Alexander , Tigno Teodore , Kouperberg Efim , Bell Randy , Severson Meryl V , Hochheimer Sven M , Marshall Scott A , Aden James , Oppenheimer Stephen M , Ecker Robert , Armonda Rocco A 
Published: March 2022

Cerebral vasospasm (VSP) is a frequent complication after aneurysmal and traumatic subarachnoid hemorrhage (SAH) and carries significant morbidity and mortality. Traumatic brain injury (TBI) is associated with the severest casualties from Operation Iraqi Freedom and Operation Enduring Freedom. From Oct. 1, 2008 the US Army Medical Department initiated a transcranial Doppler (TCD) ultrasound service for TBI; included patients were retrospectively evaluated for TCD-determined incidence of posttraumatic cerebral vasospasm and intracranial hypertension after wartime TBI.
Patients were identified using a computerized registry and a prospective TCD database maintained in the Sentient NeuroCare Services. TCD recordings of mean cerebral blood flow velocities (CBFV) and Pulsatility Indices of the anterior and posterior circulation vessels were recorded using a 2-MHz transducer (Doppler Box, DWL/Compumedics, USA, Germany/Australia). Comprehensive TCD protocol was applied in all cases: if mean CBFV equaled or exceeded 100 cm/sec., 140 cm.sec and 200 cm/sec the TCD signs of mild vasospasm, moderate vasospasm and severe vasospasm respectively were considered present. 122 patients were investigated with daily TCD studies and comprehensive TCD protocol and published diagnostic criteria for VSP and raised intracranial pressure (ICP) were applied. TCD signs of mild, moderate and severe VSP involving anterior circulation vessels were observed in 71%, 42% and 16% of patients, respectively. TCD signs of mild, moderate and severe VSP involving posterior circulation vessels were observed in 57%, 32% and 14% of patients, respectively. TCD signs of intracranial hypertension were recorded in 43%, eight patients (7%) underwent transluminal angioplasty for post-traumatic symptomatic vasospasm treatment. These findings demonstrate that cerebral arterial VSP and intracranial hypertension are frequent and significant complications of combat TBI, therefore daily TCD monitoring is recommended for their recognition and subsequent management.

Acknowledgements.
The opinions and views expressed herein belong solely to those of the authors. They are not nor should they be implied as being endorsed by the Uniformed Services University of the Health Sciences, Department of the Army, Department of the Navy, Department of Defense or any other branch of the Federal government of the United States. This paper supported in part, by the US Army Medical Research and Material Command’s Telemedicine and Advanced Technology Research Center (Fort Detrick, MD, USA).
Abstract TMP10: A 4D Patient-specific Metamorphosis-based Method to Model Ischemic Stroke Lesion Evolution from Acute Diffusion-weighted to Final T2-defined Outcome
Authors: Rekik Islem , Allassonnière Stéphanie , Carpenter Trevor K , Wardlaw Joanna M 
Published: March 2022

There is considerable interest in how well acute DWI can predict the infarct on final T2-w imaging at >1month after stroke. We estimated the 4D dynamic change, from the acute DWI to the final T2-w lesion, to assess DWI predictive ability. Our model dynamically simulates the evolution of uni- or multi-component lesions.
We applied a 4D metamorphosis, modeling the morphogenesis of the acute (<6hr) DWI lesion boundary into that of the final (90 day) T2-w in 10 representative patients, dividing the 90 days into 10 equal intervals. We estimated the mean contraction and expansion deformation velocities that drive change in the acute DWI to the final T2-w boundary, focusing on areas where the DWI volume differed from the final T2-w volume (DWI\T2).
In DWI\T2, over the 10 patients, time-evolving contraction velocity values show a rapid decrease from 0.206+/-0.0091 (mean over time, mm/9days +/- sd) to 0.00097+/-0.001 with time, indicating that contracting DWI\T2 areas were very dynamic acutely and rapidly slowed. Expansion areas displayed a rapid and quasi-monotonic fall from 0.025+/-0.01 to 0.00075+/-0.00028 showing that some parts of DWI tissue had an early high expansion velocity which slowed with time, leading to appearance of newly infarcted areas not present in the acute DWI. A high correlation index (r=0.72, p<0.001) between contraction (also expansion) velocity curves of all patients shows that the 4D evolution patterns of DWI\T2 were similar between patients.
Our imaging derived 4D model of acute DWI-final T2-W lesion evolution shows a consistent pattern, with both ‘recovery’ and ‘new’ infarct happening rapidly at early time points. This confirms that a) acute DWI lesion includes salvageable tissue and is not all statically dead, b) acute DWI lesion does not include all final T2-w dead tissue and c) the method can accurately assess and quantify early treatment response, eg in clinical trials.