bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluating Urine Cytology Slide Digitization Efficiency: A Comparative Study Using an Artificial Intelligence-Based Heuristic Scanning Simulation and Multiple Z-Plane Scanning
Authors: Hang Jen-Fan , Ou Yen-Chuan , Yang Wei-Lei , Tsao Tang-Yi , Yeh Cheng-Hung , Li Chi-Bin , Hsu En-Yu , Hung Po-Yen , Lin Ming-Yu , Hwang Yi-Ting , Liu Tien-Jen , Tung Min-Che
Published: April 2024

Introduction: Digitizing cytology slides presents challenges because of their three-dimensional features and uneven cell distribution. While multi-Z-plane scan is a prevalent solution, its adoption in clinical digital cytopathology is hindered by prolonged scanning times, increased image file sizes, and the requirement for cytopathologists to review multiple Z-plane images. Methods: This study presents heuristic scan as a novel solution, using an artificial intelligence (AI)-based approach specifically designed for cytology slide scanning as an alternative to the multi-Z-plane scan. Both the 21 Z-plane scan and the heuristic scan simulation methods were used on 52 urine cytology slides from three distinct cytopreparations (Cytospin, ThinPrep, and BD CytoRich™ [SurePath]), generating whole-slide images (WSIs) via the Leica Aperio AT2 digital scanner. The AI algorithm inferred the WSI from 21 Z-planes to quantitate the total number of suspicious for high-grade urothelial carcinoma or more severe cells (SHGUC+) cells. The heuristic scan simulation calculated the total number of SHGUC+ cells from the 21 Z-plane scan data. Performance metrics including SHGUC+ cell coverage rates (calculated by dividing the number of SHGUC+ cells identified in multiple Z-planes or heuristic scan simulation by the total SHGUC+ cells in the 21 Z-planes for each WSI), scanning time, and file size were analyzed to compare the performance of each scanning method. The heuristic scan's metrics were linearly estimated from the 21 Z-plane scan data. Additionally, AI-aided interpretations of WSIs with scant SHGUC+ cells followed The Paris System guidelines and were compared with original diagnoses. Results: The heuristic scan achieved median SHGUC+ cell coverage rates similar to 5 Z-plane scans across three cytopreparations (0.78–0.91 vs. 0.75–0.88, p = 0.451–0.578). Notably, it substantially reduced both scanning time (137.2–635.0 s vs. 332.6–1,278.8 s, p < 0.05) and image file size (0.51–2.10 GB vs. 1.16–3.10 GB, p < 0.05). Importantly, the heuristic scan yielded higher rates of accurate AI-aided interpretations compared to the single Z-plane scan (62.5% vs. 37.5%). Conclusion: We demonstrated that the heuristic scan offers a cost-effective alternative to the conventional multi-Z-plane scan in digital cytopathology. It achieves comparable SHGUC+ cell capture rates while reducing both scanning time and image file size, promising to aid digital urine cytology interpretations with a higher accuracy rate compared to the conventional single (optimal) plane scan. Further studies are needed to assess the integration of this new technology into compatible digital scanners for practical cytology slide scanning.
Trachyderini (Coleoptera, Cerambycidae): sinonimias, observações, espécies novas
Authors: Monné Miguel A. , Martins Ubirajara R.
Published: April 2024

.
Capilarização superficial de Rhinodrilus Alatus Ríghi, 1971 (Oligochaeta, Glossoscolecidae)
Authors: Höfling Elizabeth
Published: April 2024

.
Herpetofauna das dunas interiores do Rio São Francisco, Bahia, Brasil. III. Procellosaurinus: um novo gênero de Microtehdeos sem palpebra, com a redefinição do gênero Gymnophthalmus (Sauria, Teiidae).
Authors: Rodrigues Miguel Trefaut
Published: April 2024

.
Herpetofauna das dunas interiores do Rio São Francisco, Bahia, Brasil. IV. Uma nova espécie de Typhlops (Ophidia, Typhlopidae)
Authors: Rodrigues Miguel Trefaut
Published: April 2024

.
Ocorrências e conservação de baleias-francas-do-sul, Eubalaena Austraus, no Litoral do Brasil
Authors: Lodi Liliane , Siciliano Salvatore , Bellini Claudio
Published: April 2024

.
Revisão das espécies Sul-Americanas do Gênero Itumbiara Martins e Galileo, 1992 (Coleoptera, Cerambycidae, Lamiinae, Hemilophini)
Authors: Galileo Maria Helena M. , Martins Ubirajara R.
Published: April 2024

The South american species of the genus Itumbiara are revised and keyed. I. cuici, sp. n., is described from Brazil (Santa Catarina).
Chave ilustrada para identificação dos Gêneros de Cupins (Insecta: Isoptera) que ocorrem no Brasil
Authors: Constantino Reginaldo
Published: April 2024

.
Processos crimes: o universo das relações pessoais
Authors: Lara Sílvia Hunold
Published: April 2024

This paper intends to show that the crime process analyses offers many possibilities to study the daily personal aspects of domination an explotation in colonial Brazil, with special reference to the slave-master relationship.
Uma gazeta manuscrita no Brasil colonial?
Authors: Ferlini Vera Lúcia Amaral
Published: April 2024

This paper deals with a commentary and lecture of the manuscript entitled “Gazeta de Pernambuco”.
Abstract 4172: Direct Effects of 5-methyl-tetrahydrofolate on Vascular Endothelium And Superoxide Production In Human Arteries And Veins
Authors: Antoniades Charalambos , Shirodaria Cheerag , Warrick Nicolas , Cai Shijie , Leeson Paul , Taggart David , Ratnatunga Chandi , Pillai Ravi , Channon Keith
Published: April 2024

Background:
5-methyltetrahydrofolate (5MTHF), the circulating form of folic acid, reduces plasma homocysteine, but its direct effects on vascular function are unclear. We evaluated the direct effect of 5MTHF on endothelial function and superoxide (O
2
-) production in saphenous veins (SV) and internal mammary arteries (IMA) of patients undergoing CABG.

Methods:
Vasomotor responses to acetylcholine (ACh) were evaluated
ex-vivo
in vessel segments from 35 patients at baseline and after 45 minutes incubation with 5MTHF 0, 1, 10 and 100 μM. Vascular O
2
- was measured by lucigenin chemiluminescence in paired samples of SV and IMA after incubation with 5MTHF 0, 1 10 and 100 μM. The direct O
2
-scavenging capacity of 5MTHF was quantified using a xanthine/xanthine oxidase system, in comparison with vitamin C as positive control.

Results.
All the concentrations of 5MTHF similarly improved the vasomotor responses of SV to ACh (Fig a

). Whereas 5MTHF at high concentrations (100 μM) had direct O
2
- scavenging effect, no direct scavenging was observed with concentrations <10μM (Fig b

). Vitamin C was a direct O
2
- scavenger even at 1μM (Fig b

). 5MTHF decreased O
2
- in both SV and IMA (Fig c

) compared to control, although there was no difference in O
2
- production between vessels exposed to 1, 10 and 100μΜ5MTHF.

Conclusions.
5MTHF rapidly improves endothelial function and decreases O
2
- production in vessels from patients with CAD, by a mechanism other than the direct scavenging of O
2
- radicals. These data suggest that 5MTHF may have a direct effect on vascular function by modifying intracellular redox and improving NO bioavailability in human vessels.
Abstract 588: Attenuation of Flow- and Nitrate-mediated Vasodilation in End-stage Renal Disease by Inflammation, Hyperphosphatemia and Hyperparathyroidism: Correction with Fall in C-reactive Protein by Nocturnal Hemodialysis
Authors: Chan Christopher , Harvey Paula , Pierratos Andreas , Floras John S
Published: April 2024

Background: Endothelium-dependent vasodilation (EDV) and endothelium-independent vasodilation (EIV) are impaired in end-stage renal disease (ESRD), yet improve soon after conversion from conventional (CHD) to nocturnal hemodialysis (NHD).

Methods and Results: To test the hypotheses that suppression of inflammation and correction of hyperphosphatemia contribute to such improvement, dialysis dose, blood pressure (BP), brachial artery EDV and EIV, plasma C reactive protein (CRP), phosphate (Pi) and parathyroid hormone (PTH) were determined before, 1 and 2 months after conversion to NHD (n=23; mean age: 43±2 years [mean±SEM]). NHD increased dialysis dose, EDV and EIV (all p<0.05) and lowered simultaneously measured BP, Pi and PTH (all p<0.05) and CRP (from 14.8±3.9 to 6.63±2.1 mg/L after 2 months, p<0.01). Overall, there was a significant inverse relationship between EDV and log
10
CRP (r=−0.35, p=0.008). Pre-specified dichotomization by CHD Pi identified higher BP with Pi <1.8mM (n=10): (147±10/87±7 vs. 131±4/75±2 mmHg, p<0.01), yet after 1 month both groups were normotensive. In those with Pi <1.8mM, 1 month of NHD lowered CRP and increased EDV from −2.4±2.4 to 7.5±1.8% (p<0.05). In contrast, in the high Pi group, NHD lowered Pi (p<0.05) but had no significant effect on CRP, PTH or EDV (−0.8±1.1 vs. −0.6±1.6 %) but after 2 months, Pi and PTH fell and EDV and EIV improved.

Conclusions: Correction of uremia and hypertension alone does not improve endothelial and smooth muscle brachial artery dilation in ESRD; contributions of systemic inflammation, altered Pi balance and hyperparathyroidism to impaired EDV and EIV must also be addressed. We provide the first demonstration that NHD reduces CRP.
Abstract 605: ERK5 Activation Regulates PPARalpha Activity and Subsequent Cardioprotection After Ischemia/Reperfusion
Authors: Ding Bo , Yan Chen , Liu Weiming , Shishido Tetsuro , Woo Chang Hoon , McClain Carolyn , Abe Jun-Ichi
Published: April 2024

Background: The strong cardioprotective effect of erythropoietin (EPO) and heme oxygenase-1 (HO-1) have been reported, but the mechanism are not understood. Previously we found that activation of big MAP kinase 1 (BMK1/ERK5) inhibits cardiac injury after myocardial ischemia and reperfusion. The hinge-helix 1 region of peroxisome proliferator-activated receptor gamma1 (PPARgamma1) mediates interaction with extra-cellular signal-regulated kinase 5(ERK5). We hypothesize that ERK5 activation induced by insulin growth factor-1(IGF-1), erythropoietin(EPO) and heme oxygenase-1(HO-1) is a “key modulator” of PPARa activity and provides a cardioprotective effect after I/R. Thus the aim of this study was to explore the mechanism of the protective effect of EPO, HO-1 and IGF-1 via ERK5 activation.

Method and Results: We have found that EPO, HO-1 and IGF-1 stimulate ERK5 activation in the heart, and increase PPARa activity via an ERK5 dependent manner. To prove the role of ERK5 kinase/PPARa activation in IGF-1, EPO and HO-1 mediated cardioprotection after I/R, we characterized the unique role of ERK5 in IGF-1, EPO and HO-1-mediated PPARa activation. In cardiomyocytes, IGF-1, EPO and HO-1 mediate endogenous ERK5 association with endogenous PPARa but not phosphorylation of the PPARa. Activation of ERK5 by Ad-CA-MEK5a trigged the induction of mCPT-1 and PDK4, which promote fatty acid beta-oxidation (FAO) enzyme pathway via increasing PPARa transcriptional activation. Also we found that increased apoptosis in cardiomyocytes incubated by H2O2 compared to non-treated group( 3– 4 times increase H2O2 group vs. wildtype group). However HO-1 induction, EPO and IGF-1 treatment blocked the increased apoptosis induced by H2O2 stimulation. To determine the role of ERK5 kinase in EPO-mediated cardioprotection in vivo, we used the I/R mouse model in CA-MEK5a transgenic mice. Our preliminary experiments suggest a smaller infarction size in CA-MEK5a transgenic mice hearts compared to control hearts.

Conclusion: We propose a key role for PPARa and subsequent activation of FAO enzyme induced by EPO and HO-1 mediated cardioprotection. These factors are induced by ERK5 activation. These data suggest that ERK5 is a critical factor and therefore a future therapeutic target.
Abstract 606: Myocardial Protection by Glycogen Synthase Kinase-3β Inhibition during Resuscitation from Cardiac Arrest
Authors: Radhakrishnan Jeejabai , Ayoub Iyad M , Wang Sufen , Kolarova Julieta D , Taglieri Domenico M , Gazmuri Raúl J
Published: April 2024

Background:
GSK-3β functions as a “master switch” that is negatively regulated by various cardioprotective mechanisms. GSK-3β is upregulated by tyrosine 216 phosphorylation (P-Y216) and downregulated by serine 9 phosphorylation (P-S9). We investigated whether modulation of GSK-3β phosphorylation occurs during cardiac resuscitation and whether pharmacological GSK-3β inhibition improves post-resuscitation (PR) myocardial function.

Methods:
Three groups of two rats each were randomized to 8 mins of untreated VF followed by 8 mins of closed-chest resuscitation and defibrillation or to sham intervention. Rats subjected to VF received a 0.6 mg/kg bolus of the GSK-3β inhibitor SB216763 (SB21) or 0.9% NaCl before chest compression. Hearts were harvested at 10 mins PR.

Results:
Western blots with corresponding densitometries indexed to total GSK-3β are shown in Figure

. P-S9 increased in control rats (
p
= 0.052
vs
sham) and further increased in SB21-treated rats (
p
= 0.024
vs
sham). SB21 lessened PR myocardial dysfunction yielding significantly higher mean aortic pressure (109 ± 7
vs
79 ± 2 mmHg;
p
< 0.05) with numerically higher +dP/dt
max
(5.1 ± 7
vs
3.5 ± 0.2 mmHg/sec x 10
3
), cardiac index (108 ± 59
vs
76 ± 28 ml/min/kg) and left ventricular stroke work index (0.58 ± 0.24
vs
0.32 ± 0.11 mmHg x ml/kg).

Conclusions:
Increased P-S9 independent of P-Y216 suggests activation of endogenous protective pathways that may downregulate GSK-3β activity. Pharmacological inhibition of GSK-3β further increased serine 9 phosphorylation state and lessened post-resuscitation myocardial dysfunction. Thus, GSK-3β may represent an important target for myocardial protection during resuscitation.
Mean Platelet Volume and Prevalence of Peripheral Artery Disease
Authors: Berger Jeffrey S
Published: April 2024

Abstract #2371

Jeffrey S Berger, Luis H Eraso, Dawei Xie, Daohang Sha, Emile R Mohler III, Univ of Pennsylvania, Philadelphia, PA

Jeffrey S Berger, 2009 Finalist and Presenting Author
Duffy Antigen Receptor for Chemokines (Darc) Polymorphism Regulates Circulating Concentrations of Monocyte Chemoattractant Protein-1 and Other Circulating Inflammatory Mediators
Authors: Schnabel Renate B.
Published: April 2024

Abstract #1808

Renate B. Schnabel, Johannes Gutenberg Univ, Mainz, Germany; Jens Baumert, Helmholtz Zentrum München, German Res Ctr for Environmental Health, Neuherberg, Germany; Maja Barbalic, Human Genetics Ctr and Inst of Molecular Med, Univ of Texas Health Science Ctr, Houston, TX; Josée Dupuis, Dept of Biostatistics, Boston Univ Sch of Public Health, Boston, MA; Patrick T. Ellinor, Cardiovascular Res Ctr, Massachusetts General Hosp, Boston, MA; Peter Durda, Dept of Pathology, Univ of Vermont Coll of Med, Burlington, VT; Abbas Dehghan, Dept of Epidemiology, Erasmus Medical Ctr, Rotterdam, Netherlands; Joshua C. Bis, Dept of Med, Univ of Washington, Seattle, WA; Jacqueline C. Witteman, Dept of Epidemiology, Erasmus Medical Ctr, Rotterdam, Netherlands; Ron C. Hoogeveen, Human Genetics Ctr and Inst of Molecular Med, Univ of Texas Health Science Ctr, Houston, TX; Emelia J. Benjamin, Natl Heart, Lung, and Blood Inst’s and Boston Univ’s Framingham Heart Study, Framingham, MA; Wolfgang Koenig, Dept of Internal Med II –Cardiology, Univ of Ulm Medical Ctr, Ulm, Germany; Russell P. Tracy, Dept of Biochemistry, Univ of Vermont Coll of Med, Burlington, VT; CHARGE Consortium

Renate B. Schnabel, 2009 Finalist and Presenting Author
Abstract 4886: Hydrogen Peroxide Prevents Impaired Endothelium-dependent Dilation Following Acute Exertion in Chronic Exercising but Not in Sedentary Subjects
Authors: Phillips Shane A , Bian Jing-Tan , Church Emily C , Das Emon K , Vidovich Mladen , Gutterman David D
Published: April 2024

Introduction:
Exercise-induced hypertension increases reactive oxygen species (ROS) generation and threatens vascular endothelial health. Recent studies indicate conditioned subjects (EX) are protected from endothelial dysfunction observed in sedentary (SED) subjects after acute hypertension induced by weight lifting (WL).

Hypothesis:
We hypothesized that:

chronic exercise protects against endothelial dysfunction induced by acute exertion and

the mechanism of maintained dilation after acute hypertension involves hydrogen peroxide (H
2
O
2
) in microvessels from exercise trained subjects.

Methods:
Healthy, lean SED and EX subjects (runners > 15 miles/week or WL > 3x/week), underwent a single progressive 15 minute leg press WL session. Brachial artery flow- mediated dilation (FMD) and nitroglycerin (NTG; 0.4 mg) dilations were measured with ultrasound. Isolated arterioles (gluteal fad pad biopsies) from the same subjects were cannulated to assess dilation to acetylcholine (ACh; 10
−9
–10
−4
M) pre and post WL. Separately, H
2
O
2
production was assessed with DCF fluorescence.

Results:
All subjects were free of hypertension with similar blood pressure responses to WL (max SBP: 183.7±5 mmHg). Brachial artery FMD was maintained after WL in EX (+2.0±0.3%; p<0.001 vs. SED; n=48) but not SED (−3.0±0.2%; n = 28). Dilation to ACh was maintained in EX [Max dilation (MD): 87±3 %; n = 10] but not SED (50±5%; n = 10) post WL. Inhibition of NOS with LNAME eliminated baseline ACh dilation in EX but not post WL (73±6%). Indomethacin and 17-ODYA had no effect on post WL ACh responses. In EX subjects, WL increased hydrogen peroxide (DCF fluorescence ratio: 3.4±0.4; p = 0.001 vs. baseline; n = 9). The H
2
O
2
scavenger PEG-catalase (500 U/ml) reduced DCF fluorescence and ACh dilation post WL (29±7%; p<0.001 vs. pre WL) but had no effect before WL. Endothelium-independent responses to papaverine were similar pre and post WL. In conclusion, these data indicate

chronic exercise protects against microvascular endothelial dysfunction after exertion and

although NOS is responsible for ACh dilation before acute weight lifting in EX, H
2
O
2
maintains endothelium-dependent dilation in microvessels after exposure to exercise-induced hypertension.
Abstract 5038: Enhanced Endothelial-specific Insulin Sensitivity Regulates Whole Body Glucose Homeostasis and Endothelial Function
Authors: Gage Matthew , Wheatcroft Stephen , Abbas Afroze , Imrie Helen , Cubbon Richard , Surr Jessica , Dubois Eleonore , Jacoby Monique , Schurmans Stephane , Kearney Mark
Published: April 2024

Accumulating evidence now suggests that insulin resistance may promote atherosclerosis through a closely coupled association with endothelial dysfunction, and that the relationship between insulin resistance and endothelial function is reciprocal. However the role of the endothelium in whole body glucose regulation until now has remained unclear. SHIP2 is a lipid phosphatase which acts as a negative regulator of insulin signalling. In this study Cre-Lox technology is used to generate an endothelial-specific SHIP2 haploinsuffient mouse, as a model of enhanced endothelial-specific insulin sensitivity. We have investigated both the metabolic and vascular phenotype of this model to determine whether enhanced insulin signalling in endothelium modulates vascular function and whole body glucose regulation. Results described are from male EC-SHIP2
+/−
offspring compared with control sex-matched littermates at 12–16 weeks of age. EC-SHIP
+/−
mice were morphologically indistinguishable from control littermates, exhibited normal development and body and organ masses were similar in both groups. No significant differences were observed in heart rate or blood pressure. Glucose tolerance after glucose challenge was found to be significantly better in EC-SHIP
+/−
than controls (p = <0.05), with no differences in plasma insulin concentrations; fasted or after glucose challenge. Improved insulin sensitivity was confirmed in EC-SHIP
+/−
mice in insulin tolerance tests (p = <0.05). e
x vivo
vasomotor studies in aorta revealed no significant differences between EC-SHIP
+/−
and controls in contractile responses to phenylephrine or maximal relaxation to sodium nitroprusside and ACh. However, basal phosphorylation of eNOS (Ser-1177) was greater in EC-SHIP
+/−
aorta than controls. In conclusion; the results suggest endothelial partial deletion of SHIP2 confers important effects on metabolic homeostasis and endothelial function. In particular, improved glucose tolerance and insulin sensitivity in EC-SHIP
+/−
mice support a critical role for insulin signalling in endothelial cells in whole body glucose regulation.
Abstract 5041: Insulin Resistance Reduces Circulating Endothelial Progenitor Cells and Impairs Endothelial Regeneration Following Wire-induced Vascular Injury
Authors: Kahn Matthew B , Cubbon Richard , Visvambharan Hema , Yuldasheva Nadira , Kearney Mark T , Wheatcroft Stephen
Published: April 2024

Introduction: Endothelial progenitor cells (EPCs) contribute to endothelial regeneration following damage accrued through exposure to various risk factors. Type 2 diabetes is associated with reduced EPC numbers, EPC dysfunction and delayed endothelial repair. However, it remains unknown whether insulin resistance per se has an effect on EPCs or endothelial regeneration.

Methods: We assessed metabolic and endothelial function, circulating, spleen- and bone marrow-derived EPCs and endothelial regeneration following wire-injury in mice hemizygous for deletion of the insulin receptor (IR+/−) and their littermate wild type (WT) controls. Results: The metabolic phenotype of IR+/− mice was consistent with compensated insulin resistance, with hyperinsulinaemia after a glucose challenge but a normal blood glucose response to a glucose tolerance test. Endothelial function was impaired in aorta from IR+/− mice, with decreased basal nitric oxide production and blunted eNOS activity in response to insulin. Sca-1/VEGFR-2 positive EPCs, measured in peripheral blood by flow cytometry, were reduced in IR+/− mice compared to WT controls (67±6 vs 87±6 cells/100 000 events; P<0.05). Culture of mononuclear cells from peripheral blood, spleen and bone marrow revealed significantly reduced numbers of circulating EPCs in IR+/− mice compared to WT controls (P<0.05), however there was no difference in the number of spleen- and bone marrow-derived EPCs. Endothelial regeneration, assessed by Evan’s blue staining of femoral artery at intervals following denuding wire-injury, was significantly delayed in IR+/− mice compared to WT controls (reendothelialised area 35.8±4.8% vs 66.6±5.2% at day 5 following injury and 35.6±4.8% vs 59.8±6.6% at day 7 following injury; P<0.05).

Conclusions: These novel data demonstrate that mild insulin resistance reduces the number of basal circulating EPCs and delays endothelial regeneration following injury. The findings support the hypothesis that insulin resistance may promote atherosclerosis by adversely affecting the balance between endothelial damage and repair.
Abstract 5069: Loss of MHC Class II Transactivator Causes Abdominal Aortic Aneurysm
Authors: Shimizu Koichi , Asami Yukiko , Folco Eduardo J , Tang Hoi Ching , Shubiki Rica , Libby Peter
Published: April 2024

Th1 and/or Th2 cytokines produced by inflammatory cells may influence the outcome of arterial inflammation. Indeed, Th2 type cytokines predominate in human abdominal aortic aneurysm (AAA) lesions, while cells in stenotic atherosclerotic lesions preferentially express Th1 cytokines. The major histocompatibility complex (MHC) class II transactivator (C2ta) is a transcriptional co-activator responsible for IFN
γ
-inducible MHC class II expression on antigen-presenting cells. C2ta can also modulate IL-4 and MMPs. This study tested the hypothesis that C2ta deficiency could induce MMP expression and cause aortic aneurysm formation in atherogenic animals. Results: Real-time quantitative PCR and Western blot demonstrated that human AAA tissues express significantly less C2ta mRNA and lower HLA-DR protein levels than the atherosclerotic aortic tissue. In addition, human AAA tissues express significantly elevated MMP9 and MMP12 protein levels. 12-week-old male ApoE−/− and ApoE/C2ta−/− mice consumed a 1.25% cholesterol diet up to 8M. The abdominal aortic diameter below the renal artery branches of ApoE/C2ta−/− mice increased at 8M compared to the ApoE−/− mice (1.68±0.28 vs. 0.90±0.10 mm, mean± SD, p < 0.0001). The morphological analysis of the ApoE/C2ta−/− mice fed with 8M atherogenic diet showed fragmentation of the medial elastic lamellae and expanded luminal area, characterizing aortic aneurysm. ApoE/C2ta−/− mice had higher plasma levels of IL-4 and IL-10 (4.9±3.0 and 114.2±75.5 ng/mL, mean±SD, n=10) than ApoE−/− mice (1.9±2.2, p=0.0057; and 29.9±24.1 ng/mL, p=0.0062, respectively) after 8M on an atherogenic diet. Western blot and zymography showed significantly higher expression and activity of MMP9 and MMP12 in the aortic lesions of the ApoE/c2ta−/− compared to those of the ApoE−/− mice at 6M high-cholesterol diet. The aortic diameter of the triple deficient animals of ApoE/C2ta/MMP9 −/− and ApoE/C2ta/MMP12 −/− did not increase even after 8M on an atherogenic diet (0.76±0.21 mm, mean± SD, n=10; 0.68±0.10 mm, n=10, p <0.0001 vs. ApoE/C2ta−/−). Conclusion: This study illustrates a novel mechanism for Th2 dominant cytokine milieu in a subset of patients with aortic atherosclerosis and how impaired signaling of C2ta and IFN-
γ
promote AAA formation.

This research has received full or partial funding support from the American Heart Association, National Center.
Abstract 5088: Exercise Training Increases Endothelial Progenitor Cells and Decreases Asymmetrical Dimethylarginine in Patients With Intermittent Claudication
Authors: Schlager Oliver , Giurgea Aura , Schuhfried Othmar , Gschwandtner Michael , Koppensteiner Renate , Steiner Sabine
Published: April 2024

Background - Exercise training is a well-established, non-invasive method to improve peripheral arterial perfusion and walking capacity in PAD patients.

Hypothesis - We designed a prospective randomized controlled trial to test the effect of training on laboratory markers of angiogenesis.

Methods - Thirty patients with intermittent claudication were randomized to supervised training twice a week for 6 months or standard medical therapy. Endothelial progenitor cells (EPC) were assessed by whole-blood flow cytometry (co-expression of CD34+CD133+KDR+) and cell culture assays (colony forming units/CFU and circulating angiogenic cells/CAC) at baseline, 3-months and 6-months after training as well as 12-months after study begin. Plasma ADMA was determined by immunoassay. In addition, changes in maximum walking distance were recorded.

Results - EPC measured by flow cytometry increased significantly three and six months after training paralleled by a significant decrease of ADMA (asymmetric dimethylarginine), a major endogenous inhibitor of NO synthase (see table

). The number of CFUs and CACs were significantly higher after 6-months compared to baseline upon exercise (P<0.05). No differences were observed in the standard group in timecourse. However, 6-months after training cessation the number of EPC and ADMA levels were similar to baseline. Exercise training showed a benefit on treadmill maximum walking distance with a trendwise increase at 6-months (training: baseline 116.6m±12.8 (mean±SEM) vs. 6-months 149.1m±17.8, P=0.08; standard: baseline 125.2m±23.9 vs. 6-months 108m±19.9, P=0.3). The benefit was sustained 6 months after training cessation in the exercise group (training: 12-months 157.5m±18.4, P=0.07; standard: 12-months 129.5m±26.9).

Conclusions - The beneficial effect of exercise training in PAD patients might partly be due to EPC mobilization mediated by improved NO synthesis as we observed reduced ADMA levels.

EPC and ADMA levels in timecourse
Abstract 5090: Nadph Oxidase-mediated Arterial Dysfunction in Patients With Peripheral Arterial Disease
Authors: Loffredo Lorenzo , Carnevale Roberto , Cangemi Roberto , Perri Ludovica , Di Santo Serena , Mormina Paola , Basili Stefania , Pignatelli Pasquale , Violi Francesco
Published: April 2024

BACKGROUND. Peripheral arterial disease (PAD) is a clinical setting characterized by endothelial dysfunction and atherosclerosis. NADPH oxidase is believed to modulate arterial tone and oxidative stress but its role in PAD is still unclear.

OBJECTIVE. The aim of this study was to evaluate whether NADPH oxidase is implicated in determining reduced FMD and to assess if the administration of an antioxidant was able to improve arterial dilatation and gp91phox, the catalytic core of NADPH oxidase, serum levels in PAD patients.

METHODS. We performed a cross-sectional study comparing flow-mediated dilation, oxidative stress, by serum levels of 8-Hydroxy-2-deoxy-2-deoxyguanosine (8-OHdG), and NO generation, by serum levels of nitrite/nitrate (NOx), and serum gp91phox in a population of PAD patients (n=25; mean age: 63.7±7.9 years) and controls (n=40; mean age: 64.2±11.2 years). In the second part, we performed an interventional cross-over study in PAD patients to assess if the infusion of an antioxidant, propionyl-L-carnitine (PLC), vs placebo, was able to improve endothelial dysfunction and serum gp91phox levels in 20 PAD patients.

RESULTS. Compared with controls, patients with PAD had enhanced gp91phox (mean±S.E.: 21.3±3.6 vs 71.7±14; p<0.001) and 8-OHdG serum levels (mean±SD: 2.4+1.2 vs. 4.24+3.11 ng/mL; P<0.001), reduced NOx (mean±SD:17.02+6.11 vs.11.28+6.02 mM; P<0.001), and lowered FMD (mean±SD: 10.34+2.14 vs. 6.69+2.95%; P<0.001). General linear model analysis for repeated measures showed that PLC infusion was associated with an increase of FMD (from 6.6±0.6 to 11.1±1.2%, F=9.98, p=0.005) and with a reduction of serum gp91phox (from 88.2±13 to 38.6±5.9, F=9.98, p=0.006). No changes were observed after placebo treatment.

CONCLUSIONS. This study shows that in PAD patients, gp91phox is overexpressed and may contribute to reduce FMD.
Abstract 5099: Extent and Severity of Coronary Stenosis at Autopsy Varies by Sex in Fatal Cases of Coronary Heart Disease
Authors: Smilowitz Nathaniel , Hochman Judith S , Sampson Barbara A , Mangalmurti Sandeep , Siegfried Jonathan , Reynolds Harmony R
Published: April 2024

Background:
Recently, the decline in mortality from coronary heart disease (CHD) has slowed in younger age groups, particularly young women. Young women with acute coronary syndromes (ACS) less often have obstructive CHD at angiography. This could reflect pre-hospital death of women with the most severe disease.

Hypothesis:
There is a sex difference in extent and severity of coronary stenosis on post-mortem evaluation of people who died of CHD.

Methods:
Reports of NYC medical examiner autopsies conducted on women 21–54 from1/1/06 –12/31/07 were reviewed if CHD was a cause of death (COD) and cocaine toxicology was negative. Women with CHD as immediate COD were matched by age and race to males with CHD as immediate COD. We analyzed severity of coronary stenosis based on the standard definition of “significant” CHD: ≥75% cross sectional area [CSA] stenosis in a major epicardial vessel, corresponding to 50% angiographic diameter stenosis, or ≥50% CSA stenosis in the left main. We assigned coronary jeopardy scores based on the number of obstructed segments. Statistical analysis was conducted by t-test and chi-square.

Results:
Among 112 women with CHD as the immediate or contributing COD, 24 had immediate COD that were not obviously related to CHD (pneumonia, intoxication, etc). 84 cases with CHD as immediate COD were matched to men. Women were less likely to have “significant” coronary stenosis than men (68% vs. 87%, p=0.006). Among decedents with single-vessel CHD, the RCA was affected more often in women and the LAD in men. Jeopardy scores were lower in women but there was no sex difference in frequency of gross myocardial findings consistent with scarring (21% vs. 32% of men, p=0.16).

Conclusion:
Young women determined at autopsy to have died of CHD exhibit significantly less extensive and severe coronary stenosis than men. These findings are consistent with angiographic findings in women with ACS. Mechanisms of death in these cases are unknown and may include spasm or arrhythmia.
Abstract 5104: Direct Observation of Adipose Tissue-induced Leukocyte Recruitment to the Artery Wall: A Direct Link Between Obesity and Atherosclerosis
Authors: Hagita Sumihiko , Osaka Mizuko , Shimokado Kentaro , Yoshida Masayuki
Published: April 2024

Background:
Though inflammation within adipose tissues play a role in pathogenesis of metabolic syndrome, a causative connection between adipose tissue and atherosclerosis is not fully understood. The present study aimed to examine the direct effect of adipose tissue on macrovascular inflammation by intravital microscopic analysis of the femoral artery of mice after perivascular adipose tissue transplantation.

Methods and Results
Subcutaneous (SQ) or visceral (VIS) adipose tissue harvested from C57/BL6 mice was transplanted to the perivascular area of the femoral artery of recipient C57/BL6 mice. A quantitative intravital microscopic analysis was performed on the artery. The number of adherent leukocyte was increased after adipose tissue transplantation in a time-dependent manner (1day to 7days). VIS transplantation induced significantly more leukocyte accumulation than SQ at 7 days after transplantation. Simultaneous flow cytometry showed the expression of CD11b was significantly increased on peripheral neutrophils and monocytes. Interestingly, the amount of oxidative stress was not changed after transplantation. We found significant increase of MCP-1, MIP-1
β
, and IL-6 in the recipient serum after transplantation. Further, the expression level of MCP-1 was significantly increased in the donor adipose tissues.

Conclusion
These data indicate that adipose tissue directly stimulates athero-prone vascular inflammation. The underlying mechanisms seem to involve induction of MCP-1 from adipose tissues.
Abstract 5126: Platelet Specific Factor XIII Gene Expression and Embolic Propensity in Atrial Fibrillation
Authors: Gosk-Bierska Izabela , Wu Yanhong , McLeod Thomas G , Miller Dylan , Mruk Jozef , McBane Robert D , Wysokinski Waldemar E
Published: April 2024

Background and Aim: Cardioembolic stroke from non-valvular atrial fibrillation (NVAF) begins with the development of left atrial appendage thrombus (LAAT). Although nearly 15% of patients with NVAF have LAAT by transesophageal echocardiography, the annual stroke rate is 5% on average. The overall aim of this project is to identify variables associated with embolic propensity of LAAT.

Materials and Methods: LAAT specimens were obtained during cardiac surgery (MAZE procedure; n=26). Embolized thrombi (n=51) were obtained during surgical embolectomy from lower (n=36) and upper extremities (n=11) and mesenteric arteries (n=4). Platelet-rich regions within sectioned thrombi were sampled by punch biopsy from which total RNA was extracted and analyzed for expression of 5 platelet specific genes: A1 domain of factor XIII, (F13A1); integrin
α
2b
β
3
(ITGA2B); glycoprotein IX (GP9), platelet factor 4 (PF4), glycoprotein Ib (GP1BB). Gene expression was quantified using TaqMan MGB-probe based quantitative real-time polymerase chain reaction normalized to
β
2
macroglobulin using cDNAs reverse transcribed from total RNA.

Results: Factor XIII gene expression (Figure

) was significantly lower in embolic (mean fold change 0.08) compared to left atrial thrombi in situ (mean fold change 0.28; p=0.03). Expression of other genes did not show significant change by embolic status.

Conclusions: Variable Factor XIII gene expression in thrombi generated during NVAF may in part explain the propensity to embolization. Whereas Factor XIII stabilizes thrombi by crosslinking fibrin without influencing atrial attachment, this data suggests that embolization occurs through fragmentation.
Abstract 5200: Octyl-D-Carnosine Attenuates Atherogenesis in ApoE Null Mice Fed a Western Diet
Authors: Pugliese Giuseppe , Iacobini Carla , Ricci Carlo , Scipioni Angela , Giaccari Andrea , Salomone Enrica , Canevotti Renato , Lapolla Annunziata , Orioli Marica , Aldini Giancarlo , Menini Stefano
Published: April 2024

Lipid endoperoxides resulting from oxidation of unsaturated lipids are further metabolized to reactive carbonyl species (RCS), which react with proteins to generate advanced lipoxidation endproducts (ALEs). ALEs are believed to evoke an inflammatory response which participates in all stages of atherosclerosis. The endogenous dipeptide L-carnosine was shown to act as quencher of RCS derived from lipoxidation. Since it is rapidly inactivated by carnosinase, we evaluated the effect of the carnosinase-resistant octyl ester of D-carnosine (ODC, Flamma SpA, 60 mg/kg in the drinking water) vs. vehicle on the development of atherosclerosis in female apoE null mice fed a western diet (42% fat) vs. standard chow for 12 weeks. Oil red O staining of en-face aorta preparations showed a significant reduction of lipid accumulation in ODC-treated vs. untreated ApoE null mice on western diet (13.2±2.5 vs. 19.2±2.0 %, P<0.001). Morphometric evaluation of aortic lesions in sections stained with the Weigert-Van Gieson method showed significantly reduced lesion area in ODC-treated mice at the level of the aortic sinus and, particularly, of the brachiocephalic artery. ODC treatment also resulted in a more stable plaque phenotype, with less inflammation and apoptosis, and more collagen and VSMCs, resulting in reduced necrotic core formation (11.8±3.8 vs. 25.3±5.4%, P<0.0001). The gene expression level of the markers of inflammation and lesion progression F4/80, MCP-1, VCAM –1, TNF-
α
, IFN-
γ
and matrix metalloproteinase-2 and 9 and the RCS- and ALE-receptors CD36, RAGE and gelectin-3 was significantly decreased and even normalized in western diet-fed ApoE null mice treated with ODC. These data indicate that generation of RCS and ALEs from lipid peroxidation plays a major role in atherogenesis and that quenching of these compounds with a D-carnosine ester may represent a promising approach to the prevention and treatment of vascular disease.
Abstract 5206: Aortic Valve Calcification and Stenosis is Strongly Associated With Cardiac and All-cause Mortality in End-stage Renal Disease Patients
Authors: Furuhashi Kyuichi , Ishii Hideki , Kumada Yoshitaka , Aoyama Toru , Tanaka Miho , Kamoi Daisuke , Kawamura Yoshihiro , Takahashi Hiroshi , Murohara Toyoaki
Published: April 2024

Background:
Vascular or tissue calcification has been recognized as a frequent complication in patients with end-stage renal disease (ESRD). Aortic valve calcification (AVC) is especially frequent, and the presence of AVC is a strong predictor of restenosis after drug-eluting stent implantation in ESRD patients. However, its prevalence in ESRD patients and the association with adverse events remain unclear. The aim of this study was to clarify the prevalence and predictive power of AVC and aortic valve stenosis (AVS) for cardiac and all-cause mortality in ESRD patients.

Methods:
Consecutive 1,290 ESRD patients were screened by echocardiography within 1 month after initiating hemodialysis (HD). AVC was defined as bright echoes >1mm on one or more cusps of the aortic valve. AVS was also defined as pressure gradient >20mmHg. They were followed-up for 7 years.

Results:
AVC was seen in 627 patients (49%). Among patients with AVC, AVS was observed in 76 patients (12%). Patients were divided into 3 groups; those without AVC (n=663), with AVC alone (n=551) and with AVC and AVS (n=76). Mean follow-up period was 45±34months. Cardiac survival for 7 years was 93.0% in patients without AVC, 84.5% in patients with AVC alone and 69.5% in patients with AVC and AVS, respectively (p<0.0001). Cardiovascular survival was 87.6%, 76.4% and 64.1%, respectively (p=0.0004), and all-cause survival was 74.4%, 58.1% and 39.7% (p<0.0001), respectively. On Cox analysis, AVC and AVC with AVS were independently stratified as predictors of mortalities even after adjustment for gender, age, traditional risk factors, body mass index, hemoglobin, albumin, cholesterol and C-reactive protein levels (Table

).

Conclusion:
AVC was seen in about a half of ESRD patients even at initial phase of HD therapy, and was strongly associated with cardiac and all-cause mortality in this population.
Abstract 5221: Plasma Levels of Tetrahydrobiopterin and Endothelial Function Were Improved by Fenofibrate Treatment in Patients With Hypertriglyceridemia
Authors: He Li Y , Liu Shan , Mao Jie M , Feng Xin H , Feng Jie L , Wang Guang
Published: April 2024

Background:
Endothelial nitric oxide synthase (eNOS) catalytic activity becomes “uncoupled” when tetrahydrobiopterin (BH
4
) is limiting or absent which causes the endothelial function to be impaird. The objective of our study was to investigate the effects of peroxisome proliferator-activated receptor
α
(PPAR
α
) agonists fenofibrate on plasma levels of nitric oxide (NO) and BH
4
and endothelial function in patients with hypertriglyceridemia.

Methods and results:
Sixty patients with hypertriglyceridemia were randomly divided into treatment group and the control group. The treatment group (mean follow-up was 145±51 days) was treated with lifestyle changes and fenofibrate 200mg/d; the control group was treated with lifestyle changes only. At the end of the follow-up, plasma NO (99.09±35.51
μ
mol/L vs.121.98±53.27
μ
mol/L,
P
< 0.05) and BH
4
(1.48±0.79pmol/mL vs. 2.16±1.50pmol/mL,
P
< 0.05) levels were elevated and plasma homocysteine (Hcy) levels were elevated by 50.1% (
P
< 0.001) compared with the baseline, coronary flow reserve which reflected coronary endothelial function were improved (2.89±0.78 vs. 3.14±0.67,
P
< 0.05). Fenofibrate could elevate the plasma BH
4
levels (1.39±0.77 pmol/mL vs. 2.31±1.70 pmol/mL,
P
< 0.01) in patients whose baseline Hcy ≤ 15
μ
mol/L; but could not change the plasma BH
4
levels (1.71±0.83 pmol/mL vs. 1.73±0.58 pmol/mL,
P
> 0.05) in patients whose baseline Hcy > 15
μ
mol/L. Furthermore, fenofibrate could elevate plasma BH
4
levels only in patients whose Hcy levels ≤15
μ
mol/L at baseline and at the end of follow-up (1.27±0.78 pmol/mL vs. 2.47±2.07 pmol/mL,
P
< 0.05), and couldn’t change plasma BH
4
levels in patients whose Hcy levels > 15
μ
mol/L at baseline and at the end of follow-up(1.68±0.87 pmol/mL vs. 1.76±0.61 pmol/mL,
P
> 0.05).

Conclusion:
Fenofibrate can improve endothelial function in patients with hypertriglyceridemia which might relate to the increased expression of NO and BH
4
by fenofibrate. Fenofibrate might inhibit the effects of Hcy in decreasing BH
4
and impairing of the endothelial function, and elevated Hcy might partially inhibit the effects of fenofibrate in increasing BH
4
and improving the vascular endothelial function.
Abstract 5255: Kv1.3 Channels Play a Role in Coronary Metabolic Dilation
Authors: Ohanyan Vahagn , Bratz Ian N , Chilian William M
Published: April 2024

The coupling between metabolism and flow in the heart is critical for normal cardiac function because the myocardium depends on a continuous supply of oxygenated blood for aerobic metabolism and energy production. Recently we proposed that one component of this coupling is mediated by mitochondrial production of H2O2, which produces dilation through redox-dependent activation of 4-aminopyridine (4-AP) sensitive ion channels. 4-AP is thought to preferentially block the Kv1 family of ion channels, but its antagonistic effects also extend to other families of Kv channels, e.g., Kv4. Our goal was to ascertain if a particular Kv1 channel, Kv1.3, that is known to be redox sensitive, serves as a metabolic sensor in the heart to engender coupling of metabolism to flow. To accomplish this goal we implemented a murine model (C57/B6, n =10) of coronary metabolic dilation (during anesthesia) in which cardiac work (CW: product of stroke volume × heart rate × mean arterial pressure) was altered by i.v. infusion of norepinephrine (NE). Coronary blood flow (contrast echocardiography, units of ml/min per g) was simultaneously measured during the changes in CW. Arterial pressure and heart rate were measured using a Millar transducer in the abdominal aorta, and stroke volume was measured via echocardiography. NE at 2.5 and 5 ug/kg/min increased CW over baseline by 130% and 221%, respectively. Under these conditions coronary flow increased from a baseline of 2.3±0.9 to 5.2±1.5 (NE2.5) and to 7.4±1.8 (NE5) (both P<0.05 vs baseline [mean± SD]). To ascertain the role of Kv1.3 channels, we used the potent Kv1.3 channel antagonist correolide (C: 0.8 mg/kg, i.v.). Whereas correolide did not affect basal flow, the Kv1.3 antagonist blunted metabolic dilation during NE infusion: 4.3±0.9 (C+NE2.5) and 5.2±1.2 (C+NE5: P<0.05 vs NE5). At the highest dose of NE the % increase in flow under control conditions (229%) was greatly attenuated by correolide (132%). Since cardiac myocytes are not reported to express Kv1.3 channels, we do not believe the results are related to an effect of correolide on cardiac myocytes. Rather, we conclude that Kv1.3 channels play a role in coupling coronary flow to cardiac work and that mice have the ability to more than double coronary flow under high levels of cardiac work.
Abstract 5301: Fractalkine Desensitizes Platelets to Platelet Inhibition by the Endogenous Platelet Inhibitor Prostacyclin
Authors: Schaefer Andreas , Flierl Ulrike , Bauersachs Johann
Published: April 2024

Background: Fractalkine plays a pivotal role in atherogenesis. Platelet activation is a central factor in atherosclerosis progression. We previously reported that fractalkine induces platelet degranulation and P-selectin expression facilitating platelet-leukocyte adhesion. Fractalkine attenuates the bioavailability of the important endogenous platelet inhibitor nitric oxide.

Methods: The influence of preincubation of platelets with fractalkine (1
μ
g/ml) on platelet inhibition by the platelet inhibitor prostaglandin E1 (PGE1) was assessed by two assays: first, the ability to prevent PGE1-induced attenuation of ADP-induced platelet aggregation, and second, the capability to decrease PGE1-induced vasodilator-stimulated phosphoprotein (VASP)-phosphorylation determined by flow-cytometry. Samples were preincubated with fractalkine and stimulated with different concentrations of PGE1.

Results: PGE1 significantly inhibited ADP-induced platelet aggregation. In samples pre-treated with fractalkine, prevention of ADP-induced platelet aggregation by PGE1was abrogated. While secondary platelet aggregation was prevented by PGE1 (1
μ
M), preincubation with fractalkine for 10 minutes reestablished secondary platelet aggregation. These results indicate that fractalkine desensitized platelets to PGE1. PGE1-induced VASP-phosphorylation was significantly attenuated by preincubation with fractalkine in a time- and concentration-dependent pattern, whereby a maximum effect was achieved after preincubation of platelets with fractalkine for 10 minutes, which reduced PGE1 (1
μ
M)-induced VASP-phosphorylation by ~25% (p<0.01 vs. PGE1 without fractalkine).

Conclusion: Fractalkine desensitizes platelets to PGE1 suggesting that platelet inhibition by the endogenous platelet inhibitor prostacyclin is affected by fractalkine. These results indicate a new pathomechanism by which this atherogenic chemokine facilitates relevant steps leading to platelet activation and leukocyte recruitment, namely rendering platelets less responsive to endogenous platelet inhibition.