bluuebunny/crossref_metadata_2025 huggingface dataset:
Myocardial autophagic energy stress responses—macroautophagy, mitophagy, and glycophagy
Authors: Delbridge Lea M. D. , Mellor Kimberley M. , Taylor David J. R. , Gottlieb Roberta A.
Published: March 2015

An understanding of the role of autophagic processes in the management of cardiac metabolic stress responses is advancing rapidly and progressing beyond a conceptualization of the autophagosome as a simple cell recycling depot. The importance of autophagy dysregulation in diabetic cardiomyopathy and in ischemic heart disease - both conditions comprising the majority of cardiac disease burden - has now become apparent. New findings have revealed that specific autophagic processes may operate in the cardiomyocyte, specialized for selective recognition and management of mitochondria and glycogen particles in addition to protein macromolecular structures. Thus mitophagy, glycophagy, and macroautophagy regulatory pathways have become the focus of intensive experimental effort, and delineating the signaling pathways involved in these processes offers potential for targeted therapeutic intervention. Chronically elevated macroautophagic activity in the diabetic myocardium is generally observed in association with structural and functional cardiomyopathy; yet there are also numerous reports of detrimental effect of autophagy suppression in diabetes. Autophagy induction has been identified as a key component of protective mechanisms that can be recruited to support the ischemic heart, but in this setting benefit may be mitigated by adverse downstream autophagic consequences. Recent report of glycophagy upregulation in diabetic cardiomyopathy opens up a novel area of investigation. Similarly, a role for glycogen management in ischemia protection through glycophagy initiation is an exciting prospect under investigation.
Chasing cardiac physiology and pathology down the CaMKII cascade
Authors: Mattiazzi Alicia , Bassani Rosana A. , Escobar Ariel L. , Palomeque Julieta , Valverde Carlos A. , Vila Petroff Martín , Bers Donald M.
Published: March 2015

Calcium dynamics is central in cardiac physiology, as the key event leading to the excitation-contraction coupling (ECC) and relaxation processes. The primary function of Ca2+in the heart is the control of mechanical activity developed by the myofibril contractile apparatus. This key role of Ca2+signaling explains the subtle and critical control of important events of ECC and relaxation, such as Ca2+influx and SR Ca2+release and uptake. The multifunctional Ca2+-calmodulin-dependent protein kinase II (CaMKII) is a signaling molecule that regulates a diverse array of proteins involved not only in ECC and relaxation but also in cell death, transcriptional activation of hypertrophy, inflammation, and arrhythmias. CaMKII activity is triggered by an increase in intracellular Ca2+levels. This activity can be sustained, creating molecular memory after the decline in Ca2+concentration, by autophosphorylation of the enzyme, as well as by oxidation, glycosylation, and nitrosylation at different sites of the regulatory domain of the kinase. CaMKII activity is enhanced in several cardiac diseases, altering the signaling pathways by which CaMKII regulates the different fundamental proteins involved in functional and transcriptional cardiac processes. Dysregulation of these pathways constitutes a central mechanism of various cardiac disease phenomena, like apoptosis and necrosis during ischemia/reperfusion injury, digitalis exposure, post-acidosis and heart failure arrhythmias, or cardiac hypertrophy. Here we summarize significant aspects of the molecular physiology of CaMKII and provide a conceptual framework for understanding the role of the CaMKII cascade on Ca2+regulation and dysregulation in cardiac health and disease.
An interaction between glucagon-like peptide-1 and adenosine contributes to cardioprotection of a dipeptidyl peptidase 4 inhibitor from myocardial ischemia-reperfusion injury
Authors: Ihara Madoka , Asanuma Hiroshi , Yamazaki Satoru , Kato Hisakazu , Asano Yoshihiro , Shinozaki Yoshihiro , Mori Hidezo , Minamino Tetsuo , Asakura Masanori , Sugimachi Masaru , Mochizuki Naoki , Kitakaze Masafumi
Published: March 2015

Dipeptidyl peptidase 4 (DPP4) inhibitors suppress the metabolism of the potent antihyperglycemic hormone glucagon-like peptide-1 (GLP-1). DPP4 was recently shown to provide cardioprotection through a reduction of infarct size, but the mechanism for this remains elusive. Known interactions between DPP4 and adenosine deaminase (ADA) suggest an involvement of adenosine signaling in DPP4 inhibitor-mediated cardioprotection. We tested whether the protective mechanism of the DPP4 inhibitor alogliptin against myocardial ischemia-reperfusion injury involves GLP-1- and/or adenosine-dependent signaling in canine hearts. In anesthetized dogs, the coronary artery was occluded for 90 min followed by reperfusion for 6 h. A 4-day pretreatment with alogliptin reduced the infarct size from 43.1 ± 2.5% to 17.1 ± 5.0% without affecting collateral flow and hemodynamic parameters, indicating a potent antinecrotic effect. Alogliptin also suppressed apoptosis as demonstrated by the following analysis: 1) reduction in the Bax-to-Bcl2 ratio; 2) cytochrome c release, 3) an increase in Bad phosphorylation in the cytosolic fraction; and 4) terminal deoxynucleotidyl transferase dUTP nick end labeling assay. This DPP4 inhibitor did not affect blood ADA activity or adenosine concentrations. In contrast, the nonselective adenosine receptor blocker 8-( p-sulfophenyl)theophylline (8SPT) completely blunted the effect of alogliptin. Alogliptin did not affect Erk1/2 phosphorylation, but it did stimulate phosphorylation of Akt, glycogen synthase kinase-3β, and cAMP response element-binding protein (CREB). Only 8SPT prevented alogliptin-induced CREB phosphorylation. In conclusion, the DPP4 inhibitor alogliptin suppresses ischemia-reperfusion injury via adenosine receptor- and CREB-dependent signaling pathways.
Mineralocorticoid receptor blockade prevents Western diet-induced diastolic dysfunction in female mice
Authors: Bostick Brian , Habibi Javad , DeMarco Vincent G. , Jia Guanghong , Domeier Timothy L. , Lambert Michelle D. , Aroor Annayya R. , Nistala Ravi , Bender Shawn B. , Garro Mona , Hayden Melvin R. , Ma Lixin , Manrique Camila , Sowers James R.
Published: March 2015

Overnutrition/obesity predisposes individuals, particularly women, to diastolic dysfunction (DD), an independent predictor of future cardiovascular disease. We examined whether low-dose spironolactone (Sp) prevents DD associated with consumption of a Western Diet (WD) high in fat, fructose, and sucrose. Female C57BL6J mice were fed a WD with or without Sp (1 mg·kg−1·day−1). After 4 mo on the WD, mice exhibited increased body weight and visceral fat, but similar blood pressures, compared with control diet-fed mice. Sp prevented the development of WD-induced DD, as indicated by decreased isovolumic relaxation time and an improvement in myocardial performance (<Tei index) and septal annular velocity (< E′-to- A′ ratio), as assessed by echocardiography, as well as decreased diastolic relaxation time/increased diastolic initial filling rate, as assessed by MRI. The relationship between passive sarcomere length of cardiac myocytes and ventricular pressure was monitored using di-8-ANEPPS staining of the t-tubule network in hearts ex vivo. Sp administration led to longer sarcomere lengths at each pressure indicative of improved ventricular compliance in WD-fed mice. Sp also prevented left ventricular hypertrophy, interstitial fibrosis, and oxidative stress. Sp prevented the WD-induced increased expression of myocardial proinflammatory M1 macrophage markers monocyte chemoattractant protein-1 and CD11c and increased the expression of the anti-inflammatory M2 macrophage marker CD206. These findings demonstrate that WD-induced DD is associated with increased oxidant stress, fibrosis, and immune dysregulation. Mineralocorticoid receptor antagonism enhanced M2 macrophage polarization and ameliorated oxidant stress and fibrosis. This work supports a novel blood pressure-independent effect of MR antagonism as a strategy to prevent diet-induced DD in women.
Prenatal nicotinic exposure augments cardiorespiratory responses to activation of bronchopulmonary C-fibers
Authors: Zhuang Jianguo , Zhao Lei , Zang Na , Xu Fadi
Published: March 2015

Rat pups prenatally exposed to nicotine (PNE) present apneic (lethal ventilatory arrest) responses during severe hypoxia. To clarify whether these responses are of central origin, we tested PNE effects on ventilation and diaphragm electromyography (EMGdi) during hypoxia in conscious rat pups. PNE produced apnea (lethal ventilatory arrest) identical to EMGdi silencing during hypoxia, indicating a central origin of this apneic response. We further asked whether PNE would sensitize bronchopulmonary C-fibers (PCFs), a key player in generating central apnea, with increase of the density and transient receptor potential cation channel subfamily V member 1 (TRPV1) expression of C-fibers/neurons in the nodose/jugular (N/J) ganglia and neurotrophic factors in the airways and lungs. We compared 1) ventilatory and pulmonary C-neural responses to right atrial bolus injection of capsaicin (CAP, 0.5 μg/kg), 2) bronchial substance P-immunoreactive (SP-IR) fiber density, 3) gene and protein expressions of TRPV1 in the ganglia, and 4) nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) protein in bronchoalveolar lavage fluid (BALF) and TrkA and TrkB genes in the ganglia between control and PNE pups. PNE markedly strengthened the PCF-mediated apneic response to CAP via increasing pulmonary C-neural sensitivity. PNE also enhanced bronchial SP-IR fiber density and N/J ganglia neural TRPV1 expression associated with increased gene expression of TrkA in the N/G ganglia and decreased NGF and BDNF in BALF. Our results suggest that PNE enhances PCF sensitivity likely through increasing PCF density and TRPV1 expression via upregulation of neural TrkA and downregulation of pulmonary BDNF, which may contribute to the PNE-promoted central apnea (lethal ventilatory arrest) during hypoxia.
Lactate as substrate for mitochondrial respiration in alveolar epithelial type II cells
Authors: Lottes Robyn G. , Newton Danforth A. , Spyropoulos Demetri D. , Baatz John E.
Published: March 2015

Because of the many energy-demanding functions they perform and their physical location in the lung, alveolar epithelial type II (ATII) cells have a rapid cellular metabolism and the potential to influence substrate availability and bioenergetics both locally in the lung and throughout the body. A thorough understanding of ATII cell metabolic function in the healthy lung is necessary for determining how metabolic changes may contribute to pulmonary disease pathogenesis; however, lung metabolism is poorly understood at the cellular level. Here, we examine lactate utilization by primary ATII cells and the ATII model cell line, MLE-15, and link lactate consumption directly to mitochondrial ATP generation. ATII cells cultured in lactate undergo mitochondrial respiration at near-maximal levels, two times the rates of those grown in glucose, and oxygen consumption under these conditions is directly linked to mitochondrial ATP generation. When both lactate and glucose are available as metabolic substrate, the presence of lactate alters glucose metabolism in ATII to favor reduced glycolytic function in a dose-dependent manner, suggesting that lactate is used in addition to glucose when both substrates are available. Lactate use by ATII mitochondria is dependent on monocarboxylate transporter (MCT)-mediated import, and ATII cells express MCT1, the isoform that mediates lactate import by cells in other lactate-consuming tissues. The balance of lactate production and consumption may play an important role in the maintenance of healthy lung homeostasis, whereas disruption of lactate consumption by factors that impair mitochondrial metabolism, such as hypoxia, may contribute to lactic acid build-up in disease.
Glucose uptake during contraction in isolated skeletal muscles from neuronal nitric oxide synthase μ knockout mice
Authors: Hong Yet Hoi , Frugier Tony , Zhang Xinmei , Murphy Robyn M. , Lynch Gordon S. , Betik Andrew C. , Rattigan Stephen , McConell Glenn K.
Published: March 2015

Inhibition of nitric oxide synthase (NOS) significantly attenuates the increase in skeletal muscle glucose uptake during contraction/exercise, and a greater attenuation is observed in individuals with Type 2 diabetes compared with healthy individuals. Therefore, NO appears to play an important role in mediating muscle glucose uptake during contraction. In this study, we investigated the involvement of neuronal NOSμ (nNOSμ), the main NOS isoform activated during contraction, on skeletal muscle glucose uptake during ex vivo contraction. Extensor digitorum longus muscles were isolated from nNOSμ−/−and nNOSμ+/+mice. Muscles were contracted ex vivo in a temperature-controlled (30°C) organ bath with or without the presence of the NOS inhibitor NG-monomethyl-l-arginine (L-NMMA) and the NOS substrate L-arginine. Glucose uptake was determined by radioactive tracers. Skeletal muscle glucose uptake increased approximately fourfold during contraction in muscles from both nNOSμ−/−and nNOSμ+/+mice. L-NMMA significantly attenuated the increase in muscle glucose uptake during contraction in both genotypes. This attenuation was reversed by L-arginine, suggesting that L-NMMA attenuated the increase in muscle glucose uptake during contraction by inhibiting NOS and not via a nonspecific effect of the inhibitor. Low levels of NOS activity (∼4%) were detected in muscles from nNOSμ−/−mice, and there was no evidence of compensation from other NOS isoform or AMP-activated protein kinase which is also involved in mediating muscle glucose uptake during contraction. These results indicate that NO regulates skeletal muscle glucose uptake during ex vivo contraction independently of nNOSμ.
Hypoxia-inducible factor-1 modulates the expression of vascular endothelial growth factor and endothelial nitric oxide synthase induced by eccentric exercise
Authors: Rodriguez-Miguelez Paula , Lima-Cabello Elena , Martínez-Flórez Susana , Almar Mar , Cuevas María J. , González-Gallego Javier
Published: March 2015

The present study investigated the effects of acute and chronic eccentric exercise on the hypoxia-inducible factor (HIF)-1α activation response and the concomitant modulation of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) expression in rat skeletal muscle. Twenty-four male Wistar rats were randomly assigned to three experimental groups: rested control group, acutely exercised group after an intermittent downhill protocol for 90 min, and acutely exercise group with a previous eccentric training of 8 wk. HIF-1α activation, VEGF and eNOS gene expression, protein content, and promoter activation were assessed in vastus lateralis muscle biopsies. Acute eccentric exercise induced a marked activation of HIF-1α and resulted in increased VEGF and eNOS mRNA level and protein concentration. The binding of HIF-1α to the VEGF and eNOS promoters, measured by a chromatin immunoprecipitation assay, was undetectable in rested rats, whereas it was evident in acutely exercised animals. Acute exercise also increased myeloperoxidase, toll-like receptor-4, tumor necrosis factor-α, and interleukin-1β protein content, suggesting a contribution of proinflammatory stimuli to HIF-1α activation and VEGF overexpression. All of these effects were partially abolished by training. Moreover, training resulted in an increased capillary density. In summary, our findings indicate that eccentric exercise prompts an HIF-1α response in untrained skeletal muscle that contributes to the upregulation of VEGF and eNOS gene expression and is attenuated after an eccentric training program.
Prior head-down tilt does not impair the cerebrovascular response to head-up tilt
Authors: Yang Changbin , Gao Yuan , Greaves Danielle K. , Villar Rodrigo , Beltrame Thomas , Fraser Katelyn S. , Hughson Richard L.
Published: March 2015

The hypothesis that cerebrovascular autoregulation was not impaired during head-up tilt (HUT) that followed brief exposures to varying degrees of prior head-down tilt (HDT) was tested in 10 healthy young men and women. Cerebral mean flow velocity (MFV) and cardiovascular responses were measured in transitions to a 60-s period of 75° HUT that followed supine rest (control) or 15 s HDT at −10°, −25°, and −55°. During HDT, heart rate (HR) was reduced for −25° and −55°, and cardiac output was lower at −55° HDT. MFV increased during −10° HDT, but not in the other conditions even though blood pressure at the middle cerebral artery (BPMCA) increased. On the transition to HUT, HR increased only for −55° condition, but stroke volume and cardiac output transiently increased for −25° and −55°. Total peripheral resistance index decreased in proportion to the magnitude of HDT and recovered over the first 20 s of HUT. MFV was significantly less in all HDT conditions compared with the control in the first 5-s period of HUT, but it recovered quickly. An autoregulation correction index derived from MFV recovery relative to BPMCA decline revealed a delay in the first 5 s for prior HDT compared with control but then a rapid increase to briefly exceed control after −55° HDT. This study showed that cerebrovascular autoregulation is modified by but not impaired by brief HDT prior to HUT and that cerebral MFV recovered quickly and more rapidly than arterial blood pressure to protect against cerebral hypoperfusion and potential syncope.
Cardiac hypertrophy reduction in SHR by specific silencing of myocardial Na+/H+exchanger
Authors: Nolly Mariela B. , Pinilla Andrés O. , Ennis Irene L. , Cingolani Horacio E. , Morgan Patricio E.
Published: March 2015

We examined the effect of specific and local silencing of sodium/hydrogen exchanger isoform 1 (NHE1) with a small hairpin RNA delivered by lentivirus (L-shNHE1) in the cardiac left ventricle (LV) wall of spontaneously hypertensive rats, to reduce cardiac hypertrophy. Thirty days after the lentivirus was injected, NHE1 protein expression was reduced 53.3 ± 3% in the LV of the L-shNHE1 compared with the control group injected with L-shSCR (NHE1 scrambled sequence), without affecting its expression in other organs, such as liver and lung. Hypertrophic parameters as LV weight-to-body weight and LV weight-to-tibia length ratio were significantly reduced in animals injected with L-shNHE1 (2.32 ± 0.5 and 19.30 ± 0.42 mg/mm, respectively) compared with L-shSCR-injected rats (2.68 ± 0.06 and 21.53 ± 0.64 mg/mm, respectively). Histochemical analysis demonstrated a reduction of cardiomyocytes cross-sectional area in animals treated with L-shNHE1 compared with L-shSCR (309,81 ± 20,86 vs. 424,52 ± 21 μm2, P < 0.05). Echocardiography at the beginning and at the end of the treatment showed that shNHE1 expression for 30 days induced 9% reduction of LV mass. Also, animals treated with L-shNHE1 exhibited a reduced LV wall thickness without changing LV diastolic dimension and arterial pressure, indicating an increased parietal stress. In addition, midwall shortening was not modified, despite the increased wall tension, suggesting an improvement of cardiac function. Chronic shNHE1 expression in the heart emerges as a possible methodology to reduce pathological cardiac hypertrophy, avoiding potentially undesired effects caused from a body-wide inhibition of NHE1.
Hemoglobin mass and intravascular volume kinetics during and after exposure to 3,454-m altitude
Authors: Siebenmann C. , Cathomen A. , Hug M. , Keiser S. , Lundby A. K. , Hilty M. P. , Goetze J. P. , Rasmussen P. , Lundby C.
Published: March 2015

High altitude (HA) exposure facilitates a rapid contraction of plasma volume (PV) and a slower occurring expansion of hemoglobin mass (Hbmass). The kinetics of the Hbmassexpansion has never been examined by multiple repeated measurements, and this was our primary study aim. The second aim was to investigate the mechanisms mediating the PV contraction. Nine healthy, normally trained sea-level (SL) residents (8 males, 1 female) sojourned for 28 days at 3,454 m. Hbmasswas measured and PV was estimated by carbon monoxide rebreathing at SL, on every 4th day at HA, and 1 and 2 wk upon return to SL. Four weeks at HA increased Hbmassby 5.26% (range 2.5-11.1%; P < 0.001). The individual Hbmassincreases commenced with up to 12 days of delay and reached a maximal rate of 4.04 ± 1.02 g/day after 14.9 ± 5.2 days. The probability for Hbmassto plateau increased steeply after 20–24 days. Upon return to SL Hbmassdecayed by −2.46 ± 2.3 g/day, reaching values similar to baseline after 2 wk. PV, aldosterone concentration, and renin activity were reduced at HA ( P < 0.001) while the total circulating protein mass remained unaffected. In summary, the Hbmassresponse to HA exposure followed a sigmoidal pattern with a delayed onset and a plateau after ∼3 wk. The decay rate of Hbmassupon descent to SL did not indicate major changes in the rate of erythrolysis. Moreover, our data support that PV contraction at HA is regulated by the renin-angiotensin-aldosterone axis and not by changes in oncotic pressure.
Targeting the Spleen Tyrosine Kinase with Fostamatinib as a Strategy against Waldenström Macroglobulinemia
Authors: Kuiatse Isere , Baladandayuthapani Veerabhadran , Lin Heather Y. , Thomas Sheeba K. , Bjorklund Chad C. , Weber Donna M. , Wang Michael , Shah Jatin J. , Zhang Xing-Ding , Jones Richard J. , Ansell Stephen M. , Yang Guang , Treon Steven P. , Orlowski Robert Z.
Published: March 2015

Purpose: Waldenström macroglobulinemia (WMG) is a lymphoproliferative disorder characterized by good initial responses to standard therapeutics, but only a minority of patients achieve complete remissions, and most inevitably relapse, indicating a need for novel agents. B-cell receptor signaling has been linked to clonal evolution in WMG, and Spleen tyrosine kinase (Syk) is overexpressed in primary cells, suggesting that it could be a novel and rational target.

Experimental Design: We studied the impact of the Syk inhibitor fostamatinib on BCWM.1 and MWCL-1 WMG-derived cell lines both in vitro and in vivo, as well as on primary patient cells.

Results: In WMG-derived cell lines, fostamatinib induced a time- and dose-dependent reduction in viability, associated with activation of apoptosis. At the molecular level, fostamatinib reduced activation of Syk and Bruton's tyrosine kinase, and also downstream signaling through MAPK kinase (MEK), p44/42 MAPK, and protein kinase B/Akt. As a single agent, fostamatinib induced tumor growth delay in an in vivo model of WMG, and reduced viability of primary WMG cells, along with inhibition of p44/42 MAPK signaling. Finally, fostamatinib in combination with other agents, including dexamethasone, bortezomib, and rituximab, showed enhanced activity.

Conclusions: Taken together, these data support the translation of approaches targeting Syk with fostamatinib to the clinic for patients with relapsed and possibly even newly diagnosed WMG. Clin Cancer Res; 21(11); 2538–45. ©2015 AACR.
Utility of Socioeconomic Status in Predicting 30-Day Outcomes After Heart Failure Hospitalization
Authors: Eapen Zubin J. , McCoy Lisa A. , Fonarow Gregg C. , Yancy Clyde W. , Miranda Marie Lynn , Peterson Eric D. , Califf Robert M. , Hernandez Adrian F.
Published: March 2015

Background—

An individual’s socioeconomic status (SES) is associated with health outcomes and mortality, yet it is unknown whether accounting for SES can improve risk-adjustment models for 30-day outcomes among Centers for Medicare & Medicaid Services beneficiaries hospitalized with heart failure.

Methods and Results—

We linked clinical data on hospitalized patients with heart failure in the Get With The Guidelines-Heart Failure database (January 2005 to December 2011) with Centers for Medicare & Medicaid Services claims and county-level SES data from the 2012 Area Health Resources Files. We compared the discriminatory capabilities of multivariable models that adjusted for SES, patient, and hospital characteristics to determine whether county-level SES data improved prediction or changed hospital rankings for 30-day all-cause mortality and rehospitalization. After adjusting for patient and hospital characteristics, median household income (per $5000 increase) was inversely associated with odds of 30-day mortality (odds ratio, 0.97; 95% confidence interval, 0.95–1.00;
P
=0.032) and the percentage of people with at least a high school diploma (per 5 U increase) was associated with lower odds of 30-day rehospitalization (odds ratio, 0.95; 95% confidence interval, 0.91–0.99). After adjustment for county-level SES data, relative to whites, Hispanic ethnicity (odds ratio, 0.70; 95% confidence interval, 0.58–0.83) and black race (odds ratio, 0.57; 95% confidence interval, 0.50–0.65) remained significantly associated with lower 30-day mortality, but had similar 30-day rehospitalization. County-level SES did not improve risk adjustment or change hospital rankings for 30-day mortality or rehospitalization.

Conclusions—

County-level SES data are modestly associated with 30-day outcomes for Centers for Medicare & Medicaid Services beneficiaries hospitalized with heart failure, but do not improve risk adjustment models based on patient characteristics alone.
Survival After Out-of-Hospital Cardiac Arrest in Relation to Age and Early Identification of Patients With Minimal Chance of Long-Term Survival
Authors: Wissenberg Mads , Folke Fredrik , Hansen Carolina Malta , Lippert Freddy K. , Kragholm Kristian , Risgaard Bjarke , Rajan Shahzleen , Karlsson Lena , Søndergaard Kathrine Bach , Hansen Steen M. , Mortensen Rikke Normark , Weeke Peter , Christensen Erika Frischknecht , Nielsen Søren L. , Gislason Gunnar H. , Køber Lars , Torp-Pedersen Christian
Published: March 2015

Background—

Survival after out-of-hospital cardiac arrest has increased during the last decade in Denmark. We aimed to study the impact of age on changes in survival and whether it was possible to identify patients with minimal chance of 30-day survival.

Methods and Results—

Using data from the nationwide Danish Cardiac Arrest Registry (2001─2011), we identified 21 480 patients ≥18 years old with a presumed cardiac-caused out-of-hospital cardiac arrest for which resuscitation was attempted. Patients were divided into 3 preselected age-groups: working-age patients 18 to 65 years of age (33.7%), early senior patients 66 to 80 years of age (41.5%), and late senior patients >80 years of age (24.8%). Characteristics in working-age patients, early senior patients, and late senior patients were as follows: witnessed arrest in 53.8%, 51.1%, and 52.1%; bystander cardiopulmonary resuscitation in 44.7%, 30.3%, and 23.4%; and prehospital shock from a defibrillator in 54.7%, 45.0%, and 33.8% (all
P
<0.05). Between 2001 and 2011, return of spontaneous circulation on hospital arrival increased: working-age patients, from 12.1% to 34.6%; early senior patients, from 6.4% to 21.5%; and late senior patients, from 4.0% to 15.0% (all
P
<0.001). Furthermore, 30-day survival increased: working-age patients, 5.8% to 22.0% (
P
<0.001); and early senior patients, 2.7% to 8.4% (
P
<0.001), whereas late senior patients experienced only a minor increase (1.5% to 2.0%;
P
=0.01). Overall, 3 of 9499 patients achieved 30-day survival if they met 2 criteria: had not achieved return of spontaneous circulation on hospital arrival and had not received a prehospital shock from a defibrillator.

Conclusions—

All age groups experienced a large temporal increase in survival on hospital arrival, but the increase in 30-day survival was most prominent in the young. With the use of only 2 criteria, it was possible to identify patients with a minimal chance of 30-day survival.
Comparison of Self-Reported and Medicare Claims-Identified Acute Myocardial Infarction
Authors: Yasaitis Laura C. , Berkman Lisa F. , Chandra Amitabh
Published: March 2015

Background—

Cardiovascular disease is often studied through patient self-report and administrative data. However, these 2 sources provide different information, and few studies have compared them.

Methods and Results—

We compared data from a longitudinal, nationally representative survey of older Americans with matched Medicare claims. Self-reported heart attack in the previous 2 years was compared with claims-identified acute myocardial infarction (AMI) and acute coronary syndrome. Among the 3.1% of respondents with self-reported heart attack, 32.8% had claims-identified AMI, 16.5% had non-AMI acute coronary syndrome, and 25.8% had other cardiac claims; 17.3% had no inpatient visits in the previous 2.5 years. Claims-identified AMIs were found in 1.4% of respondents; of these, 67.8% reported a heart attack. Self-reports were less likely among respondents >75 years of age (62.7% versus 74.6%;
P
=0.006), with less than high school education (61.6% versus 71.4%;
P
=0.015), with at least 1 limitation in activities of daily living (59.6% versus 74.7%;
P
=0.001), or below the 25th percentile of a word recall memory test (60.7% versus 71.3%;
P
=0.019). Both self-reported and claims-identified cardiac events were associated with increased mortality; the highest mortality was observed among those with claims-identified AMI who did not self-report (odds ratio, 2.8; 95% confidence interval, 1.5–5.1) and among those with self-reported heart attack and claims-identified AMI (odds ratio, 2.5; 95% confidence interval, 1.7–3.6) or non-AMI acute coronary syndrome (odds ratio, 2.7; 95% confidence interval, 1.8–4.1).

Conclusions—

There is considerable disagreement between self-reported and claims-identified events. Although self-reported heart attack may be inaccurate, it indicates increased risk of death, regardless of whether the self-report is confirmed by Medicare claims.
Pentraxin 3 Induces Vascular Endothelial Dysfunction Through a P-selectin/Matrix Metalloproteinase-1 Pathway
Authors: Carrizzo Albino , Lenzi Paola , Procaccini Claudio , Damato Antonio , Biagioni Francesca , Ambrosio Mariateresa , Amodio Giuseppina , Remondelli Paolo , Del Giudice Carmine , Izzo Raffaele , Malovini Alberto , Formisano Luigi , Gigantino Vincenzo , Madonna Michele , Puca Annibale A. , Trimarco Bruno , Matarese Giuseppe , Fornai Francesco , Vecchione Carmine
Published: March 2015

Background—

Pentraxin 3 (PTX3), the prototype of long pentraxins, has been described to be associated with endothelial dysfunction in different cardiovascular disorders. No study has yet evaluated the possible direct effect of PTX3 on vascular function.

Methods and Results—

Through in vitro experiments of vascular reactivity and ultrastructural analyses, we demonstrate that PTX3 induces dysfunction and morphological changes in the endothelial layer through a P-selectin/matrix metalloproteinase-1 pathway. The latter hampered the detachment of endothelial nitric oxide synthase from caveolin-1, leading to an impairment of nitric oxide signaling. In vivo studies showed that administering PTX3 to wild-type mice induced endothelial dysfunction and increased blood pressure, an effect absent in P-selectin–deficient mice. In isolated human umbilical vein endothelial cells, PTX3 significantly blunted nitric oxide production through the matrix metalloproteinase-1 pathway. Finally, using ELISA, we found that hypertensive patients (n=31) have higher plasma levels of PTX3 and its mediators P-selectin and matrix metalloproteinase-1 than normotensive subjects (n=21).

Conclusions—

Our data show for the first time a direct role of PTX3 on vascular function and blood pressure homeostasis, identifying the molecular mechanisms involved. The findings in humans suggest that PTX3, P-selectin, and matrix metalloproteinase-1 may be novel biomarkers that predict the onset of vascular dysfunction in hypertensive patients.
Applying General Rules of Halakhah in Halakhic Exegesis
Authors: Zur Uri
Published: March 2015

Rather than a sequence of indeterminate differences of legal opinion, the Halakhic texts in the Bavli as it has reached us incorporate a series of meta-principles stated as general rules for resolving the debates of the Tannaim. The present article focuses on the maxims of Halakhic arbitration cited in the Bavli in the name of R. Yohanan. Formulated as unequivocal, definitive prescriptions, R. Yohanan’s maxims for the arbitration of Tannaitic disputes are actually of debatable applicability; particular instances of Halakhah running counter to the general principles underscore this ambiguity. The ambiguity is both perplexing and a passageway to insight. Can any methodic classification of approaches to it be produced to facilitate a hermeneutic for reading both R. Yohanan’s imperatives and the cases of deviation from them that the Bavli preserves? The present article takes up the challenge.
Changing the Subject: Rabbinic Legal Process in the Absence of Justification
Authors: Rosenblum Jordan D.
Published: March 2015

This essay explores how changing the subject can function as a valid legal process in classical rabbinic literature. In order to do so, it first establishes standard rabbinic legal procedure, in which the legal reasoning for arguments is debated and either supported or refuted. Next, it discusses cases that do not fit this pattern: namely, those in which a rabbi, faced with a contradictory or complex argument, changes the subject rather than his reasoning or ruling. Through a discussion of such cases, this essay argues that, while not preferable, changing the subject can in fact be a valid rabbinic legal process.
The Rabbis and the Prophets: The Case of Amos
Authors: Neusner Jacob
Published: March 2015

The Prophets of Scripture are subverted by the Rabbis of the Talmud and Midrash. In the Rabbinic canon the writings of the Prophets are represented as a mass of prooftexts, made up of one clause or sentence at a time. Scripture’s prophetic writings cited in clauses and phrases in the Rabbinic canon thus lose their integrity and cease to speak in fully coherent paragraphs and chapters. So the Rabbis of late antiquity took over writings from what they recognized as remote and ancient times and of divine origin, and they re-presented selections of those writings in accord with their own project’s requirements, glossing clauses of the prophetic Scriptures but not whole, propositional discourses. This article illustrates how they did so, portraying the formal patterns of the Rabbis’ subversive glosses.
Antecedents of the Hanukkah Oil Story
Authors: Ron Zvi
Published: March 2015

When the rabbis in the Babylonian Talmud (Shabbat 21b) recounted the miracle of the oil’s lasting for eight days as the etiology of the festival of Hanukkah, they were basing themselves on biblical antecedents, in which the dedication of the Temple/tabernacle was accompanied by the descent of heavenly fire. Although there is no trace of the legend of the oil in any source before the Talmud, an analogous story is found in 2 Maccabees 1 in relation to Nehemiah, whose dedication of the Second Temple was accomplished through the fire of the First Temple, which had in the meanwhile liquefied into naphtha and was kept in an empty cistern. Another story that adumbrates the same themes is the discovery of the lost scroll under Josiah, which leads to the purification and renewal of the Temple. In each case an object from the past survives catastrophe or the reign of bad kings to provide continuity. A final case is the narrative of the building of the Temple in Ezra 6, in which the discovery of a lost scroll in the Achaemenid summer palace authorizes the construction. The Talmudic Hanukkah story is thus seen as a midrash based on biblical precedents.
Halakhic Changes in the Interpretation of the Commandment to Educate a Child to Observe Commandments
Authors: Gilat Israel Zvi
Published: March 2015

This review shows that Jewish understanding of the nature of the obligation to educate a child to observe the commandments has changed over time and should not be regarded as fixed or absolute. Early Tannaitic halakhah focused on the age at which the child possessed the physical ability to perform the commandments, not specifically twelve for a girl or thirteen for a boy. Education was directed at encouraging the child to observe the commandment as soon as he or she was physically capable of doing so. Additionally, early law understood that every Jew must ensure that his fellow-Jew perform the commandments, not just the child’s parents. In later law, the child’s obligation was postponed to thirteen, and, in this setting, the obligation to educate a child under that age was interpreted as a distinct commandment intended to ensure that the child became accustomed to doing so. This obligation now specifically applied to the father and not to every Jew (and even not to the mother), and it was interpreted as separate from the general responsibility of a Jew towards his fellow-Jew.
Rashi’s Glosses Belaaz: Navigating Hebrew Scripture under Feudal Lanterns
Authors: Herman Shael
Published: March 2015

Amid sporadic anti-Jewish violence whipped by a crusading frenzy, Rabbi Shlomo Yitzhaki (“Rashi”) composed a commentary on the Hebrew Bible that was destined to become a vast navigational aid for God’s scriptural plan. Many of Rashi’s glosses invited medieval Jews on a spiritual pilgrimage that would dispel their sense of subjugation to temporal Christian powers. From the advent of Christianity, Jewish communities increasingly steered a course between Jewish autonomy and welfare, on one hand, and accommodation of Christian and feudal strictures, on the other. Wondering whether the cataclysmic destruction of the Second Temple in 70 c.e. signaled God’s abandonment of his people, medieval Jews’ scriptural interpretations intensified the themes of survival and internal social cohesion. To guide medieval Jewry through a middle ground between a characteristically triumphant scriptural landscape and the dispiriting Christian counterpart, Rashi frequently incorporated into his glosses French terms he transliterated into Hebrew characters. This incorporation of French was both purposeful and well-informed. As a minority community in Rashi’s Troyes, Jews lived two distinct experiences: in one, they spoke vernacular French with Christian neighbors, while, in the other, they prayed and studied the Pentateuch and Prophets in Hebrew. In this setting, the laazim communicated to Jewish readers in a specialized language akin to a password or a special handshake. Yet the glosses, because they were enveloped in Hebrew commentaries and disguised in Hebrew letters, would have eluded French-speaking Christians who could not have identified fragments of their own language hiding in plain sight.
The Mystics of the Historical Truth: A Metaphysical Commentary on Gerschom Scholem’s Idea of Jewish History
Authors: Miron Ronny
Published: March 2015

Gerschom Scholem’s perception of metaphysical truth as a law of historical reality stood behind his study of the Kabbalah. The uncovering of this truth and deciphering of the mark it leaves upon historical reality, he believed, served as the main tools in the anchoring of the Kabbalah as part of the continuity of Jewish history. The effort involved in revealing the truth seems to be an outcome of its containing hidden dimensions. Despite its metaphysical nature, historical truth does not denote an abstract element detached from human beings’ real experiences. Just as Scholem assumed that the mystical phenomenon was anchored to the historical reality of his time, he characterized the connection of mysticism to historical reality as “amazing” and “paradoxical.” These expressions reflect his fundamental understanding of history as an arena that is not only a space of discovery but also of concealment and mystery. This means that to the extent that the appearances of historical reality conceal the metaphysical truth that serves as a sort of legislative idea for it, so too in the depths of this reality the discovery of metaphysical truth takes place, finding paths—sometimes different, paradoxical, or even incomprehensible—through which it is revealed also in the historical world of phenomena.
A cultural constraints theory of police corruption: Understanding the persistence of police corruption in contemporary Indonesia
Authors: Buttle John W , Graham Davies Sharyn , Meliala Adrianus E
Published: March 2015

Despite a decade of reform, Indonesia’s police continue to be plagued by systemic corruption. This article examines the reasons for the persistence of police corruption by firstly establishing that corruption is rife and then discuses Indonesian police reform post-Suharto. The international understandings are explored with a view to developing a definition of police corruption that accounts for sociocultural and historical factors in Indonesia. There is an examination of the relevance of international theories of police corruption for Indonesia. It is argued that these theories are only partially applicable to Indonesia and the authors posit the ‘cultural constraints theory of police corruption’, which accounts for invitational, slippery slope, noble cause, and predatory theories, but recognizes the distinct nature of Indonesia.
Offender case management: Reducing the rate of reoffending by Māori
Authors: Sullivan Trudy , McDonald Michelle , Thomson Sergeant T
Published: March 2015

In New Zealand, the number of offenders who continue to commit crime after leaving prison or completing community-based sentences is high, with the likelihood of reoffending much higher for Māori. The Police, Iwi (Māori tribe) and the Department of Corrections (the New Zealand Government agency responsible for prisons and correctional facilities, community probation, and parole services) have set clear goals to reduce the level of crime and the rate of reoffending. A decrease in reoffending will benefit society in terms of reduced costs to the justice system, less crime, safer communities and fewer victims. There is growing international evidence that offender case management is effective at reducing reoffending. The collaborative approach brings together representatives from the justice system, local authorities and other organisations to work alongside offenders who are due for release from prison. This article presents the results of Project Kete, a joint initiative between A3K (an organisation that provides support for Māori clients), the Police and the Department of Corrections. Sixteen high-risk Māori offenders nearing the end of their sentences received intensive support and supervision to help them reintegrate into the community. The results are encouraging. All 16 offenders remained out of prison as at December 2014 – a 100% reduction in the expected reimprisonment rate – and the 1-year reconviction rate was 33% versus a predicted rate of 48%.
‘My heart poured forth understanding’
Authors: Warren Meredith J.C.
Published: March 2015

This paper argues that 4 Ezra 14 represents the climax of the sensory revelations experienced by Ezra, and as such, that this is the episode which finally facilitates Ezra’s understanding of divine wisdom. In each of episodes one through six Ezra is incapable of making sense of what has been revealed to him, even though Ezra’s sensory revelations escalate throughout the text, from hearing to seeing. It is only when Ezra tastes heavenly food in the final episode, the cup filled with the fiery liquid, that he is able to transcend mortal understanding. I argue that 4 Ezra 14:38–41, where Ezra ingests the liquid from the cup, participates in the hitherto undefined literary trope of hierophagy—food given by an immortal to a mortal which transforms the eater in some way. In tasting the divine liquid, Ezra surpasses ordinary hearing and sight, and consumes God’s meaning directly.
Wnt5a/Ror2 Mediates Temporomandibular Joint Subchondral Bone Remodeling
Authors: Yang T. , Zhang J. , Cao Y. , Zhang M. , Jing L. , Jiao K. , Yu S. , Chang W. , Chen D. , Wang M.
Published: March 2015

Increased subchondral trabecular bone turnover due to imbalanced bone-resorbing and bone-forming activities is a hallmark of osteoarthritis (OA). Wnt5a/Ror2 signaling, which can derive from bone marrow stromal cells (BMSCs), takes a role in modulating osteoblast and osteoclast formation. We showed previously that experimentally unilateral anterior crossbites (UACs) elicited OA-like lesions in mice temporomandibular joints (TMJs), displaying as subchondral trabecular bone loss. Herein, we tested the role of BMSC-derived Wnt5a/Ror2 signaling in regulating osteoclast precursor migration and differentiation in this process. The data confirmed the decreased bone mass, increased tartrate-resistant acid phosphatase (TRAP)–positive cell number, and enhanced osteoclast activity in TMJ subchondral trabecular bone of UAC-treated rats. Interestingly, the osteoblast activity in the tissue of TMJ subchondral trabecular bone of these UAC-treated rats was also enhanced, displaying as upregulated expressions of osteoblast markers and increased proliferation, migration, and differentiation capabilities of the locally isolated BMSCs. These BMSCs showed an increased CXCL12 protein expression level and upregulated messenger RNA expressions of Rankl, Wnt5a, and Ror2. Ex vivo data showed that their capacities of inducing migration and differentiation of osteoclast precursors were enhanced, and these enhanced capabilities were restrained after blocking their Ror2 signaling using small interfering RNA (siRNA) assays. Reducing Ror2 expression in the BMSC cell line by siRNA or blocking the downstream signalings with specific inhibitors also demonstrated a suppression of the capacity of the BMSC cell line to promote Wnt5a-dependent migration (including SP600125 and cyclosporine A) and differentiation (cyclosporine A only) of osteoclast precursors. These findings support the idea that Wnt5a/Ror2 signaling in TMJ subchondral BMSCs enhanced by UAC promoted BMSCs to increase Cxcl12 and Rankl expression, in which JNK and/or Ca2+/NFAT pathways were involved and therefore were engaged in enhancing the migration and differentiation of osteoclast precursors, leading to increased osteoclast activity and an overall TMJ subchondral trabecular bone loss in the UAC-treated rats.
Suicide by injecting lispro insulin with an intravenous cannula
Authors: Behera C , Swain Rajanikanta , Mridha Asit Ranjan , Pooniya Shashank
Published: March 2015

Suicide by injecting insulin is not uncommon both in diabetic and non-diabetic people. The victim usually uses an insulin syringe or a traditional syringe attached to a needle for the injection of insulin, of either animal or synthetic origin. We report a case of suicide by a non-diabetic physician by injecting lispro insulin through an intravenous cannula. To the best of our knowledge, the use of an intravenous cannula for the injection of insulin for suicide is unusual and is rarely reported in the medico-legal literature.
Gastro-intestinal ascariasis – an unusual autopsy case report
Authors: Kanchan Tanuj , Wasti Harihar , Acharya Jenash
Published: March 2015

Ascaris lumbricoides or roundworms’ propensity to produce large number of eggs that are resistant to extremes of environmental conditions have made them one of the highly prevalent and geographically well distributed nematodes among poor socio-economic regions throughout the world. We present an unusual case of fatal gastro-intestinal ascariasis where general neglect, and firm and prolonged reliance on traditional healing methods led to aggregation of roundworms to such an extent that otherwise seems improbable in modern times and, hence, is worth reporting.