bluuebunny/crossref_metadata_2025 huggingface dataset:
Statistical dataset on software metrics in object-oriented systems
Authors: Filó Tarcísio G.S. , Bigonha Mariza A.S. , Ferreira Kecia A.M.
Published: September 2014

This paper presents a set of statistical data on the software metrics of object-oriented systems. The data were generated from the Qualitas.class Corpus, which gathered a large amount of metrics data from the 111 systems included in Qualitas Corpus. We used the R project for Statistical Computing to generate 6 statistical graphs, 4 summarization/aggregation tables and an R script, for each of the 21 metrics evaluated in each of the 111 systems. This amounted to 13,986 graphs, 8,800 tables and 2,200 R scripts. We also utilized EasyFit to fit a large number of distributions to each dataset, which in turn provided the best fitting statistical distribution, as well as the fit ranking. We also provide a MySQL database dump that normalizes the metric measures and facilitates data manipulation tasks such as filtering and aggregation. By making this set available, we intend to help researchers in their work on software metrics.
Object-oriented model-based specification languages
Authors: Jalila A. , Mala D. Jeya
Published: September 2014

Complex, soft-real-time system development is one of the challenges in the software industry, as it is difficult to understand, test and maintain such systems. However, the software development goal is to operate reliably despite this complexity. This can be achieved by applying formal methods, which use a language that has a strong mathematical foundation for describing the system. To be more specific, model-based specification languages are used to resolve ambiguities in user requirements or detect design errors early in the software life cycle. This paper compares object-oriented model-based formal languages such as Zed (Z), Vienna Development Method (VDM) and Object Constraint Language (OCL) based on various factors. Also, the issues surrounding the application of these formal methods to various software problems are discussed in this paper. The present research work enables software developers to select an appropriate language suiting their specific requirements.
Working conference summary
Authors: Doerr Joerg , Opdahl Andreas L.
Published: September 2014

In this paper, we summarise REFSQ 2013 - the 19th International Working Conference on Requirements Engineering: Foundation for Software Quality - which took place in Essen, Germany on April 8-11 2013.
Trends and emerging areas of agile research
Authors: Falessi Davide , Oliveira Renan , Taylor Katie , Fontana Rafaela M. , Power Ken , Vallon Raoul , Giardino Carmine , Rejab Mawarny Md. , Wang Xiaofeng
Published: September 2014

The PhD symposium of XP2014, the 15th International Conference on Agile Software Development, was organized as a half-day event prior to the main conference program. Seven PhD candidates came from different research institutes across the globe to present their own research proposals at the symposium. The symposium was run in a lively and interactive manner. The candidates received constructive feedback on their proposals from all the symposium participants. In this report we describe the presented proposals, focusing on the content and feedback. Through them we can take a peek at the trends and emerging areas of agile research in the coming years.
A heuristic for architecting cloud applications
Authors: Gupta Sujoy
Published: September 2014

As access to the Internet becomes more ubiquitous, software applications and services are increasingly being deployed in the cloud. While this approach has revolutionized software and delivered great efficiencies for users and application developers, it has also brought the issues of scalability and adaptability of cloud-based applications to the forefront. All users of a cloud application share its infrastructure, which is managed by the application developer. As the number of users increases, the application has to scale along with it, if the user experience is to not degrade. Moreover, in order to survive in a highly competitive environment, the application has to adapt rapidly to evolving user needs. Therefore, the ability to architect scalable and adaptable cloud applications has become one of the most sought after skills in the software industry. In this paper, we will consider a simple recursive heuristic for iteratively architecting a cloud application for scalability and adaptability.
Heuristics-based algorithm to dynamically adapt icon sizes and layouts on touch devices
Authors: Jain Ajay , Chandra Mohit
Published: September 2014

This work1 provides an intelligent algorithm that analyzes the success (and failure) rate of a touch gesture in order to determine best size and layout of icons. Dynamic adaptation of icon size is done to best match device user's finger impression size resulting into reduction in failed tapings which would have otherwise occurred due to variations between icon size and finger's impression.

Gravity of the said problem is analyzed by conducting a survey amongst 100 plus users. The implementation is also tested by building an android gaming application. The game is then released to limited set of users where dynamic icons sizes are generated based on user's score on successful taps on rapidly changing icons.
WTTM 2013, the fifth workshop on the theory of transactional memory
Authors: Capdevielle Claire , Hans Sandeep
Published: September 2014

In conjunction with DISC 2013, the TransForm project (Marie Curie Initial Training Network) and EuroTM (COST Action IC1001) supported the 5th edition of the Workshop on the Theory of Transactional Memory (WTTM 2013). The objective of WTTM was to discuss new theoretical challenges and recent achievements in the area of transactional computing with emphasis on transactional memory. The workshop took place on October 14, 2013, in Jerusalem, Israel. This report is intended to give highlights of the problems discussed during the workshop.
Intestinal epithelial expression of TNFAIP3 results in microbial invasion of the inner mucus layer and induces colitis in IL-10-deficient mice
Authors: Murphy Stephen F. , Rhee Lesley , Grimm Wesley A. , Weber Christopher R. , Messer Jeannette S. , Lodolce James P. , Chang Jonathan E. , Bartulis Sarah J. , Nero Thomas , Kukla Renata A. , MacDougall Gordon , Binghay Charles , Kolodziej Lauren E. , Boone David L.
Published: September 2014

Tumor necrosis factor-induced protein 3 (TNFAIP3; also known as A20) negatively regulates NF-κB and MAPK signals to control inflammatory responses. TNFAIP3 also protects against TNF-induced cell death. Intestinal epithelial cell (IEC) expression of TNFAIP3 improves barrier function and tight junction integrity and prevents dextran sulfate sodium (DSS)-induced IEC death and colitis. We therefore investigated the effects of TNFAIP3 expression in IEC on immune homeostasis in the intestines of immune-compromised mice. Villin-TNFAIP3 (v-TNFAIP3) transgenic mice were interbred with IL-10−/−mice (v-TNFAIP3 × IL-10−/−) and incidence, onset, and severity of colitis was assessed. v-TNFAIP3 × IL-10−/−mice displayed severe, early onset, and highly penetrant colitis that was not observed in IL-10−/−or v-TNFAIP3 mice. V-TNFAIP3 mice displayed altered expression of mucosal cytokines, increased numbers of mucosal regulatory T cells, and altered expression of mucosal antimicrobial peptides (AMPs). Microbial colonization of the inner mucus layer of v-TNFAIP3 mice was observed, along with alterations in the microbiome, but this was not sufficient to induce colitis in v-TNFAIP3 mice. The relative sterility of the inner mucus layer observed in wild-type and IL-10−/−mice was lost in v-TNFAIP3 × IL-10−/−mice. Thus IEC-derived factors, induced by signals that are inhibited by TNFAIP3, suppress the onset of inflammatory bowel disease in IL-10−/−mice. Our results indicate that IEC expression of TNFAIP3 alters AMP expression and allows microbial colonization of the inner mucus layer, which activates an IL-10-dependent anti-inflammatory process that is necessary to prevent colitis.
β-Adrenergic receptor blockade impairs coronary exercise hyperemia in young men but not older men
Authors: Ross Amanda J. , Gao Zhaohui , Pollock Jonathan P. , Leuenberger Urs A. , Sinoway Lawrence I. , Muller Matthew D.
Published: September 2014

Patients with coronary artery disease have attenuated coronary vasodilator responses to physiological stress, which is partially attributed to a β-adrenergic receptor (β-AR)-mediated mechanisms. Whether β-ARs contribute to impaired coronary vasodilation seen with healthy aging is unknown. The purpose of this study was to investigate the role of β-ARs in coronary exercise hyperemia in healthy humans. Six young men (26 ± 1 yr) and seven older men (67 ± 4 yr) performed isometric handgrip exercise at 30% maximal voluntary contraction for 2 min after receiving intravenous propranolol, a β-AR antagonist, and no treatment. Isoproterenol, a β-AR agonist, was infused to confirm the β-AR blockade. Blood pressure and heart rate were monitored continuously, and coronary blood flow velocity (CBV, left anterior descending artery) was measured by transthoracic Doppler echocardiography. Older men had an attenuated ΔCBV to isometric exercise (3.8 ± 1.3 vs. 9.7 ± 2.1 cm/s, P = 0.02) compared with young men. Propranolol decreased the ΔCBV at peak handgrip exercise in young men (9.7 ± 2.1 vs. 2.7 ± 0.9 cm/s, P = 0.008). However, propranolol had no effect on ΔCBV in older men (3.8 ± 1.3 vs. 4.2 ± 1.9 cm/s, P = 0.9). Older men also had attenuated coronary hyperemia to low-dose isoproterenol. These data indicate that β-AR control of coronary blood flow is impaired in healthy older men.
Novel inhibitors of nuclear transport cause cell cycle arrest and decrease cyst growth in ADPKD associated with decreased CDK4 levels
Authors: Tan Matthew , Wettersten Hiromi I. , Chu Kristy , Huso David L. , Watnick Terry , Friedlander Sharon , Landesman Yosef , Weiss Robert H.
Published: September 2014

Autosomal-dominant polycystic kidney disease (ADPKD) is a progressive, proliferative renal disease. Kidneys from ADPKD patients are characterized by the presence of cysts that are marked by enhanced proliferation and apoptosis of renal tubular epithelial cells. Current treatment of this disease is supportive, as there are few if any clinically validated targeted therapeutics. Given the parallels between cystic disease and cancer, and in light of our findings of the efficacy of the nuclear transport inhibitors in kidney cancer, which has similarities to ADPKD, we asked whether such inhibitors show utility in ADPKD. In this study, we tested selective inhibitors of nuclear export (SINE) in two human ADPKD cell lines and in an in vivo mouse model of ADPKD. After effective downregulation of a nuclear exporter, exportin 1 (XPO1), with KPT-330, both cell lines showed dose-dependent inhibition of cell proliferation through G0/G1 arrest associated with downregulation of CDK4, with minimal apoptosis. To analyze mechanisms of CDK4 decrease by XPO1 inhibition, localization of various XPO1 target proteins was examined, and C/EBPβ was found to be localized in the nucleus by XPO1 inhibition, resulting in an increase of C/EBPα, which activates degradation of CDK4. Furthermore, inhibition of XPO1 with the parallel inhibitor KPT-335 attenuated cyst growth in vivo in the PKD1 mutant mouse model Pkd1v/v. Thus, inhibition of nuclear export by KPT-330, which has shown no adverse effects in renal serum chemistries and urinalyses in animal models, and which is already in phase 1 trials for cancers, will be rapidly translatable to human ADPKD.
Morning pentraxin3 levels reflect obstructive sleep apnea–related acute inflammation
Authors: Kobukai Yusuke , Koyama Takashi , Watanabe Hiroyuki , Ito Hiroshi
Published: September 2014

This study investigated morning levels of pentraxin3 (PTX3) as a sensitive biomarker for acute inflammation in patients with obstructive sleep apnea (OSA). A total of 61 consecutive patients with OSA were divided into two groups: non-to-mild ( n = 20) and moderate-to-severe ( n = 41) OSA based on their apnea-hypopnea index (AHI) score. Those patients with moderate-to-severe OSA were further divided into continuous positive airway pressure (CPAP) treated ( n = 21) and non-CPAP-treated ( n = 20) groups. Morning and evening serum PTX3 and high-sensitivity (hs) C-reactive protein (CRP) levels were measured before and after 3 mo of CPAP therapy. The baseline hs-CRP and PTX3 levels were higher in patients with moderate-to-severe OSA than in those with non-to-mild OSA. Moreover, the serum PTX3 levels, but not the hs-CRP levels, were significantly higher after than before sleep in the moderate-to-severe OSA group (morning PTX3, 1.96 ± 0.52; evening PTX3, 1.71 ± 0.44 ng/ml). OSA severity as judged using the AHI was significantly correlated with serum PTX3 levels but not hs-CRP levels. The highest level of correlation was found between the AHI and morning PTX3 levels ( r = 0.563, P < 0.001). CPAP therapy reduced evening and morning serum hs-CRP and PTX3 levels in patients with moderate-to-severe OSA; however, the reduction in PTX3 levels in the morning was greater than that in the evening (morning −29.8 ± 16.7% vs. evening −12.6 ± 26.8%, P = 0.029). Improvement in the AHI score following CPAP therapy was strongly correlated with reduced morning PTX3 levels( r = 0.727, P < 0.001). Based on these results, morning PTX3 levels reflect OSA-related acute inflammation and are a useful marker for improvement in OSA following CPAP therapy.
Shorter Leukocyte Telomere Length Is Independently Associated with Poor Survival in Patients with Bladder Cancer
Authors: Russo Alessia , Modica Federica , Guarrera Simonetta , Fiorito Giovanni , Pardini Barbara , Viberti Clara , Allione Alessandra , Critelli Rossana , Bosio Andrea , Casetta Giovanni , Cucchiarale Giuseppina , Destefanis Paolo , Gontero Paolo , Rolle Luigi , Zitella Andrea , Fontana Dario , Frea Bruno , Vineis Paolo , Sacerdote Carlotta , Matullo Giuseppe
Published: September 2014

Background: Shorter telomere length (TL) has been reported to be associated with increased risk of early death in elder individuals. Telomere shortening has been also related to chromosomal instability, which may possibly contribute to the development of several types of digestive or urogenital system cancers and smoking-related tumors. Therefore, we investigated the impact of TL on bladder cancer survival.

Methods: TL was measured in leukocyte DNA from whole peripheral blood using quantitative real-time PCR in 463 patients with bladder cancer from a total 726 cases who were followed for up to 18 years.

Results: Patients with muscle-invasive tumor/any grade had shorter telomere than patients with non–muscle-invasive tumor/high-grade and with non–muscle-invasive tumor/non–high-grade (TL reference 0.7 ± 0.2; vs. respectively, 0.8 ± 0.2, P = 3.4 × 10−2 and 0.8 ± 0.2, P = 3.6 × 10−2). Moreover, patients in the lowest quartiles of TL were associated with decreased survival after diagnosis (log-rank test, P = 3.9 × 10−4). A Cox regression adjusted by age, cancer aggressiveness, Bacillus Calmette-Guérin, radical cystectomy, radiotherapy, and chemotherapy showed an independent effect of TL on bladder cancer survival (HR, 3.9; 95% confidence interval, 1.7–9.1; P = 1.2 × 10−3).

Conclusions: Our results suggest that leukocyte TL is only partly related to tumor aggressiveness and that shorter telomeres act as independent prognostic predictor of survival in patients with bladder cancer. TL information may allow to better select therapeutic approaches in patients with the same stage and grade.

Impact: Blood leukocyte TL levels could provide an additional noninvasive prognostic marker to better predict survival and personalize therapies in patients with bladder cancer. Cancer Epidemiol Biomarkers Prev; 23(11); 2439–46. ©2014 AACR.
Withanone-Rich Combination of Ashwagandha Withanolides Restricts Metastasis and Angiogenesis through hnRNP-K
Authors: Gao Ran , Shah Navjot , Lee Jung-Sun , Katiyar Shashank P. , Li Ling , Oh Eonju , Sundar Durai , Yun Chae-Ok , Wadhwa Renu , Kaul Sunil C.
Published: September 2014

Ashwagandha is an important herb used in the Indian system of traditional home medicine, Ayurveda. Alcoholic extract (i-Extract) from its leaves and its component, withanone, were previously shown to possess anticancer activity. In the present study, we developed a combination of withanone and withaferin A, major withanolides in the i-Extract, that retained the selective cancer cell killing activity and found that it also has significant antimigratory, -invasive, and -angiogenic activities, in both in vitro and in vivo assays. Using bioinformatics and biochemical approaches, we demonstrate that these phytochemicals caused downregulation of migration-promoting proteins hnRNP-K, VEGF, and metalloproteases and hence are candidate natural drugs for metastatic cancer therapy. Mol Cancer Ther; 13(12); 2930–40. ©2014 AACR.
Prevalence of Hidradenitis Suppurativa: A Population-Based Study in Olmsted County, Minnesota
Authors: Shahi Varun , Alikhan Ali , Vazquez Benjamin G. , Weaver Amy L. , Davis Mark D.
Published: September 2014

Background: Hidradenitis suppurativa (HS) is a follicular occlusion disorder occurring in apocrine-rich regions of the skin. Estimates of the prevalence of this disorder have not been population-based. Objective: We sought to provide population-based information on the prevalence of HS in Olmsted County, Minnesota, as of January 1, 2009. Methods: The Rochester Epidemiology Project, a unique infrastructure that combines and makes accessible all medical records in Olmsted County since the 1960s, was used to collect population-based data on the prevalence of HS. Results: We identified 178 confirmed cases of HS that included 135 females and 43 males, and estimated the total sex- and age-adjusted prevalence in Olmsted County to be 127.8 per 100,000 or 0.13%. The total prevalence was significantly higher among women than men. Conclusion: This study represents the first population-based investigation on the prevalence of HS. In this population-based cohort, HS was less prevalent than suggested by previous reports.
Preoperative Low-Dose Steroid Can Prevent Respiratory Insufficiency After Thymectomy in Generalized Myasthenia Gravis
Authors: Kataoka Hiroshi , Kiriyama Takao , Kawaguchi Takeshi , Sawa Nobuhiro , Sugie Kazuma , Horikawa Hirosei , Tojo Takashi , Ueno Satoshi
Published: September 2014

Background: Postoperative respiratory insufficiency (PRI) in myasthenia gravis (MG) often occurs within several days after thymectomy and remains problematic. In limited studies reporting that preoperative steroids prevented PRI in patients with MG, high doses of steroids were used and detailed information on the use of steroids is limited. Because high-dose steroids significantly increase the risk of adverse effects, we studied 37 patients with generalized MG to investigate whether low-dose steroids might prevent PRI. Methods: The low-dose steroids were started orally, and the dose was gradually increased to the maximum level (30 mg/day). Immediately before thymectomy, patients received the maximum dose of oral steroids daily. PRI was defined as the development of restrictive dysfunction requiring mechanical ventilation within 3 days after thymectomy and total postoperative mechanical ventilation support time of >24 h. Results: The rate of PRI in the low-dose steroid use group was significantly lower than that in the no-steroid use group. The postoperative stay in the intensive care unit was shorter in the steroid use group. Conclusions: Extended thymectomy is a well-accepted surgical treatment for selected patients with MG. However, PRI remains problematic. Our results suggest that not only preoperative high-dose steroid treatment, but also low-dose steroid treatment can prevent PRI.
Endocasts: Possibilities and Limitations for the Interpretation of Human Brain Evolution
Authors: Neubauer Simon
Published: September 2014

Brains are not preserved in the fossil record but endocranial casts are. These are casts of the internal bony braincase, revealing approximate brain size and shape, and they are also informative about brain surface morphology. Endocasts are the only direct evidence of human brain evolution, but they provide only limited data (‘paleoneurology'). This review discusses some new fossil endocasts and recent methodological advances that have allowed novel analyses of old endocasts, leading to intriguing findings and hypotheses. The interpretation of paleoneurological data always relies on comparative information from living species whose brains and behavior can be directly investigated. It is therefore important that future studies attempt to better integrate different approaches. Only then will we be able to gain a better understanding about hominin brain evolution.
Metastatic Nasopharyngeal Carcinoma Outcomes in Patients on Cisplatin with Nolatrexed or 5-Fluorouracil
Authors: Zheng Jihua , Lin Jianguang , Wang Lin , Zhou Juan , Xie Bo , Xu Tianwen , Zhang Weimin
Published: September 2014

SummaryBackground: Nasopharyngeal carcinoma (NPC) is one of the most common malignant tumors in southern China. In this study, we compared the clinical efficacy and toxicity of cisplatin with nolatrexed (LP) or 5-fluorouracil (FP) for NPC. Patients and Methods: 33 patients with metastatic NPC were randomized to the LP and FP regimens. The LP regimen consisted of continuous intravenous infusions of 740 mg/m2 nolatrexed on days 1-5 and 25 mg/m2 intravenous cisplatin on days 2-4. The FP regimen consisted of continuous intravenous infusions of 600 mg/m2 5-fluorouracil on days 1-5 and 25 mg/m2 intravenous cisplatin on days 2-4. Cycles were repeated every 3 weeks until disease progression or completion of a total of 6 courses. Results: There were no significant differences in the response rates (RR), disease control rates (DCR), times to progression (TTP), and median survival times (MST) between the regimens. The toxicities of the two regimens were mostly grade I/II, but the stomatitis incidence in the patients on the LP regimen was significantly lower than that on the FP regimen. Conclusions: The efficacy of the LP regimen was similar to that of the FP regimen. The LP regimen had lower toxicity.
Inhibiting the Th17/IL-17A–Related Inflammatory Responses With Digoxin Confers Protection Against Experimental Abdominal Aortic Aneurysm
Authors: Wei Zhanjie , Wang Yu , Zhang Kailun , Liao Yaohang , Ye Ping , Wu Jie , Wang Yang , Li Feifei , Yao Yufeng , Zhou Yanzhao , Liu Jinping
Published: September 2014

Objective—

T helper 17 cells and interleukin-17A have been implicated in the progression of abdominal aortic aneurysm (AAA). Retinoic acid–related orphan receptor gamma thymus, the master transcription factor of T helper 17 cell differentiation, is selectively antagonized by digoxin. However, the effect of antagonizing retinoic acid–related orphan receptor gamma thymus on AAA has not been investigated.

Approach and Results—

We used human aortic sample analysis and 2 different experimental AAA models: (a) Angiotensin II (Ang II)–induced ApoE
−/−
male mice (Ang II/APOE model) and (b) porcine pancreatic elastase perfusion C57BL/6 mice (porcine pancreatic elastase/C57 model). In the Ang II/APOE model, all mice (n=80) were divided into 4 groups: sham group (saline+0.5% dimethyl sulfoxide treatment), control group (Ang II+0.5% dimethyl sulfoxide treatment), low-dose group (Ang II+low-dose digoxin, 20 μg/d per mouse), and high-dose group (Ang II+high-dose digoxin, 40 μg/d per mouse). All treatments began on day 0 after surgery. Efficacy was determined via aortic diameter and systolic blood pressure measurements, histopathology and protein expression, and flow cytometry analysis when euthenized. Human aortic tissue analysis showed that both interleukin-17A and retinoic acid–related orphan receptor gamma thymus increased in AAA tissues. The low-dose and high-dose groups had AAA incidences of 60% and 35%, respectively, compared with 70% in the control group. The T helper 17- and interleukin-17A–related inflammatory responses were dose-dependently attenuated by digoxin treatment. Digoxin was also highly effective in the porcine pancreatic elastase/C57 model.

Conclusions—

Digoxin attenuates experimental AAA progression in a model-independent manner. Antagonizing retinoic acid–related orphan receptor gamma thymus activity by digoxin may become a novel strategy for nonsurgical AAA treatment.
Nonequilibrium Reactivation of Na
+
Current Drives Early Afterdepolarizations in Mouse Ventricle
Authors: Edwards Andrew G. , Grandi Eleonora , Hake Johan E. , Patel Sonia , Li Pan , Miyamoto Shigeki , Omens Jeffrey H. , Heller Brown Joan , Bers Donald M. , McCulloch Andrew D.
Published: September 2014

Background—

Early afterdepolarizations (EADs) are triggers of cardiac arrhythmia driven by L-type Ca
2+
current (I
CaL
) reactivation or sarcoplasmic reticulum Ca
2+
release and Na
+
/Ca
2+
exchange. In large mammals the positive action potential plateau promotes I
CaL
reactivation, and the current paradigm holds that cardiac EAD dynamics are dominated by interaction between I
CaL
and the repolarizing K
+
currents. However, EADs are also frequent in the rapidly repolarizing mouse action potential, which should not readily permit I
CaL
reactivation. This suggests that murine EADs exhibit unique dynamics, which are key for interpreting arrhythmia mechanisms in this ubiquitous model organism. We investigated these dynamics in myocytes from arrhythmia-susceptible calcium calmodulin-dependent protein kinase II delta C (CaMKIIδC)-overexpressing mice (Tg), and via computational simulations.

Methods and Results—

In Tg myocytes, β-adrenergic challenge slowed late repolarization, potentiated sarcoplasmic reticulum Ca
2+
release, and initiated EADs below the I
CaL
activation range (–47±0.7 mV). These EADs were abolished by caffeine and tetrodotoxin (but not ranolazine), suggesting that sarcoplasmic reticulum Ca
2+
release and Na
+
current (I
Na
), but not late I
Na
, are required for EAD initiation. Simulations suggest that potentiated sarcoplasmic reticulum Ca
2+
release and Na
+
/Ca
2+
exchange shape late action potential repolarization to favor nonequilibrium reactivation of I
Na
and thereby drive the EAD upstroke. Action potential clamp experiments suggest that lidocaine eliminates virtually all inward current elicited by EADs, and that this effect occurs at concentrations (40–60 μmol/L) for which lidocaine remains specific for inactivated Na
+
channels. This strongly suggests that previously inactive channels are recruited during the EAD upstroke, and that nonequilibrium I
Na
dynamics underlie murine EADs.

Conclusions—

Nonequilibrium reactivation of I
Na
drives murine EADs.
Renal Handling of Galectin‐3 in the General Population, Chronic Heart Failure, and Hemodialysis
Authors: Meijers Wouter C. , van der Velde A. Rogier , Ruifrok Willem P. , Schroten Nicolas F. , Dokter Martin M. , Damman Kevin , Assa Solmaz , Franssen Casper F. , Gansevoort Ron T. , van Gilst Wiek H. , Silljé Herman H. , de Boer Rudolf A.
Published: September 2014

Background

Galectin‐3 is a biomarker for prognostication and risk stratification of patients with heart failure (
HF
). It has been suggested that renal function strongly relates to galectin‐3 levels. We aimed to describe galectin‐3 renal handling in
HF
.

Methods and Results

In Sprague–Dawley rats, we infused galectin‐3 and studied distribution and renal clearance. Furthermore, galectin‐3 was measured in urine and plasma of healthy controls, HF patients and hemodialysis patients. To mimic the human situation, we measured galectin‐3 before and after the artificial kidney. Infusion in rats resulted in a clear increase in plasma and urine galectin‐3. Plasma galectin‐3 in HF patients (n=101; mean age 64 years; 93% male) was significantly higher compared to control subjects (n=20; mean age 58 years; 75% male) (16.6 ng/
mL
versus 9.7 ng/
mL
,
P
<0.001), while urinary galectin‐3 in HF patients was comparable (28.1 ng/
mL
versus 35.1 ng/
mL
,
P
=0.830). The calculated galectin‐3 excretion rate was lower in HF patient (2.3 mL/min [1.5 to 3.4] versus 3.9 mL/min [2.3 to 6.4] in control subjects;
P
=0.005). This corresponded with a significantly lower fractional excretion of galectin‐3 in HF patients (2.4% [1.7 to 3.7] versus 3.0% [1.9 to 5.5];
P=
0.018). These differences, however, were no longer significant after correction for age, gender, diabetes, and smoking. HF patients who received diuretics (49%) showed significantly higher aldosterone and galectin‐3 levels. Hemodialysis patients (n=105; mean age 63 years; 65% male), without urinary galectin‐3 excretion, had strongly increased median plasma galectin‐3 levels (70.6 ng/
mL
).

Conclusions

In this small cross‐sectional study, we report that urine levels of galectin‐3 are not increased in
HF
patients, despite substantially increased plasma galectin‐3 levels. The impaired renal handling of galectin‐3 in patients with
HF
may explain the described relation between renal function and galectin‐3 and may account for the elevated plasma galectin‐3 in
HF
.
Characterizing Types of Readmission After Acute Coronary Syndrome Hospitalization: Implications for Quality Reporting
Authors: Southern Danielle A. , Ngo Jennifer , Martin Billie‐Jean , Galbraith P. Diane , Knudtson Merril L. , Ghali William A. , James Matthew T. , Wilton Stephen B.
Published: September 2014

Background

Thirty‐day readmission rates have been tied to hospital reimbursement in the United States, but remain controversial as measures of healthcare quality. We profile the timing, main diagnoses, and survival outcomes of inpatient and emergency department readmissions after acute coronary syndrome (
ACS
), based on a large regional database.

Methods and Results

Patients enrolled in the Alberta Provincial Project for Outcomes Assessment in Coronary Heart Disease (
APPROACH
) registry with an
ACS
hospitalization between April 2008 and March 2010 (n=3411) were included. Primary outcomes were inpatient and emergency department–only readmissions, at 30 days and 1 year. Predictors of 30‐day readmission were identified, and the association between 30‐day readmission status and mortality was evaluated. A total of 1170 (34.3%) patients had ≥1 hospital readmission within 30 days, reaching 2106 (61.7%) within 1 year of
ACS
discharge. Of first readmissions, 45% were emergency department only and 53% were for cardiovascular or possibly related diagnoses. Renal disease and diabetes predicted all‐cause readmissions at 30 days and 1 year, but there were no robust predictors of cardiovascular readmissions. Thirty‐day inpatient, but not emergency department, readmissions were associated with increased mortality.

Conclusions

Hospital readmissions within 30 days after discharge for
ACS
are common, and associated with increased mortality. However, our findings underline that readmissions are quite heterogeneous in nature, and that many readmissions are unrelated to index stay and thus not easily predicted with common clinical variables. All‐cause 30‐day readmission rates may be too simplistic, and perhaps even misleading, as a hospital performance metric.
Circulating Fibroblast Growth Factor‐23 and the Incidence of Atrial Fibrillation: The Atherosclerosis Risk in Communities Study
Authors: Alonso Alvaro , Misialek Jeffrey R. , Eckfeldt John H. , Selvin Elizabeth , Coresh Josef , Chen Lin Y. , Soliman Elsayed Z. , Agarwal Sunil K. , Lutsey Pamela L.
Published: September 2014

Background

Increased concentrations of circulating fibroblast growth factor 23 (
FGF
‐23) have been associated with higher risk of cardiovascular disease. The association between
FGF
‐23 and the risk of atrial fibrillation (
AF
), a common arrhythmia, is less defined. Thus, we explored whether
FGF
‐23 concentration was associated with
AF
incidence in a large community‐based cohort.

Methods and Results

We studied 12 349 men and women enrolled in the Atherosclerosis Risk in Communities (ARIC) study, without prevalent AF at baseline in 1990–1992. Serum intact FGF‐23 concentration was measured with the Kainos 2‐site ELISA. Incident AF through 2010 was ascertained from study ECGs and hospital discharge codes. Cox proportional hazards models adjusted for potential confounding factors, including kidney function, were used to estimate the association between FGF‐23 and AF risk. We identified 1572 AF events during a mean follow‐up of 17 years. In multivariable analysis, a difference of 1 SD (16 pg/
mL
) in baseline FGF‐23 was not associated with the risk of AF (hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.99, 1.09). Results were similar when FGF‐23 was modeled in quartiles (HR, 1.09; 95% CI, 0.94, 1.26, comparing extreme quartiles). Reduced kidney function was associated with increased AF risk across quartiles of FGF‐23 levels.

Conclusion

In this large community‐based cohort, baseline
FGF
‐23 levels were not associated with
AF
risk independently of kidney function. Our results do not support a major role for
FGF
‐23 as a risk factor for
AF
or as a mediator of the association between chronic kidney disease and
AF
.
Step‐Monitored Home Exercise Improves Ambulation, Vascular Function, and Inflammation in Symptomatic Patients With Peripheral Artery Disease: A Randomized Controlled Trial
Authors: Gardner Andrew W. , Parker Donald E. , Montgomery Polly S. , Blevins Steve M.
Published: September 2014

Background

This prospective, randomized, controlled clinical trial compared changes in primary outcome measures of claudication onset time (
COT
) and peak walking time (
PWT
), and secondary outcomes of submaximal exercise performance, daily ambulatory activity, vascular function, inflammation, and calf muscle hemoglobin oxygen saturation (StO
2
) in patients with symptomatic peripheral artery disease (
PAD
) following new exercise training using a step watch (
NEXT
Step) home‐exercise program, a supervised exercise program, and an attention‐control group.

Methods and Results

One hundred eighty patients were randomized. The
NEXT
Step program and the supervised exercise program consisted of intermittent walking to mild‐to‐moderate claudication pain for 12 weeks, whereas the controls performed light resistance training. Change scores for
COT
(
P
<0.001),
PWT
(
P
<0.001), 6‐minute walk distance (
P
=0.028), daily average cadence (
P
=0.011), time to minimum calf muscle StO
2
during exercise (
P
=0.025), large‐artery elasticity index (
LAEI
) (
P
=0.012), and high‐sensitivity C‐reactive protein (hs
CRP
) (
P
=0.041) were significantly different among the 3 groups. Both the
NEXT
Step home program and the supervised exercise program demonstrated a significant increase from baseline in
COT
,
PWT
, 6‐minute walk distance, daily average cadence, and time to minimum calf StO
2
. Only the
NEXT
Step home group had improvements from baseline in
LAEI
, and hs
CRP
(
P
<0.05).

Conclusions

NEXT
Step home exercise utilizing minimal staff supervision has low attrition, high adherence, and is efficacious in improving
COT
and
PWT
, as well as secondary outcomes of submaximal exercise performance, daily ambulatory activity, vascular function, inflammation, and calf muscle StO
2
in symptomatic patients with
PAD
.

Clinical Trial Registration

URL: ClinicalTrials.gov. Unique Identifier: NCT00618670.
Prevalence of Brain Arteriovenous Malformations in First-Degree Relatives of Patients With a Brain Arteriovenous Malformation
Authors: van Beijnum Janneke , van der Worp H. Bart , Algra Ale , Vandertop W. Peter , van den Berg René , Brouwer Patrick A. , van der Sprenkel Jan Willem Berkelbach , Kappelle L. Jaap , Rinkel Gabriël J.E. , Klijn Catharina J.M.
Published: September 2014

Background and Purpose—

It is uncertain whether familial occurrence of brain arteriovenous malformations (BAVMs) represents coincidental aggregation or a shared familial risk factor. We aimed to compare the prevalence of BAVMs in first-degree relatives (FDRs) of patients with BAVM and the prevalence in the general population.

Methods—

We sent a postal questionnaire to 682 patients diagnosed with a BAVM in 1 of 4 university hospitals to retrieve information about the occurrence of BAVMs among their FDRs. We calculated a prevalence ratio using the BAVM prevalence among FDRs and the prevalence from a Scottish population-based study (93 per 628 788 adults). A prevalence ratio of ≥9 with a lower limit of the 95% confidence interval of 3 was considered indicative of a shared familial risk factor.

Results—

Informed consent was given by 460 (67%) patients, who had 2992 FDRs. We identified 3 patients with a FDR with a BAVM, yielding a prevalence ratio of 6.8 (95% CI, 2.2–21).

Conclusions—

The prevalence of BAVMs in FDRs of patients with a BAVM was increased but did not meet our prespecified criterion for a shared familial risk factor. In combination with the low absolute risk of a BAVM in FDRs, our results do not support screening of FDRs for BAVMs.
Incidence, Trends, and Predictors of Ischemic Stroke 1 Year After an Acute Myocardial Infarction
Authors: Ulvenstam Anders , Kajermo Ulf , Modica Angelo , Jernberg Tomas , Söderström Lars , Mooe Thomas
Published: September 2014

Background and Purpose—

Ischemic stroke after acute myocardial infarction is an important complication. It is unknown whether the risk has changed because the treatment of acute myocardial infarction has improved during the past decade. There is also conflicting data about predictors of stroke risk.

Methods—

To obtain the 1-year incidence of stroke after acute myocardial infarction, the Register of Information and Knowledge about Swedish Heart Intensive Care Admissions database for the years 1998 to 2008 was merged with the Swedish National Patient Register (NPR). The time trend was studied by dividing the entire time period into 5 separate periods. Independent predictors were identified using a multivariable Cox proportional hazards regression model.

Results—

Between 1998 and 2008, 7185 of 173 233 patients with acute myocardial infarction had an ischemic stroke within 1 year (4.1%). There was a 20% relative risk reduction during the study period (1998–2000 versus 2007–2008) relative risk 0.80 (95% confidence interval, 0.75–0.86;
P
<0.001. Independent predictors of stroke were age, female sex, ST-segment–elevation myocardial infarction, previous stroke, previous diabetes mellitus, heart failure at admission, angiotensin-converting enzyme inhibitor treatment and atrial fibrillation. Reperfusion treatment with fibrinolysis and percutaneous coronary intervention and treatment with aspirin, P2Y12-inhibitors, and statins predicted a reduced risk of stroke.

Conclusions—

The risk of ischemic stroke within a year after myocardial infarction is substantial but has clearly been reduced during the studied time period. The major predictive factors found to correlate well with previous investigations. Reperfusion treatment, thrombocyte aggregation inhibition, and lipid lowering are the main contributors to the observed risk reduction.
Transient Receptor Potential Melastatin Subfamily Member 2 Cation Channel Regulates Detrimental Immune Cell Invasion in Ischemic Stroke
Authors: Gelderblom Mathias , Melzer Nico , Schattling Benjamin , Göb Eva , Hicking Gordon , Arunachalam Priyadharshini , Bittner Stefan , Ufer Friederike , Herrmann Alexander M. , Bernreuther Christian , Glatzel Markus , Gerloff Christian , Kleinschnitz Christoph , Meuth Sven G. , Friese Manuel A. , Magnus Tim
Published: September 2014

Background and Purpose—

Brain injury during stroke results in oxidative stress and the release of factors that include extracellular Ca
2+
, hydrogen peroxide, adenosine diphosphate ribose, and nicotinic acid adenine dinucleotide phosphate. These alterations of the extracellular milieu change the activity of transient receptor potential melastatin subfamily member 2 (TRPM2), a nonselective cation channel expressed in the central nervous system and the immune system. Our goal was to evaluate the contribution of TRPM2 to the tissue damage after stroke.

Methods—

In accordance with current quality guidelines, we independently characterized Trpm2 in a murine ischemic stroke model in 2 different laboratories.

Results—

Gene deficiency of
Trpm2
resulted in significantly improved neurological outcome and decreased infarct size. Besides an already known moderate neuroprotective effect of
Trpm2
deficiency in vitro, ischemic brain invasion by neutrophils and macrophages was particularly reduced in
Trpm2
-deficient mice. Bone marrow chimeric mice revealed that
Trpm2
deficiency in the peripheral immune system is responsible for the protective phenotype. Furthermore, experiments with mixed bone marrow chimeras demonstrated that Trpm2 is essential for the migration of neutrophils and, to a lesser extent, also of macrophages into ischemic hemispheres. Notably, the pharmacological TRPM2 inhibitor, N-(p-amylcinnamoyl)anthranilic acid, was equally protective in the stroke model.

Conclusions—

Although a neuroprotective effect of TRPM2 in vitro is well known, we can show for the first time that the detrimental role of TRPM2 in stroke primarily depends on its role in activating peripheral immune cells. Targeting TRPM2 systemically represents a promising therapeutic approach for ischemic stroke.
Nontraditional Serum Lipid Variables and Recurrent Stroke Risk
Authors: Park Jong-Ho , Lee Juneyoung , Ovbiagele Bruce
Published: September 2014

Background and Purpose—

Expert consensus guidelines recommend low-density lipoprotein cholesterol as the primary serum lipid target for recurrent stroke risk reduction. However, mounting evidence suggests that other lipid parameters might be additional therapeutic targets or at least also predict cardiovascular risk. Little is known about the effects of nontraditional lipid variables on recurrent stroke risk.

Methods—

We analyzed the Vitamin Intervention for Stroke Prevention study database comprising 3680 recent (<120 days) noncardioembolic stroke patients followed up for 2 years. Independent associations of baseline serum lipid variables with recurrent ischemic stroke (primary outcome) and the composite end point of ischemic stroke/coronary heart disease/vascular death (secondary outcomes) were assessed.

Results—

Of all variables evaluated, only triglycerides/high-density lipoprotein cholesterol (HDL-C) ratio was consistently and independently related to both outcomes: compared with the lowest quintile, the highest triglycerides/HDL-C ratio quintile was associated with stroke (adjusted hazard ratio, 1.56; 95% confidence interval, 1.05−2.32) and stroke/coronary heart disease/vascular death (1.39; 1.05−1.83), including adjustment for lipid modifier use. Compared with the lowest quintile, the highest total cholesterol/HDL-C ratio quintile was associated with stroke/coronary heart disease/vascular death (1.45; 1.03−2.03). Low-density lipoprotein cholesterol/HDL-C ratio, non-HDL-C, elevated triglycerides alone, and low HDL-C alone were not independently linked to either outcome.

Conclusions—

Of various nontraditional lipid variables, elevated baseline triglycerides/HDL-C and total cholesterol/HDL-C ratios predict future vascular risk after a stroke, but only elevated triglycerides/HDL-C ratio is related to risk of recurrent stroke. Future studies should assess the role of triglycerides/HDL-C as a potential therapeutic target for global vascular risk reduction after stroke.
Development of a German Implicit Measure of Religiosity
Authors: Bachmann Robin E.
Published: September 2014

This study addressed the lack of implicit measures of religiosity in German research by developing a German Single Category Implicit Association Test (SC-IAT) for measuring the associative religious self-concept. The SC-IAT was applied to a sample consisting of 389 German students with different subjects of study and internally consistent ( r = .72). To estimate the psychometric criteria of construct validity, SC-IAT scores were correlated to the Centrality of Religiosity Scale (CRS), whose construct psychological approach can be theoretically linked to the concept of associative representations in the research on IATs. Corresponding to the average relationship between implicit and explicit measures in literature, the correlation was moderately ( r = .33). Group comparisons relating to religious affiliation and subject of study provided initial evidence for criterion validity. There were complications with the attribute category “non-religious,” especially by participants without a religious affiliation, however, the SC-IAT could also provide a method to investigate this issue.
A revision of the Mexican Anolis (Reptilia, Squamata, Dactyloidae) from the Pacific versant west of the Isthmus de Tehuantepec in the states of Oaxaca, Guerrero, and Puebla, with the description of six new species
Authors: KÖHLER GUNTHER , PÉREZ RAÚL GÓMEZ TREJO , PETERSEN CLAUS BO P. , CRUZ FAUSTO R. MÉNDEZ DE LA
Published: September 2014

We revise the species of anoles occurring along the Pacific versant of Mexico west of the Isthmus de Tehuantepec in the states of Oaxaca, Guerrero, and Puebla. Based on our analyses of morphological and molecular genetic data, we recognize 21 species, six of which we describe as new (i.e., Anolis carlliebi sp. nov., A. immaculogularis sp. nov., A. nietoi sp. nov., A. sacamecatensis sp. nov., A. stevepoei sp. nov., and A. zapotecorum sp. nov.). Furthermore, we synonymize Anolis forbesi Smith & Van Gelder 1955 with Anolis microlepidotus Davis 1954. Of the recognized species, six have smooth ventral scales (i.e., Anolis dunni, A. gadovii, A. liogaster, A. omiltemanus, A. peucephilus, and A. taylori) and 14 have keeled ventral scales (i.e., A. boulengerianus, A. carlliebi, A. immaculogularis, A. megapholidotus, A. microlepidotus, A. nebuloides, A. nebulosus, A. nietoi, A. quercorum, A. sacamecatensis, A. stevepoei, A. subocularis, A. unilobatus, and A. zapotecorum). In one species, A. macrinii, the ventral scales vary from smooth to weakly keeled. For each species we provide color descriptions in life, color photographs in life, descriptions and illustration of hemipenis morphology (if available), description of external morphology, distribution maps based on the specimensexamined, comments on the conservation status, and natural history notes. Finally, we provide a dichotomous key for the identification of the 21 species of anoles occurring along the Pacific versant of Mexico west of the Isthmus de Tehuantepec in the states of Oaxaca, Guerrero, and Puebla.