bluuebunny/crossref_metadata_2025 huggingface dataset:
Absence of Correlation between IL-28B Gene Polymorphisms and the Clinical Presentation of Chronic Hepatitis B in an Amazon Brazilian Population
Authors: da Silva Conde Simone Regina Souza , Rocha Luciana L. , Ferreira Vanessa M. , Soares Monteiro Julius Caesar Mendes , Fonseca Filgueiras Nathália Karla , Almeida Lins Pedro Alves de , Silva dos Santos Bruna Tereza , Bonfim Freitas Felipe , da Silva Graça Ednelza , Demachki Sâmia , Ferreira de Araújo Marialva Tereza , Ishak Ricardo , Vallinoto Antonio C. R.
Published: April 2014

Objective. The present study investigated the prevalence of the IL-28B polymorphisms rs12979860 and rs8099917 in chronic hepatitis B patients from a case study in Eastern Amazonia.Methods. In total, 65 chronically infected HBV patients and 97 healthy subjects who were anti-HBc and anti-HBs positive (control group) were evaluated between May 2011 and December 2012. The groups of patients were designated as inactive carriers, chronic hepatitis without cirrhosis, and chronic hepatitis with cirrhosis based on clinical, pathological, biochemical, hematological, and virological variables. The patients were genotyped using quantitative real-time PCR.Results. The frequencies of the rs12979860 polymorphism were similar between the infected group (32.3% CC, 41.5% CT, and 26.2 TT) and the control population (35% CC, 47.4% CT, and 17.6% TT), and the frequencies of the rs8099917 polymorphism (7.7% GG, 35.4% GT, and 56.9% TT versus 7.2% GG, 35.1% GT, and 57.7% TT) were also similar in both groups. The associations between the rs12979860 and rs8099917 polymorphisms and the clinical manifestations were not statistically significant.Conclusion. In conclusion, these polymorphisms had a similar distribution between infected and control groups, indicating that they were not associated with susceptibility and the clinical evolution of hepatitis B in the examined population.
High-Resolution, Near Real-Time Simulation of Microwave Radiance Using a Simple Land-Cover Based Emissivity Prior
Authors: Katsanos Dimitrios , García-Ortega Eduardo , de Castro Manuel , Arias Enrique , Tapiador Francisco J.
Published: April 2014

Satellite simulators are used to calculate the brightness temperatureTbthat would be measured by a space borne sensor under a set of atmospheric conditions accounting for the radiometric characteristics of the sensor and the orbital parameters of the satellite. In this study, a simple approach is proposed for the parameterization of emissivity over land, a key parameter for the calculation of microwaveTb. The rationale is to simulate a large ensemble of emissivity values for each frequency and surface characteristics and then relate the most likely observed value with soil characteristics. The derived emissivity values are used for the simulation ofTband simulated radiance is then compared with satellite observations. It is shown that this method improves the simulation of radiance and that it is suitable to provide a first guess of the emissivity value (a prior) that can then be refined using iterative procedures.
Decaffeinated Green Coffee Bean Extract Attenuates Diet‐Induced Obesity and Insulin Resistance in Mice
Authors: Song Su Jin , Choi Sena , Park Taesun
Published: April 2014

This study investigated whether decaffeinated green coffee bean extract prevents obesity and improves insulin resistance and elucidated its mechanism of action. Male C57BL/6N mice (N = 48) were divided into six dietary groups: chow diet, HFD, HFD‐supplemented with 0.1%, 0.3%, and 0.9% decaffeinated green coffee bean extract, and 0.15% 5‐caffeoylquinic acid. Based on the reduction in HFD‐induced body weight gain and increments in plasma lipids, glucose, and insulin levels, the minimum effective dose of green coffee bean extract appears to be 0.3%. Green coffee bean extract resulted in downregulation of genes involved in WNT10b‐ and galanin‐mediated adipogenesis and TLR4‐mediated proinflammatory pathway and stimulation of GLUT4 translocation to the plasma membrane in white adipose tissue. Taken together, decaffeinated green coffee bean extract appeared to reverse HFD‐induced fat accumulation and insulin resistance by downregulating the genes involved in adipogenesis and inflammation in visceral adipose tissue.
On Fourier Series of Fuzzy-Valued Functions
Authors: Kadak Uğur , Başar Feyzi
Published: April 2014

Fourier analysis is a powerful tool for many problems, and especially for solving various differential equations of interest in science and engineering. In the present paper since the utilization of Zadeh’s Extension principle is quite difficult in practice, we prefer the idea of level sets in order to construct a fuzzy-valued function on a closed interval via related membership function. We derive uniform convergence of a fuzzy-valued function sequences and series with level sets. Also we study Hukuhara differentiation and Henstock integration of a fuzzy-valued function with some necessary inclusions. Furthermore, Fourier series of periodic fuzzy-valued functions is defined and its complex form is given via sine and cosine fuzzy coefficients with an illustrative example. Finally, by using the Dirichlet kernel and its properties, we especially examine the convergence of Fourier series of fuzzy-valued functions at each point of discontinuity, where one-sided limits exist.
The Antihyperglycemic Effects of Rhizoma Coptidis and Mechanism of Actions: A Review of Systematic Reviews and Pharmacological Research
Authors: Wang Hui , Mu Wei , Shang Hongcai , Lin Jia , Lei Xiang
Published: April 2014

Rhizoma Coptidis (Huang Lian in Chinese pinyin) is among the most widely used traditional Chinese herbal medicines and has a profound history of more than 2000 years of being used as a therapeutic herb. The antidiabetic effects of Rhizoma Coptidis have been extensively investigated in animal experiments and clinical trials and its efficacy as a promising antihyperglycemic agent has been widely discussed. In the meantime, findings from modern pharmacological studies have contributed the majority of its bioactivities to berberine, the isoquinoline alkaloids component of the herb, and a number of experiments testing the antidiabetic effects of berberine have been initiated. Therefore, we conducted a review of the current evidence profile of the antihyperglycemic effects of Rhizoma Coptidis as well as its main component berberine and the possible mechanism of actions, in order to summarize research evidence in this area and identify future research directions.
Effects of Urbanization Expansion on Landscape Pattern and Region Ecological Risk in Chinese Coastal City: A Case Study of Yantai City
Authors: Zhou Di , Shi Ping , Wu Xiaoqing , Ma Jinwei , Yu Junbao
Published: April 2014

Applied with remote sensing, GIS, and mathematical statistics, the spatial-temporal evolution characteristics of urbanization expansion of Yantai city from 1974 to 2009 was studied. Based on landscape pattern metrics and ecological risk index, the landscape ecological risk from the landscape pattern dynamics was evaluated. The results showed that the area of urban land increased by 189.77 km2with average expansion area of 5.42 km2 y−1from 1974 to 2009. The urbanization intensity index during 2004–2009 was 3.92 times of that during 1974–1990. The land use types of urban land and farmland changed greatly. The changes of landscape pattern metrics for land use patterns indicated that the intensity of human activities had strengthened gradually in study period. The landscape ecological risk pattern of Yantai city shaped half-round rings along the coastline. The ecological risk index decreased with increase of the distance to the coastline. The ratio of high ecological risk to subhigh ecological risk zones in 2009 was 2.23 times of that in 1990. The significant linear relationship of urbanization intensity index and regional ecological risk indicated that the anthropological economic activities were decisive factors for sustainable development of costal ecological environment.
Assessing the MODIS Crop Detection Algorithm for Soybean Crop Area Mapping and Expansion in the Mato Grosso State, Brazil
Authors: Gusso Anibal , Arvor Damien , Ricardo Ducati Jorge , Veronez Mauricio Roberto , da Silveira Luiz Gonzaga
Published: April 2014

Estimations of crop area were made based on the temporal profiles of the Enhanced Vegetation Index (EVI) obtained from moderate resolution imaging spectroradiometer (MODIS) images. Evaluation of the ability of the MODIS crop detection algorithm (MCDA) to estimate soybean crop areas was performed for fields in the Mato Grosso state, Brazil. Using the MCDA approach, soybean crop area estimations can be provided for December (first forecast) using images from the sowing period and for February (second forecast) using images from the sowing period and the maximum crop development period. The area estimates were compared to official agricultural statistics from the Brazilian Institute of Geography and Statistics (IBGE) and from the National Company of Food Supply (CONAB) at different crop levels from 2000/2001 to 2010/2011. At the municipality level, the estimates were highly correlated, withR2=0.97and RMSD = 13,142 ha. The MCDA was validated using field campaign data from the 2006/2007 crop year. The overall map accuracy was 88.25%, and the Kappa Index of Agreement was 0.765. By using pre-defined parameters, MCDA is able to provide the evolution of annual soybean maps, forecast of soybean cropping areas, and the crop area expansion in the Mato Grosso state.
Effect on Blood Pressure of Daily Lemon Ingestion and Walking
Authors: Kato Yoji , Domoto Tokio , Hiramitsu Masanori , Katagiri Takao , Sato Kimiko , Miyake Yukiko , Aoi Satomi , Ishihara Katsuhide , Ikeda Hiromi , Umei Namiko , Takigawa Atsusi , Harada Toshihide
Published: April 2014

Background. Recent studies suggest that the daily intake of lemon (Citrus limon) has a good effect on health, but this has not been confirmed in humans. In our previous studies, it was observed that people who are conscious of their health performed more lemon intake and exercise. An analysis that took this into account was required.Methodology. For 101 middle-aged women in an island area in Hiroshima, Japan, a record of lemon ingestion efforts and the number of steps walked was carried out for five months. The change rates (Δ%) of the physical measurements, blood test, blood pressure, and pulse wave measured value during the observation period were calculated, and correlations with lemon intake and the number of steps walked were considered. As a result, it was suggested that daily lemon intake and walking are effective for high blood pressure because both showed significant negative correlation to systolic blood pressure Δ%.Conclusions. As a result of multiple linear regression analysis, it was possible that lemon ingestion is involved more greatly with the blood citric acid concentration Δ% and the number of steps with blood pressure Δ%, and it was surmised that the number of steps and lemon ingestion are related to blood pressure improvement by different action mechanisms.
Serum Immunoglobulin E and Risk of Pancreatic Cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial
Authors: Olson Sara H. , Hsu Meier , Wiemels Joseph L. , Bracci Paige M. , Zhou Mi , Patoka Joseph , Reisacher William R. , Wang Julie , Kurtz Robert C. , Silverman Debra T. , Stolzenberg-Solomon Rachael Z.
Published: April 2014

Epidemiologic studies have consistently found that self-reported allergies are associated with reduced risk of pancreatic cancer. Our aim was to prospectively assess the relationship between serum immunoglobulin E (IgE), a marker of allergy, and risk. This nested case–control study within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) included subjects enrolled in 1994 to 2001 and followed through 2010. There were 283 cases of pancreatic cancer and 544 controls matched on age, gender, race, and calendar date of blood draw. Using the ImmunoCAP system, we measured total IgE (normal, borderline, elevated), IgE to respiratory allergens, and IgE to food allergens (negative or positive) in serum collected at baseline. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression. We assessed interactions with age, gender, smoking, body mass index, and time between randomization and case diagnosis. Overall, there was no association between the IgE measures and risk. We found a statistically significant interaction by baseline age: in those aged ≥65 years, elevated risks were observed for borderline total IgE (OR, 1.43; 95% CI, 0.88–2.32) and elevated total IgE (OR, 1.98; 95% CI, 1.16–3.37) and positive IgE to food allergens (OR, 2.83; 95% CI, 1.29–6.20); among participants <65 years, ORs were <1. Other interactions were not statistically significant. The reduced risk of pancreatic cancer associated with self-reported allergies is not reflected in serum IgE. Cancer Epidemiol Biomarkers Prev; 23(7); 1414–20. ©2014 AACR.
Autophagy Inhibition Augments the Anticancer Effects of Epirubicin Treatment in Anthracycline-Sensitive and -Resistant Triple-Negative Breast Cancer
Authors: Chittaranjan Suganthi , Bortnik Svetlana , Dragowska Wieslawa H. , Xu Jing , Abeysundara Namal , Leung Amy , Go Nancy E. , DeVorkin Lindsay , Weppler Sherry A. , Gelmon Karen , Yapp Donald T. , Bally Marcel B. , Gorski Sharon M.
Published: April 2014

Purpose: Triple-negative breast cancers (TNBC) are defined by a lack of expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (ERBB2/HER2). Although initially responsive to chemotherapy, most recurrent TNBCs develop resistance, resulting in disease progression. Autophagy is a lysosome-mediated degradation and recycling process that can function as an adaptive survival response during chemotherapy and contribute to chemoresistance. Our goal was to determine whether autophagy inhibition improves treatment efficacy in TNBC cells in tumors either sensitive or refractory to anthracyclines.

Experimental Design: We used in vitro and in vivo models of TNBC using cell lines sensitive to epirubicin and other anthracyclines, as well as derivative lines, resistant to the same drugs. We assessed basal autophagy levels and the effects of chemotherapy on autophagy in parental and resistant cells. Applying various approaches to inhibit autophagy alone and in combination with chemotherapy, we assessed the effects on cell viability in vitro and tumor growth rates in vivo.

Results: We demonstrated that epirubicin induced autophagic flux in TNBC cells. Epirubicin-resistant lines exhibited at least 1.5-fold increased basal autophagy levels and, when treated with autophagy inhibitors, showed a significant loss in viability, indicating dependence of resistant cells on autophagy for survival. Combination of epirubicin with the autophagy inhibitor hydroxychloroquine resulted in a significant reduction in tumor growth compared with monotherapy with epirubicin.

Conclusion: Autophagy inhibition enhances therapeutic response in both anthracycline-sensitive and -resistant TNBC and may be an effective new treatment strategy for this disease. Clin Cancer Res; 20(12); 3159–73. ©2014 AACR.
Immunotherapy for Hepatoma Using a Dual-Function Vector with Both Immunostimulatory and Pim-3–Silencing Effects
Authors: Guo Qie , Lan Peixiang , Yu Xin , Han Qiuju , Zhang Jian , Tian Zhigang , Zhang Cai
Published: April 2014

Tumorigenesis is an immortalization process in which the growth of normal cells is uncontrolled and programmed cell death is suppressed. Molecular biologic and immunologic studies have revealed that the aberrant expression of some proto-oncogenes boosts proliferation and inhibits apoptosis, which is vital for tumor development. The hypofunction of the host immune system also drives the development and metastasis of malignant tumors. Pim-3, a member of the Pim family, is aberrantly expressed in several cancers. Data suggest that Pim-3 inhibits apoptosis by phosphorylating the proapoptotic BH3-only protein Bad. Here, we constructed a dual-function small hairpin RNA (shRNA) vector containing an shRNA targeting Pim-3 and a TLR7-stimulating ssRNA. Stimulation with this bi-functional vector in vitro promoted significant apoptosis of Hepa1-6 cells by regulating the expression of apoptosis-related proteins and induced secretion of type I IFNs. Most importantly, this bi-functional vector more effectively inhibited subcutaneous Hepa1-6 cell growth than did single shRNA and ssRNA treatment in vivo. Natural killer (NK), CD4+ T, and CD8+ T cells and macrophages were required for effective tumor suppression, and CD4+ T cells were shown to play a helper role in the activation of NK cells, possibly by regulating the secretion of Th1 or Th2 cytokines. This ssRNA–shRNA bi-functional vector may represent a promising approach for tumor therapy. Mol Cancer Ther; 13(6); 1503–13. ©2014 AACR.
Paediatric Pituitary Adenomas: A Decade of Change
Authors: Guaraldi Federica , Storr Helen L. , Ghizzoni Lucia , Ghigo Ezio , Savage Martin O.
Published: April 2014

Pituitary adenomas, although rare in the paediatric age range and mostly benign, represent very challenging disorders for diagnosis and management. The recent identification of genetic alterations in young individuals with pituitary adenomas has broadened the scope of molecular investigations and contributed to the understanding of mechanisms of tumorigenesis. Recent identification of causative mutations of genes such as GNAS, PRKAR1A, MEN1 and AIP has introduced the concept of molecular screening of young apparently healthy family members. Population-based studies have reported a significantly higher number of affected subjects and genetic variations than expected. Radiological techniques have advanced, yet many microadenomas remain undetectable on scanning. However, experience with transsphenoidal and endoscopic pituitary surgery has led to higher rates of cure. Prolactinomas, corticotroph and somatotroph adenomas remain the most prevalent, with each diagnosis presenting its own challenges. As paediatric pituitary adenomas occur very infrequently within the paediatric age range, paediatric endocrine units cannot provide expert management in isolation. Consequently, close co-operation with adult endocrinology colleagues with experience of pituitary disease is strongly recommended.
The Influence of Cultural Habits on the Changing Pattern of Functional Dyspepsia
Authors: Yap Paul , Mahadeva Sanjiv , Goh Khean-Lee
Published: April 2014

Dyspepsia is a common gastroenterological problem with an estimated global prevalence between 7 and 40%. Functional dyspepsia (FD) is a major economic burden to patients and healthcare systems and significantly affects patient quality of life. The ROME III definition of FD divides it into two subgroups, epigastric pain syndrome and postprandial distress syndrome, the former being more associated with reflux disease and the latter with gastric dysmotility. The global incidence and prevalence of FD continues to rise, but the reason for this is not clear. Rising global obesity and gastroesophageal reflux disease rates may be contributing to the rise in FD. Socioeconomic and cultural demographic changes such as changing dietary habits and rapid urbanization, particularly in the developing countries, are likely to be influencing the course of FD and the way it presents.
Skin-Homing Th2/Th22 Cells in Papuloerythroderma of Ofuji
Authors: Teraki Yuichi , Inoue Yumiko
Published: April 2014

Papuloerythroderma of Ofuji (PEO) appears to be a T cell-mediated skin disease; however, the pathogenesis of PEO remains unclear. We report two cases of PEO and examine cytokine production and expression of skin-homing receptors in circulating T cells in the patients. The percentages of interleukin 4 (IL-4)-, IL-13- and IL-22-producing CD4+ and CD8+ T cells were markedly higher in the circulation of patients with PEO than in those of healthy subjects. The expression of both cutaneous lymphocyte antigen (CLA) and CC chemokine receptor 4 (CCR4) were significantly upregulated in the circulating CD4+ and CD8+ T cells. Moreover, serum levels of thymus and activation-regulated chemokine (TARC), a chemoattractant for CCR4, were increased. The number of IL-4-, IL-13- and IL-22-producing T cells, expression of CLA and CCR4 by T cells, and serum TARC levels significantly decreased after complete remission of PEO. These results suggest that skin-homing Th2/Th22 cells may play a role in the pathogenesis of PEO.
Understanding Consumer Evaluations of Personalised Nutrition Services in Terms of the Privacy Calculus: A Qualitative Study
Authors: Berezowska Aleksandra , Fischer Arnout R.H. , Ronteltap Amber , Kuznesof Sharron , Macready Anna , Fallaize Rosalind , van Trijp Hans C.M.
Published: April 2014

Background: Personalised nutrition (PN) may provide major health benefits to consumers. A potential barrier to the uptake of PN is consumers' reluctance to disclose sensitive information upon which PN is based. This study adopts the privacy calculus to explore how PN service attributes contribute to consumers' privacy risk and personalisation benefit perceptions. Methods: Sixteen focus groups (n = 124) were held in 8 EU countries and discussed 9 PN services that differed in terms of personal information, communication channel, service provider, advice justification, scope, frequency, and customer lock-in. Transcripts were content analysed. Results: The personal information that underpinned PN contributed to both privacy risk perception and personalisation benefit perception. Disclosing information face-to-face mitigated the perception of privacy risk and amplified the perception of personalisation benefit. PN provided by a qualified expert and justified by scientific evidence increased participants' value perception. Enhancing convenience, offering regular face-to face support, and employing customer lock-in strategies were perceived as beneficial. Conclusion: This study suggests that to encourage consumer adoption, PN has to account for face-to-face communication, expert advice providers, support, a lifestyle-change focus, and customised offers. The results provide an initial insight into service attributes that influence consumer adoption of PN.
N
ε
-(Carboxymethyl)lysine-Receptor for Advanced Glycation End Product Axis Is a Key Modulator of Obesity-Induced Dysregulation of Adipokine Expression and Insulin Resistance
Authors: Gaens Katrien H.J. , Goossens Gijs H. , Niessen Petra M. , van Greevenbroek Marleen M. , van der Kallen Carla J.H. , Niessen Hans W. , Rensen Sander S. , Buurman Wim A. , Greve Jan Willem M. , Blaak Ellen E. , van Zandvoort Marc A. , Bierhaus Angelika , Stehouwer Coen D.A. , Schalkwijk Casper G.
Published: April 2014

Objective—

Dysregulation of inflammatory adipokines by the adipose tissue plays an important role in obesity-associated insulin resistance. Pathways leading to this dysregulation remain largely unknown. We hypothesized that the receptor for advanced glycation end products (RAGE) and the ligand N
ε
-(carboxymethyl)lysine (CML) are increased in adipose tissue and, moreover, that activation of the CML–RAGE axis plays an important role in obesity-associated inflammation and insulin resistance.

Approach and Results—

In this study, we observed a strong CML accumulation and increased expression of RAGE in adipose tissue in obesity. We confirmed in cultured human preadipocytes that adipogenesis is associated with increased levels of CML and RAGE. Moreover, CML induced a dysregulation of inflammatory adipokines in adipocytes via a RAGE-dependent pathway. To test the role of RAGE in obesity-associated inflammation further, we constructed an obese mouse model that is deficient for RAGE (ie, RAGE
–/–
/Leptr
Db–/–
mice). RAGE
–/–
/Leptr
Db–/–
mice displayed an improved inflammatory profile and glucose homeostasis when compared with RAGE
+/+
/Leptr
Db–/–
mice. In addition, CML was trapped in adipose tissue in RAGE
+/+
/Leptr
Db–/–
mice but not in RAGE
–/–
/Leptr
Db–/–
. RAGE-mediated trapping in adipose tissue provides a mechanism underlying CML accumulation in adipose tissue and explaining decreased CML plasma levels in obese subjects. Decreased CML plasma levels in obese individuals were strongly associated with insulin resistance.

Conclusions—

RAGE-mediated CML accumulation in adipose tissue and the activation of the CML–RAGE axis are important mechanisms involved in the dysregulation of adipokines in obesity, thereby contributing to the development of obesity-associated insulin resistance.
Fibrin-Targeted Magnetic Resonance Imaging Allows In Vivo Quantification of Thrombus Fibrin Content and Identifies Thrombi Amenable for Thrombolysis
Authors: Andia Marcelo E. , Saha Prakash , Jenkins Julia , Modarai Bijan , Wiethoff Andrea J. , Phinikaridou Alkystis , Grover Steven P. , Patel Ashish S. , Schaeffter Tobias , Smith Alberto , Botnar Rene M.
Published: April 2014

Objective—

Deep venous thrombosis is a major health problem. Thrombolytic therapies are effective in recanalizing the veins and preventing post-thrombotic complications, but there is no consensus on selection criteria. The aim of this study was to investigate a fibrin-specific MRI contrast agent (EP-2104R) for the accurate quantification of thrombus’ fibrin content in vivo and for the identification of thrombus suitable for thrombolysis.

Approach and Results—

Venous thrombosis was induced in the inferior vena cava of 8- to 10-week-old male BALB/C mice and MRI performed 2, 4, 7, 10, 14, and 21 days later. Eighteen mice were scanned at each time point pre and 2 hours post injection of EP-2104R (8.0 μmol/kg) with 12 mice at each time point used to correlate fibrin contrast uptake with thrombus’ histological stage and fibrin content. Six mice at each time point were immediately subjected to intravascular thrombolytic therapy (10 mg/kg of tissue-type plasminogen activator). Mice were imaged to assess response to lytic therapy 24 hours after thrombolytic treatment. Two mice at each time point were scanned post injection of 0.2 mmol/kg of Gd-DTPA (gadolinium with diethylenetriaminepentacetate, Magnevist, Schering AG, Berlin, Germany) for control purpose. Contrast uptake was correlated positively with the fibrin content of the thrombus measured by Western blotting (
R
2
=0.889;
P
<0.001). Thrombus relaxation rate (
R
1
) post contrast and the change in visualized thrombus size on late gadolinium enhancement inversion recovery MRI pre–EP-2104R and post–EP-2104R injection were the best predictors for successful thrombolysis (area under the curve, 0.989 [95% confidence interval, 0.97–1.00] and 0.994 [95% confidence interval, 0.98–1.00] respectively).

Conclusions—

MRI with a fibrin-specific contrast agent accurately estimates thrombus fibrin content in vivo and identifies thrombi that are amenable for thrombolysis.
Matrix Metalloproteinase-13 Predominates Over Matrix Metalloproteinase-8 as the Functional Interstitial Collagenase in Mouse Atheromata
Authors: Quillard Thibaut , Araújo Haniel Alves , Franck Gregory , Tesmenitsky Yevgenia , Libby Peter
Published: April 2014

Objective—

Substantial evidence implicates interstitial collagenases of the matrix metalloproteinase (MMP) family in plaque rupture and fatal thrombosis. Understanding the compensatory mechanisms that may influence the expression of these enzymes and their functions, therefore, has important clinical implications. This study assessed in mice the relative effect of the 2 principal mouse collagenases on collagen content and other plaque characteristics.

Approach and Results—

Apolipoprotein E–deficient (apoE
−/−
) mice, MMP-13
−/−
apoE
−/−
, MMP-8
−/−
apoE
−/−
double knockout mice, and MMP-13
−/−
MMP-8
−/−
apoE
−/−
triple knockout mice consumed a high-cholesterol diet for 10 and 24 weeks. Both double knockout and triple knockout mice showed comparable atherosclerotic lesion formation compared with apoE
−/−
controls. Analysis of aortic root sections indicated that lesions of MMP-8/MMP-13–deficient and MMP-13–deficient mice accumulate more fibrillar collagen than apoE
−/−
controls and MMP-8
−/−
apoE
−/−
double knockout. We further tested the relative effect of MMPs on plaque collagenolysis using in situ zymography. MMP-13 deletion alone abrogated collagenolytic activity in lesions, indicating a predominant role for MMP-13 in this process. MMP-13 and MMP-13/MMP-8 deficiency did not alter macrophage content but associated with reduced accumulation of smooth muscle cells.

Conclusions—

These results show that among MMP interstitial collagenases in mice, MMP-13 prevails over MMP-8 in collagen degradation in atheromata. These findings provide a rationale for the identification and selective targeting a predominant collagenase for modulating key aspects of plaque structure considered critical in clinical complications, although they do not translate directly to human lesions, which also contain MMP-1.
Four-Group Classification of Left Ventricular Hypertrophy Based on Ventricular Concentricity and Dilatation Identifies a Low-Risk Subset of Eccentric Hypertrophy in Hypertensive Patients
Authors: Bang Casper N. , Gerdts Eva , Aurigemma Gerard P. , Boman Kurt , de Simone Giovanni , Dahlöf Björn , Køber Lars , Wachtell Kristian , Devereux Richard B.
Published: April 2014

Background—

Left ventricular hypertrophy (LVH; high LV mass [LVM]) is traditionally classified as concentric or eccentric based on LV relative wall thickness. We evaluated the prediction of subsequent adverse events in a new 4-group LVH classification based on LV dilatation (high LV end-diastolic volume [EDV] index) and concentricity (mass/end-diastolic volume [M/EDV]
2/3
) in hypertensive patients.

Methods and Results—

In the Losartan Intervention for Endpoint Reduction (LIFE) echocardiography substudy, 939 hypertensive patients with measurable LVM at baseline were randomized to a mean of 4.8 years of losartan- or atenolol-based treatment. Patients with LVH (LVM/body surface area ≥116 and ≥96 g/m
2
in men and woman, respectively) were divided into 4 groups—concentric nondilated (increased M/EDV, normal EDV), eccentric dilated (increased EDV, normal M/EDV), concentric dilated (increased M/EDV and EDV), and eccentric nondilated (normal M/EDV and EDV)—and compared with patients with normal LVM. Time-varying LVH classes were tested for association with all-cause and cardiovascular mortality and a composite end point of myocardial infarction, stroke, heart failure, and cardiovascular death in multivariable Cox analyses. At baseline, the LVs were categorized as eccentric nondilated in 12%, eccentric dilated in 20%, concentric nondilated in 29%, concentric dilated in 14%, and normal LVM in 25%. Treatment changed the prevalence of 4 LVH groups to 23%, 4%, 5%, and 7%; 62% had normal LVM after 4 years. In time-varying Cox analyses, compared with normal LVM, those with eccentric dilated and both concentric nondilated and dilated LVH had increased risks of all-cause or cardiovascular mortality or the composite end point, whereas the eccentric nondilated group did not.

Conclusions—

Hypertensive patients with relatively mild LVH without either increased LV volume or concentricity have similar risk of all-cause mortality or cardiovascular events because hypertensive patients with normal LVM seem to be a low-risk group.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00338260.
Sorafenib Cardiotoxicity Increases Mortality After Myocardial Infarction
Authors: Duran Jason M. , Makarewich Catherine A. , Trappanese Danielle , Gross Polina , Husain Sharmeen , Dunn Jonathan , Lal Hind , Sharp Thomas E. , Starosta Timothy , Vagnozzi Ronald J. , Berretta Remus M. , Barbe Mary , Yu Daohai , Gao Erhe , Kubo Hajime , Force Thomas , Houser Steven R.
Published: April 2014

Rationale:

Sorafenib is an effective treatment for renal cell carcinoma, but recent clinical reports have documented its cardiotoxicity through an unknown mechanism.

Objective:

Determining the mechanism of sorafenib-mediated cardiotoxicity.

Methods and Results:

Mice treated with sorafenib or vehicle for 3 weeks underwent induced myocardial infarction (MI) after 1 week of treatment. Sorafenib markedly decreased 2-week survival relative to vehicle-treated controls, but echocardiography at 1 and 2 weeks post MI detected no differences in cardiac function. Sorafenib-treated hearts had significantly smaller diastolic and systolic volumes and reduced heart weights. High doses of sorafenib induced necrotic death of isolated myocytes in vitro, but lower doses did not induce myocyte death or affect inotropy. Histological analysis documented increased myocyte cross-sectional area despite smaller heart sizes after sorafenib treatment, further suggesting myocyte loss. Sorafenib caused apoptotic cell death of cardiac- and bone-derived c-kit+ stem cells in vitro and decreased the number of BrdU+ (5-bromo-2’-deoxyuridine+) myocytes detected at the infarct border zone in fixed tissues. Sorafenib had no effect on infarct size, fibrosis, or post-MI neovascularization. When sorafenib-treated animals received metoprolol treatment post MI, the sorafenib-induced increase in post-MI mortality was eliminated, cardiac function was improved, and myocyte loss was ameliorated.

Conclusions:

Sorafenib cardiotoxicity results from myocyte necrosis rather than from any direct effect on myocyte function. Surviving myocytes undergo pathological hypertrophy. Inhibition of c-kit+ stem cell proliferation by inducing apoptosis exacerbates damage by decreasing endogenous cardiac repair. In the setting of MI, which also causes large-scale cell loss, sorafenib cardiotoxicity dramatically increases mortality.
Mkk4 Is a Negative Regulator of the Transforming Growth Factor Beta 1 Signaling Associated With Atrial Remodeling and Arrhythmogenesis With Age
Authors: Davies Laura , Jin Jiawei , Shen Weijin , Tsui Hoyee , Shi Ying , Wang Yanwen , Zhang Yanmin , Hao Guoliang , Wu Jingjing , Chen Si , Fraser James A. , Dong Nianguo , Christoffels Vincent , Ravens Ursula , Huang Christopher L.‐H. , Zhang Henggui , Cartwright Elizabeth J. , Wang Xin , Lei Ming
Published: April 2014

Background

Atrial fibrillation (
AF
), often associated with structural, fibrotic change in cardiac tissues involving regulatory signaling mediators, becomes increasingly common with age. In the present study, we explored the role of mitogen‐activated protein kinase kinase 4 (
Mkk4
), a critical component of the stress‐activated mitogen‐activated protein kinase family, in age‐associated
AF
.

Methods and Results

We developed a novel mouse model with a selective inactivation of atrial cardiomyocyte
Mkk4
(
Mkk4

ACKO

). We characterized and compared electrophysiological, histological, and molecular features of young (3‐ to 4‐month), adult (6‐month), and old (1‐year)
Mkk4

ACKO

mice with age‐matched control littermates (
Mkk4
F/F
). Aging
Mkk4

ACKO

mice were more susceptible to atrial tachyarrhythmias than the corresponding
Mkk4
F/F
mice, showing characteristic slow and dispersed atrial conduction, for which modeling studies demonstrated potential arrhythmic effects. These differences paralleled increased interstitial fibrosis, upregulated transforming growth factor beta 1 (
TGF
‐β
1
) signaling and dysregulation of matrix metalloproteinases in
Mkk4

ACKO

, compared to
Mkk4
F/F
, atria.
Mkk4
inactivation increased the sensitivity of cultured cardiomyocytes to angiotensin
II
–induced activation of
TGF
‐β
1
signaling. This, in turn, enhanced expression of profibrotic molecules in cultured cardiac fibroblasts, suggesting cross‐talk between these two cell types in profibrotic signaling. Finally, human atrial tissues in
AF
showed a
Mkk4
downregulation associated with increased production of profibrotic molecules, compared to findings in tissue from control subjects in sinus rhythm.

Conclusions

These findings together demonstrate, for the first time, that
Mkk4
is a negative regulator of the
TGF
‐β
1
signaling associated with atrial remodeling and arrhythmogenesis with age, establishing
Mkk4
as a new potential therapeutic target for treating
AF
.
Exercise, Vascular Stiffness, and Tissue Transglutaminase
Authors: Steppan Jochen , Sikka Gautam , Jandu Simran , Barodka Viachaslau , Halushka Marc K. , Flavahan Nicholas A. , Belkin Alexey M. , Nyhan Daniel , Butlin Mark , Avolio Alberto , Berkowitz Dan E. , Santhanam Lakshmi
Published: April 2014

Background

Vascular aging is closely associated with increased vascular stiffness. It has recently been demonstrated that decreased nitric oxide (
NO
)‐induced S‐nitrosylation of tissue transglutaminase (
TG
2) contributes to age‐related vascular stiffness. In the current study, we tested the hypothesis that exercise restores
NO
signaling and attenuates vascular stiffness by decreasing
TG
2 activity and cross‐linking in an aging rat model.

Methods and Results

Rats were subjected to 12 weeks of moderate aerobic exercise. Aging was associated with diminished phosphorylated endothelial nitric oxide synthase and phosphorylated vasodilator‐stimulated phosphoprotein abundance, suggesting reduced
NO
signaling.
TG
2 cross‐linking activity was significantly increased in old animals, whereas
TG
2 abundance remained unchanged. These alterations were attenuated in the exercise cohort. Simultaneous measurement of blood pressure and pulse wave velocity (
PWV
) demonstrated increased aortic stiffness in old rats, compared to young, at all values of mean arterial pressure (
MAP
). The
PWV
‐
MAP
correlation in the old sedentary and old exercise cohorts was similar. Tensile testing of the vessels showed increased stiffness of the aorta in the old phenotype with a modest restoration of mechanical properties toward the young phenotype with exercise.

Conclusions

Increased vascular stiffness during aging is associated with decreased
TG
2 S‐nitrosylation, increased
TG
2 cross‐linking activity, and increased vascular stiffness likely the result of decreased
NO
bioavailability. In this study, a brief period of moderate aerobic exercise enhanced
NO
signaling, attenuated
TG
cross‐linking activity, and reduced ex vivo tensile properties, but failed to reverse functional vascular stiffness in vivo, as measured by
PWV
.
The TLR9 Ligand, CpG‐ODN, Induces Protection against Cerebral Ischemia/Reperfusion Injury via Activation of PI3K/Akt Signaling
Authors: Lu Chen , Ha Tuanzhu , Wang Xiaohui , Liu Li , Zhang Xia , Kimbrough Erinmarie Olson , Sha Zhanxin , Guan Meijian , Schweitzer John , Kalbfleisch John , Williams David , Li Chuanfu
Published: April 2014

Background

Toll‐like receptors (
TLR
s) have been shown to be involved in cerebral ischemia/reperfusion (I/R) injury.
TLR
9 is located in intracellular compartments and recognizes CpG‐
DNA
. This study examined the effect of CpG‐
ODN
on cerebral I/R injury.

Methods and Results

C57BL/6 mice were treated with CpG‐
ODN
by i.p. injection 1 hour before the mice were subjected to cerebral ischemia (60 minutes) followed by reperfusion (24 hours). Scrambled‐
ODN
served as control‐
ODN
. Untreated mice, subjected to cerebral I/R, served as I/R control. The effect of inhibitory CpG‐
ODN
(
iCpG
‐ODN) on cerebral I/R injury was also examined. In addition, we examined the therapeutic effect of CpG‐
ODN
on cerebral I/R injury by administration of CpG‐
ODN
15 minutes after cerebral ischemia. CpG‐
ODN
administration significantly decreased cerebral I/R‐induced infarct volume by 69.7% (6.4±1.80% vs 21.0±2.85%,
P
<0.05), improved neurological scores, and increased survival rate, when compared with the untreated I/R group. Therapeutic administration of CpG‐
ODN
also significantly reduced infarct volume by 44.7% (12.6±2.03% vs 22.8±2.54%,
P
<0.05) compared with untreated I/R mice. Neither control‐
ODN
, nor
iCpG
‐ODN altered I/R‐induced cerebral injury or neurological deficits. Nissl staining showed that CpG‐
ODN
treatment preserved neuronal morphology in the ischemic hippocampus. Immunoblot showed that CpG‐
ODN
administration increased Bcl‐2 levels by 41% and attenuated I/R‐increased levels of Bax and caspase‐3 activity in ischemic brain tissues. Importantly, CpG‐
ODN
treatment induced Akt and
GSK
‐3β phosphorylation in brain tissue and cultured microglial cells.
PI
3K inhibition with
LY
294002 abolished CpG‐
ODN
‐induced protection.

Conclusion

CpG‐
ODN
significantly reduces cerebral I/R injury via a
PI
3K/Akt‐dependent mechanism. Our data also indicate that CpG‐
ODN
may be useful in the therapy of cerebral I/R injury.
Postural Tachycardia Syndrome and Inappropriate Sinus Tachycardia: Role of Autonomic Modulation and Sinus Node Automaticity
Authors: Nwazue Victor C. , Paranjape Sachin Y. , Black Bonnie K. , Biaggioni Italo , Diedrich André , Dupont William D. , Robertson David , Raj Satish R.
Published: April 2014

Background

Inappropriate sinus tachycardia (
IST
) and postural tachycardia syndrome (
POTS
) are 2 disorders characterized by sinus tachycardia. It is debated whether the pathophysiology of
IST
and
POTS
results from abnormal autonomic regulation or abnormal sinus node function. We hypothesized that intrinsic heart rate (
IHR
) after autonomic blockade would be increased in patients with
IST
but not
POTS
.

Methods and Results

We enrolled 48
POTS
patients, 8
IST
patients, and 17 healthy control (
HC
) subjects. Intravenous propranolol and atropine were given to block the sympathetic and parasympathetic limbs of the autonomic nervous system in order to determine the
IHR
. Patients with
IST
have a higher sympathetic contribution to heart rate when compared with
POTS
patients (31±13 bpm versus 12±7 bpm,
P
<0.001) and
HC
(8±4 bpm;
P
<0.001) and a trend to less parasympathetic contribution than
POTS
and
HC
(
IST
: 31±11 bpm versus
POTS
: 46±11 bpm versus
HC
: 48±11 bpm,
ANOVA
P
=0.108).
IHR
was not significantly different between
IST
and either
POTS
or
HC
(
IST
: 111±11 bpm versus
POTS
: 108±11 bpm versus
HC
: 106±12 bpm,
ANOVA
P
=0.237).

Conclusions

IST
patients have more sympathetic tone when compared with either
POTS
or
HC
, but
IST
patients do not have abnormal sinus node automaticity. These data suggest that the treatment of
IST
and
POTS
should focus on sympatholysis, reserving sinus node modification for patients with continued debilitating symptoms after beta‐blockade and possibly ivabradine.

Clinical Trial Registration

URL:
http://clinicaltrials.gov/
. Unique identifier: NCT00262470.
Relative Contributions of Sympathetic, Cholinergic, and Myogenic Mechanisms to Cerebral Autoregulation
Authors: Hamner J.W. , Tan Can Ozan
Published: April 2014

Background and Purpose—

Prior work aimed at improving our understanding of human cerebral autoregulation has explored individual physiological mechanisms of autoregulation in isolation, but none has attempted to consolidate the individual roles of these mechanisms into a comprehensive model of the overall cerebral pressure–flow relationship.

Methods—

We retrospectively analyzed this relationship before and after pharmacological blockade of α-adrenergic–, muscarinic-, and calcium channel–mediated mechanisms in 43 healthy volunteers to determine the relative contributions of the sympathetic, cholinergic, and myogenic controllers to cerebral autoregulation. Projection pursuit regression was used to assess the effect of pharmacological blockade on the cerebral pressure–flow relationship. Subsequently, ANCOVA decomposition was used to determine the cumulative effect of these 3 mechanisms on cerebral autoregulation and whether they can fully explain it.

Results—

Sympathetic, cholinergic, and myogenic mechanisms together accounted for 62% of the cerebral pressure–flow relationship (
P
<0.05), with significant and distinct contributions from each of the 3 effectors. ANCOVA decomposition demonstrated that myogenic effectors were the largest determinant of the cerebral pressure–flow relationship, but their effect was outside of the autoregulatory region where neurogenic control appeared prepotent.

Conclusions—

Our results suggest that myogenic effects occur outside the active region of autoregulation, whereas neurogenic influences are largely responsible for cerebral blood flow control within it. However, our model of cerebral autoregulation left 38% of the cerebral pressure–flow relationship unexplained, suggesting that there are other physiological mechanisms that contribute to cerebral autoregulation.
D. 41,2,3,21: Titulierte Besitzarten, Erwerbsgründeund das unum genus possidendi
Authors: Pool Eric H.
Published: April 2014

D. 41,2,3,21 turns on the issue of how possessio is to be divided. Understanding its content presupposes making a distinction that was self-evident for the Roman jurist but has never been made by later scholars of Roman law. They do not distinguish the varying ‘causes’ of possession (pro emptore … pro suo) which mark different types of lawful possession, and the ‘causes’ of acquisition (causae adquirendi) which justify obtaining possesion as by an owner. Taking a legally valid sale as an example the distinctive features of (possessio) pro emptore in contrast to emptio are established as well as their relevance for procedural practice. In particular there are no less than six forms of action in the law of inheritance for which these features are relevant. Next, the many negative effects of failing to make this distinction are indicated. There follows an in depth analysis and interpretation of the main phrases in Paul’s text: (i) quod nostrum non est; (ii) causae ad­­quirendi, in particular iustae causae traditionis; (iii) unum genus possidendi; (iv) species infinitae.
Adrian of Utrecht (1459–1523) at the crossroads of law and morality: conscience, equity, and the legal nature of Early Modern practical theology
Authors: Decock Wim
Published: April 2014

This paper investigates the interconnection between moral theology and legal thought in the work of Adrian of Utrecht (1459–1523). It is shown that early modern Catholic theology as it was practised at the University of Louvain cannot be properly understood without reference to the scholarly disputes in the law faculties. The legal character of practical theology draws on a long tradition that reaches back at least to the late medieval manuals for confessors. The legal nature of Adrian of Utrecht’s moral theology, in particular, will be illustrated through an analysis of the sixth among his Quastiones quodlibeticae (1515). In the context of a discussion on the question of whether statutory provisions are binding in conscience, Adrian develops compelling ideas about the use of equity as a tool for the interpretation of laws. He then applies this general theory to the interpretation of the precept of fraternal correction.