bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevention of vascular dysfunction and arterial hypertension in mice generated by assisted reproductive technologies by addition of melatonin to culture media
Authors: Rexhaj Emrush , Pireva Agim , Paoloni-Giacobino Ariane , Allemann Yves , Cerny David , Dessen Pierre , Sartori Claudio , Scherrer Urs , Rimoldi Stefano F.
Published: August 2015

Assisted reproductive technologies (ART) induce vascular dysfunction in humans and mice. In mice, ART-induced vascular dysfunction is related to epigenetic alteration of the endothelial nitric oxide synthase (eNOS) gene, resulting in decreased vascular eNOS expression and nitrite/nitrate synthesis. Melatonin is involved in epigenetic regulation, and its administration to sterile women improves the success rate of ART. We hypothesized that addition of melatonin to culture media may prevent ART-induced epigenetic and cardiovascular alterations in mice. We, therefore, assessed mesenteric-artery responses to acetylcholine and arterial blood pressure, together with DNA methylation of the eNOS gene promoter in vascular tissue and nitric oxide plasma concentration in 12-wk-old ART mice generated with and without addition of melatonin to culture media and in control mice. As expected, acetylcholine-induced mesenteric-artery dilation was impaired ( P = 0.008 vs. control) and mean arterial blood pressure increased (109.5 ± 3.8 vs. 104.0 ± 4.7 mmHg, P = 0.002, ART vs. control) in ART compared with control mice. These alterations were associated with altered DNA methylation of the eNOS gene promoter ( P < 0.001 vs. control) and decreased plasma nitric oxide concentration (10.1 ± 11.1 vs. 29.5 ± 8.0 μM) ( P < 0.001 ART vs. control). Addition of melatonin (10−6 M) to culture media prevented eNOS dysmethylation ( P = 0.005, vs. ART + vehicle), normalized nitric oxide plasma concentration (23.1 ± 14.6 μM, P = 0.002 vs. ART + vehicle) and mesentery-artery responsiveness to acetylcholine ( P < 0.008 vs. ART + vehicle), and prevented arterial hypertension (104.6 ± 3.4 mmHg, P < 0.003 vs. ART + vehicle). These findings provide proof of principle that modification of culture media prevents ART-induced vascular dysfunction. We speculate that this approach will also allow preventing ART-induced premature atherosclerosis in humans.
AMP-activated protein kinase inhibits transforming growth factor-β-mediated vascular smooth muscle cell growth: implications for a Smad-3-dependent mechanism
Authors: Stone Joshua D. , Holt Andrew W. , Vuncannon Jackson R. , Brault Jeffrey J. , Tulis David A.
Published: August 2015

Dysfunctional vascular growth is a major contributor to cardiovascular disease, the leading cause of morbidity and mortality worldwide. Growth factor-induced activation of vascular smooth muscle cells (VSMCs) results in a phenotypic switch from a quiescent, contractile state to a proliferative state foundational to vessel pathology. Transforming growth factor-β (TGF-β) is a multifunctional signaling protein capable of growth stimulation via Smad signaling. Although Smad signaling is well characterized in many tissues, its role in VSM growth disorders remains controversial. Recent data from our lab and others implicate the metabolic regulator AMP-activated protein kinase (AMPK) in VSM growth inhibition. We hypothesized that AMPK inhibits VSMC proliferation by reducing TGF-β-mediated growth in a Smad-dependent fashion. Treatment of rat VSMCs with the AMPK agonist AICAR significantly decreased TGF-β-mediated activation of synthetic Smad2 and Smad3 and increased inhibitory Smad7. Flow cytometry and automated cell counting revealed that AICAR reversed TGF-β-mediated cell cycle progression at 24 h and elevated cell numbers at 48 h. TGF-β/Smad signaling increased the G0/G1 inducers cyclin D1/cyclin-dependent kinase (CDK) 4 and cyclin E/CDK2; however, AICAR reversed these events while increasing cytostatic p21. The specific role of Smad3 in AMPK-mediated reversal of TGF-β-induced growth was then explored using adenovirus-mediated Smad3 overexpression (Ad-Smad3). Ad-Smad3 cells increased cell cycle progression and cell numbers compared with Ad-GFP control cells, and these were restored to basal levels with concomitant AICAR treatment. These findings support a novel AMPK target in TGF-β/Smad3 for VSMC growth control and support continued investigation of AMPK as a possible therapeutic target for reducing vascular growth disorders.
ROCK insufficiency attenuates ozone-induced airway hyperresponsiveness in mice
Authors: Kasahara David I. , Mathews Joel A. , Park Chan Y. , Cho Youngji , Hunt Gabrielle , Wurmbrand Allison P. , Liao James K. , Shore Stephanie A.
Published: August 2015

Ozone causes airway hyperresponsiveness (AHR) and pulmonary inflammation. Rho kinase (ROCK) is a key regulator of smooth muscle cell contraction and inflammatory cell migration. To determine the contribution of the two ROCK isoforms ROCK1 and ROCK2 to ozone-induced AHR, we exposed wild-type, ROCK1+/−, and ROCK2+/− mice to air or ozone (2 ppm for 3 h) and evaluated mice 24 h later. ROCK1 or ROCK2 haploinsufficiency did not affect airway responsiveness in air-exposed mice but significantly reduced ozone-induced AHR, with a greater reduction in ROCK2+/− mice despite increased bronchoalveolar lavage (BAL) inflammatory cells in ROCK2+/− mice. Compared with wild-type mice, ozone-induced increases in BAL hyaluronan, a matrix protein implicated in ozone-induced AHR, were lower in ROCK1+/− but not ROCK2+/− mice. Ozone-induced increases in other inflammatory moieties reported to contribute to ozone-induced AHR (IL-17A, osteopontin, TNFα) were not different in wild-type vs. ROCK1+/− or ROCK2+/− mice. We also observed a dose-dependent reduction in ozone-induced AHR after treatment with the ROCK1/ROCK2 inhibitor fasudil, even though fasudil was administered after induction of inflammation. Ozone increased pulmonary expression of ROCK2 but not ROCK1 or RhoA. A ROCK2 inhibitor, SR3677, reduced contractile forces in primary human airway smooth muscle cells, confirming a role for ROCK2 in airway smooth muscle contraction. Our results demonstrate that ozone-induced AHR requires ROCK. Whereas ROCK1-dependent changes in hyaluronan may contribute to ROCK1's role in O3-induced AHR, the role of ROCK2 is downstream of inflammation, likely at the level of airway smooth muscle contraction.
Tetraplegia is associated with enhanced peripheral chemoreflex sensitivity and ventilatory long-term facilitation
Authors: Sankari Abdulghani , Bascom Amy T. , Riehani Anas , Badr M. Safwan
Published: August 2015

Cardiorespiratory plasticity induced by acute intermittent hypoxia (AIH) may contribute to recovery following spinal cord injury (SCI). We hypothesized that patients with cervical SCI would demonstrate higher minute ventilation (V̇e) following AIH compared with subjects with thoracic SCI and able-bodied subjects who served as controls. Twenty-four volunteers (8 with cervical SCI, 8 with thoracic SCI, and 8 able-bodied) underwent an AIH protocol during wakefulness. Each subject experienced 15 episodes of isocapnic hypoxia using mixed gases of 100% nitrogen (N2), 8% O2, and 40% CO2to achieve oxygen saturation ≤90% followed by room air (RA). Measurements were obtained before, during, and 40 min after AIH to obtain ventilation and heart rate variability data [R-R interval (RRI) and low-frequency/high-frequency power (LF/HF)]. AIH results were compared with those of sham studies conducted in RA during the same time period. Individuals with cervical SCI had higher V̇e after AIH compared with able-bodied controls (117.9 ± 23.2% vs. 97.9 ± 11.2%, P < 0.05). RRI decreased during hypoxia in all individuals (those with cervical SCI, from 1,009.3 ± 65.0 ms to 750.2 ± 65.0 ms; those with thoracic SCI, from 945.2 ± 65.0 ms to 674.9 ± 65.0 ms; and those who were able-bodied, from 949 ± 75.0 to 682.2 ± 69.5 ms; P < 0.05). LH/HF increased during recovery in individuals with thoracic SCI and those who were able-bodied (0.54 ± 0.22 vs. 1.34 ± 0.22 and 0.67 ± 0.23 vs. 1.82 ± 0.23, respectively; P < 0.05) but remained unchanged in the group with cervical SCI. Our conclusion is that patients with cervical SCI demonstrate ventilatory long-term facilitation following AIH compared with able-bodied controls. Heart rate responses to hypoxia are acutely present in patients with cervical SCI but are absent during posthypoxic recovery.
Sympathetic control of reflex cutaneous vasoconstriction in human aging
Authors: Greaney Jody L. , Alexander Lacy M. , Kenney W. Larry
Published: August 2015

This Synthesis highlights a series of recent studies that has systematically interrogated age-related deficits in cold-induced skin vasoconstriction. In response to cold stress, a reflex increase in sympathetic nervous system activity mediates reductions in skin blood flow. Reflex vasoconstriction during cold exposure is markedly impaired in aged skin, contributing to the relative inability of healthy older adults to maintain core temperature during mild cold stress in the absence of appropriate behavioral thermoregulation. This compromised reflex cutaneous vasoconstriction in healthy aging can occur as a result of functional deficits at multiple points along the efferent sympathetic reflex axis, including blunted sympathetic outflow directed to the skin vasculature, reduced presynaptic neurotransmitter synthesis and/or release, and altered end-organ responsiveness at several loci, in addition to potential alterations in afferent thermoreceptor function. Arguments have been made that the relative inability of aged skin to appropriately constrict is due to the aging cutaneous arterioles themselves, whereas other data point to the neural circuitry controlling those vessels. The argument presented herein provides strong evidence for impaired efferent sympathetic control of the peripheral cutaneous vasculature during whole body cold exposure as the primary mechanism responsible for attenuated vasoconstriction.
FDA Approval: Ibrutinib for Patients with Previously Treated Mantle Cell Lymphoma and Previously Treated Chronic Lymphocytic Leukemia
Authors: de Claro R. Angelo , McGinn Karen M. , Verdun Nicole , Lee Shwu-Luan , Chiu Haw-Jyh , Saber Haleh , Brower Margaret E. , Chang C.J. George , Pfuma Elimika , Habtemariam Bahru , Bullock Julie , Wang Yun , Nie Lei , Chen Xiao-Hong , Lu Donghao (Robert) , Al-Hakim Ali , Kane Robert C. , Kaminskas Edvardas , Justice Robert , Farrell Ann T. , Pazdur Richard
Published: August 2015

On November 13, 2013, the FDA granted accelerated approval to ibrutinib (IMBRUVICA capsules; Pharmacyclics, Inc.) for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. On February 12, 2014, the FDA granted accelerated approval for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy. Ibrutinib is a first-in-class Bruton's tyrosine kinase (BTK) inhibitor that received all four expedited programs of the FDA: Fast-Track designation, Breakthrough Therapy designation, Priority Review, and Accelerated Approval. Both approvals were based on overall response rate (ORR) and duration of response (DOR) in single-arm clinical trials in patients with prior treatment. In MCL (N = 111), the complete and partial response rates were 17.1% and 48.6%, respectively, for an ORR of 65.8% [95% confidence interval (CI), 56.2%–74.5%]. The median DOR was 17.5 months (95% CI, 15.8–not reached). In CLL (N = 48), the ORR was 58.3% (95% CI, 43.2%–72.4%), and the DOR ranged from 5.6 to 24.2 months. The most common adverse reactions (≥30% in either trial) were thrombocytopenia, diarrhea, neutropenia, bruising, upper respiratory tract infection, anemia, fatigue, musculoskeletal pain, peripheral edema, and nausea. Clin Cancer Res; 21(16); 3586–90. ©2015 AACR.
Integrating Murine and Clinical Trials with Cabozantinib to Understand Roles of MET and VEGFR2 as Targets for Growth Inhibition of Prostate Cancer
Authors: Varkaris Andreas , Corn Paul G. , Parikh Nila U. , Efstathiou Eleni , Song Jian H. , Lee Yu-Chen , Aparicio Ana , Hoang Anh G. , Gaur Sanchaika , Thorpe Lynnelle , Maity Sankar N. , Bar Eli Menashe , Czerniak Bogdan A. , Shao Yiping , Alauddin Mian , Lin Sue-Hwa , Logothetis Christopher J. , Gallick Gary E.
Published: August 2015

Purpose: We performed parallel investigations in cabozantinib-treated patients in a phase II trial and simultaneously in patient-derived xenograft (PDX) models to better understand the roles of MET and VEGFR2 as targets for prostate cancer therapy.

Experimental Design: In the clinical trial, radiographic imaging and serum markers were examined, as well as molecular markers in tumors from bone biopsies. In mice harboring PDX intrafemurally or subcutaneously, cabozantinib effects on tumor growth, MET, PDX in which MET was silenced, VEGFR2, bone turnover, angiogenesis, and resistance were examined.

Results: In responsive patients and PDX, islets of viable pMET-positive tumor cells persisted, which rapidly regrew after drug withdrawal. Knockdown of MET in PDX did not affect tumor growth in mice nor did it affect cabozantinib-induced growth inhibition but did lead to induction of FGFR1. Inhibition of VEGFR2 and MET in endothelial cells reduced the vasculature, leading to necrosis. However, each islet of viable cells surrounded a VEGFR2-negative vessel. Reduction of bone turnover was observed in both cohorts.

Conclusions: Our studies demonstrate that MET in tumor cells is not a persistent therapeutic target for metastatic castrate-resistant prostate cancer (CRPC), but inhibition of VEGFR2 and MET in endothelial cells and direct effects on osteoblasts are responsible for cabozantinib-induced tumor inhibition. However, vascular heterogeneity represents one source of primary therapy resistance, whereas induction of FGFR1 in tumor cells suggests a potential mechanism of acquired resistance. Thus, integrated cross-species investigations demonstrate the power of combining preclinical models with clinical trials to understand mechanisms of activity and resistance of investigational agents. Clin Cancer Res; 22(1); 107–21. ©2015 AACR.
Downregulation of Critical Oncogenes by the Selective SK2 Inhibitor ABC294640 Hinders Prostate Cancer Progression
Authors: Schrecengost Randy S. , Keller Staci N. , Schiewer Matthew J. , Knudsen Karen E. , Smith Charles D.
Published: August 2015

The bioactive sphingolipid sphingosine-1-phosphate (S1P) drives several hallmark processes of cancer, making the enzymes that synthesize S1P, that is, sphingosine kinase 1 and 2 (SK1 and SK2), important molecular targets for cancer drug development. ABC294640 is a first-in-class SK2 small-molecule inhibitor that effectively inhibits cancer cell growth in vitro and in vivo. Given that AR and Myc are two of the most widely implicated oncogenes in prostate cancer, and that sphingolipids affect signaling by both proteins, the therapeutic potential for using ABC294640 in the treatment of prostate cancer was evaluated. This study demonstrates that ABC294640 abrogates signaling pathways requisite for prostate cancer growth and proliferation. Key findings validate that ABC294640 treatment of early-stage and advanced prostate cancer models downregulate Myc and AR expression and activity. This corresponds with significant inhibition of growth, proliferation, and cell-cycle progression. Finally, oral administration of ABC294640 was found to dramatically impede xenograft tumor growth. Together, these pre-clinical findings support the hypotheses that SK2 activity is required for prostate cancer function and that ABC294640 represents a new pharmacological agent for treatment of early stage and aggressive prostate cancer.

Implications: Sphingosine kinase inhibition disrupts multiple oncogenic signaling pathways that are deregulated in prostate cancer. Mol Cancer Res; 13(12); 1591–601. ©2015 AACR.
Adaptive Immune Resistance: How Cancer Protects from Immune Attack
Authors: Ribas Antoni
Published: August 2015

Adaptive immune resistance is a process in which the cancer changes its phenotype in response to a cytotoxic or proinflammatory immune response, thereby evading it. This adaptive process is triggered by the specific recognition of cancer cells by T cells, which leads to the production of immune-activating cytokines. Cancers then hijack mechanisms developed to limit inflammatory and immune responses and protect themselves from the T-cell attack. Inhibiting adaptive immune resistance is the mechanistic basis of responses to PD-1 or PD-L1–blocking antibodies, and may be of relevance for the development of other cancer immunotherapy strategies.

Significance: Several new immunotherapy strategies to treat cancer are based on inhibiting processes through which cancer adapts and evades from an immune response. Recognizing the specific adaptive resistance mechanisms in each case is likely to allow the personalized development of immunotherapies tailored to block how a particular cancer protects itself from the immune system. Cancer Discov; 5(9); 915–9. ©2015 AACR.
The Combination of 80 Years of Age and Metastatic Castration-Resistant Prostate Cancer Remain an Uphill Battle: A Case Report with Cabazitaxel as a Double-Edged Sword
Authors: Méry Benoite , Trone Jane-Chloé , Moriceau Guillaume , Falk Alexander Tuan , Guillot Aline , Pacaut Cécile , Collard Olivier , Magné Nicolas
Published: August 2015

We report the case of an 80-year-old patient who presented with a progressive prostate metastatic cancer with poor performance status. The patient had already benefitted from docetaxel and abiraterone. A new line of chemotherapy by cabazitaxel was started with good response, and there was a dramatic improvement in general status and pain symptoms. Age and performance status alone should not be limiting decision factors for elderly cancer patients.
Long-Term Administration of Neuropeptide Y in the Subcutaneous Infusion Results in Cardiac Dysfunction and Hypertrophy in Rats
Authors: Zhang Rong , Niu Huifang , Kang Xiaohui , Ban Tao , Hong Hong , Ai Jing
Published: August 2015

Background/Aims: The purpose of the present study was to clarify whether chronically elevated plasma neuropeptide Y (NPY) might affect heart function and cardiac remodeling in rats. Methods: Male Wistar rats were administered NPY (85 μg for 30 days) by mini-osmotic pump subcutaneously implanted between the scapulae. Associated indices for heart function, cardiac remodeling and hypertrophy were evaluated. Results: Compared to the sham group, the baseline systolic blood pressure (SBP) in rats administered NPY was significantly increased; cardiac function was significantly decreased, as indicated by reduced ejection fraction (EF), left ventricular end-systolic pressure (LVESP), maximum change velocity of left ventricular pressure in the isovolumic contraction or relaxation period (±dp/dtmax) and increased left ventricular end-diastolic pressure (LVEDP); hematoxylin-eosin (H&E) staining detection displayed enlarged cell areas and a consistent increase in heart-to-body weight ratios (HW/BW) was observed; quantitative real time PCR (qRT-PCR) and Western blot analysis showed markedly increased expressions of β-myosin heavy chain (β-MHC), calcineurin (CaN) and phosphorylated p38 proteins, while no changes were found in the expressions of p38 total protein and the phosphorylations of JNK and ERK. Conclusion: This study reported for the first time that long-term elevated plasma concentration of NPY could induce cardiac dysfunction and cardiac hypertrophy and this phenomenon could, in part, be mediated by the Ca2+/CaM-dependent CaN pathway and p38 mitogen-activated protein kinase (MAPK) signal pathway in rats.
New Self-Expanding Transcatheter Valve for Off-Pump Transatrial Mitral Valve-In-Ring Implantation
Authors: Ma Liang , Yu Zipu , Huber Christoph , Li Chengchen , Qian Linfeng , Jiang Jianjie , Zou Yu
Published: August 2015

Objectives: To validate a self-expanding transcatheter valve for off-pump transatrial mitral valve-in-ring (VIR) implantation via a left thoracotomy. Methods: Mitral valve annuloplasty was performed via sternotomy during cardiopulmonary bypass on 9 pigs. After successful weaning from extracorporal circulation, the custom-made, self-expanding transcatheter VIR device was deployed under fluoroscopic guidance within the annuloplasty ring via a left thoracotomy. Hemodynamic data before and after the implantation were recorded. Mitral annulus diameter and valve area were measured by echocardiography. Transvalvular and left-ventricular outflow-tract pressure gradient were measured invasively. Results: Eight successful implantations were performed. Implantation failed in 1 pig because of difficulty with technical delivery of the sheath. Mean transatrial procedure time was 12.6 ± 1.7 min. Hemodynamic status during transatrial implantation was stable, and differences were not statistically significant. Mean mitral annulus diameter and mean mitral orifice area were 2.32 ± 0.2 and 3.84 ± 0.55 cm2, respectively. Mild regurgitation was detected in 7 animals and moderate regurgitation in 1. Mean gradients were 6.1 ± 5.0 mm Hg across the device. Postmortem examination confirmed adequate positioning of devices within the annuloplasty ring. Conclusions: This custom-made transcatheter device allows for safe and reproducible off-pump transatrial mitral VIR implantations. Transatrial access is a promising route to facilitate VIR implantations. Our custom-made stent-valve may be suitable for VIR procedures.
Activated Protein C-Resistance Determination and Vascular Access Thrombosis in Populations with High Prevalence of Factor V Leiden
Authors: Androulakis Nikolaos E. , Tzenakis Nikolaos , Nioti Eleni , Spatharaki Paraskevi , Vyzoukaki Rodanthi , Papadopoulou Anastasia , Kokonozaki Maria , Alexandrakis Michael G.
Published: August 2015

Background/Aims: Factor V Leiden heterozygosity occurs in 3-8% of the general European and US populations. Activated protein C resistance (APC-R) - a non-molecular laboratory test - can efficiently demonstrate the presence of this mutation and can be performed on most coagulation analyzers. On the other hand, fistula or graft thrombosis is a common and costly complication in hemodialysis patients. Our aim was to establish the value of APC-R determination in hemodialysis patients by assessing the risk of access thrombosis in patients with increased APC-R. Methods: A total of 133 patients (81 men, mean age 64.5 ± 14.9 years and 52 women, mean age 63.6 ± 15 years) were selected. Participants were divided into 2 groups: those with access thrombosis (54 patients, 40.6%) and those with no access thrombosis (79 patients, 59.4%), and they were tested for the most common congenital or acquired thrombophilia risk factors. Results: Overall, 12 patients (9%) had an increased APC-R and 10 of them had at least 1 episode of access thrombosis (83.3%). Univariate analysis to estimate crude odds ratio (OR) showed an OR of 8.8 (95% CI 1.8-41.8) times higher risk for access thrombosis in these patients. No significant differences were found after adjusting for age, hypertension, diabetes mellitus, coronary artery disease, cerebrovascular disease, peripheral arterial disease and malignancy. Sex was also a factor influencing thrombosis, presenting a higher OR for women (OR 2.2, 95% CI 1.1-4.4). Conclusion: This study revealed a significant association between access thrombosis and increased APC-R in hemodialysis patients. This indicates that the determination of APC-R should be considered - especially, in populations with a high prevalence of Factor V Leiden - as proper anticoagulant therapy in these patients may reduce the risk of access thrombosis.
Phenotype and Genotype in a Cohort of 312 Adult Patients with Nontransfusion-Dependent Thalassemia in Northeast Thailand
Authors: Prayalaw Patcharawadee , Teawtrakul Nattiya , Jetsrisuparb Arunee , Pongudom Saranya , Fucharoen Goonnapa , Fucharoen Supan
Published: August 2015

Patients with nontransfusion-dependent thalassemia (NTDT) do not require regular blood transfusion for survival but may encounter several complications that contribute to morbidity and mortality. We report the molecular heterogeneity and hematological features of NTDT in 312 adult patients in northeast Thailand. Hemoglobin (Hb) and DNA analyses identified 177 subjects with Hb E-β-thalassemia, 1 with homozygous β⁰-thalassemia and 134 with Hb H, AEBart's and EEBart's diseases. For β-thalassemia, 12 different mutations including both β⁰- and β+-thalassemias were detected. Coinheritance of α-thalassemia as an ameliorating factor was observed in 18 of 178 cases (10.1%) with β-thalassemia. The α-globin gene triplicated haplotype (αααanti3.7) was observed in 1 case of Hb E-β⁰-thalassemia. The presence of the -158 (C→T) Gγ-XmnI polymorphism (+/+) was found to be associated with increased Hb F expression, but its frequency in the studied subjects was low. Those with α-thalassemia included 17 with deletional and 51 nondeletional Hb H, and 63 with AEBart's and 3 with EEBart's diseases. The hematological parameters of these NTDT and genotype-phenotype relationships are presented. The diverse molecular heterogeneity of NTDT underlines the importance of complete genotyping of the patient. These results should prove useful for management planning, the prediction of clinical outcome and to improve genetic counseling for NTDT patients.
Modulation of the Innate Immune Response through the Vagus Nerve
Authors: Kox Matthijs , Pickkers Peter
Published: August 2015

The innate immune system is a defense mechanism that is of vital importance to our survival. However, excessive or unwanted activation of the innate immune system, which can occur in major surgery, sepsis, trauma, ischemia-reperfusion injury and autoimmune diseases, can lead to damage of the kidneys and other organs. Therefore, therapeutic approaches aimed at attenuating the innate immune response could have beneficial effects in these conditions. The vagus nerve exerts anti-inflammatory effects through the so-called cholinergic anti-inflammatory pathway. Since its discovery, numerous animal studies have shown beneficial effects of stimulation of this pathway in models of inflammatory diseases, either through (electrical) stimulation of the vagus nerve or pharmacological approaches. However, human data are very scarce. In this review, we present an overview of the molecular and anatomical bases of the cholinergic anti-inflammatory pathway, but mainly focus on human studies. We discuss the difficulties and drawbacks associated with investigating this pathway in humans, and finally, we provide future perspectives.
Glycoprotein Ia C807T: Polymorphisms and Their Association with Platelet Function in Patients with the Acute Coronary Syndrome
Authors: Zhang Qiang , Jin Yiqi , Shi Dongmin , Gong Junrong , Liu Jing , Lu Yongyi , Tong Min , Wang Jiankang , Song Qi , Dong Jiamin , Chen Wenting , Lv Ke
Published: August 2015

Objectives: In the current study, we explored the relationship between glycoprotein Ia (GPIa) C807T polymorphisms and platelet function, and the sensitivity to dual antiplatelet treatment after percutaneous coronary intervention. Materials and Methods: We conducted a case-control study in 220 patients diagnosed with acute coronary syndrome (ACS) and 220 healthy controls. The platelet GPIa C807T genotypes of patients and controls were determined, and platelet aggregation and plasma concentrations of α-granule membrane protein (GMP-140) were assessed following stimulation with arachidonic acid and adenosine diphosphate. Results: The frequency of the GPIa T allele was higher in the ACS group than in controls. In the ACS group, platelet aggregation was significantly higher in individuals with the T allele than in those with the C allele. Dual antiplatelet treatment reduced platelet aggregation in all three genotypes, and patients carrying the CC genotype were more sensitive to antiplatelet treatment than those with the T allele, particularly the ones with the TT genotype. There were no differences in plasma GMP-140 levels. Conclusions: The GPIa C807T polymorphism might be a risk factor for the development and relapse of ACS. The GP Ia T allele may help to identify a group of patients who need more aggressive antithrombotic treatment.
Genomic and Proteomic Characterization of Acute Kidney Injury
Authors: Devarajan Prasad
Published: August 2015

The incidence and severity of acute kidney injury (AKI) is rising globally, and the associated morbidity and mortality remain high despite promising advances in experimental therapeutics. The reasons include (a) an incomplete understanding of the complex pathophysiology, (b) an inability to reliably identify risk factors for AKI and (c) a lack of biomarkers for the early prediction of AKI and its outcomes. Functional genomics, bioinformatics and proteomics have begun to uncover candidates that are emerging as biomarkers and therapeutic targets. This review will update the reader on current technologies in genomics (including targeted sequencing, genome wide association studies and transcriptome profiling) and proteomics (including gel electrophoresis and mass spectrometry methods) and their application on human AKI.
Mechanisms of Origin, Phenotypic Effects and Diagnostic Implications of Complex Chromosome Rearrangements
Authors: Poot Martin , Haaf Thomas
Published: August 2015

Complex chromosome rearrangements (CCRs) are currently defined as structural genome variations that involve more than 2 chromosome breaks and result in exchanges of chromosomal segments. They are thought to be extremely rare, but their detection rate is rising because of improvements in molecular cytogenetic technology. Their population frequency is also underestimated, since many CCRs may not elicit a phenotypic effect. CCRs may be the result of fork stalling and template switching, microhomology-mediated break-induced repair, breakage-fusion-bridge cycles, or chromothripsis. Patients with chromosomal instability syndromes show elevated rates of CCRs due to impaired DNA double-strand break responses during meiosis. Therefore, the putative functions of the proteins encoded by ATM, BLM, WRN, ATR, MRE11, NBS1, and RAD51 in preventing CCRs are discussed. CCRs may exert a pathogenic effect by either (1) gene dosage-dependent mechanisms, e.g. haploinsufficiency, (2) mechanisms based on disruption of the genomic architecture, such that genes, parts of genes or regulatory elements are truncated, fused or relocated and thus their interactions disturbed - these mechanisms will predominantly affect gene expression - or (3) mixed mutation mechanisms in which a CCR on one chromosome is combined with a different type of mutation on the other chromosome. Such inferred mechanisms of pathogenicity need corroboration by mRNA sequencing. Also, future studies with in vitro models, such as inducible pluripotent stem cells from patients with CCRs, and transgenic model organisms should substantiate current inferences regarding putative pathogenic effects of CCRs. The ramifications of the growing body of information on CCRs for clinical and experimental genetics and future treatment modalities are briefly illustrated with 2 cases, one of which suggests KDM4C(JMJD2C) as a novel candidate gene for mental retardation.
The D173G mutation in ADAMTS-13 causes a severe form of congenital thrombotic thrombocytopenic purpura
Authors: Pagliari Maria Teresa , Cairo Andrea , Abdel-Azeim Safwat , Chermak Edrisse , Lazzareschi Ilaria , Mastrangelo Stefano , Cavallo Luigi , Oliva Romina , Lancellotti Stefano , Peyvandi Flora , Cristofaro Raimondo De
Published: August 2015

Congenital thrombotic thrombocytopenic purpura (TTP) is a rare form of thrombotic microangiopathy, inherited with autosomal recessive mode as a dysfunction or severe deficiency of ADAMTS-13 (A Disinte-grin And Metalloprotease with ThromboSpondin 1 repeats Nr. 13), caused by mutations in the ADAMTS-13 gene. About 100 mutations of the ADAMTS-13 gene were identified so far, although only a few char-acterised by in vitro expression studies. A new Asp to Gly homozygous mutation at position 173 of ADAMTS-13 sequence was identified in a family of Romanian origin, with some members affected by clinical signs of TTP. In two male sons, this mutation caused a severe (< 3 %) deficiency of ADAMTS-13 activity and antigen level, associated with periodic thrombocytopenia, haemolytic anaemia and mild mental confusion. Both parents, who are cousins, showed the same mutation in heterozygous form. Expression studies of the mutant ADAMTS-13, performed in HEK293 cells, showed a severe decrease of the enzyme’s activity and secretion, although the protease was detected inside the cells. Molecular dynamics found that in the D173G mutant the interface area between the metalloprotease domain and the disintegrin-like domain significantly decreases during the simulations, while the proline-rich 20 residues linker region (LR, 285–304) between them undergoes extensive conformational changes. Inter-domain contacts are also significantly less conserved in the mutant compared to the wild-type. Both a decrease of the inter-domain contacts along with a substantial conformational rearrangement of LR interfere with the proper maturation and folding of the mutant ADAMTS-13, thus impairing its secretion.

Supplementary Material to this article is available online at www.thrombosis-online.com.
Antiplatelet drugs in patients with enhanced platelet turnover: biomarkers versus platelet function testing
Authors: Gruber Susanne , Grove Erik , Weiss Thomas , Wojta Johann , Huber Kurt , Freynhofer Matthias
Published: August 2015

Platelets are key players in atherothrombosis. Antiplatelet therapy comprising aspirin alone or with P2Y12-inhibitors are effective for prevention of atherothrombotic complications. However, there is interindividual variability in the response to antiplatelet drugs, leaving some patients at increased risk of recurrent atherothrombotic events. Several risk factors associated with high on-treatment platelet reactivity (HTPR), including elevated platelet turnover, have been identified. Platelet turnover is adequately estimated from the fraction of reticulated platelets. Reticulated platelets are young platelets, characterised by residual messenger RNA. They are larger, haemostatically more active and there is evidence that platelet turnover is a causal and prognostic factor in atherothrombotic disease. Whether platelet turnover per se represents a key factor in pathogenesis, progression and prognosis of atherothrombotic diseases (with focus on acute coronary syndromes) or whether it merely facilitates insufficient platelet inhibition will be discussed in this state-of-the art review.
Drug-Free Platelets Can Act as Seeds for Aggregate Formation During Antiplatelet Therapy
Authors: Hoefer Thomas , Armstrong Paul C. , Finsterbusch Michaela , Chan Melissa V. , Kirkby Nicholas S. , Warner Timothy D.
Published: August 2015

Objective—

Reduced antiplatelet drug efficacy occurs in conditions of increased platelet turnover, associated with increased proportions of drug-free, that is, uninhibited, platelets. Here, we detail mechanisms by which drug-free platelets promote platelet aggregation in the face of standard antiplatelet therapy.

Approach and Results—

To model standard antiplatelet therapy, platelets were treated in vitro with aspirin, the P2Y
12
receptor blocker prasugrel active metabolite, or aspirin plus prasugrel active metabolite. Different proportions of uninhibited platelets were then introduced. Light transmission aggregometry analysis demonstrated clear positive associations between proportions of drug-free platelets and percentage platelet aggregation in response to a range of platelet agonists. Using differential platelet labeling coupled with advanced flow cytometry and confocal imaging we found aggregates formed in mixtures of aspirin-inhibited platelets together with drug-free platelets were characterized by intermingled platelet populations. This distribution is in accordance with the ability of drug-free platelets to generate thromboxane A
2
and so drive secondary platelet activation. Conversely, aggregates formed in mixtures of prasugrel active metabolite–inhibited or aspirin plus prasugrel active metabolite–inhibited platelets together with drug-free platelets were characterized by distinct cores of drug-free platelets. This distribution is consistent with the ability of drug-free platelets to respond to the secondary activator ADP.

Conclusions—

These experiments are the first to image the interactions of inhibited and uninhibited platelets in the formation of platelet aggregates. They demonstrate that a general population of platelets can contain subpopulations that respond strikingly differently to overall stimulation of the population and so act as the seed for platelet aggregation.
Fibroblast Growth Factor 23 Is an Independent and Specific Predictor of Mortality in Patients With Heart Failure and Reduced Ejection Fraction
Authors: Koller Lorenz , Kleber Marcus E. , Brandenburg Vincent M. , Goliasch Georg , Richter Bernhard , Sulzgruber Patrick , Scharnagl Hubert , Silbernagel Günther , Grammer Tanja B. , Delgado Graciela , Tomaschitz Andreas , Pilz Stefan , Berger Rudolf , Mörtl Deddo , Hülsmann Martin , Pacher Richard , März Winfried , Niessner Alexander
Published: August 2015

Background—

Strategies to improve risk prediction are of major importance in patients with heart failure (HF). Fibroblast growth factor 23 (FGF-23) is an endocrine regulator of phosphate and vitamin D homeostasis associated with an increased cardiovascular risk. We aimed to assess the prognostic effect of FGF-23 on mortality in HF patients with a particular focus on differences between patients with HF with preserved ejection fraction and patients with HF with reduced ejection fraction (HFrEF).

Methods and Results—

FGF-23 levels were measured in 980 patients with HF enrolled in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study including 511 patients with HFrEF and 469 patients with HF with preserved ejection fraction and a median follow-up time of 8.6 years. FGF-23 was additionally measured in a second cohort comprising 320 patients with advanced HFrEF. FGF-23 was independently associated with mortality with an adjusted hazard ratio per 1-SD increase of 1.30 (95% confidence interval, 1.14–1.48;
P
<0.001) in patients with HFrEF, whereas no such association was found in patients with HF with preserved ejection fraction (for interaction,
P
=0.043). External validation confirmed the significant association with mortality with an adjusted hazard ratio per 1 SD of 1.23 (95% confidence interval, 1.02–1.60;
P
=0.027). FGF-23 demonstrated an increased discriminatory power for mortality in addition to N-terminal pro–B-type natriuretic peptide (
C
-statistic: 0.59 versus 0.63) and an improvement in net reclassification index (39.6%;
P
<0.001).

Conclusions—

FGF-23 is independently associated with an increased risk of mortality in patients with HFrEF but not in those with HF with preserved ejection fraction, suggesting a different pathophysiologic role for both entities.
Comparative Efficacy of Intracoronary Allogeneic Mesenchymal Stem Cells and Cardiosphere-Derived Cells in Swine with Hibernating Myocardium
Authors: Weil Brian R. , Suzuki Gen , Leiker Merced M. , Fallavollita James A. , Canty John M.
Published: August 2015

Rationale:

Allogeneic bone marrow–derived mesenchymal stem cells (MSCs) and cardiosphere-derived cells (CDCs) have each entered clinical trials, but a direct comparison of these cell types has not been performed in a large animal model of hibernating myocardium.

Objective:

Using completely blinded methodology, we compared the efficacy of global intracoronary allogeneic MSCs (icMSCs, ≈35×10
6
) and CDCs (icCDCs, ≈35×10
6
) versus vehicle in cyclosporine-immunosuppressed swine with a chronic left anterior descending coronary artery stenosis (n=26).

Methods and Results:

Studies began 3 months after instrumentation when wall thickening was reduced (left anterior descending coronary artery % wall thickening [mean±SD], 38±11% versus 83±26% in remote;
P
<0.01) and similar among groups. Four weeks after treatment, left anterior descending coronary artery % wall thickening increased similarly after icCDCs and icMSCs, whereas it remained depressed in vehicle-treated controls (icMSCs, 51±13%; icCDCs, 51±17%; vehicle, 34±3%, treatments
P
<0.05 versus vehicle). There was no change in myocardial perfusion. Both icMSCs and icCDCs increased left anterior descending coronary artery myocyte nuclear density (icMSCs, 1601±279 nuclei/mm
2
; icCDCs, 1569±294 nuclei/mm
2
; vehicle, 973±181 nuclei/mm
2
; treatments
P
<0.05 versus vehicle) and reduced myocyte diameter (icMSCs, 16.4±1.5 μm; icCDCs, 16.8±1.2 μm; vehicle, 20.2±3.7 μm; treatments
P
<0.05 versus vehicle) to the same extent. Similar changes in myocyte nuclear density and diameter were observed in the remote region of cell-treated animals. Cell fate analysis using Y-chromosome fluorescent in situ hybridization demonstrated rare cells from sex-mismatched donors.

Conclusions:

Allogeneic icMSCs and icCDCs exhibit comparable therapeutic efficacy in a large animal model of hibernating myocardium. Both cell types produced equivalent increases in regional function and stimulated myocyte regeneration in ischemic and remote myocardium. The activation of endogenous myocyte proliferation and regression of myocyte cellular hypertrophy support a common mechanism of cardiac repair.
Beyond Emboldenment: How Acquiring Nuclear Weapons Can Change Foreign Policy
Authors: Bell Mark S.
Published: August 2015

What happens to the foreign policies of states when they acquire nuclear weapons? Despite its importance, this question has not been answered satisfactorily. Nuclear weapons can facilitate six conceptually distinct foreign policy behaviors: aggression, expansion, independence, bolstering, steadfastness, and compromise. This typology of foreign policy behaviors enables scholars to move beyond simple claims of “nuclear emboldenment,” and allows for more nuanced examination of the ways in which nuclear weapons affect the foreign policies of current and future nuclear states. The typology also sheds light on Great Britain's response to nuclear acquisition. Britain used nuclear weapons to engage in greater levels of steadfastness in responding to challenges, bolstering junior allies, and demonstrating independence from the United States, but it did not engage in greater levels of aggression, expansion, or compromise. The typology and the British case demonstrate the value of distinguishing among different effects of nuclear weapons acquisition, have implications for scholars' and policymakers' understanding of the role of nuclear weapons in international politics, and suggest avenues for future research.
Corporatism as a Contested Sphere: Trade Organization in Morocco under the Vichy Regime
Authors: Ouaknine-Yekutieli Orit
Published: August 2015

This paper reviews the history of local professional associations in Morocco under the French Protectorate and focuses on the period of Vichy rule in the colony (1940-1942). It examines the partial application of corporatism in Morocco as Vichy’s preferred method of professional organization, which was expected to turn local attention away from a perceived nationalism to a seemingly benign economic activity. By investigating a local corporatist association operating in those years, this paper shows that the corporatist project unwittingly turned into a nationalist one not of its own making. The paper further examines the relationships between economy, colonialism, nationalism, racism, and Muslim-Jewish relations in Morocco during the Vichy period.
Religious Philanthropy in China, Taiwan and Hong Kong
Authors: Laliberté André
Published: August 2015

This essay argues that differences in religious ecologies, between China and the polities of Taiwan and Hong Kong are necessary but insufficient explanations for their different approaches to the reliance on religious actors for the delivery of social services. I discuss briefly two other explanations for the differences in policy outcomes: the legacies of colonial and semi-colonial rule, and the influence of ruling party ideologies, before I shift to an historical neo-institutional approach, which contrasts the path dependency of past policies of usurpation directed by the CCP at religious institutions between 1949 and 1978, and the policies of cooptation adopted in Taiwan and Hong Kong during the same period. I argue that although the Chinese government has affirmed with increasing clarity in recent years its interest in an approach that encourages the cooptation of religious institutions, the previous approach of usurpation has undermined the resources of religious institutions, left many religious actors distrustful of authorities, and continues to influence many constituencies that could oppose the approach of cooptation. To substantiate this argument, the essay proceeds as follows: it first discusses the different strategies available to states as they accumulate symbolic power, underlining the role of religious institutions in that process; then it contrasts the results achieved by religious philanthropy in Taiwan and Hong Kong in the provision of a wide array of services, on the one hand, with the difficulties faced by their counterparts in the delivery of social services in China, on the other; and finally it reviews some of the explanations for the discrepancies observed.
Old Questions, New Techniques: A Research Note on the Computational Identification of Political Elites
Authors: Hicks Jacqueline , Traag Vincent , Reinanda Ridho
Published: August 2015

This paper presents a new method of identifying a nation’s political elite using computational techniques on digitised newspaper articles. It begins by describing the three most widely used methods of identifying political elites: positional, decisional and reputational. It then introduces the “reported elite method”, exploring the kinds of elites it detects and how well it reflects the composition of political elites in our case study of Indonesia. Compared to the other existing methods, we find that our method casts a much wider net when searching for political elites, resulting in many more people from civil society, far fewer formal politicians, and challenging conventional notions of who is a political elite. The method has two major underlying assumptions: (1) the newspapers from which the texts are drawn are free and fairly representative and (2) political power can be inferred from frequent appearance in newspapers alongside other frequently appearing individuals in computational “communities” of political elite.
Positive and Negative Perceptions of Ageing Identity Compared to Lived Experience: A Comparative Study of Older People in Zambia and Northern Ireland
Authors: Ní Dhónaill Caoimhe
Published: August 2015

This research considers how people come to understand their changing sense of identity as they reach older age in two different geographical areas: Northern Ireland and Zambia. Employing an identity theory frame, it considers how perceptions of ageing, based largely on memories of older relatives, inform how strongly people identify with – and internalise – a sense of being ‘old’. The comparative framework allows exploration of the role of cultural expectations of ageing in the construction of an ageing identity. The different areas produced contrasting results. Ageing was perceived as a negative life-stage in Northern Ireland, but the lived experience was found to be positive, where the perception of ageing was largely positive in Zambia, with the lived experience being extremely negative.