bluuebunny/crossref_metadata_2025 huggingface dataset:
Cohort of estrogen-induced microRNAs regulate adrenomedullin expression
Authors: Wetzel-Strong Sarah E. , Li Manyu , Espenschied Scott T. , Caron Kathleen M.
Published: November 2015

Estrogen regulates the expression of many genes and has been correlated with differences in cardiac contraction; however, the underlying mechanisms remain poorly defined. Adrenomedullin ( Adm = gene; AM = protein) is a multifunctional peptide with inotropic actions. Previous studies have demonstrated that estrogen enhances the expression of Adm, suggesting a relationship between AM and estrogen in cardiac contraction during physiological and pathological states. In this study, female mice in a mouse model of genetic Adm overexpression, abbreviated as Adm hi/hi, were found to express 60 times more Adm in the heart than wild-type littermates, compared with the three-fold elevation of Adm previously reported in Adm hi/hi male hearts. Thus, this study sought to further investigate any functional consequences of increased cardiac Adm expression and begin exploring the mechanisms that regulate Adm expression in an estrogen-dependent fashion. This study revealed that heart function is enhanced in Adm hi/hi females, which along with Adm expression levels, was reversed following ovariectomization. Since the Adm hi/hi line was generated by the displacement of the 3′ untranslated region (UTR), the native 3′UTR was examined for estrogen-induced microRNAs target sites to potentially explain the aberrant overexpression observed in Adm hi/hi female hearts. Using a bioinformatic approach, it was determined that the mouse Adm 3′UTR contains many target sites for previously characterized estrogen-induced microRNAs. This study also determined that the novel microRNA, miR-879, is another estrogen-induced microRNA that interacts with the 3′UTR of Adm to destabilize the mRNA. Together, these studies revealed that estrogen-induced microRNAs are important for balancing cardiac Adm expression in females.
The role of calbindin-D28k on renal calcium and magnesium handling during treatment with loop and thiazide diuretics
Authors: Lee Chien-Te , Ng Hwee-Yeong , Lee Yueh-Ting , Lai Li-Wen , Lien Yeong-Hau H.
Published: November 2015

Calbindin-D28k (CBD-28k) is a calcium binding protein located in the distal convoluted tubule (DCT) and plays an important role in active calcium transport in the kidney. Loop and thiazide diuretics affect renal Ca and Mg handling: both cause Mg wasting, but have opposite effects on Ca excretion as loop diuretics increase, but thiazides decrease, Ca excretion. To understand the role of CBD-28k in renal Ca and Mg handling in response to diuretics treatment, we investigated renal Ca and Mg excretion and gene expression of DCT Ca and Mg transport molecules in wild-type (WT) and CBD-28k knockout (KO) mice. Mice were treated with chlorothiazide (CTZ; 50 mg·kg−1·day−1) or furosemide (FSM; 30 mg·kg−1·day−1) for 3 days. To avoid volume depletion, salt was supplemented in the drinking water. Urine Ca excretion was reduced in WT, but not in KO mice, by CTZ. FSM induced similar hypercalciuria in both groups. DCT Ca transport molecules, including transient receptor potential vanilloid 5 (TRPV5), TRPV6, and CBD-9k, were upregulated by CTZ and FSM in WT, but not in KO mice. Urine Mg excretion was increased and transient receptor potential subfamily M, member 6 (TRPM6) was upregulated by both CTZ and FSM in WT and KO mice. In conclusion, CBD-28k plays an important role in gene expression of DCT Ca, but not Mg, transport molecules, which may be related to its being a Ca, but not a Mg, intracellular sensor. The lack of upregulation of DCT Ca transport molecules by thiazides in the KO mice indicates that the DCT Ca transport system is critical for Ca conservation by thiazides.
Reducing αENaC expression in the kidney connecting tubule induces pseudohypoaldosteronism type 1 symptoms during K+ loading
Authors: Poulsen Søren Brandt , Praetorius Jeppe , Damkier Helle H. , Miller Lance , Nelson Raoul D. , Hummler Edith , Christensen Birgitte Mønster
Published: November 2015

Genetic inactivation of the epithelial Na+ channel α-subunit (αENaC) in the renal collecting duct (CD) does not interfere with Na+ and K+ homeostasis in mice. However, inactivation in the CD and a part of the connecting tubule (CNT) induces autosomal recessive pseudohypoaldosteronism type 1 (PHA-1) symptoms in subjects already on a standard diet. In the present study, we further examined the importance of αENaC in the CNT. Knockout mice with αENaC deleted primarily in a part of the CNT (CNT-KO) were generated using Scnn1alox/lox mice and Atp6v1b1:: Cre mice. With a standard diet, plasma Na+ concentration ([Na+]) and [K+], and urine Na+ and K+ output were unaffected. Seven days of Na+ restriction (0.01% Na+) led to a higher urine Na+ output only on days 3–5, and after 7 days plasma [Na+] and [K+] were unaffected. In contrast, the CNT-KO mice were highly susceptible to a 2-day 5% K+ diet and showed lower food intake and relative body weight, lower plasma [Na+], higher fractional excretion (FE) of Na+, higher plasma [K+], and lower FE of K+. The higher FE of Na+ coincided with lower abundance and phosphorylation of the Na+-Cl− cotransporter. In conclusion, reducing ENaC expression in the CNT induces clear PHA-1 symptoms during high dietary K+ loading.
Cat's medullary reticulospinal and subnucleus reticularis dorsalis noxious neurons form a coupled neural circuit through collaterals of descending axons
Authors: Leiras Roberto , Martín-Cora Francisco , Velo Patricia , Liste Tania , Canedo Antonio
Published: November 2015

Animals and human beings sense and react to real/potential dangerous stimuli. However, the supraspinal mechanisms relating noxious sensing and nocifensive behavior are mostly unknown. The collateralization and spatial organization of interrelated neurons are important determinants of coordinated network function. Here we electrophysiologically studied medial medullary reticulospinal neurons (mMRF-RSNs) antidromically identified from the cervical cord of anesthetized cats and found that 1) more than 40% (79/183) of the sampled mMRF-RSNs emitted bifurcating axons running within the dorsolateral (DLF) and ventromedial (VMF) ipsilateral fascicles; 2) more than 50% (78/151) of the tested mMRF-RSNs with axons running in the VMF collateralized to the subnucleus reticularis dorsalis (SRD) that also sent ipsilateral descending fibers bifurcating within the DLF and the VMF. This percentage of mMRF collateralization to the SRD increased to more than 81% (53/65) when considering the subpopulation of mMRF-RSNs responsive to noxiously heating the skin; 3) reciprocal monosynaptic excitatory relationships were electrophysiologically demonstrated between noxious sensitive mMRF-RSNs and SRD cells; and 4) injection of the anterograde tracer Phaseolus vulgaris leucoagglutinin evidenced mMRF to SRD and SRD to mMRF projections contacting the soma and proximal dendrites. The data demonstrated a SRD-mMRF network interconnected mainly through collaterals of descending axons running within the VMF, with the subset of noxious sensitive cells forming a reverberating circuit probably amplifying mutual outputs simultaneously regulating motor activity and spinal noxious afferent input. The results provide evidence that noxious stimulation positively engages a reticular SRD-mMRF-SRD network involved in pain-sensory-to-motor transformation and modulation.
Altered Innate Immune Responses in Neutrophils from Patients with Well‐ and Suboptimally Controlled Asthma
Authors: Tang Francesca S. M. , Foxley Gloria J. , Gibson Peter G. , Burgess Janette K. , Baines Katherine J. , Oliver Brian G.
Published: November 2015

Background. Respiratory infections are a major cause of asthma exacerbations where neutrophilic inflammation dominates and is associated with steroid refractory asthma. Structural airway cells in asthma differ from nonasthmatics; however it is unknown if neutrophils differ. We investigated neutrophil immune responses in patients who have good (AGood) and suboptimal (ASubopt) asthma symptom control. Methods. Peripheral blood neutrophils from AGood (ACQ < 0.75, n = 11), ASubopt (ACQ > 0.75, n = 7), and healthy controls (HC) (n = 9) were stimulated with bacterial (LPS (1 μg/mL), fMLF (100 nM)), and viral (imiquimod (3 μg/mL), R848 (1.5 μg/mL), and poly I:C (10 μg/mL)) surrogates or live rhinovirus (RV) 16 (MOI1). Cell‐free supernatant was collected after 1 h for neutrophil elastase (NE) and matrix metalloproteinase‐ (MMP‐) 9 measurements or after 24 h for CXCL8 release. Results. Constitutive NE was enhanced in AGood neutrophils compared to HC. fMLF stimulated neutrophils from ASubopt but not AGood produced 50% of HC levels. fMLF induced MMP‐9 was impaired in ASubopt and AGood compared to HC. fMLF stimulated CXCL8 but not MMP‐9 was positively correlated with FEV1 and FEV1/FVC. ASubopt and AGood responded similarly to other stimuli. Conclusions. Circulating neutrophils are different in asthma; however, this is likely to be related to airflow limitation rather than asthma control.
Influence of Rescuers’ Gender and Body Mass Index on Cardiopulmonary Resuscitation according to the American Heart Association 2010 Resuscitation Guidelines
Authors: Jaafar Ahmad , Abdulwahab Mohammad , Al-Hashemi Eman
Published: November 2015

Background and Objectives. The quality of cardiopulmonary resuscitation (CPR) is an important factor in determining its overall outcome. This study aims to test the association between rescuers’ gender, Body Mass Index (BMI), and the accuracy of chest compressions (CC) as well as ventilation, according to American Heart Association (AHA) 2010 resuscitation guidelines. Methods. The study included 72 participants of both genders. All the participants received CPR training according to AHA 2010 resuscitation guidelines. One week later, an assessment of their CPR was carried out. Moreover, the weight and height of the participants were measured in order to calculate their BMI. Results. Our analysis showed no significant association between gender and the CC depth (P=0.53) as well as between gender and ventilation (P=0.42). Females were significantly faster than males in CC (P=0.000). Regarding BMI, participants with a BMI less than the mean BMI of the study sample tended to perform CC with the correct depth (P=0.045) and to finish CC faster than those with a BMI more than the mean (P=0.000). On the other hand, no significant association was found between BMI and ventilation (P=0.187). Conclusion. CPR can be influenced by factors such as gender and BMI, as such the individual rescuer and CPR training programs should take these into account in order to maximize victims’ outcome.
Quantitative In Vivo Detection of Chlamydia muridarum Associated Inflammation in a Mouse Model Using Optical Imaging
Authors: Patel Manishkumar , Lin Shu-An , Boddicker Melissa A. , DeMaula Christopher , Connolly Brett , Bednar Bohumil , Heinrichs Jon H. , Smith Jeffrey G.
Published: November 2015

Chlamydia trachomatis is a bacterial sexually transmitted disease with over 1.3 million cases reported to the CDC in 2010. While Chlamydia infection is easily treated with antibiotics, up to 70% of infections are asymptomatic and go untreated. The current mouse model relies on invasive upper genital tract gross pathology readouts at ~60–80 days postinfection. High throughput optical imaging through the use of biomarkers has been successfully used to quickly evaluate several disease processes. Here we evaluate Neutrophil Elastase 680 (Elastase680) for its ability to measure Chlamydia muridarum associated inflammation in live mice using fluorescence molecular tomography (FMT) and In Vivo Imaging System (IVIS). Optical imaging was able to distinguish with statistical significance between vaccinated and nonvaccinated mice as well as mock‐challenged and challenged mice 2 weeks after challenge which was 9 weeks sooner than typical gross pathological assessment. Immunohistochemistry confirmed the presence of neutrophils and correlated well with both in vivo and ex vivo imaging. In this report we demonstrate that Elastase680 can be used as a molecular imaging biomarker for inflammation associated with chlamydial infection in a mouse model and that these biomarkers can significantly decrease the time for pathology evaluation and thus increase the rate of therapeutics discovery.
Titanium Oxide: A Bioactive Factor in Osteoblast Differentiation
Authors: Santiago-Medina P. , Sundaram P. A. , Diffoot-Carlo N.
Published: November 2015

Titanium and titanium alloys are currently accepted as the gold standard in dental applications. Their excellent biocompatibility has been attributed to the inert titanium surface through the formation of a thin native oxide which has been correlated to the excellent corrosion resistance of this material in body fluids. Whether this titanium oxide layer is essential to the outstanding biocompatibility of titanium surfaces in orthopedic biomaterial applications is still a moot point. To study this critical aspect further, human fetal osteoblasts were cultured on thermally oxidized and microarc oxidized (MAO) surfaces and cell differentiation, a key indicator in bone tissue growth, was quantified by measuring the expression of alkaline phosphatase (ALP) using a commercial assay kit. Cell attachment was similar on all the oxidized surfaces although ALP expression was highest on the oxidized titanium alloy surfaces. Untreated titanium alloy surfaces showed a distinctly lower degree of ALP activity. This indicates that titanium oxide clearly upregulates ALP expression in human fetal osteoblasts and may be a key bioactive factor that causes the excellent biocompatibility of titanium alloys. This result may make it imperative to incorporate titanium oxide in all hard tissue applications involving titanium and other alloys.
Reliability Modeling and Optimization Strategy for Manufacturing System Based on RQR Chain
Authors: He Yihai , He Zhenzhen , Wang Linbo , Gu Changchao
Published: November 2015

Accurate and dynamic reliability modeling for the running manufacturing system is the prerequisite to implement preventive maintenance. However, existing studies could not output the reliability value in real time because their abandonment of the quality inspection data originated in the operation process of manufacturing system. Therefore, this paper presents an approach to model the manufacturing system reliability dynamically based on their operation data of process quality and output data of product reliability. Firstly, on the basis of importance explanation of the quality variations in manufacturing process as the linkage for the manufacturing system reliability and product inherent reliability, the RQR chain which could represent the relationships between them is put forward, and the product qualified probability is proposed to quantify the impacts of quality variation in manufacturing process on the reliability of manufacturing system further. Secondly, the impact of qualified probability on the product inherent reliability is expounded, and the modeling approach of manufacturing system reliability based on the qualified probability is presented. Thirdly, the preventive maintenance optimization strategy for manufacturing system driven by the loss of manufacturing quality variation is proposed. Finally, the validity of the proposed approach is verified by the reliability analysis and optimization example of engine cover manufacturing system.
Palmitoylethanolamide, a Natural Retinoprotectant: Its Putative Relevance for the Treatment of Glaucoma and Diabetic Retinopathy
Authors: Keppel Hesselink Jan M. , Costagliola Ciro , Fakhry Josiane , Kopsky David J.
Published: November 2015

Retinopathy is a threat to the eyesight, and glaucoma and diabetes are the main causes for the damage of retinal cells. Recent insights pointed out a common pathogenetic pathway for both disorders, based on chronic inflammation. Palmitoylethanolamide (PEA) is an endogenous cell protective lipid. Since its discovery in 1957 as a biologically active component in foods and in many living organisms, around 500 scientific papers have been published on PEA’s anti-inflammatory and neuron-protective properties. PEA has been evaluated for glaucoma, diabetic retinopathy, and uveitis, pathological states based on chronic inflammation, respiratory disorders, and various pain syndromes in a number of clinical trials since the 70s of 20th century. PEA is available as a food supplement (PeaPure) and as diet food for medical purposes in Italy (Normast, PeaVera, and Visimast). These products are notified in Italy for the nutritional support in glaucoma and neuroinflammation. PEA has been tested in at least 9 double blind placebo controlled studies, among which two studies were in glaucoma, and found to be safe and effective up to 1.8 g/day, with excellent tolerability. PEA therefore holds a promise in the treatment of a number of retinopathies. We discuss PEA as a putative anti-inflammatory and retinoprotectant compound in the treatment of retinopathies, especially related to glaucoma and diabetes.
Modeling Seasonal Influenza Transmission and Its Association with Climate Factors in Thailand Using Time-Series and ARIMAX Analyses
Authors: Chadsuthi Sudarat , Iamsirithaworn Sopon , Triampo Wannapong , Modchang Charin
Published: November 2015

Influenza is a worldwide respiratory infectious disease that easily spreads from one person to another. Previous research has found that the influenza transmission process is often associated with climate variables. In this study, we used autocorrelation and partial autocorrelation plots to determine the appropriate autoregressive integrated moving average (ARIMA) model for influenza transmission in the central and southern regions of Thailand. The relationships between reported influenza cases and the climate data, such as the amount of rainfall, average temperature, average maximum relative humidity, average minimum relative humidity, and average relative humidity, were evaluated using cross-correlation function. Based on the available data of suspected influenza cases and climate variables, the most appropriate ARIMA(X) model for each region was obtained. We found that the average temperature correlated with influenza cases in both central and southern regions, but average minimum relative humidity played an important role only in the southern region. The ARIMAX model that includes the average temperature with a 4-month lag and the minimum relative humidity with a 2-month lag is the appropriate model for the central region, whereas including the minimum relative humidity with a 4-month lag results in the best model for the southern region.
Serum Galectin‐9 Levels Are Associated with Coronary Artery Disease in Chinese Individuals
Authors: Zhu Ruirui , Liu Cheng , Tang Hongxia , Zeng Qiutang , Wang Xiang , Zhu Zhengfeng , Liu Yuzhou , Mao Xiaobo , Zhong Yucheng
Published: November 2015

Background. Recently, several studies suggest that galectin‐9 (Gal‐9) might play a pivotal role in the pathogenesis of autoimmune diseases. However, the exact role of Gal‐9 in atherosclerosis remains to be elucidated. Methods. Serum Gal‐9, high‐sensitivity C‐reactive protein (hs‐CRP), interferon‐ (IFN‐) γ, interleukin‐ (IL‐) 4, IL‐17, and transforming growth factor‐ (TGF‐) β1 were measured. The effect of Gal‐9 on peripheral blood mononuclear cells (PBMC) was investigated in patients with normal coronary artery (NCA). Results. The lowest level of Gal‐9 was found in the ST‐segment elevation myocardial infarction (STEMI) group, followed by the non‐ST‐segment elevation ACS (NSTEACS), the NCA, and the stable angina pectoris (SAP) groups, respectively. Additionally, Gal‐9 was found to be independently associated with hs‐CRP, lipoprotein(a), and creatinine. Notably, Gal‐9 was also noted to be an independent predictor of the Gensini score. Moreover, Gal‐9 suppressed T‐helper 17 (Th17) and expanded regulatory T cells (Tregs), resulting in decreased IL‐17 production and increased secretion of TGF‐β1. Conclusions. Serum Gal‐9 is associated with not only coronary artery disease (CAD), but also the severity of coronary arteries stenosis. Gal‐9 can expand Tregs and suppress Th17 development in activated PBMC, implying that Gal‐9 has the potential to dampen the development of atherosclerosis and may be a new therapy for CAD.
The Effects of Intrathecal Fentanyl on Sedation Depth and Postoperative Recovery Room Delirium
Authors: Tuzun Ozgur Bulent , Bakan Nurten , Ozdemir Mehtap , Yanli Yonca , Akinci Ekinci Nuran
Published: November 2015

Background/Aim. Intrathecal anaesthesia has been shown to increase sedation level. This study aimed to evaluate the effects of intrathecal applied fentanyl with levobupivacaine on intraoperative sedation and recovery room delirium. Materials and Methods. The study included 68 patients, ASA I–III, 55–85 years. One day preoperatively, the Confusion Assessment Method (CAM) and the Mini Mental Status Test (MMST) were applied and patients were separated into two groups. In Group L 2.5 mL levobupivacaine and in Group LF 2 mL levobupivacaine and 0.5 mL fentanyl were applied intrathecally. In a supine position, following a propofol IV 1 mg kg−1 bolus to obtain Bispectral Index (BIS) of 70–85, propofol infusion was started (1 mg kg−1 st−1). With observation of SpO2, BIS, and the Observer Assessment and Alertness/Sedation Scale (OAA/SS) with the haemodynamic values, the total propofol amount was calculated. Evaluations were made of pain severity (VAS), analgesic use, transfusion requirement, and recovery room delirium. Results. In the comparison within the groups, a significant decrease was determined in HR and MAP compared to the initial values (p<0.05). A positive correlation was found between the BIS and OAA/SS values. The amounts of propofol used were similar between the groups. Conclusions. Intrathecal fentanyl and levobupivacaine had the same effect on sedation or BIS and fentanyl did not cause delirium.
Hepatocellular Carcinoma in the Pediatric Population: A Population Based Clinical Outcomes Study Involving 257 Patients from the Surveillance, Epidemiology, and End Result (SEER) Database (1973–2011)
Authors: Lau Christine S. M. , Mahendraraj Krishnaraj , Chamberlain Ronald S.
Published: November 2015

Introduction. Hepatocellular carcinoma (HCC) is a rare pediatric cancer accounting for 0.5% of all pediatric malignancies. This study examines a large cohort of HCC patients in an effort to define the factors impacting clinical outcomes in pediatric HCC patients compared to adults. Methods. Demographic and clinical data on 63,771 HCC patients (257 pediatric patients ≤ 19 and 63,514 adult patients age ≥ 20) were abstracted from the SEER database (1973–2011). Results. HCC was more common among males (59.5% pediatric and 75.1% adults) and Caucasians (50.4% and 50.5%), p<0.05. Children more often presented with fibrolamellar variant HCC (24.1% versus 0.3%, p=0.71) and advanced HCC, including distant disease (33.1% versus 20.8%, p<0.001), and tumors > 4 cm in size (79.6% versus 62.0%, p=0.02). Pediatric HCC patients undergoing surgery (13.107 versus 8.324 years, p<0.001) had longer survival than adult HCC patients. Overall mortality was lower (65.8% versus 82.0%, p<0.001) in the pediatric HCC group. Conclusion. HCC is a rare pediatric malignancy that presents most often as an advanced tumor, >4 cm in Caucasian males. Children with HCC achieve significantly longer mean overall survival compared to adults with HCC, primarily attributable to the more favorable fibrolamellar histologic variant, and more aggressive surgical intervention, which significantly improves survival.
Depressive Symptoms during an Acute Schizophrenic Episode: Frequency and Clinical Correlates
Authors: Rajkumar Ravi Philip
Published: November 2015

Introduction. Depressive symptoms are common in schizophrenia and are associated with poorer functioning, lower quality of life, and an elevated risk of suicidal behaviour. There are few studies on the occurrence and correlates of these symptoms in acutely ill patients with schizophrenia.Method.72 acutely ill patients with schizophrenia were assessed for depression using the Calgary Depression Scale for Schizophrenia (CDSS). A cut-off score of ≥6 on the CDSS was used to identify clinically significant depressive symptoms. The relationship between depression and illness variables, including psychotic symptom dimensions as measured by the Positive and Negative Syndrome Scale for Schizophrenia (PANSS), was examined.Results. Eleven (15.3%) patients had clinically significant depressive symptoms. These patients scored higher on the positive and general psychopathology scales of the PANSS and had higher rates of suicidal behavior and poorer functioning. The severity of depressive symptoms was positively correlated with the PANSS positive subscale and negatively correlated with the PANSS negative subscale.Discussion. These findings confirm previous reports that depressive symptoms in active schizophrenia is related to the severity of positive psychotic symptoms and is a risk factor for suicidal behaviour in these patients.
The Review of Nuclear Microscopy Techniques: An Approach for Nondestructive Trace Elemental Analysis and Mapping of Biological Materials
Authors: Mulware Stephen Juma
Published: November 2015

The properties of many biological materials often depend on the spatial distribution and concentration of the trace elements present in a matrix. Scientists have over the years tried various techniques including classical physical and chemical analyzing techniques each with relative level of accuracy. However, with the development of spatially sensitive submicron beams, the nuclear microprobe techniques using focused proton beams for the elemental analysis of biological materials have yielded significant success. In this paper, the basic principles of the commonly used microprobe techniques of STIM, RBS, and PIXE for trace elemental analysis are discussed. The details for sample preparation, the detection, and data collection and analysis are discussed. Finally, an application of the techniques to analysis of corn roots for elemental distribution and concentration is presented.
Numerical Solution of Heat Transfer Process in PCM Storage Using Tau Method
Authors: Heydari B. , Talati F.
Published: November 2015

Thermal energy storage units that utilize phase change materials have been widely employed to balance temporary temperature alternations and store energy in many engineering systems. In the present paper, an operational approach is proposed to the Tau method with standard polynomial bases to simulate the phase change problems in latent heat thermal storage systems, that is, the two-dimensional solidification process in rectangular finned storage with a constant end-wall temperature. In order to illustrate the efficiency and accuracy of the present method, the solid-liquid interface location and the temperature distribution of the fin for three test cases with different geometries are obtained and compared to simplified analytical results in the published literature. The results indicate that using a two-dimensional numerical approach can predict the solid-liquid interface location more accurately than the simplified analytical model in all cases, especially at the corners.
Maximizing the Efficacy of MAPK-Targeted Treatment inPTENLOF/BRAFMUT Melanoma through PI3K and IGF1R Inhibition
Authors: Herkert Barbara , Kauffmann Audrey , Mollé Sandra , Schnell Christian , Ferrat Thomas , Voshol Hans , Juengert Janina , Erasimus Hélène , Marszalek Grégory , Kazic-Legueux Malika , Billy Eric , Ruddy David , Stump Mark , Guthy Daniel , Ristov Mitko , Calkins Keith , Maira Sauveur-Michel , Sellers William R. , Hofmann Francesco , Hall Michael N. , Brachmann Saskia M.
Published: November 2015

The introduction of MAPK pathway inhibitors paved the road for significant advancements in the treatment of BRAF-mutant (BRAFMUT) melanoma. However, even BRAF/MEK inhibitor combination therapy has failed to offer a curative treatment option, most likely because these pathways constitute a codependent signaling network. Concomitant PTEN loss of function (PTENLOF) occurs in approximately 40% of BRAFMUT melanomas. In this study, we sought to identify the nodes of the PTEN/PI3K pathway that would be amenable to combined therapy with MAPK pathway inhibitors for the treatment of PTENLOF/BRAFMUT melanoma. Large-scale compound sensitivity profiling revealed that PTENLOF melanoma cell lines were sensitive to PI3Kβ inhibitors, albeit only partially. An unbiased shRNA screen (7,500 genes and 20 shRNAs/genes) across 11 cell lines in the presence of a PI3Kβ inhibitor identified an adaptive response involving the IGF1R–PI3Kα axis. Combined inhibition of the MAPK pathway, PI3Kβ, and PI3Kα or insulin-like growth factor receptor 1 (IGF1R) synergistically sustained pathway blockade, induced apoptosis, and inhibited tumor growth in PTENLOF/BRAFMUT melanoma models. Notably, combined treatment with the IGF1R inhibitor, but not the PI3Kα inhibitor, failed to elevate glucose or insulin signaling. Taken together, our findings provide a strong rationale for testing combinations of panPI3K, PI3Kβ + IGF1R, and MAPK pathway inhibitors in PTENLOF/BRAFMUT melanoma patients to achieve maximal response. Cancer Res; 76(2); 390–402. ©2015 AACR.
A Newly Developed Shear Wave Elastography Modality: With a Unique Reliability Index
Authors: Yada Norihisa , Sakurai Toshiharu , Minami Tomohiro , Arizumi Tadaaki , Takita Masahiro , Hagiwara Satoru , Ueshima Kazuomi , Ida Hiroshi , Nishida Naoshi , Kudo Masatoshi
Published: November 2015

Objective: The aim of this study was to prospectively assess the usefulness of the reliability index, namely the percentage of the net amount of effective shear wave velocity (VsN). Methods: One hundred and sixty-eight patients with chronic liver disease, who underwent ultrasound elastography, were consecutively enrolled. Shear wave measurement (SWM), FibroScan, virtual touch quantification, and shear wave elastography were performed for all patients, and the variations in the measurement results were compared with VsN. The absolute average value of the difference between SWM_Vs and Vs measured using other elastography devices is termed |ΔVs|. VsN was classified into three groups: ≥50, <50, and 0 (failure measurement). In these groups, there was a significant difference in abdominal circumference, body mass index, the distance between the ultrasound probe surface and the liver, and |ΔVs|. When the distance between the ultrasound probe surface and the liver was >2 cm, VsN tended to be significantly lower (p < 0.001). Results: When VsN was <50, |ΔVs| became high, and there was variation in the results between each device. Conclusions: The results of this study show that VsN is a useful value to decide whether Vs is appropriate or not.
The Epidemiology of Migraine Headache in General Population of Tehran, Iran
Authors: Rabiee Behnam , Zeinoddini Atefeh , Kordi Ramin , Yunesian Masud , Mohammadinejad Payam , Mansournia Mohammad A.
Published: November 2015

Background: Migraine as one of the most common types of headache is known to cause serious intervention with routine activities of affected individuals due to the devastating nature of attacks. The aim of this study was to provide epidemiological data of migraine in Iranian general population. Methods: In this cross-sectional general population study, migraine diagnoses (both episodic and chronic) were based on the International Classification of Headache Disorders. Face-to-face interviews were performed by 5 trained medical interns on a sample size of 2,300 people aged 12-65 years. Results: A total number of 2,076 subjects were enrolled for final analysis. The mean age of the subjects at the time of the study was 36.27 ± 14.56 years (age range 12-65 years). The 1-year prevalence of migraine was 27.6%. The prevalence of migraine among female subjects was significantly higher than among male subjects (36.7 vs. 21.6%, p < 0.001). The mean age of the subjects with migraine was 35.9 ± 12.96 years. Totally, 49.9% of migraine sufferers experienced at least one episode of aura. The most prevalent type of aura was numbness reported in 32.4% of migraine subjects. Conclusions: Despite the higher prevalence of migraine among Iranian general population compared to most of the other populations investigated by previous studies, these individuals experience a less severe course of disease.
Incidence and Prognosis of Spinal Hemangioblastoma: A Surveillance Epidemiology and End Results Study
Authors: Westwick Harrison J. , Giguère Jean-François , Shamji Mohammed F.
Published: November 2015

Objective: Intradural spinal hemangioblastoma are infrequent, vascular, pathologically benign tumors occurring either sporadically or in association with von Hippel-Lindau disease along the neural axis. Described in fewer than 1,000 cases, literature is variable with respect to epidemiological factors associated with spinal hemangioblastoma and their treatment. The objective of this study was to evaluate the epidemiology of intradural spinal hemangioblastoma with the Surveillance, Epidemiology and End Results (SEER) database while also presenting an illustrative case. Methods: The SEER database was queried for cases of spinal hemangioblastoma between 2000 and 2010 with the use of SEER*Stat software. Incidence was evaluated as a function of age, sex and race. Survival was evaluated with the Cox proportionate hazards ratio using IBM SPSS software evaluating age, sex, location, treatment modality, pathology and number of primaries (p = 0.05). Descriptive statistics of the same factors were also calculated. The case of a 43-year-old patient with a surgical upper cervical intramedullary hemangioblastoma is also presented. Results: In the data set between 2000 and 2010, there were 133 cases with an age-adjusted incidence of 0.014 (0.012-0.017) per 100,000 to the standard USA population. Hemangioblastoma was the tenth most common intradural spinal tumor type representing 2.1% (133 of 6,156) of all spinal tumors. There was no difference in incidence between men and women with an female:male rate ratio of 1.05 (0.73-1.50) with p = 0.86. The average age of patients was 48.0 (45.2-50.9) years, and a lower incidence was noted in patients <15 years compared to all other age groups (p < 0.05). There was no difference in incidence amongst the different races. Treatment included surgical resection in 106 (79.7%) cases, radiation with surgery in 7 (5.3%) cases, and radiation alone was used in only 1 (0.8%) case, and no treatment was performed in 17 (12.8%) cases. Mortality was noted in 12 (9%) cases, and median survival of 27.5 months (range 1-66 months) over the 10-year period. Mortality was attributable to the malignancy in 3 (2%) cases. There was no statistically significant different in Cox hazard ratios for mortality for sex, race, treatment modality, pathology or number of primaries. Conclusions: Spinal hemangioblastoma represent a small fraction of primary intradural spinal tumors, and this study did not identify any difference in incidence between genders. Surgical treatment alone was the most common treatment modality. Overall prognosis is good, with 9% observed mortality over the 10-year period, with 2% mortality attributable to the malignancy.
Twin Anemia-Polycythemia Sequence: Perinatal Management and Outcome
Authors: Ashwal Eran , Yinon Yoav , Fishel-Bartal Michal , Tsur Abraham , Chayen Benjamin , Weisz Boaz , Lipitz Shlomo
Published: November 2015

Objective: To determine the perinatal outcome of monochorionic twin pregnancies complicated by twin anemia-polycythemia sequence (TAPS). Methods: All monochorionic twins diagnosed with TAPS between 2011 and 2014 were included. Each twin pair with TAPS (study group) was compared with 2 uncomplicated monochorionic twin pairs who were matched for gestational age at delivery (control group). Neonatal morbidity and mortality were evaluated. Results: During the study period, 179 monochorionic twins were followed at our center, of whom 46 underwent laser ablation due to twin-to-twin transfusion syndrome. TAPS was diagnosed in 10 cases; 8 of them were spontaneous, and 2 occurred following laser surgery. Out of 7 patients diagnosed prenatally with TAPS, 5 cases were managed expectantly, and 2 cases were treated with intrauterine blood transfusion. The rates of severe and mild central nervous system lesions on postnatal ultrasound were similar in the TAPS group and control group (5.0 vs. 2.5%, p = 0.61, and 5.0 vs. 12.5%, p = 0.25, respectively). Additionally, severe neonatal morbidity was comparable between the groups. All neonates were alive at 1 month of age. Conclusion: The neonatal outcome of monocohorionic twins affected by TAPS is favorable and comparable to gestational age-matched uncomplicated monochorionic twins.
Mothers' Views on Longer Storage of Neonatal Dried Blood Spots for Specific Secondary Uses
Authors: van Teeffelen Sarah R. , Douglas Conor M.W. , van El Carla G. , Weinreich Stephanie S. , Henneman Lidewij , Radstake Maud , Cornel Martina C.
Published: November 2015

Background: Neonatal dried blood spots (DBS) present a wealth of data. Currently, many countries discuss DBS storage, management and use. We collected data in the Netherlands on the awareness and views of an unheard stakeholder: mothers (-to-be). Methods: A survey was conducted on an Amsterdam pregnancy fair website in 2011. We included 1,272 women who were pregnant and/or had at least one child ≤5 years old. A descriptive analysis was used to score the awareness of and views on policies regarding the length of storage and secondary use. Results: 18.9% of mothers (n = 1,272) were aware of all five current DBS screening, storage and use policies. The views were positive for all ten potential specific secondary uses. Most support was given to etiology research, while test development by a company was least supported. Extending the DBS storage beyond the 5-year status quo was approved by 67.8% of the respondents, indefinite storage was approved by 54.7%. Conclusion: Mothers indicate support of several secondary uses and prolonged storage of DBS but report a low awareness of current storage and secondary use policies. Efforts must be made to involve parents as key stakeholders in DBS policies. This could be achieved through a parent-led advisory structure.
CD36 Is a Matrix Metalloproteinase-9 Substrate That Stimulates Neutrophil Apoptosis and Removal During Cardiac Remodeling
Authors: DeLeon-Pennell Kristine Y. , Tian Yuan , Zhang Bai , Cates Courtney A. , Iyer Rugmani Padmanabhan , Cannon Presley , Shah Punit , Aiyetan Paul , Halade Ganesh V. , Ma Yonggang , Flynn Elizabeth , Zhang Zhen , Jin Yu-Fang , Zhang Hui , Lindsey Merry L.
Published: November 2015

Background—

After myocardial infarction, the left ventricle undergoes a wound healing response that includes the robust infiltration of neutrophils and macrophages to facilitate removal of dead myocytes as well as turnover of the extracellular matrix. Matrix metalloproteinase (MMP)-9 is a key enzyme that regulates post-myocardial infarction left ventricular remodeling.

Methods and Results—

Infarct regions from wild-type and MMP-9 null mice (n=8 per group) analyzed by glycoproteomics showed that of 541
N
-glycosylated proteins quantified, 45 proteins were at least 2-fold upregulated or downregulated with MMP-9 deletion (all
P
<0.05). Cartilage intermediate layer protein and platelet glycoprotein 4 (CD36) were identified as having the highest fold increase in MMP-9 null mice. By immunoblotting, CD36 but not cartilage intermediate layer protein decreased steadily during the time course post-myocardial infarction, which identified CD36 as a candidate MMP-9 substrate. MMP-9 was confirmed in vitro and in vivo to proteolytically degrade CD36. In vitro stimulation of day 7 post-myocardial infarction macrophages with MMP-9 or a CD36-blocking peptide reduced phagocytic capacity. Dual immunofluorescence revealed concomitant accumulation of apoptotic neutrophils in the MMP-9 null group compared with wild-type group. In vitro stimulation of isolated neutrophils with MMP-9 decreased neutrophil apoptosis, indicated by reduced caspase-9 expression.

Conclusions—

Our data reveal a new cell-signaling role for MMP-9 through CD36 degradation to regulate macrophage phagocytosis and neutrophil apoptosis.
Predictors of Clinical Worsening in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy
Authors: Chabriat Hugues , Hervé Dominique , Duering Marco , Godin Ophelia , Jouvent Eric , Opherk Christian , Alili Nassira , Reyes Sonia , Jabouley Aude , Zieren Nikola , Guichard Jean-Pierre , Pachai Chahin , Vicaut Eric , Dichgans Martin
Published: November 2015

Background and Purpose—

Predictors of clinical worsening in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy remain unknown. This study aims to identify demographic, clinical, and magnetic resonance imaging predictors of incident strokes, incident dementia, clinical deterioration, and death in patients with this genetically proven disease.

Methods—

Two hundred ninety subjects (mean age, 50.6±11.4 years) were assessed at baseline and followed up for 36 months. Incident clinical events were recorded, and clinical scores included the Mini Mental State Examination, Mattis Dementia Rating Scale, modified Rankin Scale, and Barthel index. The number of lacunes and microbleeds, the volume of white-matter hyperintensities, and brain parenchymal fraction were assessed on baseline magnetic resonance imaging. Data were analyzed by ANCOVA, multivariable logistic regression, and Cox proportional hazard models.

Results—

Incident stroke occurred in 55 of 278 patients (19.8%). Moderate or severe disability developed in 19 of 210 (9%) nondisabled individuals, incident dementia in 49 of 231 (20%) nondemented subjects, and 4.8% of patients died. Active smoking, the number of lacunes, and brain parenchymal fraction independently predicted incident stroke during follow-up. Gait disturbance, dementia, and brain parenchymal fraction predicted progression toward moderate or severe disability. Active smoking, disability, and brain parenchymal fraction predicted incident dementia. Age was the only significant predictor of death.

Conclusions—

Clinical assessment and brain magnetic resonance imaging aid in predicting incident clinical events and clinical deterioration in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. There is a bidirectional relationship between dementia and moderate or severe disability in predicting each other’s onset. Active smoking is a modifiable risk factor associated with clinical progression in Notch3 mutation carriers.
An Empirical Estimation of Asia's Untapped Regional Integration Potential Using Data Envelopment Analysis
Authors: Naeher Dominik
Published: November 2015

This paper uses bilateral flow data on multiple dimensions of economic integration to construct a composite index of regional integration outcomes covering 19 regions in various parts of the world. As a first step, the multidimensional indicator is used to rank regions according to their current degree of regional integration, which allows for a direct comparison of Asia's regional integration performance with those of other regions of the world. As a second step, the constructed indicator of regional integration outcomes is used as the output variable in a data envelopment analysis to estimate Asia's untapped regional integration potential.
Death and the Bishop of Rome. From Hormisdas to Sabinian
Authors: Neil Bronwen
Published: November 2015

The sixth to early seventh centuries was a dangerous period to be crowned a bishop of Rome. Over the course of ninety-two years, from 514 to 606, there were no fewer than fifteen bishops of Rome, including one anti-pope. In the decade from 526 to 536, six popes went to their graves. Very few of these bishops died in their beds. Their deaths were as significant as their lives for what they can tell us about the processes of election and the protections that their office afforded them, as well as the risks to which they were exposed. In many cases the sole witness to the manner and timing of their deaths is the Liber Pontificalis.1
Death After Life or Life After Death?
Authors: Sim David C.
Published: November 2015

The early Church Fathers accepted the notion of an intermediate state, the existence of the soul following death until its reunification with the body at the time of the final resurrection. This view is common in the modern Christian world, but it has been challenged as being unbiblical. This study reflects upon this question. Does the New Testament speak exclusively of death after life, complete lifelessness until the day of resurrection, or does it also contain the notion of life after life or immediate post-mortem existence? It will be argued that, while the doctrine of future resurrection is the most common Christian view, it was not the only one present in the Christian canon. There are hints, especially in the Gospel of Luke and the Revelation of John, that people do indeed live again immediately after death, although the doctrine of resurrection is also present. These two ideas are never coherently related to one another in the New Testament and it was the Church Fathers who first sought to  systematise them.
Does Homily Work as a Theory of Truth?
Authors: La Matina Marcello
Published: November 2015

Patristics increasingly attracts new scholars. Both philosophers and students of human sciences deserve Patristics for its richness of topics, until now discussed under the label of semantics, ontology and theory of knowledge: Fathers are especially appealing for the content of their writings. Without disavowing such an approach, my paper would like to observe how the Fathers did work. Its concern is rather the Signifier, than the Signi­ficatum. How did the Greek Fathers approach the word of God? Before any writing, they held their talks, in a special form of speech, inherited by the synagogue-proclamation and termed a homily. From a logical point of view, a homily is more profitably approached if it is seen as a “language-game,” whose goal was stating the truth-conditions of some crucial sentences proclaimed in their form of life. The homilist succeeded in his task by pairing each sentence of Holy Scripture with a sentence of his own. Thus, the truth-conditions were shown not as a matter of fact, but of replaceable pronouns and other referring expressions.
Taxonomy, conservation, geographic and potential distribution of Macrotorus Perkins (Mollinedioideae, Monimiaceae), and a key to the Neotropical genera of Monimiaceae
Authors: De Lirio Elton John , Peixoto Ariane Luna , De Siqueira Marinez Ferreira
Published: November 2015

Macrotorus is a dioecious, monotypic genus that is endemic to the Brazilian Atlantic rainforest, where it occurs in lowland, submontane and montane forests; different from most other Monimiaceae in Atlantic rainforest, which are restricted to dense, humid, montane forests. Here, an updated description of Macrotorus utriculatus is provided, including the first description of the pistillate flowers, together with the lectotypification of the species, comparison with related genera, its conservation status, geographic distribution, and modeling of potential distribution. We also provide an identification key to the Neotropical genera of Monimiaceae.