bluuebunny/crossref_metadata_2025 huggingface dataset:
SPACE–TIMES WITH INTEGRABLE SINGULARITY: BLACK–WHITE HOLES AND ASTROGENIC UNIVERSES
Authors: LUKASH VLADIMIR N. , STROKOV VLADIMIR N.
Published: January 2013

We use the phenomenological approach to study properties of space–time in the vicinity of the Schwarzschild black-hole singularity. Requiring finiteness of the Schwarzschild-like metrics we come to the notion of integrable singularity that is, in a sense, weaker than the conventional singularity and allows the (effective) matter to pass to the white-hole region. This leads to a possibility of generating a new universe there. Thanks to the gravitational field of the singularity, this universe is already born highly inflated ("singularity-induced inflation") before the ordinary inflation starts.
NUCLEATION OF SUPERCONDUCTIVITY IN A THIN DISK WITH A RING-LIKE DEFECT
Authors: BARBA-ORTEGA J. , SARDELLA EDSON , AGUIAR J. ALBINO
Published: January 2013

We report on the influence of a circular defect on the vortex configuration in a mesoscopic superconducting sample. Effects associated with the pinning force of the circular defect on the configuration and on the vortex entry fields are studied for a very thin disk. We calculate the magnetization loop, vorticity, free energy and superconducting electrons for the disk in presence of an external magnetic field applied perpendicular to the disk plane. The magnetization curves are hysteretic, with paramagnetic response in part of the downward branch, also, in this part we found a vortex–anti-vortex state.
METAL–INSULATOR TRANSITION AND THE TEMPERATURE OF THE PSEUDOGAP ANOMALY OPENING IN PRASEODYMIUM DOPED Y1-zPrzBa2Cu3O7-δ SINGLE CRYSTALS
Authors: VOVK R. V. , NAZYROV Z. F. , GOULATIS I. L. , CHRONEOS A. , PINTO SIMOES V. M.
Published: January 2013

The influence of praseodymium doping on the electrical resistivity in the ab-plane of Y 1-z Pr z Ba 2 Cu 3 O 7-δ single crystals, is investigated. It is determined that as the concentration of praseodymium (0.0 ≤ z ≤ 0.5) is rising there occurs a significant shift of the temperature regions, corresponding to the metal–insulator transitions, as well as to the regime of the implementation of the pseudogap anomaly. The part of the curves related to the metal–insulator transition are well described by means of an asymptotic dependence that corresponds to the implementation of a quantum critical regime in the system, the so-called law of the "one third".
STRESS–VELOCITY COMPLETE RADIATION BOUNDARY CONDITIONS
Authors: RABINOVICH DANIEL , GIVOLI DAN , HAGSTROM THOMAS , BIELAK JACOBO
Published: January 2013

A new high-order local Absorbing Boundary Condition (ABC) has been recently proposed for use on an artificial boundary for time-dependent elastic waves in unbounded domains, in two dimensions. It is based on the stress–velocity formulation of the elastodynamics problem, and on the general Complete Radiation Boundary Condition (CRBC) approach, originally devised by Hagstrom and Warburton in 2009. The work presented here is a sequel to previous work that concentrated on the stability of the scheme; this is the first known high-order ABC for elastodynamics which is long-time stable. Stability was established both theoretically and numerically. The present paper focuses on the accuracy of the scheme. In particular, two accuracy-related issues are investigated. First, the reflection coefficients associated with the new CRBC for different types of incident and reflected elastic waves are analyzed. Second, various choices of computational parameters for the CRBC, and their effect on the accuracy, are discussed. These choices include the optimal coefficients proposed by Hagstrom and Warburton for the acoustic case, and a simplified formula for these coefficients. A finite difference discretization is employed in space and time. Numerical examples are used to experiment with the scheme and demonstrate the above-mentioned accuracy issues.
The Voltage-Gated Calcium Channel Functions as the Molecular Switch of Synaptic Transmission
Authors: Atlas Daphne
Published: January 2013

Transmitter release is a fast Ca2+-dependent process triggered in response to membrane depolarization. It involves two major calcium-binding proteins, the voltage-gated calcium channel (VGCC) and the vesicular protein synaptotagmin (syt1). Ca2+binding triggers transmitter release with a time response of conformational changes that are too fast to be accounted for by Ca2+binding to syt1. In contrast, conformation-triggered release, which engages Ca2+binding to VGCC, better accounts for the fast rate of the release process. Here, we summarize findings obtained from heterologous expression systems, neuroendocrine cells, and reconstituted systems, which reveal the molecular mechanism by which Ca2+binding to VGCC triggers exocytosis prior to Ca2+entry into the cell. This review highlights the molecular aspects of an intramembrane signaling mechanism in which a signal is propagated from the channel transmembrane (TM) domain to the TM domain of syntaxin 1A to trigger transmitter release. It discusses fundamental problems of triggering transmitter release by syt1 and suggests a classification of docked vesicles that might explain synchronous transmitter release, spontaneous release, and facilitation of transmitter release.
Reprogrammed Cells for Disease Modeling and Regenerative Medicine
Authors: Cherry Anne B.C. , Daley George Q.
Published: January 2013

The conversion of somatic cells into pluripotent cells is transforming the way diseases are researched and treated. Induced pluripotent stem (iPS) cells' promise may soon be realized in the field of hematology, as hematopoietic stem cell transplants are already commonplace in clinics around the world. We provide a current comparison between induced pluripotent and embryonic stem cells, describe progress toward modeling hematological disorders using iPS cells, and illustrate the hurdles that must be overcome before iPS cell therapies will be available in clinics.
Psychiatry's Integration with Medicine: The Role of DSM-5
Authors: Kupfer David J. , Kuhl Emily A. , Wulsin Lawson
Published: January 2013

Mental disorders represent a significant global burden whose effects are exacerbated by gaps in diagnosis and service provision. A substantial number of individuals seek services not through specialty psychiatric clinics but through primary care. Thus, the interface between psychiatry and the rest of medicine represents an appropriate area of focus in which to improve the detection and treatment of mental disorders. Development of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) can play a key role in this process. DSM-5 is expected to include specific revisions in diagnostic criteria, chapter organization, text structure, and classification approach that are designed to improve use of DSM by nonpsychiatrist physicians. Furthermore, revisions to DSM-5 will inform development of the primary care version of DSM-5. The goal is to publish a manual that enhances clinical utility in a manner that is concise and more amenable to use in primary care.
Toward a Universal Influenza Virus Vaccine: Prospects and Challenges
Authors: Pica Natalie , Palese Peter
Published: January 2013

Current influenza virus vaccines are annually reformulated to elicit protection by generating an immune response toward the virus strains that are predicted to circulate in the upcoming influenza season. These vaccines provide limited protection in cases of antigenic mismatch, when the vaccine and the circulating viral strains differ. The emergence of unexpected pandemic viruses presents an additional challenge to vaccine production. To increase influenza virus preparedness, much work has been dedicated to the development of a universal vaccine. Focusing on regions of viral proteins that are highly conserved across virus subtypes, vaccine strategies involving the matrix 2 protein, stalk domain of the hemagglutinin, and multivalent approaches have provided broad-based protection in animal models and show much promise. This review summarizes the most encouraging advances in the field with a focus on novel vaccine designs that have yielded promising preclinical and clinical data.
Physiology of esophageal sensorimotor malfunctions in neonatal neurological illness
Authors: Jadcherla Sudarshan R. , Chan Chin Yee , Moore Rebecca , Fernandez Soledad , Shaker Reza
Published: January 2013

We aimed to define the sensorimotor characteristics of aero-digestive reflexes evoked upon midesophageal provocations in neuropathology infants. Provocative esophageal motility testing was performed in 20 neuropathology infants and 10 controls at 42.3 ± 0.6 and 38.9 ± 0.9 wk postmenstrual age. Data from 1,073 infusions were examined for the sensory thresholds, response frequencies, response magnitude of upper esophageal sphincter (UES) contractile reflexes, lower esophageal sphincter (LES) relaxation reflexes, and peristaltic reflexes using mixed statistical models. Threshold volumes for air and liquid in neuropathology and control infants were similar for all reflexes. Graded air- and liquid volume-dependent UES contractile reflex, LES relaxation reflex, and peristaltic reflex frequency recruitment were present in neuropathology and control subjects for the media ( P < 0.0001) and the reflexes ( P < 0.0001). In neuropathology infants (vs. controls), UES contractile magnitude is higher ( P < 0.0001); LES relaxation reflex occurred earlier ( P = 0.008); LES nadir duration lasted longer ( P = 0.006); secondary peristalsis is the chief method of esophageal clearance ( P < 0.0001); pharyngeal swallows and deglutition apneas are less frequent ( P = 0.001); proximal, midesophageal waveform magnitudes and duration are exaggerated ( P < 0.008). UES contractile reflex was longer with liquid than air in both groups ( P = 0.03). We concluded that 1) perception to midesophageal provocation remains preserved in neuropathology neonates; 2) sustained and exaggerated myogenic response from afferent activation is evident by increased excitatory efferent outputs to the UES and esophageal body and increased inhibitory efferent outputs to the LES; 3) dysfunctional regulation of pharyngeal swallowing and infrequent deglutition responses indicate the possibility of impaired descending modulation and central malfunctions of brainstem and vagal nuclei.
Keratinocyte growth factor-2 stimulates P-glycoprotein expression and function in intestinal epithelial cells
Authors: Saksena Seema , Priyamvada Shubha , Kumar Anoop , Akhtar Maria , Soni Vikas , Anbazhagan Arivarasu Natarajan , Alakkam Anas , Alrefai Waddah A. , Dudeja Pradeep K. , Gill Ravinder K.
Published: January 2013

Intestinal P-glycoprotein (Pgp/multidrug resistance 1), encoded by the ATP-binding cassette B1 gene, is primarily involved in the transepithelial efflux of toxic metabolites and xenobiotics from the mucosa into the gut lumen. Reduced Pgp function and expression has been shown to be associated with intestinal inflammatory disorders. Keratinocyte growth factor-2 (KGF2) has emerged as a potential target for modulation of intestinal inflammation and maintenance of gut mucosal integrity. Whether KGF2 directly regulates Pgp in the human intestine is not known. Therefore, the present studies were undertaken to determine the modulation of Pgp by KGF2 using Caco-2 cells. Short-term treatment of Caco-2 cells with KGF2 (10 ng/ml, 1 h) increased Pgp activity (∼2-fold, P < 0.05) as measured by verapamil-sensitive [3H]digoxin flux. This increase in Pgp function was associated with an increase in surface Pgp levels. The specific fibroblast growth factor receptor (FGFR) antagonist PD-161570 blocked the KGF2-mediated increase in Pgp activity. Inhibition of the mitogen-activated protein kinase (MAPK) pathway by PD-98059 attenuated the stimulatory effects of KGF2 on Pgp activity. Small-interfering RNA knockdown of Erk1/2 MAPK blocked the increase in surface Pgp levels by KGF2. Long-term treatment with KGF2 (10 ng/ml, 24 h) also significantly increased PgP activity, mRNA, protein expression, and promoter activity. The long-term effects of KGF2 on Pgp promoter activity were also blocked by the FGFR antagonist and mediated by the Erk1/2 MAPK pathway. In conclusion, our findings define the posttranslational and transcriptional mechanisms underlying stimulation of Pgp function and expression by KGF2 that may contribute to the beneficial effects of KGF2 in intestinal inflammatory disorders.
Preventive role of exercise training in autonomic, hemodynamic, and metabolic parameters in rats under high risk of metabolic syndrome development
Authors: Moraes-Silva Ivana Cinthya , Mostarda Cristiano , Moreira Edson Dias , Silva Kleiton Augusto Santos , dos Santos Fernando , de Angelis Kátia , Farah Vera de Moura Azevedo , Irigoyen Maria Claudia
Published: January 2013

High fructose consumption contributes to metabolic syndrome incidence, whereas exercise training promotes several beneficial adaptations. In this study, we demonstrated the preventive role of exercise training in the metabolic syndrome derangements in a rat model. Wistar rats receiving fructose overload in drinking water (100 g/l) were concomitantly trained on a treadmill (FT) or kept sedentary (F) for 10 wk. Control rats treated with normal water were also submitted to exercise training (CT) or sedentarism (C). Metabolic evaluations consisted of the Lee index and glycemia and insulin tolerance test (kITT). Blood pressure (BP) was directly measured, whereas heart rate (HR) and BP variabilities were evaluated in time and frequency domains. Renal sympathetic nerve activity was also recorded. F rats presented significant alterations compared with all the other groups in insulin resistance (in mg·dl−1·min−1: F: 3.4 ± 0.2; C: 4.7 ± 0.2; CT: 5.0 ± 0.5 FT: 4.6 ± 0.4), mean BP (in mmHG: F: 117 ± 2; C: 100 ± 2; CT: 98 ± 2; FT: 105 ± 2), and Lee index (in g/mm: F = 0.31 ± 0.001; C = 0.29 ± 0.001; CT = 0.27 ± 0.002; FT = 0.28 ± 0.002), confirming the metabolic syndrome diagnosis. Exercise training blunted all these derangements. Additionally, FS group presented autonomic dysfunction in relation to the others, as seen by an ∼50% decrease in baroreflex sensitivity and 24% in HR variability, and increases in sympathovagal balance (140%) and in renal sympathetic nerve activity (45%). These impairments were not observed in FT group, as well as in C and CT. Correlation analysis showed that both Lee index and kITT were associated with vagal impairment caused by fructose. Therefore, exercise training plays a preventive role in both autonomic and hemodynamic alterations related to the excessive fructose consumption.
Age-related changes in the 3D hierarchical structure of rat tibia cortical bone characterized by high-resolution micro-CT
Authors: Jast John , Jasiuk Iwona
Published: January 2013

Three-dimensional hierarchical structure of female Sprague-Dawley rat tibia cortical bone was characterized as a function of age (3, 12, 32, 42, 60, and 72 wk) using a high-resolution micro-computed tomography. At the whole bone level, 3-wk samples exhibited statistically significant differences in a mean total tissue volume, mean cortical bone volume, mean cortical bone volume density, mean periosteal perimeter, and mean cortical thickness ( P < 0.05) compared with all other ages. At the tissue level, there was a statistically significant increase in a mean canal number density and a decrease in a mean canal volume and diameter between 3-wk and 12-wk samples. While no significant variations were found between mean canal lengths, there was a dependence of mean canal orientation on age. At the cell level, there were no statistically significant differences in a lacuna number density and a lacuna volume density, and all lacunae element-based parameters displayed no dependence on age across age. In addition, at the microstructural level, the cannular indexes were reported separately for anterior, posterior, medial, and lateral anatomic regions. From 3 to 32 wk of age, there existed significantly fewer canals per volume of bone in the medial region of the tibia vs. other cross-sectional quadrants. Although there were changes with age, there were no statistically significant differences in the mean canal volume, mean canal diameter, and mean canal length between the four anatomic regions.
Development of an UPLC mass spectrometry method for measurement of myofibrillar protein synthesis: application to analysis of murine muscles during cancer cachexia
Authors: Lima Maria , Sato Shuichi , Enos Reilly T. , Baynes John W. , Carson James A.
Published: January 2013

Cachexia, characterized by skeletal muscle mass loss, is a major contributory factor to patient morbidity and mortality during cancer. However, there are no reports on the rate of myofibrillar protein synthesis (MPS) in skeletal muscles that vary in primary metabolic phenotype during cachexia, in large part because of the small-size muscles and regional differences in larger muscles in the mouse. Here, we describe a sensitive method for measurement of MPS and its application to analysis of MPS in specific muscles of mice with ( Apc Min/+) and without (C57BL/6) cancer cachexia. Mice were injected with a loading dose of deuterated phenylalanine (D5F), and myofibrillar proteins were extracted from skeletal muscles at 30 min. The relative concentrations of D5F and naturally occurring phenylalanine (F) in the myofibrillar proteins and the amino acid pool were quantified by ultra-performance liquid chromatograph (UPLC) mass spectrometry (MS). The rate of MPS was determined from D5F-to-F ratio in the protein fraction compared with the amino acid pool. The rate of MPS, measured in 2–5 mg of muscle protein, was reduced by up to 65% with cachexia in the soleus, plantaris, diaphragm, and oxidative and glycolytic regions of the gastrocnemius. The rate of MPS was significantly higher in the oxidative vs. glycolytic gastrocnemius muscle. A sufficiently sensitive UPLC MS method requiring a very small amount of muscle has been developed to measure the rate of MPS in various mouse muscles. This method should be useful for studies in other animal models for quantifying effects of cancer and anti-cancer therapies on protein synthesis in cachexia, and particularly for analysis of sequential muscle biopsies in a wide range of animal and human studies.
Neuromotor control in chronic obstructive pulmonary disease
Authors: Mantilla Carlos B. , Sieck Gary C.
Published: January 2013

Neuromotor control of skeletal muscles, including respiratory muscles, is ultimately dependent on the structure and function of the motor units (motoneurons and the muscle fibers they innervate) comprising the muscle. In most muscles, considerable diversity of contractile and fatigue properties exists across motor units, allowing a range of motor behaviors. In diseases such as chronic obstructive pulmonary disease (COPD), there may be disproportional primary (disease related) or secondary effects (related to treatment or other concomitant factors) on the size and contractility of specific muscle fiber types that would influence the relative contribution of different motor units. For example, with COPD there is a disproportionate atrophy of type IIx and/or IIb fibers that comprise more fatigable motor units. Thus fatigue resistance may appear to improve, while overall motor performance (e.g., 6-min walk test) and endurance (e.g., reduced aerobic exercise capacity) are diminished. There are many coexisting factors that might also influence motor performance. For example, in COPD patients, there may be concomitant hypoxia and/or hypercapnia, physical inactivity and unloading of muscles, and corticosteroid treatment, all of which may disproportionately affect specific muscle fiber types, thereby influencing neuromotor control. Future studies should address how plasticity in motor units can be harnessed to mitigate the functional impact of COPD-induced changes.
Evaporative cooling: effective latent heat of evaporation in relation to evaporation distance from the skin
Authors: Havenith George , Bröde Peter , Hartog Emiel den , Kuklane Kalev , Holmer Ingvar , Rossi Rene M. , Richards Mark , Farnworth Brian , Wang Xiaoxin
Published: January 2013

Calculation of evaporative heat loss is essential to heat balance calculations. Despite recognition that the value for latent heat of evaporation, used in these calculations, may not always reflect the real cooling benefit to the body, only limited quantitative data on this is available, which has found little use in recent literature. In this experiment a thermal manikin, (MTNW, Seattle, WA) was used to determine the effective cooling power of moisture evaporation. The manikin measures both heat loss and mass loss independently, allowing a direct calculation of an effective latent heat of evaporation (λeff). The location of the evaporation was varied: from the skin or from the underwear or from the outerwear. Outerwear of different permeabilities was used, and different numbers of layers were used. Tests took place in 20°C, 0.5 m/s at different humidities and were performed both dry and with a wet layer, allowing the breakdown of heat loss in dry and evaporative components. For evaporation from the skin, λeff is close to the theoretical value (2,430 J/g) but starts to drop when more clothing is worn, e.g., by 11% for underwear and permeable coverall. When evaporation is from the underwear, λeff reduction is 28% wearing a permeable outer. When evaporation is from the outermost layer only, the reduction exceeds 62% (no base layer), increasing toward 80% with more layers between skin and wet outerwear. In semi- and impermeable outerwear, the added effect of condensation in the clothing opposes this effect. A general formula for the calculation of λeff was developed.
Systemic LPS induces spinal inflammatory gene expression and impairs phrenic long-term facilitation following acute intermittent hypoxia
Authors: Huxtable A. G. , Smith S. M. C. , Vinit S. , Watters J. J. , Mitchell G. S.
Published: January 2013

Although systemic inflammation occurs in most pathological conditions that challenge the neural control of breathing, little is known concerning the impact of inflammation on respiratory motor plasticity. Here, we tested the hypothesis that low-grade systemic inflammation induced by lipopolysaccharide (LPS, 100 μg/kg ip; 3 and 24 h postinjection) elicits spinal inflammatory gene expression and attenuates a form of spinal, respiratory motor plasticity: phrenic long-term facilitation (pLTF) induced by acute intermittent hypoxia (AIH; 3, 5 min hypoxic episodes, 5 min intervals). pLTF was abolished 3 h (vehicle control: 67.1 ± 27.9% baseline; LPS: 3.7 ± 4.2%) and 24 h post-LPS injection (vehicle: 58.3 ± 17.1% baseline; LPS: 3.5 ± 4.3%). Pretreatment with the nonsteroidal anti-inflammatory drug ketoprofen (12.5 mg/kg ip) restored pLTF 24 h post-LPS (55.1 ± 12.3%). LPS increased inflammatory gene expression in the spleen and cervical spinal cord (homogenates and isolated microglia) 3 h postinjection; however, all molecules assessed had returned to baseline by 24 h postinjection. At 3 h post-LPS, cervical spinal iNOS and COX-2 mRNA were differentially increased in microglia and homogenates, suggesting differential contributions from spinal cells. Thus LPS-induced systemic inflammation impairs AIH-induced pLTF, even after measured inflammatory genes returned to normal. Since ketoprofen restores pLTF even without detectable inflammatory gene expression, “downstream” inflammatory molecules most likely impair pLTF. These findings have important implications for many disease states where acute systemic inflammation may undermine the capacity for compensatory respiratory plasticity.
Separating in vivo mechanical stimuli for postpneumonectomy compensation: imaging and ultrastructural assessment
Authors: Ravikumar Priya , Yilmaz Cuneyt , Bellotto Dennis. J. , Dane D. Merrill , Estrera Aaron S. , Hsia Connie C. W.
Published: January 2013

Following right pneumonectomy (PNX), the remaining lung expands and its perfusion more than doubles. Tissue and microvascular mechanical stresses are putative stimuli for compensatory lung growth and remodeling, but their relative contribution remains uncertain. To temporally separate expansion- and perfusion-related stimuli, we replaced the right lung of adult dogs with a customized inflated prosthesis. Four months later, the prosthesis was either acutely deflated (DEF) or kept inflated (INF). Thoracic high-resolution computed tomography (HRCT) was performed pre- and post-PNX before and after prosthesis deflation. Lungs were fixed for morphometric analysis ∼12 mo post-PNX. The INF prosthesis prevented mediastinal shift and lateral lung expansion while allowing the remaining lung to expand 27–38% via caudal elongation, associated with reversible capillary congestion in dependent regions at low inflation and 40–60% increases in the volumes of alveolar sepal cells, matrix, and fibers. Delayed prosthesis deflation led to further significant increases in lung volume, alveolar tissue volumes, and alveolar-capillary surface areas. At postmortem, alveolar tissue volumes were 33% higher in the DEF than the INF group. Lateral expansion explains ∼65% of the total post-PNX increase in left lung volume assessed in vivo or ex vivo, ∼36% of the increase in HRCT-derived (tissue + microvascular blood) volume, ∼45% of the increase in ex vivo septal extravascular tissue volume, and 60% of the increase in gas exchange surface areas. This partition agrees with independent physiological measurements obtained in these animals. We conclude that in vivo signals related to lung expansion and perfusion contribute separately and nearly equally to post-PNX growth and remodeling.
Aspirin and Other Nonsteroidal Anti-Inflammatory Drugs and Risk of Non-Hodgkin Lymphoma
Authors: Teras Lauren R. , Gapstur Susan M. , Patel Alpa V. , Thun Michael J. , Diver W. Ryan , Zhai Yusheng , Jacobs Eric J.
Published: January 2013

Few large prospective studies have examined associations between nonsteroidal anti-inflammatory drug (NSAID) use and non-Hodgkin lymphoma (NHL). We examined the association between NSAID use and NHL incidence among 149,570 participants in the Cancer Prevention Study-II Nutrition cohort. Aspirin and nonaspirin NSAID use were reported at enrollment in 1992 and updated on periodic follow-up questionnaires. During follow-up through 2007, 1,709 incident NHLs were identified. Time-dependent hazard ratios were calculated using extended Cox regression. Compared to no use, current use of 60+ NSAID pills/month (aspirin and nonaspirin NSAIDs combined) was associated with slightly higher NHL incidence (hazard ratio [HR] = 1.26, 95% confidence interval [CI], 1.04–1.53), but no association with frequency of use was observed when NSAID exposure was lagged by approximately 2 years (HR = 1.08, 95% CI, 0.88–1.32). Long duration regular use (current use of 30+ pills/month for ≥5 years) was not associated with NHL incidence (HR = 1.09, 95% CI, 0.91–1.33). In subtype analyses, current use of 60+ NSAID pills/month was associated with follicular lymphoma incidence (HR = 1.87, 95% CI, 1.08–3.24). This association persisted when NSAID exposure was lagged (HR = 1.76, 95% CI, 1.04–2.98) and was similar for aspirin and nonaspirin NSAIDs. The association of current, but not lagged, NSAID use with risk of all NHL could be attributable to use of NSAIDs to relieve symptoms of undiagnosed NHL. However, the association with follicular lymphoma persisted in analyses where NSAID use was lagged and should be investigated further. These findings are particularly important for aspirin as the risks and benefits of prophylactic daily use are weighed. Cancer Epidemiol Biomarkers Prev; 22(3); 422–8. ©2013 AACR.
New Strategies in Myelodysplastic Syndromes: Application of Molecular Diagnostics to Clinical Practice
Authors: Tothova Zuzana , Steensma David P. , Ebert Benjamin L.
Published: January 2013

An increasingly complete compendium of recurrently mutated genes in myelodysplastic syndromes (MDS) has been defined, and the application of massively parallel sequencing to identify mutations in clinical practice now promises to improve the care of patients with this disease. More than 25 recurrent MDS-associated somatic mutations have been identified, involving biologic pathways as diverse as chromatin remodeling and pre-mRNA splicing. Several of these mutations have been shown to have prognostic implications that are independent of existing risk stratification systems based on clinical and pathologic parameters. Application of these recent discoveries to diagnosis, prognosis, risk stratification, and treatment selection for patients with MDS has the potential to improve patient outcomes. Here, we review recent advances in MDS and discuss potential applications of these discoveries to clinical practice. Clin Cancer Res; 19(7); 1637–43. ©2013 AACR.
Is the European Pediatric Medicine Regulation Working for Children and Adolescents with Cancer?
Authors: Vassal Gilles , Geoerger Birgit , Morland Bruce
Published: January 2013

The European Pediatric Medicine Regulation was launched in 2007 to provide better medicines for children. Five years later, the number of new anticancer drugs in early development in the pediatric population remains low, and most children with cancer are still largely denied access to innovative drugs in Europe, as compared with the United States. We analyzed individual pediatric investigation plan (PIP) and waiver decisions for oncology drugs and all oncology drugs that have been approved for marketing authorization since 2007 in Europe. Among the 45 approved PIPs, 33% concern leukemias and lymphomas, 29% solid tumors, 13% brain tumors, and 20% a drug for supportive care. No specific PIP exists for life-threatening diseases such as high-risk neuroblastoma, whereas there are several PIPs in extremely rare malignancies in children and adolescents such as gastrointestinal stromal tumor, melanoma, thyroid cancer, and chronic myeloid leukemia. This paradoxical situation is due to approval of a PIP being driven by the adult indication. Twenty-six of 28 authorized new oncology drugs have a potentially relevant mechanism of action for pediatric malignancies, but 50% have been waived because the adult condition does not occur in children. The most striking example is crizotinib. Implementation of the pediatric regulation should no longer be driven by the adult indication but should be guided instead by the biology of pediatric tumors and the mechanism of action of a drug. This change will be achievable through voluntary PIPs submitted by Pharma or revocation of the oncology class waiver list. Clin Cancer Res; 19(6); 1315–25. ©2013 AACR.
Joint Analysis for Integrating Two Related Studies of Different Data Types and Different Study Designs Using Hierarchical Modeling Approaches
Authors: Li Rui , Conti David V. , Diaz-Sanchez David , Gilliland Frank , Thomas Duncan C.
Published: January 2013

Background: A chronic disease such as asthma is the result of a complex sequence of biological interactions involving multiple genes and pathways in response to a multitude of environmental exposures. However, methods to model jointly all factors are still evolving. Some of the current challenges include how to integrate knowledge from different data types and different disciplines, as well as how to utilize relevant external information such as gene annotation to identify novel disease genes and gene-environment inter-actions. Methods: Using a Bayesian hierarchical modeling framework, we developed two alternative methods for joint analysis of an epidemiologic study of a disease endpoint and an experimental study of intermediate phenotypes, while incorporating external information. Results: Our simulation studies demonstrated superior performance of the proposed hierarchical models compared to separate analysis with the standard single-level regression modeling approach. The combined analyses of the Southern California Children's Health Study and challenge study data suggest that these joint analytical methods detected more significant genetic main and gene-environment interaction effects than the conventional analysis. Conclusion: The proposed prior framework is very flexible and can be generalized for an integrative analysis of diverse sources of relevant biological data.
Rapid Downregulation of Innate Immune Cells, Interleukin-12 and Interleukin-23 in Generalized Pustular Psoriasis with Infliximab in Combination with Acitretin
Authors: Tang M.M. , Spanou Z. , Tang H. , Schibler F. , Pelivani N. , Yawalkar N.
Published: January 2013

Background: Generalized pustular psoriasis (GPP) is a severe inflammatory disease characterized by recurrent eruptions of sterile pustules on erythematous skin. Although tumor necrosis factor (TNF) antagonists may lead to a rapid resolution of GPP, the mechanism of action of these agents remains to be investigated. Here, we sought to evaluate markers of immune response in the skin of a patient who experienced a rapid amelioration of GPP after treatment with infliximab and acitretin. Methods: A skin biopsy was obtained before and 72 h after initiation of treatment. Immunohistochemical stainings were performed to characterize alterations of the infiltrates, the apoptosis marker caspase 3 and key cytokines like TNFα, interleukin (IL)-12, IL-23 and the chemokine CXCL8/IL-8. Results: Parallel with clinical improvement, a striking decline of neutrophils, myeloid and plasmacytoid dendritic cells, M1 macrophages and partly of CD4+ T cells was observed. There was no evidence of increased apoptosis mediated through the caspase-3 pathway. A marked reduction particularly of IL-12 and IL-23 and, to a lesser degree, of TNFα and CXCL8/IL-8 was observed. Conclusion: A swift clinical improvement of GPP by infliximab and acitretin is associated with a marked reduction particularly of innate and partially of the acquired immune cells as well as IL-12 and IL-23.
Health Education Materials for Arab Patients: Content and Design Preferences
Authors: Hashim Muhammad Jawad , Mustafa Halla , Al Abdouli Amani Obaid , Abdulla Al Reem Ahmed , AlQahtani Salama Mohamed , Almajed Salama Abdulbasit , Alzaabi Shamma Saif , Alkaabi Mariam Salem
Published: January 2013

Objective: To investigate the content and design preferences of printed health education leaflets among Arab patients. Materials and Methods: A survey questionnaire to 17 subjects (women: n = 8, men: n = 9; age range 17-70 years) and three focus-group discussions (total 16 participants) were used to assess preferences by showing samples of Arabic health education materials. The questionnaire was administered by interviewers. For the focus-group discussions, the sessions were conducted by a trained interviewer, audio recorded and analyzed thematically. The subjects' educational level was from no formal schooling to university level. Results: In survey component, all patients preferred photographs over clipart. Typeface (‘font') preferences were for Simplified Arabic in 8 subjects (47%) and Mudir MT in 7 (41%); the 16-point font size was favored by 14 (82%) patients. In the three focus-group discussions, themes that participants expressed included use of standard Arabic with local dialects, short sentences, and culturally appropriate advice with practical and quantifiable examples. Conclusions: The participants preferred health education materials to be color trifold brochures illustrated with pictures and not clipart and written in Arabic using the Simplified Arabic font in 16-point size.
Clinical Errors and Medical Negligence
Authors: Oyebode Femi
Published: January 2013

This paper discusses the definition, nature and origins of clinical errors including their prevention. The relationship between clinical errors and medical negligence is examined as are the characteristics of litigants and events that are the source of litigation. The pattern of malpractice claims in different specialties and settings is examined. Among hospitalized patients worldwide, 3-16% suffer injury as a result of medical intervention, the most common being the adverse effects of drugs. The frequency of adverse drug effects appears superficially to be higher in intensive care units and emergency departments but once rates have been corrected for volume of patients, comorbidity of conditions and number of drugs prescribed, the difference is not significant. It is concluded that probably no more than 1 in 7 adverse events in medicine result in a malpractice claim and the factors that predict that a patient will resort to litigation include a prior poor relationship with the clinician and the feeling that the patient is not being kept informed. Methods for preventing clinical errors are still in their infancy. The most promising include new technologies such as electronic prescribing systems, diagnostic and clinical decision-making aids and error-resistant systems.
Left Inguinal Adenopathy Two Years after Cytoreductive Surgery: A Rare Sign of Recurrence
Authors: Mirrakhimov Aibek E. , Nwankwo Nwabundo , Barbaryan Aram , Saba Raya , Ali Alaa M. , Kwatra Shawn G. , Hussain Nasir , Senussi Mourad H. , Velasquez Kho Erwin , Gilman Alan D.
Published: January 2013

Ovarian cancer is the second most common gynecological cancer in the Western world. Despite a good response to treatment, most patients with ovarian cancer will relapse. The abdominal, pelvic, and retroperitoneal cavities represent the most common sites of ovarian cancer recurrence, with inguinal lymph node involvement rarely reported. Herein we report the case of a 48-year-old Caucasian female who underwent successful surgical and chemotherapy treatment for ovarian epithelial cancer. Two years later, the patient was found to have painless left inguinal adenopathy, which was subsequently found to be metastatic ovarian cancer. CA-125 levels were elevated despite the lack of any foci of metabolically active tissue on imaging. Inguinal lymph node involvement is a rare sign of ovarian cancer. Despite that, it is essential to consider ovarian cancer in the differential diagnosis for inguinal lymphadenopathy in a female patient.
Linear Atrophoderma of Moulin:A Case Report and Review of the Literature
Authors: Wongkietkachorn Kuanjira , Intarasupht Julphat , Srisuttiyakorn Chutika , Aunhachoke Kobkul , Nakakes Artit , Niumpradit Nucha
Published: January 2013

Linear atrophoderma of Moulin (LAM) is a rare dermatosis in childhood and early adolescence. The exact etiology of LAM is still obscure. Several treatment modalities were reported but none was consistently successful. We report a case of LAM in which a favorable outcome was obtained with topical calcipotriol. The relevant literature is also reviewed.
Antiplatelet efficacy of prasugrel in patients with high on-clopidogrel treatment platelet reactivity and a history of coronary stenting
Authors: Bernlochner Isabell , Mayer Katharina , Morath Tanja , Orban Martin , Schulz Stefanie , Schömig Albert , Braun Siegmund , Kastrati Adnan , Sibbing Dirk
Published: January 2013

Little is known about the antiplatelet action of the 3rd generation thienopyridine prasugrel in patients showing high platelet reactivity (PR) levels on clopidogrel. Thus, we aimed to determine the antiplatelet efficacy of prasugrel loading (LD) and maintenance dose (MD) treatment in a registry of patients with high PR levels on clopidogrel and a consecutive switch over to prasugrel in a setting of routine platelet function testing. In our registry of patients treated by percutaneous coronary intervention (n=73) with high levels of PR on clopidogrel, the ADP-induced platelet aggregation (PA, in AU x min) was assessed on a Multiplate analyser 1) after clopidogrel LD, 2) after prasugrel LD and 3) on prasugrel MD (5 vs. 10 mg/day). In patients with high PR levels on clopidogrel, prasugrel LD resulted in significantly lower PA values (574 [462–698] vs. 156 [89–234] AU x min; p<0.0001). Only 2.7% of patients showed high PR (HPR, 468 AU x min) following prasugrel LD. On prasugrel MD, PA was significantly higher as compared to prasugrel LD (248 [145–406] vs. 156 [89–234] AU x min; p<0.0001) with more patients showing HPR on MD vs. LD (16.4% vs. 2.7%; p=0.009). For prasugrel MD, HPR rates were higher in 5 vs. 10 mg/day treated patients (46.2% vs. 10.0%; p=0.006). In conclusion, for patients with high PR levels on clopidogrel, prasugrel LD abolished this status in the majority of patients. However, prasugrel response variability was detected, being more pronounced on prasugrel MD vs. LD treatment. The clinical impact of these findings warrants further investigation.
Multiple Biomarkers for the Prediction of Ischemic Stroke
Authors: Prugger Christof , Luc Gérald , Haas Bernadette , Morange Pierre-Emmanuel , Ferrieres Jean , Amouyel Philippe , Kee Frank , Ducimetiere Pierre , Empana Jean-Philippe
Published: January 2013

Objective—

To simultaneously evaluate 14 biomarkers from distinct biological pathways for risk prediction of ischemic stroke, including biomarkers of hemostasis, inflammation, and endothelial activation as well as chemokines and adipocytokines.

Methods and Results—

The Prospective Epidemiological Study on Myocardial Infarction (PRIME) is a cohort of 9771 healthy men 50 to 59 years of age who were followed up over 10 years. In a nested case–control study, 95 ischemic stroke cases were matched with 190 controls. After multivariable adjustment for traditional risk factors, fibrinogen (odds ratio [OR], 1.53; 95% confidence interval [CI], 1.03–2.28), E-selectin (OR, 1.76; 95% CI, 1.06–2.93), interferon-γ-inducible-protein-10 (OR, 1.72; 95% CI, 1.06–2.78), resistin (OR, 2.86; 95% CI, 1.30–6.27), and total adiponectin (OR, 1.82; 95% CI, 1.04–3.19) were significantly associated with ischemic stroke. Adding E-selectin and resistin to a traditional risk factor model significantly increased the area under the receiver-operating characteristic curve from 0.679 (95% CI, 0.612–0.745) to 0.785 and 0.788, respectively, and yielded a categorical net reclassification improvement of 29.9% (
P
=0.001) and 28.4% (
P
=0.002), respectively. Their simultaneous inclusion in the traditional risk factor model increased the area under the receiver-operating characteristic curve to 0.824 (95% CI, 0.770–0.877) and resulted in an net reclassification improvement of 41.4% (
P
<0.001). Results were confirmed when using continuous net reclassification improvement.

Conclusion—

Among multiple biomarkers from distinct biological pathways, E-selectin and resistin provided incremental and additive value to traditional risk factors in predicting ischemic stroke.
Overexpression of SOCS3 in T Lymphocytes Leads to Impaired Interleukin-17 Production and Severe Aortic Aneurysm Formation in Mice—Brief Report
Authors: Romain Mélissa , Taleb Soraya , Dalloz Marion , Ponnuswamy Padmapriya , Esposito Bruno , Pérez Nicolas , Wang Yu , Yoshimura Akihiko , Tedgui Alain , Mallat Ziad
Published: January 2013

Objective—

Mutations of signal transducer and activator of transcription 3 (STAT3) are responsible for autosomal dominant hyperimmunoglobulin E syndrome. Recently, we reported frequent vascular abnormalities, including aneurysms in these patients, and demonstrated that STAT3 inhibition promoted aneurysm in mice. The purpose of this study was to investigate the role of cell-specific STAT3 signaling in the susceptibility to aneurysm.

Methods and Results—

C57BL/6 wild-type mice were irradiated and repopulated with bone marrow cells isolated from either wild-type mice or from mice with defective STAT3 signaling as a result of overexpression of suppressor of cytokine signaling 3 (SOCS3-Tg mice). Mice were then subjected to a validated model of abdominal aortic aneurysm induced by angiotensin II infusion for 28 days, along with repetitive injections of a neutralizing antitransforming growth factor-β antibody. We found that overexpression of SOCS3 in bone marrow–derived cells significantly increased aneurysm severity (
P
=0.04). In contrast, overexpression of SOCS3 in the vessel wall had no effect on the disease process. Surprisingly, deletion of STAT3 signaling in macrophages did not affect aneurysm development. Interestingly, however, defective STAT3 signaling in SOCS3-Tg T cells markedly increased aneurysm severity (
P
=0.01) and mortality from aneurysm rupture (
P
=0.008). Overexpression of SOCS3 in T cells significantly decreased interleukin-17 production (
P
<0.0001) and was associated with a reduction of its plasma levels (
P
=0.02).

Conclusion—

These findings clearly identify a central role for T cell-specific STAT3 signaling in the promotion of vascular aneurysm and support previous work on interleukin-17 protective role in this process.
Chronic Kidney Disease, Plasma Lipoproteins, and Coronary Artery Calcium Incidence
Authors: Lamprea-Montealegre Julio A. , McClelland Robyn L. , Astor Brad C. , Matsushita Kunihiro , Shlipak Michael , de Boer Ian H. , Szklo Moyses
Published: January 2013

Objective—

To determine the association of chronic kidney disease and coronary artery calcium (CAC) incidence, and the distribution of lipoproteins across categories of kidney function and their association with CAC risk.

Methods and Results—

We analyzed data from 2795 participants in the Multi-Ethnic Study of Atherosclerosis with no CAC (calcium score=0) at baseline enrolled at the first Multi-Ethnic Study of Atherosclerosis visit between the years 2000 and 2002. During a median follow-up of 2.4 years, incident calcium (calcium score>0 at follow-up) developed in 12%, 19%, and 27% of participants with a cystatin-c estimated glomerular filtration rate (mL/min per 1.73 m)

2

of ≥90, 60 to 89, and 30 to 59 (
P
for difference <0.001), respectively. Compared with those with normal kidney function (estimated glomerular filtration rate≥90), adjusted CAC incidence risk ratios, and 95% confidence intervals (CIs) were as follows: 1.26 (95% CI, 1.04–1.52), and 1.56 (95% CI, 1.11–2.20;
P
trend
=0.014) in those with estimated glomerular filtration rate of 60 to 89 and 30 to 59, respectively. These associations were attenuated after adjusting for a characteristic and strongly interrelated lipid phenotype (principal component 1), which was more common in those with chronic kidney disease and characterized by a predominance of triglyceride-rich lipoproteins: CAC incidence risk ratios=1.21 (95% CI, 1.00–1.46) and 1.44 (95% CI, 1.02–2.04;
P
trend
=0.06) in those with estimated glomerular filtration rate 60 to 89 and 30 to 59, respectively, after adjusting for principal component 1.

Conclusion—

Chronic kidney disease is strongly associated with CAC incidence. Part of this association is mediated through a characteristic lipid phenotype comprising elevations in triglyceride-rich lipoproteins.
Exploring the Age of Intracranial Aneurysms Using Carbon Birth Dating
Authors: Etminan Nima , Dreier Rita , Buchholz Bruce A. , Bruckner Peter , Steiger Hans-Jakob , Hänggi Daniel , Macdonald R. Loch
Published: January 2013

Background and Purpose—

There is a controversy about the time span over which cerebral aneurysms develop. In particular, it is unknown whether collagen in ruptured aneurysms undergoes more rapid turnover than in unruptured aneurysms.
14
C birth dating of collagen could be used to address this question.

Methods—

Aneurysmal domes from patients undergoing surgical treatment for ruptured or unruptured aneurysms were excised. Aneurysmal collagen was isolated and purified after pepsin digestion. Collagen from mouse tendons served as controls. F
14
C levels in collagen were analyzed by accelerator mass spectrometry and correlated with patient age and aneurysm size.

Results—

Analysis of 10 aneurysms from 9 patients (6 ruptured, 3 unruptured) revealed an average aneurysm collagen age of <5 years, generally irrespective of patient age and aneurysm size or rupture status. Interestingly, F
14
C levels correlated with patient age as well as aneurysm size in ruptured aneurysm collagen samples.

Conclusions—

Our preliminary data suggest that collagen extracted from intracranial aneurysms generally has a high turnover, associated with aneurysm size and patient age. The correlation of patient age and aneurysm F
14
C levels could explain models of aneurysm development. Although preliminary, our findings may have implications for the biological and structural stability of ruptured and unruptured intracranial aneurysms.