bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeting MYCN in Neuroblastoma by BET Bromodomain Inhibition
Authors: Puissant Alexandre , Frumm Stacey M. , Alexe Gabriela , Bassil Christopher F. , Qi Jun , Chanthery Yvan H. , Nekritz Erin A. , Zeid Rhamy , Gustafson William Clay , Greninger Patricia , Garnett Matthew J. , McDermott Ultan , Benes Cyril H. , Kung Andrew L. , Weiss William A. , Bradner James E. , Stegmaier Kimberly
Published: February 2013

Bromodomain inhibition comprises a promising therapeutic strategy in cancer, particularly for hematologic malignancies. To date, however, genomic biomarkers to direct clinical translation have been lacking. We conducted a cell-based screen of genetically defined cancer cell lines using a prototypical inhibitor of BET bromodomains. Integration of genetic features with chemosensitivity data revealed a robust correlation between MYCN amplification and sensitivity to bromodomain inhibition. We characterized the mechanistic and translational significance of this finding in neuroblastoma, a childhood cancer with frequent amplification of MYCN. Genome-wide expression analysis showed downregulation of the MYCN transcriptional program accompanied by suppression of MYCN transcription. Functionally, bromodomain-mediated inhibition of MYCN impaired growth and induced apoptosis in neuroblastoma. BRD4 knockdown phenocopied these effects, establishing BET bromodomains as transcriptional regulators of MYCN. BET inhibition conferred a significant survival advantage in 3 in vivo neuroblastoma models, providing a compelling rationale for developing BET bromodomain inhibitors in patients with neuroblastoma.

Significance: Biomarkers of response to small-molecule inhibitors of BET bromodomains, a new compound class with promising anticancer activity, have been lacking. Here, we reveal MYCN amplification as a strong genetic predictor of sensitivity to BET bromodomain inhibitors, show a mechanistic rationale for this finding, and provide a translational framework for clinical trial development of BET bromodomain inhibitors for pediatric patients with MYCN-amplified neuroblastoma. Cancer Discov; 3(3); 308–23. ©2012 AACR.

See related commentary by Schnepp and Maris, p. 255

This article is highlighted in the In This Issue feature, p. 239
Neonatal Systemic Exposure to Lipopolysaccharide Enhances Susceptibility of Nigrostriatal Dopaminergic Neurons to Rotenone Neurotoxicity in Later Life
Authors: Cai Zhengwei , Fan Lir-Wan , Kaizaki Asuka , Tien Lu-Tai , Ma Tangeng , Pang Yi , Lin Shuying , Lin Rick C.S. , Simpson Kimberly L.
Published: February 2013

Brain inflammation via intracerebral injection with lipopolysaccharide (LPS) in early life has been shown to increase risks for the development of neurodegenerative disorders in adult rats. To determine if neonatal systemic LPS exposure has the same effects on enhancement of adult dopaminergic neuron susceptibility to rotenone neurotoxicity as centrally injected LPS does, LPS (2 μg/g body weight) was administered intraperitoneally into postnatal day 5 (P5) rats and when grown to P70, rats were challenged with rotenone, a commonly used pesticide, through subcutaneous minipump infusion at a dose of 1.25 mg/kg/day for 14 days. Systemically administered LPS can penetrate into the neonatal rat brain and cause acute and chronic brain inflammation, as evidenced by persistent increases in IL-1β levels, cyclooxygenase-2 expression and microglial activation in the substantia nigra (SN) of P70 rats. Neonatal LPS exposure resulted in suppression of tyrosine hydroxylase (TH) expression, but not actual death of dopaminergic neurons in the SN, as indicated by the reduced number of TH+ cells and unchanged total number of neurons (NeuN+) in the SN. Neonatal LPS exposure also caused motor function deficits, which were spontaneously recoverable by P70. A small dose of rotenone at P70 induced loss of dopaminergic neurons, as indicated by reduced numbers of both TH+ and NeuN+ cells in the SN, and Parkinson's disease (PD)-like motor impairment in P98 rats that had experienced neonatal LPS exposure, but not in those without the LPS exposure. These results indicate that although neonatal systemic LPS exposure may not necessarily lead to death of dopaminergic neurons in the SN, such an exposure could cause persistent functional alterations in the dopaminergic system and indirectly predispose the nigrostriatal system in the adult brain to be damaged by environmental toxins at an ordinarily nontoxic or subtoxic dose and develop PD-like pathological features and motor dysfunction.
Less Invasive Surfactant Administration in Extremely Preterm Infants: Impact on Mortality and Morbidity
Authors: Klebermass-Schrehof Katrin , Wald Martin , Schwindt Jens , Grill Agnes , Prusa Andrea-Romana , Haiden Nadja , Hayde Michael , Waldhoer Thomas , Fuiko Renate , Berger Angelika
Published: February 2013

Background: A new mode of surfactant administration without intubation - less invasive surfactant administration (LISA) - has recently been described for premature infants. Objective: We report single-center outcome data of extremely premature infants who have been managed by LISA in our department. Mortality and morbidity rates of the cohort were compared to historical controls from our own center and to data of the Vermont-Oxford Neonatal Network (VONN). Patients and Methods: All infants born at 23-27 weeks' gestational age during 01/2009 and 06/2011 (n = 224) were managed by LISA and included in the study group. Results: LISA was tolerated by 94% of all infants. 68% of infants stayed on continuous positive airway pressure on day 3. The rate of mechanical ventilation was 35% within the first week and 59% during the entire hospital stay. Compared to historical controls, we found significantly higher survival rates (75.8 vs. 64.1%) and significantly less intraventricular hemorrhage (IVH) (28.1 vs. 45.9%), severe IVH (13.1 vs. 23.9%) and cystic periventricular leukomalacia (1.2 vs. 5.6%); only persistent ductus arteriousus (PDA) (74.7 vs. 52.6%) and retinopathy of prematurity (ROP) (40.5 vs. 21.1%) occurred significantly more often. Compared to VONN data, we found significantly less chronic lung disease (20.6 vs. 46.4%), severe cerebral lesions (IVH 3/4 + cystic PVL; 9.4 vs. 16.1%) and ROP (all grades) (40.5 vs. 56.5%); only PDA (74.7 vs. 63.1%) and severe ROP (> grade 2) (24.1 vs. 14.1%) occurred significantly more often in our cohort. Conclusion: Surfactant can be effectively and safely delivered via LISA and this is associated with low rates of mechanical ventilation and various adverse outcomes in extremely premature infants.
Serum Uric Acid and Outcome after Acute Ischemic Stroke: PREMIER Study
Authors: Chiquete Erwin , Ruiz-Sandoval José L. , Murillo-Bonilla Luis M. , Arauz Antonio , Orozco-Valera Diego R. , Ochoa-Guzmán Ana , Villarreal-Careaga Jorge , León-Jiménez Carolina , Barinagarrementeria Fernando , Ramos-Moreno Alma , Cantú-Brito Carlos
Published: February 2013

Background: Current evidence shows that uric acid is a potent antioxidant whose serum concentration increases rapidly after acute ischemic stroke (AIS). Nevertheless, the re-lationship between serum uric acid (SUA) levels and AIS outcome remains debatable. We aimed to describe the prognostic significance of SUA in AIS. Methods: We studied 463 patients (52% men, mean age 68 years, 13% with glomerular filtration rate <60 ml/min at hospital arrival) with AIS pertaining to the multicenter registry PREMIER, who had SUA measurements at hospital presentation. Multivariate models were constructed to analyze the association of SUA with functional outcome as assessed by the modified Rankin scale (mRS) at 30-day, 3-, 6- and 12-month follow-up. A mRS 0-1 was regarded as a very good outcome. Results: Mean SUA concentration at hospital arrival was 6.1 ± 3.7 mg/dl (362.8 ± 220.0 μmol/l). Compared with cases with higher SUA levels at hospital admission, patients with ≤4.5 mg/dl (≤267.7 μmol/l; the lowest tertile of the sample) had more cases of a very good 30-day outcome (30.5 vs. 18.9%, respectively; p = 0.004). SUA was not associated with mortality or functional dependence (mRS >2) at 30 days, or with any outcome measure at 3, 6 or 12 months poststroke. After adjustment for age, gender, stroke type and severity (NIHSS <9), time since event onset, serum creatinine, hypertension, diabetes and smoking, a SUA ≤4.5 mg/dl (≤267.7 μmol/l) was positively associated with a very good short-term outcome (odds ratio: 1.76, 95% confidence interval: 1.05-2.95; negative predictive value: 81.1%), but not at 3, 6 or 12 months of follow-up. When NIHSS was entered in the multivariate model as a continuous variable, the independent association of SUA with outcome was lost. Compared with cases with higher levels, patients with SUA ≤4.5 mg/dl (≤267.7 μmol/l) were more frequently younger than 55 years, women, with mild strokes, with normal serum creatinine and fewer had hypertension. The time since event onset to hospital arrival was not significantly associated with AIS severity or SUA levels; nevertheless, a nonsignificant tendency was observed for patients with severe strokes and high SUA levels arriving in <24 h. Conclusions: A low SUA concentration is modestly associated with a very good short-term outcome. Our findings support the hypothesis that SUA is more a marker of the magnitude of the cerebral infarction than an independent predictor of stroke outcome.
Neuroimmune Guidance Cue Semaphorin 3E Is Expressed in Atherosclerotic Plaques and Regulates Macrophage Retention
Authors: Wanschel Amarylis , Seibert Tara , Hewing Bernd , Ramkhelawon Bhama , Ray Tathagat D. , van Gils Janine M. , Rayner Katey J. , Feig Jonathan E. , O’Brien Edward R. , Fisher Edward A. , Moore Kathryn J.
Published: February 2013

Objective—

The persistence of myeloid-derived cells in the artery wall is a characteristic of advanced atherosclerotic plaques. However, the mechanisms by which these cells are retained are poorly understood. Semaphorins, a class of neuronal guidance molecules, play a critical role in vascular patterning and development, and recent studies suggest that they may also have immunomodulatory functions. The present study evaluates the expression of Semaphorin 3E (
Sema3E
) in settings relevant to atherosclerosis and its contribution to macrophage accumulation in plaques.

Approach and Results—

Immunofluorescence staining of
Sema3E
, and its receptor PlexinD1, demonstrated their expression in macrophages of advanced atherosclerotic lesions of Apoe
–/–
mice. Notably, in 2 different mouse models of atherosclerosis regression,
Sema3E
mRNA was highly downregulated in plaque macrophages, coincident with a reduction in plaque macrophage content and an enrichment in markers of reparative M2 macrophages. In vitro,
Sema3E
mRNA was highly expressed in inflammatory M1 macrophages and in macrophages treated with physiological drivers of plaque progression and inflammation, such as oxidized low-density lipoprotein and hypoxia. To explore mechanistically how
Sema3E
affects macrophage behavior, we treated macrophages with recombinant protein in the presence/absence of chemokines, including CCL19, a chemokine implicated in the egress of macrophages from atherosclerotic plaques.
Sema3E
blocked actin polymerization and macrophage migration stimulated by the chemokines, suggesting that it may immobilize these cells in the plaque.

Conclusions—

Sema3E is upregulated in macrophages of advanced plaques, is dynamically regulated by multiple atherosclerosis-relevant factors, and acts as a negative regulator of macrophage migration, which may promote macrophage retention and chronic inflammation in vivo.
Increased Serum Cholesterol Esterification Rates Predict Coronary Heart Disease and Sudden Death in a General Population
Authors: Tanaka Shin-ichiro , Yasuda Tomoyuki , Ishida Tatsuro , Fujioka Yoshio , Tsujino Takeshi , Miki Tetsuo , Hirata Ken-ichi
Published: February 2013

Objective—

Lecithin:cholesterol acyltransferase (LCAT) is thought to be important in reverse cholesterol transport. However, its association with coronary heart disease (CHD) and sudden death is controversial.

Approach and Results—

We prospectively studied 1927 individuals from the general population. Serum concentrations of apolipoprotein A-I, A-II, B, C-II, C-III, E, and LCAT activity measured as a serum cholesterol esterification rate were evaluated. We documented 61 events of CHD and sudden death during 10.9 years of follow-up. After adjustment for age and sex, LCAT activity was significantly associated with the risk of CHD and sudden death (hazard ratio, 3.02; 95% confidence interval, 1.49−6.12;
P
=0.002). In multivariate analysis adjusted for age, sex, current smoking status, history of diabetes mellitus, body mass index, systolic blood pressure, serum total cholesterol, and serum high-density lipoprotein cholesterol concentrations, the hazard ratio of LCAT activity for the risk of CHD and sudden death remained significant (hazard ratio, 3.07; 95% confidence interval, 1.35−7.01;
P
=0.008). However, when it was analyzed for men and women separately, this association remained significant only in women.

Conclusions—

Increased LCAT activity measured as a serum cholesterol esterification rate was a risk for CHD and sudden death in a Japanese general population.
Diagnosing Present and Future Permafrost from Climate Models
Authors: Slater Andrew G. , Lawrence David M.
Published: February 2013

Permafrost is a characteristic aspect of the terrestrial Arctic and the fate of near-surface permafrost over the next century is likely to exert strong controls on Arctic hydrology and biogeochemistry. Using output from the fifth phase of the Coupled Model Intercomparison Project (CMIP5), the authors assess its ability to simulate present-day and future permafrost. Permafrost extent diagnosed directly from each climate model's soil temperature is a function of the modeled surface climate as well as the ability of the land surface model to represent permafrost physics. For each CMIP5 model these two effects are separated by using indirect estimators of permafrost driven by climatic indices and compared to permafrost extent directly diagnosed via soil temperatures. Several robust conclusions can be drawn from this analysis. Significant air temperature and snow depth biases exist in some model's climates, which degrade both directly and indirectly diagnosed permafrost conditions. The range of directly calculated present-day (1986–2005) permafrost area is extremely large (~4–25 × 106 km2). Several land models contain structural weaknesses that limit their skill in simulating cold region subsurface processes. The sensitivity of future permafrost extent to temperature change over the present-day observed permafrost region averages (1.67 ± 0.7) × 106 km2 °C−1 but is a function of the spatial and temporal distribution of climate change. Because of sizable differences in future climates for the representative concentration pathway (RCP) emission scenarios, a wide variety of future permafrost states is predicted by 2100. Conservatively, the models suggest that for RCP4.5, permafrost will retreat from the present-day discontinuous zone. Under RCP8.5, sustainable permafrost will be most probable only in the Canadian Archipelago, Russian Arctic coast, and east Siberian uplands.
A Study of Response of the Equatorial Pacific SST to Doubled-CO2 Forcing in the Coupled CAM–1.5-Layer Reduced-Gravity Ocean Model
Authors: Jia Fan , Wu Lixin
Published: February 2013

The response of the equatorial Pacific SST under CO2 doubling is investigated using Community Atmosphere Model, version 3.1 (CAM3.1)–1.5-layer reduced-gravity ocean (RGO) coupled model. A robust El Niño–like warming pattern is found in the equatorial Pacific. The surface heat budget analyses suggest the El Niño–like pattern results from a weakening of the Walker circulation. In the western equatorial Pacific, all the heat flux components are important to warm the ocean, with the vast majority canceled by entraiment cooling related to increased stratification. In the central-eastern Pacific, the oceanic horizontal advections along with longwave radiation and latent heat flux act to warm the ocean, with entrainment, shortwave radiation, and horizontal diffusion acting as damping terms. An enhanced annual cycle of SST in the equatorial Pacific is also found, which is driven by the ocean dynamical adjustments to changing winds in the eastern ocean.

Although the ocean model used here is a simple reduced-gravity model, the El Niño–like response supports the results of some full ocean–atmosphere general circulation models (GCMs) performed for the World Climate Research Programme (WCRP) Coupled Model Intercomparison Project (CMIP) phase-5, indicating that the CAM3.1–RGO model can be taken as a useful and efficient tool to study equatorial Pacific response under changing climate.
“This Is My Family”
Authors: Gernhardt Ariane , Rübeling Hartmut , Keller Heidi
Published: February 2013

In the present study, we examined the family drawings of preschool-aged children from three cultural contexts that represented different aspects of autonomy and relatedness. The final sample consisted of 53 children from urban Western middle-class families from Osnabrueck, Germany; 63 children from rural Cameroonian Nso farming families; and 59 children from urban middle-class families from Ankara, Turkey. The children were of similar age and did not differ in basic drawing abilities. The family drawings varied with cultural context and the respective orientation toward autonomy and relatedness, specifically in regard to the number and position of family members, the depicted absolute and relative size of family members, the details of facial features, and the emotional expression. Additionally, the positioning and spatial arrangement of family members on the paper can be linked to the children’s familiarity with external frames of reference in drawings.
Local Regulation of Tooth Mineralization by Sphingomyelin Phosphodiesterase 3
Authors: Khavandgar Z. , Alebrahim S. , Eimar H. , Tamimi F. , McKee M.D. , Murshed M.
Published: February 2013

Sphingomyelin phosphodiesterase 3 ( Smpd3) encodes a membrane-bound enzyme that cleaves sphingomyelin to generate several bioactive metabolites. A recessive mutation called fragilitas ossium ( fro) in the Smpd3 gene leads to impaired mineralization of bone and tooth extracellular matrix (ECM) in fro/fro mice. In teeth from fro/fro mice at various neonatal ages, radiography and light and electron microscopy showed delayed mantle dentin mineralization and a consequent delay in enamel formation as compared with that in control +/fro mice. These tooth abnormalities progressively improved with time. Immunohistochemistry showed expression of SMPD3 by dentin-forming odontoblasts. SMPD3 deficiency, however, did not affect the differentiation of these cells, as shown by osterix and dentin sialophosphoprotein expression. Using a transgenic mouse rescue model ( fro/fro; Col1a1-Smpd3) in which Smpd3 expression is driven by a murine Col1a1 promoter fragment active in osteoblasts and odontoblasts, we demonstrate a complete correction of the tooth mineralization delays. In conclusion, analysis of these data demonstrates that Smpd3 expression in odontoblasts is required for tooth mineralization.
The Psychology School Mental Health Initiative
Authors: Millar Golden M. , Lean Debra , Sweet Susan D. , Moraes Sabrina C. , Nelson Victoria
Published: February 2013

Evidence suggests that schools have, by default, become the primary mental health system for students in Canada. The goal of the present study was to design, implement, and evaluate the Psychology School Mental Health Initiative (PSMHI). The PSMHI is an innovative attempt to increase the capacity of school-based psychology staff to deliver evidence-based mental health intervention to children and adolescents with mental health concerns. The conceptualization, implementation, and initial outcomes of the PSMHI are outlined. Advantages and challenges of delivering cognitive–behavioural intervention in a school setting are discussed. Preliminary data indicated that participation in the initiative increased the capacity of school psychology staff in the provision of mental health service. Furthermore, results revealed that a higher number of students with mental health issues received evidence-based intervention. Finally, recommendations for enhancing effective service delivery and the expanding role of psychology with the school system are highlighted.
Challenges and Solutions in the Implementation of the School-Based Pathway to Care Model
Authors: Kutcher Stan , Wei Yifeng
Published: February 2013

Most mental disorders often onset during the adolescent years, providing opportunities for educators, health care providers, and related stakeholders to work collaboratively in addressing adolescent mental health care needs. This report describes early implementations of various components of the School-Based Pathway to Care Model currently applied in Canada, identifies lessons learned, and suggests future directions. The School-Based Pathway to Care Model engages students, teachers, student service providers, parents/families, health care providers, and the wider community through various training programs and both formal and informal linkages between the school, community, and health providers. Preliminary evaluation of the model in whole and in part shows promising outcomes for its application in secondary schools within the wider framework of enhancing system capacity for addressing mental health needs of students. Future focus should be directed towards more rigorous research on the model and its various components.
Transversely isotropic constitutive properties modeling of tubular sandwich composite structures
Authors: Kalamkarov Alexander L , Askari Davood , Ghasemi-Nejhad Mehrdad N
Published: February 2013

Sandwich structures have been studied extensively for planar structures; however, the use of composite tubing, manufactured by pultrusion, in a bending situation where a core material can contribute to take shear stresses, can find many applications in modern structures made of composite materials. The objective of this article is to develop analytical solutions for axial effective modulus and major Poisson’s ratio of a pultruded unidirectional composite tubing filled with a core material. In this work, the unidirectional composite tubing and its core are considered to have transversely isotropic and isotropic properties, respectively. For the validation of the results, the obtained exact analytical solutions are reduced to a case where both the materials are isotropic and compared to the existing solutions for an isotropic material filling in an isotropic tube. Further validations of our exact analytical solutions for the transversely isotropic tubing and isotropic core are carried out employing a finite element analysis of the same structure, where the results show excellent agreements between the analytical solutions and the numerical results. Finally, a parametric study is conducted to investigate the variations in the effective properties of the two-phase composite cylinder based on the variations in the skin and/or core geometries and their material properties.
Optimum loading level of nanoclay in PLA nanocomposites
Authors: Pirani Sanaa I , Krishnamachari Parakalan , Hashaikeh Raed
Published: February 2013

Biodegradable polymer nanocomposites of poly(lactic acid) and nanoclay (Cloisite 30B) samples were prepared with compositions of 0%, 1%, 2%, 3%, 4%, and 5% (by mass) nanoclay using extrusion followed by injection molding. An exfoliated morphology was observed using x-ray diffraction. The nanocomposites were investigated for their mechanical properties using dynamic mechanical analysis (DMA) and tensile testing. The combination with 3% nanoclay was found to be optimum as a result of having the greatest mechanical strength. The fracture surfaces of the samples were also observed with the help of a scanning electron microscopy, and the images obtained complied with the experimental values attained for the samples, indicating more ductile fractures for those samples with greater mechanical strength. The thermal properties of the composites were studied with the help of differential scanning calorimetry and DMA data, and it was found that the trend followed by the glass transition temperature values obtained by both the methods was the same.
The Fate of Whistleblowers in Nonprofit Organizations
Authors: Rothschild Joyce
Published: February 2013

What has come to be called ‘whistleblowing’ has grown enormously in the US over recent decades and it is spreading rapidly around the world. The research on which this paper is based develops a sample of whistleblowers from all walks of life and all regions of the US. This article focuses specifically on the treatment of whistleblowers in the non-profit sector.

In examining the political meaning of the act of whistleblowing, the author describes whistleblowing as an act of parrhesia. In ancient Greece this was a citizen request to speak freely and frankly. In the case of the whistleblowers, they are moved to speak publicly and candidly, even without permission to do so, in defense of the substantive purposes of the organization that employs them.

This study finds that there is little difference in how whistleblowers are treated in the three sectors of our economy. In the majority of cases in this sample, the organizational managers against whom the whistleblowers level claims of wrongdoing, seek quickly to discredit, defame and terminate them.

The author’s research does find that most employees in non-profit organizations view their employer as reasonably open to their inputs. Nevertheless, these positive perceptions of the employer are destroyed among those employees who witness what they define as wrongful or illegal conduct on the part of their employer, and particularly where the employee brings their observations of corruption to “higher-ups” in the organization and sees no corrective action take place. The retaliation that too often follows their disclosures of corrupt practices leaves them with a magnified sense of their own integrity, a new political identity, and an indelible sense of distrust toward senior managers and hierarchal organizations in general. The paper concludes with some suggestions as to how non-profit organizations could respond in a more constructive way to dissenting viewpoints.
Proteinuria in membranous lupus nephritis: the pathology is in the podocyte
Authors: Desai N , Cimbaluk D , Lewis EJ , Whittier WL
Published: February 2013

Background

Patients with membranous lupus glomerulonephritis (MLN) can present with a broad range of urine protein excretion. The glomerular lesion underlying this functional abnormality has been presumed to be immune complexes which aggregate in the subepithelial area. However, the amount of proteinuria often fails to correlate with the quantity of immune deposits demonstrable on fluorescent and electron microscopy. The purpose of this study is to determine the correlation of alterations of the morphologic components of the glomerular capillary wall with the amount of proteinuria in MLN.

Design

We conducted a retrospective clinicopathologic study of patients with lupus nephritis ( n = 236). In those with pure MLN and proteinuria ( n = 20), the degree of immune aggregates in the capillary walls and mesangium was detailed using fluorescent and electron microscopy. The degree of foot process effacement (FPE) was detailed using electron microscopy.

Result

Eleven patients had nephrotic range proteinuria (≥3 g proteinuria/g creatinine (g/g)) and nine demonstrated subnephrotic range proteinuria (<3 g/g) (nephrotic, 8.3 ± 5.1 g/g vs. subnephrotic, 1.63 ± 0.83 g/g, p = 0.001). All patients demonstrated peripheral capillary wall granular deposits by immunofluorescence microscopy, and the degree of moderate (2 +) to severe (3 +) deposition was not different (nephrotic, 8/11, 73% vs. subnephrotic, 5/9, 55%, p = 0.64). By electron microscopy, FPE (88.6 ± 11% vs. 48.3 ± 36.1%, p = 0.002) and foot process width (1798 ± 736 nm vs. 1000 ± 333 nm, p = 0.008) was greater in the nephrotic group compared with subnephrotic. There were no other histopathologic differences between the groups.

Conclusions

In patients with MLN, a distinguishing morphologic feature of those with nephrotic range proteinuria is diffuse visceral epithelial cell FPE. We conclude that nephrotic range proteinuria in patients with MLN may be a manifestation of concomitant glomerular visceral epithelial cell dysfunction.
A Chaplain’s Story
Authors: Bodemann Christina
Published: February 2013

Julia, a 31-year-old woman, is brain dead after having suffered a cardiac arrest. This article describes a hospital chaplain's journey with her family through the tragedy of letting her die. It addresses the power of pastoral presence and prayer in a situation of loss and grief and the importance of storytelling for everyone involved in Julia's end-of-life care.
Contemporary Home Care Service and Family Medicine in Turkey
Authors: Mergen Haluk , Unluoglu Ilhami , Elcioglu Omur
Published: February 2013

Home care service is providing health care to the patient in his or her dwelling when care in the hospital is no longer required. Home care services provide not only medical services but also the social services that the human needs. Studies concerning home care services bear great importance. In this review, the authors aim to guide new studies by stating the legal and scientific point reached at the moment in Turkey.
Long-term follow-up of surgical treatment of spinal anaplastic astrocytoma in a cat
Authors: Tamura Shinji , Hori Yuko , Tamura Yumiko , Uchida Kazuyuki
Published: February 2013

A 10-year-old spayed female chinchilla feline presented with gradually progressive tetraparesis and cervical pain that had begun 1 month before the onset of a 4-day tetraplegic episode. Magnetic resonance imaging revealed a large elliptical intramedullary mass at the fourth cervical vertebrae. The mass was removed surgically and diagnosed as an anaplastic astrocytoma. No neurological abnormalities were observed 3 weeks postsurgery. Magnetic resonance at 3.5 year follow-up revealed neither mass regrowth nor recurrence of signs.
Judging patients’ pain from external cues
Authors: Igier Valérie , Sorum Paul C , Mullet Etienne
Published: February 2013

Nurses, nurse’s aides, and physicians were presented with vignettes describing elderly patients and were asked to assess their level of pain from four external cues (facial expression, verbalizations, avoidance of movements and positions, and interpersonal contact) in three conditions: when the illness was not known, when it was known to be arthritis, and when it was known to be cancer. For all health caregivers, the most important cue for judging pain was patients’ facial expression. When the nature of the illness was not known, the impact of this cue was stronger than when the nature of the illness was known.
The other ‘Hobbes’ people’: An alternative reading of Hobbes
Authors: Filippov Alexander F
Published: February 2013

This paper argues that while Hobbes has been very influential in sociological thinking, in particular through the influence of Ferdinand Tönnies and Talcott Parsons, there is an important alternative reading of Hobbes that one might call the ‘real’ Hobbes, which has remained unknown to social theory. Because these classical readings of Hobbes still inform most social theory, sociologists are in effect trapped within them. Through a careful analysis of classic interpretations of Hobbes by Tönnies and Parsons, coupled with a close reading of Hobbes’ actual texts, and his criticisms of Aristotle, this paper will suggest that a different understanding of the ‘people’ who populate Hobbes’ social universe is possible. It will be suggested that this new understanding of Hobbes also makes the contemporary understanding of the history of political philosophy more fruitful for theoretical sociology.
Towards living well with young onset dementia: An exploration of coping from the perspective of those diagnosed
Authors: Clemerson Gemma , Walsh Sue , Isaac Claire
Published: February 2013

There is increasing recognition that dementia in people under 65 years represents a unique challenge to sufferers and services alike. However, by either ignoring this population or sampling them together with older adults, current research has failed to reflect this. This study explored the specific experience of living and coping with Alzheimer’s disease in younger life from the perspective of those diagnosed. Semi-structured interviews were analysed using interpretive phenomenological analysis, and four themes were identified: ‘disruption of the life-cycle’, ‘identity’, ‘social orientation’ and ‘agency’. The experience of living and coping with young onset Alzheimer’s disease was strongly situated within an individual’s social context. Most significantly, participants felt too young to develop the disease and felt out of time with age-related psychological tasks. Coping strategies that attempted to redress and normalise the life-cycle were identified. The contributions of the study are discussed in the context of the human development literature.
Discrete event command and control for network teams with multiple military missions
Authors: Pang Chee Khiang , Hudas Greg R , Middleton Matthew B , Le Cao Vinh , Lewis Frank L
Published: February 2013

During mission execution in military applications, the US Army Training and Doctrine Command Pamphlet 525-66 Battle Command and Battle Space Awareness capabilities prescribe expectations that networked teams will perform in a reliable manner under changing mission requirements, varying resource availability and reliability, resource faults, etc. In this paper, a command and control structure is presented that allows for computer-aided execution of the networked team decision-making process, control of force resources, shared-resource dispatching, and adaptability to change based on battlefield conditions. A mathematically justified networked computing environment is provided called the Discrete Event Control (DEC) framework. DEC has the ability to provide the logical connectivity among all team participants, including mission planners, field commanders, warfighters, and robotic platforms. The proposed data management tools are developed and demonstrated with a simulation study on a realistic military ambush attack. The results show that the tasks of multiple missions are correctly sequenced in real time, and that shared resources are suitably assigned to competing tasks under dynamically changing conditions without conflicts and bottlenecks.
Aryl hydrocarbon receptor contributes to the MEK/ERK-dependent maintenance of the immature state of human dendritic cells
Authors: Aguilera-Montilla Noemí , Chamorro Sonia , Nieto Concha , Sánchez-Cabo Fátima , Dopazo Ana , Fernández-Salguero Pedro Maria , Rodríguez-Fernández Jose Luis , Pello Oscar M. , Andrés Vicente , Cuenda Ana , Alonso Bárbara , Domínguez-Soto Angeles , Sánchez-Ramón Silvia , Corbí Angel L.
Published: February 2013

Key Points

Aryl hydrocarbon receptor (AhR) mediates the ERK-dependent maintenance of the immature state of monocyte-derived dendritic cells (MDDCs). MEK-ERK regulates antigen capture, lymph node homing, and the acquisition of maturation-associated genes in MDDCs.
Determinants of endothelial function in patients with COPD
Authors: Clarenbach Christian F. , Senn Oliver , Sievi Noriane A. , Camen Giovanni , van Gestel Arnoldus J.R. , Rossi Valentina A. , Puhan Milo A. , Thurnheer Robert , Russi Erich W. , Kohler Malcolm
Published: February 2013

Chronic obstructive pulmonary disease (COPD) is associated with increased cardiovascular mortality. Endothelial dysfunction may underpin this association. This cross-sectional study aimed to determine the impact of airflow obstruction, systemic inflammation, oxidative stress, sympathetic activation, hypoxaemia and physical activity on endothelial function in COPD.

In stable COPD patients, assessments of endothelial function by flow-mediated dilatation (FMD), cardiovascular risk (Pocock score), airflow obstruction (forced expiratory volume in 1 s (FEV1)), systemic inflammation (high-sensitivity C-reactive protein and interleukin-6), oxidative stress (malondialdehyde), sympathetic activation (baroreflex sensitivity), hypoxaemia (arterial oxygen tension), hypercapnia (arterial carbon dioxide tension (PaCO2)), physical activity (steps per day) and exercise capacity (6-min walking distance) were performed. Associations between FMD and potential determinants were assessed in univariate and multivariate analyses.

106 patients (Global Initiative for Chronic Obstructive Lung Disease stage I/II 35%, stage III 25% and stage IV 40%) were included. In multivariate analysis FEV1was positively associated with FMD, independent of other significant FMD determinants from univariate analysis (sex, smoking, combined inhaled long-acting β-adrenergic and steroid medication, heart rate, baroreflex sensitivity andPaCO2) and adjusted for potential confounders (cardiovascular risk and age). In addition, the FMD and FEV1association was modified by physical activity.

The findings of this study demonstrate that the severity of airflow obstruction is a significant determinant of endothelial function in patients with COPD. A high level of physical activity seems to have a favourable effect on this association.
Gastric non-secreting neuroendocrine tumor and hypochlorhydria-related hypergastrinemia: a case report
Authors: Biolato Marco , Alfieri Sergio , Ianiro Gianluca , Pizzoferrato Marco , Gasbarrini Giovanni
Published: February 2013

Introduction

Zollinger–Ellison syndrome is characterized by recurrent peptic ulcers and diarrhea that result from gastrin-secreting neuroendocrine tumors of the gastrointestinal tract; nevertheless, severe hypergastrinemia may also have alternative pathogenetic explanations.

Case presentation

A 61-year-old woman of Caucasian origin presented with a history of epigastric pain and early satiety, severe hypergastrinemia (approximately 2000 pg/mL) and a neuroendocrine polyp in the corpus of her stomach. Chronic atrophic gastritis and intestinal metaplasia was present, but she denied use of acid suppressant drugs and the results of tests for Helicobacter pylori as well as gastric parietal cell and intrinsic factor antibodies were negative. She underwent a radical gastric tangential resection. Six months later, serum gastrin was still elevated despite lack of recurrence of tumor.

Conclusion

The clinical picture was suggestive for a hypochlorhydria-related hypergastrinemia with subsequent development of a non-secreting carcinoid. We suggest a periodic endoscopic follow-up in patients with severe hypochlorhydria-related hypergastrinemia in order to earlier detect neuroendocrine polyps.
Functional analysis of a zebrafishmyd88mutant identifies key transcriptional components of the innate immune system
Authors: van der Vaart Michiel , van Soest Joost J. , Spaink Herman P. , Meijer Annemarie H.
Published: February 2013

Toll-like receptors (TLRs) are an important class of pattern recognition receptors (PRRs) that recognize microbial and danger signals. Their downstream signaling upon ligand binding is vital for initiation of the innate immune response. In human and mammalian models, myeloid differentiation factor 88 (MYD88) is known for its central role as an adaptor molecule in interleukin 1 receptor (IL-1R) and TLR signaling. The zebrafish is increasingly used as a complementary model system for disease research and drug screening. Here, we describe a zebrafish line with a truncated version of MyD88 as the first zebrafish mutant for a TLR signaling component. We show that this immune-compromised mutant has a lower survival rate under standard rearing conditions and is more susceptible to challenge with the acute bacterial pathogens Edwardsiella tarda and Salmonella typhimurium. Microarray and quantitative PCR analysis revealed that expression of genes for transcription factors central to innate immunity (including NF-κB and AP-1) and the pro-inflammatory cytokine Il1b, is dependent on MyD88 signaling during these bacterial infections. Nevertheless, expression of immune genes independent of MyD88 in the myd88 mutant line was sufficient to limit growth of an attenuated S. typhimurium strain. In the case of infection with the chronic bacterial pathogen Mycobacterium marinum, we show that MyD88 signaling has an important protective role during early pathogenesis. During mycobacterial infection, the myd88 mutant shows accelerated formation of granuloma-like aggregates and increased bacterial burden, with associated lower induction of genes central to innate immunity. This zebrafish myd88 mutant will be a valuable tool for further study of the role of IL1R and TLR signaling in the innate immunity processes underlying infectious diseases, inflammatory disorders and cancer.
Stereoscopic particle image velocimetry measurements of the three-dimensional flow field of a descending autorotating Mahogany seed (Swietenia macrophylla)
Authors: Salcedo Erick , Treviño Cesar , Vargas Rene O. , Martínez Lorenzo A.
Published: February 2013

An experimental investigation of near field aerodynamics of wind dispersed rotary seeds has been performed using stereoscopic digital particle image velocimetry (DPIV). The detailed three-dimensional (3D) flow structure of the leading-edge vortex (LEV) of autorotating Mahogany seeds (Swietenia macrophylla) in a low-speed vertical wind tunnel are revealed for the first time. The results confirm that the presence of strong spanwise flow and strain produced by centrifugal forces through a spiral vortex are responsible for the attachment and stability of the LEV, with its core forming a cone pattern with gradual increase in vortex size. The LEV appears at 25% of the wingspan, increases in size and strength outboard along the wing, and reaches its maximum stability and spanwise velocity at 75% of the wingspan. At a region between 90% and 100% of the wingspan, the strength and stability of the vortex core decreases and the LEV re-orientation/inflection with the tip vortex takes place. In this study, the instantaneous flow structure and the instantaneous velocity and vorticity fields measured in planes parallel to the free stream direction are presented as contour plots using an inertial and a non-inertial frame of reference. Results for the mean aerodynamic thrust coefficients as a function of the Reynolds number are presented to supplement the DPIV data.
Medium-Term Rail Scheduling for an Iron Ore Mining Company
Authors: Singh Gaurav , García-Flores Rodolfo , Ernst Andreas , Welgama Palitha , Zhang Meimei , Munday Kerry
Published: February 2013

In mineral supply chains, medium-term plans are made for scheduling crews, production, and maintenance. These plans must respect constraints associated with loading and unloading, stockyard capacities, fleet capacities, and maintenance and production requirements. Additionally, compliance with grade quality depends on blending minerals from different sources. In this paper, we present an optimization tool developed for a major multinational iron ore mining company to manage the operations of its supply network in the Pilbara region of Western Australia. The tool produces plans for time horizons from a few weeks to two years, while addressing the nonlinearities that blending introduces. The plans our tool produces allow the company to ship a higher amount of iron ore than it did when it followed the plans obtained by its former manual approach. The company’s planners now rely solely on our tool because it has enabled them to schedule up to one million additional tonnes of material per annum and has reduced the planning time from five hours to less than one hour.
Experimental endocrine manipulation by contraceptive regimen in the male marmoset (Callithrix jacchus)
Authors: Wistuba Joachim , Luetjens C Marc , Ehmcke Jens , Redmann Klaus , Damm Oliver S , Steinhoff Antje , Sandhowe-Klaverkamp Reinhild , Nieschlag Eberhard , Simoni Manuela , Schlatt Stefan
Published: February 2013

Marmosets are used as preclinical model in reproductive research. In contrast to other primates, they display short gestation times rendering this species valid for exploration of effects on fertility. However, their peculiar endocrine regulation differs from a those of macaques and humans. We subjected male marmosets to previously clinically tested hormonal regimens that are known to effectively suppress spermatogenesis. Beside a control group, seven groups (each n=6) were investigated for different periods of up to 42 months: regimen I, (four groups) received testosterone undecanoate (TU) and norethisterone enanthate (NETE); regimen II, (two groups) received TU and NETE followed by NETE only; and regimen III, (one group) received NETE only. Testicular volume, cell ploidy and histology, endocrine changes and fertility were monitored weekly. TU and NETE and initial TU and NETE treatment followed by NETE failed to suppress spermatogenesis and fertility. Testicular volumes dropped, although spermatogenesis was only mildly affected; however, testicular cellular composition remained stable. Serum testosterone dropped when NETE was given alone but the animals remained fertile. Compared with controls, no significant changes were observed in sperm motility and fertility. Administration of TU and NETE affected testicular function only mildly, indicating that the regulatory role of chorionic gonadotrophin and testosterone on spermatogenesis is obviously limited and testicular function is maintained, although the endocrine axis is affected by the treatment. In conclusion, marmosets showed a different response to regimens of male contraception from macaques or men and have to be considered as a problematic model for preclinical trials of male hormonal contraception.
Low Temperature B Activation in SOI Using Optimised Vacancy Engineering Implants
Authors: Smith A.J. , Colombeau B. , Bennett N. , Gwilliam R. , Cowern N. , Sealy B.
Published: February 2013

In this study 300keV and 1MeV Si vacancy engineering implants have been used to optimise the activation of a 2keV 1×1015cm-2 B implant into SOI. Although the two implants generate a similar areal density of excess vacancies in the SOI top layer, Hall Effect measurements show that low temperature activation is possible to a greater level with the 300keV Si co-implant than with the 1MeV implant. Hall and SIMS data are consistent with a high level of activation of the B at 700°C, with no significant diffusion at the metallurgical junction depth.