bluuebunny/crossref_metadata_2025 huggingface dataset:
Adaptive Splenic Radiotherapy for Symptomatic Splenomegaly Management in Myeloproliferative Disorders
Authors: Sager Omer , Beyzadeoglu Murat , Dincoglan Ferrat , Demiral Selcuk , Uysal Bora , Gamsiz Hakan , Akin Mustafa , Gundem Esin , Dirican Bahar
Published: February 2015

Aims and Background

Symptomatic, massive splenomegaly is a debilitating complication of myeloproliferative disorders. In the study, we evaluated the use of a contemporary, individualized radiotherapeutic approach for splenic irradiation, including 3-dimensional computed tomography-based treatment planning, individualized treatment margins based on splenic motion assessment, online setup verification with volumetric image guidance at each fraction, and adaptive radiation treatment planning to account for changes in splenic size during the fractionated radiotherapy course.

Methods and Study design

Between December 2008 and January 2014, 18 patients (13 males, 5 females) with myeloproliferative disorders referred to Gulhane Military Medical Academy Radiation Oncology Department underwent 22 courses of splenic irradiation using 3-dimensional computed tomography-based treatment planning and volumetric image guidance for palliation of symptomatic splenomegaly.

Results

Median age was 64 years (range 28-79). Significant pain relief was achieved in 20 of the 22 splenic irradiation courses (90.9%). Improvement in hematological parameters was achieved in 8 of the 11 splenic irradiation courses applied for cytopenia (72.7%). At least a 50% reduction in splenic size was achieved in 18 of the 22 splenic irradiation courses (81.8%). Toxicity was manageable with supportive treatment including antiemetics and platelet or red blood cell transfusions.

Conclusions

Splenic irradiation with a contemporary radiotherapeutic approach offers safe and effective palliation of symptomatic splenomegaly in myeloproliferative disorders.
Evaluation of Stereotactic Body Radiation Therapy in the Management of Adrenal Metastases from Non-Small Cell Lung Cancer
Authors: Gamsiz Hakan , Beyzadeoglu Murat , Sager Omer , Demiral Selcuk , Dincoglan Ferrat , Uysal Bora , Onal Elif , Dirican Bahar
Published: February 2015

Aims and Background

In this retrospective analysis, we evaluated the use of stereotactic body radiation therapy in the management of adrenal metastases from non-small cell lung cancer and report our single center experience.

Methods and Study design

Fifteen non-small cell lung cancer patients (9 male, 6 female) with 17 adrenal metastases referred to Gulhane Military Medical Academy Radiation Oncology Department were treated using active breathing control-guided stereotactic body radiation therapy between December 2009 and October 2013. Dose per fraction was 10 Gy to deliver a total dose of 30 Gy over 3 consecutive days for all metastatic adrenal lesions. The mean gross tumor volume was 28.4 cc (range 6.6-101.5) and mean planning target volume was 57.4 cc (range 16.5-143.8).

Results

At a median follow-up of 16 months, local control was 86.7% and overall survival was 33.3%. Median disease-free survival was 10 months. Treatment response according to RECIST was categorized as complete response in 3 patients (20%), partial response in 5 patients (33.3%), stable disease in 5 patients (33.3%), and progressive disease in 2 patients (13.3%). Most common acute toxicity was grade 1 nausea (n = 7) and grade 1 fatigue (n = 12). There was no case of grade ≥3 acute or late toxicity.

Conclusions

Stereotactic body radiation therapy offers a safe and efficacious management strategy for adrenal metastases from non-small cell lung cancer by providing excellent local control with negligible treatment related toxicity.
Analysis of MicroRNA Expression Profile Identifies Novel Biomarkers for Non-small Cell Lung Cancer
Authors: Xu Chi , Zheng Yisheng , Lian Duohuang , Ye Shixin , Yang Jinrong , Zeng Zhiyong
Published: February 2015

Background

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer mortality. MicroRNAs (miRNAs), small noncoding RNAs, regulate the expression of genes that play roles in human cancer via posttranscriptional inhibition.

Methods

To identify the potential miRNA biomarkers in NSCLC, we downloaded the miRNA expression profile (ID: GSE29248) of NSCLC from the Gene Expression Omnibus (GEO) database and analyzed the differentially expressed miRNAs in NSCLC tissue compared with normal control tissue. Then the targets of these differentially expressed miRNAs were screened and used in network construction and functional enrichment analysis.

Results

We identified a total of 17 miRNAs that showed a significantly differential expression in NSCLC tissue. We found that miR-34b and miR-520h might play important roles in the regulation of NSCLC, miR-22 might be a novel biomarker as an oncogene, and miR-448 might promote, while miR-654-3p prevents, NSCLC progression.

Conclusions

Our study may provide the groundwork for further clinical molecular target therapy experiments in NSCLC.
Pathway Crosstalk Analysis of Non-Small Cell Lung Cancer Based on Microarray Gene Expression Profiling
Authors: Xing Chunyan , Zhang Ronghua , Cui Jiyun , Li Yonghong , Li Guanhua , Yang Yanna , Pang Longbin , Ruan Xiaoyun , Li Jun
Published: February 2015

Aims and background

Lung cancer is characterized by uncontrolled cell growth in the lung tissue. A major challenge in cancer research is the biological interpretation of the complexity of cancer somatic mutation profiles. This study examines the role of pathway crosstalk in the metastatic process of lung cancer cells based on DNA microarray analysis.

Methods

We downloaded the gene expression profile GSE10096 from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified and the gene functions of selected DEGs were further analyzed. After KEGG pathway analysis, dysfunctional pathways and dysfunctional crosstalk between pathways in two types of lung cancer cells (low metastasis, M1, and high metastasis, M5) were examined.

Results

A total of 13433 genes were filtered as DEGs, and after pathway analysis, 108 signaling pathways related to cancer signaling pathways were screened, including a host pathway hsa05223 and 79 neighbor pathways. Dysfunctional crosstalk analysis of pathways revealed that pathway crosstalk dysfunction of M1 and M5 cells mainly occurred between hsa05223 (non-small cell lung cancer) and hsa04310 (Wnt signaling pathway), and between non-small cell lung cancer and hsa04520 (adherens junction), respectively. Significant pathway crosstalk dysfunction also existed between adherens junction and other classical signaling pathways such as hsa04110 (cell cycle), hsa04310 (Wnt signaling pathway), hsa04350 (TGF-beta signaling pathway), and hsa04630 (Jak-STAT signaling pathway).

Conclusions

Our discovery will help to elucidate the molecular mechanisms of the high carcinogenic and metastatic potential of lung cancer cells. In addition, it will pave the way to developing effective therapies for lung cancer.
Improving Physicians' Communication Skills and Reducing Cancer Patients' Anxiety: A Quasi-Experimental Study
Authors: Morasso Gabriella , Caruso Anita , Belbusti Valentina , Carucci Tiziana , Chiorri Carlo , Clavarezza Valentina , De Benedetta Gabriella , D'Ovidio Silvia , luvaro Maria Domenica , Piattelli Angela , Romeo Marco , Santoni Wissya , Di Leo Silvia
Published: February 2015

Aims and Background

This study is aimed at evaluating the effectiveness of a physician-centered communication skills training program on cancer patient anxiety levels.

Methods and Study design

In this quasi-experimental study, physicians from 9 units of 5 general hospitals and 1 cancer research institute were recruited. The unit heads chose which physicians would attend the training program (treatment group) and which would not (control group). The effectiveness of the course was evaluated by assessing the evolution of state anxiety in a sample of cancer patients before and after clinical consultations.

Results

Thirty-eight physicians and 339 outpatients were assessed. Patients from the treatment and control groups did not differ in pre-examination anxiety or psychological distress levels. Patients examined by physicians from the treatment group displayed a higher decrease in state-anxiety levels compared with those examined by physicians from the control group. A higher proportion of high anxiety levels was found in women, in less educated patients, and in those with a high distress level.

Conclusions

Our findings suggest the effectiveness of the communication skills training program with reference to patient anxiety levels. Given the potential gap between training and clinical impact, further studies investigating the effect of communication training on patient outcomes are needed.
Efficacy and Safety of Long-term Tolvaptan Treatment in a Patient with SCLC and SIADH
Authors: Bordi Paola , Tiseo Marcello , Buti Sebastiano , Regolisti Giuseppe , Ardizzoni Andrea
Published: February 2015

Hyponatremia frequently occurs in patients with cancer and is mostly due to a syndrome of inappropriate antidiuresis caused by ectopic secretion of antidiuretic hormone (SIADH). Small cell lung cancer presents with SIADH in approximately 11%-15% of cases. Recently, a new class of drugs, vasopressin V2-receptor antagonists (vaptans), emerged as a promising treatment for SIADH, but efficacy and safety data in cancer patients are lacking. We present a case of SIADH, heralding small cell lung cancer and persisting after apparent complete remission of primary tumor following chemotherapy/radiotherapy, in a patient who underwent long-term treatment with tolvaptan without any serious adverse effects.
Long Progression-free Survival with Afatinib in a Patient with EGFR-unknown Lung Adenocarcinoma after Erlotinib Failure: A Case Report
Authors: Vitale Maria Giuseppa , Scagliarini Sarah , Riccardi Ferdinando , Barbato Carmela , Otero Manuela , Mocerino Carmela , Ambrosio Francesca , Cartenl Giacomo
Published: February 2015

Important therapeutic advances for patients with advanced non-small cell lung cancer (NSCLC) have recently occurred, and the development of targeted therapy has revolutionized the treatment of these patients. We report the case of an NSCLC patient with unknown EGFR mutation status who developed resistance to erlotinib and was treated with afatinib. After 19 months of therapy with afatinib, the patient is still in treatment and maintains stable disease. Emerging resistance to reversible TKIs is a significant problem. Oral irreversible TKIs such as afatinib may offer an effective treatment option after failure with reversible TKIs.
Eugenia sapoensis Jongkind from Liberia and Eugenia breteleri Jongkind from Gabon, two new forest species (Myrtales: Myrtaceae)
Authors: Jongkind Carel C.H.
Published: February 2015

Two new forest species, Eugenia sapoensis sp. nov. and Eugenia breteleri sp. nov., from Liberia and Gabon respectively, are described and illustrated here. Both are shrubs with comparatively large red fruits. They resemble each other, but E. breteleri differs from E. sapoensis in having twigs with conspicuously peeling bark, 6–8 pairs of main lateral nerves, versus 4–6 pairs, and fruits with a peduncle of 3–5 mm rather than 1– 2 mm long. Eugenia breteleri grows up to 3 m high while E. sapoensis does not grow higher than 1.4 m.
Eye morphogenesis driven by epithelial flow into the optic cup facilitated by modulation of bone morphogenetic protein
Authors: Heermann Stephan , Schütz Lucas , Lemke Steffen , Krieglstein Kerstin , Wittbrodt Joachim
Published: February 2015

The hemispheric, bi-layered optic cup forms from an oval optic vesicle during early vertebrate eye development through major morphological transformations. The overall basal surface, facing the developing lens, is increasing, while, at the same time, the space basally occupied by individual cells is decreasing. This cannot be explained by the classical view of eye development. Using zebrafish (Danio rerio) as a model, we show that the lens-averted epithelium functions as a reservoir that contributes to the growing neuroretina through epithelial flow around the distal rims of the optic cup. We propose that this flow couples morphogenesis and retinal determination. Our 4D data indicate that future stem cells flow from their origin in the lens-averted domain of the optic vesicle to their destination in the ciliary marginal zone. BMP-mediated inhibition of the flow results in ectopic neuroretina in the RPE domain. Ultimately the ventral fissure fails to close resulting in coloboma.
Analytical approximation of transit time scattering due to magnetosonic waves
Authors: Bortnik J. , Thorne R. M. , Ni B. , Li J.
Published: February 2015

Recent test particle simulations have shown that energetic electrons traveling through fast magnetosonic (MS) wave packets can experience an effect which is specifically associated with the tight equatorial confinement of these waves, known as transit time scattering. However, such test particle simulations can be computationally cumbersome and offer limited insight into the dominant physical processes controlling the wave‐particle interactions, that is, in determining the effects of the various wave parameters and equatorial confinement on the particle scattering. In this paper, we show that such nonresonant effects can be effectively captured with a straightforward analytical treatment that is made possible with a set of reasonable, simplifying assumptions. It is shown that the effect of the wave confinement, which is not captured by the standard quasi‐linear theory approach, acts in such a way as to broaden the range of particle energies and pitch angles that can effectively resonate with the wave. The resulting diffusion coefficients can be readily incorporated into global diffusion models in order to test the effects of transit time scattering on the dynamical evolution of radiation belt fluxes.
Study type and plant litter identity modulating the response of litter decomposition to warming, elevated CO2, and elevated O3: A meta‐analysis
Authors: Yue Kai , Peng Changhui , Yang Wanqin , Peng Yan , Fang Junmin , Wu Fuzhong
Published: February 2015

Plant litter decomposition is one of the most important ecosystem carbon flux processes in terrestrial ecosystems and is usually regarded as sensitive to climate change. The goal of the present study was to examine the effects of changing climate variables on litter decomposition. By synthesizing data from multiple terrestrial ecosystems, we quantified the response of the litter decomposition rate to the independent effects of warming, elevated carbon dioxide (CO2), elevated ozone (O3), and the combined effects of elevated CO2 + elevated O3. Across all case studies, warming increased the litter decomposition rate significantly by 4.4%, but this effect could be reduced as a result of the negatively significant effects of elevated CO2 and elevated CO2 + elevated O3. The combined effects of elevated CO2 + elevated O3 decreased the litter decomposition rate significantly, and the magnitude appeared to be higher than that of the elevated CO2 per se. Moreover, the study type (field versus laboratory), ecosystem type, and plant litter identity and functional traits (growth form and litter form) were all important moderators regulating the response of litter decomposition to climate warming and elevated CO2 and O3. Although litter decomposition rate may show a moderate change as a result of the effects of multiple changing climate variables, the process of litter decomposition would be strongly altered due to the differing mechanisms of the effects of each climate change variable, suggesting that the global carbon cycle and biogeochemistry could be substantially affected.
Alternative Ways to Quantify Sustained Remission: Applying the Continuity Rewarded Score and Patient Vector Graph
Authors: Jurgens Maud S. , Jacobs Johannes W. G. , Boers Maarten , van der Goes Marlies C. , van der Veen Maaike J. , Lafeber Floris P. J. G. , Bijlsma Johannes W. J. ,   on behalf of the Utrecht Arthritis Cohort study group
Published: February 2015

Objective

Although the Computer Assisted Management in Early Rheumatoid Arthritis Trial‐II (CAMERA‐II) showed favorable clinical effects in the most intensive methotrexate (MTX)–based strategy with prednisone (MTX ± prednisone) compared to that with placebo (MTX + placebo), this beneficial difference was only seen in 1 of the 3 analyses of remission. Our objective was to investigate whether the Continuity Rewarded (ConRew) score and a simple sum score would better reveal differences regarding remission between the 2 treatment arms of CAMERA‐II. Furthermore, we investigated whether the patient vector graph, which plots on patient level, would add visual information on remission compared to a conventional box plot only, which displays data on the group level.

Methods

The ConRew method, which awards continuous periods of remission with a higher score, was applied, in addition to a simple sum score of remission periods of 4 weeks. A patient vector graph was compared with box plots.

Results

Both the mean ± SD simple sum score and the ConRew score of remission were significantly higher (favorable) in the MTX + prednisone strategy group versus the MTX + placebo group, respectively: 9 ± 7 versus 12 ± 8; P = 0.003, and 23 ± 16 versus 17 ± 14; P = 0.004. The patient vector graphs show a visual pattern of more and longer periods of remission in the MTX + prednisone strategy and visually add information to the box plots.

Conclusion

The simple sum of remission periods, the ConRew score, and the patient vector graph add understanding and discrimination to the analysis of the remission outcome in CAMERA‐II.
Barriers to and Facilitators of a Career as a Physician‐Scientist Among Rheumatologists in the US
Authors: Ogdie Alexis , Shah Ami A. , Makris Una E. , Jiang Yihui , Nelson Amanda E. , Kim Alfred H. J. , Angeles‐Han Sheila T. , Castelino Flavia V. , Golding Amit , Muscal Eyal , Kahlenberg J. Michelle , Barg Frances K. ,   for the American College of Rheumatology Early Career Investigator Subcommittee of the Committee on Research
Published: February 2015

Objective

To determine perceived barriers to and facilitators of a career in rheumatology research, examine factors leading rheumatologists to leave an academic research career, and solicit ways to best support young physician‐scientists.

Methods

A web‐based survey was conducted among the domestic American College of Rheumatology (ACR) membership from January through March 2014. Inclusion criteria were ACR membership and an available e‐mail address. Non‐rheumatologists were excluded. The survey assessed demographics, research participation, barriers to and facilitators of a career in research, reasons for leaving a research career (when applicable), and ways in which the ACR could support junior investigators. Content analysis was used to extract relevant themes.

Results

Among 5,448 domestic ACR members, 502 responses were obtained (9.2% response rate). After exclusions (38 incomplete, 2 duplicates, 32 non‐rheumatologists), 430 responses were analyzed. Participants included fellows, young investigators, established investigators, mentors, clinicians, and those who previously pursued a research career but have chosen a different career path. Funding and mentoring were the most highly ranked barriers and facilitators. Protection from clinical and administrative duties, institutional support, and personal characteristics such as resilience and persistence were also ranked highly. The most commonly cited reasons for leaving an academic research career were difficulty obtaining funding and lack of department or division support.

Conclusion

This is the first study to examine barriers to and facilitators of a career in rheumatology research from the perspectives of diverse groups of rheumatologists. Knowledge of such barriers and facilitators may assist in designing interventions to support investigators during vulnerable points in their career development.
Cognitive Performance Scores for the Pediatric Automated Neuropsychological Assessment Metrics in Childhood‐Onset Systemic Lupus Erythematosus
Authors: Vega‐Fernandez Patricia , Vanderburgh White Shana , Zelko Frank , Ruth Natasha M. , Levy Deborah M. , Muscal Eyal , Klein‐Gitelman Marisa S. , Huber Adam M. , Tucker Lori B. , Roebuck‐Spencer Tresa , Ying Jun , Brunner Hermine I.
Published: February 2015

Objective

To develop and initially validate a global cognitive performance score (CPS) for the Pediatric Automated Neuropsychological Assessment Metrics (PedANAM) to serve as a screening tool of cognition in childhood lupus.

Methods

Patients (n = 166) completed the 9 subtests of the PedANAM battery, each of which provides 3 principal performance parameters (accuracy, mean reaction time for correct responses, and throughput). Cognitive ability was measured by formal neurocognitive testing or estimated by the Pediatric Perceived Cognitive Function Questionnaire‐43 to determine the presence or absence of neurocognitive dysfunction (NCD). A subset of the data was used to develop 4 candidate PedANAM‐CPS indices with supervised or unsupervised statistical approaches: PedANAM‐CPSUWA, i.e., unweighted averages of the accuracy scores of all PedANAM subtests; PedANAM‐CPSPCA, i.e., accuracy scores of all PedANAM subtests weighted through principal components analysis; PedANAM‐CPSlogit, i.e., algorithm derived from logistic models to estimate NCD status based on the accuracy scores of all of the PedANAM subtests; and PedANAM‐CPSmultiscore, i.e., algorithm derived from logistic models to estimate NCD status based on select PedANAM performance parameters. PedANAM‐CPS candidates were validated using the remaining data.

Results

PedANAM‐CPS indices were moderately correlated with each other (|r| > 0.65). All of the PedANAM‐CPS indices discriminated children by NCD status across data sets (P < 0.036). The PedANAM‐CPSmultiscore had the highest area under the receiver operating characteristic curve (AUC) across all data sets for identifying NCD status (AUC >0.74), followed by the PedANAM‐CPSlogit, the PedANAM‐CPSPCA, and the PedANAM‐CPSUWA, respectively.

Conclusion

Based on preliminary validation and considering ease of use, the PedANAM‐CPSmultiscore and the PedANAM‐CPSPCA appear to be best suited as global measures of PedANAM performance.
A Self‐Powered Angle Measurement Sensor Based on Triboelectric Nanogenerator
Authors: Wu Ying , Jing Qingshen , Chen Jun , Bai Peng , Bai Junjie , Zhu Guang , Su Yuanjie , Wang Zhong Lin
Published: February 2015

A self‐powered, sliding electrification based quasi‐static triboelectric sensor (QS‐TES) for detecting angle from rotating motion is reported. This innovative, cost‐effective, simply‐designed QS‐TES has a two‐dimensional planar structure, which consists of a rotator coated with four channel coded Cu foil material and a stator with a fluorinated ethylenepropylene film. On the basis of coupling effect between triboelectrification and electrostatic induction, the sensor generates electric output signals in response to mechanical rotating motion of an object mounted with the sensor. The sensor can read and remember the absolute angular position, angular velocity, and acceleration regardless being continuously monitored or segmented monitored. Under the rotation speed of 100 r min−1, the output voltage of the sensor reaches as high as 60 V. Given a relatively low threshold voltage of ±0.5 V for data processing, the robustness of the device is guaranteed. The resolution of the sensor is 22.5° and can be further improved by increasing the number of channels. Triggered by the output voltage signal, the rotating characteristics of the steering wheel can be real‐time monitored and mapped by being mounted to QS‐TES. This work not only demonstrates a new principle in the field of angular measurement but also greatly expands the applicability of triboelectric nanogenerator as self‐powered sensors.
Enantioselective Titanium‐Catalyzed Cyanation Reactions of Carbonyl Compounds
Authors: Pellissier Hélène
Published: February 2015

This review surveys the recent developments in enantioselective titanium‐catalyzed cyanation reactions of carbonyl compounds, covering the literature since the beginning of 2008. It well demonstrates that this reaction constitutes an important tool in organic synthesis, still attracting a considerable interest due to the potential use of enantiopure cyanohydrins as natural products and useful synthetic intermediates in the synthesis of biologically active molecules. Abbreviations: Ac: acetyl; Ar: aryl; BINOL: 1,1′‐bi‐2‐naphthol; BINOLAM: bis(diethylaminomethyl)‐1,1‘‐binaphthol; Bn: benzyl; Cy: cyclohexyl; DFT: density functional theory; DMAP: 4‐(dimethylamino)pyridine; ee: enantiomeric excess; Naph: naphthyl; r.t.: room temperature; salen: 1,2‐bis(salicylidenamino)ethane; TADDOL: α,α,α′,α′‐tetraphenyl‐2,2‐dimethyl‐1,3‐dioxolane‐4,5‐dimethanol; TEA: trimethylamine; THF: tetrahydrofuran; TMS: trimethylsilyl; Tol: tolyl.

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Practical improvements to autocovariance least‐squares
Authors: Zagrobelny Megan A. , Rawlings James B.
Published: February 2015

Identifying disturbance covariances from data is a critical step in estimator design and controller performance monitoring. Here, the autocovariance least‐squares (ALS) method for this identification is examined. For large industrial models with poorly observable states, the process noise covariance is high dimensional and the optimization problem is poorly conditioned. Also, weighting the least‐squares problem with the identity matrix does not provide minimum variance estimates. Here, ALS method to resolve these two challenges is modified. Poorly observable states using the singular value decomposition (SVD) of the observability matrix is identified and removed, thus decreasing the computational time. Using a new feasible‐generalized least‐squares estimator that approximates the optimal weighting from data, the variance of the estimates is significantly reduced. The new approach on industrial data sets provided by Praxair is successfully demonstrated. The disturbance model identified by the ALS method produces an estimator that performs optimally over a year‐long period. © 2015 American Institute of Chemical Engineers AIChE J, 61: 1840–1855, 2015
An infant with large fontanelles, aplasia cutis congenita, tessier facial cleft, polydactyly inversus, and toe syndactyly: A previously undescribed syndrome?
Authors: Jackson Jessica , Delk Paula , Farrow Emily , Griffith Christopher , Lah Melissa , Weaver David D.
Published: February 2015

We report on a 5‐month‐old female with large and widely spaced anterior and posterior fontanelles, aplasia cutis congenita, Tessier 3 oblique facial cleft, polydactyly, and syndactyly of toes. The polydactyly is unusual as an accessory finger is attached to the left fifth finger with mirrored, end‐to‐end fusion. We are naming this anomaly “polydactyly inversus.” The infant appears to have a previously unreported syndrome of unknown cause. © 2015 Wiley Periodicals, Inc.
Longitudinal polysomnographic findings in infantile Pompe disease
Authors: Kansagra Sujay , Austin Stephanie , DeArmey Stephanie , Kazi Zoheb , Kravitz Richard M , Kishnani Priya S
Published: February 2015

Infantile Pompe disease is a rare, metabolic disorder due to deficiency of the enzyme acid α‐glucosidase that degrades lysosomal glycogen. The deficiency leads to multisystem dysfunction. Neuromuscular weakness due to metabolic myopathy is present, which predisposes children to sleep‐disordered breathing. With the advent of enzyme replacement therapy (ERT), children are living longer, and there is a new natural history that is emerging. In a prior paper on our cohort of infantile Pompe disease patients, we reported a high incidence of both hypoventilation and obstructive sleep apnea (OSA). In this retrospective study, we analyzed longitudinal nocturnal polysomnography results from 10 patients with infantile‐onset Pompe disease, all of which were on enzyme replacement therapy for a mean of 34.9 months at the time of follow‐up study. Patients demonstrated relative stability in sleep disordered breathing, with a trend towards improvement in both OSA and central sleep apnea. ERT may help in the treatment of sleep apnea in this cohort. © 2015 Wiley Periodicals, Inc.
Grade II pilocytic astrocytoma in a 3‐month‐old patient with encephalocraniocutaneous lipomatosis (ECCL): Case report and literature review of low grade gliomas in ECCL
Authors: Bieser Sarah , Reis Martin , Guzman Miguel , Gauvain Karen , Elbabaa Samer , Braddock Stephen R. , Abdel‐Baki Mohamed S.
Published: February 2015

Encephalocraniocutaneous lipomatosis (ECCL) is a rare congenital syndrome with an unknown etiology. Since 1970, around 60 cases have been reported in English literature. ECCL is usually classified by cutaneous lesions and non‐progressive intracranial or spinal lipomas; however three cases of ECCL associated with low grade glioma (LGG) have been described. We report on the fourth case of LGG in a patient with ECCL; a grade II pilocytic astrocytoma with pilomyxoid features in a 3‐month‐old male, the youngest in literature. © 2015 Wiley Periodicals, Inc.
ECEL1 mutation causes fetal arthrogryposis multiplex congenita
Authors: Dohrn N. , Le V.Q. , Petersen A. , Skovbo P. , Pedersen I.S. , Ernst A. , Krarup H. , Petersen M.B.
Published: February 2015

Arthrogryposis multiplex congenita (AMC) is a descriptor for the clinical finding of congenital fixation of multiple joints. We present a consanguineous healthy couple with two pregnancies described with AMC due to characteristic findings on ultrasonography of fixated knee extension and reduced fetal movement at the gestational age of 13 weeks + 2 days and 12 weeks + 4 days. Both pregnancies were terminated and postmortem examinations were performed. The postmortem examinations confirmed AMC and suggested a diagnosis of centronuclear myopathy (CNM) due to characteristic histological findings in muscle biopsies. Whole exome sequencing (WES) was performed on all four individuals and the outcome was filtered by application of multiple filtration parameters satisfying a recessive inheritance pattern. Only one gene, ECEL1, was predicted damaging and had previously been associated with neuromuscular disease or AMC. The variant found ECEL1 is a missense mutation in a highly conserved residue and was predicted pathogenic by prediction software. The finding expands the molecular basis of congenital contractures and the phenotypic spectrum of ECEL1 mutations. The histological pattern suggestive of CNM in the fetuses can expand the spectrum of genes causing CNM, as we propose that mutations in ECEL1 can cause CNM or a condition similar to this. Further investigation of this is needed and we advocate that future patients with similar clinical presentation or proven ECEL1 mutations are examined with muscle biopsy. Secondly, this study illustrates the great potential of the clinical application of WES in couples with recurrent abortions or stillborn neonates. © 2015 Wiley Periodicals, Inc.
Direct Conversion of Bulk Metals to Size‐Tailored, Monodisperse Spherical Non‐Coinage‐Metal Nanocrystals
Authors: Luo Rui‐Chun , Li Chao , Du Xi‐Wen , Yang Jing
Published: February 2015

Monodisperse non‐noble metal nanocrystals (NCs) that are highly uniform in shapes and particle size are much desired in various advanced applications, and are commonly prepared by either thermal decomposition or reduction, where reactive organometallic precursors or/and strong reducing agents are mandatory; however, these are usually toxic, costly, or suffer a lack of availability. Bulk Group 12 metals can now be converted into ligand‐protected, highly crystalline, monodisperse spherical metal NCs with precisely controlled sizes without using any precursors and reducers. The method is based on low‐power NIR‐laser‐induced size‐selective layer‐by‐layer surface vaporization. The monodisperse Cd NCs show pronounced deep‐UV (DUV) localized surface plasmon resonance making them highly competitive DUV‐plasmonic materials. This approach will promote appreciably the emergence of a wide range of monodisperse technically important non‐coinage metal NCs with compelling functionalities.
OH‐dirigierte Alkinylierung von 2‐Vinylphenolen mit Ethinylbenziodoxolonen: ein schneller Zugang zu terminalen 1,3‐Eninen
Authors: Finkbeiner Peter , Kloeckner Ulrich , Nachtsheim Boris J.
Published: February 2015

Wir berichten über die Entwicklung der ersten direkten Alkinylierung von 2‐Vinylphenolen. Das optimierte hypervalente Iodreagens TIPS‐EBX* ermöglicht zusammen mit [(Cp*RhCl2)2] als Übergangsmetallkatalysator die Konstruktion einer Vielzahl von hochsubstituierten 1,3‐Eninen in Ausbeuten von bis zu 98 %. Diese neue C‐H‐aktivierende Methode zeichnet sich durch eine exzellente Chemoselektivität und reine (Z)‐Stereoselektivität aus, ist dabei besonders mild und toleriert viele funktionelle Gruppen. Des Weiteren wurden Modifikationen der so erhaltenen 1,3‐Enine untersucht. Unseres Wissens ist diese Reaktion das erste Beispiel einer OH‐dirigierten C‐H‐Alkinylierung mit hypervalenten Iodreagentien.
Preparation and characterization of a novel positively charged nanofiltration membrane based on polysulfone
Authors: Akbari Ahmad , Solymani Hosna , Rostami Sayed Majid Mojallali
Published: February 2015

The goal of this study was to prepare positively charged nanofiltration (NF) membranes to remove cations from aqueous solutions. A composite NF membrane was fabricated by the modification of a polysulfone ultrafiltration support. The active top layer was formed by the interfacial crosslinking polymerization of poly(ethylene imine) (PEI) with p‐xylene dichloride (XDC). Then, it was quaternized by methyl iodide (MI) to form a perpetually positively charged layer. The chemical and morphological changes of the membrane surfaces were studied by Fourier transform infrared spectroscopy, scanning electron microscopy (SEM), and atomic force microscopy. To optimize the membrane operation, the PEI solution concentration, PEI coating time, XDC concentration, crosslinking time, and MI concentration were optimized. Consequently, high water flux (5.4 L m−2 h−1 bar−1) and CaCl2 rejection (94%) values were obtained for the composite membranes at 4 bars and 30°C. The rejections of the NF membrane for different salt solutions, obtained from pH testing, followed the order Na2SO4 < MgSO4 < NaCl < CaCl2. The molecular weight cutoff was calculated by the retention of poly(ethylene glycol) solutions with different molecular weights, and finally, the stoke radius was calculated as 1.47 nm. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015, 132, 41988.
Apoptotic Mediators are Upregulated in the Skeletal Muscle of Chronic/Progressive Mouse Model of Parkinson's Disease
Authors: Erekat Nour S.
Published: February 2015

Apoptosis has been implicated in the pathogenesis of Parkinson disease (PD). Parkinson disease is characterized by skeletal muscle abnormalities. The aim of this study is to illustrate the impact of PD induction on the expression of apoptotic mediators. Twenty normal albino mice were randomly selected and equally divided in control and PD groups. Chronic Parkinsonism was induced in the PD group using 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine and probenecid (MPTP/p). After that, samples from gastrocnemius muscles were evaluated by immunohistochemistry to examine the expression of p53 and active caspase‐3 in the two groups of animals. P53 and active caspase‐3 expression was significantly higher in gastrocnemius skeletal muscle in PD mice compared with that in the control mice (P value <0.01). Furthermore, we show PD gastrocnemius muscle atrophy measured by significant reduction (P < 0.01) in the muscle fiber cross‐sectional area. Thus, our present data suggest that PD induction increased the expression of the apoptotic mediators p53 and active caspase‐3 in gastrocnemius muscle, indicating the induction of apoptosis, which was correlative with gastrocnemius muscle atrophy subsequent to the induction of PD. Anat Rec, 298:1472–1478, 2015. © 2015 Wiley Periodicals, Inc.
Brief Report: Expression of Interferon‐γ Receptor Genes in Peripheral Blood Mononuclear Cells Is Associated With Rheumatoid Arthritis and Its Radiographic Severity in African Americans
Authors: Tang Qi , Danila Maria I. , Cui Xiangqin , Parks Lauren , Baker Brandi J. , Reynolds Richard J. , Raman Chander , Wanseck Keith C. , Redden David T. , Johnson Martin R. ,   CLEAR Investigators, Bridges S. Louis
Published: February 2015

Objective

The factors responsible for radiographic severity in African American patients with rheumatoid arthritis (RA) are poorly understood. We sought to identify genes whose expression in peripheral blood mononuclear cells is associated with radiographic severity in RA.

Methods

In the first phase of the study, we performed real‐time quantitative polymerase chain reaction to analyze the expression of 182 candidate genes in 40 African American RA patients with extremes of radiographic damage (low versus high radiographic scores) and disease duration (≤2 years versus >2 years) and 20 healthy African American control subjects; the genes were selected based on plausible immune pathways. In the second phase, we analyzed the expression of the genes that were shown to be significantly associated with radiographic scores in 576 African American patients with RA and 51 African American control subjects who had not been studied previously, accounting for autoantibody status and disease duration.

Results

We observed significant differences in IFNGR1 expression between patients with RA and control subjects (adjusted P [Padj] = 6 × 10−14) and in IFNGR2 expression between RA patients with erosions and those with no erosions (Padj = 0.01 by Wilcoxon's rank sum test). We also observed significant correlations between IFNGR2 expression and radiographic scores (Padj = 0.03 for erosions, Padj = 0.04 for joint space narrowing, and Padj = 0.03 for total radiographic score [zero‐inflated negative binomial regression model]) and annualized progression rate (Padj = 0.0024 by Spearman's correlation analysis).

Conclusion

These findings have important implications with respect to the role of interferon‐γ (IFNγ) in the pathogenesis of RA and may lead to identification of a biomarker for radiographic damage. Additional studies are needed to define the cell subsets responsible for the association of IFNγ receptor gene expression with radiographic findings, which downstream mechanisms are involved, and generalizability to other RA populations.
The Rheumatoid Arthritis Risk Gene LBH Regulates Growth in Fibroblast‐like Synoviocytes
Authors: Ekwall Anna‐Karin H. , Whitaker John W. , Hammaker Deepa , Bugbee William D. , Wang Wei , Firestein Gary S.
Published: February 2015

Objective

Fibroblast‐like synoviocytes (FLS) are key players in the synovial pathology of rheumatoid arthritis (RA). Currently, there is no treatment that specifically targets these aggressive cells. By combining 3 different “omics” data sets, i.e., 1) risk genes in RA, 2) differentially expressed genes, and 3) differential DNA methylation in RA versus osteoarthritis (OA) FLS, we identified LBH (limb bud and heart development) as a candidate gene in RA. The present study was undertaken to define the role of this gene in FLS.

Methods

Synovial tissue specimens from RA and OA patients were collected at the time of joint replacement surgery. LBH expression was silenced using small interfering RNA or overexpressed using an LBH expression vector in primary FLS. Gene expression profiles were determined by microarray and assessed using Ingenuity Pathway Analysis. Effects of modified LBH expression were investigated in functional assays.

Results

LBH was expressed in the synovial lining layer in patients with RA. Transforming growth factor β1 significantly increased LBH expression in primary FLS, and platelet‐derived growth factor BB decreased it. Pathway analysis of the transcriptome of LBH‐deficient FLS compared to control FLS identified “cellular growth and proliferation” as the most significantly enriched pathway. In growth assays, LBH deficiency increased FLS proliferation. Conversely, LBH overexpression significantly inhibited cell growth. Cell cycle analysis demonstrated a marked increase in cells entering the cell cycle in LBH‐deficient FLS compared to controls. LBH did not alter apoptosis.

Conclusion

LBH is a candidate gene for synovial pathology in RA. It is regulated by growth factors and modulates cell growth in primary FLS. Our data suggest a novel mechanism for synovial intimal hyperplasia and joint damage in RA.
Endothelin Receptor Blockade Ameliorates Vascular Fragility in Endothelial Cell–Specific Fli‐1–Knockout Mice by Increasing Fli‐1 DNA Binding Ability
Authors: Akamata Kaname , Asano Yoshihide , Yamashita Takashi , Noda Shinji , Taniguchi Takashi , Takahashi Takehiro , Ichimura Yohei , Toyama Tetsuo , Trojanowska Maria , Sato Shinichi
Published: February 2015

Objective

It is generally accepted that blockade of endothelin receptors has potentially beneficial effects on vasculopathy associated with systemic sclerosis (SSc). The aim of this study was to clarify the molecular mechanism underlying these effects using endothelial cell–specific Fli‐1–knockout (Fli‐1 ECKO) mice, an animal model of SSc vasculopathy.

Methods

Levels of messenger RNA for target genes and the expression and phosphorylation levels of target proteins were determined in human and murine dermal microvascular endothelial cells by real‐time quantitative reverse transcription–polymerase chain reaction and immunoblotting, respectively. The binding of Fli‐1 to the target gene promoters was evaluated using chromatin immunoprecipitation. Expression levels of Fli‐1 and α‐smooth muscle actin in murine skin were evaluated using immunohistochemistry. Vascular structure and permeability were evaluated in mice injected with fluorescein isothiocyanate–dextran and Evans blue dye, respectively.

Results

In human dermal microvascular endothelial cells, endothelin 1 induced phosphorylation of Fli‐1 at Thr312 through the sequential activation of c‐Abl and protein kinase Cδ, leading to a decrease in Fli‐1 protein levels as well as a decrease in binding of Fli‐1 to the target gene promoters, whereas bosentan treatment reversed those effects. In Fli‐1 ECKO mice, 4 weeks of treatment with bosentan increased endothelial Fli‐1 expression, resulting in vascular stabilization and the restoration of impaired leaky vessels.

Conclusion

The vascular fragility of Fli‐1 ECKO mice was improved by bosentan through the normalization of Fli‐1 protein levels and activity in endothelial cells, which may explain, in part, the mechanism underlying the beneficial effects of endothelin receptor blockade on SSc vasculopathy.
Risk of Hospitalized Infection Among Rheumatoid Arthritis Patients Concurrently Treated With a Biologic Agent and Denosumab
Authors: Curtis Jeffrey R. , Xie Fenglong , Yun Huifeng , Saag Kenneth G. , Chen Lang , Delzell Elizabeth
Published: February 2015

Objective

Denosumab is a biologic agent used to treat osteoporosis. Its safety profile given concurrently with biologic drugs for rheumatoid arthritis (RA) has not been well studied. We evaluated hospitalized infections among patients treated with biologic agents for RA who initiated denosumab or zoledronic acid (ZA), a parenteral bisphosphonate without known associations with infection. We hypothesized that the rate of hospitalized infection with denosumab would be noninferior to ZA.

Methods

We identified RA patients enrolled in Medicare in 2006–2012 treated with biologic agents who initiated denosumab or ZA. Cox proportional hazards models compared the risk for hospitalized infection, comparing denosumab users to ZA users and adjusting for potentially confounding factors. A noninferiority margin was specified a priori to demonstrate that denosumab had no greater infection risk than ZA if the upper bound of the 95% confidence interval (95% CI) of the hazard ratio (HR) was <1.5.

Results

Eligible RA patients receiving biologic agents initiated denosumab (n = 1,354) or ZA (n = 4,460). Characteristics of the denosumab users were as follows: mean ± SD age 73.0 ± 8.9, 98.2% women, with a majority receiving infliximab (35.7%) or abatacept (18.6%). Denosumab users had a higher prevalence of prior infections (11.5% hospitalized and 48.3% outpatient) and infection‐related risk factors. The crude rate of hospitalized infections for denosumab (14.9/100 person‐years [95% CI 12.2–18.1]) was comparable to that for ZA (13.9/100 person‐years [95% CI 12.5–15.4]). After adjustment, the HR of hospitalized infection for denosumab users was noninferior to that for ZA users (HR 0.89 [95% CI 0.69–1.15]).

Conclusion

The rate of hospitalized infection among RA patients receiving denosumab concurrently with biologic agents for RA was not increased compared to those receiving zoledronate.
CCN1 (Cyr61) Is Overexpressed in Human Osteoarthritic Cartilage and Inhibits ADAMTS‐4 (Aggrecanase 1) Activity
Authors: Chijiiwa Miyuki , Mochizuki Satsuki , Kimura Tokuhiro , Abe Hitoshi , Tanaka Yukie , Fujii Yutaka , Shimizu Hidenori , Enomoto Hiroyuki , Toyama Yoshiaki , Okada Yasunori
Published: February 2015

Objective

ADAMTS‐4, also called aggrecanase 1, is considered to play a key role in aggrecan degradation in human osteoarthritic (OA) cartilage, but information about regulators of ADAMTS‐4 aggrecanase activity remains limited. We undertook this study to search for molecules that modulate ADAMTS‐4 activity.

Methods

Molecules copurified with ADAMTS‐4 from ADAMTS‐4–transfected chondrocytic cells were sequenced by nanoscale liquid chromatography tandem mass spectrometry. Binding activity was determined by immunoprecipitation and solid‐phase binding assay. Effects on ADAMTS‐4 activity were examined by aggrecan digestion assay. Expression of the binding molecule in OA cartilage and chondrocytes was examined by immunohistochemistry and reverse transcription–polymerase chain reaction.

Results

We identified CCN1 (Cyr61) as an ADAMTS‐4–binding protein and showed specific binding to the ADAMTS‐4 cysteine‐rich domain. Aggrecanase activity of ADAMTS‐4 was inhibited by interaction with CCN1. Expression of messenger RNA for CCN1 was significantly higher in human OA cartilage than in normal cartilage. CCN1 was immunolocalized to chondrocytes in OA cartilage, showing direct correlations of immunoreactivity with the Mankin score of cartilage lesions and chondrocyte cloning. CCN1 and ADAMTS‐4 were commonly coexpressed in clustered chondrocytes. CCN1 expression in OA chondrocytes was down‐regulated by interleukin‐1α (IL‐1α) and up‐regulated by transforming growth factor β (TGFβ). ADAMTS‐4 expression was induced by treatment with IL‐1α or TGFβ, but aggrecanase activity was detected only under stimulation with IL‐1α. TGFβ‐treated chondrocytes exhibited aggrecanase activity when CCN1 expression was knocked down.

Conclusion

Our findings provide the first evidence that CCN1 suppresses ADAMTS‐4 activity and that CCN1 overexpression is directly correlated with chondrocyte cloning in OA cartilage. Our results suggest that the TGFβ/CCN1 axis plays a role in chondrocyte cluster formation through inhibition of ADAMTS‐4.