bluuebunny/crossref_metadata_2025 huggingface dataset:
An internal promoter underlies the difference in disease severity between N- and C-terminal truncation mutations of Titin in zebrafish
Authors: Zou Jun , Tran Diana , Baalbaki Mai , Tang Ling Fung , Poon Annie , Pelonero Angelo , Titus Erron W , Yuan Christiana , Shi Chenxu , Patchava Shruthi , Halper Elizabeth , Garg Jasmine , Movsesyan Irina , Yin Chaoying , Wu Roland , Wilsbacher Lisa D , Liu Jiandong , Hager Ronald L , Coughlin Shaun R , Jinek Martin , Pullinger Clive R , Kane John P , Hart Daniel O , Kwok Pui-Yan , Deo Rahul C
Published: October 2015

Truncating mutations in the giant sarcomeric protein Titin result in dilated cardiomyopathy and skeletal myopathy. The most severely affected dilated cardiomyopathy patients harbor Titin truncations in the C-terminal two-thirds of the protein, suggesting that mutation position might influence disease mechanism. Using CRISPR/Cas9 technology, we generated six zebrafish lines with Titin truncations in the N-terminal and C-terminal regions. Although all exons were constitutive, C-terminal mutations caused severe myopathy whereas N-terminal mutations demonstrated mild phenotypes. Surprisingly, neither mutation type acted as a dominant negative. Instead, we found a conserved internal promoter at the precise position where divergence in disease severity occurs, with the resulting protein product partially rescuing N-terminal truncations. In addition to its clinical implications, our work may shed light on a long-standing mystery regarding the architecture of the sarcomere.
Headache in Chiari malformation: A distinct clinical entity?
Authors: Kesler Roman , Mendizabal Jorge E
Published: October 2015

A relatively common group of developmental anomalies of the posterior fossa and its contents make up the Chiari malformations. The most common of these anomalies are the Chiari malformations type I and type II. Many patients with these defects are asymptomatic, but many of them suffer from headaches. Although the prevalence of common primary headache disorders in patients with Chiari malformations is similar to that of the general population, a particular type of occipital headaches occurs more frequently in patients with a Chiari malformation. In the two patients described in the illustrative case presentations, the major complaint was headache. Both had Chiari malformation type I diagnosed. Chiari malformation should be considered in the differential diagnosis of patients who complain of exertional headache. Exertional headaches or worsening of pain during Valsalva's maneuver should prompt clinical suspicion of an underlying intracranial lesion and warrants further evaluation by appropriate neuroimaging studies.
Childhood obesity: Addressing the issue
Authors: Rudloff Loretta M , Feldmann Emily
Published: October 2015

Childhood obesity is a major health issue in pediatric practice. The old idea that "a chubby baby is a healthy baby" is not necessarily the case. Social stigmas and recidivism surrounding obesity make addressing families and their children difficult; however, with early intervention, treatment can be successful. Prevention of obesity with health maintenance surveillance and family-focused behavior modification is the foundation for a healthy lifestyle and may prove the most effective way of avoiding long-term obesity-related morbidity.
Pancreatic cystic neoplasms
Authors: Anderson Donald J , Matson Scott
Published: October 2015

Cystic neoplasms of the pancreas are relatively rare. This makes the evaluation and treatment of these tumors widely varied. The authors describe a patient who came to our hospital with complaints of abdominal pain, but no other related symptoms. Diagnostic evaluation of the patient yielded normal results, except for inspection and palpation of the abdominal areas, which revealed a large epigastric mass; this finding was confirmed subsequently by ultrasonographic examination and computed tomographic scanning. This article presents the case and reviews the literature, specifically related to diagnosis and current treatments.
Electron acceleration by parallel and perpendicular electric fields during magnetic reconnection without guide field
Authors: Bessho N. , Chen L.‐J. , Germaschewski K. , Bhattacharjee A.
Published: October 2015

Electron acceleration due to the electric field parallel to the background magnetic field during magnetic reconnection with no guide field is investigated by theory and two‐dimensional electromagnetic particle‐in‐cell simulations and compared with acceleration due to the electric field perpendicular to the magnetic field. The magnitude of the parallel electric potential shows dependence on the ratio of the plasma frequency to the electron cyclotron frequency as (ωpe/Ωe)−2 and on the background plasma density as
. In the Earth's magnetotail, the parameter ωpe/Ωe∼9 and the background (lobe) density can be of the order of 0.01 cm−3, and it is expected that the parallel electric potential is not large enough to accelerate electrons up to 100 keV. Therefore, we must consider the effect of the perpendicular electric field to account for electron energization in excess of 100 keV in the Earth's magnetotail. Trajectories for high‐energy electrons are traced in a simulation to demonstrate that acceleration due to the perpendicular electric field in the diffusion region is the dominant acceleration mechanism, rather than acceleration due to the parallel electric fields in the exhaust regions. For energetic electrons accelerated near the X line due to the perpendicular electric field, pitch angle scattering converts the perpendicular momentum to the parallel momentum. On the other hand, for passing electrons that are mainly accelerated by the parallel electric field, pitch angle scattering converting the parallel momentum to the perpendicular momentum occurs. In this way, particle acceleration and pitch angle scattering will generate heated electrons in the exhaust regions.
Arctic pathways of Pacific Water: Arctic Ocean Model Intercomparison experiments
Authors: Aksenov Yevgeny , Karcher Michael , Proshutinsky Andrey , Gerdes Rüdiger , de Cuevas Beverly , Golubeva Elena , Kauker Frank , Nguyen An T. , Platov Gennady A. , Wadley Martin , Watanabe Eiji , Coward Andrew C. , Nurser A. J. George
Published: October 2015

Pacific Water (PW) enters the Arctic Ocean through Bering Strait and brings in heat, fresh water, and nutrients from the northern Bering Sea. The circulation of PW in the central Arctic Ocean is only partially understood due to the lack of observations. In this paper, pathways of PW are investigated using simulations with six state‐of‐the art regional and global Ocean General Circulation Models (OGCMs). In the simulations, PW is tracked by a passive tracer, released in Bering Strait. Simulated PW spreads from the Bering Strait region in three major branches. One of them starts in the Barrow Canyon, bringing PW along the continental slope of Alaska into the Canadian Straits and then into Baffin Bay. The second begins in the vicinity of the Herald Canyon and transports PW along the continental slope of the East Siberian Sea into the Transpolar Drift, and then through Fram Strait and the Greenland Sea. The third branch begins near the Herald Shoal and the central Chukchi shelf and brings PW into the Beaufort Gyre. In the models, the wind, acting via Ekman pumping, drives the seasonal and interannual variability of PW in the Canadian Basin of the Arctic Ocean. The wind affects the simulated PW pathways by changing the vertical shear of the relative vorticity of the ocean flow in the Canada Basin.
Development of a Dual‐Energy Computed Tomography Scoring System for Measurement of Urate Deposition in Gout
Authors: Bayat Sara , Aati Opetaia , Rech Jürgen , Sapsford Mark , Cavallaro Alexander , Lell Michael , Araujo Elizabeth , Petsch Christina , Stamp Lisa K. , Schett Georg , Manger Bernhard , Dalbeth Nicola
Published: October 2015

Objective

To develop a semiquantitative dual‐energy computed tomography (DECT) scoring system for measurement of urate deposition in gout.

Methods

Following a structured review of images, a semiquantitative DECT urate scoring method for foot/ankle scans was developed for testing. This method included 4 regions, each scored 0–3, with a maximum total DECT urate score of 12. DECT scans from 224 patients (182 with gout, 42 without gout) were scored by 2 independent readers. Automated urate volumes were also measured. Paired scans from 8 patients receiving pegloticase were analyzed, and a timing exercise was undertaken. The properties of the DECT urate score were analyzed according to the Outcome Measures in Rheumatology (OMERACT) filter.

Results

The interreader intraclass correlation coefficient (95% confidence interval) for the DECT urate score was 0.98 (0.97–0.98). All scored regions contributed to the total DECT urate score. DECT urate scores and volumes were highly correlated (r = 0.91, P < 0.0001). Both DECT urate scores and volumes discriminated between gout and nongout control participants and between the tophaceous gout, nontophaceous gout, and control groups. Compared with urate volume, the DECT urate score had greater ability to discriminate between responders and nonresponders to pegloticase therapy (P < 0.001 for DECT urate score and P > 0.05 for volume). The mean ± SD time required for the DECT urate score was 121 ± 2 seconds and for urate volume was 240 ± 2 seconds (P = 2 × 10−31).

Conclusion

We have developed a novel semiquantitative DECT scoring method for measurement of urate deposition in the feet/ankles. This method fulfills many aspects of the OMERACT filter.
Development of a Novel Renal Activity Index of Lupus Nephritis in Children and Young Adults
Authors: Brunner Hermine I. , Bennett Michael R. , Abulaban Khalid , Klein‐Gitelman Marisa S. , O'Neil Kathleen M. , Tucker Lori , Ardoin Stacy P. , Rouster‐Stevens Kelly A. , Onel Karen B. , Singer Nora G. , Anne Eberhard B. , Jung Lawrence K. , Imundo Lisa , Wright Tracey B. , Witte David , Rovin Brad H. , Ying Jun , Devarajan Prasad
Published: October 2015

Objective

Noninvasive estimation of the degree of inflammation seen on kidney biopsy with lupus nephritis (LN) remains difficult. The objective of this study was to develop a Renal Activity Index for Lupus (RAIL) that, based solely on laboratory measures, accurately reflects histologic LN activity.

Methods

We assayed traditional LN laboratory tests and 16 urine biomarkers (UBMs) in children (n = 47) at the time of kidney biopsy. Histologic LN activity was measured by the National Institutes of Health activity index (NIH‐AI) and the tubulointerstitial activity index (TIAI). High LN‐activity status (versus moderate/low) was defined as NIH‐AI scores >10 (versus ≤10) or TIAI scores >5 (versus ≤5). RAIL algorithms that predicted LN‐activity status for both NIH‐AI and TIAI were derived by stepwise multivariate logistic regression, considering traditional biomarkers and UBMs as candidate components. The accuracy of the RAIL for discriminating by LN‐activity status was determined.

Results

The differential excretion of 6 UBMs (neutrophil gelatinase–associated lipocalin, monocyte chemotactic protein 1, ceruloplasmin, adiponectin, hemopexin, and kidney injury molecule 1) standardized by urine creatinine was considered in the RAIL. These UBMs predicted LN‐activity (NIH‐AI) status with >92% accuracy and LN‐activity (TIAI) status with >80% accuracy. RAIL accuracy was minimally influenced by concomitant LN damage. Accuracies between 71% and 85% were achieved without standardization of the UBMs. The strength of these UBMs to reflect LN‐activity status was confirmed by principal component and linear discriminant analyses.

Conclusion

The RAIL is a robust and highly accurate noninvasive measure of LN activity. The measurement properties of the RAIL, which reflect the degree of inflammatory changes as seen on kidney biopsy, will require independent validation.
Relationship Between Baseline and Early Changes in C‐Reactive Protein and Interleukin‐6 Levels and Clinical Response to Tocilizumab in Rheumatoid Arthritis
Authors: Wang Jianmei , Devenport Jenny , Low Jason M. , Yu Dale , Hitraya Elena
Published: October 2015

Objective

To clarify the relevance of measuring interleukin‐6 (IL‐6) and C‐reactive protein (CRP) levels in order to predict clinical response to tocilizumab (TCZ) in rheumatoid arthritis patients.

Methods

In a pooled, post hoc analysis of 5 pivotal trials of TCZ, we examined the distributions of baseline serum concentrations of IL‐6 and CRP, stratified by randomized treatment group, and week 24 Disease Activity Score in 28 joints (DAS28) status (DAS28 <2.6 versus DAS28 ≥2.6). Relationships between early biomarker changes and later changes in DAS28 scores were evaluated using Spearman's correlations and scatterplots. Finally, percentage changes from baseline in IL‐6 and CRP levels were evaluated.

Results

Distributions of baseline IL‐6 and CRP levels were similar for patients who achieved DAS28 scores <2.6 within 6 months of TCZ initiation and those who did not. Correlations between early changes in these 2 biomarkers and change in DAS28 scores were low (rho < 0.3 for all). Mean percentage increases from baseline in IL‐6 concentrations were observed in all treatment groups (highest in the 8 mg/kg dose group); mean percentage decreases in CRP concentrations were greater at week 2 and at all visits for the 8 mg/kg dose group.

Conclusion

Baseline serum concentrations of IL‐6 and CRP may not be predictive of clinical outcomes after TCZ treatment. Data demonstrate the efficacy of TCZ in patients across a broad range of baseline serum IL‐6 and CRP concentrations. Similarly, changes in these biomarkers after TCZ dosing are expected and may or may not correspond to changes in other clinical signs and symptoms. These results complement previous reports describing the complex interactions among biomarker changes, other therapeutic mechanisms of action, and clinical outcomes.
3D Interconnected Networks of Graphene and Flower‐Like Cobalt Oxide Microstructures with Improved Lithium Storage
Authors: Binitha Gangaja , Ashish Ajithan G. , Ramasubramonian Deivanayagam , Manikandan Palanisamy , Shaijumon Manikoth M.
Published: October 2015

A reduced graphene oxide (rGO)‐based 3D architecture with unique flower‐like cobalt oxide microstructures, uniformly embedded in a graphene hydrogel matrix (CoO–GHG) resulting in completely interconnected structures, is fabricated. The self‐assembled 3D architecture with improved porosity and conductivity exhibits excellent electrochemical performance as an anode for lithium‐ion batteries, with high reversible specific capacity (1010 mAh g−1 over 100 cycles), a long cycling lifetime, and good rate capability. The exceptional performance results from the unique 3D structure of the hybrid CoO–GHG, with highly dispersed flower‐like CoO on a conducting graphene network, providing more accessible surface sites for large lithiation/delithiation with minimum volume expansion and imparting good conductivity and short diffusion length for Li+ ions. Electrochemical studies demonstrate that these 3D architectured electrodes are promising as efficient anodes for high‐performance lithium‐ion battery devices.
Chemoselective Reductive Deoxygenation and Reduction of α‐Keto Amides by using a Palladium Catalyst
Authors: Mamillapalli N. Chary , Sekar Govindasamy
Published: October 2015

A palladium catalyst is used to synthesize 2,N‐diphenylacetamides and α‐hydroxy amides from readily available α‐keto amides by chemoselective reductive deoxygenation and chemoselective reduction using polymethylhydrosiloxane (PMHS). This methodology has the important advantage in that, just by changing the reaction solvent and temperature, the reaction can be switched from reductive deoxygenation to reduction of α‐keto amides. Using this protocol, several biologically important 2,N‐diphenylacetamide derivatives and α‐hydroxy amides were synthesized.

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Copy number variants in association with type 1 collagenopathy: Atypical osteogenesis imperfecta
Authors: Balasubramanian Meena , Cartwright Ashley , Smith Kath , Arundel Paul , Bishop Nicholas J.
Published: October 2015

We report a sibling‐pair and a 4‐year old child from two families with an atypical presentation in Osteogenesis imperfecta (OI). In the sib‐pair, the older sibling initially came to medical attention due to a fracture history (Patient 1) and she was shown to have a COL1A2 mutation. In addition, she also had developmental delay, facial dysmorphism, and a history of frequent infections which led to a search for an alternate diagnosis. ArrayCGH revealed a 4.3 Mb duplication on chromosome 19q13.42q13.43, which was confirmed by FISH analysis. On further familial analysis, the younger sibling who had no previous fracture history was also found to have the COL1A2 mutation and tested positive for the 19q13.42q13.43 duplication (Patient 2). The 19q13 duplication appears to be the cause of intellectual disability in these siblings but given that this is a chromosomal duplication, it is still possible that there is an as yet unidentified cause that may account for the combined phenotype in this family. Patient 3 was a 4‐year old child presenting with a femoral fracture, blue sclerae, developmental delay, and joint hypermobility. Genetic analyses confirmed a COL1A2 mutation but also revealed an 8.8 Mb deletion of 11q24.2q25, confirmed by G‐band chromosome analysis. We discuss the differing phenotypes in patients presenting with atypical OI and stress the need to consider ancillary investigations in individuals presenting with heterogeneous phenotypic symptoms, not entirely attributable to OI. © 2015 Wiley Periodicals, Inc.
“Sequenzanalyse” konjugierter, mikroporöser Polymere (CMPs): Defektstrukturen eines Tetrakis(4‐ethinylphenyl)stannan‐Netzwerks
Authors: Uptmoor Andrea C. , Freudenberg Jan , Schwäbel S. Thimon , Paulus Fabian , Rominger Frank , Hinkel Felix , Bunz Uwe H. F.
Published: October 2015

Zwei konjugierte, mikroporöse Polymere (CMPs) auf Basis von Tetrakis(4‐ethinylphenyl)stannan als formaler Wiederholungseinheit wurden synthetisiert und hinsichtlich ihrer BET‐Oberflächen sowie ihrer thermischen Eigenschaften untersucht. Wir beschreiben zum ersten Mal eine direkte Methode zur Evaluierung der Molekülstruktur der organischen Verstrebungen, welche die Zinnzentren in den CMPs miteinander verbinden. Die gezielte und milde Zersetzung der Zinn‐CMPs erfolgt durch die Einwirkung von Chloressigsäure, wobei die Zinn‐Kohlenstoff‐Bindungen gespalten und die überraschend diversen Strukturen der organischen Brücken gezielt evaluiert werden können.
Velocity of a Molecule Evaporated from a Water Nanodroplet: Maxwell–Boltzmann Statistics versus Non‐Ergodic Events
Authors: Abdoul‐Carime Hassan , Berthias Francis , Feketeová Linda , Marciante Mathieu , Calvo Florent , Forquet Valérian , Chermette Henry , Farizon Bernadette , Farizon Michel , Märk Tilmann D.
Published: October 2015

The velocity of a molecule evaporated from a mass‐selected protonated water nanodroplet is measured by velocity map imaging in combination with a recently developed mass spectrometry technique. The measured velocity distributions allow probing statistical energy redistribution in ultimately small water nanodroplets after ultrafast electronic excitation. As the droplet size increases, the velocity distribution rapidly approaches the behavior expected for macroscopic droplets. However, a distinct high‐velocity contribution provides evidence of molecular evaporation before complete energy redistribution, corresponding to non‐ergodic events.
Iron‐Catalyzed CαH Oxidation of Tertiary, Aliphatic Amines to Amides under Mild Conditions
Authors: Legacy Christopher J. , Wang Anqi , O'Day Brian J. , Emmert Marion H.
Published: October 2015

De novo syntheses of amides often generate stoichiometric amounts of waste. Thus, recent progress in the field has focused on precious metal catalyzed, oxidative protocols to generate such functionalities. However, simple tertiary alkyl amines cannot be used as starting materials in these protocols. The research described herein enables the oxidative synthesis of amides from simple, noncyclic tertiary alkyl amines under synthetically useful, mild conditions through a biologically inspired approach: Fe‐catalyzed CαH functionalization. Mechanistic investigations provide insight into reaction intermediates and allow the development of a mild CαH cyanation method using the same catalyst system. The protocol was further applied to oxidize the drug Lidocaine, demonstrating the potential utility of the developed chemistry for metabolite synthesis.
Long‐Term Outcomes Among Participants in the WEGENT Trial of Remission‐Maintenance Therapy for Granulomatosis With Polyangiitis (Wegener's) or Microscopic Polyangiitis
Authors: Puéchal Xavier , Pagnoux Christian , Perrodeau Élodie , Hamidou Mohamed , Boffa Jean‐Jacques , Kyndt Xavier , Lifermann François , Papo Thomas , Merrien Dominique , Smail Amar , Delaval Philippe , Hanrotel‐Saliou Catherine , Imbert Bernard , Khouatra Chahéra , Lambert Marc , Leské Charles , Ly Kim H. , Pertuiset Edouard , Roblot Pascal , Ruivard Marc , Subra Jean‐François , Viallard Jean‐François , Terrier Benjamin , Cohen Pascal , Mouthon Luc , Le Jeunne Claire , Ravaud Philippe , Guillevin Loïc ,   for the French Vasculitis Study Group
Published: October 2015

Objective

Findings from the WEGENT trial and other short‐term studies have suggested that azathioprine (AZA) or methotrexate (MTX) could effectively maintain remission of granulomatosis with polyangiitis (Wegener's) (GPA) or microscopic polyangiitis (MPA). This study was undertaken to examine whether differences in rates of relapse or adverse events would appear after discontinuation of these 2 maintenance regimens, when assessed over a longer followup period.

Methods

Long‐term outcomes in patients enrolled in the WEGENT trial were analyzed according to their randomized treatment group (AZA or MTX). Parameters at trial entry were evaluated as potential prognostic factors for death, relapse, or damage in multivariate models.

Results

Data from 10 years of followup were available for 112 (88.8%) of the 126 original trial participants. The median followup time was 11.9 years (95% confidence interval [95% CI] 11.3–12.5 years). In patients receiving AZA and those receiving MTX, the 10‐year overall survival rates were 75.1% (95% CI 64.8–86.9%) and 79.9% (95% CI 70.3–90.8%) (P = 0.56), respectively, and relapse‐free survival rates were 26.3% (95% CI 17.3–40.1%) and 33.5% (95% CI 23.5–47.7%) (P = 0.29), respectively. No between‐treatment differences were observed with regard to rates of relapse, adverse events, damage, survival without severe side effects, and survival without relapse and severe side effects. In analyses limited to the 97 patients with GPA, no between‐treatment differences in survival rates were observed. The 10‐year relapse‐free survival rate was lower in patients with GPA than in patients with MPA. However, in the multivariate analysis, anti–proteinase 3 antineutrophil cytoplasmic antibody (ANCA) positivity, and not GPA, was retained as being independently associated with the relapse rate.

Conclusion

The results of this long‐term analysis confirm that AZA and MTX are comparable treatment options for maintaining remission of GPA or MPA. Despite achieving good overall survival with these treatments, relapse rates, adverse events, and damage remain matters of concern and further studies are needed to reduce their frequency in these ANCA‐associated vasculitides.
Brief Report: Development and Validation of a Semiautomated Method to Measure Erosion Volume in Inflammatory Arthritis by Computed Tomography Scanning
Authors: Duryea Jeffrey , Russell Ruby , Gravallese Ellen M. , Kay Jonathan , Han Roger , Lu Bing , Solomon Daniel H.
Published: October 2015

Objective

Valid measurement of erosion volume in rheumatoid arthritis (RA) will facilitate the testing of treatments that may help to heal erosion. This study was undertaken to develop and validate a software method to measure erosion volume on computed tomography (CT) scans of the hand and wrist.

Methods

Duplicate CT acquisitions of both hands of 5 patients with RA were evaluated using a semiautomated software tool to measure erosion volume in the entire hand and wrist and in each of 6 subregions. Reproducibility was quantified using the intraclass correlation coefficient (ICC), root mean square standard deviation (RMSSD), and coefficient of variation (CV), and the analysis was performed at the level of the hand (n = 10) and the subject (n = 5).

Results

The ICCs between 2 repositioned acquisitions were excellent, ranging from 0.97 to 1.00. At the hand level, the RMSSD was 15.6 mm3 with a CV of 7.3%, and the CVs at the 6 regions ranged from 7.6% to 21.0%. At the subject level, the RMSSD was 31.2 mm3 with a CV of 3.7%, and the CVs at the 6 regions ranged from 0.5% to 15.8%.

Conclusion

We have developed a novel semiautomated software method to measure erosion volume on hand and wrist CT scans. The method is reproducible and can be used to detect changes in erosion volume. This will facilitate the testing of treatments intended to reduce erosion volume.
Injurious Loading of Articular Cartilage Compromises Chondrocyte Respiratory Function
Authors: Coleman Mitchell C. , Ramakrishnan Prem S. , Brouillette Marc J. , Martin James A.
Published: October 2015

Objective

To determine whether repeatedly overloading healthy cartilage disrupts mitochondrial function in a manner similar to that associated with osteoarthritis (OA) pathogenesis.

Methods

We exposed normal articular cartilage on bovine osteochondral explants to 1 day or 7 consecutive days of cyclic axial compression (0.25 MPa or 1.0 MPa at 0.5 Hz for 3 hours) and evaluated the effects on chondrocyte viability, ATP concentration, reactive oxygen species (ROS) production, indicators of oxidative stress, respiration, and mitochondrial membrane potential.

Results

Neither 0.25 MPa nor 1.0 MPa of cyclic compression caused extensive chondrocyte death, macroscopic tissue damage, or overt changes in stress–strain behavior. After 1 day of loading, differences in respiratory activities between the 0.25 MPa and 1.0 MPa groups were minimal; however, after 7 days of loading, respiratory activity and ATP levels were suppressed in the 1.0 MPa group relative to the 0.25 MPa group, an effect prevented by pretreatment with 10 mM N‐acetylcysteine. These changes were accompanied by increased proton leakage and decreased mitochondrial membrane potential, as well as by increased ROS formation, as indicated by dihydroethidium staining and glutathione oxidation.

Conclusion

Repeated overloading leads to chondrocyte oxidant‐dependent mitochondrial dysfunction. This mitochondrial dysfunction may contribute to destabilization of cartilage during various stages of OA in distinct ways by disrupting chondrocyte anabolic responses to mechanical stimuli.
Intravenous Immunoglobulin as an Immunomodulating Agent in Antineutrophil Cytoplasmic Antibody–Associated Vasculitides: A French Nationwide Study of Ninety‐Two Patients
Authors: Crickx Etienne , Machelart Irène , Lazaro Estibaliz , Kahn Jean‐Emmanuel , Cohen‐Aubart Fleur , Martin Thierry , Mania Alexandre , Hatron Pierre‐Yves , Hayem Gilles , Blanchard‐Delaunay Claire , de Moreuil Claire , Le Guenno Guillaume , Vandergheynst Frédéric , Maurier François , Crestani Bruno , Dhote Robin , Silva Nicolas Martin , Ollivier Yann , Mehdaoui Anas , Godeau Bertrand , Mariette Xavier , Cadranel Jacques , Cohen Pascal , Puéchal Xavier , Le Jeunne Claire , Mouthon Luc , Guillevin Loïc , Terrier Benjamin ,   for the French Vasculitis Study Group
Published: October 2015

Objective

Intravenous immunoglobulin (IVIG) represents a therapeutic alternative in antineutrophil cytoplasmic antibody–associated vasculitides (AAV), but its efficacy has been evaluated in only 2 small prospective trials. The aim of this study was to evaluate the efficacy and safety of IVIG in patients with AAV.

Methods

We conducted a nationwide retrospective study of patients who received IVIG as immunomodulatory therapy for AAV.

Results

A total of 92 patients (mean age 51 years) presenting with either granulomatosis with polyangiitis (Wegener's) (68%), eosinophilic granulomatosis with polyangiitis (Churg‐Strauss) (22%), or microscopic polyangiitis (10%) received at least 1 course of IVIG. Antineutrophil cytoplasmic antibodies were present in 72% during the flare that required IVIG, as determined by immunofluorescence assay. IVIG was initiated because of relapsing disease in 83% of cases. IVIG was given for a median of 6 months (range 1–156 months) and in combination with corticosteroids in 21% of the patients or with other immunosuppressive agents in 77%. Efficacy of IVIG was assessed in the entire population and in a subset of 34 patients with unmodified background therapy. Remission rates at 6 months were 56% in the entire population and 58% in the unmodified background therapy group. Refractory disease and treatment failure at 6 months were observed in 7% and 18% in the whole population and 3% and 21% in the unmodified background therapy group, respectively. Adverse events (AEs) occurred in 33%, including serious AEs in 12% and AEs leading to discontinuation of IVIG in 7%.

Conclusion

This large study shows the clinical benefit of IVIG as adjunctive therapy, with an acceptable tolerance profile, and thus supports its use in AAV patients with refractory or relapsing disease.
Oxidative C−H Activation Approach to Pyridone and Isoquinolone through an Iron‐Catalyzed Coupling of Amides with Alkynes
Authors: Matsubara Tatsuaki , Ilies Laurean , Nakamura Eiichi
Published: October 2015

An iron catalyst combined with a mild organic oxidant promotes both C−H bond cleavage and C−N bond formation, and forms 2‐pyridones and isoquinolones from an alkene‐ or arylamide and an internal alkyne, respectively. An unsymmetrical alkyne gives the pyridone derivative with high regioselectivity, this could be due to the sensitivity of the reaction to steric effects because of the compact size of iron.
Multiple criteria optimization joint analyses of microarray experiments in lung cancer: from existing microarray data to new knowledge
Authors: Camacho‐Cáceres Katia I. , Acevedo‐Díaz Juan C. , Pérez‐Marty Lynn M. , Ortiz Michael , Irizarry Juan , Cabrera‐Ríos Mauricio , Isaza Clara E.
Published: October 2015

Microarrays can provide large amounts of data for genetic relative expression in illnesses of interest such as cancer in short time. These data, however, are stored and often times abandoned when new experimental technologies arrive. This work reexamines lung cancer microarray data with a novel multiple criteria optimization‐based strategy aiming to detect highly differentially expressed genes. This strategy does not require any adjustment of parameters by the user and is capable to handle multiple and incommensurate units across microarrays. In the analysis, groups of samples from patients with distinct smoking habits (never smoker, current smoker) and different gender are contrasted to elicit sets of highly differentially expressed genes, several of which are already associated to lung cancer and other types of cancer. The list of genes is provided with a discussion of their role in cancer, as well as the possible research directions for each of them.
Association between epithelial‐mesenchymal transition and cancer stemness and their effect on the prognosis of lung adenocarcinoma
Authors: Sowa Terumasa , Menju Toshi , Sonobe Makoto , Nakanishi Takao , Shikuma Kei , Imamura Naoto , Motoyama Hideki , Hijiya Kyoko , Aoyama Akihiro , Chen Fengshi , Sato Toshihiko , Kobayashi Masashi , Yoshizawa Akihiko , Haga Hironori , Sozu Takashi , Date Hiroshi
Published: October 2015

The epithelial‐mesenchymal transition (EMT) and cancer stemness (CS) are reported to be pivotal phenomena involved in metastasis, recurrence, and drug‐resistance in lung cancer; however, their effects on tumor malignancy in clinical settings are not completely understood. The mutual association between these factors also remains elusive and are worthy of investigation. The purpose of this study was to elucidate the association between EMT and CS, and their effect on the prognosis of patients with lung adenocarcinoma. A total of 239 lung adenocarcinoma specimens were collected from patients who had undergone surgery at Kyoto University Hospital from January 2001 to December 2007. Both EMT (E‐cadherin,vimentin) and CS (CD133, CD44, aldehyde dehydrogenase) markers were analyzed through immunostaining of tumor specimens. The association between EMT and CS as well as the patients' clinical information was integrated and statistically analyzed. The molecular expression of E‐cadherin, vimentin, and CD133 were significantly correlated with prognosis (P = 0.003, P = 0.005, and P < 0.001). A negative correlation was found between E‐cadherin and vimentin expression (P < 0.001), whereas, a positive correlation was found between vimentin and CD133 expression (P = 0.020). CD133 was a stronger prognostic factor than an EMT marker. Elevated CD133 expression is the signature marker of EMT and CS association in lung adenocarcinoma. EMT and CS are associated in lung adenocarcinoma. Importantly, CD133 is suggested to be the key factor that links EMT and CS, thereby exacerbating tumor progression.
Functionalized Metal–Organic Frameworks for the Efficient Removal of Low Concentrations of Ammonia
Authors: Li Libo , Wang Yong , Yang Jiangfeng , Chen Yang , Li Jinping
Published: October 2015

The excellent ammonia adsorption properties of [Cu(bpy)2(OTf)2]n (ELM‐12; bpy=4,4′‐bipyridine, OTf=trifluoromethanesulfonate) make it unique for the removal of ammonia at low concentrations, but its instability under humid conditions restrict its practical applications. Herein, a functionalized ELM‐12@PDMS (PDMS=polydimethylsiloxane) composite was prepared by coating a nanoscale PDMS layer on the ELM‐12 surface, which significantly increased its hydrophobicity. The dynamic ammonia adsorption properties of ELM‐12 and ELM‐12@PDMS were explored by means of kinetic breakthrough measurements under dry and humid conditions. ELM‐12@PDMS can effectively capture ammonia at 100 ppm when maintained under 80 % relative humidity, which makes it promising for real applications.
Modelling strategies for horizontally loaded infill masonry / Modellierungsansätze für horizontal beanspruchtes Ausfachungsmauerwerk
Authors: Kubalski Thomas , Butenweg Christoph
Published: October 2015

The realistic modelling of seismically loaded infill masonry is a complicated task due to the complex interaction of the infill with the surrounding frame. Practical approaches, that take into consideration the non‐linear behaviour of the infill and the frame, are especially lacking at the moment. Within the framework of the European project INSYSME (Innovative Systems for Earthquake Resistant Masonry Enclosures in R.C. Buildings [1]), the behaviour of infill masonry in reinforced concrete frames is being investigated experimentally to derive different strategies for the modelling of infill masonry. In addition, systems for the improvement of the seismic behaviour will be developed. In the following, some initial results of the different modelling strategies are presented.
New standard publication on plastering and rendering of masonry / Neues Standardwerk für das Verputzen von Mauerwerk
Authors: Riechers Hans‐Joachim
Published: October 2015

The work of plastering and rendering masonry and concrete is covered by a huge range of standards and guidelines. The new publication “Guidelines for plastering and rendering masonry and concrete” presents a standard work, which clarifies the issues for designers and contractors alike.
Distinct calcium signals in developing cortical interneurons persist despite disorganization of cortex by Tbr1 KO
Authors: Easton C. R. , Dickey C. W. , Moen S. P. , Neuzil K. E. , Barger Z. , Anderson T. M. , Moody W. J. , Hevner R. F.
Published: October 2015

Cortical development involves the structuring of network features by genetically programmed molecular signaling pathways. Additionally, spontaneous ion channel activity refines neuronal connections. We examine Ca2+ fluctuations in the first postnatal week of normal mouse neocortex and that expressing knockout of the transcription factor T‐brain‐1 (Tbr1): a signaling molecule in cortical patterning and differentiation of excitatory neurons. In cortex, glutamatergic neurons express Tbr1 just before the onset of population electrical activity that is accompanied by intracellular Ca2+ increases. It is known that glutamatergic cells are disordered with Tbr1 KO such that normal laying of the cortex, with newer born cells residing in superficial layers, does not occur. However, the fate of cortical interneurons is not well studied, nor is the ability of Tbr1 deficient cortex to express normal physiological activity. Using fluorescent proteins targeted to interneurons, we find that cortical interneurons are also disordered in the Tbr1 knockout. Using Ca2+ imaging we find that population activity in mutant cortex occurs at normal frequencies with similar sensitivity to GABAA receptor blockade as in nonmutant cortex. Finally, using multichannel fluorescence imaging of Ca2+ indicator dye and interneurons labeled with red fluorescent protein, we identify an additional Ca2+ signal in interneurons distinct from population activity and with different pharmacological sensitivities. Our results show the population activity described here is a robust property of the developing network that continues in the absence of an important signaling molecule, Tbr1, and that cortical interneurons generate distinct forms of activity that may serve different developmental functions. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 705–720, 2016
Protecting military personnel from high risk dietary supplements
Authors: Deuster Patricia A. , Lieberman Harris R.
Published: October 2015

It is legal to market most naturally occurring substances as dietary supplements in the USA without manufacturers demonstrating they are safe or effective, and an endless variety of ingredients, from esoteric botanicals to unapproved pharmaceuticals, can be found in dietary supplements. Use of certain supplements can pose a risk, but since a robust reporting system does not exist in the USA it is difficult to know which are problematic and the number of adverse events (AE) resulting from their use. Certain populations, including military personnel, are more likely to use dietary supplements than the general population. Approximately 70% of military personnel take dietary supplements while about 50% of civilians do. Service members prefer supplements purported to enhance physical performance such as supposedly natural stimulants, protein and amino acids, and combination products. Since some of these may be problematic, Service members are probably at higher risk of injury than the general population. Ten percent of military populations appear to be taking potentially risky supplements, and the US Department of Defense (DoD) has taken various measures to protect uniformed personnel including education, policy changes, and restricting sales. Actions taken include launching Operation Supplement Safety (OPSS), introducing a High Risk Supplement list, educating health care professionals on reporting AE that might be associated with dietary supplements, recommending policy for reporting AE, and developing an online AE reporting system. OPSS is a DoD‐wide effort to educate service members, leaders, health care providers, military families, and retirees on how to safely select supplements. Copyright © 2015 John Wiley & Sons, Ltd.
Analysis of anabolic androgenic steroids as sulfate conjugates using high performance liquid chromatography coupled to tandem mass spectrometry
Authors: Rzeppa S. , Heinrich G. , Hemmersbach P.
Published: October 2015

Improvements in doping analysis can be effected by speeding up analysis time and extending the detection time. Therefore, direct detection of phase II conjugates of doping agents, especially anabolic androgenic steroids (AAS), is proposed. Besides direct detection of conjugates with glucuronic acid, the analysis of sulfate conjugates, which are usually not part of the routine doping control analysis, can be of high interest. Sulfate conjugates of methandienone and methyltestosterone metabolites have already been identified as long‐term metabolites. This study presents the synthesis of sulfate conjugates of six commonly used AAS and their metabolites: trenbolone, nandrolone, boldenone, methenolone, mesterolone, and drostanolone. In the following these sulfate conjugates were used for development of a fast and easy analysis method based on sample preparation using solid phase extraction with a mixed‐mode sorbent and detection by high performance liquid chromatography coupled to tandem mass spectrometry (HPLC‐MS/MS). Validation demonstrated the suitability of the method with regard to the criteria given by the technical documents of the World Anti‐Doping Agency (WADA). In addition, suitability has been proven by successful detection of the synthesized sulfate conjugates in excretion urines and routine doping control samples. Copyright © 2015 John Wiley & Sons, Ltd.
Dielectric Breakdown Properties of Polylactic Acid with Spherulite Growth
Authors: MATSUGASAKI NARU , SHINYAMA KATSUYOSHI , FUJITA SHIGETAKA
Published: October 2015

Polylactic acid (PLA) is a bioplastic and a biomass material that is made from corn starch, and so on. Having studied the potential of PLA as an electrical insulation material, the authors have demonstrated that PLA has high resistivity, high dielectric breakdown strength, and other outstanding electrical insulation properties, equivalent to those of low‐density polyethylene (LDPE) and other petroleum‐based plastics, within a temperature range from room temperature to approximately 70°C. The degree of crystallinity of PLA was increased by heat treatment, and the dielectric breakdown strength (EB) and mechanical properties of the obtained PLA with different spherulite sizes were studied. PLA heat‐treated at a temperature of 120°C or higher showed rapid increases in spherulite size. At both measurement temperatures of 25°C and 80°C, the EB showed rapid falls when the heat treatment temperature was 120°C or higher. At a measurement temperature of 25°C, the tensile strength at break and breaking elongation showed rapid falls when the heat treatment temperature was 120°C or higher.
Femtosecond Time‐Resolved Electron Microscopy
Authors: YANG JINFENG , YOSHIDA YOICHI , SHIBATA HIROMI
Published: October 2015

The revealing and understanding of ultrafast structural‐change induced dynamics not only are essential in physics, chemistry, and biology, but also are indispensable for the development of new materials, new devices, and applications. A new radio‐frequency electron gun‐based ultrafast relativistic electron microscopy (UEM) is being developed at Osaka University to for direct probing structural changes at the atomic scale with sub‐100 fs temporal resolution in materials. The first prototype femtosecond time‐resolved relativistic‐energy UEM was constructed at end of October 2012. Both relativistic‐energy electron diffraction and image measurements have been successfully performed using a femtosecond electron beam. In this paper, the development of the UEM prototype and the first experiments on relativistic‐energy electron imaging are reported.
Cell‐based therapies for cardiac repair: a meeting report on scientific observations and European regulatory viewpoints
Authors: Schüssler‐Lenz Martina , Beuneu Claire , Menezes‐Ferreira Margarida , Jekerle Veronika , Bartunek Jozef , Chamuleau Steven , Celis Patrick , Doevendans Pieter , O'Donovan Maura , Hill Jonathan , Hystad Marit , Jovinge Stefan , Kyselovič Ján , Lipnik‐Stangelj Metoda , Maciulaitis Romaldas , Prasad Krishna , Samuel Anthony , Tenhunen Olli , Tonn Torsten , Rosano Giuseppe , Zeiher Andreas , Salmikangas Paula
Published: October 2015

In the past decade, novel cell‐based products have been studied in patients with acute and chronic cardiac disease to assess whether these therapies are efficacious in improving heart function and preventing the development of end‐stage heart failure. Cardiac indications studied include acute myocardial infarction (AMI), refractory angina, and chronic heart failure (CHF). Increased clinical activity, experience, and multiple challenges faced by developers have been recognized at the regulatory level. In May 2014, the Committee for Advanced Therapies (CAT) discussed in an expert meeting various cell‐based medicinal products developed for cardiac repair, with a focus on non‐manipulated bone marrow cells, sorted bone marrow or apheresis, and expanded cells, applied to patients with AMI or CHF. The intention was to share information, both scientific and regulatory, and to examine the challenges and opportunities in this field. These aspects were considered from the quality, and non‐clinical and clinical perspectives, including current imaging techniques, with a focus on AMI and CHF. The scope of this overview is to present the European regulatory viewpoint on cell‐based therapies for cardiac repair in the context of scientific observations.
Influence of a Naphthaldiimide Substituent at the Diimine Ligand on the Photophysics and Reverse Saturable Absorption of PtII Diimine Complexes and Cationic IrIII Complexes
Authors: Liu Rui , Dandu Naveen , McCleese Christopher , Li Yuhao , Lu Taotao , Li Hui , Yost Dillon , Wang Chengzhe , Kilina Svetlana , Burda Clemens , Sun Wenfang
Published: October 2015

Two PtII complexes containing benzothiazolylfluorenyl (BTF) acetylide ligands and different diimine (NN) ligands [NN = 1,10‐phenanthroline (1), 5‐naphthaldiimide–1,10‐phenanthroline (2)] and two heteroleptic cationic IrIII complexes containing the 5‐naphthaldiimide–1,10‐phenanthroline ligand and different phenylpyridine (CN) ligands [CN = 2‐phenylpyridine (3), 2‐{3‐[7‐(benzothiazol‐2‐yl)fluoren‐2‐yl]phenyl}pyridine (4)] were synthesized and characterized. The influence of naphthaldiimide (NDI) attached to the NN ligands and benzothiazolylfluorene attached to the CN ligands on the photophysical properties of these PtII/IrIII complexes has been investigated spectroscopically and theoretically. All complexes exhibit ligand‐localized 1π,π* transitions below 400 nm, and broad and structureless metal‐to‐ligand/ligand‐to‐ligand charge transfer (1MLCT/1LLCT) transitions between 400 and 550 nm. Complexes 1 and 4 show red phosphorescence in toluene solutions at room temperature, where the emitting state is assigned predominantly to the 3π,π* state for complex 1 and 3LLCT/3MLCT states for complex 4. Incorporation of the NDI substituent to the NN ligand completely or partially quenches the emission of complexes 2–4. Complexes 1–4 all possess broad singlet transient absorption from 400 to 800 nm, which is ascribed to 1π,π*/1MLCT/1LLCT states for complex 1, and to 1NDI–· for complexes 2–4. The ns transient absorption study reveals that complex 1 exhibits a broad triplet excited‐state absorption from the 3π,π*/3MLCT states, while complexes 2–4 give moderately strong triplet excited‐state absorption from 3NDI–·. Nonlinear transmission experiments at 532 nm using nanosecond laser pulses demonstrate that these complexes all exhibit strong reverse saturable absorption (RSA) at 532 nm for ns laser pulses. Introduction of the NDI substituent to the NN ligand causes charge transfer to the NDI component, which in turn increases the RSA of the PtII complex 2 in comparison with that of the PtII complex 1; while attaching the BTF component to the CN ligands enhances the RSA of the IrIII complex 4 in comparison with that of complex 3.