bluuebunny/crossref_metadata_2025 huggingface dataset:
Cause and prevention of demyelination in a model multiple sclerosis lesion
Authors: Desai Roshni A. , Davies Andrew L. , Tachrount Mohamed , Kasti Marianne , Laulund Frida , Golay Xavier , Smith Kenneth J.
Published: January 2016

Objective

Demyelination is a cardinal feature of multiple sclerosis, but it remains unclear why new lesions form, and whether they can be prevented. Neuropathological evidence suggests that demyelination can occur in the relative absence of lymphocytes, and with distinctive characteristics suggestive of a tissue energy deficit. The objective was to examine an experimental model of the early multiple sclerosis lesion and identify pathogenic mechanisms and opportunities for therapy.

Methods

Demyelinating lesions were induced in the rat spinal dorsal column by microinjection of lipopolysaccharide, and examined immunohistochemically at different stages of development. The efficacy of treatment with inspired oxygen for 2 days following lesion induction was evaluated.

Results

Demyelinating lesions were not centered on the injection site, but rather formed 1 week later at the white–gray matter border, preferentially including the ventral dorsal column watershed. Lesion formation was preceded by a transient early period of hypoxia and increased production of superoxide and nitric oxide. Oligodendrocyte numbers decreased at the site shortly afterward, prior to demyelination. Lesions formed at a site of inherent susceptibility to hypoxia, as revealed by exposure of naive animals to a hypoxic environment. Notably, raising the inspired oxygen (80%, normobaric) during the hypoxic period significantly reduced or prevented the demyelination.

Interpretation

Demyelination characteristic of at least some early multiple sclerosis lesions can arise at a vascular watershed following activation of innate immune mechanisms that provoke hypoxia, and superoxide and nitric oxide formation, all of which can compromise cellular energy sufficiency. Demyelination can be reduced or eliminated by increasing inspired oxygen to alleviate the transient hypoxia. Ann Neurol 2016;79:591–604
Use of construction and demolition wastes as mineral fillers in hybrid wood–polymer composites
Authors: Keskisaari Anna , Butylina Svetlana , Kärki Timo
Published: January 2016

The recycling of construction materials has been the subject of much research in past years. In this study, the use of construction and demolition wastes (CDWs) as mineral fillers in hybrid wood–polymer composites was studied. Two types of waste materials were used as fillers in the composites: (1) a mixture consisting of waste mineral wool (MW) and plasterboard (PB) and (2) mixed CDWs. The performance of the composites was evaluated from their mechanical properties and water‐absorption behavior. We found in the study that the addition of mineral fillers decreased the flexural strength and modulus values of the wood–polypropylene (PP) composites. On the other hand, the exchange of part of the wood with a mineral filler resulted in an increase in the impact strength of the composite. The composite manufactured with the combination of MW and PB had the lowest water absorption. The decrease in wood loading resulted in improved dimensional stability in the hybrid wood–mineral filler–PP composites. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016, 133, 43412.
Newly Identified BRAF Mutation in Rheumatoid Arthritis
Authors: Arnoux Fanny , Fina Frederic , Lambert Nathalie , Balandraud Nathalie , Martin Marielle , Ouafik L'Houcine , Kanaan Sami B. , Roudier Jean , Auger Isabelle
Published: January 2016

Objective

Rheumatoid arthritis (RA)–associated autoantibodies include those directed at the kinase site of BRAF (v‐Raf murine sarcoma viral oncogene homolog B1), a serine–threonine kinase involved in the MAPK signaling pathway. To understand anti‐BRAF immunization, we sought to identify BRAF mutations in the peripheral blood lymphocytes (PBLs) of patients with RA.

Methods

We first cloned the major BRAF region known for mutations in the pCR2.1 vector, using genomic DNA from the PBLs of 8 RA patients. For each patient, 100 clones were sequenced. In 5 of 8 patients, we detected a new BRAF mutation in 1 clone. The frequency of this new mutation was evaluated by droplet digital polymerase chain reaction in PBLs from RA patients and controls. To test whether p.Val600Ala influences the kinase activity of BRAF, we developed an in vitro assay based on phosphorylation of MEK‐1, a major BRAF substrate.

Results

A BRAF mutation, p.Val600Ala, was identified in 1 of 8,000 PBLs and 1 of 6,000 T lymphocytes from RA patients and in 1 of 12,500 PBLs and 1 of 12,500 T lymphocytes from controls. The BRAF p.Val600Ala mutation was not correlated with the presence of anti‐BRAF autoantibodies. The p.Val600Ala mutation activated phosphorylation of MEK‐1 in vitro.

Conclusion

Most RA patients have a p.Val600Ala mutation in the BRAF gene. This mutation activates the kinase activity of BRAF. The p.Val600Ala mutation could activate the MAPK pathway, leading to the activation of T lymphocytes.
Effects of Complement C4 Gene Copy Number Variations, Size Dichotomy, and C4A Deficiency on Genetic Risk and Clinical Presentation of Systemic Lupus Erythematosus in East Asian Populations
Authors: Yih Chen Ji , Ling Wu Yee , Yin Mok Mo , Jan Wu Yeong‐Jian , Lintner Katherine E. , Wang Chin‐Man , Chung Erwin K. , Yang Yan , Zhou Bi , Wang Huanyu , Yu Denise J. H. C. , Alhomosh Alaaedin , Jones Karla , Spencer Charles H. , Nagaraja Haikady N. , Lung Lau Yu , Lau Chak‐Sing , Yung Yu C.
Published: January 2016

Objective

Human complement C4 is complex, with multiple layers of diversity. The aims of this study were to elucidate the copy number variations (CNVs) of C4A and C4B in relation to disease risk in systemic lupus erythematosus (SLE), and to compare the basis of race‐specific C4A deficiency between East Asians and individuals of European descent.

Methods

The East Asian study population included 999 SLE patients and 1,347 healthy subjects. Variations in gene copy numbers (GCNs) of total C4, C4A, and C4B, as well as C4‐Long and C4‐Short genes, were determined and validated using independent genotyping technologies. Genomic regions with C4B96 were investigated to determine the basis of the most basic C4B protein occurring concurrently with C4A deficiency.

Results

In East Asians, high GCNs of total C4 and C4A were strongly protective against SLE, whereas low and medium GCNs of total C4 and C4A, and the absence of C4‐Short genes, were risk factors for SLE. Homozygous C4A deficiency was infrequent in East Asian subjects, but had an odds ratio (OR) of 12.4 (P = 0.0015) for SLE disease susceptibility. Low serum complement levels were strongly associated with low GCNs of total C4 (OR 3.19, P = 7.3 × 10−7) and C4B (OR 2.53, P = 2.5 × 10−5). Patients with low serum complement levels had high frequencies of anti–double‐stranded DNA antibodies (OR 4.96, P = 9.7 × 10−17), hemolytic anemia (OR 3.89, P = 3.6 × 10−10), and renal disease (OR 2.18, P = 8.5 × 10−6). The monomodular‐Short haplotype found to be prevalent in European Americans with C4A deficiency, which was in linkage disequilibrium with HLA–DRB1*0301, was scarce in East Asians. Instead, most East Asian subjects with C4A deficiency were found to have a recombinant haplotype with bimodular C4‐Long and C4‐Short genes, encoding C4B1 and C4B96, which was linked to HLA–DRB1*1501. DNA sequencing revealed an E920K polymorphism in C4B96.

Conclusion

C4 CNVs and deficiency of C4A both play an important role in the risk and manifestations of SLE in East Asian and European populations.
Differential Methylation as a Biomarker of Response to Etanercept in Patients With Rheumatoid Arthritis
Authors: Plant Darren , Webster Amy , Nair Nisha , Oliver James , Smith Samantha L. , Eyre Steven , Hyrich Kimme L. , Wilson Anthony G. , Morgan Ann W. , Isaacs John D. , Worthington Jane , Barton Anne
Published: January 2016

Objective

Biologic drug therapies represent a huge advance in the treatment of rheumatoid arthritis (RA). However, very good disease control is achieved in only 30% of patients, making identification of biomarkers of response a research priority. We undertook this study to test our hypothesis that differential DNA methylation patterns may provide biomarkers predictive of response to tumor necrosis factor inhibitor (TNFi) therapy in patients with RA.

Methods

An epigenome‐wide association study was performed on pretreatment whole blood DNA from patients with RA. Patients who displayed good response (n = 36) or no response (n = 36) to etanercept therapy at 3 months were selected. Differentially methylated positions were identified using linear regression. Variance of methylation at differentially methylated positions was assessed for correlation with cis‐acting single‐nucleotide polymorphisms (SNPs). A replication experiment for prioritized SNPs was performed in an independent cohort of 1,204 RA patients.

Results

Five positions that were differentially methylated between responder groups were identified, with a false discovery rate of <5%. The top 2 differentially methylated positions mapped to exon 7 of the LRPAP1 gene on chromosome 4 (cg04857395, P = 1.39 × 10−8 and cg26401028, P = 1.69 × 10−8). The A allele of the SNP rs3468 was correlated with higher levels of methylation for both of the top 2 differentially methylated positions (P = 2.63 × 10−7 and P = 1.05 × 10−6, respectively). Furthermore, the A allele of rs3468 was correlated with European League Against Rheumatism nonresponse in the discovery cohort (P = 0.03; n = 56) and in the independent replication cohort (P = 0.003; n = 1,204).

Conclusion

We identify DNA methylation as a potential biomarker of response to TNFi therapy, and we report the association between response and the LRPAP1 gene, which encodes a chaperone of low‐density lipoprotein receptor–related protein 1. Additional replication experiments in independent sample collections are now needed.
Interferon‐γ, but Not Interleukin‐4, Suppresses Experimental Polymyositis
Authors: Yoshihashi‐Nakazato Yoko , Kawahata Kimito , Kimura Naoki , Miyasaka Nobuyuki , Kohsaka Hitoshi
Published: January 2016

Objective

C protein–induced myositis (CIM) is a mouse model of polymyositis in which activated antigen‐specific CD8+ T cells injure the muscles. Animal models of autoimmunity that have been examined in the past for the effects of the type 1 cytokine interferon‐γ (IFNγ) and the type 2 cytokine interleukin‐4 (IL‐4) are all mediated by pathogenic CD4+ T cells. In those models, the disruption of IFNγ leads to up‐regulation of IL‐17A, exacerbating the disease with neutrophil infiltration into sites of inflammation. This study was undertaken to investigate the roles of IFNγ and IL‐4, as well as IL‐17A in the absence of IFNγ, in CD8+ T cell–mediated CIM.

Methods

IFNγ−/− mice, anti–IL‐17A antibody–treated IFNγ−/− mice, IFNγ−/−IL‐17A−/− mice, IL‐4−/− mice, and wild‐type C57BL/6 mice were immunized with skeletal muscle C protein fragments to induce CIM. Muscle tissue specimens were examined histologically.

Results

IFNγ−/− mice developed myositis at a higher incidence and with greater severity than wild‐type mice. Unlike wild‐type mice, IFNγ−/− mice had infiltration of neutrophils into the endomysial sites of the affected muscles. IFNγ−/− mice treated with anti–IL‐17A antibodies and IFNγ−/−IL‐17A−/− mice developed myositis with an incidence and severity comparable to those in IFNγ−/− mice and showed neutrophil infiltration similar to that in IFNγ−/− mice. IL‐4−/− mice developed CIM comparable to that in wild‐type mice.

Conclusion

Our findings indicate that IFNγ, but not IL‐4, plays a suppressive role in the development of CIM. Unlike in CD4+ T cell–mediated autoimmune disease models, IFNγ prevents factors other than IL‐17A from exacerbating myositis and neutrophil infiltration in CD8+ T cell–mediated CIM.
Brief Report: Association of Rheumatoid Factor and Anti–Citrullinated Protein Antibody Positivity With Better Effectiveness of Abatacept: Results From the Pan‐European Registry Analysis
Authors: Gottenberg J. E. , Courvoisier D. S. , Hernandez M. V. , Iannone F. , Lie E. , Canhão H. , Pavelka K. , Hetland M. L. , Turesson C. , Mariette X. , Finckh A.
Published: January 2016

Objective

To investigate the role of rheumatoid factor (RF) status and anti–citrullinated peptide antibody (ACPA) status as predictors of abatacept (ABA) effectiveness in patients with rheumatoid arthritis (RA).

Methods

We conducted a pooled analysis of data from 9 observational RA registries in Europe (ARTIS [Sweden], ATTRA [Czech Republic], BIOBADASER [Spain], DANBIO [Denmark], GISEA [Italy], NOR‐DMARD [Norway], ORA [France], Reuma.pt [Portugal], and SCQM‐RA [Switzerland]). Inclusion criteria were a diagnosis of RA, initiation of ABA treatment, and available information on RF and/or ACPA status. The primary end point was continuation of ABA treatment. Secondary end points were ABA discontinuation for ineffectiveness or adverse events and response rates at 1 year (good or moderate response according to the European League Against Rheumatism criteria with LUNDEX adjustment for treatment continuation). Hazard ratios (HRs) and 95% confidence intervals (95% CIs) for the study end points in relation to RF and ACPA status were calculated.

Results

We identified 2,942 patients with available data on RA‐associated autoantibodies; data on RF status were available for 2,787 patients (77.0% of whom were RF positive), and data on ACPA status were available for 1,903 patients (71.3% of whom were ACPA positive). Even after adjustment for sociodemographic and disease‐ and treatment‐related confounders, RF and ACPA positivity were each associated with a lower risk of ABA discontinuation for any reason (HR 0.79 [95% CI 0.69–0.90], P < 0.001 and HR 0.78 [95% CI 0.68–0.90], P < 0.001, respectively), compared to RF‐negative and ACPA‐negative patients. Similar associations with RF and ACPA were observed for discontinuation of ABA treatment due to ineffectiveness, with HRs of 0.72 (95% CI 0.61–0.84) and 0.74 (95% CI 0.62–0.88), respectively (both P < 0.001).

Conclusion

Our results strongly suggest that positivity for RF or ACPA is associated with better effectiveness of ABA therapy.
Histone Demethylation and Toll‐like Receptor 8–Dependent Cross‐Talk in Monocytes Promotes Transdifferentiation of Fibroblasts in Systemic Sclerosis Via Fra‐2
Authors: Ciechomska Marzena , O'Reilly Steven , Przyborski Stefan , Oakley Fiona , Bogunia‐Kubik Katarzyna , van Laar Jacob M.
Published: January 2016

Objective

To investigate whether epigenetic changes can modulate monocytes to produce tissue inhibitor of metalloproteinases 1 (TIMP‐1) via Fra‐2 (an activator protein 1 [AP‐1] family member), a novel downstream mediator that promotes fibrogenesis.

Methods

AP‐1 transcription factors and TIMP‐1 expression were measured in monocytes from systemic sclerosis (SSc) patients and healthy controls. Involvement of Fra‐2 in the regulation of TIMP‐1 following treatment with Toll‐like receptor 8 (TLR‐8) agonist was investigated using a luciferase activity assay and chromatin immunoprecipitation (ChIP) analysis. Expression of TIMP‐1 and Fra‐2 was determined in response to TLR‐8 treatment and to different histone modifications, including 3′‐deazaneplanocin (DZNep) and apicidin. Fibroblasts from healthy controls were cocultured with DZNep plus TLR‐8–treated healthy control monocytes.

Results

Up‐regulation of Fra‐2 was detected in bleomycin‐challenged mice and in skin biopsy samples from SSc patients. Enhanced expression of Fra‐2 and TIMP‐1 was correlated in SSc monocytes (P = 0.021). The expression of Fra‐1 was significantly reduced (P = 0.037) in SSc monocytes. Inhibiting AP‐1 activity reduced TIMP‐1 production in TLR‐8–stimulated monocytes from healthy controls and SSc patients. ChIP experiments revealed binding of Fra‐2 to the TIMP‐1 promoter. Stimulation with DZNep plus TLR‐8 enhanced Fra‐2 and TIMP‐1 expression in healthy control monocytes, whereas TLR‐8 plus apicidin repressed Fra‐2 and TIMP‐1 expression. Finally, healthy control monocytes treated with DZNep plus TLR‐8 induced strong production of α‐smooth muscle actin in dermal fibroblasts, which was inhibited by TIMP‐1–blocking antibody.

Conclusion

These data demonstrate a novel role of histone demethylation induced by DZNep on Fra‐2–mediated TIMP‐1 production by monocytes in the presence of TLR‐8 agonist. This consequently orchestrates the transdifferentiation of fibroblasts, a key event in the pathogenesis of SSc.
Cγ1 Deficiency Exacerbates Collagen‐Induced Arthritis
Authors: Strait Richard T. , Thornton Sherry , Finkelman Fred D.
Published: January 2016

Objective

IgG antibodies protect by aggregating pathogens and activating complement and stimulatory Fcγ receptors (FcγR). Although IgG1 accounts for a large percentage of murine serum antibodies, it poorly activates complement, binds more avidly to inhibitory FcγRIIb than to stimulatory FcγRIII, and has a relatively low aggregating ability. We previously demonstrated that IgG1 protects against complement‐ and FcγR‐independent renal disease by inhibiting immune complex obstruction of glomerular capillaries. The purpose of this study was to determine whether IgG1 also protects against the complement‐ and FcγR‐dependent disorder, collagen‐induced arthritis (CIA).

Methods

CIA was induced by injecting mice with type II collagen (CII) (active model) or with IgG2a and IgG2b anti‐CII monoclonal antibodies (ArthritoMab) (passive model). Arthritis severity was assessed, and CII‐specific IgG was titered.

Results

Cγ1‐deficient C57BL/6 mice lack IgG1 (IgG1−/−); in these mice, arthritis developed at a higher frequency and was more severe compared with IgG1+/+ mice in the active model. Disease was FcγRIII‐ and C3‐dependent in both the IgG+/+ and IgG−/− mouse strains and was not influenced by interleukin‐4 receptor α in either strain. CII‐specific IgG2a/c titers were considerably higher in IgG1−/− than in IgG1+/+ mice and correlated with CIA incidence and severity. IgG1+/+ mice that developed CIA had higher CII‐specific IgG1 and IgG2a/c levels than did those without CIA. CII‐inoculated BALB/c IgG1+/+ and IgG1−/− mice had much lower CII‐specific IgG2a/c titers than did C57BL/6 mice and failed to develop CIA but developed passive CIA when given ArthritoMab.

Conclusion

The absence of a functional Cγ1 gene indirectly promotes the development of CIA, likely through increased production of IgG2a/c, an isotype that strongly activates complement and stimulatory FcγR.
Frequency of Axial Spondyloarthritis Diagnosis Among Patients Seen by US Rheumatologists for Evaluation of Chronic Back Pain
Authors: Deodhar Atul , Mease Philip J. , Reveille John D. , Curtis Jeffrey R. , Chen Su , Malhotra Kailash , Pangan Aileen L.
Published: January 2016

Objective

To determine the proportion of patients with axial spondyloarthritis (SpA) among those with chronic back pain and ≥1 of 3 SpA features in the US.

Methods

The study was conducted at rheumatology practices in the US. Patients were required to have chronic back pain for ≥3 months beginning at <45 years of age, no prior SpA diagnosis, and ≥1 of the following 3 SpA features: HLA–B27 positivity, current inflammatory back pain, and magnetic resonance imaging (MRI) or radiographic evidence of sacroiliitis. Medical history and physical examination findings, pelvic radiographs, MRIs of sacroiliac joints, C‐reactive protein (CRP) level, and HLA–B27 status were obtained. Investigators were asked if a clinical diagnosis of axial SpA could be made based on the results. Data were also analyzed separately to determine if patients fulfilled the Assessment of SpondyloArthritis international Society (ASAS) criteria for axial SpA and/or modified New York criteria for ankylosing spondylitis (AS).

Results

A total of 751 patients were enrolled (46% were existing patients in rheumatology practices, 40% were new referrals, and 14% were self referred). Among patients with available data, 319 of 697 (46%) were diagnosed as having axial SpA by the investigator, and 348 of 744 (47%) fulfilled the ASAS criteria, of whom 238 were classified as having nonradiographic axial SpA and 108 as having AS; 2 had missing data. Using investigator's clinical diagnosis as the gold standard, the specificity and sensitivity of the ASAS criteria were 79% and 81%, respectively.

Conclusion

Our findings indicate that among patients with chronic back pain for ≥3 months beginning at ages younger than 45 years, the presence of ≥1 of 3 SpA features is an effective way to identify those with possible axial SpA.
Observability Under Sampling for Nonlinear Systems
Authors: Ammar Sabeur , Massaoud Majid , Vivalda Jean‐Claude
Published: January 2016

A previous article has investigated the problem of the preservation of the observability under sampling in the framework of compact manifolds. A natural generalization of the cited result would be to extend it to the systems globally Lipschitzian defined on non compact manifolds. A simple representative of this class of systems is constituted by the set of bilinear systems, for this particular class of systems the preservation of the property of observability has been shown in a previous work. In this paper, we deal with the preservation of the observability under sampling for globally Lipschitzian systems defined on Rn.
H∞ Control for Continuous‐Time Mean‐Field Stochastic Systems
Authors: Ma Limin , Zhang Tianliang , Zhang Weihai
Published: January 2016

An H∞‐type control is considered for mean‐field stochastic differential equations (SDEs) in this paper. A stochastic bounded real lemma (SBRL) is proved for mean‐field stochastic continuous‐time systems with state‐ and disturbance‐dependent noise. Based on SBRL, a sufficient condition is given for the existence of a stabilizing H∞ controller in terms of coupled nonlinear matrix inequalities.
Optical analysis of RE3+ (RE = Pr3+, Er3+ and Nd3+):cadmium lead boro tellurite glasses
Authors: Giridhar P. , Bhushana Reddy M. , Neelima G. , Ramanaiah R. , Nagamuni Reddy K. , Sahadeva Reddy V. , Sudhakar Reddy B.
Published: January 2016

This article reports on the optical characterization of Pr3+‐, Er3+‐ and Nd3+‐doped cadmium lead boro tellurite (CLBT) glasses prepared using the melt quenching method. The visible–near infrared (Vis–NIR) absorption spectra of these glasses were analyzed systematically. On measuring the NIR emission spectra of Er3+:CLBT glasses, a broad emission band centered at 1536 nm (4I13/2 → 4I15/2) was observed, as were three NIR emission bands at 900 nm (4F3/2 → 4I9/2), 1069 nm (4F3/2 → 4I11/2) and 1338 nm (4F3/2 → 4I13/2) from Nd3+:CLBT glasses and an NIR emission band at 1334 nm (1G4 → 3H5) from Pr3+:CLBT glasses at an excitation wavelength (λex) of 514.5 nm (Ar+ laser). Copyright © 2016 John Wiley & Sons, Ltd.
Pretreatment lymphopenia is an easily detectable predictive and prognostic marker in patients with metastatic esophagus squamous cell carcinoma receiving first‐line chemotherapy
Authors: Kou Furong , Lu Zhihao , Li Jian , Zhang Xiaotian , Lu Ming , Zhou Jun , Wang Xicheng , Gong Jifang , Gao Jing , Li Jie , Li Yan , Shen Lin
Published: January 2016

To explore the influence of pretreatment lymphopenia on the toxicity and efficacy of first‐line chemotherapy in patients with metastatic esophagus squamous cell carcinoma (ESCC). In total, 215 patients were included in this retrospective study. Correlations between pretreatment lymphopenia (lymphocyte count <1 × 109/L) and the occurrence of toxicity and the efficacy of first‐line palliative chemotherapy were investigated. Pretreatment lymphopenia was found in 19.1% of the patients. The overall response rate (ORR) was 35.5% (65 of 183 patients). Patients with pretreatment lymphopenia had a lower ORR to chemotherapy compared with those without lymphopenia (22.2% vs. 38.8%, respectively; P = 0.045). Furthermore, the patients with pretreatment lymphopenia have higher grade 3–4 hematological toxicity than that of patients without pretreatment lymphopenia (19 of 41 patients, 46.3% vs. 54 of 174 patients, 31.0%; P = 0.048). Pretreatment lymphopenia was not correlated with grade 3–4 nonhematological toxicity. Multivariate analysis showed that pretreatment lymphopenia is an independent prognostic factor. Patients with pretreatment lymphopenia had a significantly shorter overall survival time than those without lymphopenia (8.2 months vs. 12.7 months; P = 0.020). This study shows that pretreatment lymphopenia is a good prognostic factor as well as a predictive factor for tumor response and chemotherapy‐related hematological toxicity in metastatic ESCC.
Angiographic predictors of 2‐year stent thrombosis in patients receiving drug‐eluting stents: Insights from the ADAPT‐DES study
Authors: Généreux Philippe , Redfors Björn , Witzenbichler Bernhard , Maehara Akiko , Yadav Mayank , Weisz Giora , Francese Dominic P. , Parvataneni Rupa , Brener Sorin J. , Mehran Roxana , Kirtane Ajay J. , Stone Gregg W.
Published: January 2016

Objectives

We sought to identify angiographic predictors of 2‐year stent thrombosis (ST) in the ADAPT‐DES study.

Background

A strong relationship between platelet reactivity and ST after implantation of drug‐eluting stents (DES) was recently confirmed in the prospective, multicenter ADAPT‐DES study.

Methods

In a pre‐specified analysis of patients enrolled in ADAPT‐DES, an independent angiographic core laboratory performed detailed angiographic analyses for all cases of ST. Patients with Academic Research Consortium definite/probable target‐lesion ST were matched with controls in a 1:2 ratio, and multivariable Cox regression models identified angiographic predictors of 2‐year ST.

Results

Among 8,582 patients who had successful percutaneous coronary intervention (PCI) and were included in the ADAPT‐DES study, 92 (1.1%) patients had ST at 2‐year follow‐up. Target lesion‐related ST was identified in 77 patients (82 lesions) who were clinically matched with 153 patients (196 lesions) without ST. Patients with ST were more likely to have longer target lesions, thrombus, moderate/severe calcification, American College of Cardiology/American Heart Association (ACC/AHA) type C lesions, and saphenous vein grafts. After adjustment for clinical covariates the angiographic variables that predicted ST were lesion complexity (ACC/AHA type C lesion, adjusted HR: 1.97, 95% CI: 1.19 to 3.26, P = 0.01) and presence of thrombus on index PCI (HR: 2.25, 95% CI: 1.40 to 3.59, P < 0.01).

Conclusions

Anatomically complex lesions and the presence of thrombus are strong predictors of 2‐year ST in the DES era. © 2016 Wiley Periodicals, Inc.
A New, Simple and Versatile Strategy for the Synthesis of Short Segments of Zigzag‐Type Carbon Nanotubes
Authors: André Etienne , Boutonnet Baptiste , Charles Pauline , Martini Cyril , Aguiar‐Hualde Juan‐Manuel , Latil Sylvain , Guérineau Vincent , Hammad Karim , Ray Priyanka , Guillot Régis , Huc Vincent
Published: January 2016

Short segments of zigzag single‐walled carbon nanotubes (SWCNTs) were obtained from a calixarene scaffold by using a completely new, simple and expedited strategy that allowed fine‐tuning of their diameters. This new approach also allows for functionalised short segments of zigzag SWCNTs to be obtained; a prerequisite towards their lengthening. These new SWCNT short segments/calixarene composites show interesting behaviour in solution. DFT analysis of these new compounds also suggests interesting photophysical behaviour. Along with the synthesis of various SWCNTs segments, this approach also constitutes a powerful tool for the construction of new, radially oriented π systems.
Capturing Transient Endoperoxide in the Singlet Oxygen Oxidation of Guanine
Authors: Lu Wenchao , Liu Jianbo
Published: January 2016

The chemistry of singlet O2 toward the guanine base of DNA is highly relevant to DNA lesion, mutation, cell death, and pathological conditions. This oxidative damage is initiated by the formation of a transient endoperoxide through the Diels–Alder cycloaddition of singlet O2 to the guanine imidazole ring. However, no endoperoxide formation was directly detected in native guanine or guanosine, even at −100 °C. Herein, gas‐phase ion–molecule scattering mass spectrometry was utilized to capture unstable endoperoxides in the collisions of hydrated guanine ions (protonated or deprotonated) with singlet O2 at ambient temperature. Corroborated by results from potential energy surface exploration, kinetic modeling, and dynamics simulations, various aspects of endoperoxide formation and transformation (including its dependence on guanine ionization and hydration states, as well as on collision energy) were determined. This work has pieced together reaction mechanisms, kinetics, and dynamics data concerning the early stage of singlet O2 induced guanine oxidation, which is missing from conventional condensed‐phase studies.
Solid‐State NMR and DFT Studies on the Formation of Well‐Defined Silica‐Supported Tantallaaziridines: From Synthesis to Catalytic Application
Authors: Hamzaoui Bilel , Pelletier Jérémie D. A. , Abou‐Hamad Edy , Chen Yin , El Eter Mohamed , Chermak Edrisse , Cavallo Luigi , Basset Jean‐Marie
Published: January 2016

Single‐site, well‐defined, silica‐supported tantallaaziridine intermediates [≡Si‐O‐Ta(η2‐NRCH2)(NMe2)2] [R=Me (2), Ph (3)] were prepared from silica‐supported tetrakis(dimethylamido)tantalum [≡Si‐O‐Ta(NMe2)4] (1) and fully characterized by FTIR spectroscopy, elemental analysis, and 1H,13C HETCOR and DQ TQ solid‐state (SS) NMR spectroscopy. The formation mechanism, by β‐H abstraction, was investigated by SS NMR spectroscopy and supported by DFT calculations. The C−H activation of the dimethylamide ligand is favored for R=Ph. The results from catalytic testing in the hydroaminoalkylation of alkenes were consistent with the N‐alkyl aryl amine substrates being more efficient than N‐dialkyl amines.
Activity Enhancement of G‐Quadruplex/Hemin DNAzyme by Flanking d(CCC)
Authors: Chang Tianjun , Gong Hongmei , Ding Pi , Liu Xiangjun , Li Weiguo , Bing Tao , Cao Zehui , Shangguan Dihua
Published: January 2016

G‐quadruplex (G4)/hemin DNAzymes have been extensively applied in bioanalysis and molecular devices. However, their catalytic activity is still much lower than that of proteinous enzymes. The G4/hemin DNAzyme activity is correlated with the G4 conformations and the solution conditions. However, little is known about the effect of the flanking sequences on the activity, though they are important parts of G4s. Here, we report sequences containing d(CCC), flanked on both ends of the G4‐core sequences remarkably enhance their DNAzyme activity. By using circular dichroism and UV‐visible spectroscopy, the d(CCC) flanking sequences were demonstrated to improve the hemin binding affinity to G4s instead of increasing the parallel G4 formation, which might explain the enhanced DNAzyme activity. Meanwhile, the increased hemin binding ability promoted the degradation of hemin within the DNAzyme by H2O2. Furthermore, the DNAzyme with d(CCC) flanking sequences showed strong tolerance to pH value changes, which makes it more suitable for applications requiring wide pH conditions. The results highlight the influence of the flanking sequences on the DNAzyme activity and provide insightful information for the design of highly active DNAzymes.
Drop forming as a basis for scaling up of the in situ coating process
Authors: Abouzeid Ahmed , Petersen Sandra , Ulrich Joachim
Published: January 2016

Cutting the costs of tablet manufacture is one of the many advantages melt crystallization offers as a technology for producing pharmaceutical coated tablets, compared to conventional tableting procedure. Other advantages include the lower number of steps needed for production, which increases productivity; the lower energy and workforce requirements; and the decreased need for stricter post‐production quality control measures while maintaining quality. The scientific term for maintaining quality is ensuring the reproducibility of experimental results. The main focus of this study is to scale up the drop‐forming process of coating, in this case of ibuprofen tablets using Lutrol. The main emphasis therefore focuses on transferring the respective optimized conditions that work for the respective system onto the industrial device. This results in the production of tablets with consistent quality in terms of geometry and coat purity. This goes in hand with the extensive modifications applied to the device for the purpose of process scale‐up. The final outcome is represented in a scaled‐up production of the coated pharmaceutical tablets through the process of melt crystallization, the reproducibility of which as a tablet manufacturing method is also proven.
A new model based on coupling of MEP/CFD/ILIA for prediction of primary atomization
Authors: Hosseinalipour Seyed Mostafa , Karimaei Hadiseh
Published: January 2016

The maximum entropy principle (MEP) is one of the first methods which was used to predict droplet size and velocity distributions of sprays. Due to some drawbacks of this model, the predicted results are not well matched with experimental data. This paper presents a different approach to improve the MEP model. It is suggested that improving the available energy source in the MEP model equation be made by numerical solution of the flow inside the injector based on CFD. This will enhance the accuracy of turbulent kinetic energy calculation of sprays. The forces acting on a liquid‐gas interface lead to the growth of disturbances originating inside the injector. In this paper, the instability analysis of wave motion on the surface of a swirling liquid sheet exposed to inner and outer gas streams is presented. However, the linear instability analysis used is different from prior analyses. A cylindrical annular liquid sheet was considered in previous studies, but in this study the instability theory is implemented on a cone‐shaped annular liquid sheet for different cone angles. Applying these procedures enhances the model predictions. The liquid sheet properties found by CFD analysis and the results of improved linear instability analysis (ILIA) are also applied to calculate the momentum source in the MEP model. By coupling these models, the MEP model can be run independently of experimental data. The proposed model was applied to predict the droplet size and velocity distributions of a hollow‐cone spray. The results show close agreement with experimental data.
High‐Efficiency Perovskite Solar Cells Employing a S,N‐Heteropentacene‐based D–A Hole‐Transport Material
Authors: Bi Dongqin , Mishra Amaresh , Gao Peng , Franckevičius Marius , Steck Christopher , Zakeeruddin Shaik Mohammed , Nazeeruddin Mohammad Khaja , Bäuerle Peter , Grätzel Michael , Hagfeldt Anders
Published: January 2016

We developed a new donor–π–acceptor‐type hole‐transport material (HTMs) incorporating S,N‐heteropentacene as π‐spacer, triarylamine as donor, and dicyanovinylene as acceptor. In addition to appropriate frontier molecular orbital energies, the new HTM showed high photo absorptivity in the visible region. Without the use of p‐dopants, solution‐processed mixed perovskite devices using the HTM achieved power conversion efficiencies of up to 16.9% and high photocurrents of up to 22.2 mA cm−2. These results demonstrate that heteroacene can be an excellent building block to prepare alternative HTMs for perovskite solar cells and hold promise for further advancement through fine‐tuning the molecular structure.
Theoretical study and optimisation of a standard deviation estimator circuit for adaptive threshold spike detection
Authors: Rummens François , Ygorra Stéphane , Mayiss Boussamba Hol C. , Renaud Sylvie , Lewis Noëlle
Published: January 2016

This paper presents a theoretical study and the resulting architecture of an analogue‐based standard deviation (SD) estimator, typically used in biomedical spike detectors to assess the noise level of bioelectrical recordings online. This well‐known circuit generated a significant inaccuracy, so the aim was to increase the efficiency of spike detection through proper calculation of the noise SD, by developing a rigorous, original theoretical study. The approach consisted of establishing behavioural models for the SD estimation circuit to obtain a transfer function and compare different controllers. This modelling approach also highlighted the parameters available and the impact of their relationships on design optimisation. The behavioural models, inherently based on approximations, were then initially validated by comparing them with actual circuit behaviour, obtained using discrete components. These comparisons revealed that the models matched the actual circuit measurements. Finally, taking into account the conclusions of our theoretical study, an integrated version of this adaptive threshold spike detector was designed using 0.35‐µm complementary metal–oxide–semiconductor technology. Simulations of this circuit revealed that the proposed controller eliminated the static error and ensured efficient spike detection. Copyright © 2016 John Wiley & Sons, Ltd.
Fine‐needle aspiration diagnosis of primary hydatid disease of the thyroid; first reported case in the USA
Authors: Dissanayake Pavithra Irushi , Chennuri Rohini , Tarjan Gabor
Published: January 2016

Echinococcosis or hydatid disease (HD) is a parasitic disease caused by species of the Echinococcus genus. Since the incidence of HD in the USA is very low and the primary HD of the thyroid is extremely rare even in endemic regions, the occurrence of primary thyroid HD is exceptional in the USA. Thyroid HD is rarely diagnosed by fine‐needle aspiration (FNA). Our literature review revealed less than ten cases of primary HD of thyroid diagnosed by FNA worldwide. Hereby, we report the first case of a primary thyroid HD diagnosed by fine‐needle aspiration in the USA. Diagn. Cytopathol. 2016;44:334–337. © 2016 Wiley Periodicals, Inc.
Pitfalls in diagnosing diabetic foot infections
Authors: Peters Edgar J.
Published: January 2016

Although the diagnosis of a diabetic foot infection is made based on clinical symptoms and signs, we also use blood laboratory, microbiological and radiological studies to make treatment decisions. All of these diagnostic studies have pitfalls that can lead to a delay in diagnosis. Such delays will likely lead to further tissue damage and to a higher chance of amputation.

One of these pitfalls is that some clinicians rely on microbiological, rather than clinical data, to diagnose infection. Though subjective by nature, clinical signs predict outcome of foot infections accurately.

Another pitfall is that microbiological data can be misleading. All wounds harbour microorganisms; therefore, a positive wound culture does not mean that a wound is infected. Furthermore, the outcome of cultures of wound swabs does not correlate well with culture results of tissue biopsies. Therapy guidance by wound swab will likely lead to overtreatment of non‐pathogenic organisms. Genotyping might have a role in identifying previously unrecognized (combinations of) pathogens in diabetic foot infection, bacteria in sessile phenotype and non‐culturable pathogens, e.g. in cases where antibiotics have already been administered.

One more pitfall is that the diagnosis of osteomyelitis remains difficult. Although the result of percutaneous bone biopsy is the reference standard for osteomyelitis, some other diagnostic modalities can aid in the diagnosis. A combination of several of these diagnostic tests is probably a good strategy to achieve a higher diagnostic accuracy. Relying on a single test will likely lead to misidentification of patients with osteomyelitis with associated overtreatment and undertreatment. Copyright © 2016 John Wiley & Sons, Ltd.
Assessment of foot perfusion in patients with a diabetic foot ulcer
Authors: Forsythe Rachael O. , Hinchliffe Robert J.
Published: January 2016

Assessment of foot perfusion is a vital step in the management of patients with diabetic foot ulceration, in order to understand the risk of amputation and likelihood of wound healing. Underlying peripheral artery disease is a common finding in patients with foot ulceration and is associated with poor outcomes. Assessment of foot perfusion should therefore focus on identifying the presence of peripheral artery disease and to subsequently estimate the effect this may have on wound healing. Assessment of perfusion can be difficult because of the often complex, diffuse and distal nature of peripheral artery disease in patients with diabetes, as well as poor collateralisation and heavy vascular calcification. Conventional methods of assessing tissue perfusion in the peripheral circulation may be unreliable in patients with diabetes, and it may therefore be difficult to determine the extent to which poor perfusion contributes to foot ulceration. Anatomical data obtained on cross‐sectional imaging is important but must be combined with measurements of tissue perfusion (such as transcutaneous oxygen tension) in order to understand the global and regional perfusion deficit present in a patient with diabetic foot ulceration. Ankle‐brachial pressure index is routinely used to screen for peripheral artery disease, but its use in patients with diabetes is limited in the presence of neuropathy and medial arterial calcification. Toe pressure index may be more useful because of the relative sparing of pedal arteries from medial calcification but may not always be possible in patients with ulceration. Fluorescence angiography is a non‐invasive technique that can provide rapid quantitative information about regional tissue perfusion; capillaroscopy, iontophoresis and hyperspectral imaging may also be useful in assessing physiological perfusion but are not widely available.

There may be a future role for specialized perfusion imaging of these patients, including magnetic resonance imaging techniques, single‐photon emission computed tomography and PET‐based molecular imaging; however, these novel techniques require further validation and are unlikely to become standard practice in the near future. Copyright © 2016 John Wiley & Sons, Ltd.
Sedentary behaviour as a new behavioural target in the prevention and treatment of type 2 diabetes
Authors: Henson Joseph , Dunstan David W. , Davies Melanie J. , Yates Thomas
Published: January 2016

Our modern day society encompasses an ecological niche in which sedentary behaviour, labour‐saving devices and energy dense foods have become the new reference of living. We now spend more time sedentary, defined as sitting, than in all other activities combined. It has recently been confirmed that the consequences of our modern chair dependency are substantial and a direct contributing factor to the ever increasing epidemic of chronic diseases witnessed within industrialized environments. Epidemiological evidence – from both cross‐sectional and prospective observational studies – has indicated that the time spent in sedentary behaviour is a distinct risk factor for several health outcomes, including type 2 diabetes mellitus, insulin resistance, all‐cause and cardiovascular disease mortality, depression and some types of cancer. Importantly, these detrimental associations remain even after accounting for time spent in moderate‐to‐vigorous physical activity, with the strongest and most persistent associations seen between sedentary time and type 2 diabetes mellitus. Importantly, experimental studies have started to confirm the observational associations, with mounting evidence showing that breaking prolonged sitting time with light ambulation is an effective strategy for improving postprandial glucose regulation. Indeed, there is even emerging evidence showing that simply substituting sitting for standing regularly throughout the day may be of sufficient stimulus to improve glucose regulation. We highlight some of the key definitions, issues and evidence underpinning the link between sedentary behaviour and chronic disease in order to better inform clinicians and patients about the importance of incorporating reduced sitting time into type 2 diabetes mellitus management and prevention pathways. Copyright © 2016 John Wiley & Sons, Ltd.
A new diabetic foot risk assessment tool: DIAFORA
Authors: Monteiro‐Soares M. , Dinis‐Ribeiro M.
Published: January 2016

Aims

This study aimed to derive a new model to classify subjects with diabetes and active diabetic foot ulcer by their risk of lower extremity amputation.

Methods

A prospective cohort study was conducted that included all subjects with diabetic foot ulcer attending our Hospital Diabetic Foot Clinic from 2010 to 2013. Variables were collected at baseline. Subjects were followed up until healing, lower extremity amputation, death or for at least 3 months. Logistic regression was used to derive the new model, and the area under the receiver operating characteristic curve was assessed to propose the model with the greatest discrimination.

Results

A total of 293 participants were included and followed for a median of 91 days. In 23.2% amputation was required, 5.1% died and 3.1% were lost. Our final model included the variables most commonly used in clinical practice for diabetic foot risk assessment (presence of neuropathy, foot deformity, peripheral arterial disease and previous foot complications) in addition to multiple diabetic foot ulcer, infection, gangrene and bone involvement. This model had an area under the receiver operating characteristic curve of 0.91 [95% confidence interval (CI) 0.87–0.95] and as classification of 0.89 (95% CI 0.84–0.93) for lower extremity amputation prediction. The high‐risk group presented a positive likelihood ratio of 5 (95% CI 3–8) and predictive value of 58 (46–71). Only one minor lower extremity amputation occurred in the low‐risk group.

Conclusions

We propose a new classification: diabetic foot risk assessment (DIAFORA). This classification was equally or more accurate for lower extremity amputation prediction in diabetic foot ulcer patients when compared with the existing ones. Copyright © 2016 John Wiley & Sons, Ltd.
Reactivity of Me‐pma RhI and IrI Complexes upon Deprotonation and Their Application in Catalytic Carbene Carbonylation Reactions
Authors: Tang Zhou , Tejel Cristina , Martinez de Sarasa Buchaca Marc , Lutz Martin , van der Vlugt Jarl Ivar , de Bruin Bas
Published: January 2016

Dehydrogenative oxidation of amines is a relevant process in metal‐mediated catalysis, with the amines being either substrates or ligands. Transformation of amine‐ into imine‐type ligands in the coordination sphere of a transition metal can be an important catalyst activation process. The behaviour of secondary pyridin‐2‐ylmethanamine (pma) ligands in the corresponding rhodium and iridium complexes upon NH deprotonation varies, depending on a number of factors. In this paper the behaviour of the Me‐pma ligand [Me‐pma = N‐methyl‐1‐(pyridin‐2‐yl)methanamine] bound to [Rh(cod)]+ and [Ir(cod)]+ was studied. Whereas the iridium amido complex could be obtained upon NH deprotonation, the rhodium complex instantaneously disproportionated into a free pma ligand and an unusual dinuclear complex, adopting a structure with two RhI metal centres hosted by a dianionic (pma‐2H)2– ligand, and with the ligand coordinating to Rh2 as an “aza‐allyl” fragment. The study gives further proof for the effect of pyridine ligation on the previously observed charge‐transfer from the ligand to the metal. Furthermore, the catalytic activity of both the Ir and the Rh species with Me‐pma in carbene carbonylation reactions to generate ketenes was studied.
A Convergent Synthesis of Gonytolide C Using an Intramolecular Oxa‐Michael Addition
Authors: Li Freda F. , Atkinson Darcy J. , Furkert Daniel P. , Brimble Margaret A.
Published: January 2016

A full account of the evolution of a convergent total synthesis of gonytolide C is reported. The assembly of the natural product core relies on a Horner–Wadsworth–Emmons (HWE) olefination followed by an intramolecular oxa‐Michael addition. Robust and efficient preparations of both HWE coupling partners were established. The synthesis enabled further investigation of an asymmetric oxa‐Michael cyclisation to prepare gonytolide C, demonstrating the utility of this strategy for synthesis of 2,2‐disubstituted chromanones.