bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of Results of Recurrence and Progression Rates of High-Grade Ta Bladder Cancer and Comparison with Results of High-Grade T1
Authors: Kilinc Muhammet Fatih , Sonmez Nurettin Cem , Dalkilic Ayhan , Arisan Serdar , Guney Soner
Published: July 2014

Introduction

We aimed to evaluate the long-term recurrence and progression rates in a Turkish population with high-grade Ta and T1 bladder cancer and to determine malign potential of high-grade Ta bladder cancer.

Methods

191 patients who had non-invasive bladder cancer were evaluated at a single institution between 2005 and 2010. Median follow-up was 55.6 months (13-108). Long-term follow-up results of recurrence and progression rates of high-grade Ta and T1 were analyzed and compared with each other.

Results

Of the 191 patients, 143 (74.9%) were high-grade T1 and 48 (25.1%) were high-grade Ta. Of the 143 patients who were high-grade T1, 39 (27.2%) responded to the induction BCG without recurrence. 33 (23%) patients had invasion deep into the muscle layer. 61 (42%) patients had recurred as high-grade T1. Of the 48 patients who were high-grade Ta, 15 (31%) responded to induction BCG without recurrence. 18 (37.5%) patients had recurrence as high-grade Ta. 12 (25%) patients had invasion deep into to the muscle layer. Of all the patients, 13 (7%) patients died of causes related to bladder cancer. In a multivariate analysis, concomitant CIS was statistically significant for the progression of high-grade Ta bladder cancer (p<0.005).

Conclusions

According to the data of the current study, the presence of concomitant CIS in patients with high-grade bladder cancers is associated with a higher risk of progression. There is a need for larger scale multi-institutional studies in order to support the hypothesis that high-grade Ta tumors should be considered as T1 tumors.
Imaging of Medullary Sponge Kidney: Notes for Urologists
Authors: Di Egidio Gioia , Masciovecchio Stefano , Saldutto Pietro , Paradiso Galatioto Giuseppe , Vicentini Carlo
Published: July 2014

The medullary sponge kidney is a malformation characterized by Bellini ducts’ ectasias and often by nephrocalcinosis. Scientific literature demonstrates and emphasizes how the Rx-urography plays a primary role to achieve diagnostic certainty in cases of suspected MSK. Pathognomonic urographic aspects in cases of medullary sponge kidney are defined as “bouquet of flowers”, “bunch of grapes” or “brush”. None of the other methods of imaging available today has the same diagnostic accuracy.
Neoadjuvant Sunitinib Effectiveness in T4 Renal Clear Cell Carcinoma: A Case Report
Authors: Ricciardulli Stefano , Del Biondo Dario , Cicero Calogero , Leo Genesio , Zeccolini Guglielmo , Celia Antonio
Published: July 2014

Introduction

Sunitinib therapy showed an improvement in survival of patients with metastatic renal cell carcinoma.

Materials and Methods

A 51-year-old man, with Eastern Cooperative Oncology Group Score (ECOG) of 0, presented at our Institute in March 2012 for macrohematuria and urinary retention. A computed tomography (CT) scan of the abdomen showed a right renal lesion. The lesion had a diameter of 15 cm and was developing towards the liver, in the absence of cleavage planes between the liver and kidney. A 12 mm finding, suspected as secondary lesion, was detected at the level of the VII hepatic segment. Neoadjuvant chemotherapy with Sunitinib was proposed.

Results

The patient underwent a ultrasound-guided biopsy, which confirmed the presence of Clear Cell Carcinoma. The patient began chemotherapy treatment in May 2012 according to the scheme SUNITINIB 50 mg daily for 4 weeks every 6 weeks. After four courses of treatment, according to RECIST criteria for solid tumors, 40% (9 cm vs 15 cm) regression of the primary tumor and 33% (8 mm vs 12 mm) regression of the secondary lesion were observed at a CT scan of the abdomen. In February 2013, Laparoscopic Adrenal-Sparing Radical Nephrectomy was performed. At a follow-up of 3 months, performed with a thorax and abdomen CT scans, there was a complete remission of hepatic secondary lesion and no areas of secondary localization of disease.

Conclusions

This case report showed the effectiveness of neoadjuvant chemotherapy with Sunitinib. The use of this chemotherapy agent can change the approach to the management of cRCC.
O contraponto paulista: os estudos de Florestan Fernandes e Oracy Nogueira no projeto Unesco de relações raciais
Authors: Maio Marcos Chor
Published: July 2014

Este artigo tem por objetivo analisar os estudos de Florestan Fernandes e de Oracy Nogueira sobre as relações raciais em São Paulo nos anos 1950 sob o patrocínio da Unesco. Professores dos mais importantes centros de ciências sociais do Brasil na época (Escola Livre de Sociologia e Política - ELSP e da Faculdade de Filosofia, Ciências e Letras - FFCL/USP), Florestan e Oracy revelam diferentes perspectivas sobre as relações entre raça e classe. Enquanto no estudo de Florestan, raça está subsumida à classe, na investigação de Oracy verifica-se que as intersecções entre raça e classe nas análises das disparidades raciais não podem ser explicadas apenas pelas desigualdades sociais. Desse modo, o ciclo de pesquisas da UNESCO revelou diferentes visões acerca do racismo no Brasil.
A Biblioteca da Real Academia dos Guardas-Marinha: a constituição e organização de um acervo especializado mediada pela formação profissional do oficialato militar-naval
Authors: Silva Carlos André Lopes da
Published: July 2014

Em 1802, era criada uma biblioteca para prover lentes e alunos da Real Academia dos Guardas-Marinha, instituição militar de ensino que formava o oficialato empregado na Marinha portuguesa, de saberes diversos relacionados com a atividade de uma marinha de guerra. Com a vinda daquela Academia junto com a Corte, a Biblioteca dos Guardas-Marinha tornou-se a primeira biblioteca pública a funcionar no Rio de Janeiro. Contudo, é a organização temática estabelecida pelo seu primeiro diretor que demonstra o entrelaçamento entre conteúdos científicos e artes mecânicas na formação profissional do oficialato militar-naval no período joanino.
A flecha e o alvo – as origens, as transformações e a função do curso de história da cartografia lecionado por Jaime Cortesão no Ministério das Relações Exteriores
Authors: Peixoto Renato Amado
Published: July 2014

Por meio da metodização dos conteúdos e do ensino da História da Cartografia, Jaime Cortesão consagrou uma narrativa e uma pedagogia da formação do território nacional em que Alexandre de Gusmão e Rio Branco passaram a figurar em conjunto. Esta fabricação serviu para o resgate do papel dos diplomatas na invenção da Nação e para a recomposição do papel do Brasil no jogo das relações internacionais após a Segunda Guerra Mundial.
Toneladas de Diplomacia num mar sem fronteiras: discussões sobre os poderes navais de Argentina, Brasil e Chile, no início do século XX
Authors: Martini Fernando Ribas De
Published: July 2014

A evolução dos poderes navais da Argentina, Brasil e Chile no início do século XX foi um tema que cruzou fronteiras não só de países, mas também dos setores das sociedades destas três nações, envolvidos em sua discussão: intelectuais, diplomatas, militares. Hoje, é um tema que cruza fronteiras entre áreas do conhecimento, como História da Ciência, da Técnica e da Tecnologia, História Diplomática, História Política, Ciências Sociais, assim como estudos de Política Externa. Este artigo discorre sobre a coincidência entre o roteiro das Conferências Pan-Americanas do início do século XX, que foram iniciativas dos Estados Unidos, e o lançamento e execução dos programas de reequipamento naval dos três países, num momento em que boa parte de sua intelectualidade discutia essas conferências sob um viés anti-americano. Também analisa o quanto essa discussão se relacionava mais a símbolos de poder naval do que ao poder real desses países.
Apresentação
Authors: Almeida Francisco Eduardo Alves de , Arias Neto José Miguel
Published: July 2014

Apresentação do dossiê Culturas Marítimas
Performatividad y representación fotográfica: dimensiones para reflexionar sobre la producción de sentido a través de las imágenes
Authors: Barrios Cleopatra
Published: July 2014

Este artigo reflete sobre a performatividade e a representação fotográfica como duas dimensões-chave que permitem compreender o lugar que ocupam e os modos de intervenção que as imagens exercem na produção e regulação de sentido dentro de uma cultura. A partir da observação de atos fotográficos específicos, este trabalho apresenta cinco seções de desenvolvimento: 1) a fotografia lida como imagem-ato, 2) a performance fotográfica, suas instâncias e articulações de recriação dialógica, 3) o trabalho de representação na per- forma fotográfica. sucesso formativo, 4) as formas de fixações parciais de sentido na visibilidade fotográfica e as formas de constituição de identidades na diferença e, por fim, 5) uma reflexão sobre a produção de sentido através da imagem fotográfica, desafios e abordagens possíveis.
Os marinheiros nacionais e a ideia republicana: circulações, revolta e apropriações (anos 1910)
Authors: Almeida Sílvia Capanema P. de
Published: July 2014

Neste artigo, discuto de que forma alguns valores e símbolos republicanos foram explorados pelos marinheiros nacionais nos anos 1910, sobretudo durante a revolta de novembro, conhecida como "revolta da chibata" e por atores que participaram dela. Nesse sentido, a viagem de um dos navios brasileiros em outubro do mesmo ano a Lisboa, testemunhando a Proclamação da República no país europeu, pode ter contribuído para a afirmação da ideia de República no meio dos marujos brasileiros, bem como outras referências e experiências estrangeiras. Essa apropriação da ideia republicana nesse meio popular e majoritariamente composto por negros, pardos e mestiços é reforçada pelos desdobramentos da noção de cidadania na época, pouco mais de duas décadas da abolição da escravidão no Brasil.
Estatuto da Terra: debates políticos e as disputas pela forma da reforma agrária no primeiro governo militar
Authors: De Salis Carmem Lúcia Gomes
Published: July 2014

Em plena vigência da ditadura, em 30 de novembro de 1964, foi promulgado pelo governo militar de Humberto Alencar Castello Branco, o Estatuto da Terra, caracterizado enquanto um conjunto de dispositivos legais que definiam, entre outros fatores, o que era propriedade da terra no Brasil, bem como, os instrumentos necessários para se realizar a Reforma Agrária. Embora tenha sido aprovado pelo Congresso ainda no primeiro ano do governo, seu processo de elaboração e tramitação constituiu-se em um período de intensas discussões políticas acerca do alcance e da natureza que esta proposta deveria assumir.  Neste sentido, o presente artigo objetiva compreender as disputas políticas que ocorreram, mesmo sobre o regime de exceção, pela forma da Reforma Agrária. Para essa análise utilizamos, especialmente os discursos parlamentares proferidos nos meses que antecederam a aprovação da lei e as colunas publicadas na grande imprensa, pois essas fontes possibilitam refletir sobre os posicionamentos de diversos agentes envolvidos, como: políticos, associações patronais e o governo.
Navegando em águas brasileiras: notas sobre a viagem do francês Pyrard de Laval à colônia brasileira (1610-1611)
Authors: Siqueira Maria Isabel de , Reis Thiago de Souza dos
Published: July 2014

A presença dos viajantes/navegadores em terras americanas após a conquista contribuiu para a circulação de informações úteis acerca do potencial dessas regiões. Os recursos naturais que as novas terras possuíam despertaram o interesse dos europeus nesses produtos visando o comércio. A visita oficial ou não de viajantes a essas terras resultou em registros das condições da terra, seus hábitos e sobre a obediência ou não às leis elaboradas pelas metrópoles para o controle das suas colônias. Nossa proposta nestas notas de pesquisa é identificar nos relatos deixados por Pyrard de Laval, escrito no início do século XVII, os hábitos, os costumes, as leis, a organização das cidades, enfim a conduta social e as relações entre Estado e sociedade na colônia portuguesa da América. Neste sentido, procuramos compreender, a partir da contribuição do autor sobre a exploração dos recursos naturais e das práticas agrícolas nos arredores da Baía de Todos os Santos, as relações lícitas e ilícitas desta dinâmica social.
C. S Forester e a criação do herói Horatio Hornblower: uma incursão na literatura naval britânica
Authors: Almeida Francisco Eduardo Alves de
Published: July 2014

Em 1899 C. S Forester nasceu no Cairo, Egito. Sua carreira na literatura incluiu livros sobre história, biografias e romances históricos, a maioria com temas voltados para a guerra no mar. Dentre seus romances navais mais conhecidos inclui-se a vida do personagem Horatio Hornblower. Forester foi um estudioso do período napoleônico e Hornblower nasceu de sua imaginação como um oficial de marinha britânico na Armada de Nelson. Em uma série de dez livros acabados e um por terminar Forester percorreu a vida de Hornblower e suas aventuras em luta constante contra Napoleão Bonaparte. Dotado de uma fértil imaginação, Forester baseou seu personagem em Horatio Lord Nelson e em Thomas Cochrane, ambos heróis britânicos desse período. Seu último livro da série, ainda incompleto, foi lançado em 1967, um ano após a sua morte. Forester é um dos mais importantes romancistas da literatura naval britânica. O que se pretende com essa investigação é descrever a trajetória de Forester e as aventuras de Hornblower na Marinha Real britânica, procurando identificar pontos de contato com personagens reais do período e analisar algumas características de sua personalidade, como imaginado por Forester.
A Marinha Brasileira no inicio do século XX: tecnologia e política
Authors: Arias Neto José Miguel
Published: July 2014

Este artigo  analisa a literatura que aborda a questão da Marinha Brasileira ao final do século XIX e no início do XX. Tal literatura possui duas vertentes a monarquista e a republicana, ambas advogando medidas de reestruturação da Marinha. Por outro lado, o trabalho analisa ainda as medidas efetivamente tomadas ou não pelos sucessivos governos republicanos, até o ano de 1910, com o objetivo de promover as reformas necessárias à adequação da Marinha aos novos tempos, novas tecnologias e novas sociabilidades. O fim da escravidão, a Revolta da Armada, a corrida armamentista internacional e a que terminou por se estabelecer entre o Chile, a Argentina e o Brasil, na América do Sul, permitem compreender tanto as propostas aventadas como os limites das reformas encetadas.
Investigations of the Thermal Shifts and Electron–Phonon Coupling Parameters of R1 and R2 Lines for Cr3+-doped Forsterite
Authors: Wu Xiao-Xuan , Zheng Wen-Chen
Published: July 2014

The thermal shifts of R1 and R2 lines in Cr3+-doped forsterite (Mg2SiO4) are studied by considering both the static contribution due to lattice thermal expansion and the vibrational contribution due to electron-phonon interaction. In the studies, the thermal expansion coefficient of the Cr3+ center is assumed reasonably as that of the corresponding cluster in the host crystal. The results suggest that for R1 and R2 lines the static contributions are opposite in sign and in magnitude about 37% and 45%, respectively, of the corresponding vibrational contributions. The true electron-phonon coupling coefficients α' (obtained by considering both contributions) increase by about 58% and 81%, respectively, for R1 and R2 lines in comparison with the corresponding parameters α obtained by considering only the vibrational contribution. It appears that for the reasonable explanation of thermal shift of spectral lines and the exact estimation of electron-phonon coupling coefficient, both the static and vibrational contributions should be taken into account
Synthesis and Antitumor Activity of Some N2-(Thien-3-yl)amidrazones
Authors: Abadleh Mohammed M. , El-Abadelah Mustafa M. , Sabri Salim S. , Mohammed Hanan H. , Zihlif Malek A. , Voelter Wolfgang
Published: July 2014

6a

A set of new N2-(thien-3-yl)amidrazones (-h) incorporating N-piperazines and related congeners has been synthesized by reacting the hydrazonoyl chloride 4(derived from 3-aminothiophene- 2-carboxylate) with the appropriate sec-cyclic amine. The antitumor activity of these compounds was evaluated on breast cancer (MCF-7) and leukemic (K562) cell lines by a cell viability assay utilizing the tetrazolium dye (MTT). The amidrazone 6d encompassing the N-piperazine moiety, was the most active against MCF-7 and K562 with IC50 of 7.28 and 9:91 μM, respectively.
Solid-state and Calculated Electronic Structure of 4-Acetylpyrazole
Authors: Frey Guido D. , Schoeller Wolfgang W. , Herdtweck Eberhardt
Published: July 2014

The crystal structure of 1-(1H-pyrazol-4-yl)ethanone (commonly known as 4-acetylpyrazole; C5H6N2O) was determined from single-crystal X-ray data at 173 K: monoclinic, space group P21/n (no. 14), a = 3.865(1), b = 5.155(1), c = 26.105(8) Å, β = 91.13(1)°, V = 520.0(2) Å3 and Z = 4. The adjacent molecules assemble into a wave-like ribbon structure in the solid state, linked by strong intermolecular N-H...N hydrogen bonds between the pyrazole rings and a weak C-H...O=C hydrogen bond involving the carbonyl group. The ribbons are stacked in the solid state via weak π interactions between the pyrazole rings.
Line-Shape Analyses of Solid-state 17O NMR Spectra for Hexagonal Ice
Authors: Yamada Kazuhiko , Deguchi Kenzo , Shimizu Tadashi , Watanabe Junji
Published: July 2014

We present the results of experimental and theoretical investigations of line shapes in solid-state 17O NMR spectra of hexagonal ice, Ih. Stationary 17O NMR spectra of Ih at temperatures from 143 to 280 K were obtained at 11.7 and 16.4 T. Line shapes changed drastically as the temperature was increased from 143 to 243 K; at 253 K and above, pseudo-isotropic line shapes appear, indicating the presence of reorientational motions. We find that Ratcliffe’s model, which involves twelve orientations and four-step jumps for water reorientational motions, is effective for analyzing the NMR spectra at temperatures below 243 K. The present analysis demonstrates that the isotropic line shapes arise from proton disorder with respect to the solid-state 17O NMR time scale, producing pseudoicosahedral motional averaging that can completely average out second-order quadrupole interactions.
Synthesis of New TGX-221 Analogs
Authors: Liu Chunjing , Li Benyi , Mitscher Lester
Published: July 2014

TGX-221 is a potent phosphoinositide 3-kinase (PI3K)β inhibitor that has great therapeutic potential to treat prostate cancer. Chemical modification of TGX-221 at positions 2 and 9 was made. Five new TGX-221 analogs with different heterocyclic substituents of morpholine, 1-methylpiperazine, aniline, and thiazole-2-amine at positions 2 and 9 were synthesized. Parallel synthetic methods were employed in SN2 replacement reactions at positions 2 and 9 of TGX-221.
Iridoid Glycosides from Lagotis alutacea
Authors: Yang Li-Juan , Zhang Na , Liu Na , Yang Xiao-Dong
Published: July 2014

One new iridoid glycoside, lagotisoside F (1), was isolated from Lagotis alutacea, along with three known analogs, lagotisoside D (2), 6-O-α-L-(4″-O-(E)-cinnamoyl) rhamnopyranosyl-catapol (3) and globularin (4). Their structures were elucidated by extensive spectroscopic analysis and by comparison with data reported in the literature. Compounds 1-4were evaluated for cytotoxic activity against HL-60, MCF-7, A549, SW480, and SMMC-7721 cells and exhibited no appreciable activity with IC50 values above 40 μM.
Los medios publicitarios en el contexto actual: en la encrucijada de la absoluta remediación
Authors: Martínez Sáez José , Breva Franch Eva
Published: July 2014

Introducción a la sección informe sobre los medios publicitarios en el contexto actual.
‘Young Rovers’ and ‘Dazzling Lady Meteors:’ Gender and Bicycle Club Culture in Turn-of-the-Century Small-Town Ontario
Authors: Beausaert Rebecca
Published: July 2014

During the bicycle “craze” of the 1890s and early 1900s, men and women across Western Europe and North America embraced this novel form of recreation and modern mode of transportation. Undoubtedly, the invention of the “safety” bicycle in 1885 aided women’s enjoyment of the machine, yet in many respects cycling remained an androcentric mode of recreation. This is most evident when examining the paternal structure of bicycle clubs. In the existing literature on cycling, however, little attention is paid to gender dynamics within clubs, especially in the context of smaller towns and rural areas. Using the towns of Tillsonburg and Ingersoll in southwestern Ontario’s Oxford County as a case study, this article examines how cycling clubs in these communities were sites of both change and resistance to the prevailing gender norms of the time. Once membership was opened to women, club activities became more heterosocial and less focused on cultivating virulent masculinity, but women were never fully accepted as full-fledged members.
“‘From Our Lips:’ Lipstick as Consumer Technology and the MAC VIVA GLAM Advertising Campaigns”
Authors: Benoit Andrea
Published: July 2014

Lipstick has remained a stable technology for over five thousand years, while influenced by social and cultural mores, and ideas about sexuality, gender and class. This is particularly evident in the twentieth century since lipstick has become a consumer technology, as evidenced by the fundraising lipstick VIVA GLAM. Made by the originally Canadian brand MAC Cosmetics, sales of VIVA GLAM generate funds for the brand's own AIDS charity, the MAC AIDS Fund. VIVA GLAM’s advertising was initially controversial because it featured drag performer RuPaul in 1995 and Canadian crooner k. d. lang in 1997. More recently, VIVA GLAM’s advertising has featured singers Cyndi Lauper and Lady Gaga and promoted safe sex behaviours amongst young heterosexual women. Lipstick’s meaning and function continues to adapt to its historical circumstances, particularly around gender norms, and VIVA GLAM is a new chapter in this cultural history of lipstick as a consumer technology.
Service social autochtone — Incorporer la vision autochtone du monde dans les stages pratiques en service social
Authors: Moeke-Pickering Taima , Partridge Cheryle
Published: July 2014

Dans cet article, nous présentons les raisons d’être, l’élaboration et la mise en place d’un programme de service social autochtone dans un établissement universitaire traditionnel. Nous nous concentrons sur le discours associé aux visions sociales autochtones concernant le service social, et le positionnement des programmes établis par les collectivités autochtones en vue de s’adapter aux conditions universitaires ayant cours. Nous montrons également comment les enseignements autochtones sont utilisés comme modèles de passage de la théorie à la pratique et comment ils reflètent la façon par laquelle les étudiantes et les étudiants incorporent dans leurs stages pratiques leur vision autochtone du monde.
In situ measurements and analysis of ocean waves in the Antarctic marginal ice zone
Authors: Meylan Michael H. , Bennetts Luke G. , Kohout Alison L.
Published: July 2014

In situ measurements of ocean surface wave spectra evolution in the Antarctic marginal ice zone are described. Analysis of the measurements shows significant wave heights and peak periods do not vary appreciably in approximately the first 80km of the ice‐covered ocean. Beyond this region, significant wave heights attenuate and peak periods increase. It is shown that attenuation rates are insensitive to amplitudes for long‐period waves but increase with increasing amplitude above some critical amplitude for short‐period waves. Attenuation rates of the spectral components of the wavefield are calculated. It is shown that attenuation rates decrease with increasing wave period. Further, for long‐period waves the decrease is shown to be proportional to the inverse of the period squared. This relationship can be used to efficiently implement wave attenuation through the marginal ice zone in ocean‐scale wave models.
Seasonal variability of the Red Sea, from satellite gravity, radar altimetry, and in situ observations
Authors: Wahr John , Smeed David A. , Leuliette Eric , Swenson Sean
Published: July 2014

Seasonal variations of sea surface height (SSH) and mass within the Red Sea are caused mostly by exchange of heat with the atmosphere and by flow through the strait opening into the Gulf of Aden to the south. That flow involves a net mass transfer into the Red Sea during fall and out during spring, though in summer there is an influx of cool water at intermediate depths. Thus, summer water in the south is warmer near the surface due to higher air temperatures, but cooler at intermediate depths. Summer water in the north experiences warming by air‐sea exchange only. The temperature affects water density, which impacts SSH but has no effect on mass. We study this seasonal cycle by combining GRACE mass estimates, altimeter SSH measurements, and steric contributions derived from the World Ocean Atlas temperature climatology. Among our conclusions are: mass contributions are much larger than steric contributions; the mass is largest in winter, consistent with winds pushing water into the Red Sea in fall and out during spring; the steric signal is largest in summer, consistent with surface warming; and the cool, intermediate‐depth water flowing into the Red Sea in spring has little impact on the steric signal, because contributions from the lowered temperature are offset by effects of decreased salinity. The results suggest that the combined use of altimeter and GRACE measurements can provide a useful alternative to in situ data for monitoring the steric signal.
Measuring Physician Adherence With Gout Quality Indicators: A Role for Natural Language Processing
Authors: Kerr Gail S. , Richards John S. , Nunziato Carl A. , Patterson Olga V. , DuVall Scott L. , Aujero Mireille , Maron David , Amdur Richard
Published: July 2014

Objective

To evaluate physician adherence with gout quality indicators (QIs) for medication use and monitoring, and behavioral modification (BM).

Methods

Gout patients were assessed for the QIs as follows: QI 1: initial allopurinol dosage <300 mg/day for patients with chronic kidney disease (CKD); QI 2: uric acid within 6 months of allopurinol start; and QI 3: complete blood count and creatinine phosphokinase within 6 months of colchicine initiation. Natural language processing (NLP) was used to analyze clinical narrative data from electronic medical records (EMRs) of overweight (body mass index ≥28 kg/m2) gout patients for BM counseling on gout‐specific dietary restrictions, weight loss, and alcohol consumption (QI 4). Additional data included sociodemographics, comorbidities, and number of rheumatology and primary care visits. QI compliance versus noncompliance was compared using chi‐square analyses and independent‐groups t‐test.

Results

In 2,280 gout patients, compliance with QI was as follows: QI 1: 92.1%, QI 2: 44.8%, and QI 3: 7.7%. Patients compliant with QI 2 had more rheumatology visits at 3.5 versus 2.6 visits (P < 0.001), while those compliant with QI 3 had more CKD (P < 0.01). Of 1,576 eligible patients, BM counseling for weight loss occurred in 1,008 patients (64.0%), low purine diet in 390 (24.8%), alcohol abstention in 137 (8.7%), and all 3 elements in 51 patients (3.2%). Regular rheumatology clinic visits correlated with frequent advice on weight loss and gout‐specific diet (P < 0.0001).

Conclusion

Rheumatology clinic attendance was associated with greater QI compliance. NLP proved a valuable tool for measuring BM as documented in the clinical narrative of EMRs.
Lifetime Medical Costs of Knee Osteoarthritis Management in the United States: Impact of Extending Indications for Total Knee Arthroplasty
Authors: Losina Elena , Paltiel A. David , Weinstein Alexander M. , Yelin Edward , Hunter David J. , Chen Stephanie P. , Klara Kristina , Suter Lisa G. , Solomon Daniel H. , Burbine Sara A. , Walensky Rochelle P. , Katz Jeffrey N.
Published: July 2014

Objective

The impact of increasing utilization of total knee arthroplasty (TKA) on lifetime costs in persons with knee osteoarthritis (OA) is understudied.

Methods

We used the Osteoarthritis Policy Model to estimate total lifetime costs and TKA utilization under a range of TKA eligibility criteria among US persons with symptomatic knee OA. Current TKA utilization was estimated from the Multicenter Osteoarthritis Study and calibrated to Health Care Cost and Utilization Project data. OA treatment efficacy and toxicity were drawn from published literature. Costs in 2013 dollars were derived from Medicare reimbursement schedules and Red Book Online. Time costs were derived from published literature and the US Bureau of Labor Statistics.

Results

Estimated average discounted (3% per year) lifetime costs for persons diagnosed with knee OA were $140,300. Direct medical costs were $129,600, with $12,400 (10%) attributable to knee OA over 28 years. OA patients spent a mean ± SD of 13 ± 10 years waiting for TKA after failing nonsurgical regimens. Under current TKA eligibility criteria, 54% of knee OA patients underwent TKA over their lifetimes. Estimated OA‐related discounted lifetime direct medical costs ranged from $12,400 (54% TKA uptake) when TKA eligibility was limited to Kellgren/Lawrence grades 3 or 4 to $16,000 (70% TKA uptake) when eligibility was expanded to include symptomatic OA with a lesser degree of structural damage.

Conclusion

Because of low efficacy of nonsurgical regimens, knee OA treatment–attributable costs are low, representing a small portion of all costs for OA patients. Expanding TKA eligibility increases OA‐related costs substantially for the population, underscoring the need for more effective nonoperative therapies.
Measurement Properties of the Western Ontario and McMaster Universities Osteoarthritis Index: A Systematic Review
Authors: Gandek Barbara
Published: July 2014

Objective

To conduct a systematic review of the measurement properties of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and to evaluate the quality of WOMAC measurement studies using COSMIN (Consensus‐Based Standards for the Selection of Health Measurement Instruments) criteria.

Methods

A search was conducted in the MEDLINE, CINAHL, Embase, PsycINFO, Scopus, and SPORTDiscus databases through September 2013. Data that assessed the WOMAC measurement model, reliability, validity, respondent burden, and equivalence across methods of administration were extracted. Overall study quality was rated following COSMIN criteria.

Results

A total of 76 articles from 22 countries were included. Internal consistency reliability was consistently high (≥0.90) for the function scale and acceptable (≥0.70) for the pain and stiffness scales. Test–retest reliability was acceptable. Score equivalence was demonstrated across paper and electronic methods of data collection. Floor and ceiling effects were low except for notable (24–38%) proportions of patients achieving the best possible scores on the pain and stiffness scales 1–23 years after arthroplasty. Five exploratory factor analyses did not support a measurement model in which the pain and function items were distinct. Correlations between the WOMAC pain and function scales were high (median 0.79). The WOMAC pain and function scales had similar correlations with other pain measures, and therefore the WOMAC pain scale did not show divergent validity. COSMIN criteria were not fully met in most studies.

Conclusion

The WOMAC scales were reliable, but its pain scale was highly related to physical function. Further research into joint‐specific pain measures that have broader content validity is needed.
Differential Regulatory Role of Pituitary Adenylate Cyclase–Activating Polypeptide in the Serum‐Transfer Arthritis Model
Authors: Botz Bálint , Bölcskei Kata , Kereskai László , Kovács Miklós , Németh Tamás , Szigeti Krisztián , Horváth Ildikó , Máthé Domokos , Kovács Noémi , Hashimoto Hitoshi , Reglődi Dóra , Szolcsányi János , Pintér Erika , Mócsai Attila , Helyes Zsuzsanna
Published: July 2014

Objective

Pituitary adenylate cyclase–activating polypeptide (PACAP) expressed in capsaicin‐sensitive sensory neurons and immune cells has divergent functions in inflammatory and pain processes. This study was undertaken to investigate the involvement of PACAP in a mouse model of rheumatoid arthritis.

Methods

Arthritis was induced in PACAP−/− and wild‐type (PACAP+/+) mice by K/BxN serum transfer. General features of the disease were investigated by semiquantitative scoring, plethysmometry, and histopathologic analysis. Mechano‐ and thermonociceptive thresholds and motor functions were also evaluated. Metabolic activity was assessed by positron emission tomography. Bone morphology was measured by in vivo micro–computed tomography, myeloperoxidase activity and superoxide production by bioluminescence imaging with luminol and lucigenin, respectively, and vascular permeability by fluorescent indocyanine green dye study.

Results

PACAP+/+ mice developed notable joint swelling, reduced grasping ability, and mechanical (but not thermal) hyperalgesia after K/BxN serum transfer. In PACAP−/− mice clinical scores and edema were significantly reduced, and mechanical hyperalgesia and motor impairment were absent, throughout the 2‐week period of observation. Metabolic activity and superoxide production increased in the tibiotarsal joints of wild‐type mice but were significantly lower in PACAP−/− animals. Myeloperoxidase activity in the ankle joints of PACAP−/− mice was significantly reduced in the early phase of arthritis, but increased in the late phase. Synovial hyperplasia was also significantly increased, and progressive bone spur formation was observed in PACAP‐deficient mice only.

Conclusion

In PACAP‐deficient mice with serum‐transfer arthritis, joint swelling, vascular leakage, hyperalgesia, and early inflammatory cell accumulation are reduced; in the later phase of the disease, immune cell function and bone neoformation are increased. Elucidation of the underlying pathways of PACAP activity may open promising new avenues for development of therapy in inflammatory arthritis.
Association of Reduced Type IX Collagen Gene Expression in Human Osteoarthritic Chondrocytes With Epigenetic Silencing by DNA Hypermethylation
Authors: Imagawa Kei , de Andrés María C. , Hashimoto Ko , Itoi Eiji , Otero Miguel , Roach Helmtrud I. , Goldring Mary B. , Oreffo Richard O. C.
Published: July 2014

Objective

To investigate whether the changes in collagen gene expression in osteoarthritic (OA) human chondrocytes are associated with changes in the DNA methylation status in the COL2A1 enhancer and COL9A1 promoter.

Methods

Expression levels were determined using quantitative reverse transcription–polymerase chain reaction, and the percentage of DNA methylation was quantified by pyrosequencing. The effect of CpG methylation on COL9A1 promoter activity was determined using a CpG‐free vector; cotransfections with expression vectors encoding SOX9, hypoxia‐inducible factor 1α (HIF‐1α), and HIF‐2α were carried out to analyze COL9A1 promoter activities in response to changes in the methylation status. Chromatin immunoprecipitation assays were carried out to validate SOX9 binding to the COL9A1 promoter and the influence of DNA methylation.

Results

Although COL2A1 messenger RNA (mRNA) levels in OA chondrocytes were 19‐fold higher than those in the controls, all of the CpG sites in the COL2A1 enhancer were totally demethylated in both samples. The levels of COL9A1 mRNA in OA chondrocytes were 6,000‐fold lower than those in controls; 6 CpG sites of the COL9A1 promoter were significantly hypermethylated in OA patients as compared with controls. Treatment with 5‐azadeoxycitidine enhanced COL9A1 gene expression and prevented culture‐induced hypermethylation. In vitro methylation decreased COL9A1 promoter activity. Mutations in the 5 CpG sites proximal to the transcription start site decreased COL9A1 promoter activity. Cotransfection with SOX9 enhanced COL9A1 promoter activity; CpG methylation attenuated SOX9 binding to the COL9A1 promoter.

Conclusion

This first demonstration that hypermethylation is associated with down‐regulation of COL9A1 expression in OA cartilage highlights the pivotal role of epigenetics in OA, involving not only hypomethylation, but also hypermethylation, with important therapeutic implications for OA treatment.
Structural Associations of Symptomatic Knee Osteoarthritis
Authors: Stoppiello Laura A. , Mapp Paul I. , Wilson Deborah , Hill Roger , Scammell Brigitte E. , Walsh David A.
Published: July 2014

Objective

Structural changes of osteoarthritis (OA) may occur in the absence of pain. In this study, we aimed to identify histopathologic features that are associated with symptomatic knee OA.

Methods

Medial tibial plateaus and synovium samples were obtained at the time of total knee replacement (TKR) surgery for OA (advanced OA group) or were obtained postmortem from subjects who had not sought medical attention for knee pain during the last year of life (non‐OA control group). To identify features of OA, we compared the patients with advanced OA with the age‐matched non‐OA controls (n = 26 per group). To identify OA features associated with symptoms, we compared two additional groups of subjects who were matched for severity of chondropathy (n = 29 per group): patients undergoing TKR for symptomatic OA (symptomatic chondropathy group) and postmortem subjects with similar severity of chondropathy who were asymptomatic during the last year of life (asymptomatic chondropathy group). The histologic features of the samples were graded, and immunoreactivities for macrophages (CD68) and nerve growth factor (NGF) in the synovium were quantified. The cellular localization of synovial NGF was determined by double immunofluorescence analysis.

Results

Advanced OA cases displayed more severe changes in the synovium (synovitis, increased synovial NGF, and CD68‐immunoreactive macrophages) and cartilage (loss of cartilage surface integrity, loss of proteoglycan, tidemark breaching, and alterations in chondrocyte morphology) than did the non‐OA controls. Synovial NGF was localized predominantly to fibroblasts and to some macrophages. The symptomatic chondropathy group displayed greater levels of synovitis, synovial NGF, and loss of cartilage integrity, in addition to alterations in chondrocyte morphology, than did the asymptomatic chondropathy group (P < 0.05 for each comparison).

Conclusion

Synovitis, increased synovial NGF, alterations in chondrocyte morphology, and loss of cartilage integrity are features of knee OA that may be associated with symptoms.
Analysis of Infections and All‐Cause Mortality in Phase II, Phase III, and Long‐Term Extension Studies of Tofacitinib in Patients With Rheumatoid Arthritis
Authors: Cohen Stanley , Radominski Sebastião C. , Gomez‐Reino Juan J. , Wang Lisy , Krishnaswami Sriram , Wood Susan P. , Soma Koshika , Nduaka Chudi I. , Kwok Kenneth , Valdez Hernan , Benda Birgitta , Riese Richard
Published: July 2014

Objective

To determine the rate of infection and all‐cause mortality across tofacitinib phase II, phase III, and long‐term extension (LTE) studies in patients with moderately to severely active rheumatoid arthritis (RA).

Methods

Pooled data from studies of tofacitinib in patients with RA were analyzed. In these studies, tofacitinib was administered as monotherapy or in combination with methotrexate or other nonbiologic disease‐modifying antirheumatic drugs. The cutoff date for inclusion of data was April 19, 2012.

Results

Across phase II, phase III, and LTE studies, 4,789 patients received tofacitinib (8,460 patient‐years of exposure). The overall rate of serious infection was 3.09 events per 100 patient‐years (95% confidence interval [95% CI] 2.73–3.49), and rates were stable over time. A Cox proportional hazards model showed that age, corticosteroid dose, diabetes, and tofacitinib dose were independently linked to the risk of serious infection. Lymphocyte counts of <0.5 × 103/mm3 were rare but were associated with an increased risk of treated and/or serious infection. Overall, all‐cause mortality rates were 0.30 events per 100 patient‐years (95% CI 0.20–0.44).

Conclusion

The overall risk of infection (including serious infection) and mortality rates in RA patients treated with tofacitinib appear to be similar to those observed in RA patients treated with biologic agents. The rates of serious infection were stable over time.
Prevention of Murine Lupus Nephritis by Targeting Multiple Signaling Axes and Oxidative Stress Using a Synthetic Triterpenoid
Authors: Wu Tianfu , Ye Yujin , Min So‐Youn , Zhu Jiankun , Khobahy Elhaum , Zhou Jason , Yan Mei , Hemachandran Sriram , Pathak Simanta , Zhou Xin J. , Andreeff Michael , Mohan Chandra
Published: July 2014

Objective

Current treatment options for lupus are far from optimal. Previously, we reported that phosphatidylinositol 3‐kinase/Akt/mammalian target of rapamycin, MEK‐1/ERK‐1,2, p38, STAT‐3, STAT‐5, NF‐κB, multiple Bcl‐2 family members, and various cell cycle molecules were overexpressed in splenic B cells in an age‐dependent and gene dose–dependent manner in mouse strains with spontaneous lupus. Since the synthetic triterpenoid methyl‐2‐cyano‐3,12‐dioxooleana‐1,9‐dien‐28‐oate (CDDO‐Me) has been shown to inhibit AKT, MEK‐1/2, and NF‐κB, and to induce caspase‐mediated apoptosis, we tested the therapeutic potential of this agent in murine lupus nephritis.

Methods

The synthetic triterpenoid CDDO‐Me or placebo was administered to 2‐month‐old B6.Sle1.Sle3 mice or MRL/lpr mice, which develop spontaneous lupus. All mice were phenotyped for disease.

Results

CDDO‐Me–treated mice exhibited significantly reduced splenic cellularity, with decreased numbers of both CD4+ T cells and activated CD69+/CD4+ T cells compared to the placebo‐treated mice. These mice also exhibited a significant reduction in serum autoantibody levels, including anti–double‐stranded DNA (anti‐dsDNA) and antiglomerular antibodies. Finally, CDDO‐Me treatment attenuated renal disease in mice, as indicated by reduced 24‐hour proteinuria, blood urea nitrogen, and glomerulonephritis. At the mechanistic level, CDDO‐Me treatment dampened MEK‐1/2, ERK, and STAT‐3 signaling within lymphocytes and oxidative stress. Importantly, the NF‐E2–related factor 2 pathway was activated after CDDO‐Me treatment, indicating that CDDO‐Me may modulate renal damage in lupus via the inhibition of oxidative stress.

Conclusion

These findings underscore the importance of AKT/MEK‐1/2/NF‐κB signaling in engendering murine lupus. Our findings indicate that the blockade of multiple signaling nodes and oxidative stress may effectively prevent and reverse the hematologic, autoimmune, and pathologic manifestations of lupus.
Oral Bisphosphonate Use and Total Knee/Hip Implant Survival: Validation of Results in an External Population‐Based Cohort
Authors: Prieto‐Alhambra Daniel , Lalmohamed Arief , Abrahamsen Bo , Arden Nigel K. , de Boer Anthonius , Vestergaard Peter , de Vries Frank
Published: July 2014

Objective

Aseptic loosening is the most common cause of revision arthroplasty. Bisphosphonates could minimize this through their antiresorptive effects. This study was undertaken to investigate the association between bisphosphonate use and implant survival.

Methods

A retrospective cohort study was conducted within the Danish nationwide registries (5.5 million residents). Using procedure codes of the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, we identified patients age ≥40 years undergoing total joint replacement in 1998–2007. We excluded users of disease‐modifying antirheumatic drugs as well as patients with rheumatoid arthritis, Paget's disease, or hip fracture. Participants were classified as bisphosphonate users if they had been receiving treatment for ≥6 months. A time‐varying exposure was used to avoid immortal time bias. Up to 6 bisphosphonate nonusers undergoing arthroplasty were matched to each bisphosphonate user, using propensity scores. Stratified Cox regression was performed to model implant survival according to bisphosphonate use. Further, we studied the associations of implant survival with duration of use, adherence (medication possession ratio), and timing of therapy initiation (preoperative/postoperative).

Results

Of 95,392 patients with a primary total joint replacement, 80,342 (84.2%) were eligible. We identified 1,590 bisphosphonate users (2.0%), and 1,558 of them (98.0%) were matched to 8,966 bisphosphonate nonusers. Twenty‐seven of the 1,558 bisphosphonate users (1.73%) and 399 of the 8,966 matched nonusers (4.45%) underwent revision surgery during the study followup period (at a median 2.61 years after the first surgery [interquartile range 1.04–5.41 years]). Cox regression showed a reduced risk of revision surgery in bisphosphonate users (hazard ratio 0.41 [95% confidence interval 0.27–0.61]). This association was strongest in patients with the longest duration of treatment and/or the best adherence.

Conclusion

Oral bisphosphonate users have a 59% reduced risk of revision surgery. This association is only present when bisphosphonates are started after arthroplasty surgery. Confirmation in randomized controlled trials is urgently needed.
Fat Metaplasia and Backfill Are Key Intermediaries in the Development of Sacroiliac Joint Ankylosis in Patients With Ankylosing Spondylitis
Authors: Maksymowych Walter P. , Wichuk Stephanie , Chiowchanwisawakit Praveena , Lambert Robert G. , Pedersen Susanne J.
Published: July 2014

Objective

Fat metaplasia in bone marrow on T1‐weighted magnetic resonance imaging (MRI) scans may develop after resolution of inflammation in patients with ankylosing spondylitis (AS) and may predict new bone formation in the spine. Similar tissue, termed backfill, may also fill areas of excavated bone in the sacroiliac (SI) joints and may reflect resolution of inflammation and tissue repair at sites of erosions. The purpose of this study was to test our hypothesis that SI joint ankylosis develops following repair of erosions and that tissue characterized by fat metaplasia is a key intermediary step in this pathway.

Methods

We used the Spondyloarthritis Research Consortium of Canada (SPARCC) SI structural lesion score (SSS) method to assess fat metaplasia, erosions, backfill, and ankylosis on MRIs of the SI joints in 147 patients with AS monitored for 2 years. Univariate and multivariate regression analyses focused first on identifying significant MRI predictors of new backfill and fat metaplasia. We then assessed the role of backfill and fat metaplasia in the development of new ankylosis. All analyses were adjusted for demographic features, treatment, and baseline and 2‐year change in SSS values for parameters of inflammation and MRI structural lesions.

Results

Resolution of inflammation and reduction of erosions were each independently associated with the development of new backfill and fat metaplasia at 2 years on multivariate analyses. Multivariate regression analysis that included demographic features, baseline and 2‐year change in parameters of inflammation and MRI structural lesion showed that reduction in erosions (P = 0.0005) and increase in fat metaplasia (P = 0.002) at 2 years was each independently associated with the development of new ankylosis.

Conclusion

Our data support a disease model whereby ankylosis develops following repair of erosions, and fat metaplasia and backfill are key intermediary steps in this pathway.