bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Factor XIII-A G185T Polymorphism on Visual Prognosis after Photodynamic Therapy for Neovascular Macular Degeneration
Authors: Parmeggiani Francesco , Costagliola Ciro , Semeraro Francesco , Romano Mario , Rinaldi Michele , Gallenga Carla , Serino Maria , Incorvaia Carlo , D’Angelo Sergio , De Nadai Katia , Dell’Omo Roberto , Russo Andrea , Gemmati Donato , Perri Paolo
Published: August 2015

Macular degenerations represent leading causes of central blindness or low vision in developed countries. Most of these severe visual disabilities are due to age-related macular degeneration (AMD) and pathologic myopia (PM), both of which are frequently complicated by subfoveal choroidal neovascularization (CNV). Photodynamic therapy with verteporfin (PDT-V) is still employed for CNV treatment in selected cases or in combined regimen. In Caucasian patients, the common polymorphism G185T of factor XIII-A gene (FXIII-A-G185T; rs5985) has been described as predictor of poor angiographic CNV responsiveness to PDT-V. Nevertheless, the prognostic implications of this pharmacogenetic determinant on long-term visual outcome after a PDT-V regimen have not been evaluated. We retrospectively selected Caucasian patients presenting with treatment-naive CNV and receiving standardized PDT-V protocol for two years. The study population included patients affected by subfoveal CNV secondary to AMD or PM. We assessed the correlations between the polymorphic allele T of FXIII-A-G185T and: (1) total number of photodynamic treatments; and (2) change in visual acuity from baseline to the end of the follow-up period. Considering a total study population of 412 patients with neovascular AMD or PM, the carriers of 185 T-allele of FXIII-A (GT or TT genotype) received a higher number of photodynamic treatments than patients without it (GG wild-type genotype) (p < 0.01; mean number of PDT-V: 5.51 vs. 3.76, respectively). Moreover, patients with 185 T-allele of FXIII-A had a more marked worsening of visual acuity at 24 months than those with the GG-185 wild genotype (p < 0.01; mean difference in logMAR visual acuity: 0.22 vs. 0.08, respectively). The present findings show that the G185T polymorphism of the FXIII-A gene is associated with significant differences in the long-term therapeutic outcomes of patients treated with standardized PDT-V protocol. The comprehensive appraisal of both anti-thrombophilic effects due to FXIII-A G185T variant and photo-thrombotic action of PDT-V toward CNV provides several clues about the rationale of this intriguing pharmacogenetic correlation. Further investigations are warranted to outline the appropriate paradigm for guiding PDT-V utilization in the course of the combined therapeutic protocol for neovascular macular degeneration.
In Silico Analysis of Correlations between Protein Disorder and Post-Translational Modifications in Algae
Authors: Kurotani Atsushi , Sakurai Tetsuya
Published: August 2015

Recent proteome analyses have reported that intrinsically disordered regions (IDRs) of proteins play important roles in biological processes. In higher plants whose genomes have been sequenced, the correlation between IDRs and post-translational modifications (PTMs) has been reported. The genomes of various eukaryotic algae as common ancestors of plants have also been sequenced. However, no analysis of the relationship to protein properties such as structure and PTMs in algae has been reported. Here, we describe correlations between IDR content and the number of PTM sites for phosphorylation, glycosylation, and ubiquitination, and between IDR content and regions rich in proline, glutamic acid, serine, and threonine (PEST) and transmembrane helices in the sequences of 20 algae proteomes. Phosphorylation, O-glycosylation, ubiquitination, and PEST preferentially occurred in disordered regions. In contrast, transmembrane helices were favored in ordered regions. N-glycosylation tended to occur in ordered regions in most of the studied algae; however, it correlated positively with disordered protein content in diatoms. Additionally, we observed that disordered protein content and the number of PTM sites were significantly increased in the species-specific protein clusters compared to common protein clusters among the algae. Moreover, there were specific relationships between IDRs and PTMs among the algae from different groups.
Ecological Recycling Agriculture to Enhance Agro-Ecosystem Services in the Baltic Sea Region: Guidelines for Implementation
Authors: Stein-Bachinger Karin , Reckling Moritz , Bachinger Johann , Hufnagel Johannes , Koker Wijnand , Granstedt Artur
Published: August 2015

Eutrophication caused by agriculture is an increasing ecological threat to the Baltic Sea. Modern, resource-efficient farming systems based on integrated plant and animal production, effective nutrient recycling and low external inputs can enhance multiple agro-ecosystem services, resulting in reduced pollution. Practical examples of such farming systems are not widespread. Therefore, the Baltic Ecological Recycling Agriculture and Society (BERAS) Implementation project aimed to foster this systemic shift. In this paper, agronomic strategies are described to improve nitrogen (N) efficiency for the conversion to ecological recycling agriculture (ERA). First, N farm gate balances of 22 farms in conversion are presented. They showed a large variation from −9 to 90 kg∙N∙ha−1∙a−1. Then, the use of guidelines and advisory tools to improve the nitrogen efficiency is described. The legume estimation trainer and nitrogen budget calculator help assess and optimize the nitrogen supply from legumes under farming conditions. The application of the crop rotation planning tool “ROTOR” guides advisors and farmers to identify agronomically and environmentally sound rotations. The tools can help overcome key agronomic constraints by implementing ERA. The necessity of accompanying measures from policy and the need to change food consumption patterns are discussed.
A New Ionone Glycoside and Three New Rhemaneolignans from the Roots of Rehmannia glutinosa
Authors: Li Meng , Wang Xiaolan , Zheng Xiaoke , Wang Jianchao , Zhao Wei , Song Kai , Zhao Xuan , Zhang Yanli , Kuang Haixue , Feng Weisheng
Published: August 2015

A new ionone glycoside, frehmaglutoside I (1), and three new rhemaneolignans A–C (2–4) were isolated from the 95% EtOH extract of the roots of Rehmannia glutinosa. Their structures were determined by extensive spectroscopic (UV, IR, HR-ESI-MS, 1D and 2D NMR) analyses. In addition, these compounds were evaluated for their protective effects on cardiocytes impaired by doxorubicin in H9c2 cells. Among them, compounds 1–3 exhibited protective effects against DOX-induced cardiotoxicity.
Carbon Nanotube/Alumina/Polyethersulfone Hybrid Hollow Fiber Membranes with Enhanced Mechanical and Anti-Fouling Properties
Authors: Feng Yi , Wang Kun , Davies Chris , Wang Huanting
Published: August 2015

Carbon nanotubes (CNTs) were incorporated into alumina/polyethersulfone hollow fibre membranes to enhance the mechanical property and the efficiency of water treatment. Results show that the incorporation of CNTs can greatly limit the formation of large surface pores, decrease the void size in support layers and improve the porosity and pore connectivity of alumina/polyethersulfone membranes. As a result of such morphology change and pore size change, both improved flux and rejection were achieved in such CNTs/alumina/polyethersulfone membranes. Moreover, the CNTs/alumina/PES membranes show higher antifouling ability and the flux recoveries after being fouled by bovine serum albumin (BSA) and humic acid were improved by 84.1% and 53.2% compared to the samples without CNT incorporation. Besides the improvement in water treatment performance, the incorporation of CNTs enhanced the tensile properties of inorganic/polymer membranes. Therefore, such CNTs/alumina/PES hollow fiber membranes are very promising candidates for good filter media in industry, considering their high efficiency and high mechanical properties.
Study on the Mechanical Properties of Stay Cable HDPE Sheathing Fatigue in Dynamic Bridge Environments
Authors: Dan Danhui , Sun Limin , Guo Yanheng , Cheng Wei
Published: August 2015

As the main force-bearing component of a cable-stayed bridge, a durable stay cable is paramount to the safety and durability of the entire bridge. High-density polyethylene (HDPE) sheathing is the main protective component of a stay cable and is the key to insuring cable durability. To address the issue of HDPE sheathing fracture on service, strain level data for in-service, HDPE bridge cable sheathing was used in this study as the basis for HDPE material aging and fatigue testing. A fatigue yield phenomenon with a yield platform on the hysteresis curve of the fatigue cycles is observed by the fatigue test. The parameters to describe this phenomenon are proposed and defined in this paper. A preliminary examination of the relationship between these parameters and the factors, such as the number of cycles, the strain amplitude, and strain rate, are presented. Based on the results obtained, it is suggested that the condition of fatigue yield of HDPE sheathing be defined as the fatigue durability limit state for the purposes of durability design, assessment, and protection of cable-stayed bridges.
Beneficial and Adverse Effects of Electro-acupuncture Assessed in the Canine Chronic Atrio-ventricular Block Model Having Severe Hypertension and Chronic Heart Failure
Authors: Cao Xin , Lu Shengfeng , Ohara Hiroshi , Nakamura Yuji , Izumi-Nakaseko Hiroko , Ando Kentaro , Zhu Bingmei , Xu Bin , Sugiyama Atsushi
Published: August 2015

Regarding the effects of electro-acupuncture for severe hypertension, we assessed its acute cardiovascular consequences with 4 subjects of the chronic atrioventricular block dogs having severe hypertension and chronic heart failure. The electro-acupuncture consisting of 2 mA at 2 Hz frequency was carried out for 30 min at Renying (ST-9) and Taichong (LR-3) every other day. Seven sessions were performed within 2 weeks. In the 1st and 7th sessions, the animals were anesthetized with pentobarbital to analyze the effects of the electro-acupuncture on cardiovascular variables. No significant change was detected in any of the basal control values of the cardiohemodynamic or electrophysiological variables between the 1st and 7th sessions. During the 1st session, electo-acupuncture produced a peak increase in mean blood pressure by 8.7% at 35 min (p<0.05), whereas during the 7th session the peak increase was 6.5% at 35 min (p=0.06). There was no significant change in the cardiac output, total peripheral resistance, a product of the heart rate and systolic blood pressure (=double product) reflecting myocardial oxygen consumption, QRS width or QT interval during the electrical stimulation in the 1st or 7th session. The results suggest that electroacupuncture may not exert lethal adverse effect except the vasopressor response, but that it can decrease the treatment-induced sympathetic response including vasopressor reaction and tachycardia. Since electro-acupuncture may have some potential to induce hypertensive crisis at the beginning, clinicians have to pay attention on its use for patients with hypertension.
Consequences of the electronic tuning of latent ruthenium-based olefin metathesis catalysts on their reactivity
Authors: Żukowska Karolina , Pump Eva , Pazio Aleksandra E , Woźniak Krzysztof , Cavallo Luigi , Slugovc Christian
Published: August 2015

Two ruthenium olefin metathesis initiators featuring electronically modified quinoline-based chelating carbene ligands are introduced. Their reactivity in RCM and ROMP reactions was tested and the results were compared to those obtained with the parent unsubstituted compound. The studied complexes are very stable at high temperatures up to 140 °C. The placement of an electron-withdrawing functionality translates into an enhanced activity in RCM. While electronically modified precatalysts, which exist predominantly in the trans-dichloro configuration, gave mostly the RCM and a minor amount of the cycloisomerization product, the unmodified congener, which preferentially exists as its cis-dichloro isomer, shows a switched reactivity. The position of the equilibrium between the cis- and the trans-dichloro species was found to be the crucial factor governing the reactivity of the complexes.
Evaluation of Health Outcomes with Etanercept Treatment in Patients with Early Nonradiographic Axial Spondyloarthritis
Authors: Dougados Maxime , Tsai Wen-Chan , Saaibi Diego L. , Bonin Randi , Bukowski Jack , Pedersen Ron , Vlahos Bonnie , Kotak Sameer
Published: August 2015

Objective.

Analyses were conducted to examine the baseline burden of illness and compare the effect of etanercept (ETN) versus placebo (PBO) on quality of life (QOL) in patients with nonradiographic axial spondyloarthritis (nr-axSpA) who failed nonsteroidal antiinflammatory drugs (NSAID).

Methods.

Patients fulfilling the Assessment of Spondyloarthritis International Society axSpA criteria, not meeting the modified New York criteria for ankylosing spondylitis (AS), who were symptomatic 3 months to 5 years, with a Bath AS Disease Activity Index score ≥ 4, and failed ≥ 2 NSAID were randomized to ETN 50 mg weekly or PBO (double-blind) for 12 weeks, followed by open-label ETN 50 mg for 92 weeks. Stable NSAID were allowed throughout our study. QOL outcomes over 24 weeks were analyzed using ANCOVA models.

Results.

At baseline, Multidimensional Fatigue Inventory (MFI; ETN mean 14.7, PBO mean 15.0), EQ-5D utility (0.52, 0.57), EQ-5D visual analog scale (56.5, 56.4), and Medical Outcomes Study (MOS) Sleep Index II (45.5, 48.1) were worse than population norms (6.6–8.0, 0.86, 82.5, and 25.8, respectively). At Week 12, Bath AS Patient Global Score, nocturnal and average back pain, MOS Short Form-36 (SF-36) physical component, and Work Productivity and Activity Index (WPAI) presenteeism and activity impairment favored ETN (p < 0.05). Nonsignificant improvements for ETN were seen in other WPAI domains, MFI, MOS-Sleep Index I and II, Hospital Anxiety and Depression Scale, EQ-5D utility score, and SF-36 mental component (p > 0.05). At Week 24, patients in the PBO group who had switched to ETN at Week 12 showed improvement in most QOL assessments, similar to that seen in patients receiving ETN for 24 weeks.

Conclusion.

Improvements favored ETN in QOL and productivity measures, with limited improvement on general QOL measures. Short disease duration, a short PBO-controlled period, and a wide range of QOL scores at baseline may have influenced improvements.
Alemtuzumab as Remission Induction Therapy in Behçet Disease: A 20-year Experience
Authors: Mohammad Aladdin J. , Smith Rona M. , Chow Yok W. , Chaudhry Afzal N. , Jayne David R.W.
Published: August 2015

Objective.

To study the efficacy and safety of anti-CD52 antibody (alemtuzumab) in the treatment of refractory and relapsing Behçet disease (BD).

Methods.

Thirty-two patients (22 women) with BD received 60 courses of alemtuzumab between 1994 and 2013. Three-dose regimens were used: 134 mg in 21 courses (Group 1), 95 mg in 18 courses (Group 2), and 60 mg in 21 courses (Group 3). Immunosuppressive drugs were stopped at the time of alemtuzumab, and prednisolone was reduced according to clinical response. Treatment response was assessed by clinical status, inflammatory activity, prednisolone dose, and the need for subsequent immunosuppressive drugs and disease relapse.

Results.

After the first alemtuzumab course, 27 of 32 patients (84%) achieved partial or complete remission (CR). Fifty of 60 courses (83%) resulted in remission (66% CR) without differences in remission rates between dosing regimens. Profound lymphocyte depletion occurred after all courses. Relapse-free survival rates were 83.6% at 6 months and 52.8% at 12 months, and were higher among Group 1 patients (Group 1: 100% and 77.8%, Group 2: 81.3% and 37.5%, and Group 3: 65.0% and 37.1%, p < 0.001). Mild to moderate infusion reactions occurred after 16 courses (27%). Eight patients (25%) developed symptomatic thyroid disease.

Conclusion.

Alemtuzumab led to remission in the majority of patients with difficult-to-treat BD. Relapse was common and may be associated with lower dosing. Adverse events included infusion reactions and new autoimmunity. Achieving complete lymphocyte depletion did not affect the remission rate or duration.
Longterm Safety of Rituximab: Final Report of the Rheumatoid Arthritis Global Clinical Trial Program over 11 Years
Authors: van Vollenhoven Ronald F. , Fleischmann Roy M. , Furst Daniel E. , Lacey Stuart , Lehane Patricia B.
Published: August 2015

Objective.

Final evaluation of the longterm safety of rituximab (RTX) in rheumatoid arthritis (RA) up to 11 years.

Methods.

Pooled observed case analysis of data from patients with moderate to severe, active RA in a global clinical trial program.

Results.

As of September 2012, 3595 patients received a mean of 4 courses (range 1–20) of RTX over 11 years [14,816 patient-years (PY)]. Of these, 1246 patients had > 5 years of followup (8970 PY). A pooled placebo population (n = 818) was included in the analysis. The overall serious infection event (SIE) rate was 3.76/100 PY (2.71/100 PY in patients observed for > 5 yrs) and comparable with rates reported previously at 9.5 years (3.94/100 PY and 3.26/100 PY, respectively). SIE rates continued to be similar before and during/after development of low immunoglobulin levels, and serious opportunistic infections remained rare. Rates of cardiac events remained consistent with previous analysis and with rates in the general RA population. No increased risk of malignancy over time was observed.

Conclusion.

This final report demonstrates that RTX remains well tolerated over time and multiple courses. No new safety risks were identified and there was no increase in the rate of any types of adverse events with prolonged exposure to RTX during 11 years of observation.
Relation of Autoimmune Cytopenia to Glandular and Systemic Manifestations in Primary Sjögren Syndrome: Analysis of 113 Korean Patients
Authors: Koh Jung Hee , Lee Jennifer , Chung So-Hyang , Kwok Seung-Ki , Park Sung-Hwan
Published: August 2015

Objective.

To investigate the characteristics of patients with primary Sjögren syndrome (pSS) who have autoimmune cytopenia.

Methods.

We analyzed 113 participants from the Korean Initiative of Primary Sjögren Syndrome, a prospective pSS cohort. Autoimmune cytopenia was defined as autoimmune origin neutropenia, anemia, and/or thrombocytopenia without vitamin or iron deficiency, or drug-induced cytopenia. To identify the association between autoimmune cytopenia and the clinical characteristics of pSS, extraglandular manifestations were analyzed according to the European League Against Rheumatism Sjögren’s syndrome disease activity index (ESSDAI) definition. Xerophthalmia was assessed with the Ocular Surface Disease Index, Schirmer I test, ocular stain score (OSS), and tear film breakup time.

Results.

The median total ESSDAI score was 2 (interquartile range 1–6). About a quarter of patients had no systemic activity. Autoimmune cytopenia was observed in 23.9% of patients (n = 27). Moderate biological features were more frequently observed in patients with autoimmune cytopenia than in patients without [10 (37%) and 11 (12.8%), respectively, p = 0.016]. Articular involvement was exhibited in 1 patient with autoimmune cytopenia, but in 23 patients (27.4%) without autoimmune cytopenia (p = 0.013). Higher OSS (p = 0.002) and lower mean Schirmer I test (p = 0.029) were observed in patients with autoimmune cytopenia than in those without. Neutrophils and lymphocytes negatively correlated with OSS (ρ = −0.204, p = 0.041 and ρ = −0.230, p = 0.020, respectively).

Conclusion.

Autoimmune cytopenia is closely associated with severe ocular surface damage in pSS. Therefore, assessment of xerophthalmia by ophthalmologists may be mandatory, particularly in patients with pSS with cytopenia, even if patients do not complain of eye dryness.
The Endothelial-mesenchymal Transition in Systemic Sclerosis Is Induced by Endothelin-1 and Transforming Growth Factor-β and May Be Blocked by Macitentan, a Dual Endothelin-1 Receptor Antagonist
Authors: Cipriani Paola , Di Benedetto Paola , Ruscitti Piero , Capece Daria , Zazzeroni Francesca , Liakouli Vasiliki , Pantano Ilenia , Berardicurti Onorina , Carubbi Francesco , Pecetti Gianluca , Turricchia Stefano , Alesse Edoardo , Iglarz Marc , Giacomelli Roberto
Published: August 2015

Objective.

High endothelin-1 (ET-1) and transforming growth factor-β (TGF-β) levels may induce in healthy endothelial cells (EC) an endothelial-to-mesenchymal transition (EndMT). The same cytokines are associated with fibrosis development in systemic sclerosis (SSc). Although EndMT has not been definitively shown in SSc, this process, potentially induced by a stimulatory loop involving these 2 cytokines, overexpressed in this disease might contribute to fibroblast accumulation in affected tissues. Macitentan (MAC), an ET-1 receptor antagonist interfering with this loop, might prevent EndMT and fibroblast accumulation.

Methods.

EC, isolated from healthy controls (HC) and patients with SSc, were treated with ET-1 and TGF-β and successively analyzed for gene and protein expressions of endothelial and mesenchymal markers, and for Sma- and Mad-related (SMAD) phosphorylation. Further, in the supernatants, we evaluated ET-1 and TGF-β production by ELISA assay. In each assay we evaluated the ability of MAC to inhibit both the TGF-β and ET-1 effects.

Results.

We showed that both TGF-β and ET-1 treatments induced an activation of the EndMT process in SSc-EC as reported in HC cells. The ELISA assays showed a mutual TGF-β and ET-1 induction in both SSc-EC and HC-EC. A statistically significant increase of SMAD phosphorylation after treatment was observed in SSc-EC. In each assay, MAC inhibited both TGF-β and ET-1 effects.

Conclusion.

Our work is the first demonstration in literature that SSc-EC, under the synergistic effect of TGF-β and ET-1, may transdifferentiate toward myofibroblasts, thus contributing to fibroblast accumulation. MAC, interfering with this processin vitro, may offer a new potential therapeutic strategy against fibrosis.
The Spirit of OMERACT: Q Methodology Analysis of Conference Characteristics Valued by Delegates
Authors: Flurey Caroline A. , Kirwan John R. , Hadridge Phillip , Richards Pamela , Grosskleg Shawna , Tugwell Peter S.
Published: August 2015

Objective.

To identify the major features of OMERACT meetings as valued by frequent participants and to explore whether there are groups of participants with different opinions.

Methods.

Using Q methodology (a qualitative and quantitative approach to grouping people according to subjective opinion), participants (who attended more than 1 OMERACT conference) sorted 66 statements relating to the “spirit of OMERACT” according to level of agreement across a normal distribution grid. Data were examined using Q factor analysis.

Results.

Of 226 potential participants, 105 responded (46%). All participants highly ranked the focus on global standardization of methods, outcome measures, data-driven research, methodological discussion, and international collaboration. Four factors describing the “spirit of OMERACT” were identified: “Evidence not eminence” (n = 31) valued the data- and evidence-driven research above personality and status; “Collaboration and collegiality” (n = 19) valued the international and cross-stakeholder collaboration, interaction, and collegiality; “Equal voices, equal votes, common goals” (n = 12) valued equality in discussion and voting, with everyone striving toward the same goal; “principles and product, not process” (n = 8) valued the principles of focusing on outcome measures and the product of guiding clinical trials, but were unsure whether the process is necessary to reach this. The factors did not segregate different stakeholder groups.

Conclusion.

Delegates value different elements of OMERACT, and thus the “spirit of OMERACT” encompasses evidence-based research, collaboration, and equality, although a small group are unsure whether the process is necessary to achieve the end result. Q methodology may prove useful for conference organizers to identify their delegates’ different needs to tailor conference content.
Association Between Infrapatellar Fat Pad Volume and Knee Structural Changes in Patients with Knee Osteoarthritis
Authors: Cai Jingyu , Xu Jianhua , Wang Kang , Zheng Shuang , He Fan , Huan Shuting , Xu Shengqing , Zhang Hui , Laslett Laura , Ding Changhai
Published: August 2015

Objective.

The function of the infrapatellar fat pad (IPFP) in knee osteoarthritis (OA) remains uncertain. This study aimed to examine cross-sectional associations between IPFP volume and knee structures in patients with knee OA.

Methods.

The study included 174 patients with clinical knee OA (mean age, 55.5 yrs). Fat-suppressed 3-D T1-weighted spoiled gradient recall magnetic resonance imaging (MRI) was used to measure the IPFP and cartilage volume. T2-weighted fast spin echo MRI was used to assess cartilage defects and bone marrow lesions (BML). Radiographic knee osteophytes and joint space narrowing (JSN) were assessed using the Osteoarthritis Research Society International atlas.

Results.

After adjustment for potential confounders, greater IPFP volume was associated with greater tibial and patellar cartilage volume (all p < 0.05), and fewer cartilage defects at all sites (OR 0.88–0.91, all p < 0.05). IPFP volume was associated with presence of BML at lateral tibial and medial femoral sites (OR 0.88–0.91, all p < 0.05) and osteophytes at lateral tibiofemoral compartment (OR 0.88, p < 0.05). IPFP volume was not significantly associated with JSN.

Conclusion.

Greater IPFP volume was associated with greater knee cartilage volume and fewer structural abnormalities, suggesting a protective role of IPFP size in knee OA.
Factor H Autoantibodies in Patients with Antiphospholipid Syndrome and Thrombosis
Authors: Foltyn Zadura Anna , Memon Ashfaque A. , Stojanovich Ljudmila , Perricone Carlo , Conti Fabrizio , Valesini Guido , Bogdanovic Gordana , Hillarp Andreas , Shoenfeld Yehuda , Sundquist Jan , Leffler Jonatan , Svensson Peter J. , Trouw Leendert A. , Blom Anna M.
Published: August 2015

Objective.

Autoantibodies to complement factor H (FH) are associated with atypical hemolytic uremic syndrome, but can also be detected in patients with rheumatoid arthritis and in patients positive for lupus anticoagulants and thus potentially antiphospholipid syndrome (APS). To our knowledge, no data are available on the association between the presence of FH autoantibodies in APS and clinical manifestations.

Methods.

We determined FH autoantibody levels using ELISA in 2 cohorts of patients with primary (PAPS) and secondary APS (SAPS) from Serbia and Italy, and an additional cohort including patients with venous thromboembolism (VTE) from Sweden.

Results.

FH autoantibodies were detected in 13.7% of patients (n = 73) with PAPS and 30.3% of patients (n = 33) with SAPS in the Serbian cohort. FH autoantibody frequency in the Italian cohort was 33.3% (n = 15) and 36% (n = 25) in PAPS and SAPS, respectively. Both FH autoantibody levels and frequencies observed in both APS cohorts were significantly higher than in matched healthy controls (5%). Further, patients with PAPS with venous thrombosis in the Serbian cohort had significantly higher levels of FH autoantibodies. Therefore, we analyzed a dedicated Swedish thrombosis cohort and found that patients with FH autoantibody positivity had higher risk of VTE recurrence (HR 2.0, 95% CI 1.2–3.3, p = 0.011) compared with the reference group of FH autoantibody–negative patients.

Conclusion.

Overall, the data indicate that in patients with APS and recurrent venous thrombosis, there are increased levels of FH autoantibodies, a finding associated with poor clinical outcome.
Hydrogel Inlay for Presbyopia: Objective and Subjective Visual Outcomes
Authors: Yoo Aeri , Kim Jae Yong , Kim Myoung Joon , Tchah Hungwon
Published: August 2015

PURPOSE:

To evaluate changes in visual performance and ocular optical quality after implantation of a corneal hydrogel inlay as a treatment for presbyopia.

METHODS:

A Raindrop Near Vision Inlay (ReVision Optics, Lake Forest, CA) was implanted monocularly on the stromal bed of a femtosecond laser-assisted generated corneal flap of non-dominant eyes of 22 patients with emmetropic presbyopia (preoperative spherical equivalent range: −0.50 to 1.00 diopters). Efficacy was determined by measuring near and distance visual acuities and ocular aberrations, and satisfaction was assessed by a patient questionnaire.

RESULTS:

The preoperative monocular uncorrected near visual acuity of the inlay inserted eye was 20/129 ± 1 Snellen (range: 20/135 to 20/61 Snellen) and improved to 20/35 ± 2 Snellen (range: 20/61 to 20/20 Snellen) (
P
< .01) at 6 months postoperatively. The monocular uncorrected distance visual acuity of the eye receiving the inlay was 20/25 ± 2 Snellen (range: 20/50 to 20/20 Snellen) preoperatively and 20/25 ± 1 Snellen (range: 20/50 to 20/20 Snellen) at 6 months postoperatively (
P
=.257). According to the questionnaire responses, 82% of patients were satisfied. This was despite near glasses needs remaining in 13.6% of the cohort and the presence of glare and a decrease in night vision in approximately 40% of patients. The primary spherical aberration coefficient Z
4
0
changed from positive to negative values in all patients (
P
< .01). However, the point spread function showed no significant change.

CONCLUSIONS:

Hydrogel corneal inlays improve uncorrected near visual acuity in patients with presbyopia with only moderate effect on visual quality. However, the satisfaction with this therapy was relatively lower in these Korean patients than that reported previously in Western patients.

[
J Refract Surg.
2015;31(7):454–460.]
A Modified Glued Transscleral Intraocular Lens Implantation: Suture-Assisted Sutureless Technique
Authors: Kara Necip
Published: August 2015

PURPOSE:

To report a modified surgical technique as an alternative procedure for sutureless fibrin glue-assisted transscleral intraocular lens (IOL) fixation.

METHODS:

Description of the modified surgical technique with an accompanying video.

RESULTS:

In the standard glued IOL fixation technique, the leading haptic is externalized using a forceps through the sclerotomy and an assistant holds the haptic while the second IOL haptic is bimanually externalized, using the handshake technique, through the other sclerotomy site. In the author’s technique, called the suture-assisted sutureless technique, IOL haptics were tied with a looped 9-0 polypropylene suture with an attached curved needle. The suture needle was fastened to the haptic, passed through the sclerotomy site, and pulled out to externalize the haptic through the sclerotomy site.

CONCLUSIONS:

This technique is an easy, feasible, and assistant-free procedure for glued IOL implantation in aphakic eyes.

[
J Refract Surg.
2015;31(7):488–491.]
Revisión taxonómica del género Luciobarbus Heckel, 1843 (Actinopterygii, Cyprinidae) del noroeste de Marruecos con la descripción de tres nuevas especies
Authors: Casal-Lopez Miriam , Perea Silvia , Yahyaoui Ahmed , Doadrio Ignacio
Published: August 2015

En Marruecos el género Luciobarbus está altamente diversificado, en comparación con la empobrecida fauna de peces de agua dulce del norte de África. Dentro de Marruecos la región norte es una de las áreas menos estudiadas, por motivos históricos y también por la poca accesibilidad en algunas de sus regiones. Los estudios filogenéticos previos para esta área han señalado la existencia de poblaciones pertenecientes al género Luciobarbus tan diferenciadas morfológica y genéticamente como otras que ya habían sido reconocidas como diferentes especies. En este trabajo describimos estas poblaciones como diferentes taxa, en base a caracteres morfológicos, merísticos y genéticos.
IRF4 Is a Critical Gene in Retinoic Acid–Mediated Plasma Cell Formation and Is Deregulated in Common Variable Immunodeficiency–Derived B Cells
Authors: Indrevær Randi L. , Moskaug Jan Ø. , Paur Ingvild , Bøhn Siv K. , Jørgensen Silje F. , Blomhoff Rune , Aukrust Pål , Fevang Børre , Blomhoff Heidi K.
Published: August 2015

In the present study, we aimed at identifying the mechanisms whereby the vitamin A metabolite all-trans retinoic acid (RA) promotes the formation of plasma cells upon stimulation of B cells via the innate immunity receptors TLR9 and RP105. Most often, differentiation of B cells involves the sequential events of class switch recombination and somatic hypermutations characteristic of germinal center reactions, followed by plasma cell formation. By studying the regulatory networks known to drive these reactions, we revealed that RA enhances the expression of the plasma cell–generating transcription factors IFN regulatory factor (IRF)4 and Blimp1, and paradoxically also activation-induced deaminase (AID) involved in somatic hypermutations/class switch recombination, in primary human B cells. IRF4 was identified as a particularly important protein involved in the RA-mediated production of IgG in TLR9/RP105-stimulated B cells. Based on kinetic studies, we present a model suggesting that the initial induction of IRF4 by RA favors AID expression. According to this model, the higher level of IRF4 that eventually arises results in sustained elevated levels of Blimp1. Regarded as a master regulator of plasma cell development, Blimp1 will in turn suppress AID expression and drive the formation of IgG-secreting plasma cells. Notably, we demonstrated IRF4 to be deregulated in B cells from common variable immunodeficiency patients, contributing to the observed aberrant expression of AID in these patients. Taken together, the present study both provides new insight into the mechanisms whereby RA induces differentiation of B cells and identifies IRF4 as a key to understand the defective functions of B cells in common variable immunodeficiency patients.
1,25(OH)2D3 Promotes the Efficacy of CD28 Costimulation Blockade by Abatacept
Authors: Gardner David H. , Jeffery Louisa E. , Soskic Blagoje , Briggs Zoe , Hou Tie Zheng , Raza Karim , Sansom David M.
Published: August 2015

Inhibition of the CD28:CD80/CD86 T cell costimulatory pathway has emerged as an effective strategy for the treatment of T cell–mediated inflammatory diseases. However, patient responses to CD28-ligand blockade by abatacept (CTLA-4-Ig) in conditions such as rheumatoid arthritis are variable and often suboptimal. In this study, we show that the extent to which abatacept suppresses T cell activation is influenced by the strength of TCR stimulation, with high-strength TCR stimulation being associated with relative abatacept insensitivity. Accordingly, cyclosporin A, an inhibitor of T cell stimulation via the TCR, synergized with abatacept to inhibit T cell activation. We also observed that 1,25-dihydroxyvitamin D3 enhanced the inhibition of T cell activation by abatacept, strongly inhibiting T cell activation driven by cross-linked anti-CD3, but with no effect upon anti-CD28 driven stimulation. Thus, like cyclosporin A, 1,25-dihydroxyvitamin D3 inhibits TCR-driven activation, thereby promoting abatacept sensitivity. Vitamin D3 supplementation may therefore be a useful adjunct for the treatment of conditions such as rheumatoid arthritis in combination with abatacept to promote the efficacy of treatment.
Cutting Edge: miR-17-92 Is Required for Both CD4 Th1 and T Follicular Helper Cell Responses during Viral Infection
Authors: Wu Tuoqi , Wieland Andreas , Lee Judong , Hale J. Scott , Han Jin-Hwan , Xu Xiaojin , Ahmed Rafi
Published: August 2015

Viral infections induce the differentiation of naive CD4 T cells into two distinct lineages, Th1 cells and T follicular helper (TFH) cells. Two recent studies demonstrated that the microRNA cluster miR-17-92 selectively promotes CD4 TFH responses. However, we show in this study that miR-17-92 expression is required for the clonal expansion of both virus-specific Th1 and TFH cells. Upon viral infection, miR-17-92–deficient CD4 T cells showed impaired clonal expansion and subsequent memory formation. Although miR-17-92 deficiency impaired the clonal expansion of both Th1 and TFH cells, the expansion of Th1 cells was more affected. Overexpression of miR-17-92 in CD4 T cells resulted in increased expansion of both virus-specific Th1 and TFH cells but selectively enhanced the Th1 response. Taken together, our data suggest that miR-17-92 is necessary for both Th1 and TFH cells to respond efficiently to viral infections and that the Th1 response is more sensitive to the level of miR-17-92 expression.
Priming of Human Resting NK Cells by Autologous M1 Macrophages via the Engagement of IL-1β, IFN-β, and IL-15 Pathways
Authors: Mattiola Irene , Pesant Matthieu , Tentorio Paolo F. , Molgora Martina , Marcenaro Emanuela , Lugli Enrico , Locati Massimo , Mavilio Domenico
Published: August 2015

The cross talk between NK cells and macrophages is emerging as a major line of defense against microbial infections and tumors. This study reveals a complex network of soluble mediators and cell-to-cell interactions allowing human classically activated (M1) macrophages, but not resting (M0) or alternatively activated (M2) macrophages, to prime resting autologous NK cells. In this article, we show that M1 increase NK cell cytotoxicity by IL-23 and IFN-β–dependent upregulation of NKG2D, IL-1β–dependent upregulation of NKp44, and trans-presentation of IL-15. Moreover, both IFN-β–dependent cis-presentation of IL-15 on NK cells and engagement of the 2B4-CD48 pathway are used by M1 to trigger NK cell production of IFN-γ. The disclosure of these synergic cellular mechanisms regulating the M1–NK cell cross talk provides novel insights to better understand the role of innate immune responses in the physiopathology of tumor biology and microbial infections.
Cutting Edge: AhR Is a Molecular Target of Calcitriol in Human T Cells
Authors: Takami Mariko , Fujimaki Kotaro , Nishimura Michael I. , Iwashima Makio
Published: August 2015

The immunoregulatory functions of vitamin D have been well documented in various immunological disorders, including multiple sclerosis, arthritis, and asthma. IL-10 is considered a chief effector molecule that promotes the vitamin D–induced immunosuppressive states of T cells and accessory cells. In this article, we demonstrate that the active form of vitamin D, 1,25-dihydroxyvitamin D3 (calcitriol), has a profound inhibitory effect on the development of human Th9, a CD4 T cell subset that is highly associated with asthma, in an IL-10–independent manner. Our data show that calcitriol represses the expression of BATF, a transcription factor essential for Th9, via suppressing the expression of aryl hydrocarbon receptor, without an increase in IL-10. The data show a novel link between vitamin D and two key transcription factors involved in T cell differentiation.
IL-3 Maintains Activation of the p90S6K/RPS6 Pathway and Increases Translation in Human Eosinophils
Authors: Esnault Stephane , Kelly Elizabeth A. B. , Shen Zhong-Jian , Johansson Mats W. , Malter James S. , Jarjour Nizar N.
Published: August 2015

IL-5 is a major therapeutic target to reduce eosinophilia. However, all of the eosinophil-activating cytokines, such as IL-5, IL-3, and GM-CSF, are typically present in atopic diseases, including allergic asthma. As a result of the functional redundancy of these three cytokines on eosinophils and the loss of IL-5R on airway eosinophils, it is important to take IL-3 and GM-CSF into account to efficiently reduce tissue eosinophil functions. Moreover, these three cytokines signal through a common β-chain receptor but yet differentially affect protein production in eosinophils. Notably, the increased ability of IL-3 to induce the production of proteins, such as semaphorin-7A, without affecting mRNA levels suggests a unique influence of IL-3 on translation. The purpose of this study was to identify the mechanisms by which IL-3 distinctively affects eosinophil function compared with IL-5 and GM-CSF, with a focus on protein translation. Peripheral blood eosinophils were used to study intracellular signaling and protein translation in cells activated with IL-3, GM-CSF, or IL-5. We establish that, unlike GM-CSF or IL-5, IL-3 triggers prolonged signaling through activation of ribosomal protein S6 (RPS6) and the upstream kinase 90-kDa ribosomal S6 kinase (p90S6K). Blockade of p90S6K activation inhibited phosphorylation of RPS6 and IL-3–enhanced semaphorin-7A translation. Furthermore, in an allergen-challenged environment, in vivo phosphorylation of RPS6 and p90S6K was enhanced in human airway compared with circulating eosinophils. Our findings provide new insights into the mechanisms underlying differential activation of eosinophils by IL-3, GM-CSF, and IL-5. These observations identify IL-3 and its downstream intracellular signals as novel targets that should be considered to modulate eosinophil functions.
DNA Methylation Regulates the Differential Expression of CX3CR1 on Human IL-7Rαlow and IL-7Rαhigh Effector Memory CD8+ T Cells with Distinct Migratory Capacities to the Fractalkine
Authors: Shin Min Sun , You Sungyong , Kang Youna , Lee Naeun , Yoo Seung-Ah , Park Kieyoung , Kang Ki Soo , Kim Sang Hyun , Mohanty Subhasis , Shaw Albert C. , Montgomery Ruth R. , Hwang Daehee , Kang Insoo
Published: August 2015

DNA methylation is an epigenetic mechanism that modulates gene expression in mammalian cells including T cells. Memory T cells are heterogeneous populations. Human effector memory (EM) CD8+ T cells in peripheral blood contain two cell subsets with distinct traits that express low and high levels of the IL-7Rα. However, epigenetic mechanisms involved in defining such cellular traits are largely unknown. In this study, we use genome-wide DNA methylation and individual gene expression to show the possible role of DNA methylation in conferring distinct traits of chemotaxis and inflammatory responses in human IL-7Rαlow and IL-7Rαhigh EM CD8+ T cells. In particular, IL-7Rαlow EM CD8+ T cells had increased expression of CX3CR1 along with decreased DNA methylation in the CX3CR1 gene promoter compared with IL-7Rαhigh EM CD8+ T cells. Altering the DNA methylation status of the CX3CR1 gene promoter changed its activity and gene expression. IL-7Rαlow EM CD8+ T cells had an increased migratory capacity to the CX3CR1 ligand fractalkine compared with IL-7Rαhigh EM CD8+ T cells, suggesting an important biological outcome of the differential expression of CX3CR1. Moreover, IL-7Rαlow EM CD8+ T cells induced fractalkine expression on endothelial cells by producing IFN-γ and TNF-α, forming an autocrine amplification loop. Overall, our study shows the role of DNA methylation in generating unique cellular traits in human IL-7Rαlow and IL-7Rαhigh EM CD8+ T cells, including differential expression of CX3CR1, as well as potential biological implications of this differential expression.
Lipoxin A4 Attenuates Constitutive and TGF-β1–Dependent Profibrotic Activity in Human Lung Myofibroblasts
Authors: Roach Katy M. , Feghali-Bostwick Carol A. , Amrani Yassine , Bradding Peter
Published: August 2015

Idiopathic pulmonary fibrosis (IPF) is a common, progressive, and invariably lethal interstitial lung disease with no effective therapy. The key cell driving the development of fibrosis is the myofibroblast. Lipoxin A4 (LXA4) is an anti-inflammatory lipid, important in the resolution of inflammation, and it has potential antifibrotic activity. However, the effects of LXA4 on primary human lung myofibroblasts (HLMFs) have not previously been investigated. Therefore, the aim of this study was to examine the effects of LXA4 on TGF-β1–dependent responses in IPF- and nonfibrotic control (NFC)–derived HLMFs. HLMFs were isolated from IPF and NFC patients and grown in vitro. The effects of LXA4 on HLMF proliferation, collagen secretion, α-smooth muscle actin (αSMA) expression, and Smad2/3 activation were examined constitutively and following TGF-β1 stimulation. The LXA4 receptor (ALXR) was expressed in both NFC- and IPF-derived HLMFs. LXA4 (10−10 and 10−8 mol) reduced constitutive αSMA expression, actin stress fiber formation, contraction, and nuclear Smad2/3, indicating regression from a myofibroblast to fibroblast phenotype. LXA4 also significantly inhibited FBS-dependent proliferation and TGF-β1–dependent collagen secretion, αSMA expression, and Smad2/3 nuclear translocation in IPF-derived HLMFs. LXA4 did not inhibit Smad2/3 phosphorylation. In summary, LXA4 attenuated profibrotic HLMF activity and promoted HLMF regression to a quiescent fibroblast phenotype. LXA4 or its stable analogs delivered by aerosol may offer a novel approach to the treatment of IPF.
Cutting Edge: Hematopoietic Stem Cell Expansion and Common Lymphoid Progenitor Depletion Require Hematopoietic-Derived, Cell-Autonomous TLR4 in a Model of Chronic Endotoxin
Authors: Liu Ailing , Wang Yujuan , Ding Ying , Baez Ineavely , Payne Kimberly J. , Borghesi Lisa
Published: August 2015

Hematopoietic stem and progenitors cells (HSPCs) are activated through TLR4 in vitro. However, it remains unclear whether in vivo TLR4 sensing by HSPCs occurs directly or via other cell intermediates. In this study, we examined the cellular mechanisms underlying murine hematopoietic stem cell (HSC) expansion and common lymphoid progenitor (CLP) depletion in a model of chronic low-dose LPS. Using adoptive-transfer approaches, we show that HSC and CLP sensitivity to chronic LPS depends on hematopoietic-derived, cell subset–autonomous TLR4. Like murine progenitors, human HSPCs are activated by TLR4 in vitro. Using humanized mice, a preclinical model relevant to human physiology, we show that persistent endotoxin increases the frequency of Ki-67+ HSCs and severely depletes CLPs and B precursors. Together, our findings show that murine HSPCs directly respond to endotoxin in vivo and that persistent LPS, a feature of several diseases of global health significance, impairs human lymphopoiesis.
Albian Foraminifera of the Yukon Territory
Authors: Chamney T P
Published: August 2015

The results of this study provide a foraminiferal reference sequence for the Albian Stage in the Yukon Territory, a previously little-known region between the Alaskan North Slope and the Canadian Western Interior.
Eighteen families, forty-three genera, and one hundred and thirty-five species of the order Foraminifera are reported from the Albian sequence. Several species recorded in previous publications are redescribed and illustrated; eighteen new species also are described and illustrated. Many of these
new species names replace previously used informal designations.
Agglutinated Foraminifera comprise 80 per cent of the recovered microfauna. Such forms are benthonic and are subjected to relatively high energy levels of current action. As a result of this, and because of prevailing less favourable marine conditions, the species undergo considerable morphological
adaptation in order to survive. An explanation of such species variations is illustrated with six textfigures portraying morphological series within related taxa.
Taxonomic parameters for several of the described species are shown to be partly subjective, and these require arbitrary divisions between two or more taxa within a morphological senes.