bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting tumour necrosis factor alleviates signs and symptoms of inflammatory osteoarthritis of the knee
Authors: Maksymowych Walter P , Russell Anthony S , Chiu Peter , Yan Alex , Jones Niall , Clare Tracey , Lambert Robert GW 
Published: October 2012

Abstract
Introduction
Inflammation associated with synovial expression of TNFα is a recognised feature of osteoarthritis (OA), although no studies have yet reported beneficial effects of anti-TNFα therapy on clinical manifestations of inflammation in OA.

Methods
We conducted an open-label evaluation of adalimumab over 12 weeks in 20 patients with OA of the knee and evidence of effusion clinically. Inclusion criteria included daily knee pain for the month preceding study enrolment and a summed pain score of 125 to 400 mm visual analogue scale on the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) pain subscale. The primary outcome was the Osteoarthritis Research Society International/Outcome Measures in Rheumatology Clinical Trials (OARSI/OMERACT) response criterion at week 12. Secondary outcomes included the WOMAC pain score 20% and 50% improvement, WOMAC stiffness and function scores, patient and physician global visual analogue scale, as well as target joint swelling.

Results
Treatment was well tolerated and completed by 17 patients with withdrawals unrelated to lack of efficacy or adverse events. By intention to treat, an OARSI/OMERACT response was recorded in 14 (70%) patients. WOMAC pain 20% and 50% responses were recorded in 14 (70%) patients and eight (40%) patients, respectively. Significant improvement was observed in mean WOMAC pain, stiffness, function, physician and patient global, as well as target joint swelling at 12 weeks (P < 0.0001 for all). After treatment discontinuation, 16 patients were available for assessment at 22 weeks and OARSI/OMERACT response compared with baseline was still evident in 10 (50%) patients.

Conclusion
Targeting TNFα may be of therapeutic benefit in OA and requires further evaluation in controlled trials.

Trial registration
ClinicalTrials.gov: NCT00686439.
TLR4-mediated IL-12 production enhances IFN-γ and IL-1β production, which inhibits TGF-β production and promotes antibody-induced joint inflammation
Authors: Kim Hye Sung , Chung Doo Hyun 
Published: October 2012

Abstract

Introduction

Toll-like receptor (TLR)4 promotes joint inflammation in mice. Despite that several studies report a functional link between TLR4 and interleukin-(IL-)1β in arthritis, TLR4-mediated regulation of the complicated cytokine network in arthritis is poorly understood. To address this, we investigated the mechanisms by which TLR4 regulates the cytokine network in antibody-induced arthritis.

Methods

To induce arthritis, we injected mice with K/BxN serum. TLR4-mediated pathogenesis in antibody-induced arthritis was explored by measuring joint inflammation, cytokine levels and histological alteration.

Results

Compared to wild type (WT) mice, TLR4-/- mice showed attenuated arthritis and low interferon (IFN)-γ, IL-12p35 and IL-1β transcript levels in the joints, but high transforming growth factor (TGF)-β expression. Injection of lipopolysaccharide (LPS) enhanced arthritis and exaggerated joint cytokine alterations in WT, but not TLR4-/- or IL-12p35-/- mice. Moreover, STAT4 phosphorylation in joint cells and intracellular IL-12p35 expression in macrophages, mast cells and Gr-1+ cells were detected in WT mice with arthritis and enhanced by LPS injection. Therefore, IL-12p35 appears to act downstream of TLR4 in antibody-induced arthritis. TLR4-mediated IL-12 production enhanced IFN-γ and IL-1β production via T-bet and pro-IL-1β production. Recombinant IL-12, IFN-γ and IL-1β administration restored arthritis, but reduced joint TGF-β levels in TLR4-/- mice. Moreover, a TGF-β blockade restored arthritis in TLR4-/- mice. Adoptive transfer of TLR4-deficient macrophages and mast cells minimally altered joint inflammation and cytokine levels in macrophage- and mast cell-depleted WT mice, respectively, whereas transfer of WT macrophages or mast cells restored joint inflammation and cytokine expression. Gr-1+ cell-depleted splenocytes partially restored arthritis in TLR4-/- mice.

Conclusion

TLR4-mediated IL-12 production by joint macrophages, mast cells and Gr-1+ cells enhances IFN-γ and IL-1β production, which suppresses TGF-β production, thereby promoting antibody-induced arthritis.
Hepatic steatosis, carotid plaques and achieving MDA in psoriatic arthritis patients starting TNF-α blockers treatment: a prospective study
Authors: Di Minno Matteo Nicola Dario , Peluso Rosario , Iervolino Salvatore , Lupoli Roberta , Russolillo Anna , Tarantino Giovanni , Scarpa Raffaele 
Published: October 2012

Abstract
Introduction
We prospectively evaluated whether hepatic steatosis (HS) and the presence of carotid plaques (CPs) impacts on achieving minimal disease activity (MDA) in psoriatic arthritis (PsA) patients starting tumor necrosis factor (TNF)-α blockers treatment.

Methods
Before starting treatment with TNF-α blockers, consecutive PsA subjects with an active disease were evaluated for the presence of the metabolic syndrome (MetS), HS and CPs. The incidence of MDA was evaluated 12 and 24 months later.

Results
Among 270 PsA subjects, 91 (33.7%) exhibited the MetS, 58 (21.5%) CPs and 76 (28.1%) HS. At the 12-month follow-up, 98 (36.3%) individuals achieved MDA. Compared with those who did, a higher prevalence of the MetS, HS and CPs was found in subjects who did not achieve the MDA (P always < 0.001). After adjusting for the MetS and for all the other demographic/clinical characteristics analyzed, the presence of HS and CPs at baseline independently predicted the risk of not achieving MDA (Hazard Ratio: 1.91, 95% confidence interval (CI): 1.04 to 3.38, P = 0.035 and Hazard Ratio: 3.21, 95%CI: 1.64 to 6.29, P = 0.001, respectively). Separate Kaplan-Meier survival models confirmed this (Log-Rank: 12.894, P < 0.001 and Log-Rank: 12.849, P < 0.001, respectively). Compared with those without, progressively increasing Hazard Ratios of not achieving MDA were found in those with HS, CPs or HS + CPs at baseline. Moreover, the presence of HS and/or CPs predicted the risk of relapse during the additional 12-month follow-up (Hazard Ratio: 2.85, 95%CI: 1.27 to 6.37, P = 0.011 and Hazard Ratio: 3.17, 95%CI: 1.57 to 6.41, P = 0.001 respectively).

Conclusions
HS and/or CPs at baseline are negative predictors of achieving and maintaining MDA.
The gene expression profiles of induced pluripotent stem cells from individuals with childhood cerebral adrenoleukodystrophy are consistent with proposed mechanisms of pathogenesis
Authors: Wang Xiao-Ming , Yik Wing Yan , Zhang Peilin , Lu Wange , Dranchak Patricia K , Shibata Darryl , Steinberg Steven J , Hacia Joseph G 
Published: October 2012

Abstract
Introduction
X-linked adrenoleukodystrophy (X-ALD) is a complex disorder with variable expressivity that affects the nervous, adrenocortical and male reproductive systems. Although ABCD1 mutations are known to provide the genetic basis for X-ALD, its pathogenesis is not fully elucidated. While elevated very long chain fatty acid (VLCFA) levels in blood and reduced VLCFA catabolic activity in cultured fibroblasts are biomarkers used to identify ABCD1 mutation carriers, the roles peroxisomal lipid metabolism play in disease etiology are unknown.

Methods
Primary skin fibroblasts from two male patients with the childhood cerebral form of the disease (CCALD) caused by ABCD1 frameshift or missense mutations and three healthy donors were transduced with retroviral vectors expressing the OCT4, SOX2, KLF4 and c-MYC factors. Candidate induced pluripotent stem cells (iPSCs) were subject to global gene expression, DNA methylation, DNA copy number variation, and genotyping analysis and tested for pluripotency through in vitro differentiation and teratoma formation. Saturated VLCFA (sVLCFA) and plasmalogen levels in primary fibroblasts and iPSCs from healthy donors as well as CCALD patients were determined through mass spectroscopy.

Results
Skin fibroblasts from CCALD patients and healthy donors were reprogrammed into validated iPSCs. Unlike fibroblasts, CCALD patient iPSCs show differentially expressed genes (DEGs) relevant to both peroxisome abundance and neuroinflammation. Also, in contrast to fibroblasts, iPSCs from patients showed no significant difference in sVLCFA levels relative to those from controls. In all cell types, the plasmalogen levels tested did not correlate with ABCD1 mutation status.

Conclusion
Normal ABCD1 gene function is not required for reprogramming skin fibroblasts into iPSCs or maintaining pluripotency. Relative to DEGs found in fibroblasts, DEGs uncovered in comparisons of CCALD patient and control iPSCs are more consistent with major hypotheses regarding disease pathogenesis. These DEGs were independent of differences in sVLCFA levels, which did not vary according to ABCD1 mutation status. The highlighted genes provide new leads for pathogenic mechanisms that can be explored in animal models and human tissue specimens. We suggest that these iPSC resources will have applications that include assisting efforts to identify genetic and environmental modifiers and screening for therapeutic interventions tailored towards affected cell populations and patient genotypes.
Evidence-Based Laboratory Medicine in Oncology Drug Development: From Biomarkers to Diagnostics
Authors: Modur Vijay , Hailman Eric , Barrett JC 
Published: October 2012

BACKGROUND
The promise of targeted therapies in molecularly defined subsets of cancer has led to a transformation of the process of drug development in oncology. To target cancer successfully and precisely requires high-quality translational data. Such data can be generated by the use of biomarkers that answer key questions in drug development.

CONTENT
Translational data for aiding in decision-making and driving cancer drug development can be generated by systematic assessments with biomarkers. Types of biomarkers that support decisions include: pharmacodynamic assessments for selecting the best compound or dosage; assessment of early tumor response with tissue biomarkers and imaging, mutation, and other assessment strategies for patient selection; and the use of markers of organ injury to detect toxicity and improve safety. Tactics used to generate biomarker data include fit-for-purpose assay validation and real-time biomarker assessments. Successfully translated and clinically informative biomarkers can mature into novel companion diagnostic tests that expand the practice of laboratory medicine.

SUMMARY
Systematic biomarker assessments are a key component of the clinical development of targeted therapies for cancer. The success of these biomarker assessments requires applying basic principles of laboratory medicine to generate the data required to make informed decisions. Successful biomarkers can transition into diagnostic tests that expand the laboratory medicine armamentarium.
Ga-vacancy activation under low energy electron irradiation in GaN-based materials
Authors: Nykänen Henri , Suihkonen Sami , Kilanski Lucasz , Sopanen Markku , Tuomisto Filip 
Published: October 2012

ABSTRACTWe present results on optical degradation of gallium nitride based materials under low energy electron beam irradiation (LEEBI). GaN thin film and GaN/InGaN quantum well samples, grown by metal-organic vapor phase epitaxy (MOVPE), were exposed to a tightly focused (ø = 2 nm, J = 0-130 kA/cm2), rapidly scanning electron beam (e-beam) with energy of 5-20 keV and dose of 0-500 μC/cm2. The irradiation severely reduced the band-to-band photoluminescence of the exposed sample areas. Performing positron annihilation spectroscopy measurements on the irradiated films revealed an important increase of Ga-vacancy concentration as a function of the irradiation dose. Based on the measurements we propose that in-grown passive VGa-Hn complexes are present in MOVPE grown GaN (and its alloys), and are activated by LEEBI.
Highly Reliable 1060nm Vertical Cavity Surface Emitting Lasers (VCSELs) For Optical Interconnect
Authors: Kamiya S. , Takaki K. , Imai S. , Yoshida J. , Funabashi M. , Kawakita Y. , Hiraiwa K. , Suzuki T. , Shimizu H. , Tsukiji N. , Ishikawa T. , Kasukawa A. 
Published: October 2012

ABSTRACTHigh reliability, low power consumption and high speed laser diodes are required for optical interconnect. We developed 1060nm VCSELs with InGaAs/GaAs strained quantum wells, oxide-confined and double intra-cavity structures for that purpose. As for the power consumption, low power dissipation of 0.14 mW/Gbps at 10 Gbps operation has been achieved. Clear eye openings up to 20 Gbps were confirmed at a low bias current of 5 mA. In the reliability test, accelerated aging tests were performed up to 5,000 hours at 6 mA in three different temperatures, 70 oC, 90 oC and 120 oC. The total number of the VCSELs was 4,898 pcs (approximately 5,000). No failure was observed. Under the normal operating condition of 40 oC and 6 mA, the total device-hours was 7.75×107 hours assuming Ea = 0.35 eV according to Telcordia GR-468-CORE. The random failure rate of 30 FIT with the confidence level (C.L.) of 90 % and 12 FIT with the C.L. of 60 % were estimated. To estimate the wear-out lifetime and the number of FITs, high stressed aging tests with 170 oC and 6 mA were performed. With the acceleration factor of Ea = 0.7 eV in the wear-out failure, the median lifetime was 3,000 hours which was equivalent to 300 years in 40 oC ambient. The FIT numbers due to the wear-out were estimated as 0.3 FIT for 10 years. Compared with the random failure rate of 30 FIT, the wear-out failure rates are considered to be negligible. In the extremely long term aging test with 90 oC and 6 mA, no wear-out trend has been observed in both threshold current and optical power up to 20,000 hours operation. These results indicate that 1060 nm VCSEL is promising light source used in optical interconnect for high performance computers and data centers.
Design for Reliability and Common Failure Mechanisms in Vertical Cavity Surface Emitting Lasers
Authors: Herrick Robert W. 
Published: October 2012

ABSTRACTVertical-Cavity Surface-Emitting Lasers are making up a large and growing share of the world’s production of semiconductor lasers. But the 850 nm GaAs quantum well VCSELs that make up most of present product are highly vulnerable to dislocation networks. In this paper, we discuss how materials selection affects the reliability of semiconductor lasers generally. We then describe the most common failure mechanisms observed in VCSELs, and what precautions are used to prevent them. We finish with a brief discussion of reliability testing and failure analysis.
Study of the Deep Levels of a GaAs/p-GaAs1−xBixHeterostructure Grown by Molecular Beam Epitaxy
Authors: Fuyuki Takuma , Kashiyama Shota , Oe Kunishige , Yoshimoto Masahiro 
Published: October 2012

ABSTRACTDeep-level densities of p-GaAs1−xBixand at the GaAs/p-GaAs1−xBixheterointerface have been shown to be sufficiently low for device applications based on the results of deep-level transient spectroscopy, isothermal capacitance transient spectroscopy and admittance spectroscopy. Although the metastable alloy of GaAs1−xBixis grown by molecular beam epitaxy at low temperature (370 °C), the deep-level density of p-GaAs1−xBixis suppressed such that it is on the order of 1015cm−3. The state density at the heterointerface was determined to be 8 · 1011cm−2eV−1, which is comparable to other III–V heterointerfaces formed at high temperatures. The surfactant-like effect of Bi is believed to prevent defect formation during low-temperature growth.
Clinical Presentation and Self-Reported Patterns of Pain and Function in Patients with Plantar Heel Pain
Authors: Klein Sandra E. , Dale Ann Marie , Hayes Marcie Harris , Johnson Jeffrey E. , McCormick Jeremy J. , Racette Brad A. 
Published: October 2012

Background: Plantar heel pain is a common disorder of the foot. The purpose of this study was to explore the relationship between duration of symptoms in plantar fasciitis patients and demographic factors, the intensity and location of pain, extent of previous treatment, and self-reported pain and function. Methods: The charts of patients presenting with plantar heel pain between June 2008 and October 2010 were reviewed retrospectively and 182 patients with a primary diagnosis of plantar fasciitis were identified. Patients with symptoms less than 6 months were identified as acute and patients with symptoms greater than or equal to 6 months were defined as having chronic symptoms. Comparisons based on duration of symptoms were performed for age, gender, body mass index (BMI), comorbidities, pain location and intensity, and a functional score measured by the Foot and Ankle Ability Measure (FAAM). Results: The two groups were similar in age, BMI, gender, and comorbidities. Pain severity, as measured by a visual analog scale, was not statistically significant between the two groups (6.6 and 6.2). The acute and chronic groups of patients reported similar levels of function on both the activity of daily living (62 and 65) and sports (47 and 45) subscales of the FAAM. Patients in the chronic group were more likely to have seen more providers and tried more treatment options for this condition. Conclusion: As plantar fasciitis symptoms extend beyond 6 months, patients do not experience increasing pain intensity or functional limitation. No specific risk factors have been identified to indicate a risk of developing chronic symptoms. Level of Evidence: III, Retrospective Comparative Study
Functional Outcomes after Ankle Arthrodesis in Elderly Patients
Authors: Strasser Nicholas L. , Turner Norman S. 
Published: October 2012

Background: Ankle arthrodesis has been the gold standard operative treatment for ankle arthritis refractory to nonoperative treatment. Although multiple studies have evaluated the outcomes after ankle fusion, none has focused on outcomes in elderly patients. The purpose of this study was to evaluate outcomes of ankle fusion in patients over the age of 70. Methods: Thirty patients (30 ankles) over the age of 70 who underwent ankle fusion were identified. Average age at the time of surgery was 74.5 years (±3.7). The Foot and Ankle Ability Measure (FAAM) was obtained postoperatively in 22 of the 23 patients still living. Radiographs were followed until union with an average followup of 2.2 years. Results Union was achieved in 27 of 30 ankles (90%). Postoperative radiographs showed 11 (36.6%) patients had progression of subtalar arthritis. The average postoperative FAAM score was 81.5 (±18.3) with an average followup of 8.5 years (±1.7). Subjectively, when asked to compare present function with their prearthritic state, the average response was 75.1% (±19.6). The average American Orthopaedic Foot and Ankle Society hindfoot score was 73.0 (±11.5). Complications included nonunion, deep infection, and adjacent joint arthritis. Conclusions: In this clinical cohort, ankle fusion was found to be effective in the treatment of ankle arthritis. Functional outcome was satisfactory and the rate of union was comparable with that previously reported in the literature for younger patients. Although total ankle arthroplasty is becoming increasingly popular, ankle arthrodesis is an effective surgical treatment option in an elderly patient population. Level of Evidence: IV, Retrospective Case Series
Partial Foot Amputation in Patients with Diabetic Foot Ulcers
Authors: Brown Matthew L. , Tang Wan , Patel Amar , Baumhauer Judith F. 
Published: October 2012

Background: Transtibial amputations (TTA) are performed for recalcitrant or infected ulcers of the midfoot, hindfoot, or ankle. This procedure results in decreased ambulatory status caused by increased oxygen demands and energy expenditure. Partial foot amputations have the advantage of being an end-bearing limb and require less work to walk, theoretically suggesting improved functional outcome. The purpose of this research was to examine the longevity, outcome, and mortality of partial foot amputations as an alternative to TTA. Methods: Retrospective chart review identified diabetic patients with transmetatarsal, Chopart's, and calcanectomy amputations for osteomyelitis or nonhealing ulcers. A control group consisted of diabetic patients who underwent TTA. A comparison between groups examined mortality, proximal ipsilateral reamputation, and a validated ambulatory functional outcome measure. Results: Eighteen TTA patients were enrolled. The 5-year mortality rate was 0.45, one patient required reamputation, and the mean postoperative ambulatory score was 2.8. Twenty-one transmetatarsal patients were enrolled. The 5-year mortality rate was 0.30, two patients required reamputation, and the mean postoperative ambulatory score was 4.3. Ten Chopart's amputation patients were enrolled. The 5-year mortality rate was 0.36, six patients required reamputation, and the mean postoperative ambulatory score was 4.3. Seventeen partial calcanectomy patients were enrolled. The 5-year mortality rate was 0.69, six patients required reamputation, and the mean postoperative ambulatory score was 4.3. Sixteen total calcanectomy patients were enrolled. The 5-year mortality rate was 0.59, five patients required reamputation, and the mean postoperative ambulatory score was 3.3. Conclusion: TTA is associated with high morbidity and mortality, which suggests that the advantage of partial foot amputations should be investigated. Only transmetatarsal amputations at 1 and 3 years were statistically lower for mortality than TTA. Partial foot amputations at the other levels failed to show statistically improved survivorship. Transmetatarsal and Chopart's amputations had high ambulatory levels and the longest durability, which suggests that these amputations may provide some ambulatory advantage. Level of Evidence: Therapeutic Level III
Vascularized Pedicle Bone Grafting for Nonunions of the Tarsal Navicular
Authors: Fishman Felicity G. , Adams Samuel B. , Easley Mark E. , Nunley James A. 
Published: October 2012

Background: Osteonecrosis and nonunions of the tarsal navicular remain a challenging clinical problem. This article presents a series of patients treated with local vascularized pedicle bone grafting to the navicular. The purpose of this study was to determine the early clinical and radiographic outcomes of this technique. Methods: Patients who underwent local vascularized pedicle bone grafting for osteonecrosis of the navicular from 2002 to 2007 were included in this study. The Ankle Osteoarthritis Scale (AOS), the Revised Foot Function Index (FFI-R), and the Short-Form 36 (SF-36) outcomes questionnaires were administered at most recent followup. Postoperative imaging was reviewed for evidence of healing. Eight patients with a mean age of 47.5 (range, 18 to 68) years were included in this study. The mean followup time was 61 (range, 32 to 72) months. Results: Two patients underwent concomitant talonavicular arthrodesis. Two patients underwent additional procedures to address continued nonunion of the navicular. Neither patient elected to complete the outcomes questionnaires. The mean postoperative FFI score was 35.2 (range, 16.6 to 59). SF-36 subscales were as follows: bodily pain, 53; general health, 55; mental health, 75; physical function, 56; role emotional, 61; role physical, 37.5; social function, 71; and vitality, 56. The mean postoperative AOS pain score was 27.9 (range, 0 to 46.2) and the average disability score was 31.4 (range, 0 to 78.2). Postoperative imaging revealed consolidation and full healing in six of eight patients. Conclusion: Vascularized pedicle bone grafting is a treatment option for patients with chronic nonunion or osteonecrosis of the navicular. Additionally, it may serve as an adjunct procedure to provide increased vascularity to talonavicular arthrodesis in cases of navicular osteonecrosis and talonavicular arthritis. Level of Evidence: IV, Retrospective Case Series