bluuebunny/crossref_metadata_2025 huggingface dataset:
Associations between dietary flavonoid intakes and bone health in a scottish population
Authors: Hardcastle Antonia C , Aucott Lorna , Reid David M , Macdonald Helen M
Published: November 2010

Flavonoids are bioactive polyphenols found particularly in fruit and vegetables, but little is known about their role in bone health in humans. The aim of this observational study was to investigate whether dietary flavonoid intake was associated with bone mineral density (BMD) and bone resorption in a large group of perimenopausal Scottish women. Over 3000 women completed a food frequency questionnaire as part of an osteoporosis screening study. The diets were analyzed for flavonoid intake using a food composition database. BMD was measured at the femoral neck (FN) and lumbar spine (LS) by dual-energy X-ray absorptiometry (DXA). Free pyridinoline (PYD) and deoxypyridinoline (DPD) were measured by high-performance liquid chromatography (HPLC) in second early morning fasted urine samples. The mean flavonoid intake of the diet was 307 ±199 mg/d. The catechin family contributed the most to flavonoid intakes (55%), and the flavones the least (<1%). Associations were found between energy-adjusted total flavonoid intakes and BMD at the FN and LS (FN r = 0.054, LS r = 0.036, p ≤ .05). Annual percent change in BMD was associated with intakes of procyanidins and catechins (p ≤ .05), and flavanones were negatively associated with bone-resorption markers (PYD r = −0.049, DPD r = –0.057, p ≤ .001). These associations were still seen after adjusting for confounders. It is concluded that dietary flavonoid intakes are associated with BMD, supporting the evidence from animal and cellular studies. © 2011 American Society for Bone and Mineral Research.
Serum uric acid is associated with bone health in older men: A cross-sectional population-based study
Authors: Nabipour Iraj , Sambrook Philip N , Blyth Fiona M , Janu Margaret R , Waite Louise M , Naganathan Vasi , Handelsman David J , Le Couteur David G , Cumming Robert G , Seibel Markus J
Published: November 2010

Serum uric acid (UA) is a strong endogenous antioxidant. Since oxidative stress has been linked to osteoporosis, we examined the association between serum UA levels and bone mineral density (BMD), prevalent vertebral and nonvertebral fractures, and laboratory measures such as calcitropic hormones and bone turnover marker levels. This cross-sectional analysis consisted of 1705 community-dwelling men aged 70 years or over who participated in the baseline part of the Concord Health and Ageing in Men Project (CHAMP), a population-based study of older men in Sydney, Australia. BMD at all sites was significantly higher among men with serum UA levels above the group median than among men with UA levels below the median. In multiple regression analyses adjusted for potential confounders, serum UA remained associated with BMD at all sites (β = 0.12 to 0.14, p < .001), serum calcium (β = 0.11, p = .001), parathyroid hormone (β = 0.09, p = .002), 25-hydroxyvitamin D (β = 0.09, p = .005), and was negatively associated with urinary excretion amino-terminal cross-linked telopeptide of type 1 collagen (β = –0.09, p = .006). Overall, serum UA accounted for 1.0% to 1.44% of the variances in BMD (R2 = 0.10 to 0.22). In multiple logistic regression analyses, above-median serum UA levels were associated with a lower prevalence of osteoporosis at the femoral neck [odds ratio (OR) = 0.42, 95% confidence interval (CI) 0.22–0.81, p = .010) and lumbar spine (OR = 0.44, 95% CI 0.23–0.86, p = .016) and a lower prevalence of vertebral (OR = 0.62, 95% CI 0.43–0.91, p = .015) and nonvertebral (OR = 0.51, 95% CI 0.29–0.89, p = .018) fractures. In conclusion, higher serum UA levels are associated with higher BMD at all skeletal sites and with a lower prevalence of vertebral and nonvertebral fractures in older men. © 2011 American Society for Bone and Mineral Research.
Oral bisphosphonates and risk of subtrochanteric or diaphyseal femur fractures in a population-based cohort
Authors: Kim Seo Young , Schneeweiss Sebastian , Katz Jeffrey N , Levin Raisa , Solomon Daniel H
Published: November 2010

Bisphosphonates are the primary therapy for postmenopausal and glucocorticoid-induced osteoporosis. Case series suggest a potential link between prolonged use of bisphosphonates and low-energy fracture of subtrochanteric or diaphyseal femur as a consequence of oversuppression of bone resorption. Using health care utilization data, we conducted a propensity score–matched cohort study to examine the incidence rates (IRs) and risk of subtrochanteric or diaphyseal femur fractures among oral bisphosphonate users compared with raloxifene or calcitonin users. A Cox proportional hazards model evaluated the risk of these fractures associated with duration of osteoporosis treatment. A total of 104 subtrochanteric or diaphyseal femur fractures were observed among 33,815 patients. The estimated IR of subtrochanteric or diaphyseal femur fractures per 1000 person-years was 1.46 [95% confidence interval (CI) 1.11–1.88] among the bisphosphonate users and 1.43 (95% CI 1.06–1.89) among raloxifene/calcitonin users. No significant association between bisphosphonate use and subtrochanteric or diaphyseal femur fractures was found [hazard ratio (HR) = 1.03, 95% CI 0.70–1.52] compared with raloxifene/calcitonin. Even with this large study size, we had little precision in estimating the risk of subtrochanteric or diaphyseal femur fractures in patients treated with bisphosphonates for longer than 5 years (HR = 2.02, 95% CI 0.41–10.00). The occurrence of subtrochanteric or diaphyseal femur fracture was rare. There was no evidence of an increased risk of subtrochanteric or diaphyseal femur fractures in bisphosphonate users compared with raloxifene/calcitonin users. However, this study cannot exclude the possibility that long-term bisphosphonate use may increase the risk of these fractures. © 2011 American Society for Bone and Mineral Research.
Once-yearly zoledronic acid and days of disability, bed rest, and back pain: Randomized, controlled HORIZON Pivotal Fracture Trial
Authors: Cauley Jane A , Black Dennis , Boonen Steven , Cummings Steven R , Mesenbrink Peter , Palermo Lisa , Man Zulema , Hadji Peyman , Reid Ian R ,   on behalf of the HORIZON Pivotal Fracture Group
Published: November 2010

The objective of this study was to determine the effect of once-yearly zoledronic acid on the number of days of back pain and the number of days of disability (ie, limited activity and bed rest) owing to back pain or fracture in postmenopausal women with osteoporosis. This was a multicenter, randomized, double-blind, placebo-controlled trial in 240 clinical centers in 27 countries. Participants included 7736 postmenopausal women with osteoporosis. Patients were randomized to receive either a single 15-minute intravenous infusion of zoledronic acid (5 mg) or placebo at baseline, 12 months, and 24 months. The main outcome measures were self-reported number of days with back pain and the number of days of limited activity and bed rest owing to back pain or a fracture, and this was assessed every 3 months over a 3-year period. Our results show that although the incidence of back pain was high in both randomized groups, women randomized to zoledronic acid experienced, on average, 18 fewer days of back pain compared with placebo over the course of the trial (p = .0092). The back pain among women randomized to zoledronic acid versus placebo resulted in 11 fewer days of limited activity (p = .0017). In Cox proportional-hazards models, women randomized to zoledronic acid were about 6% less likely to experience 7 or more days of back pain [relative risk (RR) = 0.94, 95% confidence interval (CI) 0.90–0.99] or limited activity owing to back pain (RR = 0.94, 95% CI 0.87–1.00). Women randomized to zoledronic acid were significantly less likely to experience 7 or more bed-rest days owing to a fracture (RR = 0.58, 95% CI 0.47–0.72) and 7 or more limited-activity days owing to a fracture (RR = 0.67, 95% CI 0.58–0.78). Reductions in back pain with zoledronic acid were independent of incident fracture. Our conclusion is that in women with postmenopausal osteoporosis, a once-yearly infusion with zoledronic acid over a 3-year period significantly reduced the number of days that patients reported back pain, limited activity owing to back pain, and limited activity and bed rest owing to a fracture. © 2011 American Society for Bone and Mineral Research.
Functional relevance of the BMD-associated polymorphism rs312009: Novel Involvement of RUNX2 in LRP5 transcriptional regulation
Authors: Agueda Lídia , Velázquez-Cruz Rafael , Urreizti Roser , Yoskovitz Guy , Sarrión Patricia , Jurado Susana , Güerri Roberto , Garcia-Giralt Natàlia , Nogués Xavier , Mellibovsky Leonardo , Díez-Pérez Adolfo , Marie Pierre J , Balcells Susana , Grinberg Daniel
Published: November 2010

LRP5 is an osteoporosis susceptibility gene. Association analyses reveal that individual single-nucleotide polymorphisms (SNPs) determine variation in bone mineral density (BMD) among individuals as well as fracture risk. In a previous study, we identified a lumbar spine BMD-associated SNP, rs312009, located in the LRP5 5' region. A RUNX2 binding site was identified in this region by gel-shift experiments. Here we test the functionality of this SNP and examine whether RUNX2 is indeed a regulator of LRP5 expression. Gene reporter assays were used to test rs312009 functionality. Bioinformatic predictive tools and gel-shift and gene reporter assays were used to identify and characterize additional RUNX2 binding elements in the 3.3-kb region upstream of LRP5. Allelic differences in the transcriptional activity of rs312009 were observed in two osteoblastic cell lines, the T allele being a better transcriber than the C allele. RUNX2 cotransfection in HeLa cells revealed that the LRP5 5' region responded to RUNX2 in a dose-dependent manner and that the previously identified RUNX2 binding site participated in this response. Also, RUNX2 inhibition by RNAi led to nearly 60% reduction of endogenous LRP5 mRNA in U-2 OS cells. Four other RUNX2 binding sites were identified in the 5' region of LRP5. Luciferase experiments revealed the involvement of each of them in the RUNX2 response. The allelic differences observed point to the involvement of rs312009 as a functional SNP in the observed association. To our knowledge, this is the first time that the direct action of RUNX2 on LRP5 has been described. This adds evidence to previously described links between two important bone-regulating systems: the RUNX2 transcription-factor cascade and the Wnt signaling pathway. © 2011 American Society for Bone and Mineral Research.
Unique roles of phosphorus in endochondral bone formation and osteocyte maturation
Authors: Zhang Rong , Lu Yongbo , Ye Ling , Yuan Baozhi , Yu Shibin , Qin Chunlin , Xie Yixia , Gao Tian , Drezner Marc K , Bonewald Lynda F , Feng Jian Q
Published: November 2010

The mechanisms by which inorganic phosphate (Pi) homeostasis controls bone biology are poorly understood. Here we used Dmp1 null mice, a hypophosphatemic rickets/osteomalacia model, combined with a metatarsal organ culture and an application of neutralizing fibroblast growth factor 23 (FGF-23) antibodies to gain insight into the roles of Pi in bone biology. We showed (1) that abnormal bone remodeling in Dmp1 null mice is due to reduced osteoclast number, which is secondary to a reduced ratio of RANKL/OPG expressed by osteoclast supporting cells and (2) that osteoblast extracellular matrix mineralization, growth plate maturation, secondary ossification center formation, and osteoblast differentiation are phosphate-dependent. Finally, a working hypothesis is proposed to explain how phosphate and DMP1 control osteocyte maturation. © 2011 American Society for Bone and Mineral Research.
Activation of c-Jun NH2-terminal kinase 1 increases cellular responsiveness to BMP-2 and decreases binding of inhibitory Smad6 to the type 1 BMP receptor
Authors: Liu Hui , Liu Yunshan , Viggeswarapu Manjula , Zheng Zhaomin , Titus Louisa , Boden Scott D
Published: November 2010

Bone morphogenetic protein 2 (BMP-2) plays a critical role in the differentiation of precursor cells and has been approved for clinical application to induce new bone formation. To date, unexpectedly high doses of recombinant BMP-2 have been required to induce bone healing in humans. Thus, enhancing cellular responsiveness to BMP-2 potentially has critically important clinical implications. BMP responsiveness may be modulated in part by cross-talk with other signaling pathways, including mitogen-activated protein kinases (MAPKs). c-Jun NH2-terminal kinase (JNK) is a MAPK that has been reported to be required for late-stage differentiation of preosteoblasts and BMP-2-induced differentiation of preosteoblasts and pleuripotent cells. In this study we determined that MC3T3-E1-clone 24 cells (MC-24) can be induced by BMP-2 to differentiate into mineralizing osteoblast cultures. Using this inducible system, we employed both JNK loss-of-function and gain-of-function reagents to make three key observations: (1) JNK is required for phosphorylation of Smad1 by BMP-2 and subsequent activation of Smad1 signaling and osteoblast differentiation, (2) JNK1, but not JNK2, is required for BMP-2-induced formation of mineralized nodules, and (3) JNK1 activation decreases binding of inhibitory Smad6 to the type I BMP receptor (BMPR-I) and reciprocally increases binding of Smad1, both observations that would increase responsiveness to BMP-2. Understanding this and other pathways that lead to increased cellular responsiveness to BMPs could greatly aid more cost-effective and safe clinical delivery of these important molecules. © 2011 American Society for Bone and Mineral Research.
Predictive values of neutrophil CD64 expression compared with interleukin‐6 and C‐reactive protein in early diagnosis of neonatal sepsis
Authors: Dilli Dilek , Ogˇuz Ş. Suna , Dilmen Ugˇur , Köker M. Yavuz , Kızılgün Murat
Published: November 2010

Background: Despite major advances in the management of newborn infants, neonatal sepsis (NS) remain important causes of neonatal morbidity and mortality in the newborn, mainly among preterm and low birth weight infants. Objective: The aim of this study was to investigate the usefulness of neutrophil CD64 expression alone and together with other infection markers in NS. Methods: Peripheral blood samples were taken from 109 neonates, who were categorized into three groups: proven or clinical sepsis (n=35); disease without infection (n=42); and healthy controls (n=32). Complete blood count with differential, interleukin‐6 (IL‐6), C‐reactive protein (CRP), and cell surface expression of CD64 on neutrophils have been evaluated in a prospective manner as a diagnostic aid for NS. Results: Expression of CD64 was significantly enhanced in neonates with sepsis compared with newborns with disease without infection and healthy controls (P=0.001 and P=0.001, respectively). Cutoff values of IL‐6, CRP, CD64MFI, and CD64i were 24.9 pg/ml, 4.05 mg/l, 87.7, and 4.39, respectively. Sensitivity–negative predictive values of IL‐6, CRP, and CD64MFI/CD64i were 80.0–90.6%, 80.0–88.8%, and 88.6–94.0%, respectively. Combining all three tests increased the sensitivity to 100%; however, specificity and positive predictive value decreased to 62.1 and 55.5%, respectively. Conclusions: CD64 might be used either alone or combined with IL‐6 and CRP for early diagnosis of NS. The advantages of CD64 when compared with IL‐6 and CRP are rapid quantitation, very small blood volume required, and easy handling. J. Clin. Lab. Anal. 24:363–370, 2010. © 2010 Wiley‐Liss, Inc.
Preliminary evaluation of Hitchens–Pike–Todd–Hewitt medium (HPTH) for detection of group B streptococci in pregnant women
Authors: Chaves Maurício , Pádua Rubia A.F. , Campanerut Paula A.Z. , Pelloso Sandra M. , Carvalho Maria Dalva B. , Siqueira Vera L.D. , Scodro Regiane B.L. , Cardoso Rosilene F.
Published: November 2010

We aimed to compare Hitchens–Pike–Todd–Hewitt (HPTH) enrichment broth, Todd–Hewitt broth, and direct culture onto blood sheep agar containing selective antimicrobial (ABA) in screening Group B Streptococci (GBS) carriage in pregnant women. From April to June 2007, duplicate lower vaginal and duplicate anorectal specimens of 102 pregnant women at 35 weeks of gestation or more, who were assisted at Santa Casa de Misericórdia Hospital, Maringá, Paraná, Brazil, were screened by GBS using HPTH, Todd–Hewitt broth, and ABA. Twenty‐five(24.5%) pregnant women had one or more positive culture for GBS in those media. The positive rate for each medium was 21.6% (22/102) in the HPTH, 12.8% (13/102) in ABA, and 11.8% (12/102) in Todd–Hewitt broth. HPTH seems to be a high satisfactory medium for screening GBS in vaginal and anorectal samples in pregnant women and additional studies would be interesting in a larger number of pregnant women and in different laboratories. J. Clin. Lab. Anal. 24:403–406, 2010. © 2010 Wiley‐Liss, Inc.
Evaluation of BD vacutainer SST™ II plus tubes for common tumor marker tests by Roche Diagnostics Modular E 170 analyzer
Authors: Li Zhiyan , Feng Zhenru , Yan Cunling , Yan Rong
Published: November 2010

Serum separator tubes were introduced 35 years ago and were widely used in the clinical laboratory in China for routine collection of blood because of providing a closed system that allowed for collection, transport, processing, sampling, and storage of specimens. This type of tubes facilitated rapid separation of serum from cellular constituents of blood and also prevented hemolysis upon prolonged storage. However, there were some limitations associated with gel tubes (i.e., gel and analyte stability). In order to circumvent these problems, BD released a new serum separator tube containing a new gel (BD SST™ II Plus). We investigated theperformance of BD SST™ II Plus tubes for tumor marker tests using BD Serum Glass tubes as controls. Equivalence between the BD SST™ II Plus and BD Serum Glass tubes was demonstrated for all analytes at initial time. Also, all analytes remained stable when stored in BD SST™ II Plus tubes up to 72 hr. Concentration of neuron‐specific enolase tended to increase with preservation time up to 72 hr in BD Serum Glass tubes. We conclude that BD SST™ II Plus was suitable for collection of blood and storage of serum for tumor marker tests. J. Clin. Lab. Anal. 24:418–421, 2010. © 2010 Wiley‐Liss, Inc.
Facile routes for the preparation of 3,4‐disubstituted 1,3‐oxazolidines and 1,2,5‐trisubstituted imidazolidin‐4‐ones
Authors: Catalano Alessia , Carocci Alessia , Lentini Giovanni , Di Mola Antonia , Bruno Claudio , Franchini Carlo
Published: November 2010

Facile, alternative synthetic routes to 6, (R)‐6, and (S)‐6‐3‐benzyl‐N‐(2,6‐dimethylphenyl)‐1,3‐oxazolidine‐4‐carboxamides (6), a chiral oxazolidine derivative of tocainide, are reported. The synthetic routes described herein also afforded 11‐, (R)‐11‐, and 12, which present the imidazolidin‐4‐one core and belong to a class of compounds interesting for their biological activities. All the final compounds and intermediates were fully characterized. Enantiomeric excesses of homochiral 6 and 11 were determined by capillary electrophoresis analysis using 2‐hydroxypropyl‐β‐cyclodextrin or highly sulfated γ‐cyclodextrin as chiral selectors. J. Heterocyclic Chem., (2010)
Optimization of genetic algorithm for reconstruction of cross‐phase modulation frequency‐resolved optical gating data
Authors: Vrany Boleslav , Honzatko Pavel , Kanka Jiri
Published: November 2010

We implemented a frequency‐resolved optical gating (FROG) measurement method using cross‐phase modulation in a highly birefringent microstructure optical fiber. The standard FROG data reconstruction algorithm of generalized projection failed for this setup and we successfully used the genetic algorithm (GA) instead which is less prone to get stuck to local minima. GA has several parameters that must be set up to suitable values. We describe the experimental setup and the algorithm and present our findings on what GA parameters are crucial and what are their optimal values. A single run of the algorithm takes 7 min on contemporary CPUs, making the algorithm suitable for routine laboratory work. Copyright © 2010 John Wiley & Sons, Ltd.
The method of lines for the analysis of composite‐metal lossy microstrip lines
Authors: Gao Bo , Tong Ling , Gong Xun
Published: November 2010

A full‐wave analysis of the composite‐metal microstrip lines is presented. The effects of the composite metal to the loss of the microstrip lines are accurately investigated, which are often avoided by other methods. The metal layers of the microstrip lines are considered as lossy inhomogeneous layers. The effects of the thickness of the Au layer and Ti layer are given, respectively. And the reasons that lead to the differences between them are discussed for the first time by analyzing the longitudinal electric field on the strip. The results are compared with other published data. Copyright © 2010 John Wiley & Sons, Ltd.
Trilinear multiplicative modelling of thin layer chromatography retention as a function of solute, organic modifier and its concentration
Authors: Komsta Łukasz , Radoń Małgorzata , Radkiewicz Beata , Skibiński Robert
Published: November 2010

We have recently shown in a preliminary study, that the retention in TLC, expressed as RF values, can be modelled in multiplicative trilinear way (solute×mobile phase×stationary phase), explaining almost all variance. Such possibility did not occur in the case of k or RM values. This paper is a continuation of investigation about this phenomenon. We perform here a trilinear decomposition of two datasets (normal‐phase and RP) of 35 model compounds organized differently as in the previous study: solute × modifier × concentration. The resulted models explain 96.8% of whole variance on silica and 90.33% of RP18 variance. No strict correlation with any particular molecular descriptor was found, although the mean electrotopological state index (Ms) was fairly correlated with RP contributions. The results confirm definitively a general possibility to model TLC retention in a multiplicative manner and inspire for further research in this field.
Sinonasal abnormalities in patients with graves' orbitopathy
Authors: Soler Zachary M. , Platt Michael P. , Leung Man‐kit , Mong Sandy , Metson Ralph
Published: November 2010

Objectives:

To compare radiographic sinus mucosal thickening in patients with Graves' orbitopathy versus controls and determine whether target autoantigens thought to underlie systemic manifestations of Graves' disease are present within paranasal sinus mucosa.

Study Design:

Case‐control study.

Methods:

Sinus computed tomography (CT) scans from patients with Graves' orbitopathy scheduled for orbital decompression surgery (n = 50) were compared with maxillofacial CT scans from control patients (n = 50). Scans were rated for sinus mucosal disease by two independent reviewers using the Lund‐MacKay and Harvard staging systems. Gene expression for thyrotropin receptor and type 1 insulin‐like growth factor receptor (IGF‐1R) was assessed in ethmoid mucosal samples using real‐time quantitative polymerase chain reaction (RT‐qPCR) and immunohistochemistry (IHC).

Results:

Increased sinus mucosal thickening was found in patients with Graves' orbitopathy compared with controls for both the Lund‐MacKay (6.2 vs. 2.7; P < .01) and Harvard (2.1 vs. 1.3; P < .01) systems. Compared with control scans, the Graves' orbitopathy group exhibited greater mucosal thickening in the ethmoid, frontal, and sphenoid sinuses (P < .05 for all). RT‐qPCR and IHC demonstrated gene expression for both the thyrotropin receptor and the IGF‐1R in ethmoid mucosa.

Conclusions:

Patients with Graves' orbitopathy who present for orbital decompression exhibit a higher prevalence of sinus mucosal thickening on CT scan. These findings may be explained by circulating autoantibodies to target antigens, thyrotropin receptor and IGF‐1R, associated with Graves' disease and found to be expressed in sinus mucosa. Laryngoscope, 2011
Rotigotine effects on early morning motor function and sleep in Parkinson's disease: A double‐blind, randomized, placebo‐controlled study (RECOVER)
Authors: Trenkwalder Claudia , Kies Bryan , Rudzinska Monika , Fine Jennifer , Nikl Janos , Honczarenko Krystyna , Dioszeghy Peter , Hill Dennis , Anderson Tim , Myllyla Vilho , Kassubek Jan , Steiger Malcolm , Zucconi Marco , Tolosa Eduardo , Poewe Werner , Surmann Erwin , Whitesides John , Boroojerdi Babak , Chaudhuri Kallol Ray , the RECOVER Study Group
Published: November 2010

In a multinational, double‐blind, placebo‐controlled trial (NCT00474058), 287 subjects with Parkinson's disease (PD) and unsatisfactory early‐morning motor symptom control were randomized 2:1 to receive rotigotine (2–16 mg/24 hr [n = 190]) or placebo (n = 97). Treatment was titrated to optimal dose over 1–8 weeks with subsequent dose maintenance for 4 weeks. Early‐morning motor function and nocturnal sleep disturbance were assessed as coprimary efficacy endpoints using the Unified Parkinson's Disease Rating Scale (UPDRS) Part III (Motor Examination) measured in the early morning prior to any medication intake and the modified Parkinson's Disease Sleep Scale (PDSS‐2) (mean change from baseline to end of maintenance [EOM], last observation carried forward). At EOM, mean UPDRS Part III score had decreased by −7.0 points with rotigotine (from a baseline of 29.6 [standard deviation (SD) 12.3] and by −3.9 points with placebo (baseline 32.0 [13.3]). Mean PDSS‐2 total score had decreased by −5.9 points with rotigotine (from a baseline of 19.3 [SD 9.3]) and by −1.9 points with placebo (baseline 20.5 [10.4]). This represented a significantly greater improvement with rotigotine compared with placebo on both the UPDRS Part III (treatment difference: −3.55 [95% confidence interval (CI) −5.37, −1.73]; P = 0.0002) and PDSS‐2 (treatment difference: −4.26 [95% CI −6.08, −2.45]; P < 0.0001). The most frequently reported adverse events were nausea (placebo, 9%; rotigotine, 21%), application site reactions (placebo, 4%; rotigotine, 15%), and dizziness (placebo, 6%; rotigotine 10%). Twenty‐four‐hour transdermal delivery of rotigotine to PD patients with early‐morning motor dysfunction resulted in significant benefits in control of both motor function and nocturnal sleep disturbances. © 2010 Movement Disorder Society
Bioactivity of AAV2‐neurturin gene therapy (CERE‐120): Differences between Parkinson's disease and nonhuman primate brains
Authors: Bartus Raymond T. , Herzog Christopher D. , Chu Yaping , Wilson Alistair , Brown Lamar , Siffert Joao , Johnson Eugene M. , Olanow C. Warren , Mufson Elliott J. , Kordower Jeffrey H.
Published: November 2010

Background: AAV2‐neurturin (CERE‐120) is designed to deliver the neurotrophic‐factor, neurturin, to the striatum to restore and protect degenerating nigrostriatal neurons in Parkinson's disease (PD). A common hypothesis is that following expression in the striatum, neurotrophic‐factors like neurturin (NRTN) will be transported from degenerating terminals to their cell bodies in the substantia nigra pars compacta (SNc). Methods: We tested this concept using immunohistochemistry, comparing the bioactivity of AAV2‐neurturin in brains of PD patients versus those of nonhuman primates similarly treated. Results: NRTN‐immunostaining in the targeted striatum was seen in all PD cases (mean putaminal coverage: ∼15% by volume); comparable expression was observed in young, aged, and parkinsonian monkeys. In the SNc cell bodies, however, only rare evidence of neurturin was seen in PD, while ample evidence of intense nigral‐NRTN was observed in all monkeys. NRTN‐expression was associated with occasional, sparse TH‐induction in the striatum of PD, but nothing apparent in the SNc. In primates, NRTN produced robust TH‐induction throughout the nigrostriatal neurons. Discussion: These data provide the first evidence that gene therapy can increase expression of a neurotrophic‐factor deep in the PD brain and that clear but modest enhancement of degenerating neurons can be induced. They also provide important insight regarding deficiencies in the status of nigrostriatal neurons in advanced PD, suggesting that serious axon‐transport deficits reduced the bioactivity of AAV2‐NRTN by limiting the protein exposed to the cell body. Thus, future efforts using neurotrophic‐factors to treat neurodegenerative diseases will need to target both the terminal fields and the cell bodies of degenerating neurons to assure maximal benefit is achieved. © 2010 Movement Disorder Society
Covalent VEGF protein immobilization on resorbable polymeric surfaces
Authors: Edlund U. , Sauter T. , Albertsson A.‐C.
Published: November 2010

Vascular endothelial growth factor (VEGF) type protein, a potent angiogenic effector molecule, was successfully covalently immobilized onto the surfaces of the resorbable polymers poly(L‐lactic acid) (PLLA) and poly(ε‐caprolactone) through a three‐step strategy. The surfaces were first covalently grafted with poly(acrylic acid) using non‐destructive and solvent‐free vapor‐phase grafting. A diamine spacer was coupled to the carboxylic acid pendant groups on the graft chains using 1‐ethyl‐3‐(3‐dimethylaminopropyl)‐carbodiimide hydrochloride/N‐hydroxysuccinimide chemistry and VEGF was finally covalently attached to the amine linkers. The chemistry and topography of the modified substrates were quantitatively and qualitatively verified with X‐ray photoelectron spectroscopy, attenuated total reflectance–Fourier transform infrared spectrometry, UV–VIS, scanning electron microscopy, and enzyme‐linked immunosorbent assay. Copyright © 2010 John Wiley & Sons, Ltd.
Pro‐apoptotic peptide‐polymer conjugates to induce mitochondrial‐dependent cell death
Authors: Adar Lily , Shamay Yosi , Journo Gal , David Ayelet
Published: November 2010

The treatment of cancer using pro‐apoptotic peptides requires efficient intracellular delivery to trigger mitochondrial disruption. When the widely used non‐toxic heptapeptide dimer D(KLAKLAK)2 is coupled with tumor targeting peptides that allow receptor‐mediated internalization, it disrupts negatively charged membranes and induces mitochondrial‐dependent apoptosis. Here, we describe the design, synthesis, and characterization of novel water‐soluble HPMA copolymers bearing a multivalent display of NGR motifs that can target the pro‐apoptotic drug D(KLAKLAK)2 to CD13‐overexpressing cells. D(KLAKLAK)2 was attached to the polymeric backbone through an acid‐sensitive hydrazone linker to facilitate intracellular drug release. The ability of an array of NGR motifs, with different structural conformations, to target several CD13 receptors and thus enhance the binding avidity and the pro‐apoptotic activity of D(KLAKLAK)2 in human cell lines was tested. HPMA copolymer conjugates bearing the dimeric (GNGRG)2 and cyclic (CNGRC) NGR motifs exhibited preferential binding to CD13‐overexpressing cells relative to the linear (GNGRG) targeting peptide. The binding of D(KLAKLAK)2 to the polymer facilitated rapid internalization and translocation into endosomal/lysosomal compartments. The polymer‐bound D(KLAKLAK)2 markedly increased the cytotoxicity and the pro‐apoptotic activity of the drug, relative to free D(KLAKLAK)2 and the targeted pro‐apoptotic peptide (GNGRGG‐D(KLAKLAK)2) in CD13(+) cells. This research is the first attempt to apply polymer‐conjugates with NGR motifs as targeting ligand to deliver the pro‐apoptotic D(KLAKLAK)2 sequence into CD13‐overexpressing cells and thereby to promote the death of cancer cells. Copyright © 2010 John Wiley & Sons, Ltd.
Activated oncogenic pathways and therapeutic targets in extranodal nasal‐type NK/T cell lymphoma revealed by gene expression profiling
Authors: Ng Siok‐Bian , Selvarajan Viknesvaran , Huang Gaofeng , Zhou Jianbiao , Feldman Andrew L , Law Mark , Kwong Yok‐Lam , Shimizu Norio , Kagami Yoshitoyo , Aozasa Katsuyuki , Salto‐Tellez Manuel , Chng Wee‐Joo
Published: November 2010

We performed comprehensive genome‐wide gene expression profiling (GEP) of extranodal nasal‐type natural killer/T‐cell lymphoma (NKTL) using formalin‐fixed, paraffin‐embedded tissue (n = 9) and NK cell lines (n = 5) in comparison with normal NK cells, with the objective of understanding the oncogenic pathways involved in the pathogenesis of NKTL and to identify potential therapeutic targets. Pathway and network analysis of genes differentially expressed between NKTL and normal NK cells revealed significant enrichment for cell cycle‐related genes and pathways, such as PLK1, CDK1, and Aurora‐A. Furthermore, our results demonstrated a pro‐proliferative and anti‐apoptotic phenotype in NKTL characterized by activation of Myc and nuclear factor kappa B (NF‐κB), and deregulation of p53. In corroboration with GEP findings, a significant percentage of NKTLs (n = 33) overexpressed c‐Myc (45.4%), p53 (87.9%), and NF‐κB p50 (67.7%) on immunohistochemistry using a tissue microarray containing 33 NKTL samples. Notably, overexpression of survivin was observed in 97% of cases. Based on our findings, we propose a model of NKTL pathogenesis where deregulation of p53 together with activation of Myc and NF‐κB, possibly driven by EBV LMP‐1, results in the cumulative up‐regulation of survivin. Down‐regulation of survivin with Terameprocol (EM‐1421, a survivin inhibitor) results in reduced cell viability and increased apoptosis in tumour cells, suggesting that targeting survivin may be a potential novel therapeutic strategy in NKTL. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Strategies to improve cyanine dye multi layer organic solar cells
Authors: Hany Roland , Fan Bin , de Castro Fernando Araujo , Heier Jakob , Kylberg William , Nüesch Frank
Published: November 2010

We report the status and strategies to improve the performance of cyanine dye/C60 bilayer heterojunction solar cells. Cyanines are characterized by convenience of synthesis and tunable light absorption. They have high light extinction coefficients, which offer the possibility to go around the constraints of small exciton diffusion length, and ultrathin films can be applied to fabricate multi layer organic solar cells. We optimized the cell performance by oxidative doping (with O2/water/light, or NOBF4) of the cyanine layer. Doping increased the film conductivity and induced a steep rise in the short‐circuit current and the open‐circuit voltage. The external quantum efficiency approached 80% at maximum, meaning that the full cyanine layer of 30 nm thickness was active in charge generation. We argue that cyanine aggregates may be responsible for efficient charge transport over larger distances to the heterointerface. We also describe simple processes to match the energy to the low‐lying hole‐transporting cyanine level by using a thin organic salt layer or doped polyaniline as anode buffer layer. Thereby, hole injection was facilitated and good‐performing devices (power conversion efficiency η = 3%) with a high fill factor (FF ∼60%) were fabricated. Cyanine dyes are accompanied by mobile counter ions. These ions can diffuse into adjacent layers and build up important space charge that alters the energy levels at heterojunctions. The control of the ionic space charge allows to control the flow of electronic charge carriers and to implement new functionalities unique to organic opto‐electronic devices. Copyright © 2010 John Wiley & Sons, Ltd.
Protein expression profiles distinguish between experimental invasive pulmonary aspergillosis and Pseudomonas pneumonia
Authors: Gonzales Denise A. , Torre Carlos De , Wang Honghui , Devor Christopher B. , Munson Peter J. , Ying Sai‐Xia , Kern Steven J. , Petraitiene Ruta , Levens David L. , Walsh Thomas J. , Suffredini Anthony F.
Published: November 2010

We hypothesized that invasive pulmonary aspergillosis (IPA) may generate a distinctive proteomic signature in plasma and bronchoalveolar lavage (BAL). Proteins in plasma and BAL from two neutropenic rabbit models of IPA and Pseudomonas pneumonia were analyzed by SELDI‐TOF MS. Hierarchical clustering analysis of plasma time course spectra demonstrated two clusters of peaks that were differentially regulated between IPA and Pseudomonas pneumonia (57 and 34 peaks, respectively, p<0.001). PCA of plasma proteins demonstrated a time‐dependent separation of the two infections. A random forest analysis that ranked the top 30 spectral points distinguished between late Aspergillus and Pseudomonas pneumonias with 100% sensitivity and specificity. Based on spectral data analysis, three proteins were identified using SDS‐PAGE and LC/MS and quantified using reverse phase arrays. Differences in the temporal sequence of plasma haptoglobin (p<0.001), apolipoprotein A1 (p<0.001) and transthyretin (p<0.038) were observed between IPA and Pseudomonas pneumonia, as was C‐reactive protein (p<0.001). In summary, proteomic analysis of plasma and BAL proteins of experimental Aspergillus and Pseudomonas pneumonias demonstrates unique protein profiles with principal components and spectral regions that are shared in early infection and diverge at later stages of infection. Haptoglobin, apolipoprotein A1, transthyretin, and C‐reactive protein are differentially expressed in these infections suggesting important contributions to host defense against IPA.
Protected versus unprotected dextran macroinitiators for ATRP synthesis of Dex‐g‐PMMA
Authors: Dupayage Ludovic , Nouvel Cécile , Six Jean‐Luc
Published: November 2010

The synthesis of amphiphilic dextran‐g‐poly(methyl methacrylate) glycopolymers (Dex‐g‐PMMA) is studied using “grafting from” concept and atom transfer radical polymerization. Two strategies have been examined to control the macromolecular parameters of such glycopolymers. One is involving four steps including a protection/deprotection approach and the second one only two steps. The introduction of initiators group onto a protected acetylated dextran (and directly onto dextran) was achieved resulting in protected DexAcBr (and in unprotected DexBr). These two types of polysaccharidic macroinitiators differ in term of solubility (hydrophilic DexBr vs. hydrophobic DexAcBr) and of position of the initiators groups on the glucosidic units (which are the sites of the future grafts). When evaluated as macroinitiators for ATRP of MMA, control was achieved in both cases but DexBr gave much faster polymerization and lower average grafting efficiency compared with DexAcBr or model initiator. Advantages and drawbacks of both pathways have finally been discussed. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2010
High performance semiconducting polymers containing bis(bithiophenyl dithienothiophene)‐based repeating groups for organic thin film transistors
Authors: Kim Kyung Hwan , Chung Dae Sung , Park Chan Eon , Choi Dong Hoon
Published: November 2010

New dithienothiophene‐containing conjugated polymers, such as poly(2,6‐bis(2‐thiophenyl‐3‐dodecylthiophene‐2‐yl)dithieno[3,2‐b;2′,3′‐d]thiophene, 4 and poly(2,6‐bis (2‐thiophenyl‐4‐dodecylthiophene‐2‐yl)dithieno[3,2‐b;2′,3′‐d]thiophene, 8 have been successfully synthesized via Stille coupling reactions using dodecyl‐substituted thiophene‐based monomers, bistributyltin dithienothiophene, and bistributyltin bithiophene; these polymers have been fully characterized. The main difference between the two polymers is the substitution position of the dodecyl side chains in the repeating group. Grazing‐incidence X‐ray diffraction (GI‐XRD) gave clear evidence of edge‐on orientation of polycrystallites to the substrate. The semiconducting properties of the two polymers have been evaluated in organic thin film transistors (OTFTs). The two conjugated polymers 4 and 8 exhibit fairly high hole carrier mobilities as high as μave = 0.05 cm2/Vs (ION/OFF = 3.42 × 104) and μave = 0.01 cm2/Vs, (ION/OFF = 1.3 × 105), respectively, after thermal annealing process. The solvent annealed films underwent reorganization of the molecules to induce higher crystallinity. Well‐defined atomic force microscopy (AFM) topography supported a significant improvement in TFT device performance. The hole carrier mobilities of the solvent annealed films are comparable to those obtained for a thermally annealed sample, and were one‐order higher than those obtained with a pristine sample. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2010
One‐step synthesis of ladder‐type fused poly(benzopentalene) derivatives with tunable energy levels by variable substituents
Authors: Wang Dong , Michinobu Tsuyoshi
Published: November 2010

Novel ladder‐type conjugated polymers, fused poly (benzopentalene) derivatives, were synthesized from the readily accessible 1,4‐dibromo‐2,5‐diethynylbenzene derivatives by the Pd‐catalyzed self‐polycondensation in one‐step with high yields. The low solubility of the ladder structure was suggested when the triisopropylsilyl substituents were selected. However, when longer alkyl chains were introduced into the peripheral moieties, such as the dialkylanilino (DAA) and alkyloxyphenyl groups, a high solubility was achieved and the number‐average molecular weight (Mn) reached 18,000. The UV‐Vis absorption spectral shapes of the polymers were similar to the reported dibenzopentalene derivatives, except for the bathochromically shifted end absorptions. This result suggests an extension of the π‐conjugated systems due to the polymerization. Moreover, the almost defect‐free structure of the ladder‐type polymers was confirmed by the quantitative tetracyanoethylene (TCNE) addition to the DAA‐activated alkynes. The titration experiments of TCNE to the polymers revealed the number of terminal alkynes, which enabled us to calculate the molecular weight of the polymers. The calculated molecular weight was consistent with that determined by GPC. After the TCNE addition, the polymer band gaps reasonably decreased as suggested by the UV‐Vis‐NIR absorption and electrochemical measurements. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2010
Enhanced redox stability and electrochromic properties of aromatic polyamides based on N,N‐bis(4‐carboxyphenyl)‐N′,N′‐bis(4‐tert‐butylphenyl)‐1,4‐phenylenediamine
Authors: Wang Hui‐Min , Hsiao Sheng‐Huei
Published: November 2010

A new bis(triphenylamine)‐type dicarboxylic acid monomer, N,N‐bis(4‐carboxyphenyl)‐N′,N′‐bis(4‐tert‐butylphenyl)‐1,4‐phenylenediamine, was prepared by a well‐established procedure and led to a new family of redox‐active aromatic polyamides with di‐tert‐butyl‐substituted N,N,N′,N′‐tetraphenylphenylenediamine (TPPA) segments. The resulting polyamides were amorphous with good solubility in many organic solvents, and most of them could be solution cast into flexible polymer films. The polyamides exhibited high thermal stability with glass‐transition temperatures in the range of 247–293 °C and 10% weight‐loss temperatures in excess of 500 °C. They showed well‐defined and reversible redox couples during oxidative scanning, with a strong color change from a colorless or pale yellowish neutral form to green and blue oxidized forms. They had enhanced redox stability and electrochromic performance when compared with the corresponding analogs without tert‐butyl substituents on the TPPA unit. The polyamide with TPPA units in both the diacid and diamine components shows multicolored electrochromic behavior. A polyamide containing both the cathodic coloring anthraquinone chromophore and the anodic coloring TPPA chromophore has the ability to show red, green, and blue states, toward single‐component RGB electrochromics. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011
Conjugated polymer covalently modified multiwalled carbon nanotubes for optical limiting
Authors: Niu Lijuan , Li Peipei , Chen Yu , Wang Jun , Zhang Jinjuan , Zhang Bin , Blau Werner J.
Published: November 2010

A new soluble multiwalled carbon nanotubes (MWNTs) covalently functionalized with conjugated polymer PCBF, in which the wt % of MWNTs is approximately calculated as 7.3%, and the average thickness of PCBF covalently grafted onto MWNTs is 10.4 nm, was synthesized by an amidation reaction. In contrast to the starting polymer PCBF‐NH2, grafting of PCBF onto MWNTs led to a 0.3 eV red‐shift of the N1s XPS peak at 399.7 eV assigning to N in the unreacted NH2moieties in the resulting copolymer structure and an appearance of new peak at 402 eV corresponding to N bound to the carbonyl C (i.e., NHCO). Unlike PCBF‐NH2, which only displayed a weak optical limiting response at 532 nm, Z‐scan for MWNT‐PCBF exhibited a much broader reduction in transmission and a scattering accompanying on the focus of the lens at both 532 and 1064 nm, indicating a prominent broadband optical limiting response. The thermally induced nonlinear scattering is responsible for the optical limiting. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2010
Pursuit of reinitiation efficiency of resonance‐stabilized monomeric allyl radical generated via “degradative monomer chain transfer” in allyl polymerization
Authors: Inoue Satoshi , Kumagai Takeo , Tamezawa Hajime , Aota Hiroyuki , Matsumoto Akira , Yokoyama Katsutoshi , Matoba Yasuo , Shibano Michirou
Published: November 2010

For a deeper understanding of allyl polymerization mechanism, the reinitiation efficiency of resonance‐stabilized monomeric allyl radical was pursued because in allyl polymerization it is commonly conceived that the monomeric allyl radical generated via the allylic hydrogen abstraction of growing polymer radical from monomer, i.e., “degradative monomer chain transfer,” has much less tendency to initiate a new polymer chain and, therefore, this monomer chain transfer is essentially a termination reaction. Based on the renewed allyl polymerization mechanism in our preceding article, the monomer chain transfer constant in the polymerization of allyl benzoate was estimated to be 2.7 × 10−2 at 80 °C under the polymerization condition, where the coupling termination reaction of growing polymer radical with allyl radical was negligible and, concurrently, the reinitiation reaction of allyl radical was enhanced significantly. The reinitiation efficiencies of monomeric allyl radical were pursued by the dead‐end polymerizations of allyl benzoate at 80, 105, and 130 °C using a small amount of initiators; they increased remarkably with raised temperature. Thus, the enhanced reinitiation reactivity of allyl radical at an elevated temperature could bias the well‐known degradative monomer chain transfer characteristic of allyl polymerization toward the chain transfer in common vinyl polymerization. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2010
Controlled grafting of cellulose esters using SET‐LRP process
Authors: Vlček Petr , Raus Vladimír , Janata Miroslav , Kříž Jaroslav , Sikora Antonín
Published: November 2010

Here, we present the first example of application of single‐electron transfer living radical polymerization (SET‐LRP) process to a controlled grafting of cellulose esters, cellulose diacetate (CDA), and cellulose acetate butyrate (CAB). The cellulose ester macroinitiators with various functionality densities have been prepared by acylation of the backbones with 2‐bromoisobutyryl (BrIB) and dichloroacetyl (DCA) groups, respectively. Methacrylate monomers were polymerized using DCA‐functionalized macroinitiators in the presence of pentamethyldiethylene triamine as a ligand. At 30 °C, the reaction is rather slow, reaching about 10% conversion after 3 to 6 h of polymerization, whereas the higher temperature (60 °C) perceptibly speeds up the polymerization so that methyl methacrylate (MMA) conversion is ∼30% after 5 h. Graft copolymers with random‐type and diblock‐type grafts having amphiphilic character were also synthesized. For acrylate grafting (BuA and t‐BuA), BrIB‐functionalized macroinitiators are more convenient in a combination with a low concentration of Cu(0) and Me6TREN as a ligand and polymerization is detectably faster even at the lower temperature than that of MMA. Kinetic studies show “living” character of both the graftings. Important advantages of SET‐LRP, compared with classic ATRP, are (i) higher polymerization rate, (ii) lower extent of recombination of the growing grafts and (iii) negligible coloration of the products with catalytic residua, so that the prepared polymers do not require additional careful purification. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2010