bluuebunny/crossref_metadata_2025 huggingface dataset:
Upgraded Cobas TaqMan version 2: hidden consequences at cohort level
Authors: Taylor N , Grabmeier‐Pfistershammer K , Oberkofler H , Egle A , Rieger A , Ledergerber B
Published: November 2012

The viral load quantification constitutes a cornerstone of antiretroviral therapy management. After the switch from the Cobas Ampliprep Amplicor HIV‐1 Monitor Test, v. 1,5 (CAP/CA) (Roche Diagnostics, Mannheim, Germany) to CTM2 in August 2009 at the HIV department of the General Hospital in Vienna, multiple internal reports accumulated concerning an increase of detectable HIV‐1 viral loads in patients with previous long‐term virological suppression. In order to evaluate these observations and their clinical consequences, a retrospective analysis of the number of elevated VL measurements in formerly virological suppressed patients during the first year of CTM2 use was performed. Furthermore, we monitored for consecutive numbers of repeated VL measurements, genotypic testing and for changes of antiretroviral therapy (ART). We recruited 373 of 2078 patients meeting the chosen inclusion criteria (Initiation of ART prior to August 6, 2008;≥1 VL measurement in the pre‐CTM2 period from August 6, 2008 to August 5, 2009, all VL measurements below the limit of quantification as defined by applied nucleic acid quantification assay (CAP/CA with<50 copies/mL);≥1 VL measurement during the CTM2 period from August 6, 2009 to August 5, 2010). 221 (59.2%) remained with an undetectable HIV‐1 viral load after implementation of CTM2, whereas 152 (40.8%) became detectable. The newly detected viremia showed a clear increase at the lower end of the dynamic range of quantification by CTM2. Among our 152 patients, 111 (73.0%) had viral loads ranging from 20–200 copies/mL, 6 (4.0%) between 201–400 copies/mL, while 35 (23.0%) patients showed viral loads measurements above>400 copies/mL. Of these newly detectable patients, 132 had a VL repeat and 72 became undetectable, the remaining 60 patients remained detectable. Remarkably, it was striking to find that in the group of patients who when switching to CTM2 reached at once viral loads exceeding 400 copies/mL, 48.3% became undetectable after viral load repeat using again CTM2, suggesting a high test variability at low detection limit but also beyond. Three genotypic resistance testings were performed and 16 patients underwent subsequent ART changes. In summary, the transition to CTM2 was followed by a dramatic increase of detectable viral loads in patients with stable ART and prior virological suppression, which at least in part could not be reproduced in repeat measurements.
Improving HIV‐1 tropism determination by combining geno2pheno and V3 net charge calculation
Authors: Montagna C , De Crignis E , Turriziani O , Bon I , Re M , Antonelli G , Pantaleo G , Graziosi C
Published: November 2012

Genotypic tests are the most common methods to identify patients eligible for CCR5 inhibitors administration in Europe. Among the available tools geno2pheno coreceptor (G2P) is the most used online system in routine diagnostics. This study was conceived to assess if the combination of G2P prediction with V3 peptide net charge (NC) value could improve the accuracy of tropism prediction. Sequences (129) were analyzed by G2P according to European Guidelines. NC values were calculated by the online software Peptide Property Calculator. Phenotypic assay was performed cloning the complete env gene into pcDNA 3.1 TOPO vector; infectivity of pseudotyped virions was tested on U87_CD4+CCR5+ and U87_CD4+CXCR4+ cells lines to assess viral tropism. Sequences were stratified into 3 groups according to the agreement between NC values and G2P results. Group 1: sequences assigned to the same group by both tools, group 2: sequences assigned to one group by G2P but indeterminate by NC and group 3: sequences for which G2P and NC gave discordant results. 61% of sequences predicted as X4 by G2P showed NC values higher than 5; similarly, 76% of sequences predicted as R5 by G2P had NC values below 4 (Group 1). Sequences with NC values between 4 and 5 (Group 2) were associated to different G2P predictions: 59% samples were predicted as R5‐tropic and 41% sequences as X4‐tropic. These data support the hypothesis that 4 to 5 NC values could be associated to the presence of dual/mixed‐tropic variants (DM). Sequences identified as X4 by NC value had at least one positive residue in positions known to be involved in tropism prediction (58%) and positive residues in position 32 (39%). To further verify NC‐based prediction, phenotypic assay was performed on a subset of sequences from each group. The assay confirmed the tropism prediction for group 1 sequences and demonstrated that the variants with net charge between 4 and 5 have DM tropism. Moreover, in vitro phenotyping of discordant viruses confirmed NC result, showing that this parameter is strongly associated with phenotypic assay. These results show that the combination of G2P and NC could increase the accuracy of tropism prediction and the ability to discriminate DM viruses. A more reliable identification of X4 variants would be useful for better selecting candidates for maraviroc administration, but also as a predictive marker in coreceptor switching, strongly associated to the phase of infection.
Severe Cutaneous Reactions Requiring Hospitalization in Allopurinol Initiators: A Population‐Based Cohort Study
Authors: Kim Seoyoung C. , Newcomb Craig , Margolis David , Roy Jason , Hennessy Sean
Published: November 2012

Objective

Rare but potentially life‐threatening cutaneous adverse reactions have been associated with allopurinol, but population‐based data on the incidence and mortality of such reactions are scarce.

Methods

We conducted a propensity score–matched cohort study to evaluate the incidence rate (IR) and in‐hospital mortality of hospitalization for severe cutaneous adverse reactions (SCARs) in allopurinol initiators compared to non–allopurinol users, using data from 5 large Medicaid programs. The primary outcome was identified by the principal discharge diagnosis code 695.1. A Cox proportional hazards model evaluated the relative risk of SCARs associated with the use of allopurinol and determined the relative risk of SCARs associated with allopurinol dose.

Results

During a followup period of 65,625 person‐years for allopurinol initiators, 45 were hospitalized with SCARs. The crude IR was 0.69 (95% confidence interval [95% CI] 0.50–0.92) per 1,000 person‐years. All 45 cases occurred within 365 days and 41 (91.1%) occurred within 180 days after initiating treatment with allopurinol. Twelve patients (26.7%) died during the hospitalization. The crude IR in non–allopurinol users was 0.04 (95% CI 0.02–0.08) per 1,000 person‐years. The risk of SCARs was increased in allopurinol initiators versus nonusers (hazard ratio [HR] 9.68, 95% CI 4.55–20.57). Among allopurinol initiators, the HR for high‐dosage (>300 mg/day) versus low‐dosage allopurinol was 1.30 (95% CI 0.31–5.36) after adjusting for age, comorbidities, and recent diuretic use.

Conclusion

Among allopurinol initiators, SCARs were found to be rare but often fatal, and occurred mostly in the first 180 days of treatment. The risk of SCARs was 10 times as high in allopurinol initiators as compared to allopurinol nonusers.
Tocilizumab as monotherapy or in combination with nonbiologic disease‐modifying antirheumatic drugs: Twenty‐four–week results of an open‐label, clinical practice study
Authors: Weinblatt Michael E. , Kremer Joel , Cush John , Rigby William , Teng Lichen L. , Devenport Jenny , Singh Natasha , Lepley Denise , Genovese Mark C.
Published: November 2012

Objective

To assess the safety and tolerability of tocilizumab (TCZ) as monotherapy or in combination with nonbiologic disease‐modifying antirheumatic drugs (DMARDs) in patients with moderate to severe rheumatoid arthritis (RA) who had an inadequate response at study entry to their current treatment with biologic agents or DMARDs.

Methods

This 24‐week, multicenter, open‐label, phase IIIb study conducted in the US enrolled 886 patients. Treatments were allocated to patients based on their current therapy at study entry. Patients receiving monotherapy with biologic agents were assigned to TCZ 8 mg/kg monotherapy. All other patients were randomized to either TCZ 4 mg/kg + DMARDs or TCZ 8 mg/kg + DMARDs. The primary end point was the number and percentage of patients with serious adverse events (SAEs) during 24 weeks of TCZ treatment. Efficacy assessments were evaluated as secondary outcomes. Data were analyzed descriptively.

Results

Overall, 69 patients (7.8%) reported ≥1 SAEs. The rate of SAEs per 100 person‐years was 28.3 (95% confidence interval [95% CI] 23.1–34.4) overall and was similar across treatment groups: 29.1 (95% CI 21.0–39.2), 30.3 (95% CI 22.2–40.2), and 20.6 (95% CI 10.3–36.9) in the TCZ 4/8 mg/kg + DMARDs, TCZ 8 mg/kg + DMARDs, and TCZ 8 mg/kg monotherapy groups, respectively. The most common SAEs were infections (i.e., pneumonia [1.0%] and cellulitis [0.9%]). In addition, American College of Rheumatology response rates and reductions in mean Disease Activity Score based on a 28‐joint count were generally similar among treatment groups.

Conclusion

The safety findings in this study were consistent with the previously identified safety profile of TCZ. TCZ had an AE profile consistent with prior randomized blinded studies and was effective when administered as either monotherapy or in combination with DMARDs for the treatment of RA.
Foot and Ankle Kinematics in Rheumatoid Arthritis: Influence of Foot and Ankle Joint and Leg Tendon Pathologies
Authors: Dubbeldam R. , Baan H. , Nene A. V. , Drossaers‐Bakker K. W. , van de Laar M. A. F. J. , Hermens H. J. , Buurke J. H.
Published: November 2012

Objective

From early onset of the disease, patients with rheumatoid arthritis (RA) experience walking impairments. Pathologic effects of RA on foot and ankle structures have been studied clinically, but little is known as to how they relate to kinematic changes during gait. The aim of this study was to explore the relationship between clinically observed pathologies of foot and ankle joints and leg tendons and the corresponding gait kinematics.

Methods

The gait of 25 subjects with varying stages of RA was recorded and foot and ankle kinematics were assessed. Magnetic resonance imaging was performed for each subject: first metatarsophalangeal (MTP) joint, midfoot, and hindfoot synovitis, erosion scores, and leg tendon involvement were determined. The joint alignment and motion score represented daily clinical assessment. The 95% confidence intervals of the Spearman's correlation coefficient tests were used to explore the relationships between the clinical and kinematic parameters.

Results

Maximum first MTP joint dorsiflexion at preswing was related to reduced first MTP joint passive motion, first MTP joint synovitis and erosion, midfoot synovitis and erosion, and hindfoot erosion. Midfoot pronation range of motion during single stance was related to subtalar alignment and Achilles tendon involvement. Hindfoot eversion range of motion during single stance was related to subtalar alignment and peroneus longus tendon involvement. Involvement of the tibialis posterior tendon could not be identified as an independent factor influencing foot or ankle kinematics.

Conclusion

Our findings suggest moderate to strong relationships between foot and ankle gait kinematics and structural pathologies.
All‐Polymer Bistable Resistive Memory Device Based on Nanoscale Phase‐Separated PCBM‐Ferroelectric Blends
Authors: Khan M. A. , Bhansali Unnat S. , Cha Dongkyu , Alshareef H. N.
Published: November 2012

All polymer nonvolatile bistable memory devices are fabricated from blends of ferroelectric poly(vinylidenefluoride–trifluoroethylene (P(VDF‐TrFE)) and n‐type semiconducting [6,6]‐phenyl‐C61‐butyric acid methyl ester (PCBM). The nanoscale phase separated films consist of PCBM domains that extend from bottom to top electrode, surrounded by a ferroelectric P(VDF‐TrFE) matrix. Highly conducting poly(3,4‐ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) polymer electrodes are used to engineer band offsets at the interfaces. The devices display resistive switching behavior due to modulation of this injection barrier. With careful optimization of the solvent and processing conditions, it is possible to spin cast very smooth blend films (Rrms ≈ 7.94 nm) and with good reproducibility. The devices exhibit high Ion/Ioff ratios (≈3 × 103), low read voltages (≈5 V), excellent dielectric response at high frequencies (ϵr ≈ 8.3 at 1 MHz), and excellent retention characteristics up to 10 000 s.
Quantitative Comparison of Chiral Catalysts Selectivity and Performance: A Generic Concept Illustrated with Cyclododecanone Monooxygenase as Baeyer–Villiger Biocatalyst
Authors: Fink Michael J. , Rial Daniela V. , Kapitanova Petra , Lengar Alenka , Rehdorf Jessica , Cheng Qiong , Rudroff Florian , Mihovilovic Marko D.
Published: November 2012

Within this work a generic tool for chiral catalyst evaluation is established based on the application‐oriented properties activity and selectivity; the concept aims at quantitatively comparing catalyst performance in general on a multitude of substrates. It is designed and intended to serve as decision guidance for challenges in catalysis and comprehensible information extraction from already recorded but unrefined data sets. The underlying algorithm assigns function points to catalytic entities via a statistically solid model possessing high flexibility and generates a relative ranking. This is coupled to an automated iterative refinement process towards maximum information content of results employing Shannon entropy optimization. Consequently, the developed work‐flow facilitates high distinguishability between catalysts even in low‐scattering data sets. The numerical ranking is complemented by a clearly arranged graphic representation permitting facile and reliable visual interpretation of generality or niche capabilities of catalysts. Usefulness of the title concept is demonstrated by the performance evaluation of cyclododecanone monooxygenase, a highly versatile Baeyer–Villiger enzyme. To retain broad applicability, an open‐source MATLAB® script is provided in electronic form.
Ammonolyzed MoO3 Nanobelts as Novel Cathode Material of Rechargeable Li‐Ion Batteries
Authors: Wang Xiao‐Jun , Nesper Reinhard , Villevieille Claire , Novák Petr
Published: November 2012

Through a moderate ammonolysis method, nanobelts of α‐MoO3 can be modified to HxMo(O, N)3. When reaction temperatures are kept between 200–300 °C, gaseous NH3 diffuses in‐between the oxide layers and reacts with terminal oxygen sites of MoO3. As a consequence, hydrogen is introduced into the layers and bonded to terminal oxygen, and together with the effect of nitradation, the unit cell volume significantly shrinks mostly along the b axis. The modified compound HxMo(O, N)3 exhibits not only better electronic conductivity, but also faster lithium ion mobility than regular MoO3. In addition, this ammonolyzed MoO3 exhibits enhanced electrochemical performance beyond MoO3. In the potential window 1.5–3.5 V, the specific capacity of HxMo(O, N)3 can reach more than 250 A h kg−1 and was cycled 300 times without fading. It can be considered as a novel candidate cathode material with high specific charge for rechargeable Li‐ion batteries.
Yael Bartana and Post‐traumatic Culture: Utopian Reversibility and the Case of Polish National Melancholia
Authors: Sclodnick Hilary
Published: November 2012

Mary Koszmary (2007) is one short film from a trilogy by Israeli artist Yael Bartana, which centers on the exhortations of a Polish radical politician calling for the comeback of three million Jews to Poland. This Polish trilogy focuses a lens, both artistic and psychoanalytic, on the place of the unbearable in the human psyche, reality which must be neither attended to nor acknowledged. The example of the unbearable and inassimilable which Bartana chooses is Poland's complicity and cooperation with the murder of her Jews. The Jewish genocide roughly seventy years ago involves inassimilable shame and guilt, defended against by national repression, denial and fetishistic dissociation. Bartana imagines a symptom in today's generation which both refutes and repeats the history enacted by their grandparents. Bartana assumes a deep‐set collective trauma manifesting bizarrely two generations later and conjures an unflinching picture of why failure to come to terms with and to mourn traumatic losses is relentlessly a problem in human history. The purpose of this paper is to explore the symptoms of the intergenerationally transmitted collective trauma as these symptoms translate from those of the individual traumatic condition in order to deepen our understanding of the effects of both individual and collective trauma when unresolved over time and particularly over generations. The first step toward healing is to acknowledge. Bartana's film sets up the opportunity for acknowledgment shining a clear cool light on so many modes of obfuscation. Copyright © 2012 John Wiley & Sons, Ltd.
A Study of Cyanotetrazole Oxides and Derivatives thereof
Authors: Boneberg Franziska , Kirchner Angie , Klapötke Thomas M. , Piercey Davin G. , Poller Maximilian J. , Stierstorfer Jörg
Published: November 2012

In this work we report on the syntheses of energetic salts of cyanotetrazolate‐1‐ and ‐2‐oxides; this offers a unique ability to compare the effects of tetrazole 1‐ versus 2‐oxidation. 5‐Cyanotetrazolate‐2‐oxide can be synthesized by oxidation of the 5‐cyanotetrazolate anion with Oxone, while the corresponding 1‐oxide was synthesized by the rearrangement of azidoaminofurazan. Both chemical (multinuclear NMR, IR, and Raman spectroscopies, mass spectrometry, etc.) as well as explosive (impact, friction, and static sensitivities) properties are reported for these energetic salts. Calculated explosive performances using the EXPLO5 computer code are also reported. We furthermore detail the chemistry of these two anions, and their ability to form tetrazole‐carboxamides, dihydrotetrazines, and tetrazines. The ability to hydrolyze cyanotetrazole oxides to their amides was demonstrated by two copper complexes. Several crystal structures of these species are presented in addition to full chemical characterization. Finally, the unique 1,4,‐bis(2‐N‐oxidotetrazolate)‐1,2,4,5‐tetrazine anion was characterized as an energetic material as its ammonium salt.
A Note on the Controllability and Observability for Piecewise Linear Time‐varying Impulsive Systems
Authors: Han Jing , Liu Yang , Zhao Shouwei , Yang Rongjiang
Published: November 2012

This note studies the controllability and observability for piecewise time‐varying impulsive systems. Necessary and sufficient criteria for complete controllability and observability are established. Two numerical examples are given to illustrate the utility and advantages of our criteria.
An adaptive model for highway travel time prediction
Authors: Liu Xiaobo , Chien Steven I. , Chen Mei
Published: November 2012

Traffic congestion caused by either insufficient road capacity or unexpected events has been a major problem in urban transportation networks. To disseminate accurate traveler information and reduce congestion impact, it is desirable to develop an adaptive model to predict travel time. The proposed model is practically implementable to capture dynamic traffic patterns under various conditions, which integrates the features of exponential smoothing and the Kalman filter by utilizing both real‐time and historic data. The model is simple in formulation while robust in performance in terms of accuracy and stability. With a constraint or nonconstraint smoothing factor, the proposed model is tested with both real world and simulated data and demonstrated itself a sound model that outperforms others (e.g., Kalman filter and simple exponential smoothing) specifically under recurring and nonrecurring congestion. Copyright © 2012 John Wiley & Sons, Ltd.
Elucidation of Mg2+ binding activity of adenylate kinase from Mycobacterium tuberculosisH37Rv using fluorescence studies
Authors: Meena Laxman S. , Dhakate Sanjay R. , Sahare Purushottam D.
Published: November 2012

Adenylate kinase (AK) is a small ubiquitous enzyme that catalyzes the reversible transfer of the terminal phosphate group from adenine triphosphate (ATP): magnesium ion (Mg2+) to adenine monophosphate (AMP) to form two molecules of adenine diphosphate (ADP). AK thus maintains the homeostasis of adenine nucleotides in eukaryotes and prokaryotes. Because the [ATP]/[ADP] ratio is an important parameter in energy regulation in cells, Mg2+‐activated AK has an important biological role, particularly in the case of bacteria, as imbalance in the ratio of [ATP]/[ADP] has been associated with alteration in its DNA supercoiling state. In the present study, magnesium‐binding assays were carried out by systematically varying the concentrations of Mg2+, protein, AMP, ATP, and indicator in kinetic experiments. We report evidence that during magnesium‐binding assay, the fluorescence level of the indicator “Mag‐Indo‐1” changes with protein concentration, suggesting that magnesium ions are binding to AK. The dual activity of AK both as nucleoside monophosphate and diphosphate kinases suggests that this enzyme may have a role in RNA and DNA biosynthesis in addition to its role in intracellular nucleotide metabolism. According to the proposed model, the magnesium‐activated AK exhibits an increase in its forward reaction rate compared with the inactivated form. These findings imply that Mg2+ could be an important regulator in the energy signaling network in cells.
Structural investigation of tumor differentiation factor
Authors: Roy Urmi , Sokolowska Izabela , Woods Alisa G. , Darie Costel C.
Published: November 2012

Tumor differentiation factor (TDF) is a 17 kDa protein produced by the pituitary and secreted into the bloodstream, with no definitive function and incomplete characterization. TDF has the following four cysteine (Cys) residues: Cys17, Cys70, Cys97, and Cys98. To understand the function of TDF, we (1) overexpressed and characterized recombinant TDF (rTDF); (2) investigated native, secreted TDF; and (3) assessed potential disulfide connectivities using molecular modeling. Our results from Western blotting (WB) experiments suggest that rTDF is mostly expressed as insoluble, monomeric, and dimeric forms. Mass spectrometry analysis of the overexpressed rTDF identified a peptide that is a part of TDF protein. WB of the native, secreted TDF detected it as a 50 kDa band. In addition, investigation of TDF by molecular modeling suggests that the Cys residues may form disulfide bridges between Cys17–Cys98 and Cys70–Cys17.
Solid‐phase synthesis of fusaricidin/li‐f class of cyclic lipopeptides: Guanidinylation of resin‐bound peptidyl amines
Authors: Bionda Nina , Pitteloud Jean‐Philippe , Pitteloud Jean-Philippe , Cudic Predrag
Published: November 2012

Fusaricidins/LI‐Fs and related cyclic lipopeptides represent an interesting new class of antibacterial peptides with the potential to meet the challenge of antibiotic resistance in bacteria. Our previous study (Bionda et al. ChemMedChem 2012, 7, 871–882) revealed the significance of the guanidinium group located at the termini of the lipidic tails of these cyclic lipopeptides for their antibacterial activities. Therefore, devising a synthetic strategy that will allow incorporation of guanidinium functionality into their structure is of particular practical importance. Since appropriately protected guanidino fatty acid building blocks are not commercially available, our strategy toward guanidinylated fusaricidin/LI‐F analogs include solid‐phase synthesis of a cyclic lipopeptide precursor possessing a lipidic tail with a terminal amino group followed by its conversion into corresponding guanidine. To find the optimal method for this conversion, we have examined commonly used guanidinylation reagents under the conditions compatible with standard solid‐phase peptide synthesis. Described experimental results demonstrated superiority of N,N′‐di‐Boc‐N″‐triflylguanidine in solid‐phase preparation of fusaricidin/LI‐F class of cyclic lipopeptides. The triflylguanidine reagent gave a single monoguanidinylated product in excellent yield independently of the type of solid‐support. © 2012 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 100: 160–166, 2013.
Environmental Management of End‐of‐Life Products: Nine Factors of Sustainability in Collaborative Networks
Authors: Rizzi Francesco , Bartolozzi Irene , Borghini Alessandra , Frey Marco
Published: November 2012

The paradigm of the green economy has contributed to raising the attention paid to developing sustainability‐oriented strategies for supply chain (SC) management. The responsibility of producers to extend and reverse SCs is a critical and timely topic that captures increasing concerns over the way firms can adapt their business models to interlinking technical, socio‐economic and environmental frameworks. This is particularly true when producers are not also reuse/recycle actors. By performing a critical review of the scientific literature on this field, this article develops nine elemental factors that can be considered for assessing the impacts of collaborative strategies as a means to implement extended producer responsibility (EPR) in open‐loop SCs. The resulting conceptual framework provides EPR implementation guidance under different market conditions. Inter‐organizational relationships are found to present both opportunities and threats that can be profitably managed under a systemic perspective. Implications for management and needs for further research are discussed. Copyright © 2012 John Wiley & Sons, Ltd and ERP Environment.
Evaluation of exogenous siRNA addition as a metabolic engineering tool for modifying biopharmaceuticals
Authors: Tummala Seshu , Titus Michael , Wilson Lee , Wang Chunhua , Ciatto Carlo , Thill Greg , Foster Donald , Li Chen , Szabo Zoltan , Guttman Andras , Bettencourt Brian , Jayaraman Muthuswamy , Deroot Jack , Kocisko David , Pollard Stuart , Charisse Klaus , Kuchimanchi Satya , Hinkle Greg , Milstein Stuart , Meyers Rachel , Wu Shiaw‐Lin , Karger Barry L. , Rossomando Anthony
Published: November 2012

Traditional metabolic engineering approaches, including homologous recombination, zinc‐finger nucleases, and short hairpin RNA, have previously been used to generate biologics with specific characteristics that improve efficacy, potency, and safety. An alternative approach is to exogenously add soluble small interfering RNA (siRNA) duplexes, formulated with a cationic lipid, directly to cells grown in shake flasks or bioreactors. This approach has the following potential advantages: no cell line development required, ability to tailor mRNA silencing by adjusting siRNA concentration, simultaneous silencing of multiple target genes, and potential temporal control of down regulation of target gene expression. In this study, we demonstrate proof of concept of the siRNA feeding approach as a metabolic engineering tool in the context of increasing monoclonal antibody (MAb) afucosylation. First, potent siRNA duplexes targeting fut8 and gmds were dosed into shake flasks with cells that express an anti‐CD20 MAb. Dose response studies demonstrated the ability to titrate the silencing effect. Furthermore, siRNA addition resulted in no deleterious effects on cell growth, final protein titer, or specific productivity. In bioreactors, antibodies produced by cells following siRNA treatment exhibited improved functional characteristics compared to antibodies from untreated cells, including increased levels of afucosylation (63%), a 17‐fold improvement in FCgRIIIa binding, and an increase in specific cell lysis by up to 30%, as determined in an Antibody‐Dependent Cellular Cytoxicity (ADCC) assay. In addition, standard purification procedures effectively cleared the exogenously added siRNA and transfection agent. Moreover, no differences were observed when other key product quality structural attributes were compared to untreated controls. These results establish that exogenous addition of siRNA represents a potentially novel metabolic engineering tool to improve biopharmaceutical function and quality that can complement existing metabolic engineering methods. © 2013 American Institute of Chemical Engineers Biotechnol. Prog., 2013 American Institute of Chemical Engineers Biotechnol. Prog., 29: 415–424, 2013
Physical therapy management of female chronic pelvic pain: Anatomic considerations
Authors: George Susan E. , Clinton Susan C. , Borello‐France Diane F.
Published: November 2012

The multisystem nature of female chronic pelvic pain (CPP) makes this condition a challenge for physical therapists and other health care providers to manage. This article uses a case scenario to illustrate commonly reported somatic, visceral, and neurologic symptoms and their associated health and participation impact in a female with CPP. Differential diagnosis of pain generators requires an in‐depth understanding of possible anatomic and physiologic contributors to this disorder. This article provides a detailed discussion of the relevant clinical anatomy with specific attention to complex interrelationships between anatomic structures potentially leading to the patient's pain. In addition, it describes the physical therapy management specific to this case, including examination, differential diagnosis, and progression of interventions. Clin. Anat. 26:77–88, 2013. © 2012 Wiley Periodicals, Inc.
Modulation of age‐related changes in oxidative stress markers and energy status in the rat heart and hippocampus: a significant role for ozone therapy
Authors: El‐Sawalhi Maha M. , Darwish Hebatallah A. , Mausouf Mohamed N. , Shaheen Amira A.
Published: November 2012

Oxidative stress emerges as a key player in the ageing process. Controlled ozone administration is known to promote an oxidative preconditioning or adaptation to oxidative stress. The present study investigated whether prophylactic ozone administration could interfere with the age‐related changes in the heart and the hippocampus of rats. Four groups of rats, aged about 3 months old, were used. Group 1 (Prophylactic ozone group) received ozone/oxygen mixture by rectal insufflations (0.6 mg/kg) twice/week for the first 3 months, then once/week till the age of 15 months. Group 2 (Oxygen group) received oxygen as vehicle for ozone in a manner similar to group 1. Group 3 (Aged control group) was kept without any treatment until the age of 15 months. A fourth group of rats (Adult control group) was evaluated at 3 months of age to provide baseline data. Ozone alleviated age‐associated redox state imbalance as evidenced by reduction of lipid and protein oxidation markers, lessening of lipofuscin deposition, restoration of glutathione levels in both tissues and normalization of glutathione peroxidase activity in the heart tissue. Ozone also mitigated age‐associated energy failure in the heart and the hippocampus, improved cardiac cytosolic Ca2+ homeostasis and restored the attenuated Na+, K+‐ATPase activity in the hippocampus of aged rats. These data provide new evidence concerning the anti‐ageing potential of prophylactic ozone administration. Copyright © 2012 John Wiley & Sons, Ltd.
Expression of FGF4 mRNA is mediated by mating behaviours in mice
Authors: Yan Xing‐Rong , Yang Yan‐hong , Zheng Xiao‐min , Cui Ji‐Hong , Xie Xin , Li Li‐Wen , Chen Fu‐Lin , Hua Jin‐Lian , Zhang Yu‐Sen
Published: November 2012

In mammals, breeding is preceded by species‐specific mating behaviours. In this study, we investigated whether parthenogenetic embryo quality could be improved by mating behaviours in mice. To investigate this hypothesis, female mice were mated with vasectomized Kunming white male mice after superovulation. Oocytes were collected and counted at 16 h after superovulation. The oocytes were then artificially activated by medium containing 10 mM strontium chloride and 5 µg/ml cytochalasin B. Blastocysts were obtained by cultivating activated oocytes in vitro. Expression levels of reprogramming transcription factors (i.e. Oct4, Sox2, Klf4 and c‐Myc) in oocytes, apoptosis‐related genes (i.e. Bax, Bcl2 and c‐Myc) in cumulus cells and pluripotency‐related transcription factors (i.e. Oct4, Nanog and FGF4) in blastocysts were analysed in samples collected from mated and unmated mice. Additionally, developmental competence of parthenogenetic embryos was used to assess following fibroblast growth factor 4 (FGF4) treatment. The results showed that the formation rate of blastocysts in unmated mice was significantly higher than that in mated mice (p < 0.05). Embryo development was primarily blocked at the eight‐cell stage in mated mice; however, the blastocyst formation rate did not differ significantly between groups after the addition of 25 ng/ml FGF4 to the medium at the four‐cell stage (p > 0.05). Moreover, the expression of the reprogramming factor Sox2 was significantly different in oocytes collected from mated versus unmated mice. Taken together, our results demonstrated that mating behaviours influenced embryonic development in vitro by decreasing FGF4 expression. Copyright © 2012 John Wiley & Sons, Ltd.
Predictors and outcomes after transcatheter aortic valve implantation using different approaches according to the valve academic research consortium definitions
Authors: Seiffert Moritz , Schnabel Renate , Conradi Lenard , Diemert Patrick , Schirmer Johannes , Koschyk Dietmar , Linder Matthias , Kersten Jan F. , Grosser Andrea , Wilde Sandra , Blankenberg Stefan , Reichenspurner Hermann , Baldus Stephan , Treede Hendrik
Published: November 2012

Objectives

We report the results of a large single‐center study evaluating predictors and outcomes after transcatheter aortic valve implantation (TAVI) with different devices and access routes according to the Valve Academic Research Consortium (VARC).

Background

The widespread adoption of TAVI warrants a systematic analysis of outcomes. Only few comprehensive data exist comparing different approaches as selected by a heart team.

Methods

TAVI was performed in 326 consecutive patients (mean age 80.6 ± 7.1 years, 55.5% female) at high risk for surgery with balloon‐expandable and self‐expanding devices through transfemoral or transapical access. Data were analyzed according to VARC endpoints; predictors of mortality were identified.

Results

All‐cause mortality was 10.1% (30 days) and 29.9% (1 year) overall and comparable with regard to valve or access choice (P = 0.295) despite different risk profiles at baseline. Device success and 30‐day safety endpoints were achieved in 87.1 and 21.2%. Myocardial infarction [hazard ratio (HR) 6.52], stage‐2 and −3 acute kidney injury (HR 2.52 and 6.80) and major access site complications (HR 1.96) were independent predictors of 1‐year all‐cause mortality. Device success had a protective effect (HR 0.58). Baseline predictors included body mass index <20 kg/m2 (HR 3.20), NYHA class IV (HR 1.87), left ventricular ejection‐fraction <30% (HR 2.30), higher STS‐PROM scores (HR 1.05 per percent), and age (group 75–85 years, HR 0.47).

Conclusions

Comparable results were achieved with different devices and access routes in a heart team approach. Baseline and perioperative predictors of all‐cause mortality were identified, contributing to the refinement of patient and device selection criteria for TAVI. © 2012 Wiley Periodicals, Inc.
Very late erosion of amplatzer septal occluder device presenting as pericardial pain and effusion 8 years after placement
Authors: Roberts Will T. , Parmar Jitendra , Rajathurai Thirumaran
Published: November 2012

We report the case of a very late erosion of an Amplatzer septal occluder (ASO) device more than 8 years after implant, presenting without signs of cardiac tamponade. To date, this case represents the longest period between ASO device implantation and clinical presentation following erosion. The overall rate of device erosion remains low, and the majority reported so far has occurred early, but clinicians should remain alert to the possibility of very late erosion in patients with ASO devices. © 2012 Wiley Periodicals, Inc.
Long‐term results of plaque excision combined with aggressive pharmacotherapy in high‐Risk patients with advanced peripheral artery disease (SAVE a LEG registry)
Authors: Kiesz R. Stefan , Wiernek Szymon L. , Wiernek Barbara K. , Radvany Martin G. , Buszman Piotr P. , Szymanski Radoslaw , Konkolewska Magda D. , Martin Jack L. , Buszman Pawel E.
Published: November 2012

Background

In United States alone there are more than 12 million people with peripheral artery disease (PAD). Long‐term outcomes of plaque excision in high‐risk population (patients with diabetes and patients with end stage renal disease on dialysis) are scarce.

Methods

Since November 2003, we treated 225 consecutive patients (138 male, mean age: 66.3 ± 12.4, range: 29–93) with SilverHawkTM plaque excision for critical limb ischemia or disabling claudication. A total of 367 procedures were performed treating 832 lesions (157 restenotic, 675 de novo). One hundred fifty‐five patients (68.9%) were diabetics, 74 (32.9%) were on dialysis. All patients were treated with statins, clopidogrel, aspirin, and aggressive glycemic control. The primary endpoint for our study was target lesion revascularization (TLR), and the secondary endpoint was an assessment of major adverse events (all cause death, amputation, TLR).

Results

The average time of observation was 2.2 ± 1.2 years. Procedural success rate was 99.4% with <30% residual stenosis achieved in 818 (98.9%) lesions. SilverHawk was used alone in 86.7%. No acute limb loss or major perforation occurred. Sixty (26.6%) patients had TLR. Long‐term mortality was 16.4%. Seven (3.1%) patients had to undergo major amputations and 7 (3.1%) minor amputations. Seventy (31.1%) patients had a major adverse event. Atorvastatin 80 mg was found to be independent predictor of survival, and major amputation was found to be independent predictor of mortality.

Conclusions

SilverHawk Plaque Excision combined with aggressive pharmacotherapy in this presented high‐risk population is associated with promising long‐term outcomes that compare favorably with accepted standards of care. © 2013 Wiley Periodicals, Inc.
Utility and feasibility of ultrasound‐guided access in patients with critical limb ischemia
Authors: Mustapha J.A. , Saab Fadi , Diaz Larry , Karenko Barbara , Richards Lance , Laeder Theresa , Heaney Carmen M. , Das Tony
Published: November 2012

Background

Patients with advanced peripheral vascular disease (PVD) and critical limb ischemia (CLI) require immediate revascularization to improve blood flow and prevent amputation. Vascular, and especially tibial, access is arguably a very important part of the procedure. Utilization of ultrasound (US) guidance to access the peripheral vessels will maximize success and decrease the risk of complications.

Methods

This is a retrospective analysis of patients admitted to our institution between 2010 and 2011. Eighty‐six patients with 191 lesions underwent revascularization for advanced PVD and CLI. US guidance was utilized to access the vascular bed in an antegrade or retrograde fashion in 100% of these patients. Data collected included success rate and time to access using US. Immediate in hospital and 30 day outcomes were also documented.

Results

The average age of patients was 69.8 years, with 69.7% male patients. All tibial access (33.7%) was obtained under US guidance. Obtaining vascular access using US was achieved in 95.3% of patients. At discharge, access site complications were limited to one patient (1.1%) with a pseudoaneurysm; no access complications related to the tibial vessels. At 30 days, there was one major amputation (1.1%) and one vascular access complication (1.1%).

Conclusion

US guided access is a feasible and safe procedure that can aid in accessing vascular conduits in patients with CLI. Applying this technique across the board in CLI patients decreases the risk of immediate complications and facilitates accessing tibial arteries. © 2012 Wiley Periodicals, Inc.
Imaging Catalysts at Work: A Hierarchical Approach from the Macro‐ to the Meso‐ and Nano‐scale
Authors: Grunwaldt Jan‐Dierk , Wagner Jakob B. , Dunin‐Borkowski Rafal E.
Published: November 2012

This review highlights the importance of developing multi‐scale characterisation techniques for analysing operating catalysts in their working environment. We emphasise that a hierarchy of in situ techniques that provides macro‐, meso‐ and nano‐scale information is required to elucidate and optimise catalyst performance fully. This combined methodology should ideally embrace spatially resolved and spatio‐temporal monitoring of a) the structure, catalytic activity, temperature and heat/mass transfer pattern in axial and radial directions in real reactors, b) the structure and temperature/heat/mass transport gradients in shaped catalysts and catalyst grains and c) meso‐ and nano‐scale information about particles and clusters, whose physical and electronic properties are linked directly to the micro‐kinetic behaviour of the catalysts. Techniques such as X‐ray diffraction (XRD), infrared (IR), Raman, X‐ray photoelectron spectroscopy (XPS), UV/Vis, and X‐ray absorption spectroscopy (XAS), which have mainly provided global atomic scale information, are being developed to provide the same information on a more local scale, often with sub‐second time resolution. X‐ray microscopy, both in the soft and more recently in the hard X‐ray regime, allows two‐ and three‐dimensional information to be collected down to 10 nm spatial resolution in a gas atmosphere or liquid, although this improvement is at the expense of temporal resolution. Electron microscopy, which provides excellent local atomic scale structural and spectroscopic information, is being developed towards tomographic imaging and realistic conditions, allowing gaps to be bridged in pressure, reaction conditions and length scales, up to the meso‐ and macro‐scale. In addition, new techniques such as single molecule fluorescence spectroscopy and non‐linear spectroscopic techniques are emerging. In this review, we discuss prospects for the development and combined application of both existing and new techniques for in situ catalyst characterisation.
Pressure versus Temperature Effects on Intramolecular Electron Transfer in Mixed‐Valence Complexes
Authors: Scheins Stephan , Overgaard Jacob , Timco Grigore A. , Stash Adam , Chen Yu‐Sheng , Larsen Finn K. , Christensen Mogens , Jørgensen Mads R. V. , Madsen Solveig R. , Schmøkel Mette S. , Iversen Bo B.
Published: November 2012

Mixed‐valence trinuclear carboxylates, [M3O(O2CR)6L3] (M=metal, L=terminal ligand), have small differences in potential energy between the configurations MIIMIIIMIII⇔︁ MIIIMIIMIII⇔︁MIIIMIIIMII, which means that small external changes can have large structural effects, owing to the differences in coordination geometry between M2+ and M3+ sites (e.g., about 0.2 Å for FeO bond lengths). It is well‐established that the electron transfer (ET) between the metal sites in these mixed‐valence molecules is strongly dependent on temperature and on the specific crystal environment; however, herein, for the first time, we examine the effect of pressure on the electron transfer. Based on single‐crystal X‐ray diffraction data that were measured at 15, 90, 100, 110, 130, 160, and 298 K on three different crystals, we first unexpectedly found that our batch of Fe3O (O2CC(CH3)3)6(C5H5N)3 (1) exhibited a different temperature dependence of the ET process than previous studies of compound 1 have shown. We observed a phase transition at around 130 K that was related to complete valence trapping and Hirshfeld surface analysis revealed that this phase transition was governed by a subtle competition between CH⋅⋅⋅π and π⋅⋅⋅π intermolecular interactions. Subsequent high‐pressure single‐crystal X‐ray diffraction at pressures of 0.15, 0.35, 0.45, 0.74, and 0.96 GPa revealed that it was not possible to trigger the phase transition (i.e., valence trapping) by a reduction of the unit‐cell volume, owing to this external pressure. We conclude that modulation of the ET process requires anisotropic changes in the intermolecular interactions, which occur when various directional chemical bonds are affected differently by changes in temperature, but not by the application of pressure.
Probing the Nature of the Cluster Effect Observed with Synthetic Multivalent Galactosides and Peanut Agglutinin Lectin
Authors: Almant Mehdi , Mastouri Amira , Gallego‐Yerga Laura , García Fernandez José Manuel , Ortiz Mellet Carmen , Kovensky José , Morandat Sandrine , El Kirat Karim , Gouin Sébastien G.
Published: November 2012

We designed a set of multi‐galactosides with valencies ranging from one to seven and different spacer‐arm lengths. The compounds display a high structural homology for a strict assessment of multivalent phenomena. The multimers were first evaluated by an enzyme‐linked lectin assay (ELLA) toward the peanut agglutinin (PNA). The binding affinity was shown to be dependent on the spacer‐arm length, and cluster effects were observed for the galactosides bearing the shortest and the longest linkers. The latter compounds were shown to be much more potent PNA cross‐linkers in a “sandwich assay”. Dynamic light scattering (DLS) experiments also revealed the formation of soluble aggregates between heptavalent derivatives with medium or long linkers and the labeled PNA. ELLA experiments performed with valency‐controlled clusters and labeled lectins are therefore not always devoid from aggregative processes. The precise nature of the multivalent interaction observed by ELLA for the compounds bearing the shortest linkers, which are unable to form PNA aggregates, was further investigated by atomic force microscopy (AFM). The galactosides were grafted onto the tip of a cantilever and the PNA lectin onto a gold surface. Similar unbinding forces were registered when the valency of the ligands was increased, thus showing that the multimers cannot interact more strongly with PNA. Multiple binding events to the PNA were also never observed, thus confirming that a chelate binding mode does not operate with the multivalent galactosides, probably because the linkers are too short. Altogether, these results suggest that the cluster effect that operates in ELLA with the multimers is not related to additional PNA stabilizations and can be ascribed to local concentration effects that favor a dynamic turnover of the tethered galactosides in the PNA binding sites.
Thiol‐Directed Synthesis of Highly Fluorescent Gold Clusters and Their Conversion into Stable Imaging Nanoprobes
Authors: Palmal Sharbari , Basiruddin SK , Maity Amit Ranjan , Ray Sekhar C. , Jana Nikhil R.
Published: November 2012

Fluorescent gold clusters (FGCs) with tunable emission from blue to red and quantum yields in the range of 6–17 % have been synthesized by simple modification of the conditions used for the synthesis of gold nanoparticles, namely by replacing the stronger reducing agent with a controlled amount of thiol. Various functional FGCs with hydrodynamic diameters of 5–12 nm have been successfully synthesized and used as cell labels. The results of our investigations strongly indicate that FGCs composed of Au0 are more stable imaging probes than commonly reported red/NIR‐emitting FGCs with a composition of Au0/AuI, as this combination rapidly transforms into nonfluorescent large clusters on exposure to light. The FGC‐based nanoprobes reported herein exhibit stable fluorescence upon continuous light exposure and can be used as imaging probes with low cytotoxicity.