bluuebunny/crossref_metadata_2025 huggingface dataset:
Biochemical properties and in vivo effects of the SOD1 zinc‐binding site mutant (H80G)
Authors: Son Marjatta , Srikanth Uma , Puttaparthi Krishna , Luther Christina , Elliott Jeffrey L.
Published: June 2011

J. Neurochem. (2011) 118, 891–901.

This study presents the initial characterization of transgenic mice with mutations in a primary zinc‐binding residue (H80), either alone or with a G93A mutation. H80G;G93A superoxide dismutase 1 (SOD1) transgenic mice developed paralysis with motor neuron loss, and ubiquitin inclusion‐type rather than mitochondrial vacuolar pathology. Unlike G93A SOD1‐related disease, the course was not accelerated by over‐expression of copper chaperone for SOD1. H80G SOD1 transgenic mice did not manifest disease at levels of SOD1 transgene expressed. The H80G mutation altered certain biochemical parameters of both human wild‐type SOD1 and G93A SOD1. The H80G mutation does not substantially change the age‐dependent accumulation of G93A SOD1 aggregates and hydrophobic species in spinal cord. However, both H80G;G93A SOD1 and H80G SOD1 lack dismutase activity, the ability to form homodimers, and co‐operativity with copper chaperone for SOD1, indicating that their dimerization interface is abnormal. The H80G mutation also made SOD1 susceptible to protease digestion. The H80G mutation alters the redox properties of SOD1. G93A SOD1 exists in either reduced or oxidized form, whereas H80G;G93A SOD1 and H80G SOD1 exist only in a reduced state. The inability of SOD1 with an H80G mutation to take part in normal oxidation‐reduction reactions has important ramifications for disease mechanisms and pathology in vivo.
Explaining preferences for redistribution: A unified framework to account for institutional approaches and economic self‐interest for the case of monetary transfers for families and children
Authors: MEHLKOP GUIDO , NEUMANN ROBERT
Published: June 2011

Explanations of different patterns of preferences for redistribution either highlight the role of the institutional framework in a country or highlight the importance of self‐interest and rational expectations. The study introduces a unified approach to explain differences in preferences for redistributive measures for the case of intergenerational monetary transfers for families and children. Both explanatory approaches are integrated into the action‐based Model of Frame Selection that incorporates normative motives and economic self‐interest into the process of decision making. Using a large sample that deals with questions on the approval of public policies for families and accounts for the normative importance of children and family life in Germany, evidence is provided that both approaches are valid in explaining preferences for government transfers.
Strategies to prevent or reduce acute and chronic kidney injury in liver transplantation
Authors: Saner Fuat H. , Cicinnati Vito R. , Sotiropoulos Georgios , Beckebaum Susanne
Published: June 2011

Acute kidney injury (AKI) has a major impact on short‐ and long‐term survival in liver transplant (LT) patients. There is no currently accepted uniform definition of AKI, which would facilitate standardization of the care of patients with AKI and to improve and enhance collaborative research efforts. New promising biomarkers such as neutrophil gelatinase‐associated lipocalin or kidney injury molecule‐1 have been developed for the prevention of delayed AKI treatment. Early dialysis has been shown to be beneficial in patients with AKI stage III according to the classification of the Acute Kidney Injury Network, whereas treatment with loop diuretics or dopamine is associated with worse outcome. The mainstay for the prevention of AKI seems to be avoidance of volume depletion and maintenance of a mean arterial pressure >65 mmHg. Although the aetiology of chronic kidney disease in transplant recipients may be multifactorial, calcineurin‐inhibitor (CNI)‐induced nephrotoxicity significantly contributes to the development of renal dysfunction over time after LT. The delayed introduction of CNI at minimal doses has shown to be safe and effective for the preservation of kidney function. Other strategies to overcome CNI nephrotoxicity include CNI minimization protocols or CNI withdrawal and conversion to mycophenolate mofetil or the mammalian target of rapamycin inhibitor‐based immunosuppressive regimens. However, CNI avoidance may bear a higher rejection risk. Thus, more results from randomized‐controlled studies are urgently warranted to determine which drug combinations are the most beneficial approaches for the potential introduction of CNI‐free immunosuppressive regimens.
Dental implant suprastructures using cobalt–chromium alloy compared with gold alloy framework veneered with ceramic or acrylic resin: a retrospective cohort study up to 18 years
Authors: Teigen Kyrre , Jokstad Asbjørn
Published: June 2011

Background: An association between the long‐term success and survival of implant‐supported prostheses as a function of biomaterial combinations has not been established. The use of cast cobalt–chromium for the suprastructure framework may be an alternative to the conventional approach of using type 3 gold alloys.

Materials and methods: A retrospective chart audit of all patients who had received implant‐supported fixed dental prostheses (FDP) before 1996 was identified in a private practice clinic. Data were recorded for FDPs made from four combinations of alloy frameworks and veneering material, i.e. type 3 gold and cobalt–chromium with ceramic or prefabricated acrylic teeth. The extracted data from the charts were subjected to explorative statistical tests including Kaplan–Meier survival analyses.

Results: Patients (n=198) with 270 short and extensive FDPs supported entirely by 1117 implants were identified. The average follow‐up observation periods varied between 4 and 220 months, with an average of 120 months. The success and survival, as well as event rates and types of biological and technical complications, were similar for implant‐supported FDPs using cobalt–chromium and type 3 gold alloy frameworks veneered with ceramics or prefabricated acrylic teeth. An influence of the suprastructure biomaterial combination on the clinical performance of the individual supporting implants could not be established.

Conclusions: Implant‐supported FDPs made from type 3 gold or cobalt–chromium frameworks and veneered with ceramic or prefabricated acrylic teeth demonstrate comparable clinical performance. The biomaterial combinations do not appear to influence the success or survival of the individual implants.

To cite this article: Teigen K, Jokstad A. Dental implant suprastructures using cobalt–chromium alloy compared with gold alloy framework veneered with ceramic or acrylic resin: a retrospective cohort study up to 18 years. Clin. Oral Impl. Res. 23, 2012; 853–860. doi: 10.1111/j.1600‐0501.2011.02211.x
Evaluation of a biodegradable synthetic hydrogel used as a guided bone regeneration membrane: an experimental study in dogs
Authors: Thoma Daniel S. , Dard Michel M. , Hälg Gian‐Andrea , Ramel Christian F. , Hämmerle Christoph H. F. , Jung Ronald E.
Published: June 2011

Objectives: To test whether or not an experimental polyethylene glycol (PEG) membrane maintains the bone graft volume and contributes to the preservation of the ridge contour in comparison with a commercially available synthetic membrane.

Materials and methods: In 18 dogs, all mandibular premolars and the first molars were extracted. Ten weeks later, acute standardized defects were prepared. The defects of four dogs were randomly assigned to three modalities: (1) PEG plus deproteinized bovine bone mineral (DBBM) (PEG), (2) a resorbable glycolide trimethylene carbonate membrane plus DBBM (PGA‐TMC), and (3) DBBM alone (DBBM). These dogs were then sacrificed for the baseline measurements. The remaining defects of 14 dogs were randomly assigned to (1) PEG plus DBBM, (2) PGA‐TMC plus DBBM, (3) DBBM, and (4) empty defect. The dogs were sacrificed at baseline (n=4), 4 weeks (n=7), or at 16 weeks (n=7). Mixed model regressions and the non‐parametric Brunner–Langer method were applied for statistical analysis.

Results: At baseline, equal tissue augmentation was observed in all groups. At 4 and 16 weeks, the greatest augmented area fractions were calculated for PEG (103%; 107%, respectively), followed by PGA‐TMC (98%; 91%), DBBM (85%; 78%), and empty (46%; 54%), being statistically significant different (P<0.001) between PEG and empty at 4 and 16 weeks, and PEG and DBBM at 16 weeks. The overall decrease (P≤0.01) in the amount of bone graft between baseline and 16 weeks was −14% (PEG), −22% (PGA‐TMC), and −23% (DBBM).

Conclusions: The study demonstrates that the combination of the PEG membrane with DBBM maintains the bone graft volume over time better than controls. The PEG membrane with DBBM was also the most effective method to preserve the ridge contour.

To cite this article: Thoma DS, Dard MM, Hälg G‐A, Ramel CF, Hämmerle CHF, Jung RE. Evaluation of a biodegradable synthetic hydrogel used as a guided bone regeneration membrane: an experimental study in dogs. Clin. Oral Impl. Res. 23, 2012; 160–168.  doi: 10.1111/j.1600‐0501.2011.02217.x
Influence of the crown‐to‐implant length ratio on the clinical performance of implants supporting single crown restorations: a cross‐sectional retrospective 5‐year investigation
Authors: Schneider David , Witt Lukas , Hämmerle Christoph H. F.
Published: June 2011

Purpose: The aim of this study was to investigate the influence of the crown‐to‐implant length ratio (c/i ratio) on the implant survival, changes of the marginal bone level (MBL) and the occurrence of biological and technical complications.

Material and methods: This cross‐sectional retrospective study included all patients with implants in the posterior segments supporting single crown restorations with a minimum follow‐up of 5 years. All patients were questioned and examined clinically and radiographically. The technical and biological c/i ratio and the MBL were measured on digitized periapical radiographs. The following outcome parameters in relation to the c/i ratio and the co‐factors were statistically analyzed: implant survival rate, MBL, occurrence of technical and biological complications. For statistical analysis, regression, correlation and survival analyses were applied (P<0.05).

Results: Seventy patients (mean age of 50.7 years [range 19.8–76.6 years]) with a total of 100 implants (24 Straumann type, 76 Brånemark type) were included in this study. The mean follow‐up period was 6.2 years (range 4.73–11.7 years). Six implants failed during the follow‐up period, yielding a cumulative survival rate of 95.8% at 5 years in function. The mean technical c/i ratio was 1.04 (±0.26, range 0.59–2.01). The mean biological c/i ratio was 1.48 (±0.42, range 0.82–3.24). No statistically significant influence of the technical and biological c/i ratio was found on the implant survival, MBL and occurrence of technical and biological complications. When adjusted for the biological c/i ratio, smoking was the only co‐factor significantly associated with implant failure and biological complications.

Conclusion: In the present study, the c/i ratio did not influence the clinical performance of implants supporting single crown restorations in the posterior segments of the jaw within the range tested.

To cite this article: Schneider D, Witt L, Hämmerle CHF. Influence of the crown‐to‐implant length ratio on the clinical performance of implants supporting single crown restorations: a cross‐sectional retrospective 5‐year investigation. Clin. Oral Impl. Res. 23, 2012; 169–174.  doi: 10.1111/j.1600‐0501.2011.02230.x
Increased fibroblast density in actinic cheilitis: association with tryptase‐positive mast cells, actinic elastosis and epithelial p53 and COX‐2 expression
Authors: Rojas Isolde G. , Boza Yadira V. , Spencer Maria Loreto , Flores Maritza , Martínez Alejandra
Published: June 2011

J Oral Pathol Med (2012) 41: 27–33

Background:  Actinic cheilitis (AC) is characterized by epithelial and connective tissue alterations caused by ultraviolet sunlight overexposure known as photodamage. Fibroblasts have been linked to photodamage and tumor progression during skin carcinogenesis; however, their role in early lip carcinogenesis remains unknown. The aim of this study was to assess the density of fibroblasts in AC and normal lip (NL) samples and determine their association with markers of lip photodamage.

Methods:  Fibroblasts, mast cells, p53, COX‐2, and elastin were detected in NL (n = 20) and AC (n = 28) biopsies using immunohistochemistry/histochemistry. Mast cell and fibroblast density and epithelial p53 and COX‐2 expression scores were then obtained. Elastosis was scored 1–4 according to elastin fiber density and tortuosity.

Results:  Fibroblasts, mast cells, p53, COX‐2, and elastosis were increased in AC as compared to NL (P < 0.001). Multivariate analysis showed an association between fibroblast and mast cell density at the papillary and reticular areas of AC and NL (P < 0.05). Papillary fibroblast density was also associated with epithelial p53 and COX‐2 expression (P < 0.05). Increased fibroblast density, both papillary and reticular, was found in the high elastosis group (scores 3–4) as compared to the low elastosis group (scores 1–2) (P < 0.01). Increased reticular mast cell density was detected only in the high elastosis group (P < 0.01).

Conclusions:  Fibroblasts are increased in AC, and they are associated with mast cell density, epithelial p53 and COX‐2 expression, and actinic elastosis. Therefore, fibroblasts may contribute to lip photodamage and could be considered useful markers of early lip carcinogenesis.
Halitosis and oral health‐related quality of life: a case report
Authors: Buunk‐Werkhoven YAB , Dijkstra‐le Clercq M , Verheggen‐Udding EL , de Jong N , Spreen M
Published: June 2011

To cite this article:
 
Int J Dent Hygiene
10, 2012; 3–8  DOI: 10.1111/j.1601‐5037.2011.00512.x  Buunk‐Werkhoven YAB, Dijkstra‐le Clercq M, Verheggen‐Udding EL, de Jong N, Spreen M. Halitosis and oral health‐related quality of life: a case report.

Abstract:  Objectives:  This is a clinical case of a 36‐year‐old Dutch male, patient in the Dr. S. van Mesdag Forensic Psychiatric Centre in Groningen. It demonstrates a short‐time effect of a tailored oral hygiene self‐care intervention in three sessions over a period of 3 months on halitosis and a patient’s oral health‐related quality of life (OH‐QoL).

Methods:  In addition to a dental screening and professional oral hygiene care, a semi‐structured interview was conducted by the dental hygienist, and questionnaires were administered. The questionnaires included were; the Dutch version of the Oral Health Impact Profile‐14 (OHIP‐14‐NL; used as a measurement of OH‐QoL), scales for expected social outcomes for having healthy teeth, attitudes towards oral hygiene behaviour (OHB) and dental anxiety.

Results:  Clinical observations showed an improvement in patient’s OHB, while the extreme foetor‐ex‐ore was reduced to an acceptable level. A retrospective assessment showed that patient’s attitude towards the recommended OHB together with his self‐perceived OH‐QoL had positively increased.

Conclusions:  This case highlights the value of professional individual oral hygiene instructions performed by a dental hygienist. It also illustrates that a patient’s effective OHB may play an important role in the reduction in halitosis and self‐perceived OH‐QoL. Finally, the retrospective version of the OHIP‐14‐NL may be an adequate method to assess self‐perceived OH‐QoL within a relative short period of time.
Accurate Measurement of Rare Earth Elements by ICP‐MS after Ion‐Exchange Separation: Application to Ultra‐Depleted Samples
Authors: Ulrich Marc , Bureau Sarah , Chauvel Catherine , Picard Christian
Published: June 2011

This study reports precise and accurate data for rare earth elements (REE) measured on eight geological reference materials, five enriched in REE (BE‐N, BHVO‐2, BR, BR‐24 and RGM‐1) and three very depleted in REE (BIR‐1, UB‐N and DTS‐2). Data were acquired by quadrupole ICP‐MS after isolation of the REE using an ion‐exchange chromatography procedure. All the measured REE abundances were similar within ≈ 5% (10% for the most REE‐depleted sample DTS‐2) to the high‐quality measurements previously published in the literature. We also show that by using an internal Tm spike, the reproducibility of the data was improved to ∼ 1%. Applying this technique to the analysis of ultra‐depleted rock samples (sub ng g−1), we show that significant improvements were obtained relative to the routine trace element measurement method. The chondrite‐normalised patterns were smooth instead of displaying irregularities. Although the classical method gives excellent results on REE‐rich samples, we believe that our technique improves the precision and accuracy of measurements for highly REE‐depleted rocks.
DNA barcoding of oomycetes with cytochrome c oxidase subunit I and internal transcribed spacer
Authors: ROBIDEAU GREGG P. , De COCK ARTHUR W. A. M. , COFFEY MICHAEL D. , VOGLMAYR HERMANN , BROUWER HENK , BALA KANAK , CHITTY DAVID W. , DÉSAULNIERS NICOLE , EGGERTSON QUINN A. , GACHON CLAIRE M. M. , HU CHIA‐HUI , KÜPPER FRITHJOF C. , RINTOUL TARA L. , SARHAN EHAB , VERSTAPPEN ELS C. P. , ZHANG YONGHONG , BONANTS PETER J. M. , RISTAINO JEAN B. , ANDRÉ LÉVESQUE C.
Published: June 2011

Oomycete species occupy many different environments and many ecological niches. The genera Phytophthora and Pythium for example, contain many plant pathogens which cause enormous damage to a wide range of plant species. Proper identification to the species level is a critical first step in any investigation of oomycetes, whether it is research driven or compelled by the need for rapid and accurate diagnostics during a pathogen outbreak. The use of DNA for oomycete species identification is well established, but DNA barcoding with cytochrome c oxidase subunit I (COI) is a relatively new approach that has yet to be assessed over a significant sample of oomycete genera. In this study we have sequenced COI, from 1205 isolates representing 23 genera. A comparison to internal transcribed spacer (ITS) sequences from the same isolates showed that COI identification is a practical option; complementary because it uses the mitochondrial genome instead of nuclear DNA. In some cases COI was more discriminative than ITS at the species level. This is in contrast to the large ribosomal subunit, which showed poor species resolution when sequenced from a subset of the isolates used in this study. The results described in this paper indicate that COI sequencing and the dataset generated are a valuable addition to the currently available oomycete taxonomy resources, and that both COI, the default DNA barcode supported by GenBank, and ITS, the de facto barcode accepted by the oomycete and mycology community, are acceptable and complementary DNA barcodes to be used for identification of oomycetes.
Factors affecting the views and attitudes of Scottish pharmacists to continuing professional development
Authors: Power Ailsa , Grammatiki Aikaterini , Bates Ian , Mc Kellar Susan , Johnson B Julienne , Diack H Lesley , Stewart Derek , Hudson Steve A
Published: June 2011

Objectives

To explore factors associated with Scottish pharmacists' views and attitudes to continuing professional development (CPD).

Methods

A retrospective principal component analysis of 552 (22.8%) questionnaires returned from a sample of 2420 Scottish pharmacists randomly selected from the 4300 pharmacists registered with the Royal Pharmaceutical Society of Great Britain and with a Scottish address.

Key findings

Principal component analysis of questionnaire items (n = 19) revealed four factors associated with Scottish pharmacists' views and attitudes to CPD: having positive support in the workplace, having access to resources and meeting learning needs, having confidence in the CPD process and motivation to participate in the CPD process. Community pharmacists were identified as the subgroup of pharmacists that needed most support for CPD regarding all four factors, while pharmacists working in primary care felt that they had most support in the workplace in comparison to other sectors (P < 0.05) and better access to resources and meeting learning needs when compared to community (P < 0.001) and hospital (P = 0.008) colleagues. Pharmacists working in primary care also felt more motivated to participate in the CPD process than those in the community (P < 0.001), and hospital pharmacists reported having more confidence in the CPD process compared to community pharmacists (P < 0.05).

Conclusion

Using principal component analysis has identified four factors associated with Scottish pharmacists' views and attitudes to CPD. This may provide an approach to facilitate comparison of CPD views and attitudes with intra and inter professional groupings. Further study may allow identification of good practice and solutions to common CPD issues.
GluA4 is indispensable for driving fast neurotransmission across a high‐fidelity central synapse
Authors: Yang Yi‐Mei , Aitoubah Jamila , Lauer Amanda M. , Nuriya Mutsuo , Takamiya Kogo , Jia Zhengping , May Bradford J. , Huganir Richard L. , Wang Lu‐Yang
Published: June 2011

Non‐technical summary  Localization of sound sources in the azimuth, which makes use of interaural differences in timing and/or intensity of acoustic signals, is of vital importance for most mammals. Using the small differences in time of arrival and/or intensity at the two ears requires that propagation of electric pulses in the auditory system be temporally precise. In this study, we found that elimination of GluA4, a protein particularly abundant in auditory cells, significantly impairs their ability to faithfully transmit electric signals, leading to profound deficits in auditory responses to sound stimuli in mice. Therefore, we conclude that GluA4 is indispensable for enabling information flow with high fidelity in the auditory circuitry. Our work has identified GluA4 as a potential molecular candidate involved in human hearing deficits and disorders.
Dynamic regulation of circulating microRNA during acute exhaustive exercise and sustained aerobic exercise training
Authors: Baggish Aaron L. , Hale Andrew , Weiner Rory B. , Lewis Gregory D. , Systrom David , Wang Francis , Wang Thomas J. , Chan Stephen Y.
Published: June 2011

Non‐technical summary  MicroRNA (miRNA) molecules are essential intracellular mediators of numerous biological processes including angiogenesis, inflammation, and mitochondrial metabolism. Recently, it has been shown that miRNAs are secreted into the bloodstream and that circulating miRNAs (c‐miRNAs) may serve important endocrine functions. This study examined plasma profiles of specific c‐miRNAs in healthy competitive athletes at rest and during exhaustive exercise testing, before and after a 90 day period of exercise training. In this setting, we observed four distinct patterns of c‐miRNA response to exercise: (1) c‐miRNAs up‐regulated by acute exhaustive exercise before and after sustained exercise training, (2) c‐miRNAs responsive to acute exhaustive exercise before but not after sustained exercise training, (3) c‐miRNAs responsive only to sustained exercise training, and (4) non‐responsive c‐miRNAs. These findings set the stage for further work aimed at defining the role of c‐miRNAs as fitness biomarkers and physiological mediators of exercise‐induced cardiovascular adaptation.
Effects of Inlet Temperature Uniformity and Nonuniformity on the Tip Leakage Flow and Rotor Blade Tip and Casing Heat Transfer Characteristics
Authors: Rahman Md. Hamidur , Kim Sung In , Hassan Ibrahim
Published: June 2011

High thermal load appears at the blade tip and casing of a gas turbine engine. It becomes a significant design challenge to protect the turbine materials from this severe situation. As a result of geometric complexity and experimental limitations, computational fluid dynamics tools have been used to predict blade tip leakage flow aerodynamics and heat transfer at typical engine operating conditions. In this paper, the effect of turbine inlet temperature on the tip leakage flow structure and heat transfer has been studied numerically. Uniform low (444 K) and high (800 K) inlet temperatures and nonuniform (parabolic) temperature profiles have been considered at a fixed rotor rotation speed (9500 rpm). The results showed that the change of flow properties at a higher inlet temperature yields significant variations in the leakage flow aerodynamics and heat transfer relative to the lower inlet temperature condition. Aerodynamic behavior of the tip leakage flow varies significantly with the distortion of turbine inlet temperature. For more realistic inlet condition, the velocity range is insignificant at all time instants. At a high inlet temperature, reverse secondary flow is strongly opposed by the tip leakage flow and the heat transfer fluctuations are reduced greatly.
Experimental Investigation on a Novel Electrolyte Configuration for Cylindrical Molten Carbonate Fuel Cells
Authors: Rossi Federico , Nicolini Andrea
Published: June 2011

An experimental investigation on a novel electrolyte configuration for molten carbonate fuel cells (MCFCs) is presented. A single cell facility was built. The cell is characterized by a cylindrical geometry in order to reduce the structural and thermodynamic problems which affect the lifetime of the traditional rectangular shape MCFCs. The main aim of this research is to evaluate the possibility of not installing the porous ceramic matrix in order to reduce the gas crossover problems of MCFCs and improve the cell lifetime. Thus, the new single cell was mainly constituted by the porous electrodes, the liquid electrolyte and structural disks as electrolytic support. Different solutions were studied as mechanical support for the electrolyte. Experimental tests on the proposed solutions were performed. Results suggested that the proposed adjustments are a promising solution for increasing the lifetime of cylindrical MCFCs and reducing their costs.
A Constrained Convex Approach to Modal Design Optimization of Vibrating Systems
Authors: Richiedei Dario , Trevisani Alberto , Zanardo Gabriele
Published: June 2011

This paper introduces a general and flexible design method for the inverse modal optimization of undamped vibrating systems, i.e., for the computation of mass and stiffness linear modifications ensuring the desired system eigenstructure. The technique is suitable for the design of new systems or the optimization of the existing ones and can handle several design requirements and constraints. Paramount strengths of the method are its capability to modify an arbitrary number of parameters and assigned vibration modes, as well as the possibility of dealing with mass and stiffness matrices with arbitrary topologies. To this purpose, the modification problem is formulated as a constrained inverse eigenvalue problem and then solved within the frame of convex optimization. The effectiveness of the method is assessed by applying it to two different test cases. In particular, the second investigation deals with a meaningful mechanical design application: the optimization of a system recalling an industrial vibratory feeder. The results highlight the generality of the method and its capability to ensure the achievement of the prescribed eigenstructure.
Optimized RF shielding techniques for simultaneous PET/MR
Authors: Truhn D. , Kiessling F. , Schulz V.
Published: June 2011

Purpose: Integration of positron emission tomography (PET) and magnetic resonance (MR) in a merged device requires shielding of the PET detector electronics. The authors demonstrate that a multiple shell setup exhibits advantages over a single shell shielding enclosure.Methods: A spherical shell model is used to derive analytical results. Numerical computations of the electromagnetic fields with a commercial software package (feko) and experiments are used to confirm our findings.Results: Replacing a single shell enclosure by a multilayer approach barely changes its behavior toward low frequency magnetic fields (MR gradient fields), while improving shielding at high frequencies (proton resonant frequency) by orders of magnitude.Conclusions: For a given required shielding factor at the proton resonant frequency, the eddy currents induced by the MR gradient fields may be reduced by employing a multiple shell setup.
Determination of action thresholds for electromagnetic tracking system‐guided hypofractionated prostate radiotherapy using volumetric modulated arc therapy
Authors: Zhang Pengpeng , Mah Dennis , Happersett Laura , Cox Brett , Hunt Margie , Mageras Gig
Published: June 2011

Purpose: Hypofractionated prostate radiotherapy may benefit from both volumetric modulated arc therapy (VMAT) due to shortened treatment time and intrafraction real‐time monitoring provided by implanted radiofrequency(RF) transponders. The authors investigate dosimetrically driven action thresholds (whether treatment needs to be interrupted and patient repositioned) in VMAT treatment with electromagnetic (EM) tracking.Methods: VMAT plans for five patients are generated for prescription doses of 32.5 and 42.5 Gy in five fractions. Planning target volume (PTV) encloses the clinical target volume (CTV) with a 3 mm margin at the prostate‐rectal interface and 5 mm elsewhere. The VMAT delivery is modeled using 180 equi‐spaced static beams. Intrafraction prostate motion is simulated in the plan by displacing the beam isocenter at each beam assuming rigid organ motion according to a previously recorded trajectory of the transponder centroid. The cumulative dose delivered in each fraction is summed over all beams. Two sets of 57 prostate motion trajectories were randomly selected to form a learning and a testing dataset. Dosimetric end points including CTV D95%, rectum wall D1cc, bladder wall D1cc, and urethra Dmax, are analyzed against motion characteristics including the maximum amplitude of the anterior–posterior (AP), superior–inferior (SI), and left–right components. Action thresholds are triggered when intrafraction motion causes any violations of dose constraints to target and organs at risk (OAR), so that treatment is interrupted and patient is repositioned.Results: Intrafraction motion has a little effect on CTV D95%, indicating PTV margins are adequate. Tight posterior and inferior action thresholds around 1 mm need to be set in a patient specific manner to spare organs at risk, especially when the prescription dose is 42.5 Gy. Advantages of setting patient specific action thresholds are to reduce false positive alarms by 25% when prescription dose is low, and increase the sensitivity of detecting dose limits violations by 30% when prescription dose is high, compared to a generic 2 mm action box. The sensitivity and specificity calculated from the testing dataset are consistent to the learning set, which indicates that the patient specific approach is reliable and reproducible within the scope of the prostate database.Conclusions: This work introduces a formalism for ensuring a VMAT delivery meets the most clinically important dose requirements by using patient specific and dosimetric‐driven action thresholds to hold the beam and reposition the patient when necessary. Such methods can provide improved sensitivity and specificity compared to conventional methods, which assume directionally symmetric action thresholds.
Planning strategies in volumetric modulated arc therapy for breast
Authors: Nicolini Giorgia , Fogliata Antonella , Clivio Alessandro , Vanetti Eugenio , Cozzi Luca
Published: June 2011

Purpose: In breast radiotherapy with intensity modulation, it is a well established practice to extend the dose fluence outside the limit of the body contour to account for small changes in size and position of the target and the rest of the tissues due to respiration or to possible oedema. A simple approach is not applicable with RapidArc volumetric modulated arc therapy not being based on a fixed field fluence delivery. In this study, a viable technical strategy to account for this need is presented.Methods: RapidArc (RA) plans for six breast cancer patients (three right and three left cases), were optimized (PRO version III) on the original CT data set (O) and on an alternative CT (E) generated with an artificial expansion (and assignment of soft‐tissue equivalent HU) of 10 mm of the body in the breast region and of the PTV contours toward the external direction. Final dose calculations for the two set of plans were performed on the same original CT data set O, normalizing the dose prescription (50 Gy) to the target mean. In this way, two treatment plans on the same CT set O for each patient were obtained: the no action plan (OO) and the alternative plan based on an expanded optimization (EO). Fixing MU, these two plans were then recomputed on the expanded CT data set and on an intermediate one (with expansion = 5 mm), to mimic, possible changes in size due to edema during treatment or residual displacements due to breathing not properly controlled. Aim of the study was to quantify the robustness of this planning strategy on dose distributions when either the OO or the EO strategies were adopted. For all the combinations, a DVH analysis of all involved structures is reported.Results: I. The two optimization approaches gave comparable dose distributions on the original CT data set. II. When plans were evaluated on the expanded CTs (mimicking the presence of edema), the EO approach showed improved target coverage if compared to OO: on CT_10 mm, DV = 98% [%] = 92.5 ± 0.9 and 68.5 ± 3.1, respectively, for EO and OO. Minor changes were registered in organs at risk sparing for both EO and OO. III. From dose distributions and DVHs, EO approach allowed to irradiate at near to prescription levels also the expanded fraction of the target: this would account also for residual intrafraction movements.Conclusions: The proposed plan strategy could represent a robust approach to account for moderate changes in target or body volume during the course of breast radiotherapy and to account for residual intrafractional respiratory motion in volumetric modulated arc therapy. The strategy, logistically simple to implement requiring only modifications to the standard planning workflow was routinely implemented at author's institute for treatment of breast patients with RapidArc.
Comparative Proteomic Analysis Identifies a Role for SUMO in Protein Quality Control
Authors: Tatham Michael H. , Matic Ivan , Mann Matthias , Hay Ronald T.
Published: June 2011

Changes in cellular SUMOylation occur in response to the accumulation of misfolded proteins.
HIF-1α Mediates Tumor Hypoxia to Confer a Perpetual Mesenchymal Phenotype for Malignant ProgressionA presentation from the Keystone Symposium on Epithelial Plasticity and Epithelial-to-Mesenchymal Transition, Vancouver, British Columbia, Canada, 21 to 26 January 2011.
Authors: Yoo Young-Gun , Christensen Jared , Gu Jie , Huang L. Eric
Published: June 2011

Hypoxia-induced genetic alterations induce epithelial-mesenchymal transition and tumor progression.
Coordinating Autophagy and Lysosome Regulation
Authors: Hurtley Stella M.
Published: June 2011

Starvation activates a transcriptional program controlling autophagosome formation, lysosome fusion, and substrate degradation.
Linezolid plus Rifampin as a Salvage Therapy in Prosthetic Joint Infections Treated without Removing the Implant
Authors: Gómez J. , Canovas E. , Baños V. , Martínez L. , García E. , Hernández-Torres A. , Canteras M. , Ruiz J. , Medina M. , Martínez P. , Canovas A. , Soriano A. , Clavel M.
Published: June 2011

The aim of this study is to describe our experience with linezolid plus rifampin as a salvage therapy in prosthetic joint infections (PJIs) when other antibiotic regimens failed or were not tolerated. A total of 161 patients with a documented prosthetic joint infection were diagnosed with a PJI and prospectively followed up from January 2000 to April 2007. Clinical characteristics, inflammatory markers, microbiological and radiological data, and antibiotic treatment were recorded. After a 2-year follow-up, patients were classified as cured when the prosthesis was not removed, symptoms of infection disappeared, and inflammatory parameters were within the normal range. Any other outcome was considered a failure. The mean age of the entire cohort (
n
= 161) was 67 years. Ninety-five episodes were on a knee prosthesis (59%), and 66 were on a hip prosthesis (41%). A total of 49 patients received linezolid plus rifampin: 45 due to failure of the previous antibiotic regimen and 4 due to an adverse event associated with the prior antibiotics. In no case was the implant removed. The mean (standard deviation) duration of treatment was 80.2 (29.7) days. The success rate after 24 months of follow-up was 69.4% (34/49 patients). Three patients developed thrombocytopenia and 3 developed anemia; however, it was not necessary to stop linezolid. Linezolid plus rifampin is an alternative salvage therapy when the implant is not removed.
Apoptosis-Inducing Activity of Clofazimine in Macrophages
Authors: Fukutomi Yasuo , Maeda Yumi , Makino Masahiko
Published: June 2011

Clofazimine is a riminophenazine compound which has been used for the treatment of leprosy since the 1960s. Although the drug is effective in the management of leprosy reactions because of its anti-inflammatory activity, the mechanism leading to the cessation of inflammation is not well understood. In the present study, it was shown that clofazimine exhibits apoptosis-inducing activity in macrophages. When human monocyte-derived macrophages were culturedin vitroin the presence of clofazimine, the cells exhibited a marked decrease in metabolic activity and showed shrinkage in cell size, indicating cell death. Nuclear condensation and fragmentation were also observed by Giemsa and Hoechst 33248 stains. The endonuclease inhibitor ZnCl2inhibited the clofazimine-induced cell death. Significant enhancement of caspase-3 activity was observed in clofazimine-treated macrophages and THP-1 cells. Collectively, these results suggest the apoptosis-inducing activity of clofazimine in macrophages, which may also be responsible for the antibacterial properties of clofazimine.
Self-Resistance and Cell Wall Composition in the Glycopeptide Producer Amycolatopsis balhimycina
Authors: Schäberle Till F. , Vollmer Waldemar , Frasch Hans-Jörg , Hüttel Stephan , Kulik Andreas , Röttgen Marlene , von Thaler Anna-Katharina , Wohlleben Wolfgang , Stegmann Evi
Published: June 2011

The prevailing resistance mechanism against glycopeptides in Gram-positive pathogens involves reprogramming the biosynthesis of peptidoglycan precursors, resulting in
d
-alanyl-
d
-lactate depsipeptide termini.
Amycolatopsis balhimycina
produces the vancomycin-like glycopeptide balhimycin and therefore has to protect itself from the action of the glycopeptide. We studied the roles of the accessory resistance gene orthologs
vanY
b
,
vnlR
b
, and
vnlS
b
, which are part of the balhimycin biosynthetic gene cluster (represented by the subscript “b”). The VanY
b
carboxypeptidase cleaved the terminal
d
-Ala from peptidoglycan precursors, and its heterologous expression enhanced glycopeptide resistance in
Streptomyces coelicolor
. The VanRS-like two component system VnlRS
b
was not involved in glycopeptide resistance or in the expression of the
vanHAX
glycopeptide resistance genes. Mature
A. balhimycina
peptidoglycan contained mainly tri- and tetrapeptides, with only traces of the
d
-Ala-
d
-Ala-ending pentapeptides that are binding sites for the antibiotic produced. The structure of the peptidoglycan precursor is consistent with the presence of
vanHAX
genes, which were identified outside the balhimycin synthesis cluster. Both wild-type and non-antibiotic-producing mutant strains synthesized peptidoglycan precursors ending mainly with
d
-Lac, indicating constitutive synthesis of a resistant cell wall.
A. balhimycina
could provide a model for an ancestral glycopeptide producer with constitutively expressed resistance genes.
Burkholderia cenocepacia ShvR-Regulated Genes That Influence Colony Morphology, Biofilm Formation, and Virulence
Authors: Subramoni Sujatha , Nguyen David T. , Sokol Pamela A.
Published: June 2011

Burkholderia cenocepaciais an opportunistic pathogen that primarily infects cystic fibrosis (CF) patients. Previously, we reported that ShvR, a LysR regulator, influences colony morphology, virulence, and biofilm formation and regulates the expression of an adjacent 24-kb genomic region encoding 24 genes. In this study, we report the functional characterization of selected genes in this region. A Tn5mutant with shiny colony morphology was identified with a polar mutation in BCAS0208, predicted to encode an acyl-coenzyme A dehydrogenase. Mutagenesis of BCAS0208 and complementation analyses revealed that BCAS0208 is required for rough colony morphology, biofilm formation, and virulence on alfalfa seedlings. It was not possible to complement with BCAS0208 containing a mutation in the catalytic site. BCAS0201, encoding a putative flavin adenine dinucleotide (FAD)-dependent oxidoreductase, and BCAS0207, encoding a putative citrate synthase, do not influence colony morphology but are required for optimum levels of biofilm formation and virulence. Both BCAS0208 and BCAS0201 contribute to pellicle formation, although individual mutations in each of these genes had no appreciable effect on pellicle formation. A mutant with a polar insertion in BCAS0208 was significantly less virulent in a rat model of chronic lung infection as well as in the alfalfa model. Genes in this region were shown to influence utilization of branched-chain fatty acids, tricarboxylic acid cycle substrates,l-arabinose, and branched-chain amino acids. Together, our data show that the ShvR-regulated genes BCAS0208 to BCAS0201 are required for the rough colony morphotype, biofilm and pellicle formation, and virulence inB. cenocepacia.
Beta Interferon-Mediated Activation of Signal Transducer and Activator of Transcription Protein 1 Interferes with Rickettsia conorii Replication in Human Endothelial Cells
Authors: Colonne Punsiri M. , Eremeeva Marina E. , Sahni Sanjeev K.
Published: June 2011

Infection of the endothelial cell lining of blood vessels with
Rickettsia conorii
, the causative agent of Mediterranean spotted fever, results in endothelial activation. We investigated the effects of
R. conorii
infection on the status of the Janus kinase (JAK)-signal transducer and activator of transcription protein (STAT) signaling pathway in human microvascular endothelial cells (HMECs), the most relevant host cell type, in light of rickettsial tropism for microvascular endothelium
in vivo
.
R. conorii
infection induced phosphorylation of STAT1 on tyrosine 701 and serine 727 at 24, 48, and 72 h postinfection in HMECs. Employing transcription profile analysis and neutralizing antibodies, we further determined that beta interferon (IFN-β) production and secretion are critical for STAT1 activation. Secreted IFN-β further amplified its own expression via a positive-feedback mechanism, while expression of transcription factors interferon regulatory factor 7 (IRF7) and IRF9, implicated in the IFN-β–STAT1 feedback loop, was also induced. Metabolic activity of rickettsiae was essential for the IFN-β-mediated response(s) because tetracycline treatment inhibited
R. conorii
replication, IFN-β expression, and STAT1 phosphorylation. Inclusion of IFN-β-neutralizing antibody during infection resulted in significantly enhanced
R. conorii
replication, whereas addition of exogenous IFN-β had the opposite inhibitory effect. Finally, small interfering RNA-mediated knockdown further confirmed a protective role for STAT1 against intracellular
R. conorii
replication. In concert, these findings implicate an important role for IFN-β-mediated STAT1 activation in innate immune responses of vascular endothelium to
R. conorii
infection.
Characterization of the Fibrinogen Binding Domain of Bacteriophage Lysin from Streptococcus mitis
Authors: Seo Ho Seong , Sullam Paul M.
Published: June 2011

The binding of bacteria to human platelets is a likely central mechanism in the pathogenesis of infective endocarditis. Platelet binding by
Streptococcus mitis
SF100 is mediated in part by a lysin encoded by the lysogenic bacteriophage SM1. In addition to its role in the phage life cycle, lysin mediates the binding of
S. mitis
to human platelets via its interaction with fibrinogen on the platelet surface. To better define the region of lysin mediating fibrinogen binding, we tested a series of purified lysin truncation variants for their abilities to bind this protein. These studies revealed that the fibrinogen binding domain of lysin is contained within the region spanned by amino acid residues 102 to 198 (lysin
102–198
). This region has no sequence homology to other known fibrinogen binding proteins. Lysin
102–198
bound fibrinogen comparably to full-length lysin and with the same selectivity for the fibrinogen Aα and Bβ chains. Lysin
102–198
also inhibited the binding
in vitro
of
S. mitis
to human fibrinogen and platelets. When assessed by platelet aggregometry, the disruption of the lysin gene in SF100 resulted in a significantly longer time to the onset of aggregation of human platelets than that of the parent strain. The preincubation of platelets with purified lysin
102–198
also delayed the onset of aggregation by SF100. These results indicate that the binding of lysin to fibrinogen is mediated by a specific domain of the phage protein and that this interaction is important for both platelet binding and aggregation by
S. mitis
.
Evaluation of the Safety and Immunogenicity in Rhesus Monkeys of a Recombinant Malaria Vaccine for Plasmodium vivax with a Synthetic Toll-Like Receptor 4 Agonist Formulated in an Emulsion
Authors: Lumsden Joanne M. , Pichyangkul Sathit , Srichairatanakul Utaiwan , Yongvanitchit Kosol , Limsalakpetch Amporn , Nurmukhambetova Saule , Klein Jennifer , Bertholet Sylvie , Vedvick Thomas S. , Reed Steven G. , Sattabongkot Jetsumon , Bennett Jason W. , Polhemus Mark E. , Ockenhouse Christian F. , Howard Randall F. , Yadava Anjali
Published: June 2011

Plasmodium vivaxis the major cause of malaria outside sub-Saharan Africa and inflicts debilitating morbidity and consequent economic impacts in developing countries. In order to produce aP. vivaxvaccine for global use, we have previously reported the development of a novel chimeric recombinant protein, VMP001, based on the circumsporozoite protein (CSP) ofP. vivax. Very few adjuvant formulations are currently available for human use. Our interest is to evaluate second-generation vaccine formulations to identify novel combinations of adjuvants capable of inducing strong, long-lasting immune responses. In this study rhesus monkeys were immunized intramuscularly three times with VMP001 in combination with a stable emulsion (SE) or a synthetic Toll-like receptor 4 (TLR4) agonist (glucopyranosyl lipid A [GLA]) in SE (GLA-SE). Sera and peripheral blood mononuclear cells (PBMCs) were tested for the presence of antigen-specific humoral and cellular responses, respectively. All groups of monkeys generated high titers of anti-P. vivaxIgG antibodies, as detected by enzyme-linked immunosorbent assays (ELISAs) and immunofluorescence assays. In addition, all groups generated a cellular immune response characterized by antigen-specific CD4+T cells secreting predominantly interleukin-2 (IL-2) and lesser amounts of tumor necrosis factor (TNF). We conclude that the combination of VMP001 and GLA-SE is safe and immunogenic in monkeys and may serve as a potential second-generation vaccine candidate againstP. vivaxmalaria.