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The purpose of this historical research was to analyze the 1967 restructuring of the Canadian Association of University Schools of Nursing (CAUSN) from a powerless, loose affiliation of individual nurse academics into a potentially powerful association of deans and directors. After its 1967 restructuring, CAUSN became active nationally and collaborated with the Canadian Nurses Association on doctoral education, accreditation for nursing education programs, and baccalaureate entry to practice. It also successfully implemented a national program of voluntary accreditation of baccalaureate education. The transformation of CAUSN was analyzed using primary data located in the Queen's University Archives, Kingston, Ontario, the Canadian Nurses Association Archives, Ottawa, Ontario, and from selected interviews. Secondary data was used to augment and corroborate interpretation of primary data. [ABSTRACT FROM AUTHOR]

Background: A survey of medical physics residency program directors was conducted in Spring 2021 to examine the current state of brachytherapy (BT) training during residency. In this related work, a subsequent survey of therapeutic medical physics residents in 2022 was conducted to assess the confidence and experience of the trainees. Concerns for access to high-quality and diverse training in BT have escalated in importance due to recent declines in BT utilization., Methods: A survey consisting of 26 questions was designed by a working unit of the Brachytherapy Subcommittee of the American Association of Physicists in Medicine (AAPM) and approved for distribution by the Executive Committee of the AAPM. The survey was distributed to current trainees and recent graduates of the Commission on Accreditation of Medical Physics Education Programs accredited therapeutic medical physics residency programs by the AAPM. The participant response was anonymously recorded in an online platform and subsequently analyzed using spreadsheet software., Results: The survey was distributed to 796 current medical physics residents or recent graduates over the course of 6 weeks in February and March of 2022. The survey received 736 views and a total of 182 responses were collected, with 165 respondents completing the survey in full. Among those responses, 110 had completed their residency training, with program start dates ranging from calendar years 2015 to 2021. Individual responses from the survey takers (including partial survey submissions) were evaluated and analyzed to compile results., Conclusions: Medical physics residents reported the highest levels of confidence and caseload for gynecological BT procedures when compared with other surveyed treatment techniques. This indicates opportunities to improve training and increase access to clinical caseload are needed in order to improve competency and confidence. Time constraints (clinical and rotation-based) were indicated as impediments to BT proficiency. Medical physics residents reported enthusiasm for additional training opportunities in BT, and it is evident that additional structure and programs are required to ensure adequate access to BT training during residency., (© 2024 The Author(s). Journal of Applied Clinical Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Although standardization has been shown to improve patient safety and improve the efficiency of workflows, implementation of standards can take considerable effort and requires the engagement of all clinical stakeholders. Engaging team members includes increasing awareness of the proposed benefit of the standard, a clear implementation plan, monitoring for improvements, and open communication to support successful implementation. The benefits of standardization often focus on large institutions to improve research endeavors, yet all clinics can benefit from standardization to increase quality and implement more efficient or automated workflow. The benefits of nomenclature standardization for all team members and institution sizes, including success stories, are discussed with practical implementation guides to facilitate the adoption of standardized nomenclature in radiation oncology., Competing Interests: Disclosures Susan L. Richardson is Deputy Editor for the Journal of Applied Clinical Medical Physics. Walter R. Bosch reports grant from National Cancer Institute (NCI) (U24 CA 189893); Charles S. Mayo if Chair of American Association of Physicists in Medicine (AAPM) SC-263 and the Big Data Subcommittee. Todd R. McNutt is Chairman of the board of Oncospace and holds founder shares of Common Stock. Jean M. Moran reports software licensed to Fuse Oncology and grants or contracts from the National Institutes of Health (NIH), NCI, and Blue Cross Blue Shield of Michigan. Richard A. Popple reports honoraria and research support from Varian Medical Systems and also receives royalties for the University of Alabama at Birmingham Research Foundation. Ying Xiao reports no conflicts. Elizabeth L. Covington is the Chair of AAPM Task Group TG-263U1., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The American Association of Physicists in Medicine (AAPM) is a nonprofit professional society whose primary purposes are to advance the science, education, and professional practice of medical physics. The AAPM has more than 8000 members and is the principal organization of medical physicists in the United States. The AAPM will periodically define new practice guidelines for medical physics practice to help advance the science of medical physics and to improve the quality of service to patients throughout the United States. Existing medical physics practice guidelines (MPPGs) will be reviewed for the purpose of revision or renewal, as appropriate, on their fifth anniversary or sooner. Each medical physics practice guideline represents a policy statement by the AAPM, has undergone a thorough consensus process in which it has been subjected to extensive review, and requires the approval of the Professional Council. The medical physics practice guidelines recognize that the safe and effective use of diagnostic and therapeutic radiology requires specific training, skills, and techniques, as described in each document. Reproduction or modification of the published practice guidelines and technical standards by those entities not providing these services is not authorized. The following terms are used in the AAPM practice guidelines: (1) Must and must not: Used to indicate that adherence to the recommendation is considered necessary to conform to this practice guideline. (2) Should and should not: Used to indicate a prudent practice to which exceptions may occasionally be made in appropriate circumstances. Approved by AAPM's Executive Committee April 28, 2022., (© 2023 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, LLC on behalf of The American Association of Physicists in Medicine.)

Background: Brachytherapy (BT) was the first radiotherapeutic technique used to treat human disease and remains an essential modality in radiation oncology. A decline in the utilization of BT as a treatment modality has been observed and reported, which may impact training opportunities for medical physics residents. A survey of therapeutic medical physics residency program directors was performed as part of an assessment of the current state of BT training during residency., Methods: In March 2021, a survey consisting of 23 questions was designed by a working unit of the Brachytherapy Subcommittee of the American Association of Physicists in Medicine (AAPM) and approved for distribution by the Executive Committee of the AAPM. The survey was distributed to the directors of the Commission on Accreditation of Medical Physics Education Programs (CAMPEP)-accredited therapeutic medical physics residency programs by the AAPM. The participant response was recorded anonymously in an online platform and then analyzed using MATLAB and Microsoft Excel software., Results: The survey was distributed to the program directors of 110 residency programs. Over the course of 6 weeks, 72 directors accessed the survey online, and 55 fully completed the survey. Individual responses from the directors (including partial submissions) were evaluated and analyzed. Nearly all participating programs (98%) utilize high dose rate BT treatments with 74% using low dose rate BT techniques. All programs treated gynecological sites using BT, and the next most common treatment sites were prostate (80%) and breast (53%). Overall, the residency program directors had a positive outlook toward BT as a radiotherapeutic treatment modality. Caseload and time limitations were identified as primary barriers to BT training by some programs., Conclusions: Based on the responses of the program directors, it was identified that the residency programs might benefit from additional resources such as virtual BT training, interinstitutional collaborations as well as resident fellowships. Programs might also benefit from additional guidance related to BT-specific training requirements to help program directors attest Authorized Medical Physicist eligibility for graduating residents., (© 2023 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, LLC on behalf of The American Association of Physicists in Medicine.)

While most Radiation Oncology clinics have adopted electronic charting in one form or another, no consensus document exists that provides guidelines for safe and effective use of the Radiation Oncology electronic medical records (RO-EMR). Task Group 262 was formed to provide these guidelines as well as to provide recommendations to vendors for improving electronic charting functionality in future. Guidelines are provided in the following areas: Implementation and training for the RO-EMR, acceptance testing and quality assurance (QA) of the RO-EMR, use of the RO-EMR as an information repository, use of the RO-EMR as a workflow manager, electronic charting for brachytherapy and nonstandard treatments, and information technology (IT) considerations associated with the RO-EMR. The report was based on a literature search by the task group, an extensive survey of task group members on their respective RO-EMR practices, an AAPM membership survey on electronic charting, as well as group consensus., (© 2021 American Association of Physicists in Medicine.)

Peptide macrocyclization is typically associated with the development of higher affinity and more protease stable protein ligands, and, as such, is an important tool in peptide drug discovery. Yet, within the context of a diverse library, does cyclization give inherent advantages over linear peptides? Here, we used mRNA display to create a peptide library of diverse ring sizes and topologies (monocyclic, bicyclic, and linear). Several rounds of in vitro selection against streptavidin were performed and the winning peptide sequences were analyzed for their binding affinities and overall topologies. The effect of adding a protease challenge on the enrichment of various peptides was also investigated. Taken together, the selection output yields insights about the relative abundance of binders of various topologies within a structurally diverse library.

Disorders of oxygen transport are commonly attributed to inadequate carrying capacity (anemia) but may also relate to inefficient gas exchange by red blood cells (RBCs), a process that is poorly characterized yet assumed to be rapid. Without direct measurements of gas exchange at the single-cell level, the barriers to O 2 transport and their relationship with hematological disorders remain ill defined. We developed a method to track the flow of O 2 in individual RBCs by combining ultrarapid solution switching (to manipulate gas tension) with single-cell O 2 saturation fluorescence microscopy. O 2 unloading from RBCs was considerably slower than previously estimated in acellular hemoglobin solutions, indicating the presence of diffusional barriers in intact cells. Rate-limiting diffusion across cytoplasm was demonstrated by osmotically induced changes to hemoglobin concentration (i.e., diffusive tortuosity) and cell size (i.e., diffusion pathlength) and by comparing wild-type cells with hemoglobin H (HbH) thalassemia (shorter pathlength and reduced tortuosity) and hereditary spherocytosis (HS; expanded pathlength). Analysis of the distribution of O 2 unloading rates in HS RBCs identified a subpopulation of spherocytes with greatly impaired gas exchange. Tortuosity imposed by hemoglobin was verified by demonstrating restricted diffusivity of CO 2 , an acidic gas, from the dissipative spread of photolytically uncaged H + ions across cytoplasm. Our findings indicate that cytoplasmic diffusion, determined by pathlength and tortuosity, is a major barrier to efficient gas handling by RBCs. Consequently, changes in RBC shape and hemoglobin concentration, which are common manifestations of hematological disorders, can have hitherto unrecognized and clinically significant implications on gas exchange., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)

Hydrocarbon stapled peptides are promising therapeutics for inhibition of intracellular protein-protein interactions. Here we develop a new high-throughput strategy for hydrocarbon stapled peptide discovery based on mRNA display of peptides containing α-methyl cysteine and cyclized with m-dibromoxylene. We focus on development of a peptide binder to the HPV16 E2 protein.

The vibrational properties of octahedrane (C 12 H 12 ) are calculated using density-functional theory employing two different computational methods: an all-electron Gaussian orbital approach and a Naval Research Laboratory-tight-binding scheme (NRL-TB) coupled with molecular dynamics (NRL-TBMD). Both approaches yield vibrational densities of states for octahedrane that are in good general agreement with each other. NRL Molecular Orbital Library can also provide accurate infrared and Raman spectra which can be analyzed and compared with experimental results, while NRL-TBMD can be conveniently scaled up for larger finite-temperature simulations. This latter approach is used in our paper to produce a theoretical prediction for a stable room temperature structure of octahedrane.

The ability to introduce non-canonical amino acids into peptides and proteins is facilitated by working within in vitro translation systems. Non-canonical amino acids can be introduced into these systems using sense codon reprogramming, stop codon suppression, and by breaking codon degeneracy. Here, we review how these techniques have been used to create proteins with novel properties and how they facilitate sophisticated studies of protein function. We also discuss how researchers are using in vitro translation experiments with non-canonical amino acids to explore the tolerance of the translation apparatus to artificial building blocks. Finally, we give several examples of how non-canonical amino acids can be combined with mRNA-displayed peptide libraries for the creation of protease-stable, macrocyclic peptide libraries for ligand discovery., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

A substantial barrier to the single- and multi-institutional aggregation of data to supporting clinical trials, practice quality improvement efforts, and development of big data analytics resource systems is the lack of standardized nomenclatures for expressing dosimetric data. To address this issue, the American Association of Physicists in Medicine (AAPM) Task Group 263 was charged with providing nomenclature guidelines and values in radiation oncology for use in clinical trials, data-pooling initiatives, population-based studies, and routine clinical care by standardizing: (1) structure names across image processing and treatment planning system platforms; (2) nomenclature for dosimetric data (eg, dose-volume histogram [DVH]-based metrics); (3) templates for clinical trial groups and users of an initial subset of software platforms to facilitate adoption of the standards; (4) formalism for nomenclature schema, which can accommodate the addition of other structures defined in the future. A multisociety, multidisciplinary, multinational group of 57 members representing stake holders ranging from large academic centers to community clinics and vendors was assembled, including physicists, physicians, dosimetrists, and vendors. The stakeholder groups represented in the membership included the AAPM, American Society for Radiation Oncology (ASTRO), NRG Oncology, European Society for Radiation Oncology (ESTRO), Radiation Therapy Oncology Group (RTOG), Children's Oncology Group (COG), Integrating Healthcare Enterprise in Radiation Oncology (IHE-RO), and Digital Imaging and Communications in Medicine working group (DICOM WG); A nomenclature system for target and organ at risk volumes and DVH nomenclature was developed and piloted to demonstrate viability across a range of clinics and within the framework of clinical trials. The final report was approved by AAPM in October 2017. The approval process included review by 8 AAPM committees, with additional review by ASTRO, European Society for Radiation Oncology (ESTRO), and American Association of Medical Dosimetrists (AAMD). This Executive Summary of the report highlights the key recommendations for clinical practice, research, and trials., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Human papillomaviruses are causative agents in several human diseases ranging from genital warts to ano-genital and oropharyngeal cancers. Currently only symptoms of HPV induced disease are treated; there are no antivirals available that directly target the viral life cycle. Previously, we determined that the cellular protein TopBP1 interacts with the HPV16 replication/transcription factor E2. This E2-TopBP1 interaction is essential for optimal E1-E2 DNA replication and for the viral life cycle. The drug calcein disrupts the interaction of TopBP1 with itself and other host proteins to promote cell death. Here we demonstrate that calcein blocks HPV16 E1-E2 DNA replication via blocking the viral replication complex forming at the origin of replication. This occurs at non-toxic levels of calcein and demonstrates specificity as it does not block the ability of E2 to regulate transcription. We propose that calcein or derivatives could be developed as an anti-HPV therapeutic., (Copyright © 2017 Elsevier Inc. All rights reserved.)

During capillary transit, red blood cells (RBCs) must exchange large quantities of CO 2 and O 2 in typically less than one second, but the degree to which this is rate-limited by diffusion through cytoplasm is not known. Gas diffusivity is intuitively assumed to be fast and this would imply that the intracellular path-length, defined by RBC shape, is not a factor that could meaningfully compromise physiology. Here, we evaluated CO 2 diffusivity (D CO2 ) in RBCs and related our results to cell shape. D CO2 inside RBCs was determined by fluorescence imaging of [H + ] dynamics in cells under superfusion. This method is based on the principle that H + diffusion is facilitated by CO 2 /HCO 3 - buffer and thus provides a read-out of D CO2 . By imaging the spread of H + ions from a photochemically-activated source (6-nitroveratraldehyde), D CO2 in human RBCs was calculated to be only 5% of the rate in water. Measurements on RBCs containing different hemoglobin concentrations demonstrated a halving of D CO2 with every 75 g/L increase in mean corpuscular hemoglobin concentration (MCHC). Thus, to compensate for highly-restricted cytoplasmic diffusion, RBC thickness must be reduced as appropriate for its MCHC. This can explain the inverse relationship between MCHC and RBC thickness determined from >250 animal species.

Protein methylation and acetylation play important roles in biological processes, and misregulation of these modifications is involved in various diseases. Therefore, it is critical to understand the activities of the enzymes responsible for these modifications. Herein we describe a sensitive method for ratiometric quantification of methylated and acetylated peptides via MALDI-MS by direct spotting of enzymatic methylation and acetylation reaction mixtures without tedious purification procedures. The quantifiable detection limit for peptides with our method is approximately 10 fmol. This is achieved by increasing the signal-to-noise ratio through the addition of NH4H2PO4 to the matrix solution and reduction of the matrix α-cyanohydroxycinnamic acid concentration to 2 mg/ml. We have demonstrated the application of this method in enzyme kinetic analysis and inhibition studies. The unique feature of this method is the simultaneous quantification of multiple peptide species for investigation of processivity mechanisms. Its wide buffer compatibility makes it possible to be adapted to investigate the activity of any protein methyltransferase or acetyltransferase., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The protein N-terminal methyltransferase 1 (NTMT1) catalyzes the transfer of the methyl group from the S-adenosyl-l-methionine to the protein α-amine, resulting in formation of S-adenosyl-l-homocysteine and α-N-methylated proteins. NTMT1 is an interesting potential anticancer target because it is overexpressed in gastrointestinal cancers and plays an important role in cell mitosis. To gain insight into the biochemical mechanism of NTMT1, we have characterized the kinetic mechanism of recombinant NTMT1 using a fluorescence assay and mass spectrometry. The results of initial velocity, product, and dead-end inhibition studies indicate that methylation by NTMT1 proceeds via a random sequential Bi Bi mechanism. In addition, our processivity studies demonstrate that NTMT1 proceeds via a distributive mechanism for multiple methylations. Together, our studies provide new knowledge about the kinetic mechanism of NTMT1 and lay the foundation for the development of mechanism-based inhibitors., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)

The protein N-terminal methyltransferase 1 (NTMT1) methylates the α-N-terminal amines of proteins. NTMT1 is upregulated in a variety of cancers and knockdown of NTMT1 results in cell mitotic defects. Therefore, NTMT1 inhibitors could be potential anticancer therapeutics. This study describes the design and synthesis of the first inhibitor targeting NTMT1. A novel bisubstrate analogue (NAM-TZ-SPKRIA) was shown to be a potent inhibitor (Ki = 0.20 μM) for NTMT1 and was selective versus protein lysine methyltransferase G9a and arginine methyltransferase 1. NAM-TZ-SPKRIA was found to exhibit a competitive inhibition pattern for both substrates, and mass spectrometry experiments revealed that the inhibitor substantially suppressed the methylation progression. Our results demonstrate the feasibility of using a triazole group to link an S-adenosyl-L-methionine analog with a peptide substrate to construct bisubstrate analogues as NTMT1 potent and selective inhibitors. This study lays a foundation to further discover small molecule NTMT1 inhibitors to interrogate its biological functions, and suggests a general strategy for the development of selective protein methyltransferase inhibitors.

Objectives: The purpose of this study was to investigate issues related to access to endodontic care in North Carolina for individuals who used dental public health resources such as public health clinics (PHCs) or private practices that accept Medicaid or other government-sponsored reimbursement programs private practices that accept Medicaid (PPM)., Methods: Surveys were sent to 1,195 dentists regarding frequency and type of endodontic conditions encountered, treatments provided, and perceived barriers to care. Results were analyzed using logistic regression with the level of significance set at 0.05., Results: Five hundred forty-six surveys were returned for a 45.7% response rate. Of the respondents, 79% reported frequently encountering an endodontic condition, but only 34% reported performing any type of definitive endodontic procedure. Graduates after the year 2000 were significantly more likely to perform definitive endodontic procedures (P < 0.05). Lack of insurance was the greatest barrier to care with 89% considering it a moderate to major barrier, followed by cost of the endodontic treatment (87%) and cost of the restoration following treatment (86%). PPMs were more likely to consider cost and insurance a major barrier (P < 0.05)., Conclusions: In North Carolina public health and Medicaid settings, the frequency of endodontic treatments provided was much lower than the frequency of endodontic conditions encountered that might have benefited from treatment. Graduation year was the best indicator for the provision of root canal therapy. Additionally, treatment patterns and perceptions of barriers to care are different for PHCs and PPMs., (© 2013 American Association of Public Health Dentistry.)

A working hypothesis for the pathogenesis of myotonic dystrophy type 1 (DM1) involves the aberrant sequestration of an alternative splicing regulator, MBNL1, by expanded CUG repeats, r(CUG)(exp). It has been suggested that a reversal of the myotonia and potentially other symptoms of the DM1 disease can be achieved by inhibiting the toxic MBNL1-r(CUG)(exp) interaction. Using rational design, we discovered an RNA-groove binding inhibitor (ligand 3) that contains two triaminotriazine units connected by a bisamidinium linker. Ligand 3 binds r(CUG)12 with a low micromolar affinity (K(d) = 8 ± 2 μM) and disrupts the MBNL1-r(CUG)12 interaction in vitro (K(i) = 8 ± 2 μM). In addition, ligand 3 is cell and nucleus permeable, exhibits negligible toxicity to mammalian cells, dissolves MBNL1-r(CUG)(exp) ribonuclear foci, and restores misregulated splicing of IR and cTNT in a DM1 cell culture model. Importantly, suppression of r(CUG)(exp) RNA-induced toxicity in a DM1 Drosophila model was observed after treatment with ligand 3. These results suggest ligand 3 as a lead for the treatment of DM1.

Background. Ventilator-associated pneumonia (VAP) is a worrisome, yet potentially preventable threat in critically ill patients. Evidence-based clinical practices targeting the prevention of VAP have proven effective, but the most optimal methods to ensure consistent implementation and compliance remain unknown. Methods. A retrospective study of the trend in VAP rates in a community-hospital's open medical intensive care unit (MICU) after the enactment of a nurse-led VAP prevention team. The period of the study was between April 1, 2009, and September 30, 2012. The team rounded on mechanically ventilated patients every Tuesday and Thursday. They ensured adherence to the evidence-based VAP prevention. A separate and independent infection control team monitored VAP rates. Results. Across the study period, mean VAP rate was 3.20/1000 ventilator days ±5.71 SD. Throughout the study time frame, there was an average monthly reduction in VAP rate of 0.27/1000 ventilator days, P < 0.001 (CI: -0.40--0.13). Conclusion. A nurse-led interdisciplinary team dedicated to VAP prevention rounding twice a week to ensure adherence with a VAP prevention bundle lowered VAP rates in a community-hospital open MICU. The team had interdepartmental and administrative support and addressed any deficiencies in the VAP prevention bundle components actively.

An alternative approach in determining cause, treatment, and prevention of obesity is to study those who appear resistant to the obesogenic environment. We examined appetite responses in 33 obesity resistant individuals (ORI) versus 28 obesity susceptible individuals (OSI). Fingerprick blood samples to measure ghrelin, total peptide YY (PYY), leptin, glucose, and insulin along with appetite ratings were collected at baseline and 15, 30, 60, 120, and 180 min following consumption of a standardized meal. Fasting, area under the curve (AUC), peak/nadir, and time to peak/nadir were compared. Participants completed the three factor eating questionnaire (TFEQ). No significant differences were observed for ghrelin or PYY. Higher leptin concentrations in the OSI disappeared after controlling for percent body fat (%BF). Significant differences in appetite ratings included a lower hunger nadir among OSI compared with ORI (P = 0.017). Dietary restraint (P < 0.001) and disinhibition (P < 0.001) were lower in ORI compared with OSI, with and without adjustment for %BF. Given the differential body weight of the study groups, similar observed ghrelin concentrations were unexpected, perhaps indicating OSI and ORI respond differently to the same ghrelin concentration. Also ORI response to hunger appears different as they exhibit lower levels of dietary restraint and disinhibition compared with OSI.

The overexpression of the transcription factor, E2F1, induces hypertrophy and apoptosis with cell cycle re-entry in cardiomyocytes in vitro and in vivo, suggesting that targeting E2F1 may have therapeutic potential. Accordingly, we tested the hypothesis that blocking the E2F1-mediated signal transduction pathway prevents cardiac hypertrophy by treating E2F1 knockout mice (E2F1-/-) with either isoproterenol (ISO) or Angiotensin II (ANG). Echocardi-ography was used to measure left ventricular mass index and myocardial performance index, a measure of combined systolic and diastolic left ventricular function. In control mice (E2F1+/+) both ISO and ANG treatments induced cardiac hypertrophy, and impaired ventricular function in ANG treated mice. In contrast to previously published work, E2F1-/- mice also demonstrated a similar pattern of cardiac hypertrophy and function after either treatment. Atrial natriuretic peptide, a molecular marker of hypertrophy and necropsy-determined body weight-normalized left ventricle mass were similarly increased in ISO and ANG treated E2F1+/+ and E2F-/- mice, supporting the echocardiographic data. These data indicate that E2F1 is not necessary for the development of cardiac hypertrophy although studies using an overexpression approach suggest a causal role of E2F1. The reason for this discrepancy is unclear, although it is possible that other E2F-family members (e.g., E2F2) may play a compensatory role. In conclusion, our data demonstrate that cardiac hypertrophy can be induced in an E2F1-independent fashion and suggest that in contrast to previous reports, targeting E2F1 may not be a good therapeutic approach.

Purpose: To investigate the dosimetric effect of the air inside the SAVI partial breast irradiation device., Methods: The authors have investigated how the air inside the SAVI partial breast irradiation device changes the delivered dose from the homogeneously calculated dose. Measurements were made with the device filled with air and water to allow comparison to a homogenous dose calculation done by the treatment planning system. Measurements were made with an ion chamber, TLDs, and film. Monte Carlo (MC) simulations of the experiment were done using the EGSnrc suite. The MC model was validated by comparing the water-filled calculations to those from a commercial treatment planning system., Results: The magnitude of the dosimetric effect depends on the size of the cavity, the arrangement of sources, and the relative dwell times. For a simple case using only the central catheter of the largest device, MC results indicate that the dose at the prescription point 1 cm away from the air-water boundary is about 9% higher than the homogeneous calculation. Independent measurements in a water phantom with a similar air cavity gave comparable results. MC simulation of a realistic multidwell position plan showed discrepancies of about 5% on average at the prescription point for the largest device., Conclusions: The dosimetric effect of the air cavity is in the range of 3%-9%. Unless a heterogeneous dose calculation algorithm is used, users should be aware of the possibility of small treatment planning dose errors for this device and make modifications to the treatment delivery, if necessary.

As an initial step toward the synthesis and characterization of sila-diamondoids, such as sila-adamantane (Si(10)H(16),T(d)), the synthesis of a fourfold silylated sila-adamantane molecule (C(24)H(72)Si(14),T(d)) has been reported in literature [Fischer et al., Science 310, 825 (2005)]. We present the electronic structure, ionization energies, quasiparticle gap, and the excitation energies for the Si(14)(CH(3))(24) and the exact silicon analog of adamantane Si(10)H(16) obtained at the all-electron level using the delta-self-consistent-field and transitional state methods within two different density functional models: (i) Perdew-Burke-Ernzerhof generalized gradient approximation and (ii) fully analytic density functional (ADFT) implementation with atom dependent potential. The ADFT is designed so that molecules separate into atoms having exact atomic energies. The calculations within the two models agree well, to within 0.25 eV for optical excitations. The effect of structural relaxation in the presence of electron-hole-pair excitations is examined to obtain its contribution to the luminescence Stokes shift. The spin-influence on exciton energies is also determined. Our calculations indicate overall decrease in the absorption, emission, quasiparticle, and highest occupied molecular orbital-lowest unoccupied molecular orbital gaps, ionization energies, Stokes shift, and exciton binding energy when passivating hydrogens in the Si(10)H(16) are replaced with electron donating groups such as methyl (Me) and trimehylsilyl (-Si(Me)(3)).

Declining levels of estrogen in women result in increases in gonadotropins such as luteinizing hormone (LH) through loss of feedback inhibition. LH, like estrogen, is modulated by hormone replacement therapy. However, the role of post-menopausal gonadotropin increases on cognition has not been evaluated. Here, we demonstrate that the down-regulation of ovariectomy-driven LH elevations using the gonadotropin releasing hormone super-analogue, leuprolide acetate, improves cognitive function in the Morris water maze and Y-maze tests in the absence of E2. Furthermore, our data suggest that these effects are independent of the modulation of estrogen receptors alpha and beta, or activation of CYP19 and StAR, associated with the production of endogenous E2. Importantly, pathways associated with improved cognition such as CaMKII and GluR1-Ser831 are up-regulated by leuprolide treatment but not by chronic long-term E2 replacement suggesting independent cognition-modulating properties. Our findings suggest that down-regulation of gonadotropins is as effective as E2 in modulating cognition but likely acts through different molecular mechanisms. These findings provide a potential novel protective strategy to treat menopause/age-related cognitive decline and/or prevent the development of AD.

The mechanism of quenching of the excited state of terbium and europium complexes by electron-rich reductants occurs by formation of an exciplex involving the triplet excited state of the sensitising chromophore.

While considerable evidence supports the causal relationship between increases in c-Myc (Myc) and cardiomyopathy as a part of a "fetal re-expression" pattern, the functional role of Myc in mechanisms of cardiomyopathy remains unclear. To address this, we developed a bitransgenic mouse that inducibly expresses Myc under the control of the cardiomyocyte-specific MHC promoter. In adult mice the induction of Myc expression in cardiomyocytes in the heart led to the development of severe hypertrophic cardiomyopathy followed by ventricular dysfunction and ultimately death from congestive heart failure. Mechanistically, following Myc activation, cell cycle markers and other indices of DNA replication were significantly increased suggesting that cell cycle-related events might be a primary mechanism of cardiac dysfunction. Furthermore, pathological alterations at the cellular level included alterations in mitochondrial function with dysregulation of mitochondrial biogenesis and defects in electron transport chain complexes I and III. These data are consistent with the known role of Myc in several different pathways including cell cycle activation, mitochondrial proliferation, and apoptosis, and indicate that Myc activation in cardiomyocytes is an important regulator of downstream pathological sequelae. Moreover, our findings indicate that the induction of Myc in cardiomyocytes is sufficient to cause cardiomyopathy and heart failure, and that sustained induction of Myc, leading to cell cycle re-entry in adult cardiomyocytes, represents a maladaptive response for the mature heart.

Heme is an essential cell metabolite, intracellular regulatory molecule, and protein prosthetic group. Given the known alterations in heme metabolism and redox metal distribution and the up-regulation of heme oxygenase enzyme in Alzheimer's disease (AD), we hypothesized that heme dyshomeostasis plays a key role in the pathogenesis. To begin testing this hypothesis, we used qRT-PCR to quantify the expression of aminolevulinate synthase (ALAS1) and porphobilinogen deaminase (PBGD), rate-limiting enzymes in the heme biosynthesis pathway. The relative expression of ALAS1 mRNA, the first and rate-limiting enzyme for heme biosynthesis under normal physiological conditions, was significantly (p<0.05) reduced by nearly 90% in AD compared to control. Coordinately, the relative expression of PBGD mRNA, which encodes porphobilinogen deaminase, the third enzyme in the heme synthesis pathway and a secondary rate-limiting enzyme in heme biosynthesis, was also significantly (p<0.02) reduced by nearly 60% in AD brain compared to control and significantly related to apolipoprotein E genotype (p<0.005). In contrast, the relative expression of ALAD mRNA, which encodes aminolevulinate dehydratase, the second and a non-rate-limiting enzyme for heme biosynthesis, was unchanged between the two groups. Taken together, our results suggest regulation of cerebral heme biosynthesis is profoundly altered in AD and may contribute toward disease pathogenesis by affecting cell metabolism as well as iron homeostasis.

Many different proteins associated with the cell cycle, including cyclins, cyclin-dependent kinases, and proto-oncogenes such as c-MYC (MYC), are increased in degenerating neurons. Consequently, an ectopic activation of the cell cycle machinery in neurons has emerged as a potential pathogenic mechanism of neuronal dysfunction and death in many neurodegenerative diseases, including Alzheimer's disease. However, the exact role of cell cycle re-entry during disease pathogenesis is unclear, primarily because of the lack of relevant research models to study the effects of cell cycle re-entry on mature neurons in vivo. To address this issue, we developed a new transgenic mouse model in which forebrain neurons (CaMKII-MYC) can be induced to enter the cell cycle using the physiologically relevant proto-oncogene MYC to drive cell cycle re-entry. We show that such cell cycle re-entry results in neuronal cell death, gliosis, and cognitive deficits. These findings provide compelling evidence that dysregulation of cell cycle re-entry results in neurodegeneration in vivo. Our current findings, coupled with those of previous reports, strengthen the hypothesis that neurodegeneration in Alzheimer's disease, similar to cellular proliferation in cancer, is a disease that results from inappropriate cell cycle control.

Human kallikrein-related peptidase 3 (hK3), also known as prostate-specific antigen (PSA), is a 33 kDa single chain glycoprotein belonging to the kallikrein family of serine proteases. With chymotrypsin-like enzymatic activity, hK3 is directly and indirectly involved in a number of diverse biological functions including male fertility, the regulation of cell proliferation, and the inhibition of angiogenesis. The gene encoding hK3, hKLK3, is located on chromosome 19 and its expression has been shown to be regulated by steroid hormones through androgen receptor-mediated transcription. hK3 was once thought to be exclusively expressed and secreted by prostatic epithelial cells, hence the initial name of prostate-specific antigen, but has since been isolated in several nonprostatic tissues and ongoing characterization of alternative splicing variants has found at least 13 distinct mRNA transcripts. The detection of hK3 in cerebrospinal fluid prompted the hypothesis that hK3 may be produced in the brain. To test this notion, in this study we used RT-PCR amplification of brain tissue total RNA and examined hK3 protein by immunohistochemical, and immunoblot analysis. RT-PCR revealed several hK3 mRNA transcripts in the brain. Confirming these findings, both immunohistochemical staining and western immunoblotting showed evidence for hK3 protein in neuronal cells. Taken together, our findings support the expression of hK3 in neuronal cells reinforcing the concept of hK3 as a ubiquitous protein with more multifarious biological activity than previously believed. Ongoing research seeks to elucidate the functional significance of hK3 in brain cells.

Dynamic quenching of the metal-based excited state of Eu(III) and Tb(III) complexes of sixteen different macrocyclic ligands has been studied. Quenching by urate, ascorbate and selected catechols is most effective for Tb(III) systems, and involves intermediate formation of an excited state complex (exciplex) between the electron-poor heterocyclic sensitising moiety incorporated into the ligand (tetraazatriphenylene, azaxanthone or a pyrazoyl-azaxanthone) and the electron-rich reductant. The process is sensitive to steric inhibition created by the local ligand environment; quenching is reduced as temperature increases as exciplex formation is entropically disfavoured. In contrast, iodide quenches each complex studied according to a classical collisional encounter model; increasing temperature enhances the rate of quenching, and the process is more sensitive to local electrostatic fields generated by ligand substitution, conforming to a traditional Stern-Volmer kinetic model. Quenching may be inhibited by protein association, allowing the identification of candidates for use as optical imaging probes in cellulo.

The excited states of Tb and Eu complexes of a common macrocyclic ligand are quenched preferentially by electron transfer from the urate anion, allowing the creation of a new assay to measure uric acid in biological fluids.

Several azaxanthone and azathioxanthone sensitising chromophores have been incorporated into macrocyclic ligands and form well-defined Eu and Tb complexes in polar media. Excitation of the heterocyclic chromophore in the range 330 to 382 nm leads to modest amounts of aromatic fluorescence and relatively efficient metal-based luminescence, with absolute metal-based quantum yields of up to 24% in aqueous media.

Prion diseases are associated with the accumulation of a misfolded, protease resistant form of the prion protein, PrPres. In humans there are a variety of different prion related diseases that are sporadic, inherited, or acquired by infection. Gerstmann-Straussler-Sheinker syndrome (GSS) is an inherited prion disease in which PrPres accumulates as amorphous aggregates as well as in amyloid plaques. GSS has been associated with a variety of point mutations in the prion protein: 102, 105, 117, 131, 145, 187, 198, 202, 212, 217, and 232. The F198S mutation was discovered in a large Indiana kindred. Previous studies in vitro have shown that the 198 mutation results in structural instability of the prion protein. In the current study, we demonstrate in a cell model that the F198S mutant protein can be folded properly in a cellular context, but is unable to refold to a native state after denaturation. Further, the F198S mutation significantly affects glycosylation of the mutant protein.

Recently an inorganic fullerine-like [As@Ni(12)@As(20)](3-) onion with near-perfect icosahedral symmetry in the crystalline phase was reported [M. J. Moses, J. C. Fettinger, and B. W. Eichhorn, Science 300, 778 (2003)]. This paper presents a detailed computational study in the framework of density functional theory on various aspects of this molecule. The electronic structure of the As@Ni(12)@As(20) is investigated in its neutral as well as -3 charged state together with its subunits As(20) and As@Ni(12) by the all electron linear combination of Gaussian-type orbitals method. The bonding is studied by examining the integrated charge within atomic sphere, the electron localization function, changes in the electron density distribution, and from vibrational modes. We find that strong covalent As-As bonds seen in isolated As(20) become weaker in the As@Ni(12)@As(20) and strong covalent As-Ni bonds are formed. The structural stability of all four clusters is examined by analyzing the energetics and by calculating the vibrational frequencies. Further, the infrared and Raman spectra is predicted for both the neutral and charged As@Ni(12)@As(20) clusters. Finally, the energy barrier for removal of a single arsenic atom is calculated for the neutral As@Ni(12)@As(20) cluster., ((c) 2004 American Institute of Physics.)

Xenophyophorea are giant deep-sea rhizopodial protists of enigmatic origins. Although species were described as Foraminifera or sponges in the early literature, the xenophyophoreans are currently classified either as a class of Rhizopoda or an independent phylum. To establish the phylogenetic position of Xenophyophorea, we analysed the small subunit (SSU) rRNA gene sequence of Syringammina corbicula Richardson, a newly described xenophyophorean species from the Cape Verde Plateau. The SSUrDNA analyses showed that S. corbicula is closely related to Rhizammina algaeformis, a tubular deep-sea foraminiferan. Both species branch within a group of monothalamous (single-chambered) Foraminifera, which include also such agglutinated genera as Toxisarcon, Rhabdammina, and Saccammina, and the organic-walled genera Gloiogullmia and Cylindrogullmia. Our results are congruent with observations of similar cytoplasmic organisation in Rhizammina and Syringammina. Thus, the Xenophyophorea appear to be a highly specialised group of deep-sea Foraminifera.

In this paper we report on the testing and verification of a system for IMRT delivery quality assurance that uses a cylindrical solid water phantom with a spiral trajectory for radiographic film placement. This spiral film technique provides more complete dosimetric verification of the entire IMRT treatment than perpendicular film methods, since it samples a three-dimensional dose subspace rather than using measurements at only one or two depths. As an example, the complete analysis of the predicted and measured spiral films is described for an intracranial IMRT treatment case. The results of this analysis are compared to those of a single field perpendicular film technique that is typically used for IMRT QA. The comparison demonstrates that both methods result in a dosimetric error within a clinical tolerance of 5%, however the spiral phantom QA technique provides a more complete dosimetric verification while being less time consuming. To independently verify the dosimetry obtained with the spiral film, the same IMRT treatment was delivered to a similar phantom in which LiF thermoluminescent dosimeters were arranged along the spiral trajectory. The maximum difference between the predicted and measured TLD data for the 1.8 Gy fraction was 0.06 Gy for a TLD located in a high dose gradient region. This further validates the ability of the spiral phantom QA process to accurately verify delivery of an IMRT plan.

The degree of histoincompatibility that can be tolerated, and the relative importance of matching at individual HLA class I and class II locus in bone marrow transplantation (BMT) has not been established. We hypothesized that matching for HLA-DR may not be more important than matching for HLA-A or HLA-B in selection of a donor for successful BMT. We retrospectively analyzed the outcomes of 248 consecutive pediatric patients who received allogeneic BMT from related donors (RD, n = 119) or unrelated donors (URD, n = 129). HLA-A and HLA-B were serologically matched, and HLA-DRB1 were identical by DNA typing in 69% of donor-recipient pairs. Most patients (89%) had hematologic malignancies; the rest had aplastic anemia or a congenital disorder. One HLA-A antigen mismatch was associated with a decrease in survival (p = 0.003) and a delay in granulocyte engraftment (p = 0.02) in recipients of RD marrow; as well as a decrease in survival (p = 0.02) and the development of severe acute graft-versus-host disease (GVHD) (p = 0.03) in recipients of URD marrow. One HLA-B antigen mismatch was associated with a decrease in the survival (p = 0.05) and the development of severe GVHD (p = 0.0007) in recipients of RD marrow. One HLA-DRB1 allele mismatch was associated only with a decrease in the survival (p = 0.0003) of recipients of RD marrow. Results of this study suggest that disparity in HLA-A and HLA-B antigens may not be better tolerated than disparity in HLA-DR allele in allogeneic BMT. Further studies are warranted to confirm our results.

The post-second World War period of reconstruction was a time of ferment for Canadian hospitals, and consequently, for hospital nursing work and education. Demand for hospital services, especially nursing, increased dramatically. At the same time, fewer young women were willing to enroll in hospital nurse-training programs. This article is a case study of how one voluntary western hospital - the Calgary General Hospital - grappled with the post-second World War shortage of both graduate nurses and student nurses, at a time of transition from a small, cottage-type hospital into a large, complex urban institution. The analysis offers insights into today's economically driven and politically controlled health care delivery system restructuring, while illuminating the contributions of one of Canada's least known nurse leaders - Gertrude May Hall.

Familial transthyretin (TTR) amyloidosis commonly presents with peripheral neuropathy and involvement of visceral organs. In contrast, signs of central nervous system (CNS) involvement are exceptional. We report that members of a kindred affected by a slowly progressive dementia, seizures, ataxia, hemiparesis, and decreased vision without neuropathy have TTR amyloid deposits in the leptomeninges, the brain parenchyma, and the eye. This condition, previously labeled oculoleptomeningeal amyloidosis, is linked to a mutation at codon 30 of TTR gene, resulting in the substitution of valine with glycine in this family, TTR amyloid deposits were present in the leptomeninges, especially the leptomeningeal vessels, and in the subependymal regions of the ventricular system where they disrupted the ependymal lining and resulted in amyloid-glial formations protruding into and narrowing the ventricular system. Hydrocephalus and atrophy and infarction of cerebral and cerebellar cortexes were also present. Review of the literature shows that amyloid deposition in the leptomeninges is not uncommon in TTR amyloidoses clinically characterized by peripheral neuropathy and lack of CNS signs. The present kindred, which presented exclusively with signs of CNS involvement, expands the phenotype of TTR amyloidosis and raises questions concerning the mechanisms determining phenotypic expression in TTR familial amyloidosis.

Prion diseases are thought to be caused by the conversion of the normal, or cellular, prion protein (PrPC)(PrPres). There are three familial forms of human prion disease, Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker syndrome, and fatal familial insomnia (FFI) which are all expressed at advanced age despite the congenital presence of the mutant prion protein (PrPM). The cellular mechanisms that result in the age-dependent conversion of PrPM into PrPres and the unique phenotypes associated with each PrPM are unknown. FFI and a familial type of Creutzfeldt-Jakob disease (CJD178), share the D178N mutation in the PrP gene but have distinct phenotypes linked to codon 129, the site of a methionine/valine polymorphism (129M/V). We analyzed PrP processing in cells transfected with constructs reproducing the FFI and CJD178 genotypes. The D178N mutation results in instability of the mutant PrP which is partially corrected by N-glycosylation. Hence, only the glycosylated forms of PrPM reach the cell surface whereas the unglycosylated PrPM is also under-represented in the brain of FFI patients validating the cell model. These results offer new insight into the effect of the D178N mutation on the metabolism of the prion protein.

Past research has frequently failed to find age differences in prospective memory. This article tested the possibility that age differences would be more likely to emerge on a prospective memory task that was high in self-initiated retrieval. In the 1st experiment, participants were asked to perform an action every 10 min (a time-based task presumed to be high in self-initiated retrieval); in the 2nd experiment, participants were asked to perform an action whenever a particular word was presented (an event-based task presumed to be relatively low in self-initiated retrieval). Age differences were found with the time-based task but not with the event-based task. This pattern of age differences was again found in a 3rd experiment in which a new experimental procedure was used and the nature of the prospective memory task was directly varied. Generally, the results suggest that self-initiated retrieval processes are an important component of age-related differences across both retrospective and prospective memory tasks.