Objective: Heart disease is the leading cause of firefighter line-of-duty deaths. The study objectives were to identify early atherosclerotic disease through ultrasound measurement of carotid intima-media thickness (CIMT) and risk factors predicting increased CIMT and carotid plaque. Methods: Following ultrasound evaluation of 597 Phoenix and Tucson firefighters, logistic regression was used to identify risk factors for mean CIMT greater than 75th percentile and for carotid plaque. Results: Age, low-density lipoprotein cholesterol (LDL-C) of 100 mg/dL or more, and high-density lipoprotein cholesterol were significant independent predictors of increased CIMT. Age, hypertension, LDL-C, and plasma soluble P-selectin were significant predictors of carotid plaque. Conclusions: This study supports an emphasis on traditional risk factors for atherosclerotic disease in firefighters, in particular maintaining LDL-C less than 100 mg/dL. Plasma soluble P-selectin may help identify firefighters at increased risk for carotid plaque.

OBJECTIVE:Effectiveness of periodic spirometry in medical monitoring depends on spirometry quality. We describe an intervention on spirometry quality and its impact on accuracy and precision of longitudinal measurements.METHODS:The intervention was conducted from 2005 to 2010 in a monitoring program involving approximately 2500 firefighters. Intervention supported adherence to 2005 American Thoracic Society/European Respiratory Society recommendations through monitoring of spirometry quality and longitudinal data precision, technician training, change of spirometer, and quality control.RESULTS:The percentage of forced vital capacity tests meeting the American Thoracic Society/European Respiratory Society criteria increased from 60% to 95% and the mean longitudinal forced expiratory volume in 1 second within-person variation decreased from 6% to 4%. The increased accuracy and precision of measurements and estimated rates of forced expiratory volume in 1 second decline were statistically significant.CONCLUSION:Monitoring of quality and data precision helped to recognize the need for intervention. The intervention improved accuracy and precision of spirometry measurements and their usefulness.

Microtubules are a well-validated target for anticancer therapy. Molecules that bind tubulin affect dynamic instability of microtubules causing mitotic arrest of proliferating cells, leading to cell death and tumor growth inhibition. Natural antitubulin agents such as taxanes and Vinca alkaloids have been successful in the treatment of cancer; however, several limitations have encouraged the development of synthetic small molecule inhibitors of tubulin function. We have previously reported the discovery of two novel chemical series of tubulin polymerization inhibitors, triazoles (Ouyang et al. Synthesis and structure-activity relationships of 1,2,4-triazoles as a novel class of potent tubulin polymerization inhibitors. Bioorg Med Chem Lett. 2005; 15:5154ȁ5159) and oxadiazole derivatives (Ouyang et al. Oxadiazole derivatives as a novel class of antimitotic agents: synthesis, inhibition of tubulin polymerization, and activity in tumor cell lines. Bioorg Med Chem Lett. 2006; 16:1191ȁ1196). Here, we report on the anticancer effects of a lead oxadiazole derivative in vitro and in vivo. In vitro, IMC-038525 caused mitotic arrest at nanomolar concentrations in epidermoid carcinoma and breast tumor cells, including multidrug-resistant cells. In vivo, IMC-038525 had a desirable pharmacokinetic profile with sustained plasma levels after oral dosing. IMC-038525 reduced subcutaneous xenograft tumor growth with significantly greater efficacy than the taxane paclitaxel. At efficacious doses, IMC-038525 did not cause substantial myelosuppression or peripheral neurotoxicity, as evaluated by neutrophil counts and changes in myelination of the sciatic nerve, respectively. These data indicate that IMC-038525 is a promising candidate for further development as a chemotherapeutic agent.

Microtubules are a well-validated target for anticancer therapy. Molecules that bind tubulin affect dynamic instability of microtubules causing mitotic arrest of proliferating cells, leading to cell death and tumor growth inhibition. Natural antitubulin agents such as taxanes and Vinca alkaloids have been successful in the treatment of cancer; however, several limitations have encouraged the development of synthetic small molecule inhibitors of tubulin function. We have previously reported the discovery of two novel chemical series of tubulin polymerization inhibitors, triazoles (Ouyang et al. Synthesis and structure-activity relationships of 1,2,4-triazoles as a novel class of potent tubulin polymerization inhibitors. Bioorg Med Chem Lett. 2005; 15:5154-5159) and oxadiazole derivatives (Ouyang et al. Oxadiazole derivatives as a novel class of antimitotic agents: synthesis, inhibition of tubulin polymerization, and activity in tumor cell lines. Bioorg Med Chem Lett. 2006; 16:1191-1196). Here, we report on the anticancer effects of a lead oxadiazole derivative in vitro and in vivo. In vitro, IMC-038525 caused mitotic arrest at nanomolar concentrations in epidermoid carcinoma and breast tumor cells, including multidrug-resistant cells. In vivo, IMC-038525 had a desirable pharmacokinetic profile with sustained plasma levels after oral dosing. IMC-038525 reduced subcutaneous xenograft tumor growth with significantly greater efficacy than the taxane paclitaxel. At efficacious doses, IMC-038525 did not cause substantial myelosuppression or peripheral neurotoxicity, as evaluated by neutrophil counts and changes in myelination of the sciatic nerve, respectively. These data indicate that IMC-038525 is a promising candidate for further development as a chemotherapeutic agent.

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of morbidity and mortality. Periodic spirometry is often recommended for individuals with potential occupational exposure to respiratory hazards and in medical treatment of respiratory disease, to prevent COPD or improve treatment outcome. To achieve the full potential of spirometry monitoring in preserving lung function, it is important to maintain acceptable precision of the longitudinal measurements, apply interpretive strategies that identify individuals with abnormal test results or excessive loss of lung function in a timely manner, and use the results for intervention on respiratory disease prevention or treatment modification. We describe novel, easy-to-use visual and analytical software, Spirometry Longitudinal Data Analysis software (SPIROLA), designed to assist healthcare providers in the above aspects of spirometry monitoring. Software application in ongoing workplace spirometry-based medical monitoring programs helped to identify increased spirometry data variability due to deteriorating test quality and subsequent improvement following interventions, and helped to enhance identification of individuals with excessive decline in lung function.

This article builds on and extends Richard F. Fenno Jr.'s theoretical framework on home style, demonstrating how one former member of Congress used his congressional newsletters to develop his home style. Barber B. Conable, Jr., a Republican congressman from western New York (1965-1985), successfully used his congressional newsletters to develop a primary constituency at home by presenting himself to his constituents as a teacher and explaining to them his Washington and district activities. In so doing, Conable showed how it is possible for a member of Congress to build constituent trust and support at home by focusing on the educational responsibilities of his office. The essence of Conable's home style is captured with the title of this paper-"The House Member as Teacher."

Tumors of the lacrimal sac are uncommon and carry a high rate of malignancy. These neoplasms have a tendency to spread along the lacrimal drainage system, which must be radically excised for improved outcomes. We report our experience of combined modality therapy for two cases of lacrimal sac malignancy. The first was a 50-year-old man who presented with a basaloid squamous cell carcinoma occupying the medial orbit, displaying an infiltrative growth pattern and abutting the globe on CT and MR images. The tumor responded dramatically to two cycles of paclitaxel-cisplatin-fluorouracil chemotherapy, allowing for a conservative surgical resection. The second case was an 80-year-old man with adenoid cystic carcinoma arising from the lacrimal sac with involvement of medial orbital contents. In both patients, a limited exenteration of medial orbital contents was performed, along with a medial maxillectomy. Adjuvant therapy with cisplatin chemoradiation was administered to the first patient and only radiation to the second. In this report, we highlight the benefits of combination therapy, our approach of partial exenteration of medial orbital structures with medial maxillectomy, the mode of reconstruction, and the functional results.

Objective: Spirometry-based screening programmes often conduct annual assessment of longitudinal changes in forced expiratory volume in 1 second (FEV1) to identify individuals with excessive rates of decline. Both the American Thoracic Society (ATS) and the American College of Occupational and Environmental Medicine (ACOEM) recommend a reference limit value of ⩾15% for excessive annual decline. Neither the ATS nor the ACOEM adjust this limit for the precision of the existing spirometry data. The authors propose an improved method of defining the reference limit of longitudinal annual FEV1 decline (LLD) based on the precision of the spirometry data. Method: The authors used data from four monitoring programmes and measured their data precision using a pair-wise within-person variation statistic. They then derived programme- and gender-specific absolute and relative LLD values and validated these against the 95th percentiles for observed yearly changes in FEV1. Results: The relative limit for annual decline was more practical than the absolute limit as it adjusted for gender differences in the magnitude of FEV1. The programme-specific relative limit values were in good agreement with 95th percentiles for year-to-year FEV1 changes and ranged from 6.6% to 15.8%. For individuals with COPD and bronchial hyperreactivity the 95th percentiles for year-to-year changes were about 15% and higher. Conclusions: The relative longitudinal limit for annual FEV1 decline based upon precision of measurements is valid and can be generalised to different gender and population groups. A relative limit of approximately 10% appears appropriate for good quality workplace monitoring programmes, whereas a limit of about 15% appears appropriate for clinical evaluation of individuals with an obstructive airway disease. Computer software based on the method described is available from the corresponding author.

Oxadiazole derivatives were synthesized and evaluated for their ability to inhibit tubulin polymerization and to cause mitotic arrest in tumor cells. The most potent compounds inhibited tubulin polymerization at concentrations below 1 mu M. Lead analogs caused mitotic arrest of A431 human epidermoid cells and cells derived from multi-drug resistant tumors (10, EC50 = 7.8 nM). Competition for the colchicine binding site and pharmacokinetic properties of selected potent compounds were also investigated and are reported herein, along with structure-activity relationships for this novel series of antimitotic agents. (C) 2005 Elsevier Ltd. All rights reserved.

A novel triazole-containing chemical series was shown to inhibit tubulin polymerization and cause cell cycle arrest in A431 cancer cells with EC(50) values in the single digit nanomolar range. Binding experiments demonstrated that representative active compounds of this class compete with colchicine for its binding site on tubulin. The syntheses and structure-activity relationship studies for the triazole derivatives are described herein.

Chronic inflammation contributes to carcinogenesis, but the underlying mechanisms are poorly understood. We report that aged granulocyte-macrophage colony stimulating factor (GM-CSF)-deficient mice develop a systemic lupus erythematosis (SLE)-like disorder associated with the impaired phagocytosis of apoptotic cells. Concurrent deficiency of interferon (IFN)-γ attenuates the SLE, but promotes the formation of diverse hematologic and solid neoplasms within a background of persistent infection and inflammation. Whereas activated B cells show a resistance to fas-induced apoptosis, antimicrobial therapy prevents lymphomagenesis and solid tumor development. These findings demonstrate that the interplay of infectious agents with cytokine-mediated regulation of immune homeostasis is a critical determinant of cancer susceptibility.

In developing lymphocytes, the recombination activating gene endonuclease cleaves DNA between V, D, or J coding and recombination signal (RS) sequences to form hairpin coding and blunt RS ends, which are fused to form coding and RS joins. Nonhomologous end joining (NHEJ) factors repair DNA double strand breaks including those induced during VDJ recombination. Human radiosensitive severe combined immunodeficiency results from lack of Artemis function, an NHEJ factor with in vitro endonuclease/exonuclease activities. We inactivated Artemis in murine embryonic stem (ES) cells by targeted mutation. Artemis deficiency results in impaired VDJ coding, but not RS, end joining. In addition, Artemis-deficient ES cells are sensitive to a radiomimetic drug, but less sensitive to ionizing radiation. VDJ coding joins from Artemis-deficient ES cells, which surprisingly are distinct from the highly deleted joins consistently obtained from DNA-dependent protein kinase catalytic subunit–deficient ES cells, frequently lack deletions and often display large junctional palindromes, consistent with a hairpin coding end opening defect. Strikingly, Artemis-deficient ES cells have increased chromosomal instability including telomeric fusions. Thus, Artemis appears to be required for a subset of NHEJ reactions that require end processing. Moreover, Artemis functions as a genomic caretaker, most notably in prevention of translocations and telomeric fusions. As Artemis deficiency is compatible with human life, Artemis may also suppress genomic instability in humans.

Amplification of large genomic regions associated with complex translocations (complicons) is a basis for tumor progression and drug resistance. We show that pro-B lymphomas in mice deficient for both p53 and nonhomologous end-joining (NHEJ) contain complicons that coamplify c-myc (chromosome 15) and IgH (chromosome 12) sequences. While all carry a translocated (12;15) chromosome, coamplified sequences are located within a separate complicon that often involves a third chromosome. Complicon formation is initiated by recombination of RAG1/2-catalyzed IgH locus double-strand breaks with sequences downstream of c-myc, generating a dicentric (15;12) chromosome as an amplification intermediate. This recombination event employs a microhomology-based end-joining repair pathway, as opposed to classic NHEJ or homologous recombination. These findings suggest a general model for oncogenic complicon formation.

Under visual guidance, subjects reached for and manipulated an object that varied in weight and surface texture (slipperiness). The manipulatory action was either grasping, lifting, or posting in a slot. The task was constrained or unconstrained with respect to speed, grasp pattern, and contact force. Initiation time (pre-reach), movement time (reach), and post-contact errors were measured, to examine planning for task performance at three points in time. Results indicate that in the constrained task, the manipulatory action was planned during the initiation time, but planning for object parameters was deferred until the reach interval. With relaxed task constraints, initiation times increased, and texture and manipulatory action had independent effects on premovement planning. Errors were affected interactively by all variables. The results suggest a planning process that unfolds over time, incorporating in turn the manipulatory action, object texture, and object weight. This unfolding accommodates variables proximate to the time where they will affect physical action.

Although nonhomologous end-joining (NHEJ) deficiency has been shown to accelerate lymphoma formation in mice, its role in suppressing tumors in cells that do not undergo V(D)J recombination is unclear. Utilizing a tumor-prone mouse strain (ink4a/arf−/−), we examined the impact of haploinsufficiency of a NHEJ component, DNA ligase IV (Lig4), on murine tumorigenesis. We demonstrate that lig4 heterozygosity promotes the development of soft-tissue sarcomas that possess clonal amplifications, deletions, and translocations. That these genomic alterations are relevant in tumorigenesis is supported by the finding of frequent mdm2 amplification, a known oncogene in human sarcoma. Together, these findings support the view that loss of a single lig4 allele results in NHEJ activity being sufficiently reduced to engender chromosomal aberrations that drive non-lymphoid tumorigenesis.

Previous studies have suggested that the representation of space is distorted in patients with hemispatial neglect. To examine the nature of the altered spatial representation, we developed an analog of neglect in normal subjects using bisections of the Judd visual illusion (e.g., <---<) whose direction (facing left/right/both) and fin angle (14 degrees/45 degrees/76 degrees) were orthogonally varied. Subjects made bisection errors that deviated significantly in a direction opposite to that in which the fins pointed, and these deviations decreased as fin angle increased. We replicated these findings in a second task in which subjects were given the midpoint and placed the two fins at the ends of an imaginary shaft (e.g., < x <, note: dot = true center). These findings suggest that the geometric properties of the display have a strong influence on the representation of space, and thus may be used to induce a distorted perception of space analogous to that observed in patients with visuospatial neglect.

Normal assembly and function of microtubules require maintenance of the proper levels of several proteins, including the tubulin polypeptides themselves. For example, in yeast a significant excess of beta-tubulin causes rapid microtubule disassembly and subsequent cell death. Even the modest excess of beta-tubulin produced by genetic alterations such as deletion of the minor alpha-tubulin gene TUB3 affects cell growth and can confer microtubule phenotypes. We show here that the levels of the yeast protein Pac10p affect the relative levels of the tubulin polypeptides. Cells deleted for PAC10 have the same phenotypes as do cells that express reduced levels of alpha-tubulin or Rbl2p, two proteins that bind beta-tubulin. Conversely, overexpression of Pac10p enhances the ability of alpha-tubulin or Rbl2p to suppress the lethality associated with excess beta-tubulin. However, Pac10p is itself not a beta-tubulin binding protein. Pac10 null cells show a 30% decrease in the ratio of alpha-tubulin to beta-tubulin. The results suggest that Pac10p modulates the level of alpha-tubulin in the cell, and so influences microtubule morphogenesis and tubulin metabolism.

Article Free Access Share on Spreading the word: funding faculty to train faculty in the California State University Authors: Susan Archer Computer Center, San Diego State University, San Diego, CA Computer Center, San Diego State University, San Diego, CAView Profile , James Fleming Computer Center, California State University, Northridge Computer Center, California State University, NorthridgeView Profile , Gary Jones Offices of Computing and Communications Resources, Chancellor's Office, The California State University Offices of Computing and Communications Resources, Chancellor's Office, The California State UniversityView Profile Authors Info & Claims SIGUCCS '88: Proceedings of the 16th annual ACM SIGUCCS Conference on User ServicesOctober 1988 Pages 369–371https://doi.org/10.1145/62548.62659Online:01 October 1988Publication History 0citation67DownloadsMetricsTotal Citations0Total Downloads67Last 12 Months0Last 6 weeks0 Get Citation AlertsNew Citation Alert added!This alert has been successfully added and will be sent to:You will be notified whenever a record that you have chosen has been cited.To manage your alert preferences, click on the button below.Manage my Alerts New Citation Alert!Please log in to your account Save to BinderSave to BinderCreate a New BinderNameCancelCreateExport CitationPublisher SiteeReaderPDF

We have identified a novel actin-related 60-kDa polypeptide in mammalian cells. The relatedness of this polypeptide to actin is indicated by its affinity for DNase I, two monoclonal anti-actin antibodies, and two independent peptide-specific anti-actin antibodies which bind to actin at around amino acid 244. It is not incorporated into cytoskeletal stress fibers, although it is a stable protein. Its expression (60-kDa polypeptide, pI of 5.4 to 5.5) is inhibited by the K+ ionophore, nonactin, which is known to collapse the energy-dependent translocation of cytoplasmically synthesized proteins into mitochondria.