bluuebunny/crossref_metadata_2025 huggingface dataset:
Dictionary Learning Algorithms for Sparse Representation
Authors: Kreutz-Delgado Kenneth , Murray Joseph F. , Rao Bhaskar D. , Engan Kjersti , Lee Te-Won , Sejnowski Terrence J.
Published: February 2003

Algorithms for data-driven learning of domain-specific overcomplete dictionaries are developed to obtain maximum likelihood and maximum a posteriori dictionary estimates based on the use of Bayesian models with concave/Schur-concave (CSC) negative log priors. Such priors are appropriate for obtaining sparse representations of environmental signals within an appropriately chosen (environmentally matched) dictionary. The elements of the dictionary can be interpreted as concepts, features, or words capable of succinct expression of events encountered in the environment (the source of the measured signals). This is a generalization of vector quantization in that one is interested in a description involving a few dictionary entries (the proverbial “25 words or less”), but not necessarily as succinct as one entry. To learn an environmentally adapted dictionary capable of concise expression of signals generated by the environment, we develop algorithms that iterate between a representative set of sparse representations found by variants of FOCUSS and an update of the dictionary using these sparse representations.

Experiments were performed using synthetic data and natural images. For complete dictionaries, we demonstrate that our algorithms have improved performance over other independent component analysis (ICA) methods, measured in terms of signal-to-noise ratios of separated sources. In the overcomplete case, we show that the true underlying dictionary and sparse sources can be accurately recovered. In tests with natural images, learned overcomplete dictionaries are shown to have higher coding efficiency than complete dictionaries; that is, images encoded with an overcomplete dictionary have both higher compression (fewer bits per pixel) and higher accuracy (lower mean square error).
Equivalence of Backpropagation and Contrastive Hebbian Learning in a Layered Network
Authors: Xie Xiaohui , Seung H. Sebastian
Published: February 2003

Backpropagation and contrastive Hebbian learning are two methods of training networks with hidden neurons. Backpropagation computes an error signal for the output neurons and spreads it over the hidden neurons. Contrastive Hebbian learning involves clamping the output neurons at desired values and letting the effect spread through feedback connections over the entire network. To investigate the relationship between these two forms of learning, we consider a special case in which they are identical: a multilayer perceptron with linear output units, to which weak feedback connections have been added. In this case, the change in network state caused by clamping the output neurons turns out to be the same as the error signal spread by backpropagation, except for a scalar prefactor. This suggests that the functionality of backpropagation can be realized alternatively by a Hebbian-type learning algorithm, which is suitable for implementation in biological networks.
Communicating risk in diverse communities
Authors: Wireman Jody R , Long G Cornell
Published: February 2003

Environmental risk communication involves the use of many tools and techniques to form and deliver effective messages. These messages need to inform affected communities about the potential risks and health effects resulting from exposures to environmental contaminants. More importantly, the messages need to reflect the needs, concerns, sensitivities, and knowledge base of the affected community. This risk message is based on profiling, which is simply getting to know your community (demographically, culturally, and historically) and melding this information with scientific knowledge to effectively deliver a message. Three Air Force (AF) case studies are used to discuss how effective risk-communication methods can be utilized in vastly different communities: an on-base residential population, an AF occupational setting, and a remote Alaskan community impacted by historical AF activities. We will discuss the methods used to profile affected communities, determine and deliver messages, and describe the reaction and receptiveness of the community receiving the message.
Response of F344 rats to inhalation of subclinical levels of sarin: exploring potential causes of Gulf War illness
Authors: Henderson Rogene F , Barr Edward B , Blackwell Walter B , Clark Connie R , Conn Carole A , Kalra Roma , March Thomas H , Sopori Mohan L , Tesfaigzi Yohannes , Ménache Margaret G , Mash Deborah C , Dokladny Karol , Kozak Wieslaw , Kozak Anna , Wachulec Maceij , Rudolph Karin , Kluger Matthew J , Singh Shashi P , Razani-Boroujerdi Seddigheh , Langley Raymond J
Published: February 2003

Subclinical, repeated exposures of F344 rats to sarin resulted in brain alterations in densities of chlonergic receptor subtypes that may be associated with memory loss and cognitive dysfunction. The exposures also depressed the immune system. The rat appears to be a good model for studying the effects of subclinical exposure to a nerve gas.
The use of physiologically based models to integrate diverse data sets and reduce uncertainty in the prediction of perchlorate and iodide kinetics across life stages and species
Authors: Clewell Rebecca A , Merrill Elaine A , Robinson Peter J
Published: February 2003

The effects of perchlorate on the incorporation of iodide into thyroid hormones have been studied for more than 40 years in many species and under varying exposure conditions. Nevertheless, the database for this drinking water contaminant is still incomplete, particularly with regard to human developmental risk. A method for integrating the available data and forming meaningful conclusions for risk assessment is needed. To this end, an initial suite of physiologically based pharmacokinetic (PBPK) models has been developed, which incorporates physiological data for the relevant species and life stages and kinetic data for perchlorate and iodide, as well as the interaction between the two anions. The validated models successfully describe perchlorate-induced inhibition of thyroid iodide uptake and perchlorate and iodide kinetics in the male, pregnant, lactating, fetal, and neonatal rats and the adult humans. The relationships of model-predicted internal dose metrics and kinetic parameters allow a direct comparison of internal dose metrics across life stages in rats and humans. By incorporating all the available data, these models provide a framework for species and life stage extrapolation where the lack of specific data sets would otherwise limit predictive capability. This paper demonstrates two approaches for calculating life stage-specific equivalent doses in a risk assessment for perchlorate: the direct combination of validated model predictions, and the development of preliminary PBPK models for the human-sensitive populations based on the relationship of the parameters in the validated rat and human models. Either approach can be used to perform the needed dosimetry. However, the second approach provides the advantage of a preliminary human life stage-specific PBPK model that can be used for identification of key data gaps and estimation of uncertainty.
Methods for projecting long-term dietary exposure from short-term survey data for environmental contaminants
Authors: Carrington Clark D , Bolger P Michael
Published: February 2003

Public health risk assessments often involve dietary exposures over long periods of time. However, most information about dietary consumption habits comes from short-term surveys that are conducted for periods of three days or less. When employed for characterizing long-term exposures, short-term surveys are likely to underestimate the number of persons consuming a particular food, while overestimating the amount consumed by each individual. Direct application of short-term data is particularly misleading for foods that are consumed infrequently. If a more accurate population estimate for chronic dietary intake is needed for a risk assessment, then two general techniques may be considered. The first method is simpler, while the second is more accurate. Both methods require information about the size of the population consuming the food over the long-term period. The simpler fractional adjustment method reduces consumption across the entire distribution by the ratio of consumer population sizes. Since this method will tend to underestimate high-end exposures and overestimate low-end exposures, it is most useful as a quick bounding exercise. Since short-term surveys are better at characterizing the behavior of frequent consumers, a second method employs an exponential function to reduce the low end of the population distribution by a greater amount than the high end. If available, additional information may be used to select the parameter values for the exponential adjustment. Otherwise, an uncertainty range may be used for the parameter values. Since the frequency-based method is more complex, it is most valuable when used as part of a chronic exposure simulation. Examples of both methods are given for the estimation of chronic wine consumption.
Occupational exposures during the World Trade Center disaster response
Authors: Wallingford Kenneth M , Snyder Erin M
Published: February 2003

Upon the request of the New York City Department of Health, the Centers for Disease Control and Prevention’s National Institute for Occupational Safety and Health (NIOSH) monitored occupational exposures among emergency response workers during the rescue and recovery activities at the World Trade Center disaster site from September 18 through 4 October 2001. During this period, over 1200 bulk and air samples were collected to estimate or characterize workers’ occupational exposures. Samples were collected and analyzed for asbestos, carbon monoxide (CO), chlorodifluoromethane (Freon1 22), diesel exhaust, hydrogen sulfide, inorganic acids, mercury and other metals, polynuclear aromatic hydrocarbons, respirable particulate not otherwise regulated (PNOR), respirable crystalline silica, total PNOR, and volatile organic compounds. Exposures to most of these potential hazards did not exceed NIOSH Recommended Exposure Limits or Occupational Safety and Health Administration Permissible Exposure Limits. However, one torch cutter was overexposed to cadmium and another worker (and possibly three others) was overexposed to CO. The elevated cadmium and CO levels were the result of workers using oxy-acetylene cutting torches and gasoline-powered cutting saws. Recommendations were made to ensure adequate ventilation and worker understanding when using these tools and, where possible, to substitute rechargeable, battery-powered cutting saws for gasoline-powered ones.
Spatially explicit exposure models: application to military sites
Authors: Linkov Igor , Grebenkov Alexander , Baitchorov Vladimir M
Published: February 2003

As a result of defense-related activities, large areas of valuable habitats can be physically disturbed and/or contaminated by hazardous pollutants. It is, however, important to understand that the military impact on such areas may not be wholly detrimental to the environment: their closure to the public can result in environmental conservation of large portions of habitat. Many former military ranges have been converted for civil usage; others are still actively operated for military purposes. In both cases, a major task for environmental policy- and decision-makers is to determine scientifically justified reuse and/or operation scenarios that would not result in deterioration of site habitats and that would in fact be favorable to further development of biodiversity within the areas’ existing ecosystems. Ecological risk assessment is suggested as the key process to use in facilitating the assessment of the ecological value of contaminated and/or disturbed military sites and in the development of a reuse decision protocol. We are currently developing and integrating a number of risk and habitat assessment techniques into such a protocol. This paper presents our approach to one aspect of this system: the incorporation of spatial information into ecological risk assessment. We present a software prototype that calculates radionuclide accumulation by deer foraging in areas having specified contamination patterns.
Identification of target genes responsive to JP-8 exposure in the rat central nervous system
Authors: Lin Baochuan , Ritchie Glenn D , Rossi John , Pancrazio Joseph J
Published: February 2003

Concern for the health risk associated with occupational exposure to jet fuel has emerged in the Department of Defense. Jet propulsion fuel-8 (JP-8) is the fuel used in most US and North Atlantic Treaty Organization (NATO) jet aircraft, and will be the predominant fuel both for military land vehicles and aircraft into the twenty-first century. JP-8 exhibits reduced volatility and lower benzene content as compared to JP-4, the predominant military aircraft fuel before 1992, possibly suggesting greater occupational exposure safety. However, the higher rates of occupational exposure through fueling and maintenance of increasingly larger numbers of aircraft/vehicles raise concerns with respect to toxicity. Clinical studies of workers experiencing long-term exposure to certain jet fuels demonstrated deficits in CNS function, including fatigue, neurobehavioral changes, psychiatric disorders, and abnormal electroencephalogram (EEG). In the present study, cDNA nylon arrays (Atlas Rat 1.2 Array, Clontech Laboratories, Palo Alto, CA) were utilized to measure changes in gene expression in whole brain tissue of rats exposed repeatedly to JP-8, under conditions that simulated possible real-world occupational exposure (6 h/day for 91 days) to JP-8 vapor at 1000 mg/m3. Gene expression analysis of the exposure group compared to the control group revealed a modulation of several genes, including glutathione S-transferase Yb2 subunit (GST Yb2); cytochrome P450 IIIA1 (CYP3A1); glucose-dependent insulinotropic peptide (GIP); a1-proteinase inhibitor (a1-AT); polyubiquitin; GABA transporter 3 (GAT-3); and plasma membrane Ca2+-transporting ATPase (brain isoform 2) (PMCA2). The implications of these vapor-induced changes in gene expression are discussed.
Postrelapse Survival in Osteosarcoma of the Extremities: Prognostic Factors for Long-Term Survival
Authors: Ferrari Stefano , Briccoli Antonio , Mercuri Mario , Bertoni Franco , Picci Piero , Tienghi Amelia , Del Prever Adalberto Brach , Fagioli Franca , Comandone Alessandro , Bacci Gaetano
Published: February 2003

Purpose: To identify factors that influence postrelapse survival (PRS) in patients with nonmetastatic osteosarcoma of the extremity

Patients and Methods: One hundred sixty-two patients with recurrent osteosarcoma of the extremity were retrospectively reviewed. The first-line treatment included surgery of the primary lesion and chemotherapy with methotrexate, doxorubicin, cisplatin, and ifosfamide.

Results: The projected 5-year PRS rate was 28%. Patients who had complete surgery of recurrence had a 5-year PRS of 39%, whereas for those who did not have complete surgery, PRS was 0% at 3 years (P < .0001). In the latter group, PRS was not influenced by site of recurrence and relapse-free interval (RFI), although it was influenced (P = .006) by the use of second-line chemotherapy (PRS, 53% at 12 months for patients who received chemotherapy v 12% for those who did not). In patients who had complete surgery, PRS was influenced by site of relapse (5-year PRS, lung 44%, other 19%; P < .06), RFI (5-year PRS at ≤ 24 months, 20%; at > 24 months, 60%; P < .0001), and number of lung metastases (5-year PRS, two or fewer nodules, 59%; more than two nodules, 14%; P < .0001) but not by the use of a second-line chemotherapy treatment.

Conclusion: RFI, site of metastases, and number of pulmonary nodules are the main prognostic factors for PRS in osteosarcoma. Complete surgery of recurrence is pivotal in the strategy of treatment. Patients with unresectable recurrence benefit from second-line chemotherapy, whereas our data do not support a generalized use of chemotherapy after complete surgery of first recurrence.
Phase II Study of the Efficacy and Safety of Cisplatin-Epinephrine Injectable Gel Administered to Patients With Unresectable Hepatocellular Carcinoma
Authors: Leung T.W.T. , Yu S. , Johnson P.J. , Geschwind J. , Vogl T.J. , Engelmann K. , Gores G.J. , Giovannini M. , O’Grady J. , Heneghan M. , Stewart M. , Orenberg E.K. , Thuluvath P.J.
Published: February 2003

Purpose: To study the efficacy and safety of percutaneous cisplatin-epinephrine (CDDP-EPI) injectable gel in patients with localized unresectable hepatocellular carcinoma (HCC).

Patients and Methods: Eligible patients had histologically proven HCC, no prior treatment except for surgery, and no more than three tumors (each measured ≤ 7 cm, total tumor volume ≤ 200 cm3). They were treated percutaneously under ultrasound or computed tomography (CT) guidance, with up to 10 mL of CDDP-EPI gel (1 mL contains 4 mg of CDDP and 0.1 mg of EPI) per treatment and four treatments in 6 weeks to a maximum of eight treatments. The primary end points were tumor response, defined by change of percentage of tumor necrosis according to CT criteria, and safety. Survival parameters were secondary end points.

Results: From June 1997 to April 2000, 58 patients (median age, 65 years) entered the study. All patients were assessable for safety, and 51 were assessable for efficacy. The median number of treatments was four (range, one to eight treatments). Objective response rate was 53% (27 of 51 patients), including 16 complete and 11 partial responses. Of the 27 responders, 14 (52%) subsequently developed progressive disease, but in most of them (93%), a new tumor arose at untreated liver sites. Median survival was 27 months (range, 18.4 to 35.7 months). The 1-, 2-, and 3-year survival rates were 79%, 56%, and 14% respectively. The procedure was well tolerated with only minor side effects.

Conclusion: Percutaneous local ablation with CDDP-EPI injectable gel can induce significant tumor necrosis and local control for localized unresectable HCC, and the treatment is well tolerated.
Effect of Endothelin-A Receptor Blockade With Atrasentan on Tumor Progression in Men With Hormone-Refractory Prostate Cancer: A Randomized, Phase II, Placebo-Controlled Trial
Authors: Carducci Michael A. , Padley Robert J. , Breul Jurgen , Vogelzang Nicholas J. , Zonnenberg Bernard A. , Daliani Danai D. , Schulman Claude C. , Nabulsi Azmi A. , Humerickhouse Rod A. , Weinberg Mark A. , Schmitt Jennifer L. , Nelson Joel B.
Published: February 2003

Purpose: To evaluate the efficacy and safety of atrasentan (ABT-627), an endothelin-A receptor antagonist, in the treatment of asymptomatic, hormone-refractory prostatic adenocarcinoma.

Patients and Methods: A double-blind, randomized, placebo-controlled clinical trial of hormone-refractory prostate cancer (HRPCa) patients was conducted in the United States and Europe. Two hundred eighty-eight asymptomatic patients with HRPCa and evidence of metastatic disease were randomly assigned to one of three study groups receiving a once-daily oral dose of placebo, 2.5 mg atrasentan, or 10 mg atrasentan, respectively. Primary end point was time to progression; secondary end points included time to prostate-specific antigen (PSA) progression, bone scan changes, and changes in bone and tumor markers.

Results: The three treatment groups were similar in all baseline characteristics. Median time to progression in intent-to-treat (ITT) patients (n = 288) was longer in the 10-mg atrasentan group compared with the placebo group: 183 v 137 days, respectively; (P = .13). Median time to progression in evaluable patients (n = 244) was significantly prolonged, from 129 days (placebo group) to 196 days (10-mg atrasentan group; P = .021). For both ITT and evaluable populations in the 10-mg atrasentan group, median time to PSA progression was twice that of the placebo group (155 v 71 days; P = .002). Patients who received placebo continued to have significant increases from baseline in serum (lactate dehydrogenase [LDH]), a marker of disease burden; elevations in LDH were uniformly attenuated by atrasentan in the ITT population. Headache, peripheral edema, and rhinitis were primary side effects, typically of mild to moderate severity. Quality of life was not adversely affected by atrasentan.

Conclusion: Atrasentan is an oral, targeted therapy with favorable tolerability and the potential to delay progression of HRPCa.
Radical Cystectomy for Bladder Cancer Today—A Homogeneous Series Without Neoadjuvant Therapy
Authors: Madersbacher Stephan , Hochreiter Werner , Burkhard Fiona , Thalmann George N. , Danuser Hansjörg , Markwalder Regula , Studer Urs E.
Published: February 2003

Purpose: To investigate the effect of pelvic lymph node dissection and radical cystectomy for transitional cell cancer of the bladder on recurrence-free and overall survival, pelvic recurrences, and metastatic patterns in a homogeneous group.

Patients and Methods: A consecutive series of patients undergoing pelvic lymphadenectomy and radical cystectomy between 1985 and 2000 was analyzed. All patients were staged N0, M0 preoperatively, and no patient received neoadjuvant radio/chemotherapy. Pathologic characteristics based on the 1997 tumor-node-metastasis system, recurrence-free/overall survival, and metastatic patterns were determined.

Results: Five hundred seven patients (age 66 ± 12 years) with a mean follow-up time of 45 months (range, 0.1 to 176 months) were analyzed. Five-year recurrence-free and overall survival were, respectively, 73% and 62% for patients with organ-confined, lymph node-negative tumors (n = 217; ≤ pT2, pN0) and 56% and 49% for non-organ-confined, lymph node-negative tumors (n = 166; > pT2, pN0). Positive lymph nodes were found in 124 (24%) patients who had a 5-year recurrence-free (33%) or overall (26%) survival. Isolated local recurrences were observed in 3% of patients with organ-confined tumors (≤ pT2, pN0), 11% with non-organ-confined tumors (> pT2, pN0), and 13% with positive lymph nodes (any pT, pN+). Distant metastases developed in 25% of patients with organ-confined tumors, 37% with non-organ-confined tumors, and 51% with positive lymph nodes.

Conclusion: Despite negative preoperative staging, pelvic lymphadenectomy and cystectomy for bladder cancer reveal a high percentage of unsuspected nodal metastases (24%) that have a 25% chance for long-term survival. This procedure also ensures a low pelvic recurrence rate even in lymph node-positive patients, and patients with locally advanced cancer have a 56% probability of 5-year recurrence-free survival.
Dysadherin Overexpression in Pancreatic Ductal Adenocarcinoma Reflects Tumor Aggressiveness: Relationship to E-Cadherin Expression
Authors: Shimamura Takeshi , Sakamoto Michiie , Ino Yoshinori , Sato Yasuto , Shimada Kazuaki , Kosuge Tomoo , Sekihara Hisahiko , Hirohashi Setsuo
Published: February 2003

Purpose: The E-cadherin-mediated cell adhesion system is frequently inactivated by multiple mechanisms and is involved in tumor progression in many types of cancer. Recently, we reported the cloning and characterization of dysadherin and showed that it downregulated E-cadherin and promoted metastasis. The aim of this study was to investigate the clinical significance of dysadherin expression and the relationship between dysadherin expression and E-cadherin expression in pancreatic ductal adenocarcinoma.

Patients and Methods: We examined dysadherin and E-cadherin expression in 125 surgically resected pancreatic ductal adenocarcinoma patients using immunohistochemistry.

Results: Dysadherin was expressed at the cell membrane of cancer cells, but not in nontumor duct and acinar cells. Its expression was stronger in infiltrative and poorly differentiated nests compared with well-differentiated nests. Although the correlation between the expression of dysadherin and E-cadherin was not significant, a group of patients showed reduced E-cadherin expression with dysadherin overexpression. Increased dysadherin expression was significantly correlated with distant metastasis (P = .047), high tumor grade (P = .006), positive tumor margins (P = .024), and infiltrative type of growth pattern (P = .014). A survival advantage was observed in patients with 0% to 20% dysadherin-positive cells compared with patients with 51% to 100% dysadherin-positive cells, independent of tumor-node-metastasis classification, and World Health Organization tumor grade (P = .019). A combination of increased dysadherin expression and reduced E-cadherin expression (< 90%) further worsened the prognosis.

Conclusion: In pancreatic ductal adenocarcinoma, dysadherin expression seems to reflect tumor aggressiveness and to be a positive marker of poor prognosis when considered both alone and in combination with downregulation of E-cadherin.
Intravesical Gemcitabine Therapy for Superficial Transitional Cell Carcinoma of the Bladder: A Phase I and Pharmacokinetic Study
Authors: Laufer Menachem , Ramalingam Sakkaraiappan , Schoenberg Mark P. , Haisfield-Wolf Mary Ellen , Zuhowski Eleanor G. , Trueheart Irene N. , Eisenberger Mario A. , Nativ Ofer , Egorin Merrill J.
Published: February 2003

Purpose: To determine maximum-tolerated dose, toxicities, and pharmacokinetics associated with weekly intravesical gemcitabine therapy in patients with superficial bladder cancer.

Patients and Methods: Fifteen patients with recurrent superficial transitional cell bladder carcinoma who experienced prior intravesical therapy failure were studied. Two to 4 weeks after complete transurethral resection, gemcitabine was administered intravesically, once weekly for 6 consecutive weeks. Dwell time was 2 hours. Pharmacokinetics of gemcitabine and its metabolite, 2′2′-difluorodeoxyuridine (dFdU), were studied in plasma and urine. Cystoscopy was repeated 6 weeks after therapy.

Results: Three-patient cohorts were enrolled sequentially at doses of 500, 1,000, and 1,500 mg in 100 mL 0.9% NaCl. Two patients received 2,000 mg in 100 mL. An additional four patients received 2,000 mg in 50 mL. No grade 4 toxicity or clinically relevant myelosuppression was noted. Nine of 13 evaluable patients were recurrence-free at 12 weeks. Low concentrations of gemcitabine (≤ 1 μg/mL) were present transiently in plasma of all patients receiving 2,000 mg in 50 mL. Gemcitabine was undetectable in plasma of other patients. dFdU was undetectable in plasma of patients receiving less than 1,500 mg. At doses ≥ 1,500 mg, dFdU concentrations increased until 90 to 120 minutes and then declined little, if any. Plasma dFdU concentrations implied absorption of 0.5% to 5.5% of instilled dose. Between 61% and 100% of the gemcitabine dose was accounted for in voided urine. No dFdU was measured in voided urine.

Conclusion: Intravesical gemcitabine, at doses up to 2 g/wk, is well tolerated, is associated with minimal systemic absorption, and has promising efficacy in treatment of superficial bladder cancer.
Evidence for a Role of the Adenosine 5′-Triphosphate-Binding Cassette Transporter A1 in the Externalization of Annexin I from Pituitary Folliculo-Stellate Cells
Authors: Chapman Lee P. , Epton Matthew J. , Buckingham Julia C. , Morris John F. , Christian Helen C.
Published: February 2003

Annexin 1 (ANXA1) has a well-demonstrated role in early delayed inhibitory feedback of glucocorticoids in the pituitary. ANXA1 is located in folliculo-stellate (FS) cells, and glucocorticoids act on these cells to externalize and stimulate the synthesis of ANXA1. However, ANXA1 lacks a signal sequence so the mechanism by which ANXA1 is externalized from FS cells was unknown and has been investigated. The ATP-binding cassette (ABC) transporters are a large group of transporters with varied roles that include the externalization of proteins. Glucocorticoid-induced externalization of ANXA1 from an FS cell line (TtT/GF) and rat anterior pituitary was blocked by glyburide, which inhibits ABC transporters. Glyburide also blocked the glucocorticoid inhibition of forskolin-stimulated ACTH release from pituitary tissue in vitro. RT-PCR revealed mRNA and Western blotting demonstrated protein for the ATP binding cassette A1 (ABCA1) transporter in mouse FS, TtT/GF, and A549 lung adenocarcinoma cells from which glucocorticoids also induce externalization of ANXA1. In TtT/GF cells, immunofluorescence labeling revealed a near total colocalization of cell surface ANXA1 and ABCA1. We conclude that ANXA1, which mediates the early delayed feedback of glucocorticoids in the anterior pituitary, is externalized from FS cells by an ABC transporter and that the ABCA1 transporter is a likely candidate.
Regulation of Iodothyronine Deiodinases in the Pax8−/− Mouse Model of Congenital Hypothyroidism
Authors: Friedrichsen Sönke , Christ Stephanie , Heuer Heike , Schäfer Martin K. H. , Mansouri Ahmed , Bauer Karl , Visser Theo J.
Published: February 2003

Thyroid hormones are essential for a variety of developmental and metabolic processes. Congenital hypothyroidism (CHT) results in severe defects in the development of different tissues, in particular brain. As an animal model for CHT, we studied Pax8−/− mice, which are born without a thyroid gland. We determined the expression of iodothyronine deiodinase D1 in liver and kidney, D2 in brain and pituitary, and D3 in brain, as well as serum T4, T3, and rT3 levels in Pax8−/−vs. control mice during the first 3 wk of life. In control mice, serum T4 and T3 were undetectable on the day of birth (d 0) and increased to maximum levels on d 15. In Pax8−/− mice, serum T4 and T3 remained below detection limits. Serum rT3 was high on d 0 in both groups and rapidly decreased in Pax8−/−, but not in control mice. Hepatic and renal D1 activities and mRNA levels were low on d 0 and increased in control mice roughly parallel to serum T4 and T3 levels. In Pax8−/− mice, tissue D1 activities and mRNA levels remained low. Cerebral D2 activities were low on d 0 and increased to maximum levels on d 15, which were approximately 10-fold higher in Pax8−/− than in control mice. D2 mRNA levels were higher in Pax8−/− than in control mice only on d 21. Cerebral D3 activities and mRNA levels were high on d 0 and showed a moderate decrease between d 3 and 15, with values slightly lower in Pax8−/− than in control mice. One day after the injection of 200 ng T4 or 20 ng T3/g body weight, tissue deiodinase activities and mRNA levels were at least partially restored toward control levels, with the exception of cerebral D3 activity. In conclusion, these findings show dramatic age and thyroid state-dependent changes in the expression of deiodinases in central and peripheral tissues of mice during the first 3 wk of life.
Dose-Dependent Inhibition by Ghrelin of Insulin Secretion in the Mouse
Authors: Reimer Martina Kvist , Pacini Giovanni , Ahrén Bo
Published: February 2003

Ghrelin is produced by stomach oxyntic cells and thought to be involved in the regulation of body weight and food intake. We demonstrate here that the peptide inhibits insulin secretion from overnight-incubated mouse islets in the presence of 8.3, 11.1, and 22.2 mmol/liter glucose. Ghrelin was most efficient at 1 nmol/liter and its effect disappeared by raising the dose more than 25 nmol/liter. Also, insulin secretion in the presence of high K+ concentrations (20 mmol/liter) was inhibited by ghrelin. Furthermore, when administered iv to mice together with glucose (1 g/kg), ghrelin (50 nmol/kg) inhibited both the rapid 1-min insulin response (364 ± 90 vs. 985 ± 114 pmol/liter in controls, P < 0.001) and the area under the 50 min curve of insulin concentration (12.6 ± 1.2 vs. 15.6 ± 1.2 nmol/liter × 50 min; P = 0.046) without affecting the glucose disposal rate, insulin sensitivity or glucose effectiveness, i.e. glucose disposal independent from any dynamic change in insulin. The insulinostatic effect of ghrelin was inversely related to insulin sensitivity. In contrast, ghrelin had no influence at the lower dose of 5 nmol/kg and only slightly inhibited insulin secretion at the higher dose of 150 nmol/kg. These findings therefore show that ghrelin inhibits glucose-stimulated insulin secretion in the mouse. The effect is dependent on the dose and elicited on distal signaling steps in islet cells. The results suggest that the islet β-cells are targets for ghrelin.
Proopiomelanocortin-Derived Peptides in Rat Cerebrospinal Fluid and Hypothalamic Extracts: Evidence that Secretion Is Regulated with Respect to Energy Balance
Authors: Pritchard Lynn E. , Oliver Robert L. , McLoughlin Julie D. , Birtles Susan , Lawrence Catherine B. , Turnbull Andrew V. , White Anne
Published: February 2003

Regulation of proopiomelanocortin (POMC) is an important means of controlling the central melanocortin system. It has never been established whether the spectrum of POMC-derived peptides synthesized and secreted from the hypothalamus is altered in response to changes in energy homeostasis in vivo. To monitor secretion, we analyzed peptide content of rat cerebrospinal fluid. Strikingly, both the POMC precursor and ACTH were readily detected. Moreover, levels of both were lower in samples from obese Zucker rats (fa/fa) vs. lean Zucker rats (+/+, fa/+) and from fasted vs. fed rats, whereas αMSH could not be detected. POMC levels were also decreased in hypothalamic extracts from obese and fasted animals. In contrast, despite being the most predominant peptide in extracts, αMSH levels weren’t significantly changed in any of the rat models. The ratio of precursor to derived peptides in cerebrospinal fluid was significantly higher in obese vs. lean and fed vs. fasted rats, indicating that secretion of POMC-derived peptides is differentially down-regulated during negative energy balance. In contrast to peptide analysis, we found that POMC gene expression was not significantly decreased in fasted rat hypothalami. We conclude that regulation of peptide secretion is an important mechanism by which the POMC system is controlled.
A Role for Galanin-Like Peptide in the Integration of Feeding, Body Weight Regulation, and Reproduction in the Mouse
Authors: Krasnow Stephanie M. , Fraley Gregory S. , Schuh Sonya M. , Baumgartner James W. , Clifton Donald K. , Steiner Robert A.
Published: February 2003

Galanin-like peptide (GALP) shares sequence homology with galanin and binds to galanin receptors in vitro. GALP neurons in the arcuate nucleus coexpress leptin receptors, and GALP mRNA expression is up-regulated by leptin. Based on these observations, we postulated that GALP plays a role in mediating leptin’s inhibitory effects on food intake (FI) and body weight (BW), as well as its stimulatory effect on the reproductive axis. To test these hypotheses, we performed several studies in which mice received intracerebroventricular injections of either GALP or vehicle. Acute GALP treatment elicited a dose-dependent suppression of FI and BW. Long-term treatment with GALP caused only transient reductions in FI and BW, demonstrating that the mice became refractory to continued exposure to GALP. GALP inhibited FI as early as 1 h post injection. Central injection of GALP suppressed locomotor activity and elicited the formation of a conditioned taste aversion. In male mice, serum levels of LH and testosterone were increased by GALP administration. Although we cannot rule out possible nonspecific effects of GALP on FI, the present observations are consistent with the argument that GALP is a downstream effector of leptin’s actions within the central nervous system.
The Cystatin-Related Epididymal Spermatogenic Protein Inhibits the Serine Protease Prohormone Convertase 2
Authors: Cornwall Gail A. , Cameron Angus , Lindberg Iris , Hardy Daniel M. , Cormier Nathaly , Hsia Nelson
Published: February 2003

The cystatin-related epididymal spermatogenic (CRES) protein is related to the family 2 cystatins of the cystatin superfamily of cysteine protease inhibitors. However, CRES lacks sequences important for cysteine protease inhibitory activity and is specifically expressed in reproductive and neuroendocrine tissues. Thus, CRES is distinct from cystatins and may perform unique tissue-specific functions. The purpose of the present study was to determine whether CRES functions as a protease inhibitor in in vitro assays. In contrast to mouse recombinant cystatin C, recombinant CRES did not inhibit the cysteine proteases papain and cathepsin B, suggesting that it probably does not function as a typical cystatin. CRES, however, inhibited the serine protease prohormone convertase 2 (PC2), a protease involved in prohormone processing in the neuroendocrine system, whereas cystatin C showed no inhibition. CRES did not inhibit subtilisin, trypsin, or the convertase family members, PC1 and furin, indicating that it selectively inhibits PC2. Kinetic analysis showed that CRES is a competitive inhibitor of PC2 with a Ki of 25 nm. The removal of N-terminal sequences from CRES decreased its affinity for PC2, suggesting that the N terminus may be important for CRES to function as an inhibitor. These studies suggest that CRES is a cross-class inhibitor that may regulate proprotein processing within the reproductive and neuroendocrine systems.
Dynamic relocalization of the chromosomal passenger complex proteins inner centromere protein (INCENP) and aurora-B kinase during male mouse meiosis
Authors: Parra María Teresa , Viera Alberto , Gómez Rocío , Page Jesús , Carmena Mar , Earnshaw William C. , Rufas Julio S. , Suja José A.
Published: February 2003

INCENP and aurora-B kinase are two chromosomal passenger proteins that are thought to play key roles in coordinating chromosome segregation with cytokinesis in somatic cells. Here we have analyzed their subcellular distribution, and that of phosphorylated histone H3, and the timing of their relative appearance in mouse spermatocytes during both meiotic divisions. Our results show that in mitotic spermatogonial cells, INCENP and aurora-B show the same pattern of distribution as they do in cultured somatic cells. INCENP labels the synaptonemal complex central element from zygotene up to late pachytene when it begins to relocalize to heterochromatic chromocentres. Aurora-B first appears at chromocentres in late diplotene before the initial phosphorylation of histone H3. INCENP and aurora-B concentrate at centromeres during diakinesis and appear during metaphase I as T-shaped signals at their inner domains, just below associated sister kinetochores. During late anaphase I both proteins relocalize to the spindle midzone. Both proteins colocalize at a connecting strand traversing the centromere region and joining sister kinetochores, in metaphase II centromeres. This strand disappears at the metaphase II/anaphase II transition and relocalizes to the spindle midzone. We discuss the complex dynamic relocalization of the chromosomal passenger complex during prophase I. Additionally, we suggest that this complex may regulate sister-chromatid centromere cohesion during both meiotic divisions.
Cyclic flow characteristics in an idealized asymmetric abdominal aortic aneurysm model
Authors: Yip T H , Yu S C M
Published: February 2003

The flow characteristics and the corresponding hydrodynamic stability in an idealized asymmetric abdominal aortic aneurysm (AAA) model have been investigated using a laser Doppler anemometer. A rectified sine waveform was used to simulate aortic flow conditions (Reδ = 806 and α = 12.2). The flow around the distal neck of the AAA model undergoes transition and becomes turbulent for a fraction of time shortly after the commencement of the deceleration phases at every flow cycle while the rest of the flow inside the model stayed laminar throughout the cycle. As a result of non-symmetric vortical structure development inside the model, the distribution of turbulent shear stresses was found to be highly uneven along the radial direction of the model; this is in contrast to results found by the present authors in the symmetrical AAA model. The maximum turbulent shear stress found at the straight side of the distal neck are four times more than the maximum turbulent shear stress measured at the most dilated side of the distal neck. One of the interesting biological implications of the results is that the outward dilation of the arterial wall may be a physiological response to avoid the high turbulent shear load from the momentarily turbulent blood flow.
Contact stresses in the glenoid component in total shoulder arthroplasty
Authors: Swieszkowski W , Bednarz P , Prendergast P J
Published: February 2003

Several studies of retrieved glenoid components from total shoulder arthroplasty show an erosion of the rim, surface irregularities, component fracture and wear resulting from polyethylene deformation in vivo. Particles resulting from polyethylene wear might be one of the reasons for the very high rate of glenoid component loosening found clinically. Because wear can be the result of high contact stresses, the aim of this study is to find out whether or not contact stresses are high enough to cause wear of the glenoid component and what influence the component type and geometry have on polyethylene contact stresses for different humerus abduction angles. Elasticity theory is used in a parametric study of contact stresses in several glenoid component designs. A finite element method is used to confirm the accuracy of the analytical solution. The analysis shows that the peak stress generated in glenoid components under conditions of normal living can be as high as 25 MPa; since this exceeds the polyethylene yield strength, wear and also cold flow of the components can be expected. It is predicted that more conforming components have lower contact stresses, which might result in lower wear rate and less cold flow. It is also found that a metal-backed component promotes higher contact stresses than an all-polyethylene component with the same total thickness, therefore it can be expected that metal-backed components have inferior wear properties.
Alkylation and Acetal Formation Using Supercritical Alcohol without Catalyst
Authors: Horikawa Yoshiteru , Uchino Yuki , Sako Takeshi
Published: February 2003

The aromatic ring alkylation of phenols, N-alkylation of aniline, O-alkylation of phenols and acetal formation from acetaldehyde or acetone were examined using supercritical (SC) alcohol without any catalyst. Highly selective syntheses of monoalkylated compounds were achieved for the aromatic ring alkylation and N-alkylation. The O-alkylation proceeded more preferentially than the aromatic ring alkylation for phenols which have a deactivating group. The acetal formation went on in more than 96% selectivity.
Enantioselective Photopinacolization of Benzophenone and Benzhydrol Intercalated in Mg–Al LDH Interlayers
Authors: Shichi Tetsuya , Minamikawa Yukiko , Yasuda Naoto , Yamada Naoya , Okamoto Yoshio , Takagi Katsuhiko
Published: February 2003

A novel enantioselective photochemical pinacolization utilizing the interlayer spaces of layered double hydroxide (LDH) was investigated. UV irradiation of (+)-4-(α-hydroxy-α-phenyl)methylbenzoate [benzhydrol-4-carboxylate] ions (d-BHA) with 4-benzoylbenzoate ions (BBA) gave rise to the formation of (−)-1,2-bis(4-carboxyphenyl)-1,2-bisphenyl-1,2-ethanediol (l-benzopinacol) in the LDH interlayers. Similarly, l-BHA reacts with BBA to give d-benzopinacol in the LDH. A maximum optical yield of over 60%ee was observed at the initial reaction stage.
Origin of nucleolus‐like bodies found in the nucleoplasm and cytoplasm of Vicia faba meristematic cells
Authors: SATO Seiichi , WILLSON Clare , DICKINSON Hugh G.
Published: February 2003

Cytohistochemical staining and RNase‐gold labelling have been applied to root‐tip meristematic cells of Vicia faba to study the origin and biological significance of 2 types of inclusions: one seen in the nucleoplasm and the other in the cytoplasm of early telophase cells. They have been termed “dense bodies” and “cytoplasmic nucleolus‐like bodies” (NLB), respectively. Both types of inclusions respond positively to silver staining and ribonucleoprotein (RNP) staining in a similar fashion to nucleolus. Interestingly, the dense bodies label heavily with the RNase‐gold complex, as does the nucleolus, while the cytoplasmic NLB have no affinity with the label. In most cases, the dense bodies label more heavily than the nucleolus. Light microscope surveys reveal that the dense bodies sometimes appear to be released from the surface of the nucleolus. On the other hand, prenucleolar material showing the same silver staining and RNP preferential staining characteristics as the dense bodies begin to accumulate on the surface of chromosomes in mid‐anaphase. This material does not label with RNase‐gold. These data are discussed in terms of the hypothesis that the dense bodies are derived from the nucleolus by direct budding or fragmentation, and the cytoplasmic NLB are composed of prenucleolar material that failed to attach to chromosomes.
DNA‐FLUORESCENCE OF MAMMALIAN INTRA‐NUCLEOLAR CHROMATIN DETECTED BY CONFOCAL LASER SCANNING MICROSCOPY (CLSM)
Authors: SPRING Herbert , TRENDELENBURG Michael F. , MONTAG Markus
Published: February 2003

The complex spatial DNA distribution in the mammalian interphase nucleus was investigated in Feulgen stained thick sections through mouse trophoblast giant nuclei after Lowicryl embedding. DNA‐fluorescence was visualized using confocal laser scanning microscopy. Our results show that the spatial arrangement of major interphase chromatin areas can be precisely documented, including the distribution of small intra‐nucleolar chromatin zones.
Polarizing microscope study of a contractile nanofilament system: the Acantharian myoneme
Authors: Febvre Jean , Febvre‐Chevalier Colette , Sato Hidemi
Published: February 2003

Summary—

Birefringence changes have been studied during the contraction—relaxation cycle of the myonemes (contractile organelles consisting of a bundle of nonactin filaments) in Acantharians (Protista, Actinopoda). Myonemes can either contract rapidly or undulate slowly between their anchorage points. In thin sections they appear as a large cross‐striated bundle with long clear zones (LZs) and thin transversal dense bands (TBs). The filaments (2–4 nm in diameter) are twisted in pairs in elementary microstrands. The spacing of the LZ depends on the extent of contraction [16]. A negative birefringence has been seen in vivo and in vitro. In vivo, retardation varied with the extent of relaxation of the myoneme (2.5 nm−4.4 nm). When the myoneme was tightened, it appeared to be homogeneously dark or bright in contrast depending on the orientation for the vibrating plane of polarized light. When it was partially relaxed and moved slowly, a series of birefringent bands, 0.8–2.8 μm thick, could be seen. They propagated at the same speed (about 2 μm·s−1) by successive trains, either forward or backward. Each of these birefringent bands may correspond to 4–13 contracted LZs. It is suggested that the negative birefringence of the myoneme is mainly caused by the orientation of the filaments forming the microstrands. Our results strongly suggest that the orientation of the myoneme filaments is altered during the movement and that the orientation of the filaments in the negative bands is caused by perpendicular orientation compared to the other parts of the myoneme. These observations support our previous hypothesis in which we postulated that the length of the myoneme varies in relation to the pitch of the elementary microstrands.