bluuebunny/crossref_metadata_2025 huggingface dataset:
Prostatic intraepithelial neoplasia and intestinal metaplasia in prostates of probasin‐RAS transgenic mice
Authors: Scherl Alexis , Li Jiu‐Feng , Cardiff Robert D. , Schreiber‐Agus Nicole
Published: March 2004

BACKGROUND

Activation of the RAS pathway has been implicated in the pathogenesis of many types of human cancers, including prostate cancer. Here we employed a transgenic approach to assess the potential contribution of RAS to prostate carcinogenesis.

METHODS

Probasin‐RAS (Pb‐RAS) transgenic mice were generated and shown to express high levels of activated RAS in the prostate lobes. Transgenic prostates were compared to normal controls by histology and immunohistochemistry with relevant markers.

RESULTS

Pb‐RAS transgenic prostates exhibit neoplastic changes including low‐grade prostatic intraepithelial neoplasia, and metaplastic changes towards an intestinal goblet cell phenotype. The finding of high levels of the goblet cell‐specific peptide Itf/Tff3 in these transgenic prostates is in accordance with recent microarray studies showing that ITF/TFF3 is upregulated in human prostate cancer samples.

CONCLUSIONS

The Pb‐RAS mouse model could be useful for elucidating the early events in prostate carcinogenesis, as well as for studying the mechanisms and potential prostate cancer relevance of intestinal metaplasia. © 2004 Wiley‐Liss, Inc.
Prostate cancer and polymorphism D85Y in gene for dihydrotestosterone degrading enzyme UGT2B15: Frequency of DD homozygotes increases with Gleason Score
Authors: Hajdinjak Tine , Zagradišnik Boris
Published: March 2004

BACKGROUND

Although, a functional rationale for influence of polymorphism D85Y in gene UGT2B15 on prostate cancer (PCa) exists (different Vmax of enzyme), conflicting results have been reported.

METHODS

DNA from 178 controls and 206 PCa patients with known Gleason score were genotyped using a newly developed RFLP assay, which allowed the detection of both alleles in an individual after single PCR amplification.

RESULTS

Controls: 16% DD, 52% DY; PCa patients: 23% DD, 49% DY. Subgroups of PCa: well differentiated: 11% DD, 37% DY; moderately differentiated: 22% DD, 50% DY; poorly differentiated: 34% DD, 50% DY. Correlation was confirmed between Gleason score and number of D alleles (P = 0.018) and persisted after age adjustment. When comparing controls to patients with a Gleason score of 7 or more, difference for the frequency of homozygosity DD was significant between the groups (P = 0.032, OR = 2.04).

CONCLUSIONS

Polymorphism D85Y in gene UGT2B15 correlates with differentiation of PCa. © 2004 Wiley‐Liss, Inc.
NY‐ESO‐1 protein expression and humoral immune responses in prostate cancer
Authors: Fosså Alexander , Berner Aasmund , Fosså Sophie D. , Hernes Eivor , Gaudernack Gustav , Smeland Erlend B.
Published: March 2004

BACKGROUND

Due to restricted expression in normal tissues cancer/testis (C/T) antigens represent candidate molecules for immunotherapy of cancer. NY‐ESO‐1 is a well‐studied C/T antigen with unknown expression and immunogenicity in prostate cancer (PC) patients.

METHODS

NY‐ESO‐1 expression was determined by immunohistochemistry and humoral immune responses against NY‐ESO‐1 assessed by enzyme‐linked immuno‐sorbent assay (ELISA) and Western blotting. Protein expression and serological responses were correlated with clinical findings and survival.

RESULTS

NY‐ESO‐1 expression was found in biopsies from 2 of 66 localized PC and 7/48 hormone refractory prostate cancer (HRPC) patients, respectively. Anti‐NY‐ESO‐1 antibodies were detected in sera from 1 of 112 localized PC and 18 of 95 HRPC patients. Two of four HRPC patients with NY‐ESO‐1 positive biopsies had mounted a serological response. Positive anti‐NY‐ESO‐1 titers were correlated with poor survival in HRPC patients.

CONCLUSIONS

NY‐ESO‐1 is expressed in a subset of HRPC patients and, together with other C/T antigens, may serve as a target antigen for development of immunotherapy of PC. Spontaneous serological responses against NY‐ESO‐1 may be associated with poor survival. © 2004 Wiley‐Liss, Inc.
Dielectric relaxation of KH2PO4 above room temperature
Authors: Diosa J. E. , Vargas R. A. , Albinsson I. , Mellander B.‐E.
Published: March 2004

The dispersion curves of the dielectric response of KH2PO4 were obtained from 5 Hz to 13 MHz and over the temperature range 120–206 °C for both single crystal and polycrystalline samples. Both types of samples reveal dielectric relaxation at low frequency, for example around 104 Hz at 140 °C, which shifts to higher frequencies (∼1 MHz) as the temperature increases. The relaxation frequency was determined from the peak obtained in the imaginary part of the permittivity as well as from the derivative of the real part of the permittivity. The activation energy Ea = 0.82 eV, obtained from the relaxation frequency is very close to that derived from the dc conductivity. We suggest that this dielectric relaxation could be due to the proton jump and phosphate reorientation that causes distortion and change the local lattice polarizability inducing dipoles like . (© 2004 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Thermal and spin transports in spin‐½ extended XY chain
Authors: Lou Ping
Published: March 2004

The thermal and spin Drude weights of the spin‐½ extended XY chain with three‐spin interaction model [Euro. Phys Jour. B 32, 383 (2003)] are solved exactly. It is shown that the competition between the two‐spin and three‐spin interactions in the system influences the calculated quantities and leads to its characteristic features near the quantum critical point. (© 2004 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
The spin‐3/2 Blume–Emery–Griffiths model with repulsive biquadratic coupling in an external field
Authors: Ekiz C.
Published: March 2004

The spin‐3/2 Blume–Emery–Griffiths model is solved on the Bethe lattice in the absence and presence of the external field using the iteration technique (recursion method). The phase diagrams are obtained for the coordination number q = 3, 4, 6 and 8. We confirm the existence of a staggered quadrupolar phase in addition to a ferrimagnetic and ferromagnetic ordered phases and analyze the occurence of re‐entrant boundaries inside the ordered region as a character of the coordination of the lattice. A comparison is made with the results of other approximate methods. (© 2004 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Studies on the adhesion between polytetra‐fluoroethylene film and silanized glass foil
Authors: Zhang Lihui , Chen Yashao , Dong Tao
Published: March 2004

Adhesion of plasma‐pretreated polytetrafluoroethylene (PTFE) films to glass foils silanized with 3‐aminopropyltriethoxysilane (APS) was demonstrated via thermally induced surface graft polymerization with concurrent lamination. The simultaneous thermal grafting and lamination process was carried out under atmospheric conditions in the presence of pure acrylic acid (AAc) or aqueous solutions of acrylamide (AAm) and in the absence of polymerization initiator. The chemical composition and microstructure of the modified PTFE films and glass foils were characterized by XPS. The effects of the plasma pretreatment time for the substrates, thermal grafting/lamination temperature and time and graft monomers on the adhesion strength of the PTFE/APS‐glass junction were studied. The adhesion strengths of PTFE/APS‐glass assemblies were significantly improved in the presence of AAc or AAm. The 180° peel adhesion strength of the PTFE/AAc/APS‐glass and the PTFE/AAm/APS‐glass assemblies can reach about 11.2 and 4.6 N cm−1, respectively. Analysis of the mechanically delaminated surfaces by XPS suggests that the failure modes of both assemblies involve mainly the cohesive failure in the PTFE substrate and some very small adhesion failure in the graft layer. Copyright © 2004 John Wiley & Sons, Ltd.
Theoretical analysis of interface energy for unrelaxed Ag(001)/Ni(001) twist interface boundaries with MAEAM
Authors: Ma Fei , Zhang Jian‐Min , Xu Ke‐Wei
Published: March 2004

Interfacial energies for unrelaxed Ag(001)/Ni(001) twist interface boundaries with near‐coincidence site lattices have been calculated using the modified analytical embedded atom method (MAEAM). The results show that the interfacial energies are strongly dependent on the azimuthal misorientation θ. The first six lowest interfacial energies correspond to θ = 10.3, 15.26, 6.34, 37.88, 26.57 and 12.34°, which correspond to the coincidence interface boundaries of Σ = 25/20, 13/10, 41/32, 13/10, 5/4 and 37/29, respectively. Considering only the interfacial energy, we can predict that these interface boundaries are successively preferable for epitaxial growth of silver film on (001)‐oriented nickel substrate. Copyright © 2004 John Wiley & Sons, Ltd.
After‐school as intermediary space: Theory and typology of partnerships
Authors: Noam Gil G. , Rosenbaum Tillinger Jodi
Published: March 2004

This chapter explores the nature of after‐school partnerships and sets forth a theory and typology describing the way in which the intersection of partners creates a unique intermediary space.
Ototoxicity of Ototopical Antibiotic Drops in Humans
Authors: Matz Greg , Rybak Leonard , Roland Peter S. , Hannley Maureen , Friedman Rick , Manolidis Spiros , Stewart Michael G. , Weber Peter , Owens Fred
Published: March 2004

OBJECTIVE

We sought to determine the incidence of injury to the cochlea or vestibular system from the use of ototopic antibiotic ear drops.

STUDY DESIGN

We conducted a MEDLINE search of the published literature from 1966 to the present using the search items of “ototopic antibiotics,” “ototopic drops,” “antibiotic resistance,” and others to identify pertinent articles. These articles were reviewed and graded according to evidence quality. Forty‐four articles were found; 27 articles were considered appropriate for review and 14 of these articles were thought to warrant further extensive review. The latter 14 articles dealt directly with the evaluation of either hearing loss or changes in vestibular function after the use of ototopic ear drops. We eliminated studies that did not consider hearing or vestibular function. We considered only articles in the English language, eliminating articles that not address the ototoxicity of ototopical ear drops.

RESULTS

Most of these articles were in the level 3 to 3b category. Two of the articles were in the 1b category, evaluating evidence‐based studies. An article that reviewed case reports of ototopical oto‐toxicity and a survey article are included in this study, as case reports of ototopical ototoxicity and survey articles.

CONCLUSION

We found a total of 54 cases of gentamicin vestibular toxicity and, in 24 of these patients, cochlear toxicity was also documented. Our review also found 11 cases of cochlear and 2 cases of vestibular toxicity in neomycin‐based ear drops.
An empirical model to predict the UV‐index based on solar zenith angles and total ozone
Authors: Allaart Marc , van Weele Michiel , Fortuin Paul , Kelder Hennie
Published: March 2004

The clear sky UV‐index is expressed as a function of two predictable quantities: the solar zenith angle and total ozone. This function is derived by fitting the measurements of total ozone and the UV‐index obtained from two instruments, one in the mid‐latitudes and one in the tropics. The shape of the function was chosen so that it represents the essentials of the underlying physics. This new function gives good results for all solar zenith angles between 0° and 90° and a wide range of total ozone values. Copyright © 2004 Royal Meteorological Society.
Two different methods to correct the initial conditions applied to the storm of 27 December 1999 over southern France
Authors: Hello G. , Arbogast P.
Published: March 2004

In strong baroclinic flows, small errors in the initial conditions may grow rapidly and lead to large forecast errors even at very short ranges. It is therefore of crucial importance that these initial conditions are determined carefully. In this paper we use two different but complementary methods to improve the operational analysis of a storm that caused loss of life and much material damage in France on 27 December 1999. The first method is based on the adjoint technique: an adjoint model‐run provides the sensitivity of one aspect of the forecast (the cost function) to the initial conditions. We then apply a correction whose shape is the sensitivity so that the corrected initial state better fits the observations. The second method is based on the Quasi‐Geostrophic Potential Vorticity (QGPV) inversion. A misfit between the model analysis and satellite pictures (water vapour Meteosat images, for example) leads to the subjective modification of some of the features of the potential vorticity field. The analysis is modified using the wind and temperature corrections provided by the inversion of the QGPV correction. Both methods significantly improve the forecast and may provide valuable guidance for forecasters in real time. Copyright © 2004 Royal Meteorological Society.
Suicide Risk in Patients with Somatization Disorder
Authors: Chioqueta Andrea P. , Stiles Tore C.
Published: March 2004

Summary: The aim of the study was to assess suicide risk in psychiatric outpatients with and without somatization disorder. A total sample of 120 psychiatric outpatients was used in the study, 29 of whom met diagnostic criteria for somatization disorder. The results indicated that somatization disorder was significantly associated with suicide attempts even when the effects of both a comorbid major depressive disorder and a comorbid personality disorder were statistically controlled for. The results suggest that, although a patient meets the criteria for a principal diagnosis of major depressive disorder and/or a personality disorder, it is still of significant importance to decide whether or not the patient also meets the criteria for a somatization disorder in order to more optimally assess suicide risk. The findings highlight the fact that the potential for suicide in patients with somatization disorder should not be overlooked when a diagnosable depressive disorder or personality disorder is not present.
Motives for Suicide—A Study of Australian Suicide Notes
Authors: Lester David , Wood Priscilla , Williams Christopher , Haines Janet
Published: March 2004

Summary: Analysis of a large sample of suicide notes from 262 suicides in Australia found that men less often had escape from pain as a motive for their suicides and more often had love/romantic problems. The suicides of older persons were more often motivated by escape from pain and less often had love/romantic problems.
Gesundheitsökonomische Studien in der Dermatologie – Review der Literatur, Bewertung und zugrunde liegende Aspekte der Durchführung
Authors: Rogalski Christina , Paasch Uwe , Simon Jan Christoph
Published: March 2004

Hintergrund: Behandlungsergebnisse werden mittels gesundheitsökonomischer Evaluationen objektiviert, um sie in einen wirtschaftlichen Kontext zu bringen. Gesundheitsökonomische Studien stellen einen abstrahierenden Prozeßärztlichen und pflegerischen Handelns dar, der den rationalen Umgang mit knappen Ressourcen unterstützen soll, und sollten daher vermehrt durchgeführt werden.

Methoden: Die durch Literaturrecherche gefundenen Veröffentlichungen gesundheitsökonomischer, dermatologischer Studien wurden bezüglich des Durchführungslandes, der Finanzierung, dem Durchführungszeitraum sowie dem Intervall bis zur Publikation analysiert und ein quantitativer Vergleich mit anderen Fachrichtungen vorgenommen. Anhand einer Checkliste von Kernkriterien wurde eine qualitative Einschätzung der Studien durchgeführt, um die Aussagekraft zu beurteilen.

Ergebnisse: Die Zahl der dermatologischen, gesundheitsökonomischen Studien hat sich in den letzten 20 Jahren verfünffacht. Knapp ein Drittel der untersuchten dermatologischen Studien (n = 71) wurden in den USA durchgeführt, 23,94 % in Großbritannien, 9,86 % in Schweden und 35,23 % in anderen Ländern. Das Zeitintervall bis zur Publikation betrug 0 bis 9 Jahre.

Schlußfolgerungen: Der Anstieg in der Studienzahl läßt sich möglicherweise durch den zunehmenden Klärungsbedarf der wirtschaftlichen Situation im Gesundheitssektor erklären. Die Ursache für den gravierenden Unterschied zwischen den Staaten liegt möglicherweise in der Finanzierung beziehungsweise im vorherrschenden Gesundheitssystem der durchgeführten Studien. Während in den USA die Studien überwiegend durch die pharmazeutische Industrie finanziert werden, ist es in Großbritannien und Schweden eher die öffentliche Hand. Die erhebliche Verzögerung der Publikation könnte zum einen durch lange Review‐Phasen, zum anderen durch den Transfer sowie die Auswertung großer Datenmengen bei internationalen Studien bedingt sein.

Insbesondere im Rahmen der Einführung der Diagnosis Related Groups in Deutschland ist ein wirtschaftlich verantwortungsvolles Handeln auf der Basis fundierter und qualitativ hochwertiger gesundheitsökonomischer Studien unerläßlich.
Do Mountains Exist? Towards an Ontology of Landforms
Authors: Smith Barry , Mark David M
Published: March 2004

The authors begin the paper with the question ‘Do mountains exist?’ They show that providing an answer to this question is surprisingly difficult and that the answer that one gives depends on the context in which the question is posed. Mountains clearly exist as real correlates of everyday human thought and action, and they form the archetype for geographic objects. Yet individual mountains lack many of the properties that characterize bona fide objects, and ‘mountains’ as a category also lacks many of the properties that characterize natural kinds. In the context of scientific modeling of the environment, especially of such phenomena as surface hydrology and fluvial erosion and deposition, mountains are not picked out as constituents of reality in their own right at all; rather, they are just parts of the field of elevations whose gradients shape the direction of runoff and influence the intensity of erosion. Thus, although an object-based ontology of mountains and other landforms is required to do justice to our everyday conceptions of the environment and to support spatial reasoning and natural language processing, topographic databases designed to support environmental modeling can be field-based at geographic scales.
Signatures of selection among sex-determining alleles of the honey bee
Authors: Hasselmann Martin , Beye Martin
Published: March 2004

Patterns of DNA polymorphisms are a primary tool for dissecting signatures of selection; however, the underlying selective forces are poorly understood for most genes. A classical example of diversifying selection is the complementary sex-determining locus that is found in the very large insect order Hymenoptera (bees, wasps, ants, and sawflies). The gene responsible for sex determination, the
complementary sex determiner
(
csd
), has been most recently identified in the honey bee. Females are heterozygous at this locus. Males result when there is only one functional allele present, as a result of either homozygosity (fertilized eggs) or, more commonly, hemizygosity (unfertilized eggs). The homozygotes, diploid males, do not reproduce and have zero fitness, which implies positive selection in favor of rare alleles. Large differences in
csd
cDNA sequences within and between four populations were found that fall into two major groups, types I and II. Type I consists of several allelic lineages that were maintained over an extended period, an indication of balancing selection. Diversifying selection has operated on several confined parts of the protein, as shown by an excess of nonsynonymous differences. Elevated sequence differences indicate another selected part near a repeat region. These findings have general implications about the understanding of both the function of the multiallelic mechanism and the adaptive processes on the level of nucleotide sequences. Moreover, the first
csd
sequence data are a notable basis for the avoidance of diploid males in bee selection programs by allele-assisted breeding.
The strong Nagata conjecture
Authors: Umirbaev Ualbai U. , Yu Jie-Tai
Published: March 2004

It is proved that there exist wild coordinates in the polynomial algebra in three variables over a field of characteristic zero. This result implies the famous Nagata conjecture.
Visual memory task for rats reveals an essential role for hippocampus and perirhinal cortex
Authors: Prusky G. T. , Douglas R. M. , Nelson L. , Shabanpoor A. , Sutherland R. J.
Published: March 2004

Visual recognition memory is subserved by a distributed set of neural circuits, which include structures of the temporal lobe. Conflicting experimental results regarding the role of the hippocampus in nonspatial forms of such memories have been attributed to species, task, and lesion discrepancies. We have overcome obstacles that have prevented a direct evaluation of the role of the hippocampus in this type of memory by developing for rats a nonspatial, picture-based, trial-unique, delayed matching-to-sample task that is a procedural analogue of standard visual recognition memory tasks used in primates. With this task, we demonstrate that rats have a visual memory profile, which is analogous to that in primates and depends on the function of perirhinal cortex. We also find that selective lesions of hippocampus impair delay-dependent visual memory with a profile different from that produced by damage to the perirhinal cortex. These data demonstrate that rats have a visual recognition memory system fundamentally similar to primates that depends on the function of the hippocampus.
Self-renewal capacity is a widespread property of various types of neural crest precursor cells
Authors: Trentin Andréa , Glavieux-Pardanaud Corinne , Le Douarin Nicole M. , Dupin Elisabeth
Published: March 2004

In vertebrates, trunk neural crest (NC) generates glia, neurons, and melanocytes. In addition, it yields mesectodermal derivatives (connective tissues, chondrocytes, and myofibroblasts lining the blood vessels) in the head. Previous
in vitro
clonal analyses of avian NC cells unraveled a hierarchical succession of highly pluripotent, followed by various intermediate, progenitors, suggesting a model of progressive restrictions in the multiple potentialities of a totipotent stem cell, as prevails in the hematopoietic system. However, which progenitors are able to self-renew within the hierarchy of the NC lineages is still undetermined. Here, we explored further the stem cell properties of quail NC cells by means of
in vitro
serial subcloning. We identified types of multipotent and oligopotent NC progenitors that differ in their developmental repertoire, ability to self-maintain, and response to exogenous endothelin 3 according to their truncal or cephalic origin. The most striking result is that bipotent progenitors are endowed with self-renewal properties. Thus glia–melanocyte and glia–myofibroblast progenitors behave like stem cells in that they are able both to self-renew and generate a restricted progeny. In our culture conditions, glia–myofibroblast precursors display a modest capacity to self-renew, whereas glia–melanocyte precursors respond to endothelin 3 by extensive self-renewal. These findings may explain the etiology of certain multiphenotypic NC-derived tumors in humans. Moreover, the presence of multiple stem cell phenotypes along the NC-derived lineages may account for the rarity of the “totipotent NC stem cell” and may be related to the large variety and widespread dispersion of NC derivatives throughout the body.
Differential dependence of CD4
+
CD25
+
regulatory and natural killer-like T cells on signals leading to NF-κB activation
Authors: Schmidt-Supprian Marc , Tian Jane , Grant Ethan P. , Pasparakis Manolis , Maehr René , Ovaa Huib , Ploegh Hidde L. , Coyle Anthony J. , Rajewsky Klaus
Published: March 2004

Natural killer-like (NK) T, regulatory T (T
R
), and memory type T cells display surface phenotypes reminiscent of activated T cells. Previously, we reported that the generation of T
R
cells and, to a lesser extent, of memory type T cells, depends on IκB kinase 2. Here, we show that T cell-specific ablation of IκB kinase 2, in addition, completely precludes NKT cell development. T cell antigen receptor (TCR)-induced signals to activate NF-κB are essential for mature T cell activation, leading us to hypothesize that this pathway could play an important role in the generation of the antigen-driven T cell subsets comprising T
R
, memory type T, and NKT cells. TCR-mediated NF-κB activation critically depends on Bcl10 and PKCθ. By using mice deficient for these proteins, we demonstrate that the generation of T
R
and, to a lesser extent, of memory type T cells, depends on Bcl10 and PKCθ, and therefore, most likely on NF-κB activation initiated by TCR engagement. NKT cells, on the other hand, require PKCθ for thymic development, whereas absence of Bcl10 leads primarily to the reduction of peripheral NKT cell numbers.
The arginine finger of bacteriophage T7 gene 4 helicase: Role in energy coupling
Authors: Crampton Donald J. , Guo Shenyuan , Johnson Donald E. , Richardson Charles C.
Published: March 2004

The DNA helicase encoded by gene 4 of bacteriophage T7 couples DNA unwinding to the hydrolysis of dTTP. The loss of coupling in the presence of orthovanadate (Vi) suggests that the γ-phosphate of dTTP plays an important role in this mechanism. The crystal structure of the hexameric helicase shows Arg-522, located at the subunit interface, positioned to interact with the γ-phosphate of bound nucleoside 5′ triphosphate. In this respect, it is analogous to arginine fingers found in other nucleotide-hydrolyzing enzymes. When Arg-522 is replaced with alanine (gp4-R522A) or lysine (gp4-R522K), the rate of dTTP hydrolysis is significantly decreased. dTTPase activity of the altered proteins is not inhibited by Vi, suggesting the loss of an interaction between Vi and gene 4 protein. gp4-R522A cannot unwind DNA, whereas gp4-R522K does so, proportionate to its dTTPase activity. However, gp4-R522K cannot stimulate T7 polymerase activity on double-stranded DNA. These findings support the involvement of the Arg-522 residue in the energy coupling mechanism.
Reconstruction of functionally normal and malignant human breast tissues in mice
Authors: Kuperwasser Charlotte , Chavarria Tony , Wu Min , Magrane Greg , Gray Joe W. , Carey Loucinda , Richardson Andrea , Weinberg Robert A.
Published: March 2004

The study of normal breast epithelial morphogenesis and carcinogenesis
in vivo
has largely used rodent models. Efforts at studying mammary morphogenesis and cancer with xenotransplanted human epithelial cells have failed to recapitulate the full extent of development seen in the human breast. We have developed an orthotopic xenograft model in which both the stromal and epithelial components of the reconstructed mammary gland are of human origin. Genetic modification of human stromal cells before the implantation of ostensibly normal human mammary epithelial cells resulted in the outgrowth of benign and malignant lesions. This experimental model allows for studies of human epithelial morphogenesis and differentiation
in vivo
and underscores the critical role of heterotypic interactions in human breast development and carcinogenesis.
Constitutive p21-activated Kinase (PAK) Activation in Breast Cancer Cells as a Result of Mislocalization of PAK to Focal Adhesions
Authors: Stofega Mary R. , Sanders Luraynne C. , Gardiner Elisabeth M. , Bokoch Gary M.
Published: March 2004

Cytoskeletal remodeling is critical for cell adhesion, spreading, and motility. p21-activated kinase (PAK), an effector molecule of the Rho GTPases Rac and Cdc42, has been implicated in cytoskeletal remodeling and cell motility. PAK kinase activity and subcellular distribution are tightly regulated by rapid and transient localized Rac and Cdc42 activation, and by interactions mediated by adapter proteins. Here, we show that endogenous PAK is constitutively activated in certain breast cancer cell lines and that this active PAK is mislocalized to atypical focal adhesions in the absence of high levels of activated Rho GTPases. PAK localization to focal adhesions in these cells is independent of PAK kinase activity, NCK binding, or GTPase binding, but requires the association of PAK with PIX. Disruption of the PAK–PIX interaction with competitive peptides displaces PAK from focal adhesions and results in a substantial reduction in PAK hyperactivity. Moreover, disruption of the PAK–PIX interaction is associated with a dramatic decrease of PIX and paxillin in focal adhesions, indicating that PAK localization to these structures via PIX is required for the maintenance of paxillin- and PIX-containing focal adhesions. Abnormal regulation of PAK localization and activity may contribute to the tumorigenic properties of certain breast cancer cells.
Loss of Apm1, the μ1 Subunit of the Clathrin-Associated Adaptor-Protein-1 Complex, Causes Distinct Phenotypes and Synthetic Lethality with Calcineurin Deletion in Fission Yeast
Authors: Kita Ayako , Sugiura Reiko , Shoji Hiromi , He Yi , Deng Lu , Lu Yabin , Sio Susie O. , Takegawa Kaoru , Sakaue Motoyoshi , Shuntoh Hisato , Kuno Takayoshi
Published: March 2004

Calcineurin is a highly conserved regulator of Ca2+signaling in eukaryotes. In fission yeast, calcineurin is not essential for viability but is required for cytokinesis and Cl-homeostasis. In a genetic screen for mutations that are synthetically lethal with calcineurin deletion, we isolated a mutant, cis1-1/apm1-1, an allele of the apm1+gene that encodes a homolog of the mammalian μ1A subunit of the clathrin-associated adaptor protein-1 (AP-1) complex. The cis1-1/apm1-1 mutant as well as the apm1-deleted (Δapm1) cells showed distinct phenotypes: temperature sensitivity; tacrolimus (FK506) sensitivity; and pleiotropic defects in cytokinesis, cell integrity, and vacuole fusion. Electron micrographs revealed that Δapm1 cells showed large vesicular structures associated with Golgi stacks and accumulated post-Golgi secretory vesicles. Δapm1 cells also showed the massive accumulation of the exocytic v-SNARE Syb1 in the Golgi/endosomes and a reduced secretion of acid phosphatase. These phenotypes observed in apm1 mutations were accentuated upon temperature up-shift and FK506 treatment. Notably, Apm1-GFP localized to the Golgi/endosomes, the spindle pole bodies, and the medial region. These findings suggest a role for Apm1 associated with the Golgi/endosome function, thereby affecting various cellular processes, including secretion, cytokinesis, vacuole fusion, and cell integrity and also suggest that calcineurin is involved in these events.
Cytoplasmic Dynein Nucleates Microtubules to Organize Them into Radial Arrays In Vivo
Authors: Malikov Viacheslav , Kashina Anna , Rodionov Vladimir
Published: March 2004

Numerous evidence demonstrates that dynein is crucial for organization of microtubules (MTs) into radial arrays, but its exact function in this process is unclear. Here, we studied the role of cytoplasmic dynein in MT radial array formation in the absence of the centrosome. We found that dynein is a potent MT nucleator in vitro and that stimulation of dynein activity in cytoplasmic fragments of melanophores induces nucleation-dependent formation of MT radial array in the absence of the centrosome. This new property of dynein, in combination with its known role as an MT motor that is essential for MT array organization in the absence and presence of the centrosome, makes it a unique molecule whose activity is necessary and sufficient for the formation and maintenance of MT radial arrays in cells.
A case study of high-throughput biological data processing on parallel platforms
Authors: Pekurovsky D. , Shindyalov I. N. , Bourne P. E.
Published: March 2004

Motivation: Analysis of large biological data sets using a variety of parallel processor computer architectures is a common task in bioinformatics. The efficiency of the analysis can be significantly improved by properly handling redundancy present in these data combined with taking advantage of the unique features of these compute architectures.

Results: We describe a generalized approach to this analysis, but present specific results using the program CEPAR, an efficient implementation of the Combinatorial Extension algorithm in a massively parallel (PAR) mode for finding pairwise protein structure similarities and aligning protein structures from the Protein Data Bank. CEPAR design and implementation are described and results provided for the efficiency of the algorithm when run on a large number of processors.

Availability: Source code is available by contacting one of the authors.
Comparison of Suture and Nasal Packing in Rabbit Noses
Authors: Genç Erkhan , Ergin N. Tan , Bilezikçi Banu
Published: March 2004

Objectives/Hypothesis The study aimed to detect the changes in adult rabbit nasal septal tissues after application of nasal pack or trans‐septal suture as performed during septoplasty.

Study Design Randomized double‐blind animal study.

Methods Thirty‐three adult albino Vienna rabbits were assigned into the following groups: control, suture, and nasal pack. The mucoperichondrium at one side of the nasal septum was elevated and then put into place again over the cartilage and fixed with either a nasal pack or an absorbable trans‐septal suture. The nasal packs were removed 48 hours after insertion. Rabbits were killed 6 weeks after the procedure. The nasal septa were stained with hematoxylin and eosin and examined by means of light microscopy for mucosal changes (inflammation or damage) and for thicknesses of the mucosa, the perichondrium, and the cartilage.

Results Both intranasal packs and sutures caused significant mucosal inflammation and damage when compared with the control group (χ2 test, P < .05). The mucosal thickness did not change, but the perichondrial thickness for both the nasal pack group and the suture group increased (Mann‐Whitney U test, P < .05). Also, the septal cartilage thickness was not significantly different between the suture and the nasal pack groups, but the suture group had a thinner septal cartilage than the control group (Mann‐Whitney U test, P < .05).

Conclusion The septal suture is an efficient and useful method for clinching the septal flaps over the septal cartilage. In addition, it has nearly the same effects as nasal packs on the histological appearance of the nasal septum and does not cause discomfort for the patient. The septal suture can be a preferred alternative to intranasal packing.
Airway Protection and the Laryngeal Mask Airway in Sinus and Nasal Surgery
Authors: Kaplan Andrew , Crosby Gregory J. , Bhattacharyya Neil
Published: March 2004

Objectives/Hypothesis The objective was to compare the laryngeal mask airway and endotracheal tube for airway protection from blood during sinonasal surgery.

Study Design Nonrandomized, controlled, prospective clinical trial.

Methods Patients scheduled to undergo sinonasal surgery (septoplasty and/or endoscopic sinus surgery) were prospectively enrolled and grouped according to type of airway during general anesthesia with choice of airway device based on the anesthesiologist's preference. Clinical data were tabulated by case including airway device, patient age, weight, estimated blood loss, airway pop‐off pressure, and emergence quality. At the conclusion of surgery, the airway was examined through the laryngeal mask airway or endotracheal tube with a flexible fiberoptic bronchoscope to determine the amount of blood present on the vocal cords or in the trachea. The airway device was also evaluated postoperatively for the presence of blood.

Results Seventy‐six adult patients were initially enrolled; two were excluded because fiberoptic evaluation of the airway could not be completed. Of the remaining 74 patients, an endotracheal tube and laryngeal mask airway were used in 31 and 43 patients, respectively. The two groups did not differ with respect to age, weight, estimated blood loss during surgery, pop‐off pressure, or emergence quality (all P > .05). Patients managed with an laryngeal mask airway were significantly less likely to have blood staining the airway (glottis or trachea) than patients with an endotracheal tube (19.5% vs. 84.8%, χ2 test [P < .001]). However, the endotracheal tube provided better protection than the laryngeal mask airway against distal tracheal blood contamination (3.2% vs. 14.6%, respectively [P = .110]).

Conclusion The laryngeal mask airway provides better protection of the upper airway from blood contamination during sinonasal surgery than a standard endotracheal tube, but there is a higher incidence of distal tracheal contamination. The laryngeal mask airway is a reasonable alternative to endotracheal intubation for airway management in sinonasal surgery.
Relationship of Petrous Temporal Bone Pneumatization to the Eustachian Tube Lumen
Authors: Jen Albert , Sanelli Pina C. , Banthia Vishal , Victor Jonathan D. , Selesnick Samuel H.
Published: March 2004

Objectives/Hypothesis Objectives were to determine the incidence of petrous apex pneumatization and to define the relationship between a pneumatized petrous temporal bone and the eustachian tube lumen.

Study Design Retrospective study with institutional review board approval including only adult patients.

Methods One hundred head computed tomography (ct) scans and 204 petrous temporal bone CT scans performed at a tertiary teaching hospital were reviewed. The two senior authors (s.h.s., p.c.s.) independently reviewed the petrous temporal bone CT scans for grade of pneumatization. Pneumatized CT scans were then reviewed for the presence of a direct communication with the eustachian tube lumen. Significance was determined using the χ2 test and Pearson correlation of ranks.

Results The incidence of peritubal cells opening into the eustachian tube anterior to the tympanic orifice was 92%.

Conclusion The direct communication of peritubal cells with the bony eustachian tube may play a role in the development of persistent cerebrospinal fluid rhinorrhea after cerebellopontine angle surgery.
The Impact of Laryngopharyngeal Reflux on Patient‐Reported Quality of Life
Authors: Carrau Ricardo L. , Khidr Aliaa , Crawley Joseph A. , Hillson Eric M. , Davis Judith K. , Pashos Chris L.
Published: March 2004

Objectives/Hypothesis The objectives were to assess patient‐reported outcomes, specifically, the health‐related quality of life of patients with laryngopharyngeal reflux, and to compare those reported levels with the health‐related quality of life of patients with gastroesophageal reflux disease and a general population.

Study Design Prospective study.

Methods As part of a prospective study to validate a health‐related quality of life instrument for laryngopharyngeal reflux, patient‐reported data were collected before the initiation of therapy. Use of the Short Form‐36 (SF‐36), a generic instrument, allowed the health‐related quality of life of the patients with laryngopharyngeal reflux to be compared with benchmarks existing for patients with gastroesophageal reflux disease and a general U.S. population.

Results The 117 patients with laryngopharyngeal reflux often reported multiple symptoms, most frequently, chronic throat‐clearing (85.5%), globus (82.1%), and hoarseness (80.3%). Their mean health‐related quality of life was statistically significantly worse than that of a general U.S. population in seven of the eight SF‐36 domains. The most dramatic differences between patients with laryngopharyngeal reflux and the general population were in social functioning and bodily pain (P < .001). Mean scores for patients with laryngopharyngeal reflux were significantly lower than those for patients with gastroesophageal reflux disease in social functioning (P < .001) and vitality (P = .0017). In five of the six remaining domains, patients with laryngopharyngeal reflux reported lower mean scores than did patients with gastroesophageal reflux disease, but those differences were not statistically significant.

Conclusion The study's assessment of health‐related quality of life suggests that laryngopharyngeal reflux has a significant negative impact on the lives of patients. Although its impact is similar in some respects to that of gastroesophageal reflux disease, laryngopharyngeal reflux has a more significant impact on patients' social functioning and vitality.
Vestibular Schwannoma Surgery Outcomes: Our Multidisciplinary Experience in 400 Cases Over 17 Years
Authors: Darrouzet Vincent , Martel Jacques , Enée Véronique , Bébéar Jean‐Pierre , Guérin Jean
Published: March 2004

Objectives/Hypothesis The aim of the study was to evaluate the incidence of short‐ and intermediate‐term postoperative complications after vestibular schwannoma surgery.

Study Design Retrospective review in a tertiary referral center.

Methods In 400 patients who underwent surgical removal of vestibular schwannoma from 1984 to 2000,

symptoms, preoperative evaluation, surgery, and postoperative complications were analyzed using standardized grading systems.

Results One hundred ninety‐four men and 206 women had an operation. Mean age was 53.9 years (age range, 11–78 y). Tumor size according to Koos stage was stage 1 in 39 cases, stage 2 in 122 cases, stage 3 in 87 cases, and stage 4 in 152 cases. Preoperatively, 7.5% of patients had facial nerve dysfunction. Surgical approaches were translabyrinthine in 229 patients, widened retrolabyrinthine in 128 cases, suboccipital in 42 cases, and transotic in 1 case. Mortality was 0.5%. Facial nerve was transected in 15 cases (3.7%) and immediately repaired in 5 cases. A delayed hypoglossal–to–facial nerve anastomosis was performed in 12 cases. At 1 year, House‐Brackmann grade in 70.7% of patients was 1 to 2; in 24.3%, 3 to 4; and in 5%, 5 to 6. Poor facial nerve outcome was correlated with tumor size, preoperative irradiation, and nerve dysfunction and was not correlated with the approach used. Most patients had postoperative dizziness, and 30% still had vestibular disturbances after 1 year. Nine patients (2.2%) had a cerebrospinal fluid rhinorrhea, and 24 had a cerebrospinal fluid wound leak (6%). Twenty‐two patients (5.5%) had postoperative meningitis. Two patients had a cerebellopontine angle hemorrhage, and three a brainstem infarct.

Conclusion Transpetrosal approaches (translabyrinthine, widened retrolabyrinthine) are safe for vestibular schwannoma removal, and rates of postoperative complications and sequelae are decreasing.
Timing of Human Insulin‐Like Growth Factor‐1 Gene Transfer in Reinnervating Laryngeal Muscle
Authors: Nakagawa Hideki , Shiotani Akihiro , O'Malley Bert W. , Coleman Michael E , Flint Paul W.
Published: March 2004

Objectives/Hypothesis The authors have designed a rat laryngeal paralysis model to study gene transfer strategies using a muscle‐specific expression system to enhance local delivery of human insulin‐like growth factor‐1 (hIGF‐1). In preliminary studies, a nonviral vector containing the α‐actin promoter and human hIGF‐1 sequence produced both neurotrophic and myotrophic effects 1 month after single injection of plasmid formulation into paralyzed rat thyroarytenoid muscle in vivo. Based on these findings, it is hypothesized that the effects of hIGF‐1 will enhance the results of laryngeal muscle innervation procedures. The timing of gene delivery relative to nerve repair is likely to be important, to optimize the results.

Study Design Prospective analysis.

Methods The effects of nonviral gene transfer for the delivery of hIGF‐1 were evaluated in rats treated immediately following recurrent laryngeal nerve transection and repair and in rats receiving a delayed treatment schedule, 30 days after nerve transection and repair. Gene transfer efficiency was determined using polymerase chain reaction and reverse transcriptase–polymerase chain reaction techniques. Muscle fiber diameter, motor endplate length, and percentage of motor endplates with nerve contact were examined to assess hIGF‐1 trophic effects.

Results Compared with reinnervated untreated control samples, both early and delayed hIGF‐1 transfer resulted in significant increase in muscle fiber diameter. Motor endplate length was significantly decreased and nerve/motor endplate contact was significantly increased following delayed gene transfer, but not after early treatment.

Conclusion We infer from results of the study that delayed hIGF‐1 gene transfer delivered by a single intramuscular injection will enhance the process of muscle reinnervation. The clinical relevance of these findings supports the future application of gene therapy using nonviral vectors for management of laryngeal paralysis and other peripheral nerve injuries.
A Facilitative Role for Corticosterone in the Acquisition of a Spatial Task Under Moderate Stress
Authors: Akirav Irit , Kozenicky Maya , Tal Dadi , Sandi Carmen , Venero Cesar , Richter-Levin Gal
Published: March 2004

Emotionally charged experiences alter memory storage via the activation of hormonal systems. Previously, we have shown that compared with rats trained for a massed spatial learning task in the water maze in warm water (25°C), animals that were trained in cold water (19°C) performed better and showed higher levels of the stress hormone corticosterone. Here, we examined whether manipulating the levels of corticosterone can determine the strength of spatial information acquisition and retention. Rats were injected with metyrapone (25, 50, and 75 mg/kg, i.p.) or with corticosterone (10 and 25 mg/kg, i.p.) and trained in a massed spatial task in either cold (19°C) or warm (25°C) water. We found that whereas animals injected with vehicle performed well in the spatial task in cold water (moderate stress), rats injected with the intermediate metyrapone dose showed impairment in performance. Moreover, whereas animals injected with vehicle on average did not perform well in warm water (mild stress), rats injected with the lower corticosterone dose showed improvement in performance in warm water. These two mirror experiments of corticosterone blockade and enhancement strongly suggest that corticosterone is instrumental in the acquisition and retention of the spatial learning task.
Human Central Auditory Plasticity Associated With Tone Sequence Learning
Authors: Gottselig Julie Marie , Brandeis Daniel , Hofer-Tinguely Gilberte , Borbély Alexander A. , Achermann Peter
Published: March 2004

We investigated learning-related changes in amplitude, scalp topography,
and source localization of the mismatch negativity (MMN), a neurophysiological
response correlated with auditory discrimination ability. Participants (n =
32) underwent two EEG recordings while they watched silent films and ignored
auditory stimuli. Stimuli were a standard (probability = 85%) and two deviant
(probability = 7.5% each for high [HD] and low [LD]) eight-tone sequences that
differed in the frequency of one tone. Between recordings, subjects practiced
discriminating the HD or LD from the standard for 6 min. The amplitude of the
LD MMN increased significantly across recordings in both groups, whereas the
amplitude of the HD MMN did not. The LD was easier to discriminate than was
the HD. Thus, practicing either discrimination increased the MMN for the
easier discrimination. Learning and changes in the LD MMN amplitude were
highly correlated. Source localizations of event-related potentials (ERPs) to
all stimuli revealed bilateral sources in superior temporal regions. Compared
with the standard ERP, the LD ERP revealed a stronger source in the left
superior temporal region in both recordings, whereas the right-sided source
became stronger after learning. Consistent with prior studies of auditory
plasticity in animals and humans, tone sequence learning induced rapid
neurophysiological plasticity in the human central auditory system. The
results also suggest that there is asymmetric hemispheric involvement in tone
sequence discrimination learning and that discrimination difficulty influences
the time course of learning-related neurophysiological changes.