bluuebunny/crossref_metadata_2025 huggingface dataset:
Bilateral corticospinal projections arise from each motor cortex in the macaque monkey: A quantitative study
Authors: Lacroix Steve , Havton Leif A. , McKay Heather , Yang Hong , Brant Adam , Roberts Jeffrey , Tuszynski Mark H.
Published: April 2004

The corticospinal projection is considered to influence fine motor function through nearly exclusively contralateral projections from the cortex in primates. However, unilateral lesions to this system in various species are frequently followed by significant functional improvement, raising the possibility that bilateral projections of this pathway may exist or emerge after injury. To examine the detailed anatomy and projections of the corticospinal motor neurons in rhesus monkeys (n = 4), we injected the high‐resolution anterograde tracer biotinylated dextran amine (BDA) into 126 sites centered about the right lower extremity (LE) primary motor cortex. Projection and termination patterns were quantified at lumbar levels L1, L4, and L7 and mapped by using serial‐section reconstructions. Notably, a mean of 10.1 ± 0.6% (± SEM) of corticospinal tract (CST) axons descended in the lateral CST ipsilateral to the cortical BDA injection, and 87.9 ± 1.0% of total CST axons projected in the contralateral lateral CST. The ipsilateral ventral CST contained only 1.0 ± 0% of all projecting CST axons, whereas the contralateral ventral CST contained 0.3 ± 0.2% of all axons. In addition, a minor dorsal column CST projection was identified. Measurement of BDA‐labeled terminals in the spinal cord gray matter revealed that 11.2 ± 2.2% of CST axons terminated ipsilateral to the side of cortical injection, and the remainder terminated contralaterally. As previously reported, most CST axons terminated in spinal cord laminae V–VIII, as well as the laterodorsal motoneuronal group of lamina IX (which innervates distal extremity muscles). Notably, many CST axons crossed the spinal cord midline (mean 19.9 ± 4.9 axons per 40‐μm‐thick section). Detailed single‐axon reconstructions revealed that most ipsilaterally projecting lateral CST axons terminated in ipsilateral gray matter. Notably, we found that the bouton‐like swellings of many ipsilateral CST axons descending in the dorsolateral tract were located within Rexed's lamina IX, in close proximity to motoneuronal somata. Thus, bilateral projections of corticospinal axons originating from a single motor cortex could contribute to bilateral control of spinal motor neurons and to the highly evolved degree of fine motor control in primates. Furthermore, bilateral CST projections from a single motor cortex could represent a potential source of plasticity after injury, as well as a target of therapeutic effort in neural regeneration strategies. J. Comp. Neurol. 473:147–161, 2004. © 2004 Wiley‐Liss, Inc.
Immunocytochemical localization of aromatase in sensory and integrating nuclei of the hindbrain in Japanese quail (Coturnix japonica)
Authors: Evrard Henry C. , Harada Nobuhiro , Balthazart Jacques
Published: April 2004

The distribution of the estrogen synthesizing enzyme (aromatase) in the hindbrain (rhombencephalon and mesencephalon) of male adult quail was investigated by immunocytochemistry. Aromatase‐immunoreactive neuronal structures (perikarya and fibers bearing punctate structures) were observed in sensory (trigeminal, solitary tract, vestibular, optic tectum) and integrating (parabrachial, periaqueductal, cerulean, raphe) nuclei. Besides the expression of aromatase in these well‐delineated nuclei, dense to scattered networks of immunoreactive fibers were found dispersed throughout the hindbrain and, in particular, in its rostral and dorsal parts. To a lesser extent, they were also present throughout the premotor nuclei of the reticular formation and in various fiber tracts. In contrast, no immunoreactive signal was found in motor nuclei, and in most of the statoacoustic (cerebellum, cochlear, olive, pontine, part of vestibular) nuclei. The expression of aromatase in perikarya and fibers in areas of the adult hindbrain where estrogen receptors have been identified previously suggests a role for estrogens locally produced in the regulation of sensory and integrating functions, contrary to the widespread assumption that these functions are regulated exclusively by steroids produced in the gonads. J. Comp. Neurol. 473:194–212, 2004. © 2004 Wiley‐Liss, Inc.
Prion protein (PrPc) immunocytochemistry and expression of the green fluorescent protein reporter gene under control of the bovine PrP gene promoter in the mouse brain
Authors: Bailly Yannick , Haeberlé Anne‐Marie , Blanquet‐Grossard Françoise , Chasserot‐Golaz Sylvette , Grant Nancy , Schulze Tobias , Bombarde Guy , Grassi Jacques , Cesbron Jean‐Yves , Lemaire‐Vieille Catherine
Published: April 2004

Expression of the cellular prion protein (PrPc) by host cells is required for prion replication and neuroinvasion in transmissible spongiform encephalopathies. As a consequence, identification of the cell types expressing PrPc is necessary to determine the target cells involved in the cerebral propagation of prion diseases. To identify the cells expressing PrPc in the mouse brain, the immunocytochemical localization of PrPc was investigated at the cellular and ultrastructural levels in several brain regions. In addition, we analyzed the expression pattern of a green fluorescent protein reporter gene under the control of regulatory sequences of the bovine prion protein gene in the brain of transgenic mice. By using a preembedding immunogold technique, neuronal PrPc was observed mainly bound to the cell surface and presynaptic sites. Dictyosomes and recycling organelles in most of the major neuron types also exhibited PrPc antigen. In the olfactory bulb, neocortex, putamen, hippocampus, thalamus, and cerebellum, the distribution pattern of both green fluorescent protein and PrPc immunoreactivity suggested that the transgenic regulatory sequences of the bovine PrP gene were sufficient to promote expression of the reporter gene in neurons that express immunodetectable endogenous PrPc. Transgenic mice expressing PrP‐GFP may thus provide attractive murine models for analyzing the transcriptional activity of the Prnp gene during prion infections as well as the anatomopathological kinetics of prion diseases. J. Comp. Neurol. 473:244–269, 2004. © 2004 Wiley‐Liss, Inc.
Prognostic markers in node‐negative breast cancer: A prospective study
Authors: Kute T. E. , Russell G. B. , Zbieranski N. , Long R. , Johnston S. , Williams H. , Stackhouse C. , Wilkins L. , Evans I. , Berry P. , Rimmer K. , Tucker E.
Published: April 2004

Background

Despite years of research, it is still unclear which women with node‐negative (N–) breast cancer will need adjuvant chemotherapy and which women are being treated unnecessarily. Our goal was to determine which factors best predicted disease free survival (DFS) or cancer‐specific overall survival (OS) and, therefore, select the correct patients for treatment. A total of 11 parameters were measured: estrogen receptor (ER), progesterone receptor (PR), age, race, ploidy status, %G0/G1 (% non‐DNA synthesis), %S (% S‐phase), cathepsin D status, size, stage, and histologic grade.

Results

In this prospective study, we followed 556 N– patients diagnosed between 1991 and 1996. The tumors were 56% ER+, 51% PR+, 30% diploid, with a mean %S of 8.9%. The level of cathepsin D ranged from 0.50 to 155 pmol/mg of protein with a mean of 42.9 pmol/mg of protein. There were 87 recurrences (16%) and 72 cancer deaths (13%), with a median follow‐up of 7.8 years. Ploidy status (p = 0.01), S‐phase activity (p = 0.003), G1 phase activity (p = 0.02) and age (p = 0.01) were able to significantly predict DFS in a univariate manner. All of the measurable factors were significant or borderline significant in predicting OS in a univariate manner except for age, race, and ER status. In multivariate analysis with S‐phase included, it was the only remaining factor in DFS and OS; with S‐phase excluded, age and ploidy status remained as factors for DFS in stepwise regression, while PR, size, and cathepsin D were the remaining factors that predicted cancer‐specific OS. The effect of adjuvant treatment on prognosis was also analyzed.

Conclusions

Both biochemical and clinical parameters have the potential to predict prognosis for N– breast cancer. In this large prospective clinical trial, with a median follow‐up of 7.8 years, no individual marker adequately predicted the prognosis for an individual patient. %S activity was the best independent marker, but only 77% of the tumors provided this value. Subset analysis provided improved prognostication, but there were limits to its utility. These data represents a definitive study starting in 1991 and ending in 2002. © 2004 Wiley‐Liss, Inc.
Experimental assessment of RED in wired/wireless networks
Authors: Zhang Chi , Khanna Manav , Tsaoussidis Vassilis
Published: April 2004

The Internet is a heterogeneous environment comprising wired and wireless components, and transport protocols with different error recovery strategies. We use simulations to study the behaviour of random early detection (RED) gateways in such heterogeneous environments. We investigate two issues: (i) the performance trade‐offs of the dropping policy of RED over Drop‐Tail's, and (ii) the impact of RED's active queue management on more sophisticated protocols such as TCP‐SACK. Some of our results indicate that RED does not deal adequately with heterogeneity. In particular, it may happen that RED applies congestion avoidance techniques even when wireless errors force some senders to back off prior to actual congestion. Our scenarios involve a non‐monotonic transmission behaviour of transport protocols within one and the same congestion epoch; RED may escalate further bandwidth under‐utilization by applying false congestion avoidance tactics. Furthermore, our results indicate that RED's dropping policy of ‘proportional’ fairness, which is realized through a Send‐more/Drop‐more scheme, can also penalize sophisticated protocols like TCP‐SACK, which attempt to recover more aggressively from wireless losses. In summary, our results call for further investigation of RED's efficiency in heterogeneous networks and naturally raise the concern of RED's compliance with the end‐to‐end argument. Copyright © 2004 John Wiley & Sons, Ltd.
Providing and verifying advanced IP services in hierarchical DiffServ networks‐the case of GEANT
Authors: Liakopoulos Athanassios , Maglaris Basil , Bouras Christos , Sevasti Afrodite
Published: April 2004

The differentiated services (DiffServ) framework is widely proposed as an efficient method for providing advanced IP services to large‐scale networks, with QoS requirements. However, the provisioning of such services in production networks has proved to be more difficult than initially expected, in defining, setting and verifying appropriate Service Level Agreements (SLAs). GEANT, the Gigabit core pan‐European research network, on a pilot basis introduced ‘Premium IP’ service, offering bounded delay and negligible packet loss to the European National Research & Education Networks (NRENs) that it interconnects. However, large scale provisioning of this new service requires the definition of efficient interaction procedures between administrative domains involved and methods for SLA monitoring. This paper focuses on these issues and presents the experience acquired from the early experiments in GEANT, as an example of hierarchical Gigabit multi‐domain environment, enabled with QoS provisioning to its constituent NRENs. This model scales more efficiently than the common peering Internet Service provider (ISP) commercial paradigm. Finally, we outline other options that promise QoS, such as Layer 2 VPNs in MPLS backbones, with non‐standard (yet) mechanisms. Copyright © 2004 John Wiley & Sons, Ltd.
Tropospheric ducting phenomena over the Hellenic region
Authors: Isaakidis Stergios A. , Xenos Thomas D. , Dris Nicholas A.
Published: April 2004

The variation of the refractivity profiles of the troposphere and especially of the ducting effect, affects the radio wave propagation causing various phenomena such as refraction, fading and interference between radio‐stations. In this work, the tropospheric ducting phenomena over the Hellenic region are studied using data from Helleniko and Thessaloniki Airports for the time period from 1991 to 1999. The data are analysed, corrected and enhanced using interpolation techniques and after a final statistical process the ducting conditions over the Hellenic region are summarized. Copyright © 2004 John Wiley & Sons, Ltd.
Thiamine and benfotiamine prevent increased apoptosis in endothelial cells and pericytes cultured in high glucose
Authors: Beltramo E. , Berrone E. , Buttiglieri S. , Porta M.
Published: April 2004

Background

High glucose induces pathological alterations in small and large vessels, possibly through increased formation of AGE, activation of aldose reductase and protein kinase C, and increased flux through the hexosamine pathway. We showed previously that thiamine and benfotiamine correct delayed replication and increase lactate production in endothelial cells subjected to high glucose. We now aim at verifying the effects of thiamine and benfotiamine on cell cycle, apoptosis, and expression of adhesion molecules in endothelial cells and pericytes, under high ambient glucose.

Methods

Human umbilical vein endothelial cells and bovine retinal pericytes were cultured in normal (5.6 mmol/L) or high (28 mmol/L) glucose, with or without thiamine or benfotiamine, 50 or 100 µmol/L. Apoptosis was determined by two separate ELISA methods, measuring DNA fragmentation and caspase‐3 activity, respectively. Cell cycle and integrin subunits α3, α5, and β1 concentration were measured by flow cytometry.

Results

Apoptosis was increased in high glucose after 3 days of culture, both in endothelium and pericytes. Thiamine and benfotiamine reversed such effects. Neither cell cycle traversal nor integrin concentrations were modified in these experimental conditions.

Conclusions

Thiamine and benfotiamine correct increased apoptosis due to high glucose in cultured vascular cells. Further elucidations of the mechanisms through which they work could help set the basis for clinical use of this vitamin in the prevention and/or treatment of diabetic microangiopathy. Copyright © 2004 John Wiley & Sons, Ltd.
Report of the National Institutes of Health workshop on overcoming barriers to treatment research in anorexia nervosa
Authors: Agras W. Stewart , Brandt Harry A. , Bulik Cynthia M. , Dolan‐Sewell Regina , Fairburn Christopher G. , Halmi Katherine A. , Herzog David B. , Jimerson David C. , Kaplan Allan S. , Kaye Walter H. , le Grange Daniel , Lock James , Mitchell James E. , Rudorfer Matthew V. , Street Linda L. , Striegel‐Moore Ruth , Vitousek Kelly M. , Walsh B. Timothy , Wilfley Denise E.
Published: April 2004

Objective

Anorexia nervosa (AN) is associated with serious medical morbidity and has the highest mortality rate of all psychiatric disorders. The National Institutes of Health (NIH) Workshop on Overcoming Barriers to Treatment Research in Anorexia Nervosa convened on September 26–27, 2002 to address the dearth of treatment research in this area. The goals of this workshop were to discuss the stages of illness and illness severity, pharmacologic interventions, psychological interventions, and methodologic considerations.

Method

The program consisted of a series of brief presentations by moderators, each followed by a discussion of the topic by workshop participants, facilitated by the session chair.

Results

This report summarizes the major discussions of these sessions and concludes with a set of recommendations related to the development of treatment research in AN based on these findings.

Discussion

It is crucial that treatment research in this area be prioritized. © 2004 by Wiley Periodicals, Inc. Int J Eat Disord 35: 509–521, 2004.
Sociocultural influences on attitudes to weight and eating: Results of a natural experiment
Authors: Wardle Jane , Watters Rachel
Published: April 2004

Objective

Exposure to teenage culture is widely believed to contribute to concerns about weight in children and adolescents. The current study tested the hypothesis that greater exposure to older girls at school would be associated with thinner size ideals, increased concern about weight, and more dieting.

Method

Participants (n = 200) were 9 and 11‐year‐old girls. The age of the oldest pupils in the school defined the exposure variable. Nine‐year‐olds in junior schools (oldest pupils = 11) and 11‐year‐olds in middle schools (oldest pupils = 13) were defined as nonexposed. Nine‐year‐olds in middle schools (oldest pupils = 13) and 11‐year‐olds in secondary schools (oldest pupils = 18) were defined as exposed. Girls were weighed and measured and completed measures of ideal size, perceived weight, body esteem, eating attitudes, dieting, and self‐esteem.

Results

Being at a school with older pupils was associated with having a thinner ideal, feeling more overweight, having more friends who had dieted, scoring higher on the Child Eating Attitudes Test, and having lower self‐esteem. Effects were strongest among the 9‐year‐olds.

Discussion

Exposure to older girls in school may accelerate the development of negative attitudes to weight and eating. © 2004 by Wiley Periodicals, Inc. Int J Eat Disord 35: 589–596, 2004.
Reliability assessment of the somatomorphic matrix
Authors: Cafri Guy , Roehrig Megan , Thompson J. Kevin
Published: April 2004

Objective

The appearance of muscularity is an emerging topic of research interest within the body image field. However, the most widely used measure to assess attitudes toward muscularity, the somatomorphic matrix, lacks pertinent reliability data.

Method

In response to this dearth of information, the current study assessed the test‐retest reliability of this measure in samples of men and women.

Results

Surprisingly, the somatomorphic matrix demonstrated inadequate reliability for the majority of assessed rating protocols.

Discussion

The implications of this finding on assessment of the muscularity construct are discussed. © 2004 by Wiley Periodicals, Inc. Int J Eat Disord 35: 597–600, 2004.
Network‐scale dynamics of grain‐size sorting: implications for downstream fining, stream‐profile concavity, and drainage basin morphology
Authors: Gasparini Nicole M. , Tucker Gregory E. , Bras Rafael L.
Published: April 2004

We explore the link between channel‐bed texture and river basin concavity in equilibrium catchments using a numerical landscape evolution model. Theory from homogeneous sediment transport predicts that river basin concavity directly increases with bed sediment size. If the effective grain size on a river bed governs its concavity, then natural phenomena such as grain‐size sorting and channel armouring should be linked to concavity. We examine this hypothesis by allowing the bed sediment texture to evolve in a transport‐limited regime using a two grain‐size mixture of sand and gravel. Downstream ﬁning through selective particle erosion is produced in equilibrium. As the channel‐bed texture adjusts downstream so does the local slope. Our model predicts that it is not the texture of the original sediment mixture that governs basin concavity. Rather, concavity is linked to the texture of the sorted surface layer. Two different textural regimes are produced in the experiments: a transitional regime where the mobility of sand and gravel changes with channel‐bed texture, and a sand‐dominated region where the mobility of sand and gravel is constant. The concavity of these regions varies depending on the median gravel‐ or sand‐grain size, erosion rate, and precipitation rate. The results highlight the importance of adjustments in both surface texture and slope in natural rivers in response to changes in ﬂuvial and sediment inputs throughout a drainage network. This adjustment can only be captured numerically using multiple grain sizes or empirical downstream ﬁning rules. Copyright © 2004 John Wiley & Sons, Ltd.
Coastal dune fields at the São Francisco River strandplain, northeastern Brazil: morphology and environmental controls
Authors: Barbosa Liana Maria , Dominguez José Maria Landim
Published: April 2004

Extensive coastal dune ﬁelds occur on the Quaternary strandplain associated with the São Francisco River mouth. Two different generations of dunes are identiﬁed. One is inactive, already ﬁxed by vegetation, comprising parabolic dunes. The other generation is active, bordering the present‐day shoreline and transgressing over the inactive dune ﬁeld. Three morphological provinces in the active coastal dune ﬁelds are recognized. On the updrift side of the São Francisco River mouth, they are: (a) sand‐sheet with shrub coppice and shadow dunes; (b) isolated dunes of the barchan‐transversal type up to 5 m high, and interdune areas; and (c) a 23 m high compound dune, with superimposed small dunes. The same provinces are recognized on the downdrift side of the river mouth, with two important exceptions: the barchan‐transversal and compound dunes are replaced, respectively, by (i) zibar‐type dunes up to 5 m high, and (ii) a 19 m high precipitation dune, which is associated with numerous blowouts. The prevailing eastern winds from August to January favour the development of the aeolian bedforms and the migration of dunes. The shoreline orientation almost transversal to the winds and the great supply of ﬁne‐grained sediments contribute to the formation of barchan‐transversal types and compound dunes in the updrift side. On the other hand, in the downdrift side the shoreline orientation is almost parallel to the prevailing winds. This fact, in association with a coarser grain size in the beachface, favours the formation of zibar‐type and precipitation dunes with numerous blowouts. The rate of migration of individual dunes is about 20 to 24 m per year. This study suggests that the aeolian sedimentation is a relatively recent phenomenon at the Quaternary strandplain of the São Francisco River. The ﬁrst generation of dune ﬁelds initiated some time after 3000 years BP and the second generation originated some centuries ago. Copyright © 2004 John Wiley & Sons, Ltd.
Geomorphological surfaces of different age and origin in granite landscapes: an evaluation of the Schmidt hammer test
Authors: Ericson Kerstin
Published: April 2004

Granite landforms in Sierra Nevada, California, and the southern part of Sweden were used to test whether a Schmidt hammer can be used to distinguish surfaces of different age and origin. Based on 3260 readings, statistically signiﬁcant differences were obtained from surfaces formed and/or affected by different geomorphological processes. Aeolian, ﬂuvial or glacially polished surfaces yield higher values than surfaces exposed to surface weathering, which are distinguishable from surfaces at a weathering front caused by deep weathering. Copyright © 2004 John Wiley & Sons, Ltd.
Rational regime model of alluvial channel morphology and response
Authors: Eaton Brett C. , Church Michael , Millar Robert G.
Published: April 2004

A theoretical model is developed for predicting equilibrium alluvial channel form. The concept of greatest relative stability, achieved by maximizing resistance to ﬂow in the ﬂuvial system, is presented as the basis for an optimization condition for alluvial systems. Discharge, sediment supply (quantity and calibre) and valley gradient are accepted as independent governing variates. The model is used to deﬁne a dimensionless alluvial state space characterized by aspect ratio (W/d), relative roughness (D/d), and dimensionless shear stress (τ*) or, equivalently, channel slope (S). Each alluvial state exhibits unique values of Froude number and sediment concentration. The range of alluvial states for constant values of relative bank strength (parameterized by an apparent friction angle, ϕ′) forms a single plane in the state space (W/d, D/d, τ* or S). The scaling relations produced by the model are consistent with laboratory channels exhibiting a range of bank strengths, and with the behaviour of natural channels. Copyright © 2004 John Wiley & Sons, Ltd.
Robustness of alternative non‐linearity tests for SETAR models
Authors: Chan Wai‐Sum , Ng Man‐Wai
Published: April 2004

In recent years there has been a growing interest in exploiting potential forecast gains from the non‐linear structure of self‐exciting threshold autoregressive (SETAR) models. Statistical tests have been proposed in the literature to help analysts check for the presence of SETAR‐type non‐linearities in an observed time series. It is important to study the power and robustness properties of these tests since erroneous test results might lead to misspecified prediction problems. In this paper we investigate the robustness properties of several commonly used non‐linearity tests. Both the robustness with respect to outlying observations and the robustness with respect to model specification are considered. The power comparison of these testing procedures is carried out using Monte Carlo simulation. The results indicate that all of the existing tests are not robust to outliers and model misspecification. Finally, an empirical application applies the statistical tests to stock market returns of the four little dragons (Hong Kong, South Korea, Singapore and Taiwan) in East Asia. The non‐linearity tests fail to provide consistent conclusions most of the time. The results in this article stress the need for a more robust test for SETAR‐type non‐linearity in time series analysis and forecasting. Copyright © 2004 John Wiley & Sons, Ltd.
Entorhinal deafferentation induces the expression of profilin mRNA in the reactive microglial cells in the hippocampus
Authors: Dong Jing‐Hui , Ying Guo‐Xin , Zhou Chang‐Fu
Published: April 2004

Profilin has been identified as an actin monomer sequestering protein and is thought to be a key regulator of actin polymerization in many fundamental cellular processes. We report the expression of profilin mRNA in the murine hippocampus following transections of the entorhinal afferents. Northern blot analysis showed that transcript of profilin was upregulated in a transient manner in the deafferented rat hippocampus by 1.5‐, 1.9‐, 1.4‐, and 1.1‐fold of controls, respectively, at 1, 3, 7, and 15 days post‐lesion. In situ hybridization confirmed the temporal upregulation of profilin mRNA in the deafferented zones of the mouse hippocampus, which showed a remarkable increase as early as at 1 day post‐lesion, reached maximal level at 3 days post‐lesion, and returned to the control level at 15 days post‐lesion. The expression modulation of profilin mRNA was observed to occur specifically in the entorhinally denervated zones: the stratum lacunosum‐moleculare of the hippocampus and the outer molecular layer of the dentate gyrus. The combination of in situ hybridization for profilin mRNA with lectin cytochemistry for Griffonia simplicifolia IB4 showed that the cells expressing profilin transcript in the denervated zones are activated microglial cells. The results suggest that the spatial and temporal upregulation of profilin mRNA in the hippocampus is induced by entorhinal deafferentation and profilin is involved in microglial activation associated with morphological change, migration, and phagocytic behavior of microglial cells. © 2004 Wiley‐Liss, Inc.
Heterogeneity and potentiation of AMPA type of glutamate receptors in rat cultured microglia
Authors: Hagino Yukiko , Kariura Yukihiro , Manago Yoshimasa , Amano Taiju , Wang Bing , Sekiguchi Masayuki , Nishikawa Kaori , Aoki Shunsuke , Wada Keiji , Noda Mami
Published: April 2004

α‐amino‐hydroxy‐5‐methyl‐isoxazole‐4‐propionate (AMPA) receptor in rat cultured microglia were analyzed precisely using flop‐ and flip‐preferring allosteric modulators of AMPA receptors, 4‐[2‐(phenylsulfonylamino)ethylthio]‐2,6‐difluoro‐phenoxyacetamide (PEPA) and cyclothiazide (CTZ), respectively. Glutamate (Glu)‐ or kainite (KA)‐induced currents were completely inhibited by a specific blocker of AMPA receptor, LY300164, indicating that functional Glu‐receptors in cultured microglia are mostly AMPA receptor but not KA receptor in many cells. Glu‐ and KA‐induced currents were potentiated by PEPA and CTZ in a concentration‐dependent manner. The ratio of the potentiation by PEPA to the potentiation by cyclothiazide varied with cells between 0.1 and 0.9, suggesting cell‐to‐cell heterogeneity of AMPA receptor subunits expressed in microglia. Quantitative RT‐PCR revealed that GluR1‐3 mainly occurred in the flip forms, which agreed with the stronger potentiation of receptor currents by CTZ vs. PEPA. Finally, the potentiation of microglial AMPA receptors by PEPA and CTZ inhibited the Glu‐induced release of tumor necrosis factor‐α (TNF‐α) unpredictably. The increase in TNF‐α release by Glu or KA required extracellular Na+ and Ca2+ ions but not mitogen‐activated protein kinase (MAPK), suggesting the effects of PEPA and CTZ were not due to the inhibition of MAPK. These results suggest that potentiation of microglial AMPA receptors serves as a negative feedback mechanism for the regulation of TNF‐α release and may contribute to the ameliorating effects of allosteric modulators of AMPA receptors. © 2004 Wiley‐Liss, Inc.
33S NMR shieldings and chemical bonding in compounds of sulfur
Authors: Chesnut D. B. , Quin L. D.
Published: April 2004

Sulfur nuclear magnetic resonance (NMR) chemical shieldings have been determined at the correlation‐including density functional theory scaled B3LYP/6‐311+G(nd,p)//B3LYP/6‐311+G(d,p) and modified MP2/6‐311+G(nd,p) estimated infinite order Møller‐Plesset levels with n = 2 for sulfur. The calculations span the range of sulfur shieldings and show agreement with experiment of about 3% of the shielding range. The atoms‐in‐molecules delocalization index and a covalent bond order from specific localized orbitals in the DFT approach are used to characterize sulfur's bonding and to relate it, where possible, to the calculated shieldings. © 2004 Wiley Periodicals, Inc. Heteroatom Chem 15:216–224, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20000
Application of alkoxy‐λ6‐sulfanenitriles as strong alkylating reagents
Authors: Hao Wei , Fujii Takayoshi , Dong Tiaoling , Wakai Youko , Yoshimura Toshiaki
Published: April 2004

Alkoxy‐λ6‐sulfanenitriles were found to be versatile alkylating reagents toward various nucleophiles bearing at least one proton such as methanol, phenol, thiophenols, carboxylic acids, p‐toluenesulfonic acid, hydrochloric acid, and primary and secondary amines. Reactivity of the alkoxy group of the λ6‐sulfanenitriles showed an opposite trend to the usual SN2 character, i.e. Me (1a), Pr (1b), and Bu (1d) ≪ i‐Pr (1c). In the presence of p‐TsOH, alkyl tosylates were predominantly formed instead of the alkylation products of nucleophiles. In addition, even a sterically hindered substrate, neopentyloxy‐λ6‐sulfanenitrile, was found to undergo an SN2 reaction toward thiophenol without any rearrangement product to give neopentyl phenyl sulfide in good yield. © 2004 Wiley Periodicals, Inc. Heteroatom Chem 15:193–198, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20006
Disilyl dithiophosphonates in the synthesis of open chain and cyclic organothiophosphorus compounds
Authors: Nizamov Il'yas S. , Sergeenko Gul'nur G. , Nizamov Il'nar D. , Popovich Yan E. , Khaibullin Ravil N. , Al'metkina Lyubov A. , Abalonin Boris E. , Batyeva Elvira S. , Krivolapov Dmitry B. , Litvinov Igor A.
Published: April 2004

O‐(Trimethylsiloxy)alkyl S‐trimethylsilyl aryldithiophosphonates 7a–d were obtained by the reaction of 2,4‐diaryl‐1,3,2,4‐dithiadiphosphetane‐2,4‐disulfides 5a,b with disilyl derivatives of glycols 6a,c and salicyl alcohol 6b. The reactions of mixed O,S‐bis(trimethylsilyl) 2,4‐di(3,5‐di‐tert‐butyl‐4‐hydroxyphenyl)dithiophosphonate 1 and S‐silyl aryldithiophosphonates 7a,b with S,S‐diethyldithiodiphenylgermane 2, dichlorodiphenylgermane 8a, and dichlorodiphenylstannane 8b were studied. The structure of hexaphenyl‐2,4,6,1,3,5‐trithiatrigerminane 11 was established by X‐ray single crystal diffraction. © 2004 Wiley Periodicals, Inc. Heteroatom Chem 15:225–232, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20009
Combining phosphinidene units with malonate anion: Synthesis of highly functional phosphine complexes
Authors: Compain Carine , Huy Ngoc Hoa Tran , Mathey François
Published: April 2004

Malonate anion traps the [RP‐W(CO)5] bridge of 7‐phosphanorbornadiene complexes 1–3 to give functional secondary phosphine complexes [RP(H)‐CH(CO2Et)2]W(CO)5 (7–9). Metalation of these complexes by NaH in THF occurs at the malonic CH group, but the alkylation of the resulting carbanions preferentially takes place at phosphorus. When R stands for β‐chloroethyl, the corresponding carbanion cyclizes to give the functional phosphirane complex 11. © 2004 Wiley Periodicals, Inc. Heteroatom Chem 15:258–262, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20014
Selective hippocampal damage in rhesus monkeys impairs spatial memory in an open‐field test
Authors: Hampton Robert R. , Hampstead Benjamin M. , Murray Elisabeth A.
Published: April 2004

The hippocampus is critical for remembering locations in a wide variety of species, including humans. However, recent findings from monkeys following selective hippocampal lesions have been equivocal. To approximate more closely the situations in which rodents and birds are tested, we used a spatial memory task in which rhesus monkeys (Macaca mulatta) moved about freely in a large room, on a tether. We used MRI‐guided stereotaxic surgery to produce selective hippocampal lesions in five monkeys, and retained five unoperated control monkeys. In the study phase of each trial of the matching‐to‐location task, monkeys found food in one site in an array of identical foraging sites. During the test, which occurred after a delay, monkeys could return to the site where the food had been found during study to obtain more food. In Experiment 1, normal monkeys showed a small significant tendency to return directly to a site where they had previously found food that day. Operated monkeys showed no such matching tendency. In Experiment 2, further training produced reliable matching‐to‐location performance in both groups at short delays, but monkeys with selective hippocampal lesions rapidly forgot the location of the food. In Experiment 3, we tested whether monkeys used a “cognitive map” to encode the location of the hidden food, by requiring them to relocate the food from a starting location different from that used during study. As a group, monkeys were more accurate than expected by chance, indicating that they did encode the rewarded location with respect to allocentric landmarks; however, both groups of monkeys were significantly worse at relocating the food when required to approach from a different location. In Experiment 4, probe trials using symmetrical test arrays found no evidence for egocentric coding of the rewarded location. © 2004 Wiley‐Liss, Inc.
Inhibition of a complement regulator in vivo enhances antibody therapy in a model of mammary adenocarcinoma
Authors: Imai Masaki , Ohta Rieko , Okada Noriko , Tomlinson Stephen
Published: April 2004

Membrane‐bound complement regulatory proteins provide tumor cells with protection from antibody and complement in vitro. However, complement regulators are widely expressed on normal tissue, and inhibiting the function of complement regulatory proteins on tumor cells in vivo has not been investigated due to the absence of appropriate tumor‐targeting strategies. Using a mouse model of rat mammary adenocarcinoma, we demonstrate that tumor‐specific targeting of a complement regulator with a blocking antibody has functional consequences with regard to both complement deposition on tumor cells and the efficacy of monoclonal antibody therapy. Rat adenocarcinoma 13762 cells express Crry, a widely expressed rodent regulator of complement activation, and are recognized by C595 MAb, an anti‐MUC1 MAb in clinical trials. Anti‐rat Crry 5I2 MAb and F(ab)2 enhanced complement deposition on C595 MAb‐sensitized 13762 cells in vitro. In vivo, C595 MAb bound to 13762 tumors, albeit not specifically, but was not therapeutic when administered after tumor challenge. However, the coadministration of 5I2 MAb with C595 MAb resulted in enhanced complement deposition and significantly delayed tumor onset and reduced tumor growth; 5I2 MAb alone also enhanced complement deposition and reduced tumor growth but less effectively than when combined with C595 MAb; 5I2 MAb alone did not directly activate mouse complement, but its inhibitory effect on Crry enhanced complement deposition following complement activation by both the alternative pathway and by natural IgM reactive to 13762 cells present in mouse serum. Our proof of principle study shows that inhibiting the function of a tumor‐expressed complement regulatory protein enhances immune‐mediated clearance of tumor cells and improves prospects for successful immunotherapy. The results justify further research and development of targeting strategies to inhibit or downregulate complement regulatory proteins on tumor cells. © 2004 Wiley‐Liss, Inc.
Irradiated C6 glioma cells induce angiogenesis in vivo and activate endothelial cells in vitro
Authors: Parthymou Anastasia , Kardamakis Dimitris , Pavlopoulos Ionnis , Papadimitriou Evangelia
Published: April 2004

Malignant gliomas are angiogenesis dependent and present a remarkable degree of resistance to radiotherapy. In the present work, we studied the effect of irradiation of C6 glioma cells on their proliferation and activation in vitro and on glioma cell‐induced angiogenesis in vivo and in vitro. Irradiation of C6 glioma cells decreased cell proliferation in a dose‐dependent manner. Interestingly, metalloproteinase‐2 and ‐9 expression and secretion, as well as integrin αv expression, increased with elevated doses of X rays 48 hr after irradiation and was mostly evident at the higher doses used. When pre‐irradiated C6 cells were implanted on nonirradiated chicken embryo chorioallantoic membranes (CAMs), there was a significant dose‐dependent increase in tumor induced angiogenesis, compared to angiogenesis induced by nonirradiated cells. Similar results were obtained when C6 cells were irradiated 48 hr after their inocculation onto nonirradiated CAMs. In the same line, conditioned medium from irradiated C6 cells significantly increased endothelial cell proliferation and migration in vitro, in a manner dependent on the dose of X rays. These results explain at least in part the low effectiveness of radiation therapy of malignant gliomas and support the notion that inhibition of angiogenesis in parallel with radiotherapy may represent a new therapeutic approach. © 2004 Wiley‐Liss, Inc.
Inhibition of the invasion capacity of carcinoma cells by WX‐UK1, a novel synthetic inhibitor of the urokinase‐type plasminogen activator system
Authors: Ertongur Suna , Lang Stephan , Mack Brigitte , Wosikowski Katja , Muehlenweg Bernd , Gires Olivier
Published: April 2004

The overall survival rate of patients suffering from carcinomas has remained poor and nearly unchanged over the last decades. This is mainly due to the so‐called minimal residual disease, i.e., remaining tumor cells that overcome surgery and/or radiotherapy and are the cause of locoregional and distant metastases. To metastasize, tumor cells take advantage of proteases to invade and remodel surrounding tissues. Here, we analyzed the efficiency of WX‐UK1, a novel 3‐amidinophenylalanine‐based inhibitor of the uPA system, at inhibiting the invasive capacity of carcinoma cells. First, uPAR expression was characterized in different carcinoma cell lines, including SCCHN, breast and cervical carcinoma. Thereafter, the invasive potential of these cell lines was determined using Matrigel invasion chambers and a spheroid cocultivation model with human fibroblasts. uPAR expression levels correlated positively with invasion capacity, which could be significantly inhibited by WX‐UK1. A decrease of tumor cell invasion by up to 50% was achieved in both models with the SCCHN line FaDu and the cervical carcinoma line HeLa after treatment with WX‐UK1. Thus, our results demonstrate the potential of WX‐UK1 in vitro as a promising adjuvant antimetastatic therapy of carcinomas. © 2004 Wiley‐Liss, Inc.
Pretreatment evaluation of combined HIF‐1α, p53 and p21 expression is a useful and sensitive indicator of response to radiation and chemotherapy in esophageal cancer
Authors: Sohda Makoto , Ishikawa Hitoshi , Masuda Norihiro , Kato Hiroyuki , Miyazaki Tatsuya , Nakajima Masanobu , Fukuchi Minoru , Manda Ryokuhei , Fukai Yasuyuki , Sakurai Hideyuki , Kuwano Hiroyuki
Published: April 2004

Tumor hypoxia has been known to be associated with resistance to radiation and chemotherapy (CRT). Hypoxia‐inducible factor‐1α (HIF‐1α), a transcription factor induced by hypoxic condition, plays a major role in the pleiotropic response observed under hypoxic conditions. It encodes proteins that play key roles in critical development and physiologic processes, including angiogenesis, glucose transport and erythropoiesis. On the other hand, cell cycle‐ and apoptosis‐control genes p53 and p21 may play major roles in the tumor response to cytotoxic agents such as radiation and chemotherapy. Previous reports have suggested that the regulation of p53 and p21 is HIF‐1‐dependent. Our aim was to evaluate the expression of the HIF‐1α, p53 and p21 proteins by immunohistochemistry in biopsy specimens of esophageal squamous cell carcinoma, which were obtained endoscopically from 65 patients before CRT, and then determine whether the levels of expression of these proteins predicted the clinical effectiveness of CRT in individual cancers. Also, to assess the relationship between expression of these proteins and cell death and cellular proliferation activity, we evaluated Ki67 expression and the apoptosis index (TUNEL). HIF‐1α expression in esophageal cancer was significantly and negatively related to the response to CRT, independently of p53 and p21 expression. Interestingly, 44.4% (12/27) of the HIF‐1α‐negative group showed a complete response to therapy. There was no significant correlation between the expression of HIF‐1α, p53 and p21 and proliferation and apoptosis. HIF‐1α overexpression may predict resistance to CRT and may be a helpful guide in choosing between therapeutic strategies, such as intensive combined modality therapy vs. palliative therapy. Combined immunohistochemical evaluation of HIF‐1α, p53 and p21 protein expression at the pretreatment biopsy is a very useful and powerful indicator of sensitivity to CRT in human esophageal cancer. Our data also indicate the importance of having a clear grasp of the degree of hypoxia (HIF‐1α) of a tumor, rather than its cellular character (proliferation and apoptosis), to indicate the likely impact of CRT. © 2004 Wiley‐Liss, Inc.
Evaluation of mRNA expression of estrogen receptor β and its isoforms in human normal and neoplastic endometrium
Authors: Skrzypczak Maciej , Bieche Ivan , Szymczak Sylwia , Tozlu Sengul , Lewandowski Sebastian , Girault Igor , Radwanska Katarzyna , Szczylik Cezary , Jakowicki Jerzy A. , Lidereau Rosette , Kaczmarek Leszek
Published: April 2004

Endometrial cancer is well known to be estrogen‐dependent. Two estrogen receptor types, ERα and ERβ, are major mediators of a diversity of biologic functions of estrogen and play an important role in estrogen‐dependent tissues and cancers. Cloning of ERβ was followed by the discovery of a variety of its isoforms. Using real‐time RT‐PCR, the relative expression levels of ERβ1, ERβ2 (ERβcx), ERβ3, ERβ4 and ERβ5 were studied. We observed coexpression of ERβ isoforms in the endometrium and upregulation of the ERβ5 transcript in malignant endometrium. We also observed downregulation of ERβ2Δ5 transcript in neoplastic endometrium, using a semiquantitative method. Our results suggest that analyzing the changes in ERβ and its isoforms may be important in the diagnosis, prognosis and treatment of endometrial cancer. © 2004 Wiley‐Liss, Inc.
Effect of fibrous capsule formation on doxorubicin distribution in radiofrequency ablated rat livers
Authors: Blanco Elvin , Qian Feng , Weinberg Brent , Stowe Nicholas , Anderson James M. , Gao Jinming
Published: April 2004

In this study, we report the histological findings of a combined therapy using radiofrequency ablation and intratumoral drug delivery in rat livers, with special attention to wound‐healing processes and their effects on drug transport in post‐ablated tissue. Doxorubicin‐loaded millirods were implanted in rat livers that had undergone medial lobe ablation. Millirods and liver samples were retrieved upon animal sacrifice at time points ranging from 1 h to 8 days. Results demonstrate a clearly defined area of coagulative necrosis within the ablation boundary. The wound‐healing response, complete with the appearance of inflammatory cells, neovascularization, and the formation of a fibrous capsule, was also observed. At the 8‐day time point, fluorescence imaging analysis showed a higher concentration of doxorubicin localized within the ablation region, with its distribution hampered primarily by fibrous capsule formation at the boundary. Given the variant nature of ablated liver, a mathematical model devised previously by our laboratory describes the data well up to 4 days, but loses reliability at 8 days. These results provide useful mechanistic insights into the wound‐healing response after radiofrequency ablation and polymer millirod implantation, as well as the impact this natural corollary has on drug distribution. © 2004 Wiley Periodicals, Inc. J Biomed Mater Res 69A: 398–406, 2004
Variation in surface texture measurements
Authors: Macdonald Warren , Campbell Patricia , Fisher John , Wennerberg Ann
Published: April 2004

Surface texture influences cellular response to implants, implant wear, and fixation, yet measurement and reporting of surface texture can be confusing and ambiguous. Seven specimens of widely different surface textures were submitted to three internationally renowned laboratories for surface texture characterization. The specimens were from dental implants, orthopedic implants, and femoral heads. Areas to be measured were clearly marked; simplified instructions were supplied but specific measurement parameters were not requested. Techniques used included contact profilometry, two‐ and three‐dimensional laser profilometry, and atomic force microscopy. Four to thirteen parameters were reported, 2D or 3D, including Ra or Sa; only three were common to all centers. The results varied by as much as ±300–1000%, depending on technique and surface type. Some surfaces were not measurable by some techniques. One dental implant surface was reported with Ra of 0.17, 0.85, 1.9, and 4.4 μm. The CoCr femoral head ranged from an Ra of 0.011 to 0.10 μm; the zirconia head from 0.006 to 0.05 μm. Similar variability was reported for the other parameters. Useful surface texture characterization requires reporting of all measurement parameters. Comparisons between studies may be compromised if differences in technique are not considered. © 2004 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 70B: 262–269, 2004