bluuebunny/crossref_metadata_2025 huggingface dataset:
The structural basis of Janus kinase 2 inhibition by a potent and specific pan-Janus kinase inhibitor
Authors: Lucet Isabelle S. , Fantino Emmanuelle , Styles Michelle , Bamert Rebecca , Patel Onisha , Broughton Sophie E. , Walter Mark , Burns Christopher J. , Treutlein Herbert , Wilks Andrew F. , Rossjohn Jamie
Published: September 2005

JAK2, a member of the Janus kinase (JAK) family of protein tyrosine kinases (PTKs), is an important intracellular mediator of cytokine signaling. Mutations of the JAK2 gene are associated with hematologic cancers, and aberrant JAK activity is also associated with a number of immune diseases, including rheumatoid arthritis. Accordingly, the development of JAK2-specific inhibitors has tremendous clinical relevance. Critical to the function of JAK2 is its PTK domain. We report the 2.0 Å crystal structure of the active conformation of the JAK2 PTK domain in complex with a high-affinity, pan-JAK inhibitor that appears to bind via an induced fit mechanism. This inhibitor, the tetracyclic pyridone 2-tert-butyl-9-fluoro-3,6-dihydro-7H-benz[h]-imidaz[4,5-f]isoquinoline-7-1, was buried deep within a constricted ATP-binding site, in which extensive interactions, including residues that are unique to JAK2 and the JAK family, are made with the inhibitor. We present a structural basis of high-affinity JAK-specific inhibition that will undoubtedly provide an invaluable tool for the further design of novel, potent, and specific therapeutics against the JAK family.
Cell cycle and centromere FISH studies in premature centromere division
Authors: Corona-Rivera Alfredo , Salamanca-Gomez Fabio , Bobadilla-Morales Lucina , Corona-Rivera Jorge R , Palomino-Cueva Cesar , Garcia-Cobian Teresa A , Corona-Rivera Enrique
Published: September 2005

Background

Mitotic configurations consistent in split centromeres and splayed chromatids in all or most of the chromosomes or premature centromere division (PCD) have been described in three categories. (1) Low frequency of PCD observed in colchicines-treated lymphocyte cultures from normal individuals. (2) High frequency of PCD with mosaic variegated aneuploidy. (3) High frequency of PCD as a sole chromosome abnormality observed in individuals with no recognizable clinical pattern. We report four members of a family with the third category of PCD.

Methods

Cell cycle duration assessed by average generation time using differential sister chromatid stain analysis and FISH studies of DNA centromere sequences in PCD individuals, are included and compared with previously reported PCD individuals from 9 families.

Results

We observed PCD in colchicine-treated cultures from the propositus, his father, and two paternal aunts but not in his mother and four other paternal and maternal family members, as well as in untreated cultures from the propositus and his father. We observed cytological evidence of active centromeres by Cd stain. Significative cell cycle time reduction in anaphases of PCD individuals (average generation time of 21.8 h;SD 0.4) with respect to individuals without PCD (average generation time of 31.8 h;SD 3.9) was observed (P < 0.005, Student t-test for independent samples). Increased cell proliferation kinetics was observed in anaphasic cells of individuals with PCD, by differential sister chromatid stain analysis. FISH studies revealed the presence of alpha satellite DNA from chromosomes 1, 13, 21/18, X, all centromeres, and CENP-B box sequences in metaphasic and anaphasic cells from PCD individuals.

Conclusion

This report examines evidences of a functional relationship between PCD and cell cycle impairment. It seems that essential centromere integrity is present in these cases.
A rare cause of specific cough in a child: the importance of following-up children with chronic cough
Authors: Barr Richard Lloyd , McCrystal David John , Perry Christopher Francis , Chang Anne B
Published: September 2005

For many years, the term 'specific cough' has been used as a clinical cough descriptor in children to signify the likelihood of an underlying disease causing the cough. In this case study, we describe a child with specific cough caused by a rare carcinoma, a mucoepidermoid carcinoma of the bronchus. The cough only totally resolved after the primary cause was successfully treated. This report highlights the importance of following up children with cough, especially those with specific cough.
On the relationship between prosody and pragmatic ability in Swedish children with language impairment
Authors: Samuelsson Christina , Nettelbladt Ulrika , Lofqvist Anders
Published: September 2005

A previous study has shown that Swedish children with language impairment have prosodic problems at different levels of language. The aim of this study is to investigate prosodic problems at the discourse level in two of the children to see whether they are related to pragmatic problems. Prosodic and pragmatic abilities were assessed by perceptual and acoustic evaluations. The children s communication checklist (CCC) was used to evaluate the children 's pragmatic abilities and analysis of spontaneous speech samples was made. The results of the perceptual evaluations showed that the children have prosodic problems at the discourse level. The acoustic analysis also provided some support of this result. According to the CCC and the analysis of spontaneous speech samples the children had pragmatic problems. The results support the assumption that the prosodic problems at the discourse level are related to the pragmatic problems and indicate that the prosodic problems might be secondary to the pragmatic problems. However, far-reaching generalizations can not be made from this case study of two children.
The antagonistic relevance of development studies
Authors: Mohan Giles , Wilson Gordon
Published: September 2005

This paper discusses relevance in development studies. We argue that current debates around relevance assume a hegemonic view of development, which is bolstered by the high levels of research funding from key policy-making institutions. We feel relevance can be pluralized and radicalized, but that this requires us to be ideologically transparent and to examine other ways of undertaking and validating knowledge production. This involves first, acknowledging the material and ethical connectedness, but not sameness, of people; secondly, a relational tension between discipline and interdiscipline; thirdly, that problem-framing and influencing involves ‘researchers’ and ‘users’, whereby ‘users’ include students, practitioners, decision-makers and ‘the poor’. Further, we argue that such dialogic approaches require alternative criteria for rigour. Positivistic criteria imply a distinctive form of rationality, but if rationality is also pluralized then alternative epistemologies and methodologies of working with multiple rationalities is necessary.
A Simple Field Method to Qualify the State of Saturation in Capillary Barriers
Authors: Burnotte F , Cabral AR , Lefebvre G
Published: September 2005

A simple and straightforward field method to rapidly qualify the state of saturation of moisture retaining layers (MRL) is proposed and the details of its calibration and operation, described. The technique is based on the simple fact that if gas samples cannot be taken from a stainless tube that is inserted to the desired depth within the MRL, the air filled voids at that depth are not interconnected and the material can be qualified, for all practical purposes, as saturated. In this case, the threshold degree of saturation beyond which gas flux substantially decreases (approximately 85%), has been attained. In several sites covered with deinking by-products (DBP), an industrial residue that can be used as alternative construction material for landfills and acid-producing mine sites covers, it has been often impossible to collect gas samples below approximately 20 cm from the surface of the DBP layer. The question was thus to know if this is a reliable indicator that the threshold degree of saturation has or not been attained and that the layer is performing its role of gas barrier. In order to answer this question, a calibration was performed in the laboratory and in the field. The calibration consisted mainly on attempting to extract gas from samples compacted at different degrees of saturation. The results show that the threshold degree of saturation for DBP is attained at approximately 83%.
A True Triaxial Apparatus for Soil Testing with Mixed Boundary Conditions
Authors: Alshibli KA , Williams HS
Published: September 2005

The mechanical description of a new true triaxial apparatus for soil testing is presented. The design took into consideration flexibility in accommodating different specimen sizes, easy assembly procedure, and well-controlled boundary conditions. The apparatus can perform stress-controlled and strain controlled experiments. It is well instrumented with load, displacement, and pressure sensors and has the capabilities to capture strain localization and shear band development. Verification experiments were conducted on F-75 Ottawa sand to study the influence of b-value (b = (σ2 − σ3)/(σ1 − σ3)) on stress-strain and volumetric behavior of sand. The results show that the specimen stiffness increases, and the amount of post-peak softening increases as b-value increases. The peak and critical state friction angles and the rate of dilation increase as b-value increases from 0 to 0.25, followed by a smaller increase in the friction angles and no change in the rate of dilation as b-value increases. Specimens failure is characterized by nonuniform deformations that initiate during the hardening regime before the peak stress; however, shear bands become visible on the specimen surface during the post peak softening at which specimens' volumetric strain changes from dilative behavior to the constant volume condition.
Thermal Creep of Irradiated Zircaloy Cladding
Authors: Tsai H , Billone MC
Published: September 2005

As part of an effort to investigate spent-fuel behavior during dry-cask storage, thermal creep tests are being performed with defueled Zircaloy-4 cladding segments from two pressurized water reactors — Surry at ≈36 GWd/MTU burnup and H. B. Robinson at ≈67 GWd/MTU burnup, with corresponding fast (E > 1 MeV) fluence levels of 7×1025 and 14×1025 n/m2. The Surry rods are particularly relevant because they were stored in an inert-atmosphere (He) cask for 15 years. The Robinson rods were received after reactor discharge and pool storage. Commensurate with their high burnup, the Robinson cladding has significant waterside corrosion and hydrogen uptake. Test results to-date indicate good creep ductility for both claddings in the 360–400°C and 160–250 MPa (hoop-stress) regime. Partial recovery of radiation hardening may have occurred during the long tests at 400°C, which led to improved creep ductility. Creep-rate sensitivity is significant for stress and even more so for temperature. The higher hydrogen content in the Robinson material appears to have no detrimental effect on creep behavior at the test temperature. One Robinson sample, which ruptured in the weld region at 205°C during cooling from 400°C under stress (190 MPa), precipitated all visible hydrides in the radial direction.
Field-Collected and AGDISP-Predicted Spray Flux from an Aerial Application
Authors: Hoffmann WC
Published: September 2005

As computer models are increasingly being integrated into modern agricultural operations, the comparison of field-collected data to the model prediction improves the confidence that aerial applicators, researchers, and regulators have in the model. The field-collected data were compared to the AGDISP model predictions for the tests conducted in soybeans and cotton and over a concrete runway on two different days. The meteorological effects on spray movement were then explored by analyzing individual replications in the spray trials. The effect of varying the surface roughness coefficient over the range of values for bare ground (i.e., runways) in the AGDISP model on downwind spray movement was determined. The final analyses presented showed the dramatic decrease in downwind spray movement as a result of increasing canopy height as predicted by the AGDISP model.

The AGDISP model predicted 1–6 times higher levels of spray materials than that measured by field samplers. The model predictions were 1–3 times greater than the field collected data in the runway studies and 2–6 times greater in the canopy studies. Surface roughness coefficients over bare ground had minimal impacts as predicted by the AGDISP model. When the actual weather conditions of one of the treatments in this study were input into the AGDISP model, a 1.5 m/s increase in wind speed resulted in a 100% increase in the spray flux at 50 m from the application site. When crop height inputs into the AGDISP model were changed from 0.3 m to 1.3 m, the spray flux decreased by 20-fold, demonstrating the dramatic filtering effect that a canopy can have on a spray cloud and will serve as a stimulus for future studies designed to fully characterize the effect of crop canopy on spray movement.
Flight Line Variability in Rotary Atomizer Drop Size Distribution
Authors: Teske ME , Thistle HW , Reardon RC , Davies DC , Cormier G , Cameron RS , LeClerc MY , Karipot A
Published: September 2005

An extensive data set generated with a highly instrumented aircraft provides 0.2-s interval data of aircraft and mechanical release system behavior during aerial application. These unique data previously provided an excellent source of information on the variability of aerial application parameters along individual flight lines and enabled a sensitivity analysis to bound the variability in the expected deposition patterns. They also showed how this variability might impact any error bounds established around the time-averaged predictions generated by the AGDISP model. This paper quantifies the variability in the drop size distribution generated by the rotary atomizers and makes suggestions with regard to possible implications of this variability on the variability of deposition predictions across any spray application involving their use. The measured variability may not be unique to rotary atomizers, as a sensitivity study of hydraulic atomizers gives similar results.
Opportunities for Standardization of Beryllium Sampling and Analysis
Authors: Brisson MJ , Ekechukwu AA , Ashley K , Jahn SD
Published: September 2005

Since the U. S. Department of Energy (DOE) published the DOE Beryllium Rule (10 CFR 850) in 1999, DOE sites have been required to measure beryllium in air filter and surface wipe samples for purposes of worker protection and for release of materials from beryllium-controlled areas. Measurements in the nanogram range on a filter or wipe are typically required. Industrial hygiene laboratories have applied methods from various analytical compendia, and a number of issues have emerged concerning sampling and analysis practices. As a result, a committee of analytical chemists, industrial hygienists, and laboratory managers was formed in November 2003 to address the issues. The committee developed a baseline questionnaire and distributed it to DOE sites and other agencies in the U.S., Canada, and the U.K. The results of the questionnaire are presented in this paper. These results confirmed that a wide variety of practices was in use in the areas of sampling, sample preparation, and analysis. Additionally, although these laboratories are generally accredited by the American Industrial Hygiene Association (AIHA), there are inconsistencies in execution among accredited laboratories. As a result, there are significant opportunities for development of standard methods that could improve consistency. The current availabilities and needs for standard methods are further discussed in a companion paper.
Alkaloid Content of the Seeds from Erythroxylum Coca var. Coca
Authors: Casale JF , Toske SG , Colley VL
Published: September 2005

Alkaloid extracts from the seeds of Erythroxylum Coca var. Coca grown in the Chapare Valley of Bolivia were subjected to gas and liquid chromatographic-mass spectrometric analyses. Several alkaloids from these seeds were detected and characterized, including methylecgonidine, tropine, 3α-acetoxytropane, ecgonine methyl ester, cuscohygrine, N-norbenzoyltropine, benzoyltropine, hexanoylecgonine methyl ester, cocaine, cis-cinnamoylcocaine, and trans-cinnamoylcocaine. Methylecgonidine was determined to be the primary constituent and not an analytical artifact. Additionally, two significant new uncharacterized alkaloids were established as present. Recent evidence suggests that some cocaine processors are adding this seed extraction material to cocaine extracted from coca leaf and may impact cocaine impurity signature profiles.
Drug Smuggling Using Clothing Impregnated with Cocaine
Authors: McDermott SD , Power JD
Published: September 2005

A case study is presented where a woman travelling from South America to the Republic of Ireland was detained at Dublin Airport and articles of clothing she had in her luggage were found to be impregnated with cocaine. The study shows that the amount of powder recovered from the garments was approximately 14% of the total weight of the garments. The cocaine was in the form of cocaine hydrochloride and the purity was approximately 80%. An examination of the garments under filtered light highlighted the areas exposed to cocaine and indicated that the method of impregnation was by pouring liquid containing cocaine onto the clothing.
Autosomal STR Frequencies in Afghanistan Population
Authors: Berti A , Barni F , Virgili A , Iacovacci G , Franchi C , Rapone C , Di Carlo A , Oddo CM , Lago G
Published: September 2005

Buccal cells were collected by buccal brushes (Sterile Omni Swab, Whatman International Ltd.) from healthy, random Afghanian individuals. DNA was extracted by Chelex method (1). DNA samples were quantified using AmpFℓSTR® Quantifiler (Ap plied Biosystems, Foster City, CA) by Real time 7000 (Applied Biosystems, Foster City, CA), one nanogram of the samples obtained from the previous phase was amplified by GeneAmp® PCR System 9600 (Applied Biosystems, Foster City, CA). Simultaneous amplifications of 16 STRs loci (multiplexed PCR) were performed by using AmpFℓSTR® Identifiler™ (Applied Biosystems, Foster City, CA) according to the user manual recommendations (2).
Long-Term Testing of Trenchless Pipe Liners
Authors: Barbero E , Rangarajan S
Published: September 2005

Due to increasing costs and inconveniences in replacing deteriorated sewer pipelines by conventional excavation methods, the trenchless or “no-dig” technology is being used extensively. In this manuscript, a testing method is proposed to determine the long-term creep behavior of encased polymer and felt-reinforced polymer liners used in sewer rehabilitation. Long-term tests are conducted on liner samples encased in steel pipes, installed by the industries participating in the research project. The thicknesses of the polymer liners are selected according to the typical use of each product in the field. Three samples each of five liner materials are tested under constant external hydrostatic pressure to find their long-term structural properties. A pressure regulator, pressure transducer, and several pressure gages at different points in the water line are used to maintain constant hydraulic pressure in the gap between the steel host and the polymer liner. A method is proposed for sealing the ends of the encased liner samples for testing. The long-term creep data are collected with strain gages bonded along the inner circumference of the liner and connected to a data acquisition system (DAS). A data reduction method is proposed to separate the membrane and bending strains in order to compute the creep compliance. The temperature of the liners is monitored continuously with the use of a thermocouple. The strain data collected from the DAS are compensated for differences in temperature throughout the period of testing, initial deformation, and coefficient of thermal expansion. Several viscoelastic models are investigated in order to fit the data. The data are used to predict the long-term modulus used in the design of trenchless rehabilitation projects.
Investigations of Testing Methodology in Wood Abrasion Tests Promoted with Loose Abrasive Grains
Authors: Ohtani T , Kamasaki K
Published: September 2005

The wear properties for wood were examined using 2-body and 3-body abrasion tests. The testing methodologies were designed so that the results from the two methods could be compared. The results showed that the 3-body abrasive wear rate for the axial, radial, and tangential sections dispersed at higher applied surface pressures. As a result, the 3-body abrasion test did not wear continuously, unlike the 2-body abrasion test at equivalent applied surface pressures. The critical value below which the 3-body abrasion test is valid could be estimated by the applied surface pressure and the wood specimen's and the counterface material's yield stresses. The number of contacting abrasive grains in the valid region of the 3-body abrasion test was found to agree approximately with that of 2-body abrasion. However, when the 3-body abrasion test was conducted above the critical value, the number of contacting abrasive grains decreased with repeated friction.
Involvement of the Dorsal Striatum in Cue-Controlled Cocaine Seeking
Authors: Vanderschuren Louk J. M. J. , Di Ciano Patricia , Everitt Barry J.
Published: September 2005

Through association with the interoceptive effects of drugs of abuse, neutral environmental stimuli can gain motivational properties themselves, becoming conditioned reinforcers that can evoke craving and relapse to drug seeking. Nucleus accumbens dopamine (DA) neurotransmission plays an important role in the reinforcing effect of cocaine itself, but, unlike nucleus accumbens glutamate, it seems not to mediate the conditioned reinforcing properties of cocaine-paired stimuli. Dorsal striatal DA transmission, in contrast, has been shown to be enhanced during cocaine seeking under a second-order schedule of reinforcement, which depends on the conditioned reinforcing properties of cocaine-associated stimuli. Therefore, the aim of the present study was to evaluate the role of DA and glutamate transmission in the dorsal striatum in cue-controlled cocaine seeking. Infusion of the DA receptor antagonist α-flupenthixol into the dorsal striatum decreased cocaine seeking under a second-order schedule of reinforcement. In addition, intradorsal striatal infusion of the AMPA/kainate (KA) receptor antagonistLY293558(3SR, 4aRS, 6RS, 8aRS-6-[2-(iH-tetrazol-5-yl)ethyl]-1,2,3,4,4a,5,6,7,8,8a-decahydroiso-quinoline-3-carboxylic acid), but not the NMDA receptor antagonist AP-5, also decreased cue-controlled cocaine seeking. These data show that stimulation of DA and AMPA/KA receptors in the dorsal striatum is critical for well established drug seeking that depends on the reinforcing effects of cocaine-associated stimuli. In addition, given the importance of the dorsal striatum in stimulus–response habit learning, these data suggest that the habitual or compulsive quality of persistent drug seeking depends on dorsal striatal mechanisms.
Balance of Monosynaptic Excitatory and Disynaptic Inhibitory Responses of the Globus Pallidus Induced after Stimulation of the Subthalamic Nucleus in the Monkey
Authors: Kita Hitoshi , Tachibana Yoshihisa , Nambu Atsushi , Chiken Satomi
Published: September 2005

The subthalamic nucleus (STN) plays a pivotal role in controlling the activity of both the external and internal segments of the globus pallidus (GPe and GPi, respectively). Both nuclei receive monosynaptic excitatory and disynaptic GPe-mediated inhibitory inputs from the STN. Thus, we investigated the balance of these antagonistic inputs that may determine the overall response of pallidum to STN activation in monkeys. Single stimulation of the STN evoked a short-latency excitation followed by a weak inhibition in GPe neurons and a short-latency, very short-duration excitation followed by a strong inhibition in GPi neurons. Burst high-frequency stimulation (BHFS) (10 stimuli with 100 Hz) of the STN (STN-BHFS) evoked powerful excitatory responses in GPe neurons. Local injection of a mixture of 1, 2, 3, 4-tetrahydro-6-nitro-2, 3-dioxobenzo[f]quinoxaline-7-sulfonamide (NBQX; AMPA/kainate receptor blocker) and 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP; NMDA receptor blocker) greatly diminished or abolished excitatory responses to the STN stimulation. In contrast to the GPe, STN-BHFS evoked a predominantly inhibitory response in GPi neurons. The inhibition could be blocked either by a local application of the GABAAreceptor antagonist gabazine or by an injection of an NBQX/CPP/gabazine mixture into the GPe. STN-BHFS induced weak excitatory or inhibitory responses in a small number of phasically active putamen neurons. These data suggest that with single stimulation and during STN-BHFS, the STN-GPe excitatory response dominates over the STN-GPe-GPe recurrent inhibition in the GPe, whereas the STN-GPe-GPi inhibitory response dominates over the STN-GPi excitatory response in the GPi.
Coding for the Initiation of Pseudopregnancy by Temporally Patterned Activation of Amygdalar NMDA Receptors
Authors: Lehmann Michael L. , McKellar Heather , Erskine Mary S.
Published: September 2005

Female rats modulate the number and interval between the intromissions the female receives during mating. This patterned vaginocervical stimulation (VCS) is critical for triggering long-term changes in prolactin (PRL) secretion necessary for pregnancy or pseudopregnancy (P/PSP). Previous work has shown that NMDA receptor activation in the posterodorsal medial amygdala (MEApd) is required at the time of mating for VCS to induce the twice-daily PRL surges characteristic of P/PSP. The current studies examined whether patterned activation of glutamate receptors within the MEApd induces P/PSP. In anesthetized, cycling females, three 0.27μg NMDA infusions given at 30 min intervals into the MEApd initiated P/PSP, whereas a single NMDA infusion of the same total dose (0.8 μg) had no effect. In conscious, freely behaving females, three infusions of an excitatory amino acid (EAA) mixture applied at the same interval were more effective in initiating P/PSP and nocturnal PRL surges than were single infusions at the same or higher concentrations. Infusion intervals of 5 and 60 min as well as continuous 1 h infusion did not induce P/PSP. Finally, a synergistic effect was observed between EAA and mating stimulation, because a subthreshold EAA infusion combined with subthreshold numbers of intromissions induced P/PSP. These results demonstrate that repeated, properly spaced, temporally discreet periods of glutamate receptor activation within the MEApd, which mimic mating stimulation, encode for P/PSP. Such findings suggest that single intromissions normally release individually subthreshold quanta of glutamate within the MEApd that summate to induce P/PSP.
Proprioceptor Regulation of Motor Circuit Activity by Presynaptic Inhibition of a Modulatory Projection Neuron
Authors: Beenhakker Mark P. , DeLong Nicholas D. , Saideman Shari R. , Nadim Farzan , Nusbaum Michael P.
Published: September 2005

Phasically active sensory systems commonly influence rhythmic motor activity via synaptic actions on the relevant circuit and/or motor neurons. Using the crab stomatogastric nervous system (STNS), we identified a distinct synaptic action by which an identified proprioceptor, the gastropyloric muscle stretch receptor (GPR) neuron, regulates the gastric mill (chewing) motor rhythm. Previous work showed that rhythmically stimulating GPR in a gastric mill-like pattern, in the isolated STNS, elicits the gastric mill rhythm via its activation of two identified projection neurons, modulatory commissural neuron 1 (MCN1) and commissural projection neuron 2, in the commissural ganglia. Here, we determine how activation of GPR with a behaviorally appropriate pattern (active during each gastric mill retractor phase) influences an ongoing gastric mill rhythm via actions in the stomato gastric ganglion, where the gastric mill circuit is located. Stimulating GPR during each retractor phase selectively prolongs that phase and thereby slows the ongoing rhythm. This selective action on the retractor phase results from two distinct GPR actions. First, GPR presynaptically inhibits the axon terminals of MCN1, reducing MCN1 excitation of all gastric mill neurons. Second, GPR directly excites the retractor phase neurons. Because MCN1 transmitter release occurs during each retractor phase, these parallel GPR actions selectively reduce the buildup of excitatory drive to the protractor phase neurons, delaying each protractor burst. Thus, rhythmic proprioceptor feedback to a motor circuit can result from a global reduction in excitatory drive to that circuit, via presynaptic inhibition, coupled with a phase-specific excitatory input that prolongs the excited phase by delaying the onset of the subsequent phase.
Electrical Coupling between Interneurons with Different Excitable Properties in the Stratum Lacunosum-Moleculare of the Juvenile CA1 Rat Hippocampus
Authors: Zsiros Veronika , Maccaferri Gianmaria
Published: September 2005

Electrical coupling among GABAergic interneurons is believed to play an essential role in shaping synchronized brain network activity related to cognition and behavior. We have studied the rules governing the electrical coupling between hippocampal interneurons located in stratum lacunosum-moleculare of the CA1 hippocampus. The most frequently recorded interneuron subtype had short multipolar dendrites and a dense local axonal arborization, typical of neurogliaform cells. Electrical excitability in this class of interneurons was heterogeneous. Although injection of small current steps evoked late spiking, larger steps triggered different types of firing patterns. Trains of action potentials ranged from clearly adapting to highly irregular, with clustered or mostly regular spikes. Electrotonic and action potentials could be propagated to the coupled cells; the coupling coefficient for electrotonic signals was 0.035, which compared with 0.005 for action potentials. Electrical coupling was reversibly blocked by application of carbenoxolone. Multiple simultaneous recordings indicated that interneurons with similar and different firing patterns were electrically coupled. This visual impression was quantitatively confirmed by principal component analysis applied to variables related to membrane excitability. In fact, the probability of finding electrically coupled neurons in our sample was not dependent on the excitable properties of the cells tested and was ∼0.34. The presence of diffuse electrical coupling among hippocampal interneurons of stratum lacunosum-moleculare with different excitability is a novel finding with important implications. For example, the promiscuity of electrical connections may endow inhibitory networks with a large degree of flexibility and regulate the computational power of the hippocampus during different synchronized states.
Withdrawal from Chronic Nicotine Administration Impairs Contextual Fear Conditioning in C57BL/6 Mice
Authors: Davis Jennifer A. , James John R. , Siegel Steven J. , Gould Thomas J.
Published: September 2005

The effects of acute nicotine administration (0.09 mg/kg nicotine), chronic nicotine administration (6.3 mg/kg/d nicotine for 14 d), and withdrawal from chronic nicotine administration on fear conditioning in C57BL/6 mice were examined. Mice were trained using two coterminating conditioned stimulus (30 s; 85 dB white noise)–unconditioned stimulus (2 s; 0.57 mA foot shock) pairings and tested 24 h later for contextual and cued fear conditioning. Acute nicotine administration enhanced contextual fear conditioning, chronic nicotine administration had no effect on contextual fear conditioning, and withdrawal from chronic nicotine administration impaired contextual fear conditioning. Plasma nicotine concentrations were similar after acute and chronic treatment and were within the range reported for smokers. During withdrawal, concentrations of nicotine were undetectable. An acute dose of nicotine (0.09 mg/kg) during withdrawal from chronic nicotine treatment reversed withdrawal-associated deficits in contextual fear conditioning. The results suggest that tolerance to the effects of nicotine on contextual fear conditioning develops with chronic nicotine treatment at a physiologically relevant dose, and withdrawal from this chronic nicotine treatment is associated with impairments in contextual fear conditioning. These findings provide a model of how the effects of nicotine on learning may contribute to the development and maintenance of nicotine addiction.
Theoretical predictions of hydrolysis and complex formation of group-4 elements Zr, Hf and Rf in HF and HCl solutions
Authors: Pershina Valeria , Trubert D. , Le Naour C. , Kratz Jens Volker
Published: September 2005

Fully relativistic molecular density–functional calculations of the electronic structures of hydrated, hydrolyzed and fluoride/chloride complexes have been performed for group–4 elements Zr, Hf, and element 104, Rf. Using the electronic density distribution data, relative values of the free energy change for hydrolysis and complex formation reactions were defined. The results show the following trend for the first hydrolysis step of the cationic species: Zr > Hf > Rf in agreement with experiments. For the complex formation in HF solutions, the trend to a decrease from Zr to Hf is continued with Rf, provided no hydrolysis takes place. At pH > 0, further fluorination of hydrolyzed species or fluoro–complexes has an inversed trend in the group Rf ≥ Zr > Hf, with the difference between the elements being very small. For the complex formation in HCl solutions, the trend is continued with Rf, so that Zr > Hf > Rf independently of pH. A decisive energetic factor in hydrolysis or complex formation processes proved to be a predominant electrostatic metal–ligand interaction. Trends in theKd(distribution coefficient) values for the group–4 elements are expected to follow those of the complex formation.
Current Knowledge and Future Directions of the Selective Epidermal Growth Factor Receptor Inhibitors Erlotinib (Tarceva®) and Gefitinib (Iressa®)
Authors: Siegel-Lakhai Wandena S. , Beijnen Jos H. , Schellens Jan H.M.
Published: September 2005

The CME activity for this article is forthcoming.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com

Gefitinib (Iressa®; AstraZeneca Pharmaceuticals, Wilmington, DE, http://www.astrazeneca-us.com) and erlotinib (Tarceva®; OSI Pharmaceuticals, Inc., Melville, NY, http://www.osip.com) are so-called small molecules that selectively inhibit epidermal growth factor receptor (EGFR) tyrosine kinase activity. Both drugs received registration approval by the U.S. Food and Drug Administration (FDA) for the second- and third-line treatment of non-small cell lung cancer (NSCLC), but the failure of gefitinib to show a survival advantage over placebo has resulted in a discussion about the registration of gefitinib. Recently published results have revealed that mutations in the tyrosine kinase domain of EGFR are strongly associated with increased gefitinib and erlotinib sensitivity in patients with advanced NSCLC. Here, we present the current knowledge and the future directions of the EGFR tyrosine kinase inhibitors gefitinib and erlotinib.
Clinical Pharmacology Issues Relevant to the Dosing and Toxicity of Chemotherapy Drugs in the Elderly
Authors: Wasil Tarun , Lichtman Stuart M.
Published: September 2005

Learning Objectives

After completing this course, the reader will be able to: Describe pharmacokinetic changes associated with aging.Describe concepts of geriatric assessment.Describe the treatment of common malignancies in the elderly with emphasis on pharmacokinetic change.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com

Persons over the age of 65 years are the fastest growing segment of the U.S. population. In the next 30 years, they will comprise more than 20% of the population. Fifty percent of all cancers occur in this age group, and therefore, there is an expected rise in the total cancer burden. Data are becoming available that will better guide the use of chemotherapy in the older patient population. In this paper, information regarding age-related physiologicchanges and their relationship to pharmacology, functional status, and hematopoiesis is presented. The adjuvant treatment of breast and colon cancer, as well as the primary therapy of aggressive non-Hodgkin lymphoma is reviewed. The treatment of more advanced breast, ovarian, and non-small cell lung cancer is also discussed.
Lymphomas and Chylous Ascites: Review of the Literature
Authors: Almakdisi Tony , Massoud Samuel , Makdisi George
Published: September 2005

Learning Objectives

After completing this course, the reader will be able to: Describe how common medical diseases can cause chylous ascites.Interpret the chylous ascites fluids analysis.Manage chylous ascites based on ethiology.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com

Chylous ascites is a rare and challenging clinical condition that occurs as a result of disruption of the abdominal lymphatics. We include a review of the literature describing the etiology, diagnosis, and therapy of chylous ascites.
Update: Laughter: The Best Medicine?
Authors: Penson Richard T. , Partridge Rosamund A. , Rudd Pandora , Seiden Michael V. , Nelson Jill E. , Chabner Bruce A. , Lynch Thomas J.
Published: September 2005

Learning Objectives

After completing this course, the reader will be able to: Appreciate the impact of humor in the interaction between patients and caregivers.Understand the literature and evidence base for the positive and negative roles of humor in oncology.Better connect with patients.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com

Shortly before his death in 1995, Kenneth B. Schwartz, a cancer patient at Massachusetts General Hospital (MGH) founded The Kenneth B. Schwartz Center at MGH. The Schwartz Center is a nonprofit organization dedicated to supporting and advancing compassionate health care delivery, which provides hope to the patient and support to caregivers and encourages the healing process. The center sponsors the Schwartz Center Rounds, a monthly multidisciplinary forum where caregivers reflect on important psychosocial issues faced by patients, their families, and their caregivers, and gain insight and support from fellow staff members. The diagnosis of cancer is incredibly stressful, and treatments are arduous. Humor may help to ease the pain, show the human side of the health care team, and help everyone cope. Whether the patient uses humor to lighten the mood of a difficult consultation with their physician, or health care workers use it to help cheer each other through the day, humor and laughter can be valuable tools. Humor can soften the isolation experienced by both patients and staff. When used sensitively, respecting the gravity of the situation, humor can build the connection among the caregiver, patient, and family. However, insensitive joking is offensive and distressing, and experience suggests a variable acceptance of humor by patients with life-threatening illnesses, making humor a high-risk strategy, and it can be a pejorative maker of an adversive power differential. The medical literature contains little on humor, and very little research has been conducted on this common aspect of human communication. Through an examination of physician and nurse experiences, the role of humor in medicine is reviewed.
On the Impact of Macroscopic Phase Separation on Solidification Microstructures
Authors: Wu M. H. , Ludwig A. , Pelzer M. , Postl U.
Published: September 2005

A term “macroscopic phase separation” is used to describe the relative motion between different phases during solidification. This paper reports three of the latest multiphase modelling results to demonstrate the role of the phase separation in solidification and the formation of the microstructure and macrosegregation.
Simple Flow Rules for Modeling the Behaviour of Inhomogeneous Viscoplastic Materials
Authors: Montheillet F. , Damamme G.
Published: September 2005

The “Iso‐W” approach recently proposed to generate simple flow rules for two phase materials is extended to nonlinear viscoplastic constituents and generalized, which produces three families of models. Comparison with the Hashin‐Shtrikman bounds leads to select the variant assuming strain rate compatibility and stress equilibrium. The “Iso‐W” assumption is in fairly well agreement with the Mori‐Tanaka and self‐consistent models for mixtures of both linear and nonlinear materials.
A CTLA4high genotype is associated with myasthenia gravis in thymoma patients
Authors: Chuang Wen‐Yu , Ströbel Philipp , Gold Ralf , Nix Wilfred , Schalke Berthold , Kiefer Reinhard , Opitz Andreas , Klinker Erdwine , Müller‐Hermelink Hans K. , Marx Alexander
Published: September 2005

Myasthenia gravis (MG) in thymoma patients depends critically on intratumorous generation and export of mature autoreactive CD4+ T cells. Why non‐MG thymomas fail to produce CD4+ T cells is unknown. We studied three single‐nucleotide polymorphisms of the cytotoxic T‐lymphocyte–associated antigen 4(CTLA4) gene in thymoma patients, nonthymoma early‐onset MG patients, and control subjects. Surprisingly, the CTLA4high genotype +49A/A, which is protective against several autoimmune diseases, exerted a prominent predisposing effect to paraneoplastic MG in thymoma patients. The unusual disease association with a CTLA4high genotype implies a unique pathogenesis of paraneoplastic MG, with high CTLA4 levels possibly supporting the nontolerogenic selection of CD4+ T cells in MG‐associated thymomas. Ann Neurol 2005;58:644–648
Paraneoplastic encephalitis, psychiatric symptoms, and hypoventilation in ovarian teratoma
Authors: Vitaliani Roberta , Mason Warren , Ances Beau , Zwerdling Theodore , Jiang Zhilong , Dalmau Josep
Published: September 2005

We report four young women who developed acute psychiatric symptoms, seizures, memory deficits, decreased level of consciousness, and central hypoventilation associated with ovarian teratoma (OT) and cerebrospinal fluid (CSF) inflammatory abnormalities. Three patients recovered with treatment of the tumor or immunosuppression and one died of the disorder. Five other OT patients with a similar syndrome and response to treatment have been reported. Our patients' serum or CSF showed immunolabeling of antigens that were expressed at the cytoplasmic membrane of hippocampal neurons and processes and readily accessed by antibodies in live neurons. Immunoprobing of a hippocampal‐expression library resulted in the isolation of EFA6A, a protein that interacts with a member of the two‐pore‐domain potassium channel family and is involved in the regulation of the dendritic development of hippocampal neurons. EFA6A‐purified antibodies reproduced the hippocampal immunolabeling of all patients' antibodies and colocalized with them at the plasma membrane. These findings indicate that in a young woman with acute psychiatric symptoms, seizures, and central hypoventilation, a paraneoplastic immune‐mediated syndrome should be considered. Recognition of this disorder is important because despite the severity of the symptoms, patients usually recover. The location and function of the isolated antigen suggest that the disorder is directly mediated by antibodies. Ann Neurol 2005;58:594–604
Systemic juvenile rheumatoid arthritis: Cognitive function and social adjustment
Authors: Feldmann Reinhold , Weglage Josef , Roth Johannes , Foell Dirk , Frosch Michael
Published: September 2005

In contrast with other systemic rheumatic diseases in childhood, no systematic studies exist that focus on possible long‐term risks for central nervous system involvement in systemic juvenile rheumatoid arthritis (SJRA). We investigated 31 children and adolescents with SJRA, aged 6 to 24 years (mean, 12.5 years; standard deviation, 4.3 years), with mean disease duration of 6.2 years (standard deviation, 3.5 years; range, 0.6–14 years) for their cognitive and fine motor abilities. We also examined 31 matched healthy control subjects. In addition, parents assessed social activities and social and emotional problems in their children. Patients and control subjects performed within normal limits of intelligence quotient, memory and learning, attention, and fine motor scores. Less social activities were reported for patients. Patients and control subjects, however, had normal social and emotional problem scores. SJRA, although a burdensome chronic disease, is not associated with cognitive impairment or increased social and emotional problems. Cognitive performance and social adjustment of young patients with SJRA are not affected by disease activity and duration. Ann Neurol 2005;58:605–609
Interactive and dynamic visualizations in teaching and learning of anatomy: A cognitive load perspective
Authors: Khalil Mohammed K. , Paas Fred , Johnson Tristan E. , Payer Andrew F.
Published: September 2005

With the increasing use of computers in the classroom and the advancement of information technology, a requirement to investigate and evaluate different strategies for the presentation of verbal information in interactive and dynamic visualizations has risen to a high level of importance. There is a need for research efforts that apply cognitive load theory (CLT), cognitive learning strategies, and established principles of multimedia design to conduct empirical research that will add to our knowledge of designing and developing dynamic visualizations for teaching and learning anatomy. The impact of improved teaching and learning of anatomical sciences and the development of a set of guiding principles to facilitate the design and development of effective dynamic visualizations represent a significant achievement for medical education with wide application. This theoretical paper presents the foundations of CLT, cognitive learning strategies, and principles of multimedia design to guide the needed research on dynamic visualizations. Anat Rec (Part B: New Anat) 286B:8–14, 2005. © 2005 Wiley‐Liss, Inc.
Investigation of radical‐based damage of RNase A in aqueous solution and lipid vesicles
Authors: Torreggiani Armida , Tamba Maurizio , Manco Immacolata , Faraone‐Mennella M. R. , Ferreri Carla , Chatgilialoglu C.
Published: September 2005

The γ‐irradiation of bovine pancreatic ribonuclease A (RNase A) in aqueous solution were investigated at different doses by vibrational spectroscopy as well as enzymatic assay, electrophoresis, and HPLC analysis. Both functional and structural changes of the protein were caused by attack of H• atoms and •OH radicals. In particular, Raman spectroscopy was shown to be a useful tool in identifying conformational changes of the protein structure and amino acidic residues that are preferential sites of the radical attack (i.e., tyrosine and methionine). After partial structural changes by the initial radical attack, the internal sulfur‐containing amino acid residues were rendered susceptible to transformation. By using the biomimetic model of dioleoyl phosphatidyl choline vesicle suspensions containing RNase A, the damage to methione residues could be connected to a parallel alteration of membrane unsaturated lipids. In fact, thiyl radical species formed from protein degradation can diffuse into the lipid bilayer and cause isomerization of the naturally occurring cis double bonds. As a consequence, trans unsaturated fatty acids are formed in vesicles and can be considered to be markers of this protein damage. © 2005 Wiley Periodicals, Inc. Biopolymers 81: 39–50, 2006

This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com