bluuebunny/crossref_metadata_2025 huggingface dataset:
Neurosteroid Effects on GABAergic Synaptic Plasticity in Hippocampus
Authors: Hsu Fu-Chun , Waldeck Robert , Faber Donald S. , Smith Sheryl S.
Published: May 2006

We have previously reported that short-term (48–72 h) exposure to the GABA-modulatory steroid 3α-OH-5α-pregnan-20-one (3α,5α-THP) increases expression of the α4 subunit of the GABAAreceptor (GABAR) in the hippocampus of adult rats. This change in subunit composition was accompanied by altered pharmacology and an increase in general excitability associated with acceleration of the decay time constant (τ) for GABA-gated current of pyramidal cells acutely isolated from CA1 hippocampus similar to what we have reported following withdrawal from the steroid after chronic long-term administration. Because GABAR can be localized to either synaptic or extrasynaptic sites, we tested the hypothesis that this change in receptor kinetics is mediated by synaptic GABAR. To this end, we evaluated the decay kinetics of TTX-resistant miniature inhibitory postsynaptic currents (mIPSCs) recorded from CA1 pyramidal cells in hippocampal slices following 48-h treatment with 3α,5α/β-THP (10 mg/kg, ip). Hormone treatment produced a marked acceleration in the fast decay time constant (τfast) of GABAergic mIPSCs. This effect was prevented by suppression of α4-subunit expression with antisense (AS) oligonucleotide, suggesting that hormone treatment increases α4-containing GABAR subsynaptically. This conclusion was further supported by pharmacological data from 3α,5β-THP-treated animals, demonstrating a bimodal distribution of τs for individual mIPSCs following bath application of the α4-selective benzodiazepine RO15–4513, with a shift to slower values. Because 40–50% of the individual τs were also shifted to slower values following bath application of the non–α4-selective benzodiazepine agonist lorazepam (LZM), we suggest that the number of GABAR synapses containing α4 subunits is equivalent to those that do not following 48-h administration of 3α,5β-THP. The decrease in GABAR-mediated charge transfer resulting from accelerated current decay may then result in increased excitability of the hippocampal circuitry, an effect consistent with the increased behavioral excitability we have previously demonstrated.
Hyperalgesia and Neural Excitability Following Injuries to Central and Peripheral Branches of Axons and Somata of Dorsal Root Ganglion Neurons
Authors: Song Xue-Jun , Vizcarra Carlos , Xu Dong-Sheng , Rupert Ronald L. , Wong Zheng-Nan
Published: May 2006

We examined thermal hyperalgesia, excitability of dorsal root ganglion (DRG) neurons, and antinociceptive effects of N-methyl-d-aspartate (NMDA) receptor antagonists in rats with injury to different regions of DRG neurons. The central or peripheral branches of axons of DRG neurons were injured by partial dorsal rhizotomy (PDR) and chronic constriction injury of sciatic nerve (CCI), respectively, or the somata injured by chronic compression of DRG (CCD). Thermal hyperalgesia was evidenced by significantly shortened latencies of foot withdrawal to radiant heat stimulation of the plantar surface. Intracellular recordings were obtained in vitro from L4and/or L5ganglia. There are four principle findings: 1) PDR as well as CCD and CCI induced thermal hyperalgesia; 2) PDR produced significantly less severe and shorter duration hyperalgesia than CCD and CCI; 3) intrathecal administration of NMDA receptor antagonistsd-2-amino-5-phosphonovaleric acid (APV) and dizocilpine maleate (MK-801) inhibited thermal hyperalgesia in PDR, CCD, and CCI rats. Pretreatment of APV and MK-801 delayed the emergence of hyperalgesia for 48–72 h, while posttreatment inhibited hyperalgesia for 24–36 h; and 4) CCD and CCI increased excitability of DRG neurons as judged by the significantly lowered threshold currents and action potential voltage thresholds and increased incidence of repetitive discharges. However, PDR did not alter the excitability of DRG neurons. These findings indicate that injury to the dorsal root, compared with injury to the peripheral nerve or DRG somata has different effects on the development of hyperalgesia. These contributions involve different changes in DRG membrane excitability, but each involves pathways (presumably in the spinal cord) that depend on NMDA receptors.
Recruitment of Local Inhibitory Networks by Horizontal Connections in Layer 2/3 of Ferret Visual Cortex
Authors: Tucker Thomas R. , Katz Lawrence C.
Published: May 2006

To investigate how neurons in cortical layer 2/3 integrate horizontal inputs arising from widely distributed sites, we combined intracellular recording and voltage-sensitive dye imaging to visualize the spatiotemporal dynamics of neuronal activity evoked by electrical stimulation of multiple sites in visual cortex. Individual stimuli evoked characteristic patterns of optical activity, while delivering stimuli at multiple sites generated interacting patterns in the regions of overlap. We observed that neurons in overlapping regions received convergent horizontal activation that generated nonlinear responses due to the emergence of large inhibitory potentials. The results indicate that co-activation of multiple sets of horizontal connections recruit strong inhibition from local inhibitory networks, causing marked deviations from simple linear integration.
Endogenous Acetylcholine and Nicotine Activation Enhances GABAergic and Glycinergic Inputs to Cardiac Vagal Neurons
Authors: Wang Jijiang , Wang Xin , Irnaten Mustapha , Venkatesan Priya , Evans Cory , Baxi Sunit , Mendelowitz David
Published: May 2006

The heart slows during expiration and heart rate increases during inspiration. This cardiorespiratory interaction is thought to occur by increased inhibitory synaptic events to cardiac vagal neurons during inspiration. Since cholinergic receptors have been suggested to be involved in this cardiorespiratory interaction, we tested whether endogenous cholinergic activity modulates GABAergic and glycinergic neurotransmission to cardiac vagal neurons in the nucleus ambiguus, whether nicotine can mimic this facilitation, and we examined the nicotinic receptors involved. Cardiac vagal neurons in the rat were labeled with a retrograde fluorescent tracer and studied in an in vitro slice using patch-clamp techniques. Application of neostigmine (10 μM), an acetylcholinerase inhibitor, significantly increased the frequency of both GABAergic and glycinergic inhibitory postsynaptic currents (IPSCs) in cardiac vagal neurons. Exogenous application of nicotine increased the frequency and amplitude of both GABAergic and glycinergic IPSCs. The nicotinic facilitation of both GABAergic and glycinergic IPSCs were insensitive to 100 nM α-bungarotoxin but were abolished by dihydro-β-erythrodine (DHβE) at a concentration (3 μM) specific for α4β2 nicotinic receptors. In the presence of TTX, nicotine increased the frequency of GABAergic and glycinergic miniature synaptic events, which were also abolished by DHβE (3 μM). This work demonstrates that there is endogenous cholinergic facilitation of GABAergic and glycinergic synaptic inputs to cardiac vagal neurons, and activation of α4β2 nicotinic receptors at presynaptic terminals facilitates GABAergic and glycinergic neurotransmission to cardiac vagal neurons. Nicotinic facilitation of inhibitory neurotransmission to premotor cardiac parasympathetic neurons may be involved in generating respiratory sinus arrhythmia.
Rhythmically Discharging Basal Forebrain Units Comprise Cholinergic, GABAergic, and Putative Glutamatergic Cells
Authors: Manns Ian D. , Alonso Angel , Jones Barbara E.
Published: May 2006

The basal forebrain plays important roles in arousal, learning, and memory by stimulating cortical activation characterized by rhythmic slow theta and high-frequency beta-gamma activities. Although cholinergic neurons play a significant part in these roles, other, including GABAergic, neurons appear to contribute. Using juxtacellular labeling with neurobiotin of neurons recorded within the magnocellular preoptic-substantia innominata area in urethan-anesthetized rats, we show that in addition to cells that are cholinergic or GABAergic, other cells that are neither fire rhythmically in correlation with stimulation-induced rhythmic slow activity on the cortex. Neurons with the characteristics of the noncholinergic/nonGABAergic cells contain phosphate-activated glutaminase (PAG), the synthetic enzyme for transmitter glutamate and may thus be glutamatergic. Within their oscillatory spike trains, putative glutamatergic neurons fire at a lower frequency (∼20 Hz) than the GABAergic neurons (∼40 Hz) and the cholinergic neurons (average: 75 Hz), whose spike trains include high-frequency bursts. The three groups all discharge rhythmically at a slow frequency in correlation with rhythmic slow activity recorded on the prefrontal, entorhinal, piriform and olfactory bulb cortices. The predominant slow frequency corresponds to the respiratory-olfactory rhythm, which is commonly slower than, yet can be as fast as, the hippocampal theta rhythm during certain coordinated behaviors, such as sniffing-whisking. While stimulating higher frequency beta-gamma activities, putative glutamatergic together with GABAergic and cholinergic cells may thus collectively modulate rhythmic slow activity and thereby promote coherent processing and plasticity across distributed cortical networks during coordinated behaviors and states.
Effect of Neuritic Cables on Conductance Estimates for Remote Electrical Synapses
Authors: Prinz Astrid A. , Fromherz Peter
Published: May 2006

The conductance of electrical synapses is usually estimated from voltage recordings at the neuronal somata under the assumption that each cell is isopotential. This approach neglects effects of intervening neurites. For a cell pair with unbranched neurites and an electrical synapse at their ends, we used cable theory to derive an analytical expression that relates the synaptic conductance to voltage recordings at the cell bodies and to the neurite properties. The equation implies that the conventional method significantly underestimates the actual synapse conductance if the neurite length is comparable to the electrotonic length constant and if the synaptic conductance is similar to the serial neurite conductance. For an experimental test, we cultured pairs of snail neurons on protein patterns, resulting in a geometry that matched the theoretical model. Using the isopotential theory, we estimated the synapse conductances and found them to be rather weak. To obtain the cable properties, we recorded spatiotemporal maps of signal propagation in the neurites using a voltage-sensitive dye. Fits of these maps to a passive cable model showed that the snail neurons are electrotonically rather compact. Given these features of our experimental system, the synaptic conductances derived with the nonisopotential model deviated from the estimates of the isopotential theory by about 13%. This discrepancy, although small, shows that even in electrotonically compact neurons coupled by weak synapses the impact of the neuritic cables on conductance estimates cannot be neglected. When applied to less compact and more strongly coupled cell pairs in vivo, our approach can supply the realistic estimates of synaptic conductances that are necessary for a better understanding of the role of electrical coupling in neural systems.
Functional Alterations of Cat Abducens Neurons After Peripheral Tetanus Neurotoxin Injection
Authors: González-Forero David , de la Cruz Rosa R. , Delgado-Garcı́a JoséMarı́a , Álvarez Francisco J. , Pastor Ángel M.
Published: May 2006

Tetanus neurotoxin (TeNT) cleaves synaptobrevin, a protein involved in synaptic vesicle docking and fusion, thereby preventing neurotransmitter release and causing a functional deafferentation. We injected TeNT into the lateral rectus muscle of adult cats at 0.5 or 5 ng/kg (low and high dose, respectively). In the periphery, TeNT slightly slowed motor axon conduction velocity, and at high doses, partially blocked neuromuscular transmission. TeNT peripheral actions displayed time courses different to the more profound and longer-lasting central actions. Central effects were first observed 2 days postinjection and reversed after 1 mo. The low dose induce depression of inhibitory inputs, whereas the high dose produce depression of both inhibitory and excitatory inputs. Simultaneous recordings of eye movement and neuronal firing revealed that low-dose injections specifically reduced inhibition of firing during off-directed saccadic movements, while high-dose injections of TeNT affected both inhibitory and excitatory driven firing patterns. Motoneurons and abducens interneurons were both affected in a similar way. These alterations resulted in modifications in all discharge characteristic analyzed such as background firing, threshold for recruitment, and firing sensitivities to both eye position and velocity during spontaneous movements or vestibulo-ocular reflexes. Removal of inhibition after low-dose injections also altered firing patterns, and although firing activity increased, it did not result in muscle tetanic contractions. Removal of inhibition and excitation by high-dose injections resulted in a decrease in firing modulation with eye movements. Our findings suggest that the distinct behavior of oculomotor and spinal motor output following TeNT intoxication could be explained by their different interneuronal and proprioceptive control.
Muscarinic and Nicotinic Presynaptic Modulation of EPSCs in the Nucleus Accumbens During Postnatal Development
Authors: Zhang Liming , Warren Richard A.
Published: May 2006

We have studied the modulatory effects of cholinergic agonists on excitatory postsynaptic currents (EPSCs) in nucleus accumbens (nAcb) neurons during postnatal development. Recordings were obtained in slices from postnatal day 1 (P1) to P27 rats using the whole cell patch-clamp technique. EPSCs were evoked by local electrical stimulation, and all experiments were conducted in the presence of bicuculline methchloride in the bathing medium and with QX-314 in the recording pipette. Under these conditions, postsynaptic currents consisted of glutamatergic EPSCs typically consisting of two components mediated by AMPA/kainate (KA) and N-methyl-d-aspartate (NMDA) receptors. The addition of acetylcholine (ACh) or carbachol (CCh) to the superfusing medium resulted in a decrease of 30–60% of both AMPA/KA- and NMDA-mediated EPSCs. In contrast, ACh produced an increase (≈35%) in both AMPA/KA and NMDA receptor-mediated EPSCs when administered in the presence of the muscarinic antagonist atropine. These excitatory effects were mimicked by the nicotinic receptor agonist 1,1-dimethyl-4-phenyl-piperazinium iodide (DMPP) and blocked by the nicotinic receptor antagonist mecamylamine, showing the presence of a cholinergic modulation mediated by nicotinic receptors in the nAcb. The antagonistic effects of atropine were mimicked by pirenzepine, suggesting that the muscarinic depression of the EPSCs was mediated by M1/M4receptors. In addition, the inhibitory effects of ACh on NMDA but not on AMPA/KA receptor-mediated EPSC significantly increased during the first two postnatal weeks. We found that, under our experimental conditions, cholinergic agonists produced no changes on membrane holding currents, on the decay time of the AMPA/KA EPSC, or on responses evoked by exogenous application of glutamate in the presence of tetrodotoxin, but they produced significant changes in paired pulse ratio, suggesting that their action was mediated by presynaptic mechanisms. In contrast, CCh produced consistent changes in the membrane and firing properties of medium spiny (MS) neurons when QX-314 was omitted from the recording pipette solution, suggesting that this substance actually blocked postsynaptic cholinergic modulation. Together, these results suggest that ACh can decrease or increase glutamatergic neurotransmission in the nAcb by, respectively, acting on muscarinic and nicotinic receptors located on excitatory terminals. The cholinergic modulation of AMPA/KA and NMDA receptor-mediated neurotransmission in the nAcb during postnatal development could play an important role in activity-dependent developmental processes in refining the excitatory drive on MS neurons by gating specific inputs.
Biophysical Properties and Ionic Signature of Neuronal Progenitors of the Postnatal Subventricular Zone In Situ
Authors: Wang D. D. , Krueger D. D. , Bordey A.
Published: May 2006

Previous studies have reported the presence of neuronal progenitors in the subventricular zone (SVZ) and rostral migratory stream (RMS) of the postnatal mammalian brain. Although many studies have examined the survival and migration of progenitors after transplantation and the factors influencing their proliferation or differentiation, no information is available on the electrophysiological properties of these progenitors in a near-intact environment. Thus we performed whole cell and cell-attached patch-clamp recordings of progenitors in brain slices containing either the SVZ or the RMS from postnatal day 15 to day 25 mice. Both regions displayed strong immunoreactivity for nestin and neuron-specific class III β-tubulin, and recorded cells displayed a morphology typical of the neuronal progenitors known to migrate throughout the SVZ and RMS to the olfactory bulb. Recorded progenitors had depolarized zero-current resting potentials (mean more depolarized than –28 mV), very high input resistances (about 4 GΩ), and lacked action potentials. Using the reversal potential of K+currents through a cell-attached patch a mean resting potential of –59 mV was estimated. Recorded progenitors displayed Ca2+-dependent K+currents and TEA-sensitive-delayed rectifying K+(KDR) currents, but lacked inward K+currents and transient outward K+currents. KDRcurrents displayed classical kinetics and were also sensitive to 4-aminopyridine and α-dendrotoxin, a blocker of Kv1 channels. Na+currents were found in about 60% of the SVZ neuronal progenitors. No developmental changes were observed in the passive membrane properties and current profile of neuronal progenitors. Together these data suggest that SVZ neuronal progenitors display passive membrane properties and an ionic signature distinct from that of cultured SVZ neuronal progenitors and mature neurons.
Mu-opioid Receptors Facilitate the Propagation of Excitatory Activity in Rat Hippocampal Area CA1 by Disinhibition of all Anatomical Layers
Authors: McQuiston A. Rory , Saggau Peter
Published: May 2006

Hippocampal μ-opioid receptors (MORs) have been implicated in memory formation associated with opiate drug abuse. MORs modulate hippocampal synaptic plasticity acutely, when chronically activated, and during drug withdrawal. At the network level, MORs increase excitability in area CA1 by disinhibiting pyramidal cells. The precise inhibitory interneuron subtypes affected by MOR activation are unknown; however, not all subtypes are inhibited, and specific interneuron subtypes have been shown to preferentially express MORs. Here we investigate, using voltage-sensitive dye imaging in brain slices, the effect of MOR activation on the patterns of inhibition and on the propagation of excitatory activity in rat hippocampal CA1. MOR activation augments excitatory activity evoked by stimulating inputs in stratum oriens [i.e., Schaffer collateral and commissural pathway (SCC) and antidromic], stratum radiatum (i.e., SCC), and stratum lacunosum-moleculare (SLM; i.e., perforant path and thalamus). The augmented excitatory activity is further facilitated as it propagates through the CA1 network. This was observed as a proportionately larger increase in amplitudes of excitatory activity at sites distal from where the activity was evoked. This facilitation was observed for excitatory activity propagating from all three stimulation sites. The augmentation and facilitation were prevented by GABAAreceptor antagonists (bicuculline, 30 μM), but not by GABABreceptor antagonists (CGP 55845, 10 μM). Furthermore, MOR activation inhibited IPSPs in all layers of area CA1. These findings suggest that MOR-induced suppression of GABA release onto GABAAreceptors augments all inputs to CA1 pyramidal cells and facilitates the propagation of excitatory activity through the network of area CA1.
TNP-ATP-Resistant P2X Ionic Current on the Central Terminals and Somata of Rat Primary Sensory Neurons
Authors: Tsuzuki Kenzo , Ase Ariel , Séguéla Philippe , Nakatsuka Terumasa , Wang Cong-Yi , She Jin-Xiong , Gu Jianguo G.
Published: May 2006

P2X receptors have been suggested to be expressed on the central terminals of Aδ-afferent fibers innervating dorsal horn lamina V and play a role in modulating sensory synaptic transmission. These P2X receptors have been widely thought to be P2X2+3receptors. However, we have recently found that P2X receptor-mediated modulation of sensory transmission in lamina V is not inhibited by trinitrophenyl-adenosine triphosphate (TNP-ATP), a potent antagonist of P2X1, P2X3homomers, and P2X2+3heteromers. To provide direct evidence for the presence of TNP-ATP-resistant P2X receptors on primary afferent fibers, we examined α,β-methylene-ATP (αβmeATP)-evoked currents and their sensitivity to TNP-ATP in rat dorsal root ganglion (DRG) neurons. αβmeATP evoked fast currents, slow currents, and mixed currents that contained both fast and slow current-components. Fast currents and fast current components in the mixed currents were both completely inhibited by 0.1 μM TNP-ATP ( n = 14). Both slow currents and slow-current components in the mixed currents showed broad spectrum of sensitivity to 1 μM TNP-ATP, ranging from complete block (TNP-ATP-sensitive) to little block (TNP-ATP-resistant). TNP-ATP-resistant currents evoked by 10 μM αβmeATP could be largely inhibited by 10 μM iso-pyridoxalphosphate-6-azophenyl-2′,4′-disulphonic acid. Cells with P2X currents that were highly resistant to TNP-ATP were found to be insensitive to capsaicin. These results suggest that TNP-ATP-resistant P2X receptor subtypes are expressed on capsaicin-insensitive Aδ-afferent fibers and play a role in modulating sensory transmission to lamina V neurons.
A protein evolution model with independent sites that reproduces site-specific amino acid distributions from the Protein Data Bank
Authors: Bastolla Ugo , Porto Markus , Roman H Eduardo , Vendruscolo Michele
Published: May 2006

Background

Since thermodynamic stability is a global property of proteins that has to be conserved during evolution, the selective pressure at a given site of a protein sequence depends on the amino acids present at other sites. However, models of molecular evolution that aim at reconstructing the evolutionary history of macromolecules become computationally intractable if such correlations between sites are explicitly taken into account.

Results

We introduce an evolutionary model with sites evolving independently under a global constraint on the conservation of structural stability. This model consists of a selection process, which depends on two hydrophobicity parameters that can be computed from protein sequences without any fit, and a mutation process for which we consider various models. It reproduces quantitatively the results of Structurally Constrained Neutral (SCN) simulations of protein evolution in which the stability of the native state is explicitly computed and conserved. We then compare the predicted site-specific amino acid distributions with those sampled from the Protein Data Bank (PDB). The parameters of the mutation model, whose number varies between zero and five, are fitted from the data. The mean correlation coefficient between predicted and observed site-specific amino acid distributions is larger than  = 0.70 for a mutation model with no free parameters and no genetic code. In contrast, considering only the mutation process with no selection yields a mean correlation coefficient of  = 0.56 with three fitted parameters. The mutation model that best fits the data takes into account increased mutation rate at CpG dinucleotides, yielding  = 0.90 with five parameters.

Conclusion

The effective selection process that we propose reproduces well amino acid distributions as observed in the protein sequences in the PDB. Its simplicity makes it very promising for likelihood calculations in phylogenetic studies. Interestingly, in this approach the mutation process influences the effective selection process, i.e. selection and mutation must be entangled in order to obtain effectively independent sites. This interdependence between mutation and selection reflects the deep influence that mutation has on the evolutionary process: The bias in the mutation influences the thermodynamic properties of the evolving proteins, in agreement with comparative studies of bacterial proteomes, and it also influences the rate of accepted mutations.
Attribution of physical complaints to the air disaster in Amsterdam by exposed rescue workers: an epidemiological study using historic cohorts
Authors: Slottje Pauline , Smidt Nynke , Twisk Jos WR , Huizink Anja C , Witteveen Anke B , van Mechelen Willem , Smid Tjabe
Published: May 2006

Background

In 1992 a cargo aircraft crashed into a residential area of Amsterdam. A troublesome aftermath followed, with rumors on potential toxic exposures and health consequences. Health concerns remained even though no excess morbidity was predicted in retrospective risk evaluations. This study aimed to assess to what extent the rescue workers attribute long-term physical complaints to this disaster, including its aftermath, and to examine associations between such attribution and types of exposure and background variables.

Methods

Historic cohort study that collected questionnaire data on occupational disaster exposure, attribution of physical complaints, and background variables on average 8.5 years post-disaster. For the present study the workers who were exposed to the disaster were selected from the historic cohort, i.e. the professional firefighters (n = 334), police officers (n = 834), and accident and wreckage investigators (n = 241) who performed disaster-related tasks.

Results

Across the three occupational groups, a consistent percentage (ranging from 43% to 49%) of exposed workers with long-term physical complaints attributed these to the disaster, including its aftermath. Those with more physical complaints attributed these to a stronger degree. Multivariate logistic regression analyses showed that attribution was significantly more often reported by firefighters who rescued people, and by police officers who reported the identification and recovery of or search for victims and human remains, clean-up, or security and surveillance of the disaster area; who witnessed the immediate disaster scene; who had a close one affected by the disaster; and who perceived the disaster as the worst thing that ever happened to them. Age, sex and educational level were not significantly associated with attribution.

Conclusion

This study provides further cross-sectional evidence for the role of causal attribution in post-disaster subjective physical health problems. After on average 8.5 years, almost a third (32%) of all the exposed workers, and almost half (45%) of the exposed workers with physical complaints, attributed these complaints to the disaster, including its aftermath. The similarity of the results across the occupational groups suggests a general rather than an occupation-specific attribution process. Longitudinal studies are needed to determine whether causal disaster attribution leads to persistence of post-disaster complaints and health care utilization.
Principles underlying the design of "The Number Race", an adaptive computer game for remediation of dyscalculia
Authors: Wilson Anna J , Dehaene Stanislas , Pinel Philippe , Revkin Susannah K , Cohen Laurent , Cohen David
Published: May 2006

Background

Adaptive game software has been successful in remediation of dyslexia. Here we describe the cognitive and algorithmic principles underlying the development of similar software for dyscalculia. Our software is based on current understanding of the cerebral representation of number and the hypotheses that dyscalculia is due to a "core deficit" in number sense or in the link between number sense and symbolic number representations.

Methods

"The Number Race" software trains children on an entertaining numerical comparison task, by presenting problems adapted to the performance level of the individual child. We report full mathematical specifications of the algorithm used, which relies on an internal model of the child's knowledge in a multidimensional "learning space" consisting of three difficulty dimensions: numerical distance, response deadline, and conceptual complexity (from non-symbolic numerosity processing to increasingly complex symbolic operations).

Results

The performance of the software was evaluated both by mathematical simulations and by five weeks of use by nine children with mathematical learning difficulties. The results indicate that the software adapts well to varying levels of initial knowledge and learning speeds. Feedback from children, parents and teachers was positive. A companion article [1] describes the evolution of number sense and arithmetic scores before and after training.

Conclusion

The software, open-source and freely available online, is designed for learning disabled children aged 5–8, and may also be useful for general instruction of normal preschool children. The learning algorithm reported is highly general, and may be applied in other domains.
Impact of functionalised community mental health teams on in-patient care
Authors: Commander Martin , Disanyake Lallana
Published: May 2006

Aims and Method

A before-and-after design was used to evaluate whether the routine implementation of functionalised community mental health teams (CMHTs) would reduce demand for in-patient care. Residents of west Birmingham, aged 16–64 years, who were in hospital between 23 March 1992 and 22 September 1992 were identified. The same period was studied in 2003 by which time the newly introduced teams were well established.

Results

The number of people in hospital fell by one-third between 1992 and 2003. There was no change in the number of admissions by each patient or the length of stay. The percentage identified as Black, single, living with other adults, resident in hostels and unemployed increased, as did the proportion with schizophrenia or manic depression and those detained compulsorily.

Clinical Implications

Functionalised CMHTs can decrease the use of in-patient care in inner-city areas. They may also attenuate, but by no means halt, the rise in compulsory admissions seen across the UK in the past decade.
Prognostic Factors in Children With Extragonadal Malignant Germ Cell Tumors: A Pediatric Intergroup Study
Authors: Marina Neyssa , London Wendy B. , Frazier A. Lindsay , Lauer Stephen , Rescorla Frederick , Cushing Barbara , Malogolowkin Marcio H. , Castleberry Robert P. , Womer Richard B. , Olson Thomas
Published: May 2006

Purpose

To investigate prognostic factors for pediatric extragonadal malignant germ cell tumors (PEMGCT).

Materials and Methods

Between 1990 and 1996, patients with stage I through IV PEMGCT were eligible for a trial of cisplatin dose intensity. We retrospectively investigated prognostic factors for PEMGCT, including age, stage, primary site, treatment, and elevated alfa fetoprotein by univariate and multivariate analysis.

Results

The 165 patients had a median age of 1.9 years (range, 3 days to 18.5 years); 109 were female; and 99 had alfa fetoprotein ≥ 10,000. There were 30 stage I/II, 61 stage III, and 74 stage IV tumors; primary sites included 88 sacrococcygeal, 39 thoracic, and 38 others. The 5-year overall survival (OS) and event-free survival (EFS) rates with standard deviations were 83.4% ± 3.7% and 79.0% ± 4.1%, respectively. Univariate analysis identified age ≥ 12 years as a highly significant prognostic factor for EFS (5-year EFS, 48.9% ± 15.6% v 84.1% ± 3.9%; P < .0001) and for OS (5-year OS, 53.7% ± 14.9% v 88.5% ± 3.4%; P < .0001), whereas treatment was of borderline significance (P = .0777). Multivariate Cox proportional hazards regression identified only age ≥ 12 years as a significant prognostic factor for EFS (P = .0002). In multivariate Cox regression for OS, the combination of age and primary site was highly significant (P < .0001). Patients ≥ 12 years of age with thoracic tumors had six times the risk of death compared with patients younger than 12 years with other primaries.

Conclusion

Age is the most predictive factor of EFS in PEMGCT. There is a significant interaction between age and primary site, suggesting that patients ≥ 12 years of age with thoracic tumors are a biologically distinct group.
Global Optimality Conditions for Discrete and Nonconvex Optimization—With Applications to Lagrangian Heuristics and Column Generation
Authors: Larsson Torbjörn , Patriksson Michael
Published: May 2006

The well-known and established global optimality conditions based on the Lagrangian formulation of an optimization problem are consistent if and only if the duality gap is zero. We develop a set of global optimality conditions that are structurally similar but are consistent for any size of the duality gap. This system characterizes a primal–dual optimal solution by means of primal and dual feasibility, primal Lagrangian ε-optimality, and, in the presence of inequality constraints, a relaxed complementarity condition analogously called δ-complementarity. The total size ε + δ of those two perturbations equals the size of the duality gap at an optimal solution. Further, the characterization is equivalent to a near-saddle point condition which generalizes the classic saddle point characterization of a primal–dual optimal solution in convex programming. The system developed can be used to explain, to a large degree, when and why Lagrangian heuristics for discrete optimization are successful in reaching near-optimal solutions. Further, experiments on a set-covering problem illustrate how the new optimality conditions can be utilized as a foundation for the construction of new Lagrangian heuristics. Finally, we outline possible uses of the optimality conditions in column generation algorithms and in the construction of core problems.
Noise Reduction of Coincidence Detector Output by the Inferior Colliculus of the Barn Owl
Authors: Christianson G. Björn , Peña José Luis
Published: May 2006

A recurring theme in theoretical work is that integration over populations of similarly tuned neurons can reduce neural noise. However, there are relatively few demonstrations of an explicit noise reduction mechanism in a neural network. Here we demonstrate that the brainstem of the barn owl includes a stage of processing apparently devoted to increasing the signal-to-noise ratio in the encoding of the interaural time difference (ITD), one of two primary binaural cues used to compute the position of a sound source in space. In the barn owl, the ITD is processed in a dedicated neural pathway that terminates at the core of the inferior colliculus (ICcc). The actual locus of the computation of the ITD is before ICcc in the nucleus laminaris (NL), and ICcc receives no inputs carrying information that did not originate in NL. Unlike in NL, the rate-ITD functions of ICcc neurons require as little as a single stimulus presentation per ITD to show coherent ITD tuning. ICcc neurons also displayed a greater dynamic range with a maximal difference in ITD response rates approximately double that seen in NL. These results indicate that ICcc neurons perform a computation functionally analogous to averaging across a population of similarly tuned NL neurons.
Cortical Sequence of Word Perception in Beginning Readers
Authors: Parviainen Tiina , Helenius Päivi , Poskiparta Elisa , Niemi Pekka , Salmelin Riitta
Published: May 2006

Efficient analysis of written words in normal reading is likely to reflect use of neural circuits formed by experience during childhood rather than an innate process. We investigated the cortical sequence of word perception in first-graders (7–8 years old), with special emphasis on occipitotemporal cortex in which, in adults, letter-string-sensitive responses are detected at 150 ms after stimulus. To identify neural activation that is sensitive to either the amount of basic visual features or specifically to letter strings, we recorded whole-head magnetoencephalography responses to words embedded in three different levels of noise and to symbol strings. As was shown previously in adults, activation reflecting stimulus nonspecific visual feature analysis was localized to occipital cortex in children. It was followed by letter-string-sensitive activation in the left occipitotemporal cortex and, subsequently, in the temporal cortex. These processing stages were correlated in timing and activation strength. Compared with adults, however, the timing of activation was clearly delayed in children, and the delay was progressively increased from occipital to occipitotemporal and further to temporal areas. This finding is likely to reflect increasing immaturity of the underlying neural generators when advancing from low-level visual analysis to higher-order areas involved in written word perception. When a salient occipitotemporal letter-string-sensitive activation was detected (10 of 18 children), its strength was correlated with phonological skills, in line with the known relevance of phonological awareness in reading acquisition.
Pragmatic contributions to the interpretation of a will
Authors: Kaplan Jeffrey P.
Published: May 2006

The ultimate meaning of a holographic will lacking all conventional indicia of sentence boundaries (capitalization, punctuation) was the subject of litigation. At the sentence level, the will was ambiguous, but syntactic and (especially) pragmatic analysis led to a clear construal of the text. The main evidence derived from an application of Grice's maxim of quantity, with support from the maxim of relevance. The linguistic analysis was echoed by the court's decision.
Variable robustness of nonstandard /r/ in English: evidence from accent disguise
Authors: Lindsey Geoff , Hirson Allen
Published: May 2006

In forensic phonetics it is valuable to identify speech features which are robust, that is, show little variability for a given speaker. This study was prompted by a case in which threatening telephone calls with apparent accent disguise exhibited standard English /r/, while the interviewed suspect exhibited /r/ pronunciations of a type traditionally described as ‘defective’. An experiment was conducted in which subjects with standard and nonstandard /r/ read sentences in their native accent and then in imitation of a different accent exhibiting standard /r/. Acoustic analysis and auditory assessment suggest that /r/ is nonstandard if its F3 is above about 2000 Hz for men and above about 2350 Hz for women. Of five subjects whose native /r/ was judged nonstandard, three were able to produce standard /r/ in the assumed accent. The results are discussed, including the possibility that degree of native nonstandardness in /r/ may be a predictor of ability to modify it.
Listeners and disguised voices: the imitation and perception of dialectal accent
Authors: Markham Duncan
Published: May 2006

This paper presents an experimental investigation into whether a group of speakers could produce convincing text readings in various dialectal accents of Swedish, and the performance of listeners in identifying the accents and determining whether the accents were natural or a disguise. It was observed that individual speakers vary greatly in their ability to produce plausible imitations of accents and to mask their own dialectal background. Examination of the listeners’ perceptual strategies contributes an important dimension to the understanding of reasoning processes in earwitnesses. The linguistically trained listeners were found to use combinations of accent markers as cues to the degree of naturalness, although some of the judgements reflected misconceptions or preconceived ideas about the possible forms of specific accents. The hazards of using speakers with certain accent features in voice line-ups and the potential problems associated with earwitness accent identification are discussed.
Reading the rights: a cautionary tale of comprehension and comprehensibility
Authors: Cotterill Janet
Published: May 2006

The UK police caution, delivered to suspects on arrest, has undergone a number of rewrites, most recently in 1995 as a reaction to the Criminal Justice and Public Order Act, 1994. This paper analyses the role played by police officers when delivering the caution in influencing its comprehensibility, by means of an in situ study of 100 detained persons and 50 police officers. Findings indicate that there is considerable variability in the paraphrases provided by officers, and that some paraphrases may in fact result in the explanation of suspects’ rights being less comprehensible than the caution itself. The paper argues that asking linguistically untrained officers to provide paraphrases which are graded for both language and comprehensibility is unreasonable; finally, the use of standardized paraphrases – along similar lines to pattern jury instructions – is discussed.
Moving Targets: Recognition of Alkyl Groups
Authors: Schramm Michael P. , Rebek Julius
Published: May 2006

Alkyl chains can adopt seemingly unusual conformations, such as helices, when bound to natural and synthetic hydrophobic receptors. This plasticity allows the alkanes to assume shapes that are congruent to the receptor's space and fill that space properly. We describe here the use of cavitands and capsules as tools that expose the forces involved in the molecular recognition of hydrocarbons. Studies using NMR spectroscopy reveal how attractive interactions and solvophobic forces are maximized in solution through unprecedented contortions of alkanes and hint at a new generation of nanoscale mechanical devices.
Is the optical rotation sign/absolute configuration relationship still a problem? Examples taken from unnatural quaternary aminoacids
Authors: Ferron Laurent , Guillen Frédéric , Coste Servane , Coquerel Gérard , Plaquevent Jean‐Christophe
Published: May 2006

The optical rotation sign/absolute configuration relationships of several α‐methyl‐α‐arylglycines have been reinvestigated by crystallographic methods, as they have been found to be inconsistent in recent literature. Assignments previously made by enzymatic resolution, by analogy with natural tertiary aminoacids were found to be erroneous in the case of these quaternary aminoacids. Chirality, 2006. © 2006 Wiley‐Liss, Inc.
Expression of epithelial membrane protein‐2 is associated with endometrial adenocarcinoma of unfavorable outcome
Authors: Wadehra Madhuri , Natarajan Sathima , Seligson David B. , Williams Carmen J. , Hummer Amanda J. , Hedvat Cyrus , Braun Jonathan , Soslow Robert A.
Published: May 2006

BACKGROUND

Epithelial membrane protein 2 (EMP2) is an estrus‐regulated tetraspan protein that is required for endometrial competence in blastocyst implantation. EMP2 controls surface levels of several classes of integrin and other cell‐interaction molecules, and their trafficking to glycolipid‐enriched lipid raft domains is important in receptor signaling. These features suggest that EMP2 may contribute to neoplastic traits of endometrial cancer. The objective of this study was to determine the prevalence of EMP2 expression in endometrial neoplasms and its clinical significance.

METHODS

EMP2 immunophenotype, histologic diagnosis, grade, the presence of lymphovascular invasion, disease stage, and clinical follow‐up were determined for 99 endometrial cancers.

RESULTS

Significant EMP2 expression (EMP2 positive) was observed in 12 of 99 cancers (9 endometrioid [6 International Federation of Gynecology and Obstetrics Grade 3], 1 serous, 1 mixed endometrioid and serous, and 1 mixed endometrioid and clear cell), and weak EMP2 expression was observed in 11 cancers. EMP2‐positive tumors were more likely than others to be myometrium invasive, high stage, and recurrent, persistent, or fatal. The overall median survival for patients with EMP2‐positive tumor was only 23 months, whereas the medial survival was not reached for patients with EMP2‐weak and EMP2‐negative tumors. The median disease‐free interval was only 11 months for patients with EMP2‐positive tumors and was not reached for patients with EMP2‐weak and EMP2‐negative tumors. A multivariate analysis of disease‐free survival demonstrated independent, negative prognostic significance for EMP2 expression, high stage, and high‐risk histologic subtypes.

CONCLUSIONS

EMP2 expression is a feature of some prognostically unfavorable endometrial cancers. Its utility for clinical decision making and its biologic role in endometrial cancer deserves further study in a larger series of patients. Cancer 2006. © 2006 American Cancer Society.
Innovation im deutschen Großbrückenbau durch Zustimmung im Einzelfall – Erstmalige Anwendung von großen Schrägkabeln aus Litzenbündeln
Authors: Schellenberg Türk
Published: May 2006

Seit 1936 verbindet der Rügendamm mit seiner Klappbrücke über den Ziegelgraben die Hansestadt Stralsund und die Insel Rügen ‐ Deutschlands größte Insel. Vor allem in der Ferienzeit und an den Wochenenden kommt es zu Staus und langen Wartezeiten im Straßenverkehr. Durch die zweite Strelasundquerung, ein zirka 2830 m langes Brückenbauwerk, welches ab dem Jahr 2007 Stralsund mit Rügen verbinden wird, sollen diese Verkehrsbeeinträchtigungen beendet werden.
Chemical composition and antimicrobial activity of the essential oil of Phlomis ferruginea Ten. (Lamiaceae) growing wild in Southern Italy
Authors: Formisano Carmen , Senatore Felice , Bruno Maurizio , Bellone Gabriella
Published: May 2006

The essential oil of aerial parts of Phlomis ferruginea (Lamiaceae), growing wild in Southern Italy, was obtained by hydrodistillation and analysed by GC and GC–MS. 60 compounds, representing 92.3% of the oil, were identified. The major components were β‐caryophyllene (15.6%), hexadecanoic acid (12.8%), germacrene D (8.9%), caryophyllene oxide (6.7%) and α‐thujone (5.5%). The evaluation of antimicrobial activity against some bacterial species has been tested. Copyright © 2006 John Wiley & Sons, Ltd.
Differentiation of mononuclear precursors into osteoclasts on the surface of Si‐substituted hydroxyapatite
Authors: Botelho C. M. , Brooks R. A. , Spence G. , McFarlane I. , Lopes M. A. , Best S. M. , Santos J. D. , Rushton N. , Bonfield W.
Published: May 2006

In healthy bone, resorption and synthesis are in perfect coordination. In previous studies we demonstrated that the incorporation of silicon into the hydroxyapatite (HA) lattice enhances the proliferation and differentiation of human osteoblasts. Therefore, the aim of this study was to demonstrate the effect of silicon‐substituted HA (0.8 and 1.5 wt % Si‐HA) on the differentiation of mononuclear cells into osteoclasts, using two different starting cultures, peripheral blood mononuclear cells (PBMC) and monocytes expressing the CD14 antigen (CD14+). Through this study, it was possible to demonstrate that Si‐HA allows the differentiation of mononuclear cells into mature osteoclasts, independent of the starting culture, PBMC or CD14+. Most of the cells on the surface of the materials expressed osteoclastic markers: actin rings, several nuclei, positivity for tartrate‐resistant acid phosphatase (TRAP), and vitronectin receptor. In the presence of osteoclasts, a higher release of calcium and phosphate into the medium from the 1.5 wt % Si‐HA substrate was detected when compared to the HA substrate; therefore, these results indicate higher osteoclastic resorptive activity on the 1.5 wt % Si‐HA surface. Si‐HA can be resorbed by cellular mechanisms and have a stimulatory effect on osteoclasts, although the underlying mechanism is still poorly understood. © 2006 Wiley Periodicals, Inc. J Biomed Mater Res, 2006