bluuebunny/crossref_metadata_2025 huggingface dataset:
A Randomized Quasi-Monte Carlo Simulation Method for Markov Chains
Authors: L'Ecuyer Pierre , Lécot Christian , Tuffin Bruno
Published: September 2008

We introduce and study a randomized quasi-Monte Carlo method for the simulation of Markov chains up to a random (and possibly unbounded) stopping time. The method simulates n copies of the chain in parallel, using a (d+1)-dimensional, highly uniform point set of cardinality n, randomized independently at each step, where d is the number of uniform random numbers required at each transition of the Markov chain. The general idea is to obtain a better approximation of the state distribution, at each step of the chain, than with standard Monte Carlo. The technique can be used in particular to obtain a low-variance unbiased estimator of the expected total cost when state-dependent costs are paid at each step. It is generally more effective when the state space has a natural order related to the cost function.

We provide numerical illustrations where the variance reduction with respect to standard Monte Carlo is substantial. The variance can be reduced by factors of several thousands in some cases. We prove bounds on the convergence rate of the worst-case error and of the variance for special situations where the state space of the chain is a subset of the real numbers. In line with what is typically observed in randomized quasi-Monte Carlo contexts, our empirical results indicate much better convergence than what these bounds guarantee.
Efficient Computation of Hedging Parameters for Discretely Exercisable Options
Authors: Kaniel Ron , Tompaidis Stathis , Zemlianov Alexander
Published: September 2008

We propose an algorithm to calculate confidence intervals for the values of hedging parameters of discretely exercisable options using Monte Carlo simulation. The algorithm is based on a combination of the duality formulation of the optimal stopping problem for pricing discretely exercisable options and Monte Carlo estimation of hedging parameters for European options. We show that the width of the confidence interval for a hedging parameter decreases, with an increase in the computer budget, asymptotically at the same rate as the width of the confidence interval for the price of the option. The method can handle arbitrary payoff functions, general diffusion processes, and a large number of random factors. We also present a fast, heuristic, alternative method and use our method to evaluate its accuracy.
Optimal Position-Based Warehouse Ordering in Divergent Two-Echelon Inventory Systems
Authors: Axsäter Sven , Marklund Johan
Published: September 2008

A continuous-review two-echelon inventory system with one central warehouse and a number of nonidentical retailers is considered. The retailers face independent Poisson demand and apply standard (R, Q) policies. The retailer order quantities are fixed integer multiples of a certain batch size, representing the smallest pallet or container size transported in the system. A warehouse order may consist of one or several such batches. We derive a new policy for warehouse ordering, which is optimal in the broad class of position-based policies relying on complete information about the retailer inventory positions, transportation times, cost structures, and demand distributions at all facilities. The exact analysis of the new policy includes a method for determining the expected total inventory holding and backorder costs for the entire system. The class of position-based policies encompasses both the traditional installation-stock and echelon-stock (R, Q) policies, as well as the more sophisticated policies recently analyzed in the literature. The value of more carefully incorporating a richer information structure into the warehouse ordering policy is illustrated in a numerical study.
The Innovest Austrian Pension Fund Financial Planning Model InnoALM
Authors: Geyer Alois , Ziemba William T.
Published: September 2008

This paper describes the financial planning model InnoALM we developed at Innovest for the Austrian pension fund of the electronics firm Siemens. The model uses a multiperiod stochastic linear programming framework with a flexible number of time periods of varying length. Uncertainty is modeled using multiperiod discrete probability scenarios for random return and other model parameters. The correlations across asset classes, of bonds, stocks, cash, and other financial instruments, are state dependent using multiple correlation matrices that correspond to differing market conditions. This feature allows InnoALM to anticipate and react to severe as well as normal market conditions. Austrian pension law and policy considerations can be modeled as constraints in the optimization. The concave risk-averse preference function is to maximize the expected present value of terminal wealth at the specified horizon net of expected discounted convex (piecewise-linear) penalty costs for wealth and benchmark targets in each decision period. InnoALM has a user interface that provides visualization of key model outputs, the effect of input changes, growing pension benefits from increased deterministic wealth target violations, stochastic benchmark targets, security reserves, policy changes, etc. The solution process using the IBM OSL stochastic programming code is fast enough to generate virtually online decisions and results and allows for easy interaction of the user with the model to improve pension fund performance. The model has been used since 2000 for Siemens Austria, Siemens worldwide, and to evaluate possible pension fund regulation changes in Austria.
The development of a clinically useful tool for predicting the development of psychological disorder following injury
Authors: Mason S. , Farrow T. F. D. , Fawbert D. , Smith R. , Bath P. A. , Hunter M. , Woodruff P. W. , Turpin G.
Published: September 2008

Objectives

To identify factors significantly associated with post‐traumatic stress disorder (PTSD), anxiety, and depression at 3 months post‐injury; to develop a generic model to predict the occurrence of PTSD, anxiety, and depression at 3 months post‐injury; and to validate this model in a test data set of patients.

Design

Prospective cohort study.

Methods

Participants were 823 patients attending an emergency department (ED) following accidental injury. Baseline questionnaires were completed, with 1 and 3 months postal follow‐ups. Predictor variables demonstrating significant associations with two of the three outcome measures (3‐month HAD anxiety and depression scores and PTSD symptoms) were included in multivariate regression models for each outcome. Non‐significant predictor variables were removed until all remaining independent variables made the most significant contribution to each of the three models. Models were validated using a test dataset.

Results

Previous history of mental health problems, neuroticism score and having PTSD symptoms at 1 month predicted adverse outcomes at 3 months. When used on the test datasets, the areas under the receiver operating curve (ROC) curve for the models predicting outcomes at 3 months were: PTSD=0.91 (sensitivity=88.5%); anxiety=0.87 (sensitivity=93.7%); and depression=0.87 (sensitivity=96.7%).

Conclusions

The final model performed moderately well across the three outcomes and may be useful clinically as a generic rule‐out tool to identify those who will not require follow up, watchful waiting or intervention.
Uncoupled modes and all-angle negative refraction in walled honeycomb photonic crystals
Authors: Lin Ken-Ming , Guo G. Y.
Published: September 2008

Left-handed materials have superlensing effects that enable them to surmount the optical diffraction limit. A photonic crystal is able to mimic some properties of all-angle left-landed materials. In this study, the all-angle negative refraction criteria of photonic crystals are evaluated. The MIT Photonic-Bands program is employed to calculate the band structure of walled honeycomb photonic crystals, and the finite-difference time-domain method is used to provide a snapshot of the electric field distribution inside and outside the honeycomb photonic crystals. The results indicate that the all-angle negative refraction phenomena of the honeycomb photonic crystals are correlated with the orientation of the photonic crystals. Furthermore, the role of the uncoupled modes varies based on their orientation to the all-angle negative refraction photonic crystals, in one case assisting negative refraction and in the other case preventing it. The results suggest that symmetric properties should not be ignored when considering the negative refraction of photonic crystals.
Anomalous dispersion and negative group velocity in a coherence-free cold atomic medium
Authors: Brown William G. A. , McLean Russell , Sidorov Andrei , Hannaford Peter , Akulshin Alexander
Published: September 2008

We have observed the propagation of an approximately 35 ns long light pulse with a negative group velocity through a laser-cooled 85Rb atomic medium. The anomalous dispersion results from linear atom–light interaction and is unrelated to long-lived ground-state coherences often associated with fast light in atomic media. The observed negative group velocity (−c/360) in the Rb magneto-optical trap for a pulse attenuated by less than 50% is in good agreement with the value of dispersion measured independently by a rf heterodyne method. The spectral region of anomalous dispersion is between 15 and 40 MHz, which is an order of magnitude wider than that typically associated with ground-state coherences.
Sinnvoller Einsatz von Tumormarkern / Sensible use of tumor markers
Authors: Stieber Petra , Heinemann Volker
Published: September 2008

Als Tumormarker werden heute alle nachweisbaren oder messbaren Substanzen zusammengefasst, die auf einen Tumor hinweisen oder zu seiner Charakterisierung und Messung seiner Ausbreitung und Therapieansprechen beitragen können. Humorale zirkulierende Tumormarkersubstanzen als Vorstufen normaler Antigene, ektopisch gebildete Hormone oder Enzyme, ontogenetisch alte reaktivierte Antigene, hybridom-definierte Muzine und Zytokeratine sind unter den Tumormarkern von besonderem Interesse.

Es gibt bis heute keinen tumorspezifischen Biomarker, alle bislang bekannten Tumormarker sind physiologisch beim Menschen im Blut nachweisbar. Ihre diagnostische Bedeutung liegt mehr in der Quantität denn in der Qualität. Die gemessene Tumormarkerkonzentration reflektiert Tumormasse und -ausbreitung und ist primär von der Tumorblutversorgung abhängig. Im Einzelnen stellt sie ein integrales Maß aus der im Tumor vorhandenen Tumormarker-Expression, -Synthese, -Freisetzung, dem im Organismus ablaufenden Tumormarker-Katabolismus und der Tumormarker-Exkretion dar. Tumormarker-Änderungen ohne Korrelation zur Tumormasse können deshalb auch durch Störungen von Katabolismus und der Exkretion (Leber-, Niereninsuffizienz), durch Freisetzung infolge invasiver diagnostischer Maßnahmen (Endoskopie, Biopsie, Katheterisierung) oder durch akute Therapieeinwirkung (Operation, Radio-, Chemotherapie) auftreten.

Wegen Standardisierungsproblemen zwischen gleichen Tumormarker-Tests verschiedener Hersteller, muss bei einer punktuellen Diagnostik, z.B. mittels PSA die Interpretation immer auf den assayspezifischen Referenzangaben erfolgen und bei Verlaufsbestimmungen eines Patienten der gleiche Test vom selben Hersteller (evtl. im gleichen Labor bestimmt) herangezogen werden, das Testergebnis ist zusammen mit dem jeweils verwendeten Test und Hersteller anzugeben.

Von den potenziellen Indikationen für den Einsatz zirkulierender Tumormarker ist die zur Früherkennung/Screening eines Tumors bis auf die umstrittene von PSA beim Prostatakarzinom unrealistisch, die zur Tumorlokalisation (PSA; HTG) und für die Diagnose begrenzt, die für die Prognose zunehmend von Bedeutung und die für die Therapie-Überwachung und Rezidiverkennung die meist verwandte, im Kontext mit endoskopischen und bildgebenden Verfahren.

Unter kritischer Auswahl von Tumormarkern nach Zieltumor, bei Verlaufsbestimmungen unter Verwendung der gleichen Tests und unter Berücksichtigung eines verwertbaren Informationsgehalts leisten Tumormarker einen wichtigen Beitrag zur Diagnostik, Prognosefindung, Beurteilung der Therapieantwort und Rezidiverkennung. Die Qualität des Untersuchers geht besonders auf dem Sektor der onkologischen Labordiagnostik signifikant in die Qualität des erhobenen Befundes ein.
Regelungsansätze für genetische Tests und die Zunahme des individualisierten genetischen Wissens / Regulatory approaches for genetic tests and the increase in individualized genetic knowledge
Authors: Fuchs Michael
Published: September 2008

Seit kurzem ist in den USA ein gesetzliches Verbot von Diskriminierungen aufgrund genetischer Informationen in Kraft. Die deutsche Bundesregierung hat mit den Eckpunkten für ein Gendiagnostikgesetz einen Schritt hin zur gesetzlichen Regelung unternommen. Der Artikel stellt die möglichen Ansatzpunkte einer Regulierung, insbesondere für prädiktive genetische Tests vor, analysiert, welche davon in Deutschland und den USA umgesetzt werden sollen, und fragt nach der Angemessenheit und Konsistenz. Eine weitere Anforderung an ein insgesamt wünschenswertes Gesetz ist seine Praktikabilität und Durchsetzbarkeit.
Array-CGH in der Routinediagnostik bei geistiger Entwicklungsstörung / Array CGH in the routine diagnostic work-up of mental retardation
Authors: Heinrich Uwe , von Voss Hubertus , Rost Imma
Published: September 2008

Die Array-CGH (Comparative Genomic Hybridization) ist heute zum unverzichtbaren Bestandteil der Diagnostik von mentalen Entwicklungsstörungen (mental retardation) im Kindesalter geworden. Eine Nachuntersuchung im eigenen Patientenkollektiv bei primär chromosomal unauffälligen Kindern mit mentalen Entwicklungsstörungen (n=194) ergab bei 17 Patienten (9%) mit der BAC- (Bacterial Artificial Chromosome) Array-CGH den Nachweis einer chromosomalen Imbalance als Ursache. Zur eindeutigen und schnellen Validierung von auffälligen CGH-Ergebnissen hat sich in einer kleinen Pilotstudie an 10 Patienten, insbesondere bei chromosomalen Duplikationen, der Einsatz einer zweiten, oligonukleotidbasierten Array-CGH-Plattform bewährt (sog. Kreuzvalidierung). Aufgrund unserer eigenen und der Erfahrungen anderer Arbeitsgruppen wird derzeit ein Stufenkonzept bei der genetischen Diagnostik von Kindern mit mentaler Retardierung unter kombiniertem Einsatz der BAC- und Oligonukelotid-Array-CGH sowie der Fluoreszenz-in-situ-Hybridisierung (FISH) empfohlen.
Genexpressionsstudien mit Microarrays und SAGE: Biologische und analytische Grundlagen / Gene expression studies with microarrays and SAGE: biological and analytical principles
Authors: Müller Holger , Neumaier Michael , Hoffmann Georg
Published: September 2008

Diese Arbeit setzt eine im Jahr 2003 begonnene Publikationsserie über die Analytik und Auswertung von Genexpressionsstudien der Arbeitsgruppe Bioinformatik der DGKL e.V. (www.dgkl.de/bioinformatik) fort. Sie beschreibt die beiden wichtigsten Techniken für die Erfassung genomweiter Expressionsprofile, DNA-Microarrays (Biochips) und Serial Analysis of Gene Expression (SAGE), aus dem kritischen Blickwinkel der Labordiagnostik.

Als Expressionsprofil bezeichnet man eine Liste aller in einem Gewebe vorkommenden mRNA-Spezies (Transkripte) mit Angabe der zugehörigen Menge. Von den 10 bis 20 pg Gesamt-RNA pro Zelle sind nur 1 bis 5% mRNA, die sich auf ca. 35000 zelltypspezifische Transkripte verteilen. So liegen die meisten in extrem geringen Mengen von rund einem Molekül pro Zelle vor, einige jedoch in 10000-fach höherer Konzentration. Das bedeutet eine erhebliche analytische Herausforderung.

Beide Verfahren haben Stärken und Schwächen: Microarray-Experimente liefern mit weniger Aufwand in kürzerer Zeit semi-quantitative Ergebnisse, können aber nur bekannte Genprodukte analysieren. SAGE ist extrem kosten- und zeitaufwendig und schwer zu interpretieren, zählt aber definierte Sequenzabschnitte und entdeckt prinzipiell jede in der Probe vorkommende mRNA. Bedingt durch die Vielzahl und mangelnde Standardisierbarkeit der analytischen und präanalytischen Teilschritte leiden beide Verfahren unter Präzisions- und Richtigkeitsproblemen und können auch divergierende Aussagen liefern. Ein Signal, das mit Microarrays hoch exprimiert erscheint, kann mit SAGE nicht nachweisbar sein und umgekehrt. Neuere Verfahren der Hochdurchsatz-Sequenzierung könnten dazu beitragen, die Lücke zwischen den beiden Techniken zu schließen.
CEA, CYFRA 21-1, NSE, and ProGRP in the diagnosis of lung cancer: a multivariate approach / CEA, CYFRA 21-1, NSE und ProGRP in der Diagnostik des Lungenkarzinoms: eine multivariate Analyse
Authors: Gruber Christine , Hatz Rudolf , Reinmiedl Judith , Nagel Dorothea , Stieber Petra
Published: September 2008

We retrospectively studied the single and combined diagnostic value of carcinoembryonic antigen (CEA), cytokeratin fragment 19 (CYFRA 21-1), neuron specific enolase (NSE) and pro-gastrin-releasing peptide (ProGRP), which were routinely analysed in patients with lung tumours of unknown origin at the time of admission to hospital. Inclusion criteria were the determination of CEA (AxSYM/Abbott), CYFRA 21-1 (ElecSys/Roche) and NSE (Kryptor/Brahms). We examined 1747 patients, where 1325 suffered from lung cancer (LC; small cell lung cancer, SCLC: n=194; non-small cell lung cancer, NSCLC: n=1015; others: n=116), 318 from benign lung diseases and 104 from lung metastases due to another primary malignancy. As ProGRP (ELISA ALSI/IBL) became available only recently, there are less data points of this marker. In total, 99.8% of LC patients released at least one of the four biomarkers (defined as values exceeding the median of healthy controls), and for the discrimination between benign disease (BD) and malignant lung disease each marker reached 100% tumour specificity at high levels (CEA: 20 ng/mL; CYFRA 21–1: 40 ng/mL; NSE: 45 ng/mL; ProGRP: 250 pg/mL). At a specificity of >99%, ProGRP reached the highest diagnostic efficacy for SCLC with 57% true positive results, CEA had the highest capacity (17%) to detect malignant lung tumours in general and adenocarcinomas of the lung with 29%. CYFRA 21-1 was dominant for squamous cell carcinomas (12%). Combining the four markers leads with the prerequisite of high specificity (>99%) to 50% true positives for malignant lung tumours, 44% for NSCLC, 36% for squamous cell carcinomas, 53% for adenocarcinomas, and 78% for SCLC, respectively. In cases of lung tumours of unknown origin, the combined use of CEA, CYFRA 21-1, NSE and ProGRP is useful for the differentiation between benign and primary or secondary malignant disease and suggests the assignment to histological subtypes.
Einsatz der Genchiptechnologie in der Erregerdiagnostik / Use of DNA microarrays in microbiological diagnostics
Authors: Cullen Paul , Funke Harald , Klein Hanns-Georg , Langmann Thomas , Neumaier Michael
Published: September 2008

Seit der Geburt der Mikrobiologie vor etwas mehr als 100 Jahren hat sich die technische Grundlage der Keimzüchtung und -identifizierung kaum geändert. Rasche Fortschritte in der Molekularbiologie und die Entwicklung hochparalleler Ansätze, wie die sogenannte Genchip-Technologie während der letzten Jahre, versprechen jedoch eine schnellere, genauere und breitere Identifizierung von Erregern und ihrer Resistenzen gegen Antibiotika. Vor diesem Hintergrund wird gelegentlich sogar der Untergang der klassischen Bakteriologie heraufbeschworen. Wie aus den beschriebenen Beiträgen hervorgeht, liegt jedoch ein solches Szenario immer noch in der Zukunft. Die Gründe hierfür sind einerseits die hohen technischen Anforderungen an automatisierbare molekularbiologische Methoden, andererseits unzureichende Kenntnisse der genetischen Grundlagen der Resistenzentwicklung. Weitere Probleme sind die nicht ausreichende Sensitivität sowie die prinzipielle Unfähigkeit solcher Systeme, vitale von bereits abgetöteten Bakterien unterscheiden zu können.
Requirement of Myeloid Cells for Axon Regeneration
Authors: Barrette Benoit , Hébert Marc-André , Filali Mohammed , Lafortune Kathleen , Vallières Nicolas , Gowing Geneviève , Julien Jean-Pierre , Lacroix Steve
Published: September 2008

The role of CD11b+myeloid cells in axonal regeneration was assessed using axonal injury models and CD11b-TKmt-30mice expressing a mutated HSV-1 thymidine kinase (TK) gene regulated by the myeloid-specific CD11b promoter. Continuous delivery of ganciclovir at a sciatic nerve lesion site greatly decreased the number of granulocytes/inflammatory monocytes and macrophages in the distal stump of CD11b-TKmt-30mice. Axonal regeneration and locomotor function recovery were severely compromised in ganciclovir-treated CD11b-TKmt-30mice. This was caused by an unsuitable growth environment rather than an altered regeneration capacity of neurons. In absence of CD11b+cells, the clearance of inhibitory myelin debris was prevented, neurotrophin synthesis was abolished, and blood vessel formation/maintenance was severely compromised in the sciatic nerve distal stump. Spinal cord-injured axons also failed to regenerate through peripheral nerve grafts in the absence of CD11b+cells. Therefore, myeloid cells support axonal regeneration and functional recovery by creating a growth-permissive milieu for injured axons.
Evaluating the Negative or Valuing the Positive? Neural Mechanisms Supporting Feedback-Based Learning across Development
Authors: van Duijvenvoorde Anna C. K. , Zanolie Kiki , Rombouts Serge A. R. B. , Raijmakers Maartje E. J. , Crone Eveline A.
Published: September 2008

How children learn from positive and negative performance feedback lies at the foundation of successful learning and is therefore of great importance for educational practice. In this study, we used functional magnetic resonance imaging (fMRI) to examine the neural developmental changes related to feedback-based learning when performing a rule search and application task. Behavioral results from three age groups (8–9, 11–13, and 18–25 years of age) demonstrated that, compared with adults, 8- to 9-year-old children performed disproportionally more inaccurately after receiving negative feedback relative to positive feedback. Additionally, imaging data pointed toward a qualitative difference in how children and adults use performance feedback. That is, dorsolateral prefrontal cortex and superior parietal cortex were more active after negative feedback for adults, but after positive feedback for children (8–9 years of age). For 11- to 13-year-olds, these regions did not show differential feedback sensitivity, suggesting that the transition occurs around this age. Pre-supplementary motor area/anterior cingulate cortex, in contrast, was more active after negative feedback in both 11- to 13-year-olds and adults, but not 8- to 9-year-olds. Together, the current data show that cognitive control areas are differentially engaged during feedback-based learning across development. Adults engage these regions after signals of response adjustment (i.e., negative feedback). Young children engage these regions after signals of response continuation (i.e., positive feedback). The neural activation patterns found in 11- to 13-year-olds indicate a transition around this age toward an increased influence of negative feedback on performance adjustment. This is the first developmental fMRI study to compare qualitative changes in brain activation during feedback learning across distinct stages of development.
Constraint-Induced Movement Therapy in the Adult Rat after Unilateral Corticospinal Tract Injury
Authors: Maier Irin C. , Baumann Kaspar , Thallmair Michaela , Weinmann Oliver , Scholl Jeannette , Schwab Martin E.
Published: September 2008

Smaller spinal cord injuries often allow some degree of spontaneous behavioral improvements because of structural rearrangements within different descending fiber tracts or intraspinal circuits. In this study, we investigate whether rehabilitative training of the forelimb (forced limb use) influences behavioral recovery and plastic events after injury to a defined spinal tract, the corticospinal tract (CST). Female adult Lewis rats received a unilateral CST injury at the brainstem level. Use of the contralateral impaired forelimb was either restricted, by a cast, or forced, by casting the unimpaired forelimb immediately after injury for either 1 or 3 weeks. Forced use of the impaired forelimb was followed by full behavioral recovery on the irregular horizontal ladder, whereas animals that could not use their affected side remained impaired. BDA (biotinylated dextran amine) labeling of the intact CST showed lesion-induced growth across the midline where CST collaterals increased their innervation density and extended fibers toward the ventral and the dorsal horn in response to forced limb use. Gene chip analysis of the denervated ventral horn revealed changes in particular for growth factors, adhesion and guidance molecules, as well as components of synapse formation suggesting an important role for these factors in activity-dependent intraspinal reorganization after unilateral CST injury.
Reactive Oxygen Species Derived from NOX1/NADPH Oxidase Enhance Inflammatory Pain
Authors: Ibi Masakazu , Matsuno Kuniharu , Shiba Dai , Katsuyama Masato , Iwata Kazumi , Kakehi Tomoko , Nakagawa Takayuki , Sango Kazunori , Shirai Yasuhito , Yokoyama Takahiko , Kaneko Shuji , Saito Naoaki , Yabe-Nishimura Chihiro
Published: September 2008

The involvement of reactive oxygen species (ROS) in an augmented sensitivity to painful stimuli (hyperalgesia) during inflammation has been suggested, yet how and where ROS affect the pain signaling remain unknown. Here we report a novel role for the superoxide-generating NADPH oxidase in the development of hyperalgesia. In mice lackingNox1(Nox1−/Y), a catalytic subunit of NADPH oxidase, thermal and mechanical hyperalgesia was significantly attenuated, whereas no change in nociceptive responses to heat or mechanical stimuli was observed. In dorsal root ganglia (DRG) neurons ofNox1+/Y, pretreatment with chemical mediators bradykinin, serotonin, or phorbol 12-myristate 13-acetate (PMA) augmented the capsaicin-induced calcium increase, whereas this increase was significantly attenuated in DRG neurons ofNox1−/Y. Concomitantly, PMA-induced translocation of PKCε was markedly perturbed inNox1−/YorNox1+/YDRG neurons treated with ROS-scavenging agents. In cells transfected with tagged PKCε, hydrogen peroxide induced translocation and a reduction in free sulfhydryls of full-length PKCε but not of the deletion mutant lacking the C1A domain. These findings indicate that NOX1/NADPH oxidase accelerates the translocation of PKCε in DRG neurons, thereby enhancing the TRPV1 activity and the sensitivity to painful stimuli.
Inhibitors of CytochromecRelease with Therapeutic Potential for Huntington's Disease
Authors: Wang Xin , Zhu Shan , Pei Zhijuan , Drozda Martin , Stavrovskaya Irina G. , Del Signore Steven J. , Cormier Kerry , Shimony Ethan M. , Wang Hongyan , Ferrante Robert J. , Kristal Bruce S. , Friedlander Robert M.
Published: September 2008

Release of mitochondrial cytochromecresulting in downstream activation of cell death pathways has been suggested to play a role in neurologic diseases featuring cell death. However, the specific biologic importance of cytochromecrelease has not been demonstrated in Huntington's disease (HD). To evaluate the role of cytochromecrelease, we screened a drug library to identify new inhibitors of cytochromecrelease from mitochondria. Drugs effective at the level of purified mitochondria were evaluated in a cellular model of HD. As proof of principle, one drug was chosen for in depth evaluationin vitroand a transgenic mouse model of HD. Our findings demonstrate the utility of mitochondrial screening to identify inhibitors of cell death and provide further support for the important functional role of cytochromecrelease in HD. Given that many of these compounds have been approved by the Food and Drug Administration for clinical usage and cross the blood–brain barrier, these drugs may lead to trials in patients.
Fidelity of Complex Spike-Mediated Synaptic Transmission between Inhibitory Interneurons
Authors: Roberts Michael T. , Bender Kevin J. , Trussell Laurence O.
Published: September 2008

Complex spikes are high-frequency bursts of Na+spikes, often riding on a slower Ca2+-dependent waveform. Although complex spikes may propagate into axons, given their unusual shape it is not clear how reliably these bursts reach nerve terminals, whether their spikes are efficiently transmitted as a cluster of postsynaptic responses, or what function is served by such a concentrated postsynaptic signal. We examined these questions by recording from synaptically coupled pairs of cartwheel cells, neurons which fire complex spikes and form an inhibitory network in the dorsal cochlear nucleus. Complex spikes in the presynaptic soma were reliably propagated to nerve terminals and elicited powerful, temporally precise postsynaptic responses. Single presynaptic neurons could prevent their postsynaptic partner from firing complex but not simple spikes, dramatically reducing dendritic Ca2+signals in the postsynaptic neuron. We suggest that rapid transmission of complex spikes may control the susceptibility of neighboring neurons to Ca2+-dependent plasticity.
Ischemia Enhances Activation by Ca2+and Redox Modification of Ryanodine Receptor Channels from Rat Brain Cortex
Authors: Bull Ricardo , Finkelstein José Pablo , Gálvez Jorge , Sánchez Gina , Donoso Paulina , Behrens María Isabel , Hidalgo Cecilia
Published: September 2008

Cerebral ischemia stimulates Ca2+influx and thus increases neuronal intracellular free [Ca2+]. Using a rat model of cerebral ischemia without recirculation, we tested whether ischemia enhances the activation by Ca2+of ryanodine receptor (RyR) channels, a requisite feature of RyR-mediated Ca2+-induced Ca2+release (CICR). To this aim, we evaluated how single RyR channels from endoplasmic reticulum vesicles, fused into planar lipid bilayers, responded to cytoplasmic [Ca2+] changes. Endoplasmic reticulum vesicles were isolated from the cortex of rat brains incubated without blood flow for 5 min at 37°C (ischemic) or at 4°C (control). Ischemic brains displayed increased oxidative intracellular conditions, as evidenced by a lower ratio (∼130:1) of reduced/oxidized glutathione than controls (∼200:1). Single RyR channels from ischemic or control brains displayed the same three responses to Ca2+reported previously, characterized by low, moderate, or high maximal activity. Relative to controls, RyR channels from ischemic brains displayed with increased frequency the high activity response and with lower frequency the low activity response. Both control and ischemic cortical vesicles contained the RyR2 and RyR3 isoforms in a 3:1 proportion, with undetectable amounts of RyR1. Ischemia reduced [3H]ryanodine binding and total RyR protein content by 35%, and increased at least twofold endogenous RyR2S-nitrosylation andS-glutathionylation without affecting the corresponding RyR3 endogenous levels.In vitroRyRS-glutathionylation but notS-nitrosylation favored the emergence of high activity channels. We propose that ischemia, by enhancing RyR2S-glutathionylation, allows RyR2 to sustain CICR; the resulting amplification of Ca2+entry signals may contribute to cortical neuronal death.
Molecular Specification and Patterning of Progenitor Cells in the Lateral and Medial Ganglionic Eminences
Authors: Tucker Eric S. , Segall Samantha , Gopalakrishna Deepak , Wu Yongqin , Vernon Mike , Polleux Franck , LaMantia Anthony-Samuel
Published: September 2008

We characterized intrinsic and extrinsic specification of progenitors in the lateral and medial ganglionic eminences (LGE and MGE). We identified seven genes whose expression is enriched or restricted in either the LGE [biregional cell adhesion molecule-related/downregulated by oncogenes binding protein (Boc), Frizzled homolog 8 (Fzd8),Ankrd43(ankyrin repeat domain-containing protein 43), andIkzf1(Ikaros family zinc finger 1)] or MGE [Map3k12 binding inhibitory protein 1 (Mbip); zinc-finger, SWIM domain containing 5 (Zswim5); andAdamts5[a disintegrin-like and metallopeptidase (reprolysin type) with thrombospondin type 1 motif, 5]].Boc,Fzd8,Mbip, andZswim5are apparently expressed in LGE or MGE progenitors, whereas the remaining three are seen in the postmitotic mantle zone. Relative expression levels are altered and regional distinctions are lost for each gene in LGE or MGE cells propagated as neurospheres, indicating that these newly identified molecular characteristics of LGE or MGE progenitors depend on forebrain signals not available in the neurosphere assay. Analyses ofPax6Sey/Sey,Shh−/−, andGli3XtJ/XtJmutants suggests that LGE and MGE progenitor identity does not rely exclusively on previously established forebrain-intrinsic patterning mechanisms. Among a limited number of additional potential patterning mechanisms, we found that extrinsic signals from the frontonasal mesenchyme are essential for Shh- and Fgf8-dependent regulation of LGE and MGE genes. Thus, extrinsic and intrinsic forebrain patterning mechanisms cooperate to establish LGE and MGE progenitor identity, and presumably their capacities to generate distinct classes of neuronal progeny.
Another Barrier to Regeneration in the CNS: Activated Macrophages Induce Extensive Retraction of Dystrophic Axons through Direct Physical Interactions
Authors: Horn Kevin P. , Busch Sarah A. , Hawthorne Alicia L. , van Rooijen Nico , Silver Jerry
Published: September 2008

Injured axons of the adult CNS undergo lengthy retraction from the initial site of axotomy after spinal cord injury. Macrophage infiltration correlates spatiotemporally with this deleterious phenomenon, but the direct involvement of these inflammatory cells has not been demonstrated. In the present study, we examined the role of macrophages in axonal retraction within the dorsal columns after spinal cord injuryin vivoand found that retraction occurred between days 2 and 28 after lesion and that the ends of injured axons were associated with ED-1+ cells. Clodronate liposome-mediated depletion of infiltrating macrophages resulted in a significant reduction in axonal retraction; however, we saw no evidence of regeneration. We used time-lapse imaging of adult dorsal root ganglion neurons in anin vitromodel of the glial scar to examine macrophage–axon interactions and observed that adhesive contacts and considerable physical interplay between macrophages and dystrophic axons led to extensive axonal retraction. The induction of retraction was dependent on both the growth state of the axon and the activation state of the macrophage. Only dystrophic adult axons were susceptible to macrophage “attack.” Unlike intrinsically active cell line macrophages, both primary macrophages and microglia required activation to induce axonal retraction. Contact with astrocytes had no deleterious effect on adult dystrophic axons, suggesting that the induction of extensive retraction was specific to phagocytic cells. Our data are the first to indicate a direct role of activated macrophages in axonal retraction by physical cell–cell interactions with injured axons.
Region and Sex Differences in Constituent Dopamine Neurons and Immunoreactivity for Intracellular Estrogen and Androgen Receptors in Mesocortical Projections in Rats
Authors: Kritzer Mary F. , Creutz Lela M.
Published: September 2008

Many cortical and prefrontal functions show sex differences in their development, adult capacity, and dysfunction in disorders like schizophrenia. Correlations between circulating gonadal hormones and certain prefrontal functions have also been identified in humans and experimental animal models. Although multiple mechanisms may be involved, such hormone sensitivities/sex differences could be related to gonadal steroid actions on another regulator of cortical/prefrontal cortical function, the mesocortical dopamine system. Thus, although it is well known that perturbations in prefrontal dopamine signaling induce behavioral deficits, it is also known that several endpoints of these afferents are sensitive to gonadal steroids and/or are sexually dimorphic. This study explored possible substrates for this in two ways: by comparing the distributions of immunoreactivity for intracellular estrogen (α and β) and androgen receptors among retrogradely labeled dopaminergic and nondopaminergic mesocortical neurons projecting to prefrontal, premotor, and primary motor cortices, areas in which male rat dopamine axons are differentially hormone-sensitive; and by comparing anatomical data in males and females. These analyses revealed region-, cell-, and sex-specific specializations in receptor localization that paralleled established patterns of mesocortical hormone sensitivity, including the androgen sensitivity of dopamine axons and dopamine-dependent functions in prefrontal cortex. It was also found that the proportions of dopamine neurons making up mesocortical projections were ∼30% in males, whereas in females, significantly more constituent cells were dopaminergic. Together, these features may be part of the neurobiology giving mesocortical afferents their hormone sensitivities and/or sex differences in physiology, function, and dysfunction in disease.
Systemic Inflammation Alters the Kinetics of Cerebrovascular Tight Junction Disruption after Experimental Stroke in Mice
Authors: McColl Barry W. , Rothwell Nancy J. , Allan Stuart M.
Published: September 2008

Systemic inflammatory events, such as infection, increase the risk of stroke and are associated with worse outcome, but the mediators of this clinically important effect are unknown. Our aim here was to elucidate mechanisms contributing to the detrimental effects of systemic inflammation on mild ischemic brain injury in mice. Systemic inflammation was induced in mice by peripheral interleukin-1β (IL-1β) challenge and focal cerebral ischemia by transient middle cerebral artery occlusion (MCAo). Systemic inflammation caused an alteration in the kinetics of blood–brain barrier (BBB) disruption through conversion of a transient to a sustained disruption of the tight junction protein, claudin-5, and also markedly exacerbated disruption to the cerebrovascular basal lamina protein, collagen-IV. These alterations were associated with a systemic inflammation-induced increase in neurovascular gelatinolytic activity that was mediated by a fivefold increase in neutrophil-derived matrix metalloproteinase-9 (MMP-9) in the brains of IL-1β-challenged mice after MCAo. Specific inhibition of MMP-9 abrogated the effects of systemic inflammation on the sustained but not the acute disruption of claudin-5, which was associated with phosphorylation of cerebrovascular myosin light chain. MMP-9 inhibition also attenuated the deleterious impact of systemic inflammation on brain damage, edema, neurological deficit, and incidence of hemorrhagic transformation. These data indicate that a transformation from transient to sustained BBB disruption caused by enhanced neutrophil-derived neurovascular MMP-9 activity is a critical mechanism underlying the exacerbation of ischemic brain injury by systemic inflammation. These mechanisms may contribute to the poor clinical outcome in stroke patients presenting with antecedent infection.
State-Dependent Presynaptic Inhibition Regulates Central Pattern Generator Feedback to Descending Inputs
Authors: Blitz Dawn M. , Nusbaum Michael P.
Published: September 2008

Central pattern generators (CPGs) provide feedback to their projection neuron inputs. However, it is unknown whether this feedback is regulated and how that might shape CPG output. We are studying feedback from the pyloric CPG to identified projection neurons that regulate the gastric mill CPG, in the crab stomatogastric nervous system. Both CPGs are located in the stomatogastric ganglion (STG) and are influenced by projection neurons originating in the paired commissural ganglia (CoGs). Two extrinsic inputs [ventral cardiac neurons (VCNs) and postoesophageal commissure (POC) neurons] trigger distinct gastric mill rhythms despite acting via the same projection neurons [modulatory commissural neuron 1 (MCN1); commissural projection neuron 2 (CPN2)]. These projection neurons receive feedback inhibition from the pyloric CPG interneuron anterior burster (AB), resulting in their exhibiting pyloric-timed activity during the retraction phase of the VCN- and POC-triggered gastric mill rhythms. However, during the gastric mill protraction phase, MCN1/CPN2 exhibit pyloric-timed activity during the POC-triggered rhythm but fire tonically during the VCN-triggered rhythm. Here, we show that the latter, tonic activity pattern results from the elimination of AB inhibition of MCN1/CPN2, despite persistent AB actions within the STG and AB action potentials still propagating into each CoG. This loss of pyloric-timed AB input likely results from presynaptic inhibition of AB in each CoG because, when a secondary rhythmic AB burst initiation zone in the CoG is activated, the associated action potentials are selectively suppressed during the VCN protraction phase. Thus, rhythmic CPG feedback can be locally regulated, in a state-dependent manner, enabling the same projection neurons to drive multiple motor patterns from the same neuronal circuit.
Octopamine Regulates Sleep inDrosophilathrough Protein Kinase A-Dependent Mechanisms
Authors: Crocker Amanda , Sehgal Amita
Published: September 2008

Sleep is a fundamental process, but its regulation and function are still not well understood. TheDrosophilamodel for sleep provides a powerful system to address the genetic and molecular mechanisms underlying sleep and wakefulness. Here we show that aDrosophilabiogenic amine, octopamine, is a potent wake-promoting signal. Mutations in the octopamine biosynthesis pathway produced a phenotype of increased sleep, which was restored to wild-type levels by pharmacological treatment with octopamine. Moreover, electrical silencing of octopamine-producing cells decreased wakefulness, whereas excitation of these neurons promoted wakefulness. Because protein kinase A (PKA) is a putative target of octopamine signaling and is also implicated inDrosophilasleep, we investigated its role in the effects of octopamine on sleep. We found that decreased PKA activity in neurons rendered flies insensitive to the wake-promoting effects of octopamine. However, this effect of PKA was not exerted in the mushroom bodies, a site previously associated with PKA action on sleep. These studies identify a novel pathway that regulates sleep inDrosophila.
Metabolic Environment in Substantia Nigra Reticulata Is Critical for the Expression and Control of Hypoglycemia-Induced Seizures
Authors: Velíšek Libor , Velíšková Jana , Chudomel Ondřej , Poon Ka-Lai , Robeson Kimberly , Marshall Barbara , Sharma Archana , Moshé Solomon L.
Published: September 2008

Seizures represent a common and serious complication of hypoglycemia. Here we studied mechanisms of control of hypoglycemic seizures induced by insulin injection in fasted and nonfasted rats. We demonstrate that fasting predisposes rats to more rapid and consistent development of hypoglycemic seizures. However, the fasting-induced decrease in baseline blood glucose concentration cannot account for the earlier onset of seizures in fasted versus nonfasted rats. Data obtained with c-Fos immunohistochemistry and [14C]2-deoxyglucose uptake implicate a prominent involvement of the substantia nigra reticulata (SNR) among other structures in the hypoglycemic seizure control. This is supported by data showing that fasting decreases the SNR expression of KATPchannels, which link metabolism with activity, and is further confirmed with microinfusions of KATPchannel agonist and antagonist. Data obtained with whole-cell and perforated patch recordings from SNR neurons in slicesin vitrodemonstrate that both presynaptic and postsynaptic KATPchannels participate in the failure of the SNR to control hypoglycemic seizures. The results suggest that fasting and insulin-induced hypoglycemia can lead to impairment in the function of the SNR, leading thus to hypoglycemic seizures.
Time Constants of h Current in Layer II Stellate Cells Differ along the Dorsal to Ventral Axis of Medial Entorhinal Cortex
Authors: Giocomo Lisa M. , Hasselmo Michael E.
Published: September 2008

Chronic recordings in the medial entorhinal cortex of behaving rats have found grid cells, neurons that fire when the rat is in a hexagonal array of locations. Grid cells recorded at different dorsal–ventral anatomical positions show systematic changes in size and spacing of firing fields. To test possible mechanisms underlying these differences, we analyzed properties of the hyperpolarization-activated cation currentIhin voltage-clamp recordings from stellate cells in entorhinal slices from different dorsal–ventral locations. The time constant of h current was significantly different between dorsal and ventral neurons. The time constant of h current correlated with membrane potential oscillation frequency and the time constant of the sag potential in the same neurons. Differences in h current could underlie differences in membrane potential oscillation properties and contribute to grid cell periodicity along the dorsal–ventral axis of medial entorhinal cortex.
A Dominant Role of GTRAP3-18 in Neuronal Glutathione Synthesis
Authors: Watabe Masahiko , Aoyama Koji , Nakaki Toshio
Published: September 2008

Glutathione is an essential reductant which protects cells and is reduced in neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. Neurons rely mainly on extracellular cysteine for glutathione synthesis and a cysteine transporter termed excitatory amino acid carrier 1 (EAAC1). However, the mechanisms underlying neuronal cysteine uptake have remained elusive. Herein, we show glutamate transport-associated protein for EAAC1 (GTRAP3-18) to interact with EAAC1 at the plasma membrane and thereby regulate neuronal glutathione levels. Glutathione increased in the mouse brain as well as in primary cultured neurons, when the GTRAP3-18 protein level was decreased by genetic manipulations, whereas glutathione decreased when GTRAP3-18 was increased. Furthermore, glutathione contents that had been increased, by a translocator and activator of EAAC1, were suppressed by increased cell surface GTRAP3-18 protein. Our results demonstrate GTRAP3-18 to dominantly and negatively determine the intracellular glutathione contents in neurons.
Behavioral Recovery in MPTP-Treated Monkeys: Neurochemical Mechanisms Studied by Intrastriatal Microdialysis
Authors: Boulet Sabrina , Mounayar Stéphanie , Poupard Annie , Bertrand Anne , Jan Caroline , Pessiglione Mathias , Hirsch Etienne C. , Feuerstein Claude , François Chantal , Féger Jean , Savasta Marc , Tremblay Léon
Published: September 2008

Parkinson's disease (PD) patients express motor symptoms only after 60–80% striatal dopamine (DA) depletion. The presymptomatic phase of the disease may be sustained by biochemical modifications within the striatum. We used an appropriate specific1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkey model (Mounayar et al., 2007) to study the compensatory mechanisms operating in recovery from PD motor symptoms. We assessed the levels of DA and its metabolites (DOPAC, homovanillic acid), GABA, glutamate (Glu), serotonin (5-HT) and its metabolite (5HIAA) by repeated intracerebral microdialysis in awake animals before exposure to MPTP during full expression of the motor symptoms induced by MPTP and after recovery from these symptoms. Measurements were obtained from two functionally and anatomically different striatal areas: the associative-limbic territory and sensorimotor territory. Animals with motor symptoms displayed an extremely large decrease in levels of DA and its metabolites and an increase in Glu and GABA levels, as reported by other studies. However, we show here for the first time that serotonin levels increased in these animals. We found that increases in DA levels in the sensorimotor and/or associative-limbic territory and high levels of 5-HT and of its metabolite, 5HIAA, were associated with recovery from motor symptoms in this model. Determining whether similar changes in DA and 5-HT levels are involved in the compensatory mechanisms delaying the appearance of motor symptoms in the early stages of PD might make it possible to develop new treatment strategies for the disease.