bluuebunny/crossref_metadata_2025 huggingface dataset:
Biopsy of peripheral lymph nodes: a useful tool to diagnose opportunistic diseases in HIV-infected patients
Authors: Ramos Carina Guedes , Goldani Luciano Zubaran
Published: October 2010

Peripheral lymphadenopathy is commonly present in HIV-infected patients and has a wide spectrum of differential diagnoses. We carried out a cross-sectional study of peripheral lymph node biopsies performed from January 2004 to December 2008 in HIV-infected patients who attended a tertiary-care hospital in southern Brazil. Only 60 of 210 peripheral lymph node biopsies performed (28%) were non-diagnostic. The most common diagnoses included: mycobacteriosis (105 cases; 50.2%); lymphoma (19 cases; 9.0%); systemic mycosis (12 cases; 5.7%) including histoplasmosis, cryptococcosis and histoplasmosis; and metastatic cancer (2.9%). Peripheral lymph node biopsy is a simple and useful tool to diagnose opportunistic diseases in HIV-infected patients.
Quantitative evaluation of siRNA delivery in vivo
Authors: Pei Yi , Hancock Paula J. , Zhang Hangchun , Bartz René , Cherrin Craig , Innocent Nathalie , Pomerantz Colin J. , Seitzer Jessica , Koser Martin L. , Abrams Marc T. , Xu Yan , Kuklin Nelly A. , Burke Paul A. , Sachs Alan B. , Sepp-Lorenzino Laura , Barnett Stanley F.
Published: October 2010

Effective small interfering RNA (siRNA)–mediated therapeutics require the siRNA to be delivered into the cellular RNA-induced silencing complex (RISC). Quantitative information of this essential delivery step is currently inferred from the efficacy of gene silencing and siRNA uptake in the tissue. Here we report an approach to directly quantify siRNA in the RISC in rodents and monkey. This is achieved by specific immunoprecipitation of the RISC from tissue lysates and quantification of small RNAs in the immunoprecipitates by stem–loop PCR. The method, expected to be independent of delivery vehicle and target, is label-free, and the throughput is acceptable for preclinical animal studies. We characterized a lipid-formulated siRNA by integrating these approaches and obtained a quantitative perspective on siRNA tissue accumulation, RISC loading, and gene silencing. The described methodologies have utility for the study of silencing mechanism, the development of siRNA therapeutics, and clinical trial design.
Reference Dependence in Multilocation Newsvendor Models: A Structural Analysis
Authors: Ho Teck-Hua , Lim Noah , Cui Tony Haitao
Published: October 2010

We propose a behavioral theory to predict actual ordering behavior in multilocation inventory systems. The theory rests on a well-known stylized fact of human behavior: people's preferences are reference dependent. We incorporate reference dependence into the newsvendor framework by assuming that there are psychological costs of leftovers and stockouts. We also hypothesize that the psychological aversion to leftovers is greater than the disutility for stockouts. We then experimentally test the proposed theory in both the centralized and decentralized inventory structures using subjects motivated by substantial financial incentives. Consistent with the proposed theory, actual orders exhibit the so-called “pull-to-center” bias and the degree of bias is greater in the high-profit margin than in the low-profit margin condition. These systematic biases are shown to eliminate the risk-pooling benefit when the demands across store locations are strongly correlated. Because the proposed model nests the standard inventory and ex post inventory error minimization theories as special cases, one can systematically evaluate the predictive power of each alternative using the generalized likelihood principle. We structurally estimate all three theories using the experimental data, and the estimation results strongly suggest that the proposed behavioral theory captures actual orders and profits better. We also conduct two experiments to validate the behavioral model by manipulating the relative salience of the psychological costs of leftovers versus that of stockouts to alleviate the pull-to-center bias.
Conditional Coskewness in Stock and Bond Markets: Time-Series Evidence
Authors: Yang Jian , Zhou Yinggang , Wang Zijun
Published: October 2010

In the context of a three-moment intertemporal capital asset pricing model specification, we characterize conditional coskewness between stock and bond excess returns using a bivariate regime-switching model. We find that both conditional U.S. stock coskewness (the relation between stock return and bond volatility) and bond coskewness (the relation between bond return and stock volatility) command statistically and economically significant negative ex ante risk premiums. The impacts of stock and bond coskewness on the conditional stock and bond premiums are quite robust to various model specifications and various sample periods, and also hold in another major developed country (the United Kingdom). The findings also carry important implications for portfolio management.
Modeling of the Thermohydrodynamic and Reactive Behavior of Compacted Clay for High-Level Radionuclide Waste-Management Systems
Authors: Juncosa Ricardo , Navarro Vicente , Delgado Jordi , Vázquez Ana
Published: October 2010

Bentonite is often proposed as an engineered-buffer material in high-level radionuclide waste-management systems. For effective design of the barrier that will provide protection over the long time periods required, the physical/thermal/chemical processes taking place in the barrier material must be understood thoroughly. These processes, which interact, include the flow of water and gas, the flow of heat, and the transport and reaction of chemical constituents. The purpose of this study was to better understand the processes that occurred in a small-scale experiment within a confined bentonite space. A conceptual and mathematical model (FADES-CHEM) was built in order to simulate the results of an experiment conducted in 2000, and thereby to gain a better understanding of the controlling processes. In that experiment, a block of compacted bentonite was placed in an air-tight cell and subjected, for 6 months, to simultaneous heating and hydration from opposite sides. The bentonite block was then sliced into five sections each of which was then analyzed in order to obtain a series of physicochemical parameters illustrating the changes that had occurred. Before modeling, the chemical composition of the bentonite pore waters was restored in order to account for different processes such as gas outgassing and cell cooling. Modeling indicated that gas-pressure build up was a relevant process when computing the saturation of bentonite, and the computations in the present study suggested that evaporation/condensation processes played a crucial role in the final distribution of the water content. Gas pressure and evaporation/ condensation also affected the geochemical system, and the numerical model developed gives results that were consistent with the experimental values and trends observed. The model reproduced the results obtained and enable use at the repository scale and over longer time frames, provided that adequate data are available.
Structural Change in Celadonite and Cis-Vacant Illite by Electron Radiation in Tem
Authors: Kogure Toshihiro , Drits Victor A.
Published: October 2010

High-resolution transmission electron microscopy (HRTEM) images of two dioctahedral micas, celadonite and cis-vacant (cv) illite, were examined in detail to understand the effects of electron radiation on their structures during image acquisition. Celadonite, a dioctahedral mica with Fe and Mg as major octahedral cations, originally has a trans-vacant (tv) octahedral sheet but the contrast in the highresolution transmission electron microscopy (HRTEM) images indicates a different cation distribution in the sheet. Furthermore, the β angle for the 1M polytype derived from the HRTEM images is ~98.5º, which is considerably smaller than that (~100.5º) reported for celadonite. In previous works, cation migration from the tv to cv-like configurations and a decrease in the β angle after dehydroxylation of celadonite/ glauconite by heating were reported. The same phenomenon, dehydroxylation and subsequent cation migration, probably occurs by electron radiation in TEM. However, the new cation-distribution models derived from HRTEM images along the [100] and [110] directions are not in agreement. On the other hand, the contrast in a number of HRTEM images from an illite specimen in which cv-illite is dominant is the same as that for the tv-dioctahedral layer. This result is also interpreted as cation migration accompanied by dehydroxylation in TEM, as reported in heated cv-illite. The increased β angle (~102.5º) from that in the natural state (101.5º) estimated from the HRTEM images also supports this interpretation. This phenomenon is a large obstacle to the investigation of phyllosilicates containing Al-rich cv and Mg,Fe-rich tv 2:1 layers, using HRTEM.
Unresolved Issues Regarding Homework Assignments in Cognitive and Behavioural Therapies: An Expert Panel Discussion at AACBT
Authors: Kazantzis Nikolaos , Arntz Arnoud R. , Borkovec Thomas , Holmes Emily A. , Wade Tracey
Published: October 2010

This article presents a panel discussion on the integration of homework assignments into cognitive behaviour therapy sessions. The panel comprised experts in research and practice who had been invited as keynote presenters for the 32nd National Conference for the Australian Association of Cognitive and Behaviour Therapy. Experts responded to questions about the definition of homework, the mechanism by which homework produces its effects, and the relative importance of homework adherence for effective therapy. Interwoven through the discussion was an emphasis on a collaborative approach to homework, as well as specific recommendations for the integration of homework into sessions. Selected case illustrations were also discussed.
Relapse Prevention: A Critique and Proposed Reconceptualisation
Authors: Thakker Jo , Ward Tony
Published: October 2010

Relapse prevention (RP) plays a significant role in current treatments and post-treatment approaches to substance abuse problems. It is also widely used in a number of other problem areas, including other addictive behaviours and sexual offending. The widespread use of RP in various fields is due to both its clearly articulated theoretical basis, which has significant face validity, and its transferability into clinical practice. Also, there is a growing (though arguably still modest) body of empirical evidence that demonstrates its efficacy in a range of therapeutic contexts. However, arguably, in terms of both the theoretical underpinnings and the practical application of RP there is room for improvement. This article hypothesises that one of the key weaknesses of RP is that it takes a generally unconstructive approach to the therapeutic process through the use of negative concepts and avoidance goals. It is suggested that a ‘good lives’ framework of psychological wellbeing can provide a means of remedying these weaknesses of the traditional RP model. It is argued that a good lives framework can lead to a more optimistic approach to the prevention of relapse among individuals with substance use problems.
Mindfulness-Based Intervention on Distressing Hallucination-Like Experiences in a Nonclinical Sample
Authors: Langer Álvaro I. , Cangas Adolfo J. , Gallego José
Published: October 2010

The presence of psychotic-like experiences in the general population has been amply reported. Nevertheless, the degree of concern or anxiety that such experiences may generate is an aspect that has not received as much appraisal. In this sense, mindfulness is an approach to intervention based on the modification of the individual's relationship with the symptoms, instead of their elimination. The goal of the present study is to compare the effect of mindfulness training on distressing hallucination-like experiences. Eighteen participants were assigned to the experimental group, and they received 8 sessions of mindfulness training; 20 participants were assigned to a control group that viewed 8 sessions of a video forum. The results showed that upon completing the mindfulness training, there was a significant and large effect on the decrease of anxiety caused by hallucination-like experiences. These results were maintained at the 16-week follow-up. The repercussions of these results are underlined.
Incorporating Feminist Standpoint Theory
Authors: Ahlström Kristoffer
Published: October 2010

As has been noted by Alvin Goldman, there are some very interesting similarities between his Veritistic Social Epistemology (VSE) and Sandra Harding's Feminist Standpoint Theory (FST). In the present paper, it is argued that these similarities are so significant as to motivate an incorporation of FST into VSE, considering that (i) a substantial common ground can be found; (ii) the claims that go beyond this common ground are logically compatible; and (Hi) the generality of VSE not only does justice to the inclusive ambition of FST, but even solves a well-discussed problem for the latter.
Contractualist Account of Reasons for Being Moral Defended
Authors: Suikkanen Jussi
Published: October 2010

I will begin this paper by identifying the problem within the theory of ethics, which contractualism as a moral theory is attempting to address. It is not that of solving the problem of moral motivation like the ‘arch-contractualist’, Thomas Scanlon, often claims, but rather that of describing a class of fundamental moral reasons – contractualist reasons for short. In the second section, I will defend the contractualist idea of how the nature of these moral reasons provides us with sufficient, independent tools to construct the content of public moral principles. The rest of my paper is defensive. It addresses the main challenges set to the contractualist account of moral reasons. In the third section, I will discuss a frequent objection according to which the contractualist reasons are a redundant addition to the space of moral reasons. In the fourth section, I will examine the worry that acting from these reasons would not lead to morally admirable action but rather to vice. In the last section, I will investigate the criticism according to which the normative force of the contractualist reasons is insufficient for rationalising our moral actions in certain difficult circumstances. In this section, we get to the heart of the matter – what the reasons contractualism describes truly are, and how they can explain the generally overriding strength of our moral requirements. I hope to conclude that even after these serious challenges contractualism remains a philosophically viable account of morality's rationalistic appeal.
Sonic Hedgehog Regulates Discrete Populations of Astrocytes in the Adult Mouse Forebrain
Authors: Garcia A. Denise R. , Petrova Ralitsa , Eng Liane , Joyner Alexandra L.
Published: October 2010

Astrocytes are an essential component of the CNS, and recent evidence points to an increasing diversity of their functions. Identifying molecular pathways that mediate distinct astrocyte functions, is key to understanding how the nervous system operates in the intact and pathological states. In this study, we demonstrate that the Hedgehog (Hh) pathway, well known for its roles in the developing CNS, is active in astrocytes of the mature mouse forebrainin vivo. Using multiple genetic approaches, we show that regionally distinct subsets of astrocytes receive Hh signaling, indicating a molecular diversity between specific astrocyte populations. Furthermore, we identified neurons as a source of Sonic hedgehog (Shh) in the adult forebrain, suggesting that Shh signaling is involved in neuron–astrocyte communication. Attenuation of Shh signaling in postnatal astrocytes by targeted removal of Smoothened, an obligate Shh coreceptor, resulted in upregulation of GFAP and cellular hypertrophy specifically in astrocyte populations regulated by Shh signaling. Collectively, our findings demonstrate a role for neuron-derived Shh in regulating specific populations of differentiated astrocytes.
Rescue of Impaired Fear Extinction and Normalization of Cortico-Amygdala Circuit Dysfunction in a Genetic Mouse Model by Dietary Zinc Restriction
Authors: Whittle Nigel , Hauschild Markus , Lubec Gert , Holmes Andrew , Singewald Nicolas
Published: October 2010

Fear extinction is impaired in neuropsychiatric disorders, including posttraumatic stress disorder. Identifying drugs that facilitate fear extinction in animal models provides leads for novel pharmacological treatments for these disorders. Zinc (Zn) is expressed in neurons in a cortico-amygdala circuit mediating fear extinction, and modulates neurotransmitter systems regulating extinction. We previously found that the 129S1/SvImJ mouse strain (S1) exhibited a profound impairment in fear extinction, coupled with abnormalities in the activation of the extinction circuit. Here, we tested the role of Zn in fear extinction in S1 and C57BL/6N reference strain (B6) by feeding the mice a Zn-restricted diet (ZnR) and testing for fear extinction, as well as neuronal activation of the extinction circuit via quantification of the immediate-early genes c-Fos and Zif268. Results showed that (preconditioning or postconditioning) ZnR completely rescued deficient extinction learning and long-term extinction retrieval in S1 and expedited extinction learning in B6, without affecting fear acquisition or fear expression. The extinction-facilitating effects of ZnR were associated with the normalization of Zif268 and/or c-Fos expression in cortico-amygdala regions of S1. Specifically, ZnR increased activity in infralimbic cortex, lateral and basolateral amygdala nuclei, and lateral central amygdala nucleus, and decreased activity in prelimbic and insular cortices and medial central amygdala nucleus. ZnR also increased activation in the main intercalated nucleus and decreased activation of the medial paracapsular intercalated mass in S1. Our findings reveal a novel role for Zn in fear extinction and further support the utility of the S1 model for identifying extinction facilitating drugs.
Spike Timing and Information Transmission at Retinogeniculate Synapses
Authors: Rathbun Daniel L. , Warland David K. , Usrey W. Martin
Published: October 2010

This study examines the rules governing the transfer of spikes between the retina and the lateral geniculate nucleus (LGN) with the goal of determining whether the most informative retinal spikes preferentially drive LGN responses and what role spike timing plays in the process. By recording from monosynaptically connected pairs of retinal ganglion cells and LGN neuronsin vivoin the cat, we show that relayed spikes are more likely than nonrelayed spikes to be evoked by stimuli that match the receptive fields of the recorded cells and that an interspike interval-based mechanism contributes to the process. Relayed spikes are also more reliable in their timing and number where they often achieve the theoretical limit of minimum variance. As a result, relayed spikes carry more visual information per spike. Based on these results, we conclude that retinogeniculate processing increases sparseness in the neural code by selectively relaying the highest fidelity spikes to the visual cortex.
Complex Cells in the Cat Striate Cortex Have Multiple Disparity Detectors in the Three-Dimensional Binocular Receptive Fields
Authors: Sasaki Kota S. , Tabuchi Yuka , Ohzawa Izumi
Published: October 2010

Along the visual pathway, neurons generally become more specialized for signaling a limited subset of stimulus attributes and become more invariant to changes in the stimulus position within the receptive fields (RFs). One of the likely mechanisms underlying such invariance appears to be pooling of detectors located at different positions. Does such spatial pooling occur for disparity-selective neurons in primary visual cortex? To examine whether the three-dimensional (3D) binocular RFs are constructed by pooling detectors for binocular disparity, we investigated binocular interactions in the 3D space for neurons in the cat striate cortex. Approximately one-third of complex cells showed the spatial pooling of disparity detectors to a significant degree, whereas the majority of simple cells did not. The degree of spatial pooling of disparity detectors along the preferred orientation axis was generally larger than that along the axis orthogonal to the orientation axis. We then reconstructed 3D binocular RFs in their complete form and examined their structures. Disparity tuning curves were compared across positions along the orientation axis in the RFs. A small population of cells appeared to show a gradual shift of the preferred disparity along this axis, indicating that they can potentially signal inclination in the 3D space. However, the majority of cells exhibited a position-invariant disparity tuning. Finally, disparity tuning curves were examined for all oblique angles in addition to horizontal and vertical. Tunings were broadest along the orientation axis as the disparity energy model predicts.
Membrane Anchoring Subunits Specify Selective Regulation of RGS9·Gβ5 GAP Complex in Photoreceptor Neurons
Authors: Cao Yan , Kolesnikov Alexander V. , Masuho Ikuo , Kefalov Vladimir J. , Martemyanov Kirill A.
Published: October 2010

The RGS9·Gβ5 complex is the key regulator of neuronal G-protein signaling and shows remarkable selectivity of subunit composition. In retinal photoreceptors, RGS9·Gβ5 is bound to the membrane anchor R9AP and the complex regulates visual signaling. In the basal ganglia neurons, RGS9·Gβ5 is instead associated with a homologous protein, R7BP, and regulates reward circuit. Switching this selective subunit composition of the complex in rod photoreceptors allowed us to study the molecular underpinning of signaling specificity in diverse G-protein pathways. We have found that both membrane anchoring subunits play a conserved role in regulating protein levels of RGS9·Gβ5 and enhancing the ability of RGS·Gβ5 complexes to stimulate GTPase activity of G proteins. However, notable differences exist in the subcellular targeting of alternatively configured complexes. Unlike R9AP, which relies on passive targeting mechanisms for the delivery to the outer segments of the photoreceptors, R7BP is excluded from this location and is instead specifically targeted to the plasma membrane. R7BP-containing complexes could be rerouted to the outer segments, where they are capable of regulating the phototransduction cascade by the active targeting signals derived from rhodopsin. These findings illustrate the diversity of the G-protein signaling regulation by RGS·Gβ5 complexes achieved by differential recruitment of the membrane anchors.
Brain Dynamics Underlying Training-Induced Improvement in Suppressing Inappropriate Action
Authors: Manuel Aurelie L. , Grivel Jeremy , Bernasconi Fosco , Murray Micah M. , Spierer Lucas
Published: October 2010

Inhibitory control, a core component of executive functions, refers to our ability to suppress intended or ongoing cognitive or motor processes. Mostly based on Go/NoGo paradigms, a considerable amount of literature reports that inhibitory control of responses to “NoGo” stimuli is mediated by top-down mechanisms manifesting ∼200 ms after stimulus onset within frontoparietal networks. However, whether inhibitory functions in humans can be trained and the supporting neurophysiological mechanisms remain unresolved. We addressed these issues by contrasting auditory evoked potentials (AEPs) to left-lateralized “Go” and right NoGo stimuli recorded at the beginning versus the end of 30 min of active auditory spatial Go/NoGo training, as well as during passive listening of the same stimuli before versus after the training session, generating two separate 2 × 2 within-subject designs. Training improved Go/NoGo proficiency. Response times to Go stimuli decreased. During active training, AEPs to NoGo, but not Go, stimuli modulated topographically with training 61–104 ms after stimulus onset, indicative of changes in the underlying brain network. Source estimations revealed that this modulation followed from decreased activity within left parietal cortices, which in turn predicted the extent of behavioral improvement. During passive listening, in contrast, effects were limited to topographic modulations of AEPs in response to Go stimuli over the 31–81 ms interval, mediated by decreased right anterior temporoparietal activity. We discuss our results in terms of the development of an automatic and bottom-up form of inhibitory control with training and a differential effect of Go/NoGo training during active executive control versus passive listening conditions.
Clan Mentality: Evidence That the Medial Prefrontal Cortex Responds to Close Others
Authors: Krienen Fenna M. , Tu Pei-Chi , Buckner Randy L.
Published: October 2010

Kinship, friendship alliances, and perceptions of others' beliefs guide social interactions and are central to cohesive group behavior. Under certain conditions, brain systems that involve regions along the frontal midline increase activity when inferences are drawn about others who share a similar view to one's own (similarity). A prominent hypothesis is that these regions contribute to social cognition by simulating the other person's perspective based on one's own experience. An alternative is that certain regions process the social relevance of the person (closeness) to oneself and contribute to the assessment akin to signals that govern behavioral approach responses. These alternatives were explored across four functional magnetic resonance imaging experiments (n= 98). Experiment 1 localized the target midline regions in the rostral anterior cingulate cortex and anterior medial prefrontal cortex by having participants make personal judgments. The two dimensions (similarity, closeness) were crossed in experiment 2 using actual friends of the participant and unknown others. Making judgments about oneself and friends resulted in increased midline response relative to unknown others regardless of whether the friends shared similar views as the participant. Experiment 3 revealed that similarity was not a factor even when close others were not included. Experiment 4 directly contrasted two extremes: participants made inferences about similar, unknown others and dissimilar friends. Judgments about the close others again increased blood oxygenation level-dependent response along the frontal midline. These results encourage further exploration of the idea that frontal systems linked with limbic circuits facilitate assessment of the relevance or personal significance in social contexts.
Haploinsufficiency in Peptidylglycine α-Amidating Monooxygenase Leads to Altered Synaptic Transmission in the Amygdala and Impaired Emotional Responses
Authors: Gaier Eric D. , Rodriguiz Ramona M. , Ma Xin-Ming M. , Sivaramakrishnan Shobhana , Bousquet-Moore Danielle , Wetsel William C. , Eipper Betty A. , Mains Richard E.
Published: October 2010

The mammalian amygdala expresses various neuropeptides whose signaling has been implicated in emotionality. Many neuropeptides require amidation for full activation by peptidylglycine α-amidating monooxygenase (PAM), a transmembrane vesicular cuproenzyme and regulator of the secretory pathway. Mice heterozygous for thePamgene (PAM+/−) exhibit physiological and behavioral abnormalities related to specific peptidergic pathways. In the present study, we evaluated emotionality and examined molecular and cellular responses that characterize neurophysiological differences in the PAM+/−amygdala. PAM+/−mice presented with anxiety-like behaviors in the zero maze that were alleviated by diazepam. PAM+/−animals were deficient in short- and long-term contextual and cued fear conditioning and required higher shock intensities to establish fear-potentiated startle than their wild-type littermates. Immunohistochemical analysis of the amygdala revealed PAM expression in pyramidal neurons and local interneurons that synthesize GABA. We performed whole-cell recordings of pyramidal neurons in the PAM+/−amygdala to elucidate neurophysiological correlates of the fear behavioral phenotypes. Consistent with these observations, thalamic afferent synapses in the PAM+/−lateral nucleus were deficient in long-term potentiation. This deficit was apparent in the absence and presence of the GABAAreceptor antagonist picrotoxin and was abolished when both GABAAand GABABreceptors were blocked. Both evoked and spontaneous excitatory signals were enhanced in the PAM+/−lateral nucleus. Phasic GABAergic signaling was also augmented in the PAM+/−amygdala, and this difference comprised activity-independent and -dependent components. These physiological findings represent perturbations in the PAM+/−amygdala that may underlie the aberrant emotional responses in the intact animal.
Partial Deficiency or Short-Term Inhibition of 11β-Hydroxysteroid Dehydrogenase Type 1 Improves Cognitive Function in Aging Mice
Authors: Sooy Karen , Webster Scott P. , Noble June , Binnie Margaret , Walker Brian R. , Seckl Jonathan R. , Yau Joyce L. W.
Published: October 2010

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) regenerates active glucocorticoids (GCs) from intrinsically inert 11-keto substrates inside cells, including neurons, thus amplifying steroid action. Excess GC action exerts deleterious effects on the hippocampus and causes impaired spatial memory, a key feature of age-related cognitive dysfunction. Mice with complete deficiency of 11β-HSD1 are protected from spatial memory impairments with aging. Here, we tested whether lifelong or short-term decreases in 11β-HSD1 activity are sufficient to alter cognitive function in aged mice. Aged (24 months old) heterozygous male 11β-HSD1 knock-out mice, with ∼60% reduction in hippocampal 11β-reductase activity throughout life, were protected against spatial memory impairments in the Y-maze compared to age-matched congenic C57BL/6J controls. Pharmacological treatment of aged C57BL/6J mice with a selective 11β-HSD1 inhibitor (UE1961) for 10 d improved spatial memory performance in the Y-maze (59% greater time in novel arm than vehicle control). These data support the use of selective 11β-HSD1 inhibitors in the treatment of age-related cognitive impairments.
Attenuation of Activity in an Endogenous Analgesia Circuit by Ongoing Pain in the Rat
Authors: Ferrari Luiz F. , Gear Robert W. , Levine Jon D.
Published: October 2010

Analgesic efficacy varies depending on the pain syndrome being treated. One reason for this may be a differential effect of individual pain syndromes on the function of the endogenous pain control circuits at which these drugs act to produce analgesia. To test this hypothesis, we examined the effects of diverse (i.e., ongoing inflammatory, neuropathic, or chronic widespread) pain syndromes on analgesia induced by activation of an opioid-mediated, noxious stimulus-induced endogenous pain control circuit. This circuit was activated by subdermal capsaicin injection at a site remote from the site of nociceptive testing. Analgesia was not affected by carrageenan-induced inflammatory pain or the early phase of oxaliplatin neuropathy (a complication of cancer chemotherapy). However, the duration of analgesia was markedly shorter in the late phase of oxaliplatin neuropathy and in alcoholic neuropathy. A model of fibromyalgia syndrome produced by chronic unpredictable stress and proinflammatory cytokines also shortened analgesia duration, but so did the same stress alone. Therefore, since chronic pain can activate neuroendocrine stress axes, we tested whether they are involved in the attenuation of analgesic duration induced by these pain syndromes. Rats in which the sympathoadrenal axis was ablated by adrenal medullectomy showed normal duration pain-induced analgesia in groups with either late-phase oxaliplatin neuropathy, alcoholic neuropathy, or exposure to sound stress. These results support the suggestion that pain syndromes can modulate activity in endogenous pain control circuits and that this effect is sympathoadrenal dependent.
Amyloid Precursor Protein Cleavage-Dependent and -Independent Axonal Degeneration Programs Share a Common Nicotinamide Mononucleotide Adenylyltransferase 1-Sensitive Pathway
Authors: Vohra Bhupinder P. S. , Sasaki Yo , Miller Bradley R. , Chang Jufang , DiAntonio Aaron , Milbrandt Jeffrey
Published: October 2010

Axonal degeneration is a hallmark of many debilitating neurological disorders and is thought to be regulated by mechanisms distinct from those governing cell body death. Recently, caspase 6 activation via amyloid precursor protein (APP) cleavage and activation of DR6 was discovered to induce axon degeneration after NGF withdrawal. We tested whether this pathway is involved in axonal degeneration caused by withdrawal of other trophic support, axotomy or vincristine exposure. Neurturin deprivation, like NGF withdrawal activated this APP/DR6/caspase 6 pathway and resulted in axonal degeneration, however, APP cleavage and caspase 6 activation were not involved in axonal degeneration induced by mechanical or toxic insults. However, loss of surface APP (sAPP) and caspase 6 activation were observed during axonal degeneration induced by dynactin 1(Dctn1) dysfunction, which disrupts axonal transport. Mutations in Dctn1 are associated with motor neuron disease and frontal temporal dementia, thus suggesting that the APP/caspase 6 pathway could be important in specific types of disease-associated axonal degeneration. The NGF deprivation paradigm, with its defined molecular pathway, was used to examine the context of Nmnat-mediated axonal protection. We found that although Nmnat blocks axonal degeneration after trophic factor withdrawal, it did not prevent loss of axon sAPP or caspase 6 activation within the axon, suggesting it acts downstream of caspase 6. These results indicate that diverse insults induce axonal degeneration via multiple pathways and that these degeneration signals converge on a common, Nmnat-sensitive program that is uniquely involved in axonal, but not cell body, degeneration.
Intrinsic Plasticity Complements Long-Term Potentiation in Parallel Fiber Input Gain Control in Cerebellar Purkinje Cells
Authors: Belmeguenai Amor , Hosy Eric , Bengtsson Fredrik , Pedroarena Christine M. , Piochon Claire , Teuling Eva , He Qionger , Ohtsuki Gen , De Jeu Marcel T. G. , Elgersma Ype , De Zeeuw Chris I. , Jörntell Henrik , Hansel Christian
Published: October 2010

Synaptic gain control and information storage in neural networks are mediated by alterations in synaptic transmission, such as in long-term potentiation (LTP). Here, we show using bothin vitroandin vivorecordings from the rat cerebellum that tetanization protocols for the induction of LTP at parallel fiber (PF)-to-Purkinje cell synapses can also evoke increases in intrinsic excitability. This form of intrinsic plasticity shares with LTP a requirement for the activation of protein phosphatases 1, 2A, and 2B for induction. Purkinje cell intrinsic plasticity resembles CA1 hippocampal pyramidal cell intrinsic plasticity in that it requires activity of protein kinase A (PKA) and casein kinase 2 (CK2) and is mediated by a downregulation of SK-type calcium-sensitive K conductances. In addition, Purkinje cell intrinsic plasticity similarly results in enhanced spine calcium signaling. However, there are fundamental differences: first, while in the hippocampus increases in excitability result in a higher probability for LTP induction, intrinsic plasticity in Purkinje cells lowers the probability for subsequent LTP induction. Second, intrinsic plasticity raises the spontaneous spike frequency of Purkinje cells. The latter effect does not impair tonic spike firing in the target neurons of inhibitory Purkinje cell projections in the deep cerebellar nuclei, but lowers the Purkinje cell signal-to-noise ratio, thus reducing the PF readout. These observations suggest that intrinsic plasticity accompanies LTP of active PF synapses, while it reduces at weaker, nonpotentiated synapses the probability for subsequent potentiation and lowers the impact on the Purkinje cell output.
TheGli3Hypomorphic MutationPdnCauses Selective Impairment in the Growth, Patterning, and Axon Guidance Capability of the Lateral Ganglionic Eminence
Authors: Magnani Dario , Hasenpusch-Theil Kerstin , Jacobs Erin C. , Campagnoni Anthony T. , Price David J. , Theil Thomas
Published: October 2010

Previous studies have defined a requirement for Sonic hedgehog (Shh) signaling in patterning the ventral telencephalon, a major source of the neuronal diversity found in the mature telencephalon. The zinc finger transcription factor Gli3 is a critical component of the Shh signaling pathway and its loss causes major defects in telencephalic development.Gli3is expressed in a graded manner along the dorsoventral axis of the telencephalon but it is unknown whetherGli3expression levels are important for dorsoventral telencephalic patterning. To address this, we used theGli3hypomorphic mouse mutantPolydactyly Nagoya(Pdn). We show that inPdn/Pdnembryos, the telencephalic expression ofGli3remains graded, butGli3mRNA and protein levels are reduced, resulting in an upregulation ofShhexpression and signaling. These changes mainly affect the development of the lateral ganglionic eminence (LGE), with some disorganization of the medial ganglionic eminence mantle zone. The pallial/subpallial boundary is shifted dorsally and the production of postmitotic neurons is reduced. Moreover, LGE pioneer neurons that guide corticofugal axons into the LGE do not form properly, delaying the entry of corticofugal axons into the ventral telencephalon.Pdn/Pdnmutants also show severe pathfinding defects of thalamocortical axons in the ventral telencephalon. Transplantation experiments demonstrate that the intrinsic ability of thePdnventral telencephalon to guide thalamocortical axons is compromised. We conclude that correctGli3levels are particularly important for the LGE's growth, patterning, and development of axon guidance capabilities.
Apolipoprotein E4 Causes Age- and Tau-Dependent Impairment of GABAergic Interneurons, Leading to Learning and Memory Deficits in Mice
Authors: Andrews-Zwilling Yaisa , Bien-Ly Nga , Xu Qin , Li Gang , Bernardo Aubrey , Yoon Seo Yeon , Zwilling Daniel , Yan Tonya Xue , Chen Ligong , Huang Yadong
Published: October 2010

Apolipoprotein E4 (apoE4) is the major genetic risk factor for Alzheimer's disease. However, the underlying mechanisms are unclear. We found that female apoE4 knock-in (KI) mice had an age-dependent decrease in hilar GABAergic interneurons that correlated with the extent of learning and memory deficits, as determined in the Morris water maze, in aged mice. Treating apoE4-KI mice with daily peritoneal injections of the GABAAreceptor potentiator pentobarbital at 20 mg/kg for 4 weeks rescued the learning and memory deficits. In neurotoxic apoE4 fragment transgenic mice, hilar GABAergic interneuron loss was even more pronounced and also correlated with the extent of learning and memory deficits. Neurodegeneration and tauopathy occurred earliest in hilar interneurons in apoE4 fragment transgenic mice; eliminating endogenous Tau prevented hilar GABAergic interneuron loss and the learning and memory deficits. The GABAAreceptor antagonist picrotoxin abolished this rescue, while pentobarbital rescued learning deficits in the presence of endogenous Tau. Thus, apoE4 causes age- and Tau-dependent impairment of hilar GABAergic interneurons, leading to learning and memory deficits in mice. Consequently, reducing Tau and enhancing GABA signaling are potential strategies to treat or prevent apoE4-related Alzheimer's disease.
Isolation of Tracheal Aspirate Mesenchymal Stromal Cells Predicts Bronchopulmonary Dysplasia
Authors: Popova Antonia P. , Bozyk Paul D. , Bentley J. Kelley , Linn Marisa J. , Goldsmith Adam M. , Schumacher Robert E. , Weiner Gary M. , Filbrun Amy G. , Hershenson Marc B.
Published: October 2010

BACKGROUND:

We have isolated mesenchymal stem cells (MSCs) from tracheal aspirates of premature infants with respiratory distress. Under the influence of transforming growth factor β, MSCs differentiate into α-smooth-muscle actin–expressing myofibroblasts. Myofibroblasts are increased in the lungs of patients with bronchopulmonary dysplasia (BPD), a chronic lung disease of prematurely born infants.

OBJECTIVE:

We tested whether isolation of MSCs from tracheal aspirates of premature infants with respiratory distress during the first week of life correlates with BPD.

METHODS:

Eighty-four infants born at a gestational age of <33 weeks and requiring mechanical ventilation were studied. Aspirates were collected during suctioning and centrifuged. Cell pellets were resuspended in culture medium and plated. Adherent cells were grown to confluence.

RESULTS:

MSCs were isolated from the tracheal aspirates of 56 infants; 28 aspirate samples showed no MSCs. There was no statistical difference in gestational age or birth weight between the MSC and no-MSC groups. In the MSC group, 12 infants died and 25 developed BPD, as defined by a requirement for supplemental oxygen at 36 weeks' postmenstrual age. In the no-MSC group, 6 infants died and 1 developed BPD. Accounting for potential influences of gender, birth weight, gestational age, number of tracheal aspirate samples taken, and the duration of endotracheal intubation (up to 7 days), isolation of MSCs increased the adjusted odds ratio of BPD more than 21-fold (95% confidence interval: 1.82–265.85).

CONCLUSIONS:

Isolation of tracheal aspirate MSCs predicts the development of BPD, which suggests that MSCs play an important role in the pathogenesis of this disease.
Evidence for an Association Between Infant Mortality and a Carnitine Palmitoyltransferase 1A Genetic Variant
Authors: Gessner Bradford D. , Gillingham Melanie B. , Birch Stephanie , Wood Thalia , Koeller David M.
Published: October 2010

OBJECTIVE:

Alaska Native and other circumpolar indigenous populations have historically experienced high infant mortality rates, for unknown reasons. Through routine newborn screening, Alaskan and Canadian indigenous infants have been found to have a high frequency of a single sequence variant (c.1436C→T) in the gene coding for carnitine palmitoyltransferase type 1A (CPT1A). We sought to determine whether these 2 findings were related.

METHODS:

As part of a quality control exercise at the Alaskan Newborn Metabolic Screening Program, we conducted genotyping for 616 consecutively born, Alaska Native infants and reviewed their medical records. We conducted an ecological analysis comparing Census area–level variant CPT1A allele frequency and historical Alaska Native infant, postneonatal, and neonatal mortality rates.

RESULTS:

Infant death was identified for 5 of 152 infants homozygous for the c.1436C→T sequence variant (33 deaths per 1000 live births), 2 of 219 heterozygous infants (9 deaths per 1000 live births), and 0 of 245 infants carrying no copies of the variant allele (χ2 = 9.2; P = .01). All 7 cases of infant death had some evidence of an infectious process at the time of death, including 5 with respiratory infections. Census areas with the highest frequency of the variant allele had the highest historical infant, postneonatal, and neonatal mortality rates.

CONCLUSIONS:

Our data provide preliminary evidence that a highly prevalent CPT1A variant found among Alaska Native and other indigenous circumpolar populations may help explain historically high infant mortality rates. Larger definitive studies are needed.
Euthanasia and other decisions at the end of life (Proposal for a more lucid terminology and some thoughts on the legal framework of medical treatment)
Authors: Vadász Gábor
Published: October 2010

Az életvégi orvosi döntéseknek csak egyike az eutanázia javallata. E kérdéskörnek a betegágy melletti klinikai történésekkel összefüggő szabatos meghatározása az etikai, a jogi és az orvosi szakirodalomban nem teljes körű. A különböző életvégi események csoportosítására tett kísérlet ez az írás, amelynek célja annak tisztázása, hogy közülük
melyek nem sorolhatók a passzív eutanázia fogalomkörébe.
Az eutanázia nem jogi kategória. A közkeletűen használt két kifejezés az aktív és a passzív eutanázia, egyszerűsítések, amelyek különböző célú cselekményt takarnak, amelyeknek a szakmai szakszövegekben történő használata zavaró is lehet és félreértésekre adhat okot. Az életvégi terápiás döntéseket a
céljukra tekintettel
különböztetjük meg. A MOK meghatározásából kiindulva és gyűjtőfogalmat használva, csak
az a cselekmény eutanázia, amikor a cselekvésnek vagy nem cselekvésnek célja, kegyelemből, szenvedő embertárs érdekében, életének a megrövidítése vagy kioltása.
Ismertetjük az aktív, a passzív és a kényszereutanázia fogalmait. Az indirekt és az intermedier eutanázia fogalmait, mint félremagyarázásokra okot adókat, nem használjuk. Nem tartjuk egyértelmű kizáró oknak az eutanázia fogalomköréből a laikusok segítségét és részvételét a kivitelezésben, és nem tartjuk csak orvoshoz köthető fogalomnak. Ismertetjük azokat az életvégi orvosi döntéseket, amelyeket nem sorolunk a passzív eutanázia fogalomkörébe, ezek: a hasztalanná vált kezelés és életfenntartó eljárások visszavonása, a beteg elengedése, a terápia eszkalációjának ellenjavallata, a palliatív terápia alkalmazása, a szenvedés csillapítását szolgáló kezelés, a kompromisszumos medicina, az újjáélesztés javallatának mérlegelése és a költséghatékony terápia választása. Érintjük az élő végrendelet kérdéskörét, működésképtelenségének okát és viszonyát az aktív és passzív eutanáziához. Az életmentő és életfenntartó kezelés jogi szabályozásának a kérdése kapcsán foglalkozunk az egészségügyi jogalkotástól elvárható szellemiséggel. Orv. Hetil., 2010,
43,
1769–1775.
Pressure Studies for 1111 and 11 Type Iron-based Superconductors
Authors: Takahashi Hiroki , Okada Hironari , Takahashi Hiroyuki , Kamihara Yoichi , Matsuishi Satoru , Hirano Masahiro , Hosono Hideo , Mizuguchi Yoshikazu , Takano Yoshihiko
Published: October 2010

In the recent development of the studies in iron-based superconductors, high-pressure experiments have been played an important role. Large enhancement of Tc with applying pressure and pressure-induced superconductivity were reported in LaFeAsO1-xFx. In this work, electrical, magnetic and structural measurements on 1111 type Ca(Fe1-xCox)AsF and 11 type Fe(Se1-xTex)0.92 under high pressure have been performed. For Ca(Fe1-xCox)AsF, the substitution of Co suppressed the magnetic and structural transitions and raised superconductivity. Pressure-induced superconductivity was observed for x = 0.0 and 0.05. The highest Tc was obtained in parent compound under high pressure, in contrast to LaFeAsO1-xFx. These results suggest that the substitution of Co increases carrier concentration and induces disorder in the FeAs superconducting layer. For FeTe0.92, pressure-induced superconductivity was not detected under high pressure up to 19 GPa, although the resistive anomaly due to the structural and magnetic phase transition was suppressed by applying pressure.