bluuebunny/crossref_metadata_2025 huggingface dataset:
Polyarteritis Nodosa Resistant to Conventional Treatment in a Pediatric Patient
Authors: González-Fernández María Angeles , García-Consuegra Julia
Published: April 2007

Objective:

To report the case of a child diagnosed with polyarteritis nodosa (PAN) that was unresponsive to conventional treatment alone but improved with the addition of iloprost and bosentan to her drug regimen.

Case Summary:

A 3-year-old girl who had been diagnosed with PAN was referred to our hospital from another region. With conventional treatment of high doses of a corticosteroid and cyclophosphamide, her condition resolved. Six months later, our patient had a relapse that required hospital admission. In this second hospital stay, some cutaneous lesions evolved into digital necrosis. Off-label therapeutic alternatives, including a single dose (2 g/kg) of intravenous immunoglobulin (IVIG), intravenous iloprost 2 ng/kg/min over 6 h for 5 days and, approximately 4 wk later, oral bosentan 37.25 mg twice daily for 4 wk followed by 62.5 mg twice daily for 8 wk, were added to the conventional regimen to treat the serious cutaneous manifestations. Her fingers improved very slowly, and she was discharged on gradually tapered doses of oral corticosteroids, bosentan, and monthly pulsed injections of cyclophosphamide. The digital necrosis and other cutaneous lesions had resolved completely 6 months after the second discharge.

Discussion:

The dosages of IVIG and iloprost were based on those used for PAN, Raynaud's phenomenon, and digital necrosis in children. The use of bosentan for vasculitis had not been reported in children before the treatment of our patient, so its dosage was based on that used to produce vasodilation in children with pulmonary hypertension.

Conclusions:

Digital necrosis and cutaneous manifestations not resolved with conventional PAN treatment improved within 5 days with iloprost and 12 weeks with bosentan.
Written Versus Oral Recommendations Made by Pharmacy Students During Internal Medicine Rotations
Authors: Pound Melanie W , Miller Susan M
Published: April 2007

Background:

Pharmacy students use a variety of methods to communicate with physicians during clinical rotations regarding pharmacotherapy concerns. Documented acceptance rates for oral or written recommendations, when studied individually, range between 64% and 95%.

Objective:

To compare the acceptance rates of written versus oral recommendations made by pharmacy students on internal medicine (IM) rotations.

Methods:

Fourth-year pharmacy students completing an IM rotation made oral or written recommendations to physicians at a large, community-based medical center from November 2005 through April 2006 (excluding December). The types of recommendations and outcomes of the interventions were recorded using a data collection form. The primary endpoint was to determine differences in acceptance rates for written versus oral recommendations. Secondary endpoints included comparing the recommendation types and their corresponding acceptance rates. Additionally, the acceptance rates for evidence-based medicine (EBM) interventions were determined.

Results:

A total of 625 recommendations were made by 10 pharmacy students during the 5 month study period; 47.5% of these were oral. A total of 82.8% of oral recommendations were accepted compared with 54.2% of written recommendations (p< 0.0001). Over 90% of the total recommendations were drug related. Overall, 68% of these recommendations were accepted. The major types of drug-related recommendations were indication for use (42.7%), inappropriate dose (17.2%), inappropriate route (11.3%), inappropriate drug (8.5%), and duplicate therapy (6.5%). The remaining types of interventions were laboratory related (6.4%) and requests for drug information (3.2%). A total of 227 (36.3%) recommendations were based on EBM guidelines, with an acceptance rate of 67.8%.

Conclusions:

Pharmacy student recommendations are well received by IM physicians. Oral recommendations are accepted at a statistically significantly higher percentage compared with written recommendations. High acceptance rates for recommendations may have the ability to positively impact patient care.
Patients' Use and Perception of Medication Information Leaflets
Authors: Nathan Joseph P , Zerilli Tina , Cicero Lorraine A , Rosenberg Jack M
Published: April 2007

Background:

Federal law mandates that at least 95% of patients receive useful written information with new medications. Recent data concerning whether patients read such leaflets are lacking.

Objectives:

To evaluate whether patients read non–manufacturer-developed leaflets and assess patients' opinions concerning the understandability and usefulness of these leaflets.

Methods:

Patients were surveyed at 32 community pharmacies in the New York City metropolitan area. The main outcome measures were the percentage of patients who read the leaflet provided with new and refilled medications and the perceived understandability and usefulness of the leaflet. Descriptive statistics were used to analyze the results.

Results:

A total of 307 patients were surveyed. For leaflets provided with new medications, 151 (49.2%), 65 (21.2%), 49 (16.0%), and 42 (13.7%) reported reading the leaflets always, often, seldom, or never, respectively. For refilled medications, 64 (21.6%), 41 (13.9%), 78 (26.4%), and 113 (38.2%) of the 296 respondents reported reading the leaflets always, often, seldom, or never, respectively. Of 267 patients who read the leaflets provided with new or refilled prescriptions at least seldom, 258 (96.6%) responded to the question concerning its understandability and 257 (96.3%) responded to the question concerning its usefulness. One hundred forty-five (56.2%), 89 (34.5%), 22 (8.5%), and 2 (0.8%) reported that the leaflet was very easy, somewhat easy, somewhat difficult, and very difficult to understand, respectively, and 164 (63.8%), 90 (35.0%), and 3 (1.2%) reported that the leaflet was very useful, somewhat useful, and not useful, respectively.

Conclusions:

Approximately two-thirds of the patients surveyed reported reading the leaflets provided with new medications at least often. The majority reported the leaflets to be useful and easy to understand. Pharmacists should advocate reading the leaflet and promote it as a useful resource. The leaflet should not replace the pharmacist's obligation to provide verbal counseling.
Plasma Membrane Ca2+ATPase 2 Contributes to Short-Term Synapse Plasticity at the Parallel Fiber to Purkinje Neuron Synapse
Authors: Empson Ruth M. , Garside Molly L. , Knöpfel Thomas
Published: April 2007

Plasma membrane Ca2+ATPase 2 (PMCA2) is a fast, highly effective mechanism to control resting cytosolic Ca2+and Ca2+excursions in neurons and other excitable cells. The strong expression of PMCA2 in the cerebellum and the cerebellar behavioral deficits presented by PMCA2−/− knock-out mice all point to its importance for cerebellar circuit dynamics. Here, we provide direct functional evidence for the influence of presynaptic PMCA2-mediated Ca2+extrusion for short-term plasticity at cerebellar parallel fiber to Purkinje neuron synapses. Dramatic structural alterations to the Purkinje neurons in the absence of PMCA2 also suggest a strong influence of this fast PMCA2 isoform for development and maintenance of cerebellar function.
Ipsilateral Whiskers Suppress Experience-Dependent Plasticity in the Barrel Cortex
Authors: Glazewski Stanislaw , Benedetti Brett L. , Barth Alison L.
Published: April 2007

Each cerebral hemisphere processes sensory input from both sides of the body, but the impact of this convergence on shaping and modifying receptive field properties remains controversial. Here we investigated the effect of chronic deprivation of ipsilateral sensory whiskers on receptive field plasticity in primary somatosensory cortex. In the absence of ipsilateral whiskers, cortical receptive fields were significantly larger than control after 1 week. Removal of all but a single whisker from one side of the face [single-whisker experience (SWE)] has been shown to result in the expansion of the cortical area responding to the spared whisker. We compared the effects of SWE in the presence (SWE-unilateral) and absence (SWE-bilateral) of ipsilateral whiskers. SWE-bilateral deprivation results in a significant increase in neuronal responses to spared whisker stimulation both in its cognate barrel column and in adjacent, surrounding barrel columns compared with control and SWE-unilateral deprived animals. Surround receptive fields in deprived columns were maintained in SWE-bilateral treated animals but depressed in SWE-unilateral animals. The increase in spared whisker responses was progressive with longer deprivation periods. These data show that ipsilateral whiskers can constrain receptive field size in the barrel cortex.
Mice Lacking Protease Nexin-1 Show Delayed Structural and Functional Recovery after Sciatic Nerve Crush
Authors: Lino Maria Maddalena , Atanasoski Suzana , Kvajo Mirna , Fayard Bérengère , Moreno Eliza , Brenner Hans Rudolf , Suter Ueli , Monard Denis
Published: April 2007

Multiple molecular mechanisms influence nerve regeneration. Because serine proteases were shown to affect peripheral nerve regeneration, we performed nerve crush experiments to study synapse reinnervation in adult mice lacking the serpin protease nexin-1 (PN-1). PN-1 is a potent endogenous inhibitor of thrombin, trypsin, tissue plasminogen activators (tPAs), and urokinase plasminogen activators. Compared with the wild type, a significant delay in synapse reinnervation was detected in PN-1 knock-out (KO) animals, which was associated with both reduced proliferation and increased apoptosis of Schwann cells. Various factors known to affect Schwann cells were also altered. Fibrin deposits, tPA activity, mature BDNF, and the low-affinity p75 neurotrophin receptor were increased in injured sciatic nerves of mutant mice. To test whether the absence of PN-1 in Schwann cells or in the axon caused delay in reinnervation, PN-1 was overexpressed exclusively in the nerves of PN-1 KO mice. Neuronal PN-1 expression did not rescue the delayed reinnervation. The results suggest that Schwann cell-derived PN-1 is crucial for proper reinnervation through its contribution to the autocrine control of proliferation and survival. Thus, the precise balance between distinct proteases and serpins such as PN-1 can modulate the overall impact on the kinetics of recovery.
Subcellular Arrangement of Molecules for 2-Arachidonoyl-Glycerol-Mediated Retrograde Signaling and Its Physiological Contribution to Synaptic Modulation in the Striatum
Authors: Uchigashima Motokazu , Narushima Madoka , Fukaya Masahiro , Katona Istvan , Kano Masanobu , Watanabe Masahiko
Published: April 2007

Endogenous cannabinoids (endocannabinoids) mediate retrograde signals for short- and long-term suppression of transmitter release at synapses of striatal medium spiny (MS) neurons. An endocannabinoid, 2-arachidonoyl-glycerol (2-AG), is synthesized from diacylglycerol (DAG) after membrane depolarization and Gq-coupled receptor activation. To understand 2-AG-mediated retrograde signaling in the striatum, we determined precise subcellular distributions of the synthetic enzyme of 2-AG, DAG lipase-α (DAGLα), and its upstream metabotropic glutamate receptor 5 (mGluR5) and muscarinic acetylcholine receptor 1 (M1). DAGLα, mGluR5, and M1were all richly distributed on the somatodendritic surface of MS neurons, but their subcellular distributions were different. Although mGluR5 and DAGLα levels were highest in spines and accumulated in the perisynaptic region, M1level was lowest in spines and was rather excluded from the mGluR5-rich perisynaptic region. These subcellular arrangements suggest that mGluR5 and M1might differentially affect endocannabinoid-mediated, depolarization-induced suppression of inhibition (DSI) and depolarization-induced suppression of excitation (DSE) in MS neurons. Indeed, mGluR5 activation enhanced both DSI and DSE, whereas M1activation enhanced DSI only. Importantly, DSI, DSE, and receptor-driven endocannabinoid-mediated suppression were all abolished by the DAG lipase inhibitor tetrahydrolipstatin, indicating 2-AG as the major endocannabinoid mediating retrograde suppression at excitatory and inhibitory synapses of MS neurons. Accordingly, CB1cannabinoid receptor, the main target of 2-AG, was present at high levels on GABAergic axon terminals of MS neurons and parvalbumin-positive interneurons and at low levels on excitatory corticostriatal afferents. Thus, endocannabinoid signaling molecules are arranged to modulate the excitability of the MS neuron effectively depending on cortical activity and cholinergic tone as measured by mGluR5 and M1receptors, respectively.
Triangulating a Cognitive Control Network Using Diffusion-Weighted Magnetic Resonance Imaging (MRI) and Functional MRI
Authors: Aron Adam R. , Behrens Tim E. , Smith Steve , Frank Michael J. , Poldrack Russell A.
Published: April 2007

The ability to stop motor responses depends critically on the right inferior frontal cortex (IFC) and also engages a midbrain region consistent with the subthalamic nucleus (STN). Here we used diffusion-weighted imaging (DWI) tractography to show that the IFC and the STN region are connected via a white matter tract, which could underlie a “hyperdirect” pathway for basal ganglia control. Using a novel method of “triangulation” analysis of tractography data, we also found that both the IFC and the STN region are connected with the presupplementary motor area (preSMA). We hypothesized that the preSMA could play a conflict detection/resolution role within a network between the preSMA, the IFC, and the STN region. A second experiment tested this idea with functional magnetic resonance imaging (fMRI) using a conditional stop-signal paradigm, enabling examination of behavioral and neural signatures of conflict-induced slowing. The preSMA, IFC, and STN region were significantly activated the greater the conflict-induced slowing. Activation corresponded strongly with spatial foci predicted by the DWI tract analysis, as well as with foci activated by complete response inhibition. The results illustrate how tractography can reveal connections that are verifiable with fMRI. The results also demonstrate a three-way functional–anatomical network in the right hemisphere that could either brake or completely stop responses.
Telomere Protection Mechanisms Change during Neurogenesis and Neuronal Maturation: Newly Generated Neurons Are Hypersensitive to Telomere and DNA Damage
Authors: Cheng Aiwu , Shin-ya Kazuo , Wan Ruiqian , Tang Sung-chun , Miura Takumi , Tang Hongyang , Khatri Rina , Gleichman Marc , Ouyang Xin , Liu Dong , Park Hae-Rong , Chiang Jeffrey Y. , Mattson Mark P.
Published: April 2007

Telomeres are DNA–protein complexes at the ends of eukaryotic chromosomes that play an important role in maintaining the integrity of the genome. In proliferative stem cells and cancer cells, telomere length is maintained by telomerase, and telomere structure and functions are regulated by telomere-associated proteins. We find that telomerase levels are high in embryonic cortical neural progenitor cells (NPCs) and low in newly generated neurons (NGNs) and mature neurons (MNs). In contrast, telomere repeat-binding factor 2 (TRF2) expression is undetectable in early brain developmentin vivoand in cultured NPCs and is expressed at progressively higher levels as NPCs cease proliferation and differentiate into postmitotic neurons. The telomere-disrupting agent telomestatin induces a DNA damage response and apoptosis in NGNs (which have low levels of TRF2 and telomerase), whereas NPCs (which have high levels of telomerase) and MNs (which have high levels of TRF2) are resistant to telomere damage. Overexpression of TRF2 in NGNs protects them against death induced by telomestatin and other DNA-damaging agents. Knockdown of TRF2 expression in MNs and knock-out of telomerase reverse transcriptase in NPCs increased their sensitivity to telomere- and DNA-damaging agents but did not affect the vulnerability of NGNs. These findings suggest that TRF2 and telomerase function as distinct telomere protection mechanisms during the processes of neurogenesis and neuronal maturation and that hypersensitivity of NGNs to telomere damage results from relative deficiencies of both telomerase and TRF2.
Rac1 Controls the Formation of Midline Commissures and the Competency of Tangential Migration in Ventral Telencephalic Neurons
Authors: Chen Lei , Liao Guanghong , Waclaw Ronald R. , Burns Kevin A. , Linquist Diana , Campbell Kenneth , Zheng Yi , Kuan Chia-Yi
Published: April 2007

Previous studies using dominant-mutant constructs have implicated Rac1 GTPase in neuritogenesis and neuronal migration. However, overexpression of dominant mutants generally blocks Rho–GTPase activity; thus, it may not reveal the specific or physiological functions of Rac1. To address this issue, we have applied a conditional gene-targeting strategy, using Foxg1–Cre mice to delete Rac1 in the ventricular zone (VZ) of telencephalon and Dlx5/6–Cre–IRES (internal ribosomal entry site)–EGFP (enhanced green fluorescent protein) (Dlx5/6–CIE) in the subventricular zone (SVZ) of ventral telencephalon, respectively. Surprisingly, the deletion of Rac1 in VZ progenitors did not prevent axonal outgrowth of telencephalic neurons. However, the anterior commissure was absent, and the corpus callosal as well as hippocampal commissural axons failed to cross the midline in Rac1/Foxg1–Cre knock-out embryos. The thalamocortical and corticothalamic axons also showed defasciculation or projection defects. These results suggest that Rac1 controls axon guidance rather than neuritogenesis. In addition, although Rac1/Foxg1–Cre knock-out embryos showed delayed radial migration of cortical projection neurons and severe impairment of tangential migration by the ventral telencephalon-derived interneurons, deletion of Rac1 in the SVZ by Dlx5/6–CIE mice produced no discernible defects in tangential migration. These contrasting effects of Rac1 deletion on tangential migration suggest that Rac1 is dispensable for cellular motility per se during neuronal migration. Together, these results underscore the challenge of deciphering the biological functions of Rac1, and Rho–GTPases in general, during mammalian brain development. Moreover, they indicate that Rac1 has a critical role in axon guidance and in acquisition of migratory competency during differentiation of the progenitors for the ventral telencephalon-derived interneurons.
GABAergic Control of Adult Hippocampal Neurogenesis in Relation to Behavior Indicative of Trait Anxiety and Depression States
Authors: Earnheart John C. , Schweizer Claude , Crestani Florence , Iwasato Takuji , Itohara Shigeyoshi , Mohler Hanns , Lüscher Bernhard
Published: April 2007

Stressful experiences in early life are known risk factors for anxiety and depressive illnesses, and they inhibit hippocampal neurogenesis and the expression of GABAAreceptors in adulthood. Conversely, deficits in GABAergic neurotransmission and reduced neurogenesis are implicated in the etiology of pathological anxiety and diverse mood disorders. Mice that are heterozygous for the γ2 subunit of GABAAreceptors exhibit a modest functional deficit in mainly postsynaptic GABAAreceptors that is associated with a behavioral, cognitive, and pharmacological phenotype indicative of heightened trait anxiety. Here we used cell type-specific and developmentally controlled inactivation of the γ2 subunit gene to further analyze the mechanism and brain substrate underlying this phenotype. Heterozygous deletion of the γ2 subunit induced selectively in immature neurons of the embryonic and adult forebrain resulted in reduced adult hippocampal neurogenesis associated with heightened behavioral inhibition to naturally aversive situations, including stressful situations known to be sensitive to antidepressant drug treatment. Reduced adult hippocampal neurogenesis was associated with normal cell proliferation, indicating a selective vulnerability of postmitotic immature neurons to modest functional deficits in γ2 subunit-containing GABAAreceptors. In contrast, a comparable forebrain-specific GABAAreceptor deficit induced selectively in mature neurons during adolescence lacked neurogenic and behavioral consequences. These results suggest that modestly reduced GABAAreceptor function in immature neurons of the developing and adult brain can serve as a common molecular substrate for deficits in adult neurogenesis and behavior indicative of anxious and depressive-like mood states.
Molecular Nature of Anomalous L-Type Calcium Channels in Mouse Cerebellar Granule Cells
Authors: Koschak Alexandra , Obermair Gerald J. , Pivotto Francesca , Sinnegger-Brauns Martina J. , Striessnig Jörg , Pietrobon Daniela
Published: April 2007

Single-channel analysis revealed the existence of neuronal L-type Ca2+channels (LTCCs) with fundamentally different gating properties; in addition to LTCCs resembling cardiac channels, LTCCs with anomalous gating were identified in a variety of neurons, including cerebellar granule cells. Anomalous LTCC gating is mainly characterized by long reopenings after repolarization following strong depolarizations or trains of action potentials. To elucidate the unknown molecular nature of anomalous LTCCs, we performed single-channel patch-clamp recordings from cerebellar granule cells of wild-type, Cav1.3−/−and Cav1.2DHP−/−[containing a mutation in the Cav1.2 α1subunit that eliminates dihydropyridine (DHP) sensitivity] mice. Quantitative reverse transcription-PCR revealed that Cav1.2 accounts for 89% and Cav1.3 for 11% of the LTCC transcripts in wild-type cerebellar granule cells, whereas Cav1.1 and Cav1.4 are expressed at insignificant levels. Anomalous LTCCs were observed in neurons of Cav1.3−/−mice with a frequency not different from wild type. In the presence of the DHP agonist (+)-(S)-202-791, the typical prepulse-induced reopenings of anomalous LTCCs after repolarization were shorter in Cav1.2DHP−/−neurons than in Cav1.3−/−neurons. Reopenings in Cav1.2DHP−/−neurons in the presence of the DHP agonist were similar to those in wild-type neurons in the absence of the agonist. These data show that Cav1.2α1subunits are the pore-forming subunits of anomalous LTCCs in mouse cerebellar granule cells. Given the evidence that Cav1.2 channels are specifically involved in sustained Ras-MAPK (mitogen-activated protein kinase)-dependent cAMP response element-binding protein phosphorylation and LTCC-dependent hippocampal long-term potentiation (LTP) (Moosmang et al., 2005), we discuss the hypothesis that anomalous rather than cardiac-type Cav1.2 channels are specifically involved in LTCC-dependent and gene transcription-dependent LTP.
Electrophysiological Properties of AMPA Receptors Are Differentially Modulated Depending on the Associated Member of the TARP Family
Authors: Kott Sabine , Werner Markus , Körber Christoph , Hollmann Michael
Published: April 2007

The family of AMPA receptors is encoded by four genes that are differentially spliced to result in thefliporflopversions of the four subunits GluR1 to GluR4. GluR2 is further modified at the so-called Q/R site by posttranscriptional RNA editing. Delivery of AMPA receptors to the plasma membrane and synaptic trafficking are controlled by transmembrane AMPA receptor regulatory proteins (TARPs). Additionally, TARPs influence essential electrophysiological properties of AMPA receptor channels such as desensitization and agonist efficacies. Here, we compare the influence of all known TARPs (γ2, γ3, γ4, and γ8) on agonist-induced currents of the four AMPA receptor subunits, includingflipandflopsplice variants and editing variants. We show that, although agonist-induced currents of all homomeric AMPA receptor subunits as well as all heteromeric combinations tested are significantly potentiated when coexpressed with members of the TARP family inXenopus laevisoocytes, the extent of TARP-mediated increase in agonist-induced responses is highly dependent on both the AMPA receptor subunit and the coexpressed TARP. Moreover, we demonstrate that the splice variant of the AMPA receptor plays a key role in determining the modulation of electrophysiological properties by associated TARPs. We furthermore present evidence that individual TARP–AMPA receptor interactions control the degree of desensitization of AMPA receptors. Consequently, because of their subunit-specific impact on the electrophysiological properties, TARPs play a major role as modulatory subunits of AMPA receptors and thus contribute to the functional diversity of AMPA receptors encountered in the CNS.
Altered NMDA Receptor Trafficking in a Yeast Artificial Chromosome Transgenic Mouse Model of Huntington's Disease
Authors: Fan Mannie M. Y. , Fernandes Herman B. , Zhang Lily Y. J. , Hayden Michael R. , Raymond Lynn A.
Published: April 2007

Overactivation of NMDA receptors (NMDARs) is believed to play a role in degeneration of striatal medium-sized spiny neurons (MSNs) in Huntington's disease (HD). This hereditary disorder is caused by an expansion >35 in the polyglutamine (polyQ) region of the protein huntingtin (htt). Previous work has shown that NMDAR current, calcium signaling, and/or toxicity are enhanced in striatal MSNs in a variety of transgenic mice and cellular models of HD, but whether the enhancement is specific for MSNs or correlated with mutant htt (mhtt) polyQ length is not known. Furthermore, the mechanism underlying the increase in NMDAR activity has not been elucidated. Here we report polyQ length-dependent enhancement of peak NMDAR current density by mhtt in cultured MSNs, but not cortical neurons, from the yeast artificial chromosome (YAC) transgenic HD mouse model. We also observed a shift of NMDAR subunits NR1 and NR2B from internal pools to the plasma membrane and a significantly faster rate of NMDAR insertion to the surface in YAC72 MSNs. In comparing YAC72 with wild-type striatal tissue, subcellular fractionation revealed a relative enrichment of NR1 C2′-containing NMDARs in the vesicle/microsome-enriched fraction, and coimmunoprecipitation experiments demonstrated an increased proportion of NR1 C2′ isoforms associated with NR2 subunits, which may contribute to faster forward trafficking of these receptors. Our results suggest that altered NMDAR trafficking may underlie potentiation of NMDAR-mediated current and toxicity in the YAC72 HD mouse model. This polyQ length-dependent, neuronal-specific change in NMDAR activity induced by mhtt may contribute to selective neuronal degeneration in HD.
β-Site Amyloid Precursor Protein Cleaving Enzyme 1 Levels Become Elevated in Neurons around Amyloid Plaques: Implications for Alzheimer's Disease Pathogenesis
Authors: Zhao Jie , Fu Yifan , Yasvoina Marina , Shao Peizhen , Hitt Brian , O'Connor Tracy , Logan Sreemathi , Maus Erika , Citron Martin , Berry Robert , Binder Lester , Vassar Robert
Published: April 2007

β-Site amyloid precursor protein cleaving enzyme 1 (BACE1) (β-secretase) initiates generation of β-amyloid (Aβ), which plays an early role in Alzheimer's disease (AD). BACE1 levels are increased in postmortem AD brain, suggesting BACE1 elevation promotes Aβ production and AD. Alternatively, the BACE1 increase may be an epiphenomenon of late-stage AD. To distinguish between these possibilities, we analyzed BACE1 elevation using a highly specific BACE1 antibody, BACE-Cat1, made in BACE1−/− mice, which mount a robust anti-BACE1 immune response. Previous BACE1 immunohistochemical studies lack consistent results because typical BACE1 antibodies produce nonspecific background, but BACE-Cat1 immunolabels BACE1 only. BACE1 elevation was recapitulated in two amyloid precursor protein (APP) transgenic mouse lines. 5XFAD mice form amyloid plaques at young ages and exhibit neuron loss. In contrast, Tg2576 form plaques at a more advanced age and do not show cell death. These two mouse lines allow differentiation between early Aβ-induced events and late phenomena related to neuron death. BACE1 levels became elevated in parallel with amyloid burden in each APP transgenic, starting early in 5XFAD and late in Tg2576. The increase in BACE1 protein occurred without any change in BACE1 mRNA level, indicating a posttranscriptional mechanism. In APP transgenic and AD brains, high BACE1 levels were observed in an annulus around Aβ42-positive plaque cores and colocalized with neuronal proteins. These results demonstrate that amyloid plaques induce BACE1 in surrounding neurons at early stages of pathology before neuron death occurs. We conclude that BACE1 elevation is most likely triggered by the amyloid pathway and may drive a positive-feedback loop in AD.
Specific Alterations of Extracellular Endocannabinoid Levels in the Nucleus Accumbens by Ethanol, Heroin, and Cocaine Self-Administration
Authors: Caillé Stéphanie , Alvarez-Jaimes Lily , Polis Ilham , Stouffer David G. , Parsons Loren H.
Published: April 2007

Ethanol and opiate self-administration are sensitive to manipulations of cannabinoid CB1receptor function and, from this, a role for the endogenous cannabinoid system in the modulation of drug reward has been hypothesized. However, directin vivoevidence of drug-induced alterations in brain endocannabinoid (eCB) formation has been lacking. To address this issue, we explored the effect of drug self-administration on interstitial eCB levels in the nucleus accumbens (NAc) shell usingin vivomicrodialysis. Ethanol, heroin, and cocaine were compared because the rewarding properties of ethanol and heroin are reduced by CB1receptor inactivation, whereas cocaine reward is less sensitive to these manipulations. Ethanol self-administration significantly increased dialysate 2-arachidonoylglycerol (2-AG) levels with no concomitant change in dialysate anandamide (AEA) concentrations. Conversely, heroin self-administration significantly increased dialysate AEA levels, and induced a subtle but significant decrease in dialysate 2-AG levels. In each case, the relative change in dialysate eCB content was significantly correlated with the amount of drug consumed. In contrast, cocaine self-administration did not alter dialysate levels of either AEA or 2-AG. Local infusion of the CB1antagonist SR 141716A into the NAc significantly reduced ethanol, but not cocaine, self-administration. Together with our previous observation that intra-NAc SR 141716A reduces heroin self-administration, these data provide novelin vivosupport for an eCB involvement in the motivational properties of ethanol and heroin but not cocaine. Furthermore, the selective effects of ethanol and heroin on interstitial 2-AG and AEA provide new insight into the distinct neurochemical profiles produced by these two abused substances.
Removal of GABA within Adult Modulatory Systems Alters Electrical Coupling and Allows Expression of an Embryonic-Like Network
Authors: Ducret Eric , Le Feuvre Yves , Meyrand Pierre , Fénelon Valérie S.
Published: April 2007

The maturation and operation of neural networks are known to depend on modulatory neurons. However, whether similar mechanisms may control both adult and developmental plasticity remains poorly investigated. To examine this issue, we have used the lobster stomatogastric nervous system (STNS) to investigate the ontogeny and role of GABAergic modulatory neurons projecting to small pattern generating networks. Using immunocytochemistry, we found that modulatory input neurons to the stomatogastric ganglion (STG) express GABA only after metamorphosis, a time that coincides with the developmental switch from a single to multiple pattern generating networks within the STNS. We demonstrate that blocking GABA synthesis with 3-mercapto-propionic acid within the adult modulatory neurons results in the reconfiguration of the distinct STG networks into a single network that generates a unified embryonic-like motor pattern. Using dye-coupling experiments, we also found that gap-junctional coupling is greater in embryos and GABA-deprived adults exhibiting the unified motor pattern compared with control adults. Furthermore, GABA was found to diminish directly the extent and strength of electrical coupling within adult STG networks. Together, these observations suggest the acquisition of a GABAergic phenotype by modulatory neurons after metamorphosis may induce the reconfiguration of the single embryonic network into multiple adult networks by directly decreasing electrical coupling. The findings also suggest that adult neural networks retain the ability to express typical embryonic characteristics, indicating that network ontogeny can be reversed and that changes in electrical coupling during development may allow the segregation of multiple distinct functional networks from a single large embryonic network.
Brain Oscillations Control Timing of Single-Neuron Activity in Humans
Authors: Jacobs Joshua , Kahana Michael J. , Ekstrom Arne D. , Fried Itzhak
Published: April 2007

A growing body of animal research suggests that neurons represent information not only in terms of their firing rates but also by varying the timing of spikes relative to neuronal oscillations. Although researchers have argued that this temporal coding is critical in human memory and perception, no supporting data from humans have been reported. This study provides the first analysis of the temporal relationship between brain oscillations and single-neuron activity in humans. Recording from 1924 neurons, we find that neuronal activity in various brain regions increases at specific phases of brain oscillations. Neurons in widespread brain regions were phase locked to oscillations in the theta- (4–8 Hz) and gamma- (30– 90 Hz) frequency bands. In hippocampus, phase locking was prevalent in the delta- (1–4 Hz) and gamma-frequency bands. Individual neurons were phase locked to various phases of theta and delta oscillations, but they only were active at the trough of gamma oscillations. These findings provide support for the temporal-coding hypothesis in humans. Specifically, they indicate that theta and delta oscillations facilitate phase coding and that gamma oscillations help to decode combinations of simultaneously active neurons.
Plexin-B2 Controls the Development of Cerebellar Granule Cells
Authors: Friedel Roland H. , Kerjan Géraldine , Rayburn Helen , Schüller Ulrich , Sotelo Constantino , Tessier-Lavigne Marc , Chédotal Alain
Published: April 2007

Cerebellar granule cell progenitors proliferate postnatally in the upper part of the external granule cell layer (EGL) of the cerebellum. Postmitotic granule cells differentiate and migrate, tangentially in the EGL and then radially through the molecular and Purkinje cell layers. The molecular control of the transition between proliferation and differentiation in cerebellar granule cells is poorly understood. We show here that the transmembrane receptor Plexin-B2 is expressed by proliferating granule cell progenitors. To study Plexin-B2 function, we generated a targeted mutation of mousePlexin-B2. MostPlexin-B2−/−mutants die at birth as a result of neural tube closure defects. Some mutants survive but their cerebellum cytoarchitecture is profoundly altered. This is correlated with a disorganization of the timing of granule cell proliferation and differentiation in the EGL. Many differentiated granule cells migrate inside the cerebellum and keep proliferating. These results reveal that Plexin-B2 controls the balance between proliferation and differentiation in granule cells.
T-Type and L-Type Ca2+Conductances Define and Encode the Bimodal Firing Pattern of Vestibulocerebellar Unipolar Brush Cells
Authors: Diana Marco A. , Otsu Yo , Maton Gilliane , Collin Thibault , Chat Mireille , Dieudonné Stéphane
Published: April 2007

Cerebellar unipolar brush cells (UBCs) are glutamatergic interneurons that receive direct input from vestibular afferents in the form of a unique excitatory synapse on their dendritic brush. UBCs constitute independent relay lines for vestibular signals, and their inherent properties most likely determine how vestibular activity is encoded by the cerebellar cortex. We now demonstrate that UBCs are bimodal cells; they can either fire high-frequency bursts of action potentials when stimulated from hyperpolarized potentials or discharge tonically during sustained depolarizations. The two functional states can be triggered by physiological-like activity of the excitatory input and are encoded by distinct Ca2+-signaling systems. By combining complementary strategies, consisting of molecular and electrophysiological analysis and of ultrafast acousto-optical deflector-based two-photon imaging, we unraveled the identity and the subcellular localization of the Ca2+conductances activating in each mode. Fast inactivating T-type Ca2+channels produce low-threshold spikes, which trigger the high-frequency bursts and generate powerful Ca2+transients in the brush and, to a much lesser extent, in the soma. The tonic firing mode is encoded by a signalization system principally composed of L-type channels. Ca2+influx during tonic firing produces a linear representation of the spike rate of the cell in the form of a widespread and sustained Ca2+concentration increase and regulates cellular excitability via BK potassium channels. The bimodal firing pattern of UBCs may underlie different coding strategies of the vestibular input by the cerebellum, thus likely increasing the computational power of this structure.
The Doublecortin-Expressing Population in the Developing and Adult Brain Contains Multipotential Precursors in Addition to Neuronal-Lineage Cells
Authors: Walker Tara L. , Yasuda Takahiro , Adams David J. , Bartlett Perry F.
Published: April 2007

Doublecortin (DCX) has recently been promulgated as a selective marker of cells committed to the neuronal lineage in both the developing and the adult brain. To explore the potential of DCX-positive (DCX+) cells more stringently, these cells were isolated by flow cytometry from the brains of transgenic mice expressing green fluorescent protein under the control of the DCX promoter in embryonic, early postnatal, and adult animals. It was found that virtually all of the cells (99.9%) expressing high levels of DCX (DCXhigh) in the embryonic brain coexpressed the neuronal marker βIII-tubulin and that this population contained no stem-like cells as demonstrated by lack of neurosphere formationin vitro. However, the DCX+population from the early postnatal brain and the adult subventricular zone and hippocampus, which expressed low levels of DCX (DCXlow), was enriched for neurosphere-forming cells, with only a small subpopulation of these cells coexpressing the neuronal markers βIII-tubulin or microtubule-associated protein 2. Similarly, the DCXlowpopulation from embryonic day 14 (E14) brain contained neurosphere-forming cells. Only the postnatal cerebellum and adult olfactory bulb contained some DCXhighcells, which were shown to be similar to the E14 DCXhighcells in that they had no stem cell activity. Electrophysiological studies confirmed the heterogeneous nature of DCX+cells, with some cells displaying characteristics of immature or mature neurons, whereas others showed no neuronal characteristics whatsoever. These results indicate that DCXhighcells, regardless of location, are restricted to the neuronal lineage or are bone fide neurons, whereas some DCXlowcells retain their multipotentiality.
Timing-Dependent Modulation of Associative Plasticity by General Network Excitability in the Human Motor Cortex
Authors: Nitsche Michael A. , Roth Amelie , Kuo Min-Fang , Fischer Anja K. , Liebetanz David , Lang Nicolas , Tergau Frithjof , Paulus Walter
Published: April 2007

Associative neuroplasticity, which encompasses the modification of synaptic strength by coactivation of two synaptic inputs, has been linked to learning processes. Because unlimited plasticity destabilizes neuronal networks, homeostatic rules were proposed and experimentally proven that control for the amount and direction of plasticity dependent on background network activity. Accordingly, low background activity would enhance facilitatory plasticity, whereas high background activity would inhibit it.

However, the impact of background excitability on associative plasticity has not been studied so far in humans. Facilitatory associative plasticity was induced by paired associative stimulation (PAS) in the human motor cortex, whereas background activity was enhanced or diminished by transcranial direct current stimulation (tDCS). When applied before PAS, excitability-enhancing tDCS also boosted the efficacy of PAS, whereas excitability-diminishing tDCS turned it into inhibition. Thus, previous background activity does not influence associative plasticity homeostatically. When tDCS and PAS were applied simultaneously, now in accordance with homeostatic rules of neuroplasticity, reduced background activity resulted in a prolonged excitability enhancement by PAS, whereas enhanced background activity turned it into inhibition. We conclude that background network activity can influence associative plasticity homeostatically. However, only simultaneous modulation of both parameters is in accordance with homeostatic concepts. These findings might be of importance for the development of plasticity-inducing stimulation protocols supporting information processing in humans.
HIV-1 Vpr Causes Neuronal Apoptosis andIn VivoNeurodegeneration
Authors: Jones Gareth J. , Barsby Nicola L. , Cohen Éric A. , Holden Janet , Harris Kim , Dickie Peter , Jhamandas Jack , Power Christopher
Published: April 2007

Despite the introduction of highly active antiretroviral therapy, dementia caused by human immunodeficiency virus-1 (HIV-1) infection remains a devastating and common neurological disorder. Although the mechanisms governing neurodegeneration during HIV-1 infection remain uncertain, the HIV-1 accessory protein, viral protein R (Vpr), has been proposed as a neurotoxic protein. Herein, we report that Vpr protein and transcript were present in the brains of HIV-infected persons. Moreover, soluble Vpr caused neuronal apoptosis, involving cytochromecextravasation, p53 induction, and activation of caspase-9 while exerting a depressive effect on whole-cell currents in neurons (p< 0.05), which was inhibited by iberiotoxin. Vpr-activated glial cells secreted neurotoxins in a concentration-dependent manner (p< 0.001). Transgenic (Tg) mice expressing Vpr in brain monocytoid cells displayed the transgene principally in the basal ganglia (p< 0.05) and cerebral cortex (p< 0.01) compared with hindbrain expression. Vpr was released from cultured transgenic macrophages, which was cytotoxic to neurons and was blocked by anti-Vpr antibody (p< 0.05). Neuronal injury was observed in Tg animals compared with wild-type littermates, chiefly affecting GAD65 (p< 0.01) and vesicular acetylcholine transferase (p< 0.001) immunopositive neuronal populations in the basal ganglia. There was also a loss of subcortical synaptophysin (p< 0.001) immunoreactivity as well as an increase in activated caspase-3, which was accompanied by a hyperexcitable neurobehavioral phenotype (p< 0.05). Thus, HIV-1 Vpr caused neuronal death through convergent pathogenic mechanisms with ensuingin vivoneurodegeneration, yielding new insights into the mechanisms by which HIV-1 injures the nervous system.
A meszezés hatása a talaj mikrobiális biomassza mennyiségére két savanyú homoktalajon
Authors: Filep Tibor , Szili-Kovács Tibor
Published: April 2007

Tenyészedény-kísérletben vizsgáltuk két savanyú homoktalaj (Kisvárda és Nyírlugos) szubsztrát indukált respirációját (SIR) és mikrobiális biomasszá-jának C-tartalmát (MBC) a mészkezelések függvényében. Jelzőnövényként zabot(Avena sativaL.) alkalmaztunk. A kezelések a következők voltak: kont-roll, a számított mészadag fele, a számított mészadag, a számított mészadag másfélszerese. Összesen két tenyészidőn keresztül vizsgáltuk a kezelés-hatásokat, úgy, hogy mindkét tenyészidőben 3-3 alkalommal talajmintát vettünk, és meghatároztuk a minták respirációját, majd ebből a mikrobiális biomassza-C értékeit. Megállapítottuk, hogy a meszezés növelte a talaj respirációját és ezzel a mikrobiális biomassza-C-t (MBC) is, azonban a maximális mészadagoknál sok esetben tapasztaltuk az értékek stagnálását, visszaesését. A jelenség oka az, hogy nagy mészadagoknál a mikroorganizmusok N-ellátottsága nem kielégítő annak következtében, hogy a talaj viszonylag kis mennyiségű gyorsan mineralizálható szerves anyagot tartalmaz.
Adalékanyagok, vörös csenkesz és Zn-toleráns arbuszkuláris mikorrhiza gombák szerepe a nehézfémekkel szennyezett gyöngyösoroszi bányameddő remediációjában
Authors: Simon László , Biró Borbála
Published: April 2007

A nehézfémekkel szennyezett (Cd: 15,0, Cu: 336, Mn: 568, Pb: 1919, Zn: 3306 mg·kg-1), erősen savanyú kémhatású (pH(KCl) 3,73), Gyöngyösorosziból származó bányameddőt adalékok (1% CaCO3, 5% szennyvíziszap komposzt, és 7,5% m/m zeolit) kijuttatásával stabilizáltuk. A mésszel, illetve mész, szennyvíziszap komposzt és zeolit kombinációjával kezelt bányameddőn tenyész-edényes kísérletben vörös csenkeszt neveltünk. A kultúrák egy részét Zn-toleráns arbuszkuláris mikorrhiza gombákkal is kezeltük. Megállapítottuk, hogy kombinált kezelés esetén kevésbé csökken le a közeg pH-ja a 12 hetes növénynevelés során, mint a csak meszezésben részesült kultúrákban. A kombinált kezelés előnyösen hatott a tesztnövények Ca-, K- és P-felvételére, és lecsökkent a növények Mn- és Zn-felvétele a csak meszezésben részesült kultúrákhoz képest. A vörös csenkesz gyökerének erős mikorrhizáltságát csak mész, szennyvíziszap komposzt és zeolit együttes kijuttatása esetén tapasztaltuk. A mikorrhizált kultúrákban - tendenciaként - a hajtások nehézfém-akkumuláció-jának csökkenését (Cd: 35-55, Cu: 10-34, Mn: 14-55, Zn: 22-44%-kal) figyeltük meg. A mikorrhiza kolonizáció nem befolyásolta szignifikánsan a kultúrák szárazanyaghozamát. Eredményeinkből arra következtethetünk, hogy a gyöngyösoroszi bányameddőben lévő fémeket többféle adalék kombinált kijuttatásával lehet eredményesen stabilizálni, és ezen a közegen arbuszkulált mikorrhiza gombákkal szimbiózisban élő vörös csenkesz telepíthető meg. Az eredményes fitoremediációhoz tehát komplex megközelítés szükséges, melyben a különféle adalékoknak, a magasabb rendű növényeknek és az arbuszkuláris mikorrhiza gombáknak egyaránt fontos szerepe van.