bluuebunny/crossref_metadata_2025 huggingface dataset:
Treatment and prognostic impact of transient leukemia in neonates with Down syndrome
Authors: Klusmann Jan-Henning , Creutzig Ursula , Zimmermann Martin , Dworzak Michael , Jorch Norbert , Langebrake Claudia , Pekrun Arnulf , Macakova-Reinhardt Katarina , Reinhardt Dirk
Published: January 2008

Approximately 10% of the neonates with Down syndrome (DS) exhibit a unique transient leukemia (TL). Though TL resolves spontaneously in most patients, early death and development of myeloid leukemia (ML-DS) may occur. Prognostic factors as well as treatment indication are currently uncertain. To resolve that issue, we prospectively collected clinical, biologic, and treatment data of 146 patients with TL. The 5-year overall survival (OS) and event-free survival (EFS) were 85% plus or minus 3% and 63% plus or minus 4%, respectively. Multivariate analysis revealed a correlation between high white blood cell (WBC) count, ascites, preterm delivery, bleeding diatheses, failure of spontaneous remission, and the occurrence of early death. Treatment with cytarabine (0.5-1.5 mg/kg) was administered to 28 patients with high WBC count, thrombocytopenia, or liver dysfunction. The therapy had a beneficial effect on the outcome of those children with risk factors for early death (5-year EFS, 52% ± 12% vs 28% ± 11% [no treatment]; P = .02). Multivariate analysis demonstrated its favorable prognostic impact. A total of 29 (23%) patients with TL subsequently developed ML-DS. Patients with ML-DS with a history of TL had a significantly better 5-year EFS (91% ± 5%) than those without documented TL (70% ± 4%), primarily due to a lower relapse rate. A history of TL may therefore define a lower-risk ML-DS subgroup. This study was registered at www.clinicaltrials.gov as no. NCT 00111345.
Quantification of the CBD-FITC conjugates surface coating on cellulose fibres
Authors: Pinto Ricardo , Amaral António L , Ferreira Eugénio C , Mota Manuel , Vilanova Manuel , Ruel Katia , Gama Miguel
Published: January 2008

Background

Cellulose Binding Domains (CBD) were conjugated with fluorescein isothiocyanate (FITC). The surface concentration of the Binding Domains adsorbed on cellulose fibres was determined by fluorescence image analysis.

Results

For a CBD-FITC concentration of 60 mg/L, a coating fraction of 78% and 110% was estimated for Portucel and Whatman fibres, respectively. For a saturating CBD concentration, using Whatman CF11 fibres, a surface concentration of 25.2 × 10-13 mol/mm2 was estimated, the equivalent to 4 protein monolayers. This result does not imply the existence of several adsorbed protein layers.

Conclusion

It was verified that CBDs were able to penetrate the fibres, according to confocal microscopy and TEM-immunolabelling analysis. The surface concentration of adsorbed CBDs was greater on amorphous fibres (phosphoric acid swollen) than on more crystalline ones (Whatman CF11 and Sigmacell 20).
Down-regulation of transforming growth factor-β type II receptor (TGF-βRII) protein and mRNA expression in cervical cancer
Authors: Diaz-Chavez Jose , Hernandez-Pando Rogelio , Lambert Paul F , Gariglio Patricio
Published: January 2008

Background

Cervical carcinogenesis is a multistep process initiated by "high risk" human papillomaviruses (HR-HPV), most commonly HPV16. The infectionper seis, however, not sufficient to induce malignant conversion. Transforming Growth Factor β (TGF-β) inhibits epithelial proliferation and altered expression of TGF-β or its receptors may be important in carcinogenesis. One cofactor candidate to initiate neoplasia in cervical cancer is the prolonged exposure to sex hormones. Interestingly, previous studies demonstrated that estrogens suppress TGF-β induced gene expression. To examine the expression of TGF-β2, TGF-βRII, p15 and c-myc we usedin situRT-PCR, real-time PCR and immunohistochemistry in transgenic mice expressing the oncogene E7 of HPV16 under control of the human Keratin-14 promoter (K14-E7 transgenic mice) and nontransgenic control mice treated for 6 months with slow release pellets of 17β-estradiol.

Results

Estrogen-induced carcinogenesis was accompanied by an increase in the incidence and distribution of proliferating cells solely within the cervical and vaginal squamous epithelium of K14-E7 mice. TGF-β2 mRNA and protein levels increased in K14-E7 transgenic mice as compared with nontransgenic mice and further increased after hormone-treatment in both nontransgenic and transgenic mice. In contrast, TGF-βRII mRNA and protein levels were decreased in K14-E7 transgenic mice compared to nontransgenic mice and these levels were further decreased after hormone treatment in transgenic mice. We also observed that c-myc mRNA levels were high in K14-E7 mice irrespective of estrogen treatment and were increased in estrogen-treated nontransgenic mice. Finally we found that p15 mRNA levels were not increased in K14-E7 mice.

Conclusion

These results suggest that the synergy between estrogen and E7 in inducing cervical cancer may in part reflect the ability of both factors to modulate TGF-β signal transduction.
Regulation of Sox9 activity by crosstalk with nuclear factor-κB and retinoic acid receptors
Authors: Rockel Jason S , Kudirka Julie C , Guzi Andrew J , Bernier Suzanne M
Published: January 2008

Introduction

Sox9 and p300 cooperate to induce expression of cartilage-specific matrix proteins, including type II collagen, aggrecan and link protein. Tumour necrosis factor (TNF)-α, found in arthritic joints, activates nuclear factor-κB (NF-κB), whereas retinoic acid receptors (RARs) are activated by retinoid agonists, including all-trans retinoic acid (atRA). Like Sox9, the activity of NF-κB and RARs depends upon their association with p300. Separately, both TNF-α and atRA suppress cartilage matrix gene expression. We investigated how TNF-α and atRA alter the expression of cartilage matrix genes.

Methods

Primary cultures of rat chondrocytes were treated with TNF-α and/or atRA for 24 hours. Levels of transcripts encoding cartilage matrix proteins were determined by Northern blot analyses and quantitative real-time PCR. Nuclear protein levels, DNA binding and functional activity of transcription factors were assessed by immunoblotting, electrophoretic mobility shift assays and reporter assays, respectively.

Results

Together, TNF-α and atRA diminished transcript levels of cartilage matrix proteins and Sox9 activity more than each factor alone. However, neither agent altered nuclear levels of Sox9, and TNF-α did not affect protein binding to the Col2a1 48-base-pair minimal enhancer sequence. The effect of TNF-α, but not that of atRA, on Sox9 activity was dependent on NF-κB activation. Furthermore, atRA reduced NF-κB activity and DNA binding. To address the role of p300, we over-expressed constitutively active mitogen-activated protein kinase kinase kinase (caMEKK)1 to increase p300 acetylase activity. caMEKK1 enhanced basal NF-κB activity and atRA-induced RAR activity. Over-expression of caMEKK1 also enhanced basal Sox9 activity and suppressed the inhibitory effects of TNF-α and atRA on Sox9 function. In addition, over-expression of p300 restored Sox9 activity suppressed by TNF-α and atRA to normal levels.

Conclusion

NF-κB and RARs converge to reduce Sox9 activity and cartilage matrix gene expression, probably by limiting the availability of p300. This process may be critical for the loss of cartilage matrix synthesis in inflammatory joint diseases. Therefore, agents that increase p300 levels or activity in chondrocytes may be useful therapeutically.
A long-term follow-up study investigating health-related quality of life and resource use in survivors of severe sepsis: comparison of recombinant human activated protein C with standard care
Authors: Longo Christopher J , Heyland Daren K , Fisher Harold N , Fowler Robert A , Martin Claudio M , Day Andrew G
Published: January 2008

Introduction

Recombinant human activated protein C (APC) therapy has been shown to reduce short-term mortality in patients with severe sepsis. However, survivors of sepsis may have long-term complications affecting health-related quality of life (HRQoL) and resource utilization. The objective of this study was to evaluate prospectively the effect of APC on long-term HRQoL and resource utilization compared with a nonrandomized control group that received standard care.

Methods

This was an observational cohort study at nine Canadian intensive care units. Patients with severe sepsis who survived to 28 days were recruited. Patients who received APC formed the treatment group and those that did not formed the standard care group. Patients who did not receive APC because of central nervous system bleeding risk were excluded from the standard care group. HRQoL (determined using the 36-item Short Form) and resource use were recorded at 28 days, and 3, 5 and 7 months.

Results

One hundred patients were enrolled (64 in the standard care group and 36 in the APC group), with 70 patients completing all follow-up visits. Over the 6 months of follow up, APC-treated patients exhibited statistically significantly better scores for the physical component score (P = 0.04) and trends toward improvements in physical functioning (P = 0.12), role physical (P = 0.10) and bodily pain (P = 0.14) as compared with standard care patients. Shorter hospital length of stay was observed for the APC group (36 days versus 48 days; P = 0.05).

Conclusion

These findings challenge earlier assumptions suggesting equivalent HRQoL and resource use in APC-treated and standard care patients who survive severe sepsis.
Stem Cell Heterogeneity
Authors: YOSHIDA SHOSEI , NABESHIMA YO‐ICHI , NAKAGAWA TOSHINORI
Published: January 2008

Abstract:In order to assess the behavior of the spermatogonia that contribute to the stem cell system in steady‐state mouse spermatogenesis, a series of pulse‐labeling experiments of a subset of “undifferentiated spermatogonial” was performed using transgenic approaches. The results suggest that, in addition to the spermatogonial population that actually acts as the stem cells (actual stem cell compartment), a second set of undifferentiated spermatogonia also exists that possesses the potential to self‐renew, but does not normally do so (potential stem cell compartment). The potential stem cells turn over rather rapidly, suggesting that they act as the transit amplifying cells in the normal situation. The potential stem cells seem to change their mode from transientamplification to self‐renewal upon transplantation, regeneration, or loss of actual stem cells that occurs during the long reproduction period. Such a heterogeneous composition of the stem cell system may be important for the robustness of overall spermatogenesis.
From Gonocytes to Testicular Cancer
Authors: RAJPERT‐DE MEYTS EWA , HOEI‐HANSEN CHRISTINA E.
Published: January 2008

Abstract: Testicular germ‐cell tumors occur primarily in young individuals, and the tumors in this age group (seminomas or nonseminomas) are derived from a preinvasive precursor cell called carcinoma in situ (CIS) or intratubular germ‐cell neoplasia. These tumors have been a growing problem, especially in highly developed industrialized countries. A hypothesis was put forward that CIS originates from arrested fetal germ cells, thus testicular cancer is a developmental disease of germ‐cell differentiation. This notion was supported by comparative studies of the gene expression at the protein and RNA level, which demonstrated a close similarity of CIS to primordial germ cells and gonocytes with many features of embryonic stem cells. The arrest of germ‐cell differentiation is thus the key first event, which may be followed by malignant transformation and overt germ‐cell cancer in young adult age, usually after puberty. In most cases the arrest/delay of germ‐cell differentiation is caused by testicular dysgenesis, a multifactorial and complex syndrome that has a broad spectrum of phenotypes ranging from moderate impairment of spermatogenesis to severe disorders of sexual development and differentiation. The most severe cases are a result of inherited genetic aberrations, but the etiology of the common sporadic testicular cancer must involve environmental factors, including maternal lifestyle and possibly an early exposure to endocrine disruptors. The effects of environmental factors are likely modulated by genomic variation (polymorphisms), thus explaining the individual susceptibility and population‐level differences in the incidence of testicular cancer.
Identification of Testis‐Specific Male Contraceptive Targets
Authors: JOHNSTON DANIEL S. , JELINSKY SCOTT A. , ZHI YU , FINGER JOSHUA N. , KOPF GREGORY S. , WRIGHT WILLIAM W.
Published: January 2008

Abstract: In an effort to identify novel targets for the development of nonhormonal male contraceptives, genome‐wide transcriptional profiling of the rat testis was performed. Specifically, enzymatically purified spermatogonia plus early spermatocyctes, pachytene spermatocytes, round spermatids, and Sertoli cells was analyzed along with microdissected rat seminiferous tubules at stages I, II–III, IV–V, VI, VIIa,b, VIIc,d, VIII, IX– XI, XII, XIII–XIV of the cycle of the seminiferous epithelium using RAE 230_2.0 microarrays. The combined analysis of these studies identified 16,971 expressed probe sets on the array. How these expression data, combined with additional bioinformatic data analysis and quantitative reverse transcriptase polymerase chain reaction (qRT‐PCR) analysis, led to the identification of 58 genes that have 1000‐fold higher expression transcriptionally in the testis when compared to over 20 other nonreproductive tissues is described. The products of these genes may play important roles in testicular and/or sperm function, and further investigation on their utility as nonhormonal contraceptive targets is warranted. Moreover, these microarray data have been used to expedite the identification of a mutation in RIKEN cDNA 2410004F06 gene as likely being responsible for spermatogenic failure in a line of infertile mice generated by N‐ethyl‐N‐nitrosourea (ENU) mutagenesis. The microarray data and the qRT‐PCR data described are available in the Mammalian Reproductive Genetics database (http://mrg.genetics.washington.edu/).
Impaired Plasma Nonesterified Fatty Acid Tolerance Is an Early Defect in the Natural History of Type 2 Diabetes
Authors: Brassard P. , Frisch F. , Lavoie F. , Cyr D. , Bourbonnais A. , Cunnane S. C. , Patterson B. W. , Drouin R. , Baillargeon J.-P. , Carpentier A. C.
Published: January 2008

Context: Abnormal plasma nonesterified fatty acid (NEFA) metabolism may play a role in the development of type 2 diabetes.

Objectives: Our objectives were to demonstrate whether there is a defect in insulin-mediated suppression of plasma NEFA appearance (RaNEFA) and oxidation (OxNEFA) during enhanced intravascular triacylglycerol lipolysis early in the natural history of type 2 diabetes, and if so, to determine whether other mechanisms than reduced insulin-mediated suppression of intracellular lipolysis are involved.

Design: These are cross-sectional studies.

Setting: The studies were performed at an academic clinical research center.

Participants: Nine healthy subjects with both parents with type 2 diabetes (FH+) and nine healthy subjects with no first-degree relatives with type 2 diabetes (FH−) with similar anthropometric features were included in the studies.

Interventions: Pancreatic clamps and iv infusion of stable isotopic tracers ([1,1,2,3,3-2H5]-glycerol and [U-13C]-palmitate or [1,2-13C]-acetate) were performed while intravascular triacylglycerol lipolysis was simultaneously clamped by iv infusion of heparin plus Intralipid at low (fasting) and high insulin levels. Oral nicotinic acid (NA) was used to inhibit intracellular lipolysis.

Main Outcome Measures: RaNEFA and OxNEFA were determined.

Results: During heparin plus Intralipid infusion at high plasma insulin levels, and despite similar intravascular lipolytic rates, FH+ had higher RaNEFA and OxNEFA than FH− (RaNEFA: 17.4 ± 6.3 vs. 9.2 ± 4.2; OxNEFA: 4.5 ± 1.8 vs. 2.3 ± 1.5 μmol/kg lean body mass/min), independent of NA intake, gender, age, and body composition. In the presence of NA, insulin-mediated suppression of RaNEFA was still observed in FH−, but not in FH+.

Conclusions: Increased RaNEFA and OxNEFA during intravascular lipolysis at high insulin levels occur early in the natural history of type 2 diabetes.
Multi-Matrix System Mesalamine: To Use or Not To Use
Authors: Kale-Pradhan Pramodini B , Pradhan Rohan S , Wilhelm Sheila M
Published: January 2008

Objective:

To evaluate the role of Multi-Matrix System (MMX) mesalamine in the treatment of ulcerative colitis (UC).

Data Sources:

Literature was obtained through searches of MEDLINE (1966–October 2007) and a bibliographic review of published articles. Key terms used in the searches included ulcerative colitis, mesalamine, MMX, SPD476, and Lialda.

Study Selection and Data Extraction:

All English-language articles that were identified through the search were evaluated. All primary literature was included in the review.

Data Synthesis:

The standard treatment for the induction and maintenance of remission in patients with mi Id-to-moderate UC is aminosalicylate products (mesalamine, sulfasalazine, batasalazide, olsalazine). Current mesalamine formulations are not idea) for long-term treatment due to issues with patient adherence secondary to complex dosing regimens and high pill burden. Clinical studies show that MMX mesalamine achieves clinical and endoscopic remission more frequently compared with placebo or mesalamine enema. Patients receiving MMX mesalamine achieved statistically significant clinical and endoscopic remission when compared with those taking placebo (34.1% vs 12.9%; p < 0.001 with 2.4 g/day vs placebo, and 29.2% vs 12.9%; p = 0.009 with 4.8 g/day vs placebo). Similarly, in another study, significantly more patients achieved remission in the MMX mesalamine groups compared with patients in the placebo group (40.5% vs 22.1% with 2.4 g/day vs placebo; p = 0.01, and 41.2% vs 22.1% with 4.8 g/day vs placebo; p = 0.007). MMX mesalamine is well tolerated, with headache, flatulence, and abdominal pain being the most frequently reported adverse events.

Conclusions:

Current evidence supports the use of MMX mesalamine for treatment of mi Id-to-moderate UC by demonstrating that MMX mesalamine 2.4–4.8 g daily induces remission. It has the advantage of once-daily dosing regimens with lower pill burden than comparable products and, as an oral agent, may have better patient acceptability compared with topical mesalamine formulations. Therefore, MMX mesalamine is an option in patients with UC. The cost of MMX mesalamine is comparable to that of oral and rectal formulations of mesalamine. Further pharmacoeconomic studies are warranted to examine the cost impact of MMX mesalamine.
Legends of the Follies: fact and fiction in the performance history of three songs from the Ziegfeld Follies
Authors: Ommen Ann
Published: January 2008

Florenz Ziegfeld, Jr. is a legend, both in the history of Broadway and in American popular culture. It is therefore hardly surprising that his most famous Broadway productions, the Ziegfeld Follies, are often characterized according to legendary stories about their creator, their star performers, and their appeal with American audiences. Historical evidence, however, often differs significantly from what these legendary stories suggest. This study examines the performance history of three songs Shine On, Harvest Moon, My Man, and A Pretty Girl Is Like a Melody from their original performances in the Ziegfeld Follies to the renditions seen in MGM'sThe Great Ziegfeldof 1936. It reveals that the legends of how these songs were first performed and received in the Ziegfeld Follies are largely untrue, exaggerations based on performances other than the originals.
Nicholson Baker, Double Fold: Libraries and the Assault on Paper
Authors: Cybulski Walter
Published: January 2008

In
The Open Archival Information System Reference Model: Introductory Guide
Authors: Lavoie Brian F.
Published: January 2008

The impact of digital information environments has been remarkably universal, extending to industry, government, and the academy; to business persons, scientists, engineers, and scholars of the humanities; to the individual in the workplace and the individual in the home. Vast quantities of information in digital form – text, images, audio, video, Web pages, computer programs, databases – are produced, exchanged, and used in a variety of settings, for myriad purposes. These diverse applications of digital technology rest on a common foundation of shared benefits, including powerful search and retrieval capabilities, network delivery, perfect duplication, and interoperability.
Effects of Ibotenate and 192IgG-Saporin Lesions of the Nucleus Basalis Magnocellularis/Substantia Innominata on Spontaneous Sleep and Wake States and on Recovery Sleep after Sleep Deprivation in Rats
Authors: Kaur Satvinder , Junek Adrienne , Black Michelle A. , Semba Kazue
Published: January 2008

The basal forebrain (BF) is known for its role in cortical and behavioral activation, and has been postulated to have a role in compensatory mechanisms after sleep loss. However, specific neuronal phenotypes responsible for these roles are unclear. We investigated the effects of ibotenate (IBO) and 192IgG-saporin (SAP) lesions of the caudal BF on spontaneous sleep–waking and electroencephalogram (EEG), and recovery sleep and EEG after 6 h of sleep deprivation (SD). Relative to artificial CSF (ACSF) controls, IBO injections decreased parvalbumin and cholinergic neurons in the caudal BF by 43 and 21%, respectively, and cortical acetylcholinesterase staining by 41%. SAP injections nonsignificantly decreased parvalbumin neurons by 11%, but significantly decreased cholinergic neurons by 69% and cortical acetylcholinesterase by 84%. IBO lesions had no effect on sleep–wake states but increased baseline delta power in all states [up to 62% increase during non-rapid eye movement (NREM) sleep]. SAP lesions transiently increased NREM sleep by 13%, predominantly during the dark phase, with no effect on EEG. During the first 12 h after SD, animals with IBO and SAP lesions showed lesser rebound NREM sleep (32 and 77% less, respectively) and delta power (78 and 53% less) relative to ACSF controls. These results suggest that noncholinergic BF neurons promote cortical activation by inhibiting delta waves, whereas cholinergic BF neurons play a nonexclusive role in promoting wake. Intriguingly, these results also suggest that both types of BF neurons play important roles, probably through different mechanisms, in increased NREM sleep and EEG delta power after sleep loss.
Reduced Brainstem Inhibition during Anticipated Pelvic Visceral Pain Correlates with Enhanced Brain Response to the Visceral Stimulus in Women with Irritable Bowel Syndrome
Authors: Berman Steven M. , Naliboff Bruce D. , Suyenobu Brandall , Labus Jennifer S. , Stains Jean , Ohning Gordon , Kilpatrick Lisa , Bueller Joshua A. , Ruby Kim , Jarcho Johanna , Mayer Emeran A.
Published: January 2008

Cognitive factors such as fear of pain and symptom-related anxiety play an important role in chronic pain states. The current study sought to characterize abnormalities in preparatory brain response before aversive pelvic visceral distention in irritable bowel syndrome (IBS) patients and their possible relationship to the consequences of distention. The brain functional magnetic resonance imaging (fMRI) blood oxygen level-dependent (BOLD) response to anticipated and delivered mild and moderate rectal distention was recorded from 14 female IBS patients and 12 healthy controls. During cued anticipation of distention, activity decreased in the insula, supragenual anterior cingulate cortex (sACC), amygdala, and dorsal brainstem (DBS) of controls. IBS patients showed less anticipatory inactivation. Group differences were significant in the right posterior insula and bilateral DBS. Self-rated measures of negative affect during scanning were higher in patients than controls (p< 0.001), and the anticipatory BOLD decreases in DBS were inversely correlated with these ratings. During subsequent distention, both groups showed activity increases in insula, dorsal ACC, and DBS and decreases in the infragenual ACC. The increases were more extensive in patients, producing significant group differences in dorsal ACC and DBS. The amplitude of the anticipatory decrease in the pontine portion of DBS was associated with greater activation during distention in right orbitofrontal cortex and bilateral sACC. Both regions have been associated previously with corticolimbic inhibition and cognitive coping. Deficits in preparatory inhibition of DBS, including the locus ceruleus complex and parabrachial nuclei, may interfere with descending corticolimbic inhibition and contribute to enhanced brain responsiveness and perceptual sensitivity to visceral stimuli in IBS.
Dopamine and Corticotropin-Releasing Factor Synergistically Alter Basolateral Amygdala-to-Medial Prefrontal Cortex Synaptic Transmission: Functional Switch after Chronic Cocaine Administration
Authors: Orozco-Cabal Luis , Liu Jie , Pollandt Sebastian , Schmidt Kady , Shinnick-Gallagher Patricia , Gallagher Joel P.
Published: January 2008

Basolateral amygdala (BLA) neurons provide a major excitatory input to medial prefrontal cortex (mPFC)–layer V pyramidal neurons. Under stressful conditions, commonly associated with chronic cocaine abuse, altered BLA-to-mPFC synaptic transmission could lead to defective emotional information processing and decision making within the mPFC and result in misguided and inappropriate behaviors. We examined the effects of cocaine administered chronicallyin vivoon EPSCs recorded from a putative BLA–mPFC pathwayin vitroand their modulation by dopamine (DA), corticotropin-releasing factor (CRF), and their combination (DA plus CRF). In saline-treated animals, activation of D1/5receptors depressed BLA–mPFC EPSCs, whereas CRF1receptor activation alone had no effect on EPSCs. Activating D1/5and CRF1receptors in combination, however, worked synergistically through presynaptic and postsynaptic mechanisms to depress EPSCs to levels greater than D1/5receptor activation alone. After chronic cocaine administration, the function of DA1/5and CRF receptors switched from inhibitory to excitatory. In slices from cocaine-treated animals, putative BLA–mPFC EPSCs were depressed through a presynaptic mechanism. Now, activation of either D1/5or CRF2receptors increased the cocaine-induced, depressed EPSCs. Additionally, simultaneous activation of presynaptic D1/5and CRF2receptors led to further enhancement of EPSCs. These data indicate that CRF acting synergistically with DA normally potentiates D1/5-induced synaptic depression. However, after chronic cocaine, the combined synergistic actions of DA and CRF switched polarity to enhance facilitation of BLA–mPFC glutamatergic transmission. Also unmasked after acute withdrawal from chronic cocaine are endogenous, tonic-inhibitory D2-like and tonic-facilitatory CRF2receptor actions. These multiple functional and receptor changes may underlie the altered, possibly aberrant, decision-making process after chronic cocaine.
Effects of pH Buffering on Horizontal and Ganglion Cell Light Responses in Primate Retina: Evidence for the Proton Hypothesis of Surround Formation
Authors: Davenport Christopher M. , Detwiler Peter B. , Dacey Dennis M.
Published: January 2008

Negative feedback from horizontal cells to cone photoreceptors is regarded as the critical pathway for the formation of the antagonistic surround of retinal neurons, yet the mechanism by which horizontal cells accomplish negative feedback has been difficult to determine. Recent evidence suggests that feedback uses a novel, non-GABAergic pathway that directly modulates the calcium current in cones. In non-mammalian vertebrates, enrichment of retinal pH buffering capacity attenuates horizontal cell feedback, supporting one model in which feedback occurs by horizontal cell modulation of the extracellular pH in the cone synaptic cleft. Here we test the effect of exogenous pH buffering on the response dynamics of H1 horizontal cells and the center-surround receptive field structure of parasol ganglion cells in the macaque monkey retina. Enrichment of the extracellular buffering capacity with HEPES selectively attenuates surround antagonism in parasol ganglion cells. The H1 horizontal cell light response includes a slow, depolarizing component that is attributed to negative feedback to cones. This part of the response is attenuated by HEPES and other pH buffers in a dose-dependent manner that is correlated with predicted buffering capacity. The selective effects of pH buffering on the parasol cell surround and H1 cell light response suggests that, in primate retina, horizontal cell feedback to cones is mediated via a pH-dependent mechanism and is a major determinant of the ganglion cell receptive field surround.
Noradrenergic Signaling in Infralimbic Cortex Increases Cell Excitability and Strengthens Memory for Fear Extinction
Authors: Mueller Devin , Porter James T. , Quirk Gregory J.
Published: January 2008

Emotional arousal strengthens memory. This is most apparent in aversive conditioning, in which the stress-related neurotransmitter norepinephrine (NE) enhances associations between sensory stimuli and fear-inducing events. In contrast to conditioning, extinction decreases fear responses, and is thought to form a new memory. It is not known, however, whether NE is necessary for extinction learning. Previous work has shown that the infralimbic prefrontal cortex (IL) is a site of extinction consolidation. Here, we show that blocking noradrenergic β-receptors in IL before extinction training impaired retrieval of extinction the following day, consistent with a weakened extinction memory. We further found that the sequelae of β-receptor activation, including protein kinase A (PKA), gene transcription and translation in IL, are necessary for extinction. To determine whether activation of this cascade modulates IL excitability, we measured the response of IL pyramidal neurons to injected current. NE increased the excitability of IL neurons in a β-receptor- and PKA-dependent manner. We suggest that NE released in IL during fear extinction activates a PKA-mediated molecular cascade that strengthens extinction memory. Thus, emotional arousal evoked by conditioned fear paradoxically promotes the subsequent extinction of that fear, thereby ensuring behavioral flexibility.
A Maximum Entropy Model Applied to Spatial and Temporal Correlations from Cortical NetworksIn Vitro
Authors: Tang Aonan , Jackson David , Hobbs Jon , Chen Wei , Smith Jodi L. , Patel Hema , Prieto Anita , Petrusca Dumitru , Grivich Matthew I. , Sher Alexander , Hottowy Pawel , Dabrowski Wladyslaw , Litke Alan M. , Beggs John M.
Published: January 2008

Multineuron firing patterns are often observed, yet are predicted to be rare by models that assume independent firing. To explain these correlated network states, two groups recently applied a second-order maximum entropy model that used only observed firing rates and pairwise interactions as parameters (Schneidman et al., 2006; Shlens et al., 2006). Interestingly, with these minimal assumptions they predicted 90–99% of network correlations. If generally applicable, this approach could vastly simplify analyses of complex networks. However, this initial work was done largely on retinal tissue, and its applicability to cortical circuits is mostly unknown. This work also did not address the temporal evolution of correlated states. To investigate these issues, we applied the model to multielectrode data containing spontaneous spikes or local field potentials from cortical slices and cultures. The model worked slightly less well in cortex than in retina, accounting for 88 ± 7% (mean ± SD) of network correlations. In addition, in 8 of 13 preparations, the observed sequences of correlated states were significantly longer than predicted by concatenating states from the model. This suggested that temporal dependencies are a common feature of cortical network activity, and should be considered in future models. We found a significant relationship between strong pairwise temporal correlations and observed sequence length, suggesting that pairwise temporal correlations may allow the model to be extended into the temporal domain. We conclude that although a second-order maximum entropy model successfully predicts correlated states in cortical networks, it should be extended to account for temporal correlations observed between states.
Unregulated Cytosolic Dopamine Causes Neurodegeneration Associated with Oxidative Stress in Mice
Authors: Chen Linan , Ding Yunmin , Cagniard Barbara , Van Laar Amber D. , Mortimer Amanda , Chi Wanhao , Hastings Teresa G. , Kang Un Jung , Zhuang Xiaoxi
Published: January 2008

The role of dopamine as a vulnerability factor and a toxic agent in Parkinson's disease (PD) is still controversial, yet the presumed dopamine toxicity is partly responsible for the “DOPA-sparing” clinical practice that avoids usingl-3,4-dihydroxyphenylalanine (l-DOPA), a dopamine precursor, in early PD. There is a lack of studies on animal models that directly isolate dopamine as one determining factor in causing neurodegeneration. To address this, we have generated a novel transgenic mouse model in which striatal neurons are engineered to take up extracellular dopamine without acquiring regulatory mechanisms found in dopamine neurons. These mice developed motor dysfunctions and progressive neurodegeneration in the striatum within weeks. The neurodegeneration was accompanied by oxidative stress, evidenced by substantial oxidative protein modifications and decrease in glutathione. Ultrastructural morphologies of degenerative cells suggest necrotic neurodegeneration. Moreover,l-DOPA accelerated neurodegeneration and worsened motor dysfunction. In contrast, reducing dopamine input to striatum by lesioning the medial forebrain bundle attenuated motor dysfunction. These data suggest that pathology in genetically modified striatal neurons depends on their dopamine supply. These neurons were also supersensitive to neurotoxin. A very low dose of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (5 mg/kg) caused profound neurodegeneration of striatal neurons, but not midbrain dopamine neurons. Our results provide the firstin vivoevidence that chronic exposure to unregulated cytosolic dopamine alone is sufficient to cause neurodegeneration. The present study has significant clinical implications, because dopamine replacement therapy is the mainstay of PD treatment. In addition, our model provides an efficientin vivoapproach to test therapeutic agents for PD.
Retinal Ganglion Cells Downregulate Gene Expression and Lose Their Axons within the Optic Nerve Head in a Mouse Glaucoma Model
Authors: Soto Ileana , Oglesby Ericka , Buckingham Brian P. , Son Janice L. , Roberson Elisha D. O. , Steele Michael R. , Inman Denise M. , Vetter Monica L. , Horner Philip J. , Marsh-Armstrong Nicholas
Published: January 2008

Little is known about molecular changes occurring within retinal ganglion cells (RGCs) before their death in glaucoma. Taking advantage of the fact that γ-synuclein (Sncg) mRNA is expressed specifically and highly in adult mouse RGCs, we show in the DBA/2J mouse model of glaucoma that there is not only a loss of cells expressing this gene, but also a downregulation of gene expression of Sncg and many other genes within large numbers of RGCs. This downregulation of gene expression within RGCs occurs together with reductions in FluoroGold (FG) retrograde transport. Surprisingly, there are also large numbers of Sncg-expressing cells without any FG labeling, and among these many that have a marker previously associated with disconnected RGCs, accumulation of phosphorylated neurofilaments in their somas. These same diseased retinas also have large numbers of RGCs that maintain the intraocular portion while losing the optic nerve portion of their axons, and these disconnected axons terminate within the optic nerve head. Our data support the view that RGC degeneration in glaucoma has two separable stages: the first involves atrophy of RGCs, whereas the second involves an insult to axons, which causes the degeneration of axon portions distal to the optic nerve head but does not cause the immediate degeneration of intraretinal portions of axons or the immediate death of RGCs.
Constitutively Active TRPC3 Channels Regulate Basal Ganglia Output Neurons
Authors: Zhou Fu-Wen , Matta Shannon G. , Zhou Fu-Ming
Published: January 2008

A hallmark of the GABA projection neurons of the substantia nigra pars reticulata (SNr), a key basal ganglia output nucleus, is its depolarized membrane potential and rapid spontaneous spikes that encode the basal ganglia output. Parkinsonian movement disorders are often associated with abnormalities in SNr GABA neuron firing intensity and/or pattern. A fundamental question remains regarding the molecular identity of the ion channels that drive these neurons to a depolarized membrane potential. We show here that SNr GABA projection neurons selectively express type 3 canonical transient receptor potential (TRPC3) channels. These channels are tonically active and mediate an inward, Na+-dependent current, leading to a substantial depolarization in these neurons. Inhibition of TRPC3 channels induces hyperpolarization, decreases firing frequency, and increases firing irregularity. These data demonstrate that TRPC3 channels play important roles in ensuring the appropriate firing intensity and pattern in SNr GABA projection neurons that are crucial to movement control.
The Dysphoric Component of Stress Is Encoded by Activation of the Dynorphin κ-Opioid System
Authors: Land Benjamin B. , Bruchas Michael R. , Lemos Julia C. , Xu Mei , Melief Erica J. , Chavkin Charles
Published: January 2008

Stress is a complex human experience having both positive and negative motivational properties. When chronic and uncontrollable, the adverse effects of stress on human health are considerable and yet poorly understood. Here, we report that the dysphoric properties of chronic stress are encoded by the endogenous opioid peptide dynorphin acting on specific stress-related neuronal circuits. Using different forms of stress presumed to evoke dysphoria in mice, we found that repeated forced swim and inescapable footshock both produced aversive behaviors that were blocked by a κ-opioid receptor (KOR) antagonist and absent in mice lacking dynorphin. Injection of corticotropin-releasing factor (CRF) or urocortin III, key mediators of the stress response, produced place aversion that was also blocked by dynorphin gene deletion or KOR antagonism. CRF-induced place aversion was blocked by the CRF2receptor antagonist antisauvigine-30, but not by the CRF1receptor antagonist antalarmin. In contrast, place aversion induced by the KOR agonist U50,488 was not blocked by antisauvigine-30. These results suggest that the aversive effects of stress were mediated by CRF2receptor stimulation of dynorphin release and subsequent KOR activation. Using a phospho-selective antibody directed against the activated KOR to image sites of dynorphin action in the brain, we found that stress and CRF each caused dynorphin-dependent KOR activation in the basolateral amygdala, nucleus accumbens, dorsal raphe, and hippocampus. The convergence of stress-induced aversive inputs on the dynorphin system was unexpected, implicates dynorphin as a key mediator of dysphoria, and emphasizes κ-receptor antagonists as promising therapeutics.
Induction of the Phase II Detoxification Pathway Suppresses Neuron Loss inDrosophilaModels of Parkinson's Disease
Authors: Trinh Kien , Moore Katherine , Wes Paul D. , Muchowski Paul J. , Dey Joyoti , Andrews Laurie , Pallanck Leo J.
Published: January 2008

α-Synuclein aggregates are a common feature of sporadic Parkinson's disease (PD), and mutations that increase α-synuclein abundance confer rare heritable forms of PD. Although these findings suggest that α-synuclein plays a central role in the pathogenesis of this disorder, little is known of the mechanism by which α-synuclein promotes neuron loss or the factors that regulate α-synuclein toxicity. To address these matters, we tested candidate modifiers of α-synuclein toxicity using aDrosophilamodel of PD. In the current work, we focused on phase II detoxification enzymes involved in glutathione metabolism. We find that the neuronal death accompanying α-synuclein expression inDrosophilais enhanced by loss-of-function mutations in genes that promote glutathione synthesis and glutathione conjugation. This neuronal loss can be overcome by genetic or pharmacological interventions that increase glutathione synthesis or glutathione conjugation activity. Moreover, these same pharmacological agents suppress neuron loss inDrosophila parkinmutants, a loss-of-function model of PD. Our results suggest that oxidative stress is a feature of α-synuclein toxicity and that induction of the phase II detoxification pathway represents a potential preventative therapy for PD.
Homer Interactions Are Necessary for Metabotropic Glutamate Receptor-Induced Long-Term Depression and Translational Activation
Authors: Ronesi Jennifer A. , Huber Kimberly M.
Published: January 2008

Group I metabotropic glutamate receptors (mGluRs) induce a form of long-term synaptic depression (mGluR-LTD) in area CA1 of the hippocampus that requires rapid protein synthesis. Although much is known about the mechanisms underlying mGluR-LTD, it is unclear how mGluRs couple to the effectors necessary for translation initiation. A clue comes from work in the mouse model of Fragile X syndrome [Fmr1knock-out (KO) mice], where group 1 mGluR stimulation of protein synthesis is absent and mGluRs are less associated with the postsynaptic scaffolding protein Homer (Giuffrida et al., 2005). Here, we examined the role of Homer interactions in mGluR-LTD and mGluR signaling to protein synthesis machinery in wild-type andFmr1KO animals. A peptide that mimics the C-terminal tail of mGluR5 (mGluR5ct), shown previously to disrupt Homer interactions with mGluRs, blocks mGluR-LTD and mGluR-signaling to protein synthesis initiation in wild-type animals. Disruption of mGluR–Homer interactions selectively blocks mGluR activation of the phosphoinositide 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR), but not ERK (extracellular signal-regulated kinase), pathway and translation of a 5′ terminal oligopyrimidine tract containing mRNA, Elongation factor 1α. InFmr1KO mice, mGluR-LTD is insensitive to disruption of Homer interactions and mGluR activation of PI3K-mTOR is lost. Our results find specific roles for Homer in mGluR signaling and plasticity and suggest that reduced mGluR–Homer interactions inFmr1KO mice lead to a deficit in mGluR stimulation of translation initiation.
Oxytocin-Induced Postinhibitory Rebound Firing Facilitates Bursting Activity in Oxytocin Neurons
Authors: Israel Jean-Marc , Poulain Dominique A. , Oliet Stéphane H. R.
Published: January 2008

During parturition and lactation, neurosecretory oxytocin (OT) neurons in the hypothalamus achieve pulsatile hormone secretion by coordinated bursts of firing that occur throughout the neuronal population. This activity is partly controlled by somatodendritic release of OT, which facilitates the onset and recurrence of synchronized bursting. To further investigate the cellular mechanisms underlying the control exerted by OT on the activity of its own neurons, we studied the effects of the peptide on membrane potential and synaptic activity in OT neurons in hypothalamic organotypic slice cultures. Bath application of low concentrations of OT (<100 nm) facilitated GABAAreceptor-mediated inhibitory transmission through a presynaptic mechanism without affecting membrane potential and excitatory glutamatergic synaptic activity. The facilitatory action of OT on GABAergic transmission was dose-dependent, starting at 25 nmand disappearing at concentrations >100 nm. As shown previously, higher concentrations of OT (>500 nm) had the opposite effect, inhibiting GABAAreceptors via a postsynaptic mechanism. Surprisingly, OT-mediated facilitation of GABAergic transmission promoted action potential firing in 40% of the neurons. Each action potential occurred at the end of the repolarizing phase of an inhibitory potential. Pharmacological dissection revealed that this firing involved the activation of low-threshold activated calcium channels. Detailed statistical analysis showed that OT-mediated firing upregulated bursting activity in OT neurons. It is thus likely to optimize OT secretion and, as a consequence, facilitate delivery and milk ejection in mammals.
The Social Dynamics of Technical Innovation in the Computing World*
Authors: Kling Rob , Gerson Elihu M.
Published: January 2008

The “computing world,” all those people and groups that collectively produce computers and computer‐based services is an especially complex, dynamic and diffuse social world. Technical innovation is a dominant feature of the world. It is organized to provide a continuous flow of innovations from participants who specialize in innovation through many other participants to the final consumers of computer‐based services. Technical innovations often flow across a large number of “markets” which are composed of only a few classes of participants such as “innovators” and “vendors” or of “users” and “consumers.”

This paper identifies the major orientations taken on by participants in the computing world and examines some of the markets across which innovations are negotiated. The computing world is organized so that each market is biased in favor of innovations moving from suppliers to their customers. From this viewpoint, “innovation” is a dominant structural interest in computing around which participants organize their activities and to which they must continually adjust.
Personal Acts1
Authors: Stone Gregory P.
Published: January 2008

Personal acts, whether carried on alone or with others, are amenable to the same mode of analysis as joint actions. They are concerted. This article deals with six dimensions of the orchestration of such concerts—self, role and role‐taking, personal appearace, situations, out‐of‐awareness contexts, and symbols. Comments are made and questions raised about these dimensions that are not often made or raised in the literature of symbolic interaction. A rudimentary paradigm has been established which needs further systematizarjon and specification but may well guide future research even in its present state.
The Professionalization of Medical Students: Developing Competence And A Cloak of Competence*
Authors: Haas Jack , Shaffir William
Published: January 2008

This paper describes how medical students in an innovative educational setting adopt a cloak of competence as a critical part of the professionalization process. Faced with inordinate and variable expectations to develop and display competence, students professionalize by distancing themselves from those they interact with and by adopting and manipulating the symbols of their new status. Students were observed to engage in impression management to convince others and themselves that they are competent and confident to face the immense responsibilities of their privileged role. The data were collected by means of participant observation and interviews.
Can Labeling Theory Be Saved?*,1
Authors: Glassner Barry , Corzine Jay
Published: January 2008

Despite numerous criticisms during the last decade, labeling theory has maintained pre‐eminence among theories of deviance. The critiques of the positivists, neo‐Marxists, and phenomenologists are reviewed along with their respective prescriptions for the development of a more satisfactory theory of deviance. While the changes advocated by the first two groups are rejected on logical and empirical grounds, some of the suggestions of the phenomenologists are viewed as necessary corrections to labeling theory. Recommendations are made that call for 1) consideration of ‘categorical’, ‘contextual’, and ‘potential’ labeling, 2) application and development of the labeling perspective in substantive areas other than deviance, and 3) construction of explicit and defensible ethical positions for persons involved in labeling studies.