bluuebunny/crossref_metadata_2025 huggingface dataset:
Highly Ordered Structures Self-assembled by NaDC under Metal-ion-mediation
Authors: Wang Ying-Te , Yan Xiao-Qing , Ma Hui-Li , Jin Wei-Jun
Published: November 2006

Sodium deoxycholate self-assembled into fan-like structural aggregates with uniform size and shape. Additional metal ions led the aggregates to transfer from fan-like to fractal aggregates. The fractal aggregates might provide an insight into understanding the formation of a gallstone because fractal structures were found in human being gallstones.
Photoluminescence of Eu(DBM)3Phen-embedded Silica Nanospheres Synthesized in Microemulsion
Authors: Wang Yan , Qin Weiping , Zhang Jisen , Cao Chunyan , Zhang Jishuang , Lü Shaozhe , Jin Ye , Wei Guodong , Wang Guofeng , Wang Lili
Published: November 2006

Eu(DBM)3Phen-embedded silica nanospheres were synthesized through a simple water-in-oil (W/O) microemulsion method. TEM observation indicates that the nanospheres are ≈40 nm in diameter and with a uniform core/shell structure. Compared to Eu(DBM)3Phen complex, the nano-hybrid-spheres shows similar emissions of Eu3+ ions under 355-nm excitation. By dynamic analysis at low temperature and laser selective excitation spectra, we found that there are two luminescent centers formed in the nanohybrids.
CdS Quantum Dots Sensitized TiO2 Sandwich Type Photoelectrochemical Solar Cells
Authors: Tachibana Yasuhiro , Akiyama Hitomi Y , Ohtsuka Yasuhide , Torimoto Tsukasa , Kuwabata Susumu
Published: November 2006

For the first time, we report highly stable CdS quantum dots sensitized TiO2 sandwich type photoelectrochemical solar cells. A unique combination of a sensitized electrode and a polysulfide electrolyte has provided the most stable solar cell with the highest IPCE of approximately 70%.
Crystal Structure and Magnetic Property of Two Novel 1-D Cobalt(II) Assemblies
Authors: Masuhara Naoji , Hayami Shinya , Motokawa Natsuko , Shuto Aya , Inoue Katsuya , Maeda Yonezo
Published: November 2006

Two novel one-dimensional (1-D) cobalt(II) self-assemblies, [Co(pyterpy)(NCS)2] (1) and [Co(pyterpy)(SO4)]·(CH3OH)(C2H5OH)(H2O) (2) (pyterpy = 4′-(4″′-pyridyl)-2,2′:6′,2″-terpyridine) were synthesized and characterized. Compound 1 forms a linear chain, and compound 2 forms a zigzag chain. It is thought that the structural differences are caused by binding counter anions as coligands.
Visual Color Sensor for Indole Vapors
Authors: Kohno Yoshiumi , Okubo Takeshi , Matsushima Ryoka
Published: November 2006

Based on the Ehrlich reaction in solid film, a color sensor has been developed for selective detection of indole and pyrrole vapors in environmental or workplace air. It will be suitable for real-time monitoring since neither pre-treatments of the air sample nor heavy instrumentations are needed.
Relationship Between Pharmaceutical Company User Fees and Drug Approvals in Canada and Australia: A Hypothesis-Generating Study
Authors: Lexchin Joel
Published: November 2006

Background:

Since the early- to mid-1990s, drug companies have paid fees for a variety of activities carried out by the Therapeutic Products Directorate in Canada and the Therapeutic Goods Administration in Australia.

Objective:

To explore whether changes in approval times for new active substances and in the percentage of new drug submissions receiving positive decisions coincided with the level of user fees.

Methods:

Data were collected from a range of Canadian and Australian government publications on the following topics: total funding for and workload of the regulatory agencies, the percentage of income that came from tax revenue and user fees, the percentage of new drug submissions that received a positive decision, and—for Canada only—the percent of submissions that were approved on first review.

Results:

In both countries, there was a moderate-to-strong positive association between the level of industry funding and the percent of submissions that received a positive decision and a moderate-to-strong (Canada) and moderate (Australia) negative association between the level of industry funding and approval times.

Conclusions:

Changes observed in both countries are favorable to the pharmaceutical industry. Other than user fees leading to a pro-industry bias in the regulatory authorities, other possible explanations include a more efficient use of resources, a smaller workload (Canada), an improvement in the quality of drug submissions (Canada), and more resources (Australia). Further research strategies are needed to either confirm or refute the hypothesis that the level of industry funding affects decisions made in drug regulatory systems.
Febuxostat: A Selective Xanthine Oxidase Inhibitor for the Treatment of Hyperuricemia and Gout
Authors: Bruce Susan P
Published: November 2006

Objective:

To review the pharmacology, pharmacokinetics, clinical trial data, safety profile, precautions, and place in therapy of febuxostat, a novel nonpurine xanthine oxidase inhibitor in development for the treatment of hyperuricemia and gout.

Data Sources:

Available studies and abstracts were identified through MEDLINE (1990–November 2006), Science Citation Index, International Pharmaceutical Abstracts, Cochrane Databases, and the American College of Rheumatology and European League Against Rheumatism Web sites. Key search terms were febuxostat, TMX-67, TEI-6720, hyperuricemia, and gout.

Study Selection and Data Extraction:

All available studies describing the pharmacology of febuxostat were included. Human studies formed the basis for discussion of clinical parameters, including pharmacokinetics, pharmacodynamics, efficacy, and safety of febuxostat.

Data Synthesis:

Febuxostat significantly reduces uric acid levels within 2 weeks after initiation of therapy and up to 48% by the end of 104 weeks of therapy. Approximately 60% of patients achieved the primary goal of serum uric acid less than 6 mg/dL during the last 3 months following once-daily administration of febuxostat 80 mg or 120 mg for at least 52 weeks. The most common adverse reactions to febuxostat were abnormal results from liver function tests, diarrhea, headache, arthralgias, and musculoskeletal symptoms. Due to its potency, patients are at an increased risk of experiencing gout flares for at least the first year of therapy. Up to 70% of patients in clinical trials experienced gout flares despite concomitant prophylactic treatment with colchicine or naproxen. Additional clinical trial evidence supports the efficacy and safety of febuxostat in the treatment of hyperuricemia and gout.

Conclusions:

Febuxostat is a promising alternative to allopurinol for the treatment of gout and hyperuricemia. The optimal length of prophylactic therapy, clinical significance of abnormal liver function tests results during therapy, and safety in patients with moderate or severe renal insufficiency warrant further investigation.
Breast-Feeding During Maternal Use of Azathioprine
Authors: Moretti Myla E , Verjee Zul , Ito Shinya , Koren Gideon
Published: November 2006

Objective:

To report the clinical outcome of infants whose mothers were taking azathioprine while nursing and to quantify the transfer of 6-mercaptopurine (6-MP), its active metabolite, into breast milk.

Case Summary:

We report on a series of 4 patients treated with azathioprine while lactating. Breast milk samples were analyzed for 6-MP in 2 of the mothers. Several milk samples per patient were analyzed; levels of 6-MP were undetectable by high performance liquid chromatography (limit of detection 5 ng/mL). Therefore, the absolute relative infant dose would have been less than 0.09% of the maternal weight-adjusted dose. No adverse effects were encountered in any of the 4 infants.

Discussion:

A large number of women of reproductive age are treated with azathioprine for a range of chronic conditions that require immunosuppression, such as systemic lupus erythematosus or solid organ transplants. Similar to other antimetabolites, the drug has generally been contraindicated for use during breast-feeding because of the theoretical concern for toxicity in the nursing infant. The available literature in this area is sparse and dated. The data presented here confirm published reports of minimal 6-MP excretion into milk, suggesting that significant systemic adverse effects in the infant are unlikely.

Conclusions:

Maternal azathioprine use during lactation does not appear to pose a significant immediate clinical risk to the suckling infant. Continued monitoring and long-term assessment of these infants are warranted.
Statins and Progression of Calcified Aortic Stenosis
Authors: Chua Doson , Kalb Kelli
Published: November 2006

Objective:

To review the evidence evaluating the efficacy of statins in reducing the progression of calcified aortic stenosis (AS).

Data Sources:

MEDLINE, EMBASE, and PubMed were searched (all up to November 2006) for studies evaluating the use of statins to reduce the progression of calcified AS. Search terms included statin, HMG CoA reductase inhibitor, calcified AS, valve stenosis, and calcified stenosis. Additional primary trials were located by searching references noted in review articles.

Study Selection and Data Extraction:

Clinical trials published in the English language were selected for review. Primary efficacy outcomes evaluated were changes in aortic valve measurements, hemodynamic measures of AS, and change in measures of AS severity.

Data Synthesis:

TWO prospective clinical trials and 5 retrospective studies were included in this review. All of the retrospective studies demonstrated that statin use was associated with a statistically significant delay in the progression of AS. One prospective observation trial showed benefit of statin use; however, a large, randomized, double-blind, prospective trial showed no benefit of statin use in decreasing the progression of AS.

Conclusions:

An association between statin use and a delay in AS progression has been observed in retrospective studies; however, prospective trials showed conflicting results. Currently, statins cannot be recommended for medical treatment of AS until larger trials are conducted.
Androgen Deprivation in Veterans with Prostate Cancer: Implications for Skeletal Health
Authors: Wilcox Andrew , Carnes Molly L , Moon Timothy D , Tobias Renee , Baade Heather , Stamos Emily , Elliott Mary E
Published: November 2006

Background:

Common risk factors for osteoporosis in older men include smoking, heavy use of alcohol, propensity to falls, and use of bone-toxic medications such as prednisone. There is also increasing appreciation of the skeletal risk faced by men receiving androgen deprivation therapy (ADT) for prostate cancer. Measures to prevent bone loss in such patients are available.

Objective:

To test the following hypotheses in a population of veterans receiving ADT for prostate cancer: (1) fracture risk factors in addition to androgen deprivation would be found in most patients, (2) bone mass measurements would be assessed in a minority of patients, and (3) a minority of the subjects would receive bisphosphonate therapy or have contraindications for such treatment.

Methods:

We conducted a retrospective chart review of male veterans receiving ADT from 1993 through 2001, at the Veterans Affairs Medical Center, Madison, WI.

Results:

One hundred and seventy-four subjects met study criteria, with a mean age of 76 years and median duration of 21 months of ADT. Eighty-one percent had risk factors in addition to ADT. Only 13% underwent bone density measurement by dual energy X-ray absorptiometry (DXA) and, of those measured, more than half had osteoporosis. Only 19% of the men received both calcium and vitamin D supplements. Antiresorptive therapy was provided to 11% of men, although more than two-thirds had no contraindications to therapy. A total of 24 men sustained a fracture after starting ADT. For men who did undergo bone density measurement, 77% received antiresorptive therapy. Of those who exhibited osteoporosis by DXA scan, 85% received antiresorptive therapy.

Conclusions:

Male veterans receiving ADT for prostate cancer received inadequate evaluation and treatment for osteoporosis. Based on our data, a simple and practical strategy to prompt further evaluation and improved care may be to undertake bone density measurements in men prior to or soon after commencing ADT.
Clozapine Effective in Olanzapine-Induced Pisa Syndrome
Authors: Arora Manu , Praharaj Samir Kumar , Sarkar Sukanto
Published: November 2006

Objective:

To report a case of olanzapine-induced Pisa syndrome that improved after treatment with clozapine.

Case Summary:

A 22-year-old male with paranoid schizophrenia presented with insidious onset tonic truncal flexion with axial rotation and difficulty in walking after exposure to olanzapine in doses up to 15 mg/day for 9 months. An objective causality assessment suggested that Pisa syndrome was probably related to olanzapine. There was improvement in his symptoms after 6 weeks of treatment with clozapine in doses gradually titrated to 350 mg/day.

Discussion:

Pisa syndrome is a type of dystonia that has been associated with both typical and atypical antipsychotics. Both acute and insidious onset cases have been described in the literature, which have different course and treatment response. Clozapine was found to be effective in reducing the severity of olanzapine-induced Pisa syndrome.

Conclusion:

Clozapine may be a useful treatment option for Pisa syndrome that has been caused by olanzapine.
Human Vascular Endothelial Growth Factor Protects Axotomized Retinal Ganglion CellsIn Vivoby Activating ERK-1/2 and Akt Pathways
Authors: Kilic Ülkan , Kilic Ertugrul , Järve Anne , Guo Zeyun , Spudich Annett , Bieber Katja , Barzena Uxue , Bassetti Claudio L. , Marti Hugo H. , Hermann Dirk M.
Published: November 2006

Based on its trophic effects on neurons and vascular cells, vascular endothelial growth factor (VEGF) is a promising candidate for the treatment of neurodegenerative diseases. To evaluate the therapeutic potential of VEGF, we here examined effects of this growth factor on the degeneration of axotomized retinal ganglion cells (RGCs), which, as CNS-derived neurons, offer themselves in an excellent way to study neuroprotectionin vivo. Making use of a transgenic mouse line that constitutively expresses human VEGF under a neuron-specific enolase promoter, we show that (1) the VEGF-transgenic retina overexpresses human VEGF, (2) RGCs carry the VEGF receptor-2, and (3) vascular networks in normal and axotomized VEGF-transgenic (tg) retinas do not differ from control animals. After axotomy, RGCs of VEGF-tg mice were protected against delayed degeneration, as compared with wild-type littermates. Western blots revealed increased phosphorylated ERK-1/2 and Akt and reduced phosphorylated p38 and activated caspase-3 levels in axotomized VEGF-transgenic retinas. Intravitreous injections of pharmacological ERK-1/2 (PD98059) or Akt (LY294002) inhibitors showed that VEGF exerts neuroprotection by dual activation of ERK-1/2 and Akt pathways. In view that axotomy-induced RGC death occurs slowly and considering that RGCs are CNS-derived neurons, we predict the clinical implementation of VEGF in neurodegenerative diseases of both brain and retina.
Neurocytoma Is a Tumor of Adult Neuronal Progenitor Cells
Authors: Sim Fraser J. , Keyoung H. Michael , Goldman James E. , Kim Dong Kyu , Jung Hee-Won , Roy Neeta S. , Goldman Steven A.
Published: November 2006

Central neurocytoma (CN) is a rare periventricular tumor, whose derivation, lineage potential, and molecular regulation have been mostly unexplored. We noted that CN cells exhibited an antigenic profile typical of neuronal progenitor cellsin vivo, yetin vitrogenerated neurospheres, divided in response to bFGF (basic fibroblast growth factor), activated the neuroepithelial enhancer of the nestin gene, and gave rise to both neuron-like cells and astrocytes. When CN gene expression was compared with that of both normal adult VZ (ventricular zone) and E/nestin:GFP (green fluorescent protein)-sorted native neuronal progenitors, significant overlap was noted. Marker analysis suggested that the gene expression pattern of CN was that of a proneuronal population; glial markers were conspicuously absent, suggesting that the emergence of astroglia from CN occurred only with passage. The expression pattern of CN was distinguished from that of native progenitor cells by a cohort of differentially expressed genes potentially involved in both the oncogenesis and phenotypic restriction of neurocytoma. These included both IGF2 and several components of its signaling pathway, whose sharp overexpression implicated dysregulated autocrine IGF2 signaling in CN oncogenesis. Both receptors and effectors of canonical wnt signaling, as well as GDF8 (growth differentiation factor 8), PDGF-D, and neuregulin, were differentially overexpressed by CN, suggesting that CN is characterized by the concurrent overactivation of these pathways, which may serve to drive neurocytoma expansion while restricting tumor progenitor phenotype. This strategy of comparing the gene expression of tumor cells to that of the purified native progenitors from which they derive may provide a focused approach to identifying transcripts important to stem and progenitor cell oncogenesis.
A Sex-Specific Role of Type VII Adenylyl Cyclase in Depression
Authors: Hines Lisa M. , Hoffman Paula L. , Bhave Sanjiv , Saba Laura , Kaiser Alan , Snell Larry , Goncharov Igor , LeGault Lucie , Dongier Maurice , Grant Bridget , Pronko Sergey , Martinez Larry , Yoshimura Masami , Tabakoff Boris
Published: November 2006

Major depression represents a complex mental disorder. The identification of biological markers that define subtypes of major depressive disorder would greatly facilitate appropriate medical treatments, as well as provide insight into etiology. Reduced activity of the cAMP signaling system has been implicated in the etiology of major depression. Previous work has shown low adenylyl cyclase activity in platelets and postmortem brain tissue of depressed individuals. Here, we investigate the role of the brain type VII isoform of adenylyl cyclase (AC7) in the manifestation of depressive symptoms in genetically modified animals, using a combination ofin vivobehavioral experiments, gene expression profiling, and bioinformatics. We also completed studies with humans on the association of polymorphisms in the AC7 gene with major depressive illness (unipolar depression) based on Diagnostic and Statistical Manual of Mental Disorders IV criteria. Collectively, our results demonstrate a sex-specific influence of the AC7 gene on a heritable form of depressive illness.
Disruption of Primary Motor Cortex before Learning Impairs Memory of Movement Dynamics
Authors: Richardson Andrew G. , Overduin Simon A. , Valero-Cabré Antoni , Padoa-Schioppa Camillo , Pascual-Leone Alvaro , Bizzi Emilio , Press Daniel Z.
Published: November 2006

Although multiple lines of evidence implicate the primary motor cortex (M1) in motor learning, the precise role of M1 in the adaptation to novel movement dynamics and in the subsequent consolidation of a memory of those dynamics remains unclear. Here we used repetitive transcranial magnetic stimulation (rTMS) to dissociate the contribution of M1 to these distinct aspects of motor learning. Subjects performed reaching movements in velocity-dependent force fields over three epochs: a null-field baseline epoch, a clockwise-field learning epoch (15 min after the baseline epoch), and a clockwise-field retest epoch (24 h after the learning epoch). Half of the subjects received 15 min of 1 Hz rTMS to M1 between the baseline and learning epochs. Subjects given rTMS performed identically to control subjects during the learning epoch. However, control subjects performed with significantly less error than rTMS subjects in the retest epoch on the following day. These results suggest that M1 is not critical to the network supporting motor adaptation per se but that, within this network, M1 may be important for initiating the development of long-term motor memories.
Operant Conditioning of H-Reflex Can Correct a Locomotor Abnormality after Spinal Cord Injury in Rats
Authors: Chen Yi , Chen Xiang Yang , Jakeman Lyn B. , Chen Lu , Stokes Bradford T. , Wolpaw Jonathan R.
Published: November 2006

This study asked whether operant conditioning of the H-reflex can modify locomotion in spinal cord-injured rats. Midthoracic transection of the right lateral column of the spinal cord produced a persistent asymmetry in the muscle activity underlying treadmill locomotion. The rats were then either exposed or not exposed to an H-reflex up-conditioning protocol that greatly increased right soleus motoneuron response to primary afferent input, and locomotion was reevaluated. H-reflex up-conditioning increased the right soleus burst and corrected the locomotor asymmetry. In contrast, the locomotor asymmetry persisted in the control rats. These results suggest that appropriately selected reflex conditioning protocols might improve function in people with partial spinal cord injuries. Such protocols might be especially useful when significant regeneration becomes possible and precise methods for reeducating the regenerated spinal cord neurons and synapses are needed for restoring effective function.
The ducky2JMutation inCacna2d2Results in Reduced Spontaneous Purkinje Cell Activity and Altered Gene Expression
Authors: Donato Roberta , Page Karen M. , Koch Dietlind , Nieto-Rostro Manuela , Foucault Isabelle , Davies Anthony , Wilkinson Tonia , Rees Michele , Edwards Frances A. , Dolphin Annette C.
Published: November 2006

The mouse mutant ducky and its allele ducky2Jrepresent a model for absence epilepsy characterized by spike-wave seizures and cerebellar ataxia. These mice have mutations inCacna2d2, which encodes the α2δ-2 calcium channel subunit. Of relevance to the ataxic phenotype, α2δ-2 mRNA is strongly expressed in cerebellar Purkinje cells (PCs). TheCacna2d2du2Jmutation results in a 2 bp deletion in the coding region and a complete loss of α2δ-2 protein. Here we show thatdu2J/du2Jmice have a 30% reduction in somatic calcium current and a marked fall in the spontaneous PC firing rate at 22°C, accompanied by a decrease in firing regularity, which is not affected by blocking synaptic input to PCs. At 34°C,du2J/du2JPCs show no spontaneous intrinsic activity.Du2J/du2Jmice also have alterations in the cerebellar expression of several genes related to PC function. At postnatal day 21, there is an elevation of tyrosine hydroxylase mRNA and a reduction in tenascin-C gene expression. Althoughdu2J/+ mice have a marked reduction in α2δ-2 protein, they show no fall in PC somatic calcium currents or increase in cerebellar tryrosine hydroxylase gene expression. However,du2J/+ PCs do exhibit a significant reduction in firing rate, correlating with the reduction in α2δ-2. A hypothesis for future study is that effects on gene expression occur as a result of a reduction in somatic calcium currents, whereas effects on PC firing occur as a long-term result of loss of α2δ-2 and/or a reduction in calcium currents and calcium-dependent processes in regions other than the soma.
Release Probability-Dependent Scaling of the Postsynaptic Responses at Single Hippocampal GABAergic Synapses
Authors: Biró Ágota A. , Holderith Noémi B. , Nusser Zoltan
Published: November 2006

The amount of neurotransmitter released after the arrival of an action potential affects the strength and the trial-to-trial variability of postsynaptic responses. Most studies examining the dependence of synaptic neurotransmitter concentration on the release probability (Pr) have focused on glutamatergic synapses. Here we asked whether univesicular or multivesicular release characterizes transmission at hippocampal GABAergic synapses. We used multiple probability functional analysis to derive quantal parameters at inhibitory connections between cannabinoid receptor- and cholecystokinin (CCK)-expressing interneurons and CA3 pyramidal cells. After the recordings, the cells were visualized and reconstructed at the light-microscopic level, and the number of boutons mediating the IPSCs was determined using electron microscopy (EM). The number of active zones (AZs) per CCK-immunopositive bouton was determined from three-dimensional EM reconstructions, thus allowing the calculation of the total number of AZs for each pair. Our results reveal an approximate fivefold discrepancy between the numbers of functionally determined release sites (17.4 ± 3.2) and structurally identified AZs (3.7 ± 0.9). Channel modeling predicts that a fivefold to sevenfold increase in the peak synaptic GABA concentration is required for the fivefold enhancement of the postsynaptic responses. Kinetic analysis of the unitary IPSCs indicates that the increase in synaptic GABA concentration is most likely attributable to multivesicular release. This change in the synaptic GABA concentration transient together with extremely low postsynaptic receptor occupancy permits aPr-dependent scaling of the postsynaptic response generated at a single hippocampal GABAergic synaptic contact.
Cell-Autonomous β-Catenin Signaling Regulates Cortical Precursor Proliferation
Authors: Woodhead Gregory J. , Mutch Christopher A. , Olson Eric C. , Chenn Anjen
Published: November 2006

Overexpression of β-catenin, a protein that functions in both cell adhesion and signaling, causes expansion of the cerebral cortical precursor population and cortical surface area enlargement. Here, we find that focal elimination of β-catenin from cortical neural precursorsin vivocauses premature neuronal differentiation. Precursors within the cerebral cortical ventricular zone exhibit robust β-catenin-mediated transcriptional activation, which is downregulated as cells exit the ventricular zone. Targeted inhibition of β-catenin signaling during embryonic development causes cortical precursor cells to prematurely exit the cell cycle, differentiate into neurons, and migrate to the cortical plate. These results show that β-catenin-mediated transcriptional activation functions in the decision of cortical ventricular zone precursors to proliferate or differentiate during development, and suggest that the cell-autonomous signaling activity of β-catenin can control the production of cortical neurons and thus regulate cerebral cortical size.
Accelerated Accumulation of Misfolded Prion Protein and Spongiform Degeneration in aDrosophilaModel of Gerstmann–Sträussler–Scheinker Syndrome
Authors: Gavin Brendan A. , Dolph Maria J. , Deleault Nathan R. , Geoghegan James C. , Khurana Vikram , Feany Mel B. , Dolph Patrick J. , Supattapone Surachai
Published: November 2006

Prion diseases are CNS disorders that can occur in sporadic, infectious, and inherited forms. Although all forms of prion disease are associated with the accumulation of pathogenic conformers of the prion protein, collectively termed PrPSc, the mechanisms by which PrPScmolecules form and cause neuronal degeneration are unknown. Using the bipartite galactosidase-4–upstream activating sequence expression system, we generated transgenicDrosophila melanogasterheterologously expressing either wild-type (WT) or mutant, disease-associated (P101L) mouse PrP molecules in cholinergic neurons. Transgenic flies expressing neuronal P101L PrP molecules exhibited severe locomotor dysfunction and premature death as larvae and adults. These striking clinical abnormalities were accompanied by age-dependent accumulation of misfolded PrP molecules, intracellular PrP aggregates, and neuronal vacuoles. In contrast, transgenic flies expressing comparable levels of WT PrP displayed no clinical, pathological, or biochemical abnormalities. These results indicate that transgenicDrosophilaexpressing neuronal P101L PrP specifically exhibit several hallmark features of human Gerstmann–Sträussler–Scheinker (GSS) syndrome. Because the rates of abnormal PrP accumulation and clinical progression are highly accelerated inDrosophilacompared with the rates of these processes in rodents or humans, the P101L mutant may be used for future genetic and pharmacologic studies as a novel invertebrate model of GSS.
Nav1.7 Mutant A863P in Erythromelalgia: Effects of Altered Activation and Steady-State Inactivation on Excitability of Nociceptive Dorsal Root Ganglion Neurons
Authors: Harty T. Patrick , Dib-Hajj Sulayman D. , Tyrrell Lynda , Blackman Rachael , Hisama Fuki M. , Rose John B. , Waxman Stephen G.
Published: November 2006

Inherited erythromelalgia/erythermalgia (IEM) is a neuropathy characterized by pain and redness of the extremities that is triggered by warmth. IEM has been associated with missense mutations of the voltage-gated sodium channel Nav1.7, which is preferentially expressed in most nociceptive dorsal root ganglia (DRGs) and sympathetic ganglion neurons. Several mutations occur in cytoplasmic linkers of Nav1.7, with only two mutations in segment 4 (S4) and S6 of domain I. We report here a simplex case with an alanine 863 substitution by proline (A863P) in S5 of domain II of Nav1.7. The functional effect of A863P was investigated by voltage-clamp analysis in human embryonic kidney 293 cells and by current-clamp analysis to determine the effects of A863P on firing properties of small DRG neurons. Activation of mutant channels was shifted by −8 mV, whereas steady-state fast inactivation was shifted by +10 mV, compared with wild-type (WT) channels. There was a marked decrease in the rate of deactivation of mutant channels, and currents elicited by slow ramp depolarizations were 12 times larger than for WT. These results suggested that A863P could render DRG neurons hyperexcitable. We tested this hypothesis by studying properties of rat DRG neurons transfected with either A863P or WT channels. A863P depolarized resting potential of DRG neurons by +6 mV compared with WT channels, reduced the threshold for triggering single action potentials to 63% of that for WT channels, and increased firing frequency of neurons when stimulated with suprathreshold stimuli. Thus, A863P mutant channels produce hyperexcitability in DRG neurons, which contributes to the pathophysiology of IEM.
Contribution of TRPM8 Channels to Cold Transduction in Primary Sensory Neurons and Peripheral Nerve Terminals
Authors: Madrid Rodolfo , Donovan-Rodríguez Tansy , Meseguer Victor , Acosta Mari Carmen , Belmonte Carlos , Viana Félix
Published: November 2006

Transient receptor potential melastatin 8 (TRPM8) is the best molecular candidate for innocuous cold detection by peripheral thermoreceptor terminals. To dissect out the contribution of this cold- and menthol-gated, nonselective cation channel to cold transduction, we identified BCTC [N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)piperazine-1-carboxamide] as a potent and full blocker of recombinant TRPM8 channels. In cold-sensitive trigeminal ganglion neurons of mice and guinea pig, responses to menthol were abolished by BCTC. In contrast, the effect of BCTC on cold-evoked responses was variable but showed a good correlation with the presence or lack of menthol sensitivity in the same neuron, suggesting a specific blocking action of BCTC on TRPM8 channels. The biophysical properties of native cold-gated currents (Icold), and the currents blocked by BCTC were nearly identical, consistent with a role of this channel in cold sensing at the soma. The temperature activation threshold of native TRPM8 channels was significantly warmer than those reported in previous expression studies. The effect of BCTC on nativeIcoldwas characterized by a dose-dependent shift in the temperature threshold of activation.

The role of TRPM8 in transduction was further investigated in the guinea pig cornea, a peripheral territory densely innervated with cold thermoreceptors. All cold-sensitive terminals were activated by menthol, suggesting the functional expression of TRPM8 channels in their membrane. However, the spontaneous activity and firing pattern characteristic of cold thermoreceptors was totally immune to TRPM8 channel blockade with BCTC or SKF96365 (1-[2-(4-methoxyphenyl)-2-[3-(4-methoxyphenyl)propoxy]ethyl-1H-imidazole hydrochloride). Cold-evoked responses in corneal terminals were also essentially unaffected by these drugs, whereas responses to menthol were completely abolished. The minor impairment in the ability to transduce cold stimuli by peripheral corneal thermoreceptors during TRPM8 blockade unveils an overlapping functional role for various thermosensitive mechanisms in these nerve terminals.
A Gain-of-Function Mutation in Synaptotagmin-1 Reveals a Critical Role of Ca2+-Dependent SolubleN-Ethylmaleimide-Sensitive Factor Attachment Protein Receptor Complex Binding in Synaptic Exocytosis
Authors: Pang Zhiping P. , Shin Ok-Ho , Meyer Alexander C. , Rosenmund Christian , Südhof Thomas C.
Published: November 2006

Synaptotagmin-1, the Ca2+sensor for fast neurotransmitter release, was proposed to function by Ca2+-dependent phospholipid binding and/or by Ca2+-dependent solubleN-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex binding. Extensivein vivodata support the first hypothesis, but testing the second hypothesis has been difficult because no synaptotagmin-1 mutation is known that selectively interferes with SNARE complex binding. Using knock-in mice that carry aspartate-to-asparagine substitutions in a Ca2+-binding site of synaptotagmin-1 (the D232N or D238N substitutions), we now show that the D232N mutation dramatically increases Ca2+-dependent SNARE complex binding by native synaptotagmin-1, but leaves phospholipid binding unchanged. In contrast, the adjacent D238N mutation does not significantly affect SNARE complex binding, but decreases phospholipid binding. Electrophysiological recordings revealed that the D232N mutation increased Ca2+-triggered release, whereas the D238N mutation decreased release. These data establish that fast vesicle exocytosis is driven by a dual Ca2+-dependent activity of synaptotagmin-1, namely Ca2+-dependent binding both to SNARE complexes and to phospholipids.
CD47 Promotes Neuronal Development through Src- and FRG/Vav2-Mediated Activation of Rac and Cdc42
Authors: Murata Takaaki , Ohnishi Hiroshi , Okazawa Hideki , Murata Yoji , Kusakari Shinya , Hayashi Yuriko , Miyashita Motoaki , Itoh Hiroshi , Oldenborg Per-Arne , Furuya Nobuhiko , Matozaki Takashi
Published: November 2006

The development of axons and dendrites is controlled by small GTP-binding proteins of the Rho family, but the upstream signaling mechanisms responsible for such regulation remain unclear. We have now investigated the role of the transmembrane protein cluster of differentiation 47 (CD47) in this process with hippocampal neurons. CD47-deficient neurons manifested markedly impaired development of dendrites and axons, whereas overexpression of CD47 promoted such development. Interaction of SH2 domain-containing protein tyrosine phosphatase substrate-1 (SHPS-1) with CD47 also induced the formation of dendritic filopodia and spines. These effects of CD47 were prevented by inhibition of either cell division cycle 42 (Cdc42) or Rac. In CD47-deficient neurons, autophosphorylation of Src was markedly reduced. In addition, overexpression of CD47 promoted the autophosphorylation of Src. Inhibition of Src family kinases indeed prevented CD47-promoted dendritic development. Inhibition of either FGD1-related Cdc42-guanine nucleotide exchange factor (GEF) (FRG) or Vav2, which is a GEF for Cdc42 and Rac and is activated by Src, also prevented the effects of CD47 on dendritic development. These results indicate that CD47 promotes development of dendrites and axons in hippocampal neurons in a manner dependent, at least in part, on activation of Cdc42 and Rac mediated by Src as well as by FRG and Vav2.
Distinct Patterns of Striatal Medium Spiny Neuron Activity during the Natural Sleep–Wake Cycle
Authors: Mahon Séverine , Vautrelle Nicolas , Pezard Laurent , Slaght Seán J. , Deniau Jean-Michel , Chouvet Guy , Charpier Stéphane
Published: November 2006

Striatal medium-sized spiny neurons (MSNs) integrate and convey information from the cerebral cortex to the output nuclei of the basal ganglia. Intracellular recordings from anesthetized animals show that MSNs undergo spontaneous transitions between hyperpolarized and depolarized states. State transitions, regarded as necessary for eliciting action potential firing in MSNs, are thought to control basal ganglia function by shaping striatal output. Here, we use an anesthetic-free rat preparation to show that the intracellular activity of MSNs is not stereotyped and depends critically on vigilance state. During slow-wave sleep, much as during anesthesia, MSNs displayed rhythmic step-like membrane potential shifts, correlated with cortical field potentials. However, wakefulness was associated with a completely different pattern of temporally disorganized depolarizing synaptic events of variable amplitude. Transitions from slow-wave sleep to wakefulness converted striatal discharge from a cyclic brisk firing to an irregular pattern of action potentials. These findings illuminate different capabilities of information processing in basal ganglia networks, suggesting in particular that a novel style of striatal computation is associated with the waking state.
Rapid Activation of Inwardly Rectifying Potassium Channels by Immobile G-Protein-Coupled Receptors
Authors: Lober Robert M. , Pereira Miguel A. , Lambert Nevin A.
Published: November 2006

G-protein-coupled receptors (GPCRs) mediate slow synaptic transmission and many other effects of small molecule and peptide neurotransmitters. In the standard model of GPCR signaling, receptors and G-proteins diffuse laterally within the plane of the plasma membrane and encounter each other by random collision. This model predicts that signaling will be most efficient if both GPCRs and G-proteins are free to diffuse, thus maximizing collision frequency. However, neuronal GPCRs are often recruited to and enriched at specific synaptic locations, suggesting receptor mobility is restricted in these cells. Here, we test the hypothesis that restricting GPCR mobility impairs signaling in neurons by limiting the frequency of collisions between receptors and G-proteins. μ-Opioid receptors (MORs) were immobilized on the surface of cerebellar granule neurons by avidin-mediated cross-linking, and inwardly rectifying potassium (GIRK) channels were used as rapid indicators of G-protein activation. Mobile and immobile MORs activated GIRK channels with the same onset kinetics and agonist sensitivity in these neurons. In a heterologous expression system, GFP (green fluorescent protein)-tagged GαoAsubunits remained mobile after cross-linking, but their mobility was reduced in the presence of immobile MORs, suggesting that these receptors and subunits were transiently precoupled. In addition, channel activation could be reconstituted with immobile GPCRs, G-protein heterotrimers, and GIRK channels. These results show that collision frequency is not rate-limiting for G-protein activation in CNS neurons, and are consistent with the idea that signaling components are compartmentalized or preassembled.
p38 Mitogen-Activated Protein Kinase Contributes to Adenosine A1Receptor-Mediated Synaptic Depression in Area CA1 of the Rat Hippocampus
Authors: Brust Tyson B. , Cayabyab Francisco S. , Zhou Ning , MacVicar Brian A.
Published: November 2006

Adenosine is arguably the most potent and widespread presynaptic modulator in the CNS, yet adenosine receptor signal transduction pathways remain unresolved. Here, we demonstrate a novel mechanism in which adenosine A1receptor stimulation leads to p38 mitogen-activated protein kinase (MAPK) activation and contributes to the inhibition of synaptic transmission. Western blot analysis indicated that selective A1receptor activation [withN6-cyclopentyladenosine (CPA)] resulted in rapid increases in phosphorylated p38 (phospho-p38) MAPK immunoreactivity in membrane fractions, and decreases in phospho-p38 MAPK in cytosolic fractions. Immunoprecipitation with a phospho-p38 MAPK antibody revealed constitutive association of this phosphoprotein with adenosine A1receptors. Phospho-p38 MAPK activation by A1receptor stimulation induced translocation of PP2a (protein phosphatase 2a) to the membrane. We then examined the actions of p38 MAPK activation in A1receptor-mediated synaptic inhibition. Excitatory postsynaptic field potentials evoked in area CA1 of the rat hippocampus markedly decreased in response to adenosine (10 μm), the A1receptor agonist CPA (40 nm), or a 5 min exposure to hypoxia. These inhibitory responses were mediated by A1receptor activation because the selective antagonist DPCPX (8-cyclopentyl-1,3-dipropylxanthine) (100 nm) prevented them. In agreement with the biochemical analysis, the selective p38 MAPK inhibitor SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole] (25 μm) blocked the inhibitory actions of A1receptor activation, whereas both the inactive analog SB202474 [4-ethyl-2-(p-methoxyphenyl)-5-(4′-pyridyl)-1H-imidazole] (25 μm) and the ERK 1/2 (extracellular signal-regulated kinase 1/2) MAPK inhibitor PD98059 [2′-amino-3′-methoxyflavone] (50 μm) were ineffective. In contrast, the p38 MAPK inhibitors did not inhibit GABAB-mediated synaptic depression. These data suggest A1receptor-mediated p38 MAPK activation is a crucial step underlying the presynaptic inhibitory effect of adenosine on CA3–CA1 synaptic transmission.
Directional Cuing of Target Choice in Human Smooth Pursuit Eye Movements
Authors: Garbutt Siobhan , Lisberger Stephen G.
Published: November 2006

Perceptual attention and target choice for movement have many features in common. In particular, both generally are based on selection of a particular location in space. To ask whether motor control, like attention, also can exhibit target choice based on nonspatial features of the stimulus, we assessed the initiation of smooth pursuit eye movements when two targets move in different directions after human subjects have been cued which direction or color to track. The direction cue consisted of a patch of dots undergoing either 0% coherent motion or 50% coherent motion in the direction of motion of one of the subsequent targets. After a delay, the fixation spot was extinguished and two spots moved across the same small region of the visual field, one in the cued direction (“target”) and one in an orthogonal direction (“distracter”). After the 0% coherent cue, pursuit was approximately the vector average of responses to the two motions presented singly. After the 50% coherent cue, the initial pursuit response was biased strongly toward the target that moved in the cued direction. The impact of the cued direction persisted over delays of up to 1000 ms. Other cues about the direction of upcoming target motion biased the response similarly. Cues about target color also biased pursuit in the direction of motion of the cued target but were considerably less effective than cues indicating the direction of target motion. We conclude that target choice for movement, like perceptual attention, can be based on the features of the chosen target and not only its location in space.
Monkey Dorsolateral Prefrontal Cortex Sends Task-Selective Signals Directly to the Superior Colliculus
Authors: Johnston Kevin , Everling Stefan
Published: November 2006

The dorsolateral prefrontal cortex (DLPFC) has been implicated in the ability to perform complex behaviors requiring the implementation of cognitive control. A central supposition of models of prefrontal function is that the DLPFC engages control by selectively modulating the activity of target structures to which it is connected, but no studies in the primate have directly investigated DLPFC output signals. Here, we recorded the activity of DLPFC neurons identified as sending a direct projection to the superior colliculus, a midbrain oculomotor structure, while monkeys performed alternating blocks of trials in which they had to look toward a flashed peripheral stimulus (prosaccades) and trials in which they had to look away from the stimulus in the opposite direction (antisaccades). We report the first direct evidence that the primate DLPFC sends task-selective signals to a target structure. This supports the notion that the DLPFC orchestrates the activity of other brain areas in accordance with task requirements.
Rethinking the Fear Circuit: The Central Nucleus of the Amygdala Is Required for the Acquisition, Consolidation, and Expression of Pavlovian Fear Conditioning
Authors: Wilensky Ann E. , Schafe Glenn E. , Kristensen Morten P. , LeDoux Joseph E.
Published: November 2006

In the standard model of pavlovian fear learning, sensory input from neutral and aversive stimuli converge in the lateral nucleus of the amygdala (LA), in which alterations in synaptic transmission encode the association. During fear expression, the LA is thought to engage the central nucleus of the amygdala (CE), which serves as the principal output nucleus for the expression of conditioned fear responses. In the present study, we reexamined the roles of LA and CE. Specifically, we asked whether CE, like LA, might also be involved in fear learning and memory consolidation. Using functional inactivation methods, we first show that CE is involved not only in the expression but also the acquisition of fear conditioning. Next, we show that inhibition of protein synthesis in CE after training impairs fear memory consolidation. These findings indicate that CE is not only involved in fear expression but, like LA, is also involved in the learning and consolidation of pavlovian fear conditioning.
Introduction to “The Impact of the Hurricanes of 2005 on New Orleans and the Gulf Coast of the United States”
Authors: PAREDES J. ANTHONY
Published: November 2006

In this introduction, I briefly compare anthropological notice of Hurricanes Katrina and Rita in 2005 to that of the more powerful Hurricane Camille in 1969 and note pertinent developments in the intervening 36 years, especially the emergence of an anthropological specialty in the study of natural disasters. An overview of the collection follows with comments on particular strengths of each article and suggestions for some of their wider implications for research and public policy. I conclude with a consideration of possible avenues for further anthropological research on hurricanes in general and questions on recovery from Katrina, Rita, and ensuing floods specifically, thus providing a wide‐angle perspective on this “In Focus” endeavor—impacts of hurricanes, disaster anthropology, and both short‐term and long‐term culture change.
A Preliminary Assessment of Social and Economic Impacts Associated with Hurricane Katrina
Authors: PETTERSON JOHN S. , STANLEY LAURA D. , GLAZIER EDWARD , PHILIPP JAMES
Published: November 2006

Storm surge and wind associated with Hurricane Katrina caused many deaths and the destruction of property and public infrastructure along the coasts of Louisiana, Mississippi, and Alabama. The devastation was predicted, and absent massive and immediate action, the next major storm will inevitably produce additional disastrous outcomes. Somewhat less predictable are the many social changes associated with the hurricane and public sector response to the event. We characterize some of the more salient human consequences across multiple sectors of the economy—including energy, finance, construction, housing, gaming, and commercial fisheries. We examine how preexisting social trends were amplified, otherwise‐latent social and cultural distinctions were exacerbated, and national resources and funds intended for broad‐scale “recovery” were converted into instruments of capital formation and further concentration of wealth. We conclude with a discussion exploring public policy and other implications of the disaster in a context of ever‐increasing global, environmental, and social challenges.