bluuebunny/crossref_metadata_2025 huggingface dataset:
EGF induces coalescence of different lipid rafts
Authors: Hofman Erik G. , Ruonala Mika O. , Bader Arjen N. , van den Heuvel Dave , Voortman Jarno , Roovers Rob C. , Verkleij Arie J. , Gerritsen Hans C. , van Bergen en Henegouwen Paul M. P.
Published: July 2008

The suggestion that microdomains may function as signaling platforms arose from the presence of growth factor receptors, such as the EGFR, in biochemically isolated lipid raft fractions. To investigate the role of EGFR activation in the organization of lipid rafts we have performed FLIM analyses using putative lipid raft markers such as ganglioside GM1 and glycosylphosphatidylinositol (GPI)-anchored GFP (GPI-GFP). The EGFR was labeled using single domain antibodies from Llama glama that specifically bind the EGFR without stimulating its kinase activity. Our FLIM analyses demonstrate a cholesterol-independent colocalization of GM1 with EGFR, which was not observed for the transferrin receptor. By contrast, a cholesterol-dependent colocalization was observed for GM1 with GPI-GFP. In the resting state no colocalization was observed between EGFR and GPI-GFP, but stimulation of the cell with EGF resulted in the colocalization at the nanoscale level of EGFR and GPI-GFP. Moreover, EGF induced the enrichment of GPI-GFP in a detergent-free lipid raft fraction. Our results suggest that EGF induces the coalescence of the two types of GM1-containing microdomains that might lead to the formation of signaling platforms.
Identification of two partners from the bacterial Kef exchanger family for the apical plasma membrane V-ATPase of Metazoa
Authors: Day Jonathan P. , Wan Susan , Allan Adrian K. , Kean Laura , Davies Shireen A. , Gray Joe V. , Dow Julian A. T.
Published: July 2008

The vital task of vectorial solute transport is often energised by a plasma membrane, proton-motive V-ATPase. However, its proposed partner, an apical alkali-metal/proton exchanger, has remained elusive. Here, both FlyAtlas microarray data and in situ analyses demonstrate that the bacterial kefB and kefC (members of the CPA2 family) homologues in Drosophila, CG10806 and CG31052, respectively, are both co-expressed with V-ATPase genes in transporting epithelia. Immunocytochemistry localises endogenous CG10806 and CG31052 to the apical plasma membrane of the Malpighian (renal) tubule. YFP-tagged CG10806 and CG31052 both localise to the plasma membrane of Drosophila S2 cells, and when driven in principal cells of the Malpighian tubule, they localise specifically to the apical plasma membrane. V-ATPase-energised fluid secretion is affected by overexpression of CG10806, but not CG31052; in the former case, overexpression causes higher basal rates, but lower stimulated rates, of fluid secretion compared with parental controls. Overexpression also impacts levels of secreted Na+ and K+. Both genes rescue exchanger-deficient (nha1 nhx1) yeast, but act differently; CG10806 is driven predominantly to the plasma membrane and confers protection against excess K+, whereas CG31052 is expressed predominantly on the vacuolar membrane and protects against excess Na+. Thus, both CG10806 and CG31052 are functionally members of the CPA2 gene family, colocalise to the same apical membrane as the plasma membrane V-ATPase and show distinct ion specificities, as expected for the Wieczorek exchanger.
Divergent polarization mechanisms during vertebrate epithelial development mediated by the Crumbs complex protein Nagie oko
Authors: Bit-Avragim Nana , Hellwig Nicole , Rudolph Franziska , Munson Chantilly , Stainier Didier Y. S. , Abdelilah-Seyfried Salim
Published: July 2008

The zebrafish MAGUK protein Nagie oko is a member of the evolutionarily conserved Crumbs protein complex and functions as a scaffolding protein involved in the stabilization of multi-protein assemblies at the tight junction. During zebrafish embryogenesis, mutations in nagie oko cause defects in both epithelial polarity and cardiac morphogenesis. We used deletion constructs of Nagie oko in functional rescue experiments to define domains essential for cell polarity, maintenance of epithelial integrity and cardiac morphogenesis. Inability of Nagie oko to interact with Crumbs proteins upon deletion of the PDZ domain recreates all aspects of the nagie oko mutant phenotype. Consistent with this observation, apical localization of Nagie oko within the myocardium and neural tube is dependent on Oko meduzy/Crumbs2a. Disruption of direct interactions with Patj or Lin-7, two other members of the Crumbs protein complex, via the bipartite L27 domains produces only partial nagie oko mutant phenotypes and does not impair correct junctional localization of the truncated Nagie oko deletion protein within myocardial cells. Similarly, loss of the evolutionarily conserved region 1 domain, which mediates binding to Par6, causes only a subset of the nagie oko mutant epithelial phenotypes. Finally, deletion of the C-terminus, including the entire guanylate kinase and the SH3 domains, renders the truncated Nagie oko protein inactive and recreates all features of the nagie oko mutant phenotype when tested in functional complementation assays. Our observations reveal a previously unknown diversity of alternative multi-protein assembly compositions of the Crumbs–Nagie-oko and Par6-aPKC protein complexes that are highly dependent on the developmental context.
Live cell imaging and electron microscopy reveal dynamic processes of BAF-directed nuclear envelope assembly
Authors: Haraguchi Tokuko , Kojidani Tomoko , Koujin Takako , Shimi Takeshi , Osakada Hiroko , Mori Chie , Yamamoto Akitsugu , Hiraoka Yasushi
Published: July 2008

Assembly of the nuclear envelope (NE) in telophase is essential for higher eukaryotic cells to re-establish a functional nucleus. Time-lapse, FRAP and FRET analyses in human cells showed that barrier-to-autointegration factor (BAF), a DNA-binding protein, assembled first at the distinct `core' region of the telophase chromosome and formed an immobile complex by directly binding with other core-localizing NE proteins, such as lamin A and emerin. Correlative light and electron microscopy after live cell imaging, further showed that BAF formed an electron-dense structure on the chromosome surface of the core, close to spindle microtubules (MTs) prior to the attachment of precursor NE membranes, suggesting that MTs may mediate core assembly of BAF. Disruption of the spindle MTs consistently abolished BAF accumulation at the core. In addition, RNAi of BAF eliminated the core assembly of lamin A and emerin, caused abnormal cytoplasmic accumulation of precursor nuclear membranes and resulted in a significant delay of NE assembly. These results suggest that the MT-mediated BAF accumulation at the core facilitates NE assembly at the end of mitosis.
An investigation of the flow and overall performance in a water-jet axial flow pump based on computational fluid dynamics and inverse design method
Authors: Gao H , Lin W L , Du Z H
Published: July 2008

A new inverse design method based on non-constant distribution of circulation and axial velocity along the radial direction is used to design a pump impeller and a stator. The radial distribution of axial velocity at the design flowrate is calculated when an empirical radial distribution of circulation is given. Computational fluid dynamics (CFD) modelling of the overall performance and the detailed flow field is performed using TASCflow software. A standard k—ɛ turbulence model combined with standard wall functions is used. A frozen rotor approach is employed to simulate the rotor—stator coupling flow field. The overall performances of the water-jet pump and the radial distribution of velocity components at the exit of the impeller are also measured. Good agreement of the overall performance, such as the pressure rise, the power, and the efficiency, between CFD and experiment is obtained. The detailed velocity fields from inviscid analysis, CFD, and experiment are compared and investigated.
Effect of large-scale kinetic power extraction on time-dependent estuaries
Authors: Polagye B , Malte P , Kawase M , Durran D
Published: July 2008

An open and important question in tidal in-stream energy conversion is the level of kinetic power extraction that is possible without unacceptable environmental degradation. In general, the effects of large-scale kinetic power extraction on estuary-scale fluid mechanics are not well understood. In this paper, these effects are quantified for an idealized estuary using a one-dimensional, time-dependent numerical model. The numerical domain consists of a long, wide inlet and basin connected by a constricted channel. Kinetic power densities within this constriction are suitable for in-stream energy conversion. Modelling shows that the extraction of kinetic power has a number of effects, including: (a) reduction of the volume of water exchanged through the estuary over the tidal cycle; (b) reduction of the tidal range landward of the array; and (c) reduction of the kinetic power density in the tidal channel. These impacts are strongly dependent on the magnitude of kinetic power extraction, estuary geometry, tidal regime, and non-linear turbine dynamics. It is shown that it may be misleading to relate these impacts to the fraction of kinetic energy extracted from the system. Results highlight the importance of time-dependent modelling and the incorporation of non-linear turbine dynamics.
Transonic turbine vane tests in a new miniature cascade facility
Authors: Povey T , Oldfield M L G , Haselbach F
Published: July 2008

A new two-dimensional mini-cascade blow-down tunnel, with eight vane passages of only 20 mm true chord, 15 mm pitch, and 40 mm span, has been developed for testing gas turbine nozzle guide vane profiles at transonic exit Mach numbers ( M) and realistic Reynolds numbers ( Re) with a quick turnaround and high accuracy. The small size of the cascade has many advantages. Vane profiles can be tested at adjustable engine representative Re at room temperature with exit static pressures above atmospheric and Re and M can be independently varied. The mass flow is small and the long run times (>3 min) allow downstream traversing with a three-hole miniature probe. The inaccuracies inherent in the traditional method of mounting the vanes/blades on pegs in the Schlieren windows have been eliminated by accurately computer numerical control (CNC) machining the whole cascade of vanes integral with the tunnel side walls, with re-usable, plug-in Schlieren windows. Cascades of new test vane profiles are quickly machined and tested, with a fast turn-around for comparative studies.

A new Schlieren photography lens arrangement is demonstrated, which captures numerous flow visualization images per run directly into a digital SLR camera.

Lower-than-atmospheric exhaust pressures were achieved by using a long exhaust designed to maximize exit flow dynamic pressure recovery using the self-ejector pumping effect. Exhaust pressures as low as 0.7 bar were achieved using the self-pumping exhaust, allowing M up to 1.6 with 3 bar inlet pressure and an exhaust at atmospheric pressure. An analytical model is developed for the mildly supersonic exit flow condition and validated against experimental data. Excellent agreement is achieved.

Results presented for a typical transonic cascade show that the tunnel performs well in the subsonic and low supersonic region, but, as the exit M increases, shock-wave reflections from the free jet boundary, seen on the Schlieren, cause non-periodicity. Deep in the cascade, the flow is still periodic and can be used for investigations of loss and shock boundary-layer interaction. Interestingly, if the downstream pressure is reduced further to give even higher (but unrealistic) M, the cascade becomes axially supersonic and excellent periodicity is restored.

Schlieren results are compared with computational fluid dynamics (CFD) simulations of the tunnel flow, and the loss measurements are validated against measurements conducted using a large-scale cascade at Göttingen.
Effect of a behavioural health and specialty care telemedicine programme on goal attainment for youths in juvenile detention
Authors: Fox Karen C , Connor Pamela , McCullers Elizabeth , Waters Teresa
Published: July 2008

We conducted a pre-post study of the effect of a telepsychiatry counselling service on youths housed in three juvenile detention facilities. In the first year of the telemedicine programme, 321 psychiatry consultations were conducted via telemedicine; in the second year of the programme, 573 psychiatry consultations were conducted. Records for 190 students were then examined by two raters. The total number of behavioural goals for each adolescent increased from 8.2 in the pre-telemedicine year to 8.7 in the first year of telemedicine and then to 10.0 in the second year ( P < 0.05). In Year 2 of the study, subjects also had a significantly higher number of goals in four of the five categories: education, family, health and social skills ( P < 0.05). Although other changes at the youth detention facilities or in the juvenile justice system may have been partly responsible for the effects observed, the study suggests that telemedicine may be useful for improving the rate of attainment of goals associated with family relations and personality/behaviour.
The use of videoconferencing for mental health services in Finland
Authors: Ohinmaa Arto , Roine Risto , Hailey David , Kuusimäki Marja-Leena , Winblad Ilkka
Published: July 2008

The utilization of telemental health (TMH) services in Finland was surveyed in 2006. In total, 135 health-care units provided responses. Eighty-four responses were received from primary care units (health-care centres and clinics) and eight from other clinics, in all hospital districts. The overall rate of TMH consultations was 4 per 100,000 population. The highest TMH consultation per population ratio, 22 per 100,000, was in northern Finland. Most of the sites used telepsychiatry services for less than 10% of clinical outpatient services. The sites with over 20% utilization of clinical TMH services from all psychiatric consultations were all rural health centres. Compared with Finland, the utilization rates of TMH were higher in Canada; that might be due to differences between the countries in the organization of mental health services in primary and specialized care. In Finland TMH consultations made up only a very small proportion of all mental health services. The use of TMH was particularly common in remote areas; however, there were many rural centres that did not utilize clinical TMH. TMH was widely utilized for continuing and medical education.
A paediatric therapeutic alliance occurs with distance intervention
Authors: Lingley-Pottie Patricia , McGrath Patrick J
Published: July 2008

We investigated whether a distance therapeutic alliance occurs when children receive manualized, cognitive-behavioural treatment via telephone, in the absence of face-to-face contact. The therapeutic alliance scores were measured in 55 child–parent pairs. The mean total Working Alliance Inventory child scores were 236 (95% confidence interval [CI]: 232, 240) and the mean parent scores were 245 (95% CI: 242, 247). Parent scores were significantly higher than child scores, although the difference may not be clinically meaningful. This study provides evidence that a strong therapeutic alliance does occur between child–coach and parent–coach pairs when treatment is delivered from a distance by non-professionals. The term ‘child’ encompasses both children and adolescents.
Feasibility of a home-based telerehabilitation system compared to usual care: arm/hand function in patients with stroke, traumatic brain injury and multiple sclerosis
Authors: Huijgen Barbara CH , Vollenbroek-Hutten Miriam MR , Zampolini Mauro , Opisso Eloy , Bernabeu Montse , Van Nieuwenhoven Johan , Ilsbroukx Stephan , Magni Riccardo , Giacomozzi Claudia , Marcellari Velio , Marchese Sandro Scattareggia , Hermens Hermie J
Published: July 2008

We conducted a randomized controlled multicentre trial to investigate the feasibility of a telerehabilitation intervention for arm/hand function (the Home Care Activity Desk [HCAD] training) in a home setting. Usual care was compared to HCAD training. The hypothesis was that the clinical outcomes of the HCAD intervention would be at least the same as those measured after a period of usual care for patients with stroke, traumatic brain injury (TBI) and multiple sclerosis (MS) with respect to their arm/hand function. Eighty-one patients with affected arm/hand function resulting from either stroke, MS or TBI were recruited in Italy, Spain and Belgium; 11 were lost during follow-up (14%). The outcome measures were the Action Research Arm Test (ARAT) and the Nine Hole Peg Test (NHPT). There were no significant differences between the two groups on the outcome measures (ARAT and NHPT); in both groups, patients maintained or even improved their arm/hand function. The HCAD training was found to be as feasible as usual care in terms of clinical outcomes, and both therapists and patients were satisfied with the HCAD intervention. A telerehabilitation intervention using HCAD may increase the efficiency of care.
International telepsychiatry: a study of patient acceptability
Authors: Mucic Davor
Published: July 2008

An international telepsychiatry service was established between Denmark and Sweden for cross-cultural patient groups, such as asylum seekers, refugees and migrants. Over an 18-month period starting in mid 2006, 30 patients were treated by telepsychiatry (21 men and 9 women). The patients received mental health care by videoconferencing from providers who spoke the patients' own language, i.e. without the assistance of interpreters. The total number of telepsychiatry sessions was 203 (range 1–22; average 6.8 sessions per patient). Patients completed a satisfaction questionnaire at the end of treatment. Seven patients (23%) were not able to complete a questionnaire, due to illiteracy and/or a psychotic condition. The rest of the patients ( n=23) reported a high level of acceptance and satisfaction with telepsychiatry, as well as a willingness to use it again or recommend it to others. Any disadvantages of telemedicine were compensated by the fact that the doctor and patient spoke the same language and had similar cultural and/or national references. Mentally ill asylum seekers, refugees and migrants are under-served in their mother tongue and telepsychiatry can improve access to scarce health-care resources.
Use of mobile phone cameras for after-hours triage in primary care
Authors: Jayaraman Chandra , Kennedy Paul , Dutu Gaelle , Lawrenson Ross
Published: July 2008

Mobile phone images might be useful in after-hours triage of primary care. We conducted a study to identify population access to mobile phone cameras and to assess the clinical usefulness of mobile phone cameras. The survey was conducted among 480 patients attending two rural New Zealand practices. There were significantly more Maori owners compared to non-Maori ( P = 0.002). Age was a significant factor influencing the ownership of mobile phones. We also conducted a clinical quiz among health professionals to assess how the provision of images on a mobile phone and on CD-ROM (to simulate the image that would be seen if email was used to transmit the images) influenced diagnostic confidence. Ten photographable clinical conditions were used to quiz 30 health professionals who were randomized into three groups of 10 each on diagnostic confidence. Images were found to significantly increase diagnostic confidence in all cases except one. It appears that mobile phone cameras are generally acceptable to patients and likely to be of practical use to rural practitioners in a range of clinical scenarios.
Satisfaction with care in post-stroke patients undergoing a telerehabilitation programme at home
Authors: Piron Lamberto , Turolla Andrea , Tonin Paolo , Piccione Francesco , Lain Lisa , Dam Mauro
Published: July 2008

We conducted a pilot telerehabilitation study with post-stroke patients with arm motor impairment. We compared the degree of satisfaction of patients undergoing a virtual reality (VR) therapy programme at home (Tele-VR group) to satisfaction experienced by those undergoing the same VR therapy in a hospital setting (VR-group). The rehabilitation equipment used a 3D motion tracking system to create a virtual environment in which the patient's movement was represented. In tele-therapy, the patient equipment was installed in their homes, connected to the hospital by four ISDN lines at a total bandwidth of 512 kbit/s. Rehabilitation data were transmitted via one line and videoconferencing via the other three. Ten patients with mild to intermediate arm motor impairment due to an ischaemic stroke, were randomized into VR or Tele-VR groups. A questionnaire was used at the end of treatment to measure each patient's degree of satisfaction. Tele-VR treated patients showed median values equal to or higher than the VR group patients in all 12 items investigated, except one. In motor performance, the Tele-VR group improved significantly ( P ≤ 0.05), while the VR group showed no significant change. Patients assigned to the Tele-VR group were able to engage in therapy at home and the videoconferencing system ensured a good relationship between the patient and the physical therapist whose physical proximity was not required.
Caregivers' acceptance of electronic documentation in nursing homes
Authors: Yu Ping , Hailey David , Li Haocheng
Published: July 2008

A comparative study was conducted in two Australian nursing homes operated by the same organization. One home had implemented an electronic documentation system and the other remained paper-based. Survey questionnaires were answered by 14 of the 17 caregivers at the electronic documentation site (82%) and 10 of the 23 caregivers at the paper documentation site (43%). They provided opinions about satisfaction with their home's documentation system, and the training and support provided. Information was also obtained on the caregivers' attitudes towards using electronic documentation. The caregivers at the electronic documentation site quickly adapted to the use of the new technology after receiving effective training and support. Caregivers at both homes were satisfied with their homes' documentation system, and had positive attitudes towards using electronic documentation systems. As an important communication tool, electronic nursing documentation may lead to improved efficacy of telemedicine in nursing home settings.
Acetaminophen Overdose with Altered Acetaminophen Pharmacokinetics and Hepatotoxicity Associated with Premature Cessation of Intravenous N-Acetylcysteine Therapy
Authors: Smith Silas W , Howland Mary Ann , Hoffman Robert S , Nelson Lewis S
Published: July 2008

Objective

To report a case of erratic absorption, double peak serum concentrations, and hepatotoxicity following premature cessation of intravenous N-acetylcysteine (NAC) treatment in the setting of a massive acetaminophen overdose.

Case Summary:

A 78-year-old man reportedly ingested approximately 96 immediate-release acetaminophen 500-mg tablets (48 g) over a one-hour period in an apparent suicide attempt. The acetaminophen concentration at 2.25 hours was 264 μg/mL. Intravenous NAC was initiated 5 hours postingestion. At 6.25 hours postingestion, the acetaminophen concentration was 281 μg/mL. Following administration of intravenous NAC for 21 hours, therapy was discontinued despite a residual acetaminophen concentration of 116 μg/mL. The patient experienced hepatotoxicity, coagulopathy, and renal injury. Pharmacokinetic analysis revealed significantly prolonged acetaminophen absorption and a second peak acetaminophen concentration of 228 μg/mL approximately 48 hours post ingestion. Direct in-hospital monitoring of the patient made a second ingestion unlikely.

Discussion:

Acetaminophen overdose is usually effectively managed with NAC. Patients with massive ingestions may have altered absorption kinetics due to acetaminophen's solubility being exceeded, physiologically or chemically altered gastrointestinal emptying or motility, or other factors. These patients may benefit from gastrointestinal decontamination and prolonged NAC therapy.

Conclusions:

In patients with massive acetaminophen ingestion, erratic absorption may occur, and toxic serum concentrations may persist beyond a standard 21–hour course of intravenous NAC therapy. Acetaminophen concentrations and aminotransferase levels should be evaluated at the completion of the intravenous NAC infusion to ensure complete elimination of acetaminophen and absence of hepatotoxicity and to exclude the need lor prolonged treatment.
Association Between Selective Serotonin-Reuptake Inhibitors, Second-Generation Antipsychotics, and Neuroleptic Malignant Syndrome
Authors: Stevens Debra L
Published: July 2008

Objective

To review the published reports of neuroleptic malignant syndrome (NMS) associated with the use of selective serotonin-reuptake inhibitors (SSRIs) and second-generation antipsychotics.

Data Source:

Information was selected from a MEDLINE search of English-language literature (1950–May 2008). Manual search of all published cases indexed in MEDLINE (English language only) of NMS associated with second-generation antipsychotics was also performed.

Study Selection And Data Extraction:

Pertinent information from all reports obtained was included, with specific emphasis on patient age, sex, second-generation antipsychotic involved, SSRI or other antidepressant involved, time of onset of NMS symptoms in relation to medication changes, treatment administered, and outcome of the reaction.

Data Synthesis:

NMS has been reported with every second-generation antipsychotic agent. It is unclear whether concomitant therapy with other agents may increase the risk of NMS development via pharmacodynamic or pharmacokinetic mechanisms or both, The suggested pharmacodynamic mechanism for increased risk of NMS with concomitant use of SSRIs is the effect of serotonin on dopamine release. Serotonin further inhibits dopamine release and thereby may worsen a hypodopaminergic state induced by antipsychotics. Pharmacokinetic factors may also play a role in some NMS cases involving an SSRI by increasing antipsychotic concentrations. An examination of case reports seems to indícale that at least in some casos, a temporal relationship exists with the addition of an SSRI to existing antipsychotic therapy.

Conclusions:

The use of SSRIs may be associated with an increased risk of NMS development in (hose receiving second-generation antipsychotics. Clinicians should closely monitor patients for the potential development of NMS.
Racial Differences in Sleep Medication Use: A Cross-Sectional Study of the Johnston County Osteoarthritis Project
Authors: Allen Kelli D , Renner Jordan B , DeVellis Brenda , Helmick Charles G , Jordan Joanne M
Published: July 2008

Background

Little is known about racial differences in the use of sleep medications.

Objectives:

To compare sleep medication use among African Americans and whites with self-reported current sleep problems.

Methods

Participants were 1910 individuals (69% female. 34% African American, 66% white) from the Johnston County Osteoarthritis Project. We examined racial differences in self-reported current use of prescription, nonprescription, herbal, and other medications for sleep. Muitivariable logistic regression models controlled for age, sex, education, health insurance, symptomatic hip or knee osteoarthritis, depressive symptoms, obesity, fair or poor general health, and self-reported annual days of sleep problems. Models were conducted separately for the whole sample and for men and women.

Results:

Among participants with current sleep problems, 31% were using one or more types of sleep medication: 17% prescription, 12% nonprescription, 1% herbal, and 3% other products. African Americans were less likely than whites to be using any sleep medication (25% vs 35%; p < 0.001), prescription sleep medication (14% vs 19%; p = 0.003), and nonprescription sleep medication (10% vs 13%; p = 0.048). These racial differences persisted in multivariable models. In sex-stratified analyses, there were significant racial differences in sleep medication use only among women.

Conclusions:

African Americans were less likely than whites to report current use of prescription and nonprescription sleep medications; those results appeared to be largely driven by racial differences among women. Additional research should study possible underlying factors and determine whether these racial differences impact clinical outcomes.
Hedgehog Signaling Regulates Sensory Cell Formation and Auditory Function in Mice and Humans
Authors: Driver Elizabeth Carroll , Pryor Shannon P. , Hill Patrick , Turner Joyce , Rüther Ulrich , Biesecker Leslie G. , Griffith Andrew J. , Kelley Matthew W.
Published: July 2008

Auditory perception is mediated through a finite number of mechanosensory hair cells located in a specialized sensory epithelium within the inner ear. The formation of the appropriate number of hair cells and the location of those cells is crucial for normal auditory function. However, the factors that regulate the formation of this epithelium remain poorly understood. Truncating mutations in the transcription factorGLI3, a downstream effector of the Hedgehog (HH) pathway, lead to a partial loss of HH signaling and cause Pallister-Hall syndrome (PHS). Here, we report that cochleae from a mouse model of PHS (Gli3Δ699), which produces only the truncated, repressor form of GLI3, have a variably penetrant phenotype that includes an increase in the size of the sensory epithelium and the development of large ectopic sensory patches in Kölliker's organ (KO). Consistent with the mouse model, some PHS individuals exhibit hearing loss across a broad range of frequencies. Moreover, inhibition of HH signalingin vitroresults in an increase in the size of the prosensory domain, a precursor population that gives rise to the sensory epithelium, whereas treatment with Sonic hedgehog (SHH) inhibits prosensory formation. Finally, we demonstrate that HH signaling within the cochlea regulates expression of prosensory markers and that the effects of HH in KO are dependent on activation of Notch, an inducer of prosensory fate. These results suggest that HH signaling plays a key role in the specification, size, and location of the prosensory domain, and therefore of hair cells, within the cochlea.
The Time Course of Transmitter at Glycinergic Synapses onto Motoneurons
Authors: Beato Marco
Published: July 2008

The concentration of transmitter in the synaptic cleft and its clearance time are one of the main determinants of synaptic strength. We estimated the time course of glycine at rat lumbar motoneurons synapses in spinal cord slices by recording synaptic currents in the presence of a low-affinity competitive antagonist at glycine receptors [2-(3-carboxypropyl)-3-amino-6-(4-methoxyphenyl)pyridazinium (SR-95531)]. Data were analyzed by using the established activation mechanism for glycine receptors and our measurements of SR-95531 binding rates. We show that this technique alone is not sufficient to determine simultaneously the peak concentration of transmitter and its clearance time. However, we found that block of the glial glycine transporter prolongs the glycine transient. This observation puts additional constraints on the range of possible values of the time course of glycine, indicating that glycine reaches a peak concentration of 2.2–3.5 mmand is cleared from the cleft with a time constant of 0.6–0.9 ms.
Nogo-A and Myelin-Associated Glycoprotein Differently Regulate Oligodendrocyte Maturation and Myelin Formation
Authors: Pernet Vincent , Joly Sandrine , Christ Franziska , Dimou Leda , Schwab Martin E.
Published: July 2008

Nogo-A is one of the most potent oligodendrocyte-derived inhibitors for axonal regrowth in the injured adult CNS. However, the physiological function of Nogo-A in development and in healthy oligodendrocytes is still unknown. In the present study, we investigated the role of Nogo-A for myelin formation in the developing optic nerve. By quantitative real-time PCR, we found that the expression of Nogo-A increased faster in differentiating oligodendrocytes than that of the major myelin proteins MBP (myelin basic protein), PLP (proteolipid protein)/DM20, and CNP (2′,3′-cyclic nucleotide 3′-phosphodiesterase). The analysis of optic nerves and cerebella of mice deficient for Nogo-A (Nogo-A−/−) revealed a marked delay of oligodendrocyte differentiation, myelin sheath formation, and axonal caliber growth within the first postnatal month. The combined deletion of Nogo-A and MAG caused a more severe transient hypomyelination. In contrast to MAG−/−mice, Nogo-A−/−mutants did not present abnormalities in the structure of myelin sheaths and Ranvier nodes. The common binding protein for Nogo-A and MAG, NgR1, was exclusively upregulated in MAG−/−animals, whereas the level of Lingo-1, a coreceptor, remained unchanged. Together, our results demonstrate that Nogo-A and MAG are differently involved in oligodendrocyte maturationin vivo, and suggest that Nogo-A may influence also remyelination in pathological conditions such as multiple sclerosis.
Fluorescence Changes of Genetic Calcium Indicators and OGB-1 Correlated with Neural Activity and CalciumIn VivoandIn Vitro
Authors: Hendel Thomas , Mank Marco , Schnell Bettina , Griesbeck Oliver , Borst Alexander , Reiff Dierk F.
Published: July 2008

Recent advance in the design of genetically encoded calcium indicators (GECIs) has further increased their potential for direct measurements of activity in intact neural circuits. However, a quantitative analysis of their fluorescence changes (ΔF)in vivoand the relationship to the underlying neural activity and changes in intracellular calcium concentration (Δ[Ca2+]i) has not been given. We used two-photon microscopy, microinjection of synthetic Ca2+dyes andin vivocalibration of Oregon-Green-BAPTA-1 (OGB-1) to estimate [Ca2+]iat rest and Δ[Ca2+]iat different action potential frequencies in presynaptic motoneuron boutons of transgenicDrosophilalarvae. We calibrated ΔFof eight different GECIsin vivoto neural activity, Δ[Ca2+]i, and ΔFof purified GECI protein at similar Δ[Ca2+]in vitro. Yellow Cameleon 3.60 (YC3.60), YC2.60, D3cpv, and TN-XL exhibited twofold higher maximum ΔFcompared with YC3.3 and TN-L15in vivo. Maximum ΔFof GCaMP2 and GCaMP1.6 were almost identical. Small Δ[Ca2+]iwere reported best by YC3.60, D3cpv, and YC2.60. The kinetics of Δ[Ca2+]iwas massively distorted by all GECIs, with YC2.60 showing the slowest kinetics, whereas TN-XL exhibited the fastest decay. Single spikes were only reported by OGB-1; all GECIs were blind for Δ[Ca2+]iassociated with single action potentials. YC3.60 and D3cpv tentatively reported spike doublets.In vivo, theKD(dissociation constant) of all GECIs was shifted toward lower values, the Hill coefficient was changed, and the maximum ΔFwas reduced. The latter could be attributed to resting [Ca2+]iand the optical filters of the equipment. These results suggest increased sensitivity of new GECIs but still slow on rates for calcium binding.
Cortical Action Potential Backpropagation Explains Spike Threshold Variability and Rapid-Onset Kinetics
Authors: Yu Yuguo , Shu Yousheng , McCormick David A.
Published: July 2008

Neocortical action potential responsesin vivoare characterized by considerable threshold variability, and thus timing and rate variability, even under seemingly identical conditions. This finding suggests that cortical ensembles are required for accurate sensorimotor integration and processing. Intracellularly, trial-to-trial variability results not only from variation in synaptic activities, but also in the transformation of these into patterns of action potentials. Through simultaneous axonal and somatic recordings and computational simulations, we demonstrate that the initiation of action potentials in the axon initial segment followed by backpropagation of these spikes throughout the neuron results in a distortion of the relationship between the timing of synaptic and action potential events. In addition, this backpropagation also results in an unusually high rate of rise of membrane potential at the foot of the action potential. The distortion of the relationship between the amplitude time course of synaptic inputs and action potential output caused by spike backpropagation results in the appearance of high spike threshold variability at the level of the soma. At the point of spike initiation, the axon initial segment, threshold variability is considerably less. Our results indicate that spike generation in cortical neurons is largely as expected by Hodgkin–Huxley theory and is more precise than previously thought.
Presynaptic and Postsynaptic Amplifications of Neuropathic Pain in the Anterior Cingulate Cortex
Authors: Xu Hui , Wu Long-Jun , Wang Hansen , Zhang Xuehan , Vadakkan Kunjumon I. , Kim Susan S. , Steenland Hendrik W. , Zhuo Min
Published: July 2008

Neuropathic pain is caused by a primary lesion or dysfunction in the nervous system. Investigations have mainly focused on the spinal mechanisms of neuropathic pain, and less is known about cortical changes in neuropathic pain. Here, we report that peripheral nerve injury triggered long-term changes in excitatory synaptic transmission in layer II/III neurons within the anterior cingulate cortex (ACC). Both the presynaptic release probability of glutamate and postsynaptic glutamate AMPA receptor-mediated responses were enhanced after injury using the mouse peripheral nerve injury model. Western blot showed upregulated phosphorylation of GluR1 in the ACC after nerve injury. Finally, we found that both presynaptic and postsynaptic changes after nerve injury were absent in genetic mice lacking calcium-stimulated adenylyl cyclase 1 (AC1). Our studies therefore provide direct integrative evidence for both long-term presynaptic and postsynaptic changes in cortical synapses after nerve injury, and that AC1 is critical for such long-term changes. AC1 thus may serve as a potential therapeutic target for treating neuropathic pain.
Small-Molecule Protein Tyrosine Phosphatase Inhibition as a Neuroprotective Treatment after Spinal Cord Injury in Adult Rats
Authors: Nakashima Shojiro , Arnold Sheila A. , Mahoney Edward T. , Sithu Srinivas D. , Zhang Y. Ping , D'Souza Stanley E. , Shields Christopher B. , Hagg Theo
Published: July 2008

Spinal cord injury causes progressive secondary tissue degeneration, leaving many injured people with neurological disabilities. There are no satisfactory neuroprotective treatments. Protein tyrosine phosphatases inactivate neurotrophic factor receptors and downstream intracellular signaling molecules. Thus, we tested whether the peroxovanadium compound potassium bisperoxo(1,10-phenanthroline)oxovanadate (V) [bpV(phen)], a stable, potent and selective protein tyrosine phosphatase inhibitor, would be neuroprotective after a thoracic spinal cord contusion in adult rats. Intrathecal bpV(phen) infusions through a lumbar puncture rescued dorsal column sensory axons innervating the nucleus gracilis and white matter at the injury epicenter. At the most effective dose, essentially all of these axons and most of the white matter at the epicenter were spared (vs ∼60% with control infusions). bpV(phen) treatments started 4 h after contusion were fully effective. This treatment greatly improved and normalized sensorimotor function in a grid-walking test and provided complete axonal protection over 6 weeks. The treatment rescued sensory-evoked potentials that disappeared after dorsal column transection. bpV(phen) affected early degenerative mechanisms, because the main effects were seen at 7 d and lasted beyond the treatment period. The neuroprotection appeared to be mediated by rescue of blood vessels. bpV(phen) reduced apoptosis of cultured endothelial cells. These results show that a small molecule, used in a clinically relevant manner, reduces loss of long-projecting axons, myelin, blood vessels, and function in a model relevant to the most common type of spinal cord injury in humans. They reveal a novel mechanism of spinal cord degeneration involving protein tyrosine phosphatases that can be targeted with therapeutic drugs.
SCLIP Is Crucial for the Formation and Development of the Purkinje Cell Dendritic Arbor
Authors: Poulain Fabienne E. , Chauvin Stéphanie , Wehrlé Rosine , Desclaux Mathieu , Mallet Jacques , Vodjdani Guilan , Dusart Isabelle , Sobel André
Published: July 2008

Cerebellar Purkinje cells elaborate one of the most complex dendritic arbors among neurons to integrate the numerous signals they receive from the cerebellum circuitry. Their dendritic differentiation undergoes successive, tightly regulated phases of development involving both regressive and growth events. Although many players regulating the late phases of Purkinje cell dendritogenesis have been identified, intracellular factors controlling earlier phases of dendritic development remain mostly unknown. In this study, we explored the biological properties and functions of SCLIP, a protein of the stathmin family, in Purkinje cell dendritic differentiation and cerebellum development. Unlike the other stathmins, SCLIP is strongly expressed in Purkinje cells during cerebellar development and accumulates in their dendritic processes at a critical period of their formation and outgrowth. To reveal SCLIP functions, we developed a lentiviral-mediated approach on cerebellar organotypic cultures to inhibit or increase its expression in Purkinje cells in their tissue environment. Depletion of SCLIP promoted retraction of the Purkinje cell primitive process and then prevented the formation of new dendrites at early stages of postnatal development. It also prevented their elongation and branching at later phases of differentiation. Conversely, SCLIP overexpression promoted dendritic branching and development. Together, our results demonstrate for the first time that SCLIP is crucial for both the formation and proper development of Purkinje cell dendritic arbors. SCLIP appears thus as a novel and specific factor that controls the early phases of Purkinje cell dendritic differentiation during cerebellum development.
Salicylate Enables Cochlear Arachidonic-Acid-Sensitive NMDA Receptor Responses
Authors: Ruel Jérôme , Chabbert Christian , Nouvian Régis , Bendris Rim , Eybalin Michel , Leger Claude Louis , Bourien Jérôme , Mersel Marcel , Puel Jean-Luc
Published: July 2008

Currently, many millions of people treated for various ailments receive high doses of salicylate. Consequently, understanding the mechanisms by which salicylate induces tinnitus is an important issue for the research community. Behavioral testing in rats have shown that tinnitus induced by salicylate or mefenamate (both cyclooxygenase blockers) are mediated by cochlear NMDA receptors. Here we report that the synapses between the sensory inner hair cells and the dendrites of the cochlear spiral ganglion neurons express NMDA receptors. Patch-clamp recordings and two-photon calcium imaging demonstrated that salicylate and arachidonate (a substrate of cyclooxygenase) enabled the calcium flux and the neural excitatory effects of NMDA on cochlear spiral ganglion neurons. Salicylate also increased the arachidonate content of the whole cochleain vivo. Single-unit recordings of auditory nerve fibers in adult guinea pig confirmed the neural excitatory effect of salicylate and the blockade of this effect by NMDA antagonist. These results suggest that salicylate inhibits cochlear cyclooxygenase, which increased levels of arachidonate. The increased levels of arachidonate then act on NMDA receptors to enable NMDA responses to glutamate that inner hair cells spontaneously release. This new pharmacological profile of salicylate provides a molecular mechanism for the generation of tinnitus at the periphery of the auditory system.
Frequency-Dependent Glycinergic Inhibition Modulates Plasticity in Hippocampus
Authors: Keck Tara , Lillis Kyle P. , Zhou Yu-Dong , White John A.
Published: July 2008

Previous studies have demonstrated the presence of functional glycine receptors (GlyRs) in hippocampus. In this work, we examine the baseline activity and activity-dependent modulation of GlyRs in region CA1. We find that strychnine-sensitive GlyRs are open in the resting CA1 pyramidal cell, creating a state of tonic inhibition that “shunts” the magnitude of EPSPs evoked by electrical stimulation of the Schaffer collateral inputs. This GlyR-mediated shunting conductance is independent of the presynaptic stimulation rate; however, pairs of presynaptic and postsynaptic action potentials, repeated at frequencies above 5 Hz, reduce the GlyR-mediated conductance and increase peak EPSP magnitudes to levels at least 20% larger than those seen with presynaptic stimulation alone. We refer to this phenomenon as rate-dependent efficacy (RDE). Exogenous GlyR agonists (glycine, taurine) block RDE by preventing the closure of postsynaptic GlyRs. The GlyR antagonist strychnine blocks postsynaptic GlyRs under all conditions, occluding RDE. During RDE, GlyRs are less responsive to local glycine application, suggesting that a reduction in the number or sensitivity of membrane-inserted GlyRs underlies RDE. By extending the RDE induction protocol to include 500 paired presynaptic and postsynaptic spikes, we can induce long-term synaptic depression (LTD). Manipulations that lead to reduced functionality of GlyRs, either pharmacologically or through RDE, also lead to increased LTD. This result suggests that RDE contributes to long-term synaptic plasticity in the hippocampus.
Der Gegenschlag der Ärztezunft? Medizin und Poesie in Tat'jana Tolstajas Erzählung „Poėt i muza”
Authors: Henseler Daniel
Published: July 2008

This article looks at Tatyana Tolstaya's short story Poėt i muza (1986). Tolstaya conceptualizes her story as a commentary to Pushkin's poem Ja pamjatnik sebe vozdvig nerukotvornyj (1836) and thus presents her own conception of the immortality of the poet. As my contribution argues, Poėt i muza also refers to Anton Chekhov's story Poprygun'ja (1892). Both references, those to Pushkin and those to Chekhov, shed light on a topic of Tolstaya's story that has been little researched so far: this is the clash of the world of arts (i. e., poetry) with the world of sciences (medicine). In Chekhov's as well as in Tolstaya's work this conflict erupts in a marriage, with an artist and a doctor being the respective participants.
Phantastische Objekte. Stanisław Lems Beitrag zur Semantik1
Authors: Kuße Holger
Published: July 2008

Being an empiricist, Lem advocated an extensional semantics, a fundamental aspect of which is the distinction between designata with and designata without an empirical extension (pol. nazwy puste). The latter include fantastic objects, such as flying snails, dwarves, computers that hypnotise etc. Referring to Lem's classification of the Fantastic, the paper raises the question of the possibility and usefulness of creating terms that are not empirically extensional, which is the main question in the theory of language and communication in Lem's theoretical publications as well as in his works of fiction. Since Lem saw definitions of such terms in texts (of any length), and since the meaning of a text always depends on the situation in which it is embedded, Lem's semantics can be described as partial contextualism. Linguistic signs are considered being representations of facts and objects in the world. But they represent extra-linguistic facts always in pragmatic situations (contexts). And the overall pragmatic situation determines the possibilities and limitations of the production and reception of signs and meanings. Against this background, dealing with fantastic objects as part of literature meant for Lem pacing out the borders of communication.
The Writing of Paranoia: Jean-Jacques Rousseau and the Paradoxes of Celebrity
Authors: Lilti Antoine
Published: July 2008

This article proposes a historical account of Rousseau's paranoid writings by showing how he experienced the contradictions of celebrity, which deeply transformed his status as a writer and his relations with readers. It thus stresses some hitherto unnoticed paradoxes of the eighteenthcentury public sphere.