bluuebunny/crossref_metadata_2025 huggingface dataset:
Two alternative recessive quantitative trait loci influence resistance to spring black stem and leaf spot in Medicago truncatula
Authors: Kamphuis Lars G , Lichtenzveig Judith , Oliver Richard P , Ellwood Simon R
Published: March 2008

Background

Knowledge of the genetic basis of plant resistance to necrotrophic pathogens is incomplete and has been characterised in relatively few pathosystems. In this study, the cytology and genetics of resistance to spring black stem and leaf spot caused by Phoma medicaginis, an economically important necrotrophic pathogen of Medicago spp., was examined in the model legume M. truncatula.

Results

Macroscopically, the resistant response of accession SA27063 was characterised by small, hypersensitive-like spots following inoculation while the susceptible interaction with accessions A17 and SA3054 showed necrotic lesions and spreading chlorosis. No unique cytological differences were observed during early infection (<48 h) between the resistant and susceptible genotypes, except pathogen growth was restricted to one or a few host cells in SA27063. In both interactions reactive oxygen intermediates and phenolic compounds were produced, and cell death occurred. Two F2 populations segregating for resistance to spring black stem and leaf spot were established between SA27063 and the two susceptible accessions, A17 and SA3054. The cross between SA27063 and A17 represented a wider cross than between SA27063 and SA3054, as evidenced by higher genetic polymorphism, reduced fertility and aberrant phenotypes of F2 progeny. In the SA27063 × A17 F2 population a highly significant quantitative trait locus (QTL, LOD = 7.37; P < 0.00001) named resistance to the necrotroph
P

homa

m

edicaginis one (rnpm1) genetically mapped to the top arm of linkage group 4 (LG4). rnpm1 explained 33.6% of the phenotypic variance in the population's response to infection depicted on a 1–5 scale and was tightly linked to marker AW256637. A second highly significant QTL (LOD = 6.77; P < 0.00001), rnpm2, was located on the lower arm of LG8 in the SA27063 × SA3054 map. rnpm2 explained 29.6% of the phenotypic variance and was fine mapped to a 0.8 cM interval between markers h2_16a6a and h2_21h11d. rnpm1 is tightly linked to a cluster of Toll/Interleukin1 receptor-nucleotide binding site-leucine-rich repeat (TIR-NBS-LRR) genes and disease resistance protein-like genes, while no resistance gene analogues (RGAs) are apparent in the genomic sequence of the reference accession A17 at the rnpm2 locus.

Conclusion

The induction of defence responses and cell death in the susceptible interaction following infection by P. medicaginis suggested this pathogen is not negatively affected by these responses and may promote them. A QTL for resistance was revealed in each of two populations derived from crosses between a resistant accession and two different susceptible accessions. Both loci are recessive in nature, and the simplest explanation for the existence of two separate QTLs is the occurrence of host genotype-specific susceptibility loci that may interact with undetermined P. medicaginis virulence factors.
The use of advanced tracking technologies for the analysis of mobility in Alzheimer's disease and related cognitive diseases
Authors: Shoval Noam , Auslander Gail K , Freytag Tim , Landau Ruth , Oswald Frank , Seidl Ulrich , Wahl Hans-Werner , Werner Shirli , Heinik Jeremia
Published: March 2008

Background

One of the more common behavioral manifestations of dementia-related disorders is severe problems with out-of-home mobility. Various efforts have been attempted to attain a better understanding of mobility behavior, but most studies are based on institutionalized patients and the assessment usually relies on reports of caregivers and institutional staff, using observational approaches, activity monitoring, or behavioral checklists. The current manuscript describes the research protocol of a project that measures mobility in Alzheimer's disease and related cognitive disorders in an innovative way, by taking advantage of advanced tracking technologies.

Methods/design

Participants are 360 demented persons, mildly cognitively impaired persons, and unimpaired controls aged ≥ 65 in Israel and Germany. Data regarding space-time activities will be collected via a GPS tracking kit for a period of 4 weeks in 3 waves (one year apart) with the same participants (using a repeated measures design). Participants will be interviewed by use of a battery of instruments prior to and following GPS data collection. Further, a family member will complete a questionnaire both before and after data tracking.

Statistical analyses will strive to explain differences in mobility based on a wide range of socio-structural, clinical, affect-related and environmental variables. We will also assess the impact of the use of advanced tracking technology on the quality of life of dementia patients and care givers, as well as its potential as a diagnostic tool. Systematic assessment of ethical issues involved in the use of tracking technology will be an integral component of the project.

Discussion

This project will be able to make a substantial contribution to basic as well as applied and clinical aspects in the area of mobility and cognitive impairment research. The innovative technologies applied in this study will allow for assessing a range of dimensions of out-of-home mobility, and provide better quality data.
Gene targeting in adult rhesus macaque fibroblasts
Authors: Meehan Daniel T , Zink Mary Ann , Mahlen Melissa , Nelson Marilu , Sanger Warren G , Mitalipov Shoukhrat M , Wolf Don P , Ouellette Michel M , Norgren Robert B
Published: March 2008

Background

Gene targeting in nonhuman primates has the potential to produce critical animal models for translational studies related to human diseases. Successful gene targeting in fibroblasts followed by somatic cell nuclear transfer (SCNT) has been achieved in several species of large mammals but not yet in primates. Our goal was to establish the protocols necessary to achieve gene targeting in primary culture of adult rhesus macaque fibroblasts as a first step in creating nonhuman primate models of genetic disease using nuclear transfer technology.

Results

A primary culture of adult male fibroblasts was transfected with hTERT to overcome senescence and allow long term in vitro manipulations. Successful gene targeting of the HPRT locus in rhesus macaques was achieved by electroporating S-phase synchronized cells with a construct containing a SV40 enhancer.

Conclusion

The cell lines reported here could be used for the production of null mutant rhesus macaque models of human genetic disease using SCNT technology. In addition, given the close evolutionary relationship and biological similarity between rhesus macaques and humans, the protocols described here may prove useful in the genetic engineering of human somatic cells.
Developmental patterning of glutamatergic synapses onto retinal ganglion cells
Authors: Morgan Josh L , Schubert Timm , Wong Rachel OL
Published: March 2008

Background

Neurons receive excitatory synaptic inputs that are distributed across their dendritic arbors at densities and with spatial patterns that influence their output. How specific synaptic distributions are attained during development is not well understood. The distribution of glutamatergic inputs across the dendritic arbors of mammalian retinal ganglion cells (RGCs) has long been correlated to the spatial receptive field profiles of these neurons. Thus, determining how glutamatergic inputs are patterned onto RGC dendritic arbors during development could provide insight into the cellular mechanisms that shape their functional receptive fields.

Results

We transfected developing and mature mouse RGCs with plasmids encoding fluorescent proteins that label their dendrites and glutamatergic postsynaptic sites. We found that as dendritic density (dendritic length per unit area of dendritic field) decreases with maturation, the density of synapses along the dendrites increases. These changes appear coordinated such that RGCs attain the mature average density of postsynaptic sites per unit area (areal density) by the time synaptic function emerges. Furthermore, stereotypic centro-peripheral gradients in the areal density of synapses across the arbor of RGCs are established at an early developmental stage.

Conclusion

The spatial pattern of glutamatergic inputs onto RGCs arises early in synaptogenesis despite ensuing reorganization of dendritic structure. We raise the possibility that these early patterns of synaptic distributions may arise from constraints placed on the number of contacts presynaptic neurons are able to make with the RGCs.
Human breast cancer cell lines contain stem-like cells that self-renew, give rise to phenotypically diverse progeny and survive chemotherapy
Authors: Fillmore Christine M , Kuperwasser Charlotte
Published: March 2008

Introduction

The phenotypic and functional differences between cells that initiate human breast tumors (cancer stem cells) and those that comprise the tumor bulk are difficult to study using only primary tumor tissue. We embarked on this study hypothesizing that breast cancer cell lines would contain analogous hierarchical differentiation programs to those found in primary breast tumors.

Methods

Eight human breast cell lines (human mammary epithelial cells, and MCF10A, MCF7, SUM149, SUM159, SUM1315 and MDA.MB.231 cells) were analyzed using flow cytometry for CD44, CD24, and epithelial-specific antigen (ESA) expression. Limiting dilution orthotopic injections were used to evaluate tumor initiation, while serial colony-forming unit, reconstitution and tumorsphere assays were performed to assess self-renewal and differentiation. Pulse-chase bromodeoxyuridine (5-bromo-2-deoxyuridine [BrdU]) labeling was used to examine cell cycle and label-retention of cancer stem cells. Cells were treated with paclitaxol and 5-fluorouracil to test selective resistance to chemotherapy, and gene expression profile after chemotherapy were examined.

Results

The percentage of CD44+/CD24- cells within cell lines does not correlate with tumorigenicity, but as few as 100 cells can form tumors when sorted for CD44+/CD24-/low/ESA+. Furthermore, CD44+/CD24-/ESA+ cells can self-renew, reconstitute the parental cell line, retain BrdU label, and preferentially survive chemotherapy.

Conclusion

These data validate the use of cancer cell lines as models for the development and testing of novel therapeutics aimed at eradicating cancer stem cells.
Experimental evaluation of wrinkling limit diagrams for aluminium alloy 5052 sheets annealed at different temperatures
Authors: Narayanasamy R , Satheeesh J , Narayanan C S
Published: March 2008

The sheet-metal-forming operations are principal processes in the automotive industry. Aluminium alloy 5052 sheet is a widely used material in the automotive industry. With the aim of finding the safe working strains for this metal under various forming processes, a set of wrinkling limit diagrams in terms of strain and strain increment ratios and a forming limit diagram with a wrinkling limit curve superimposed have been constructed for the same sheet metal with 2.0 mm thickness annealed at four different temperatures. It has been found that the onset of wrinkling takes place when the ratio (dε r/dε θ) of strain increments or the ratio (ε r/ε θ) of strain reaches a critical value during the drawing process. Further it was observed that, the higher the annealing temperature, the greater was the safe strain region, because of higher normal anisotropy and strain hardening index values.
Design of a waveform tracking system for a piezoelectric actuator
Authors: Hu Z , Farson D F
Published: March 2008

In this work an adaptive model-based predictive control (AMPC) is designed for high-frequency waveform tracking by a PZT bimorph actuator in industrial vibratory feeding. Since the actuator has a narrow bandwidth and significant dynamic hysteresis, the waveform tracking process contains both linear and non-linear errors and the coupling effect between these two needs to be considered before effective compensation can be implemented to obtain a precise vibration trajectory. In the adaptive control, two parallel loops were employed, a linear compensation loop and a non-linear offset loop, to suppress the hybrid errors and let the error eventually converge to an acceptable level by iteration. Since the system varies much more slowly than the control loops, a quasi-time invariant system is assumed in the modelling process and a single-layer neural network is used to compensate the system floating adaptively. Due to the fact that in this application the smoothness of the actuator motion waveform is of critical importance to ensure the mechanical force configuration required in industrial application, each driving waveform must be adapted as a whole, not as a series of discrete input points. Therefore instead of applying a set-point tracking method, a self-tuning process is used in the predictive filter design of the current cycle, and corresponding control is delayed to waveform generation of the next cycle. The control algorithm is then implemented into experiment for vibratory feeding and the result shows satisfactory hysteresis suppression and good waveform tracking.
Non-linear analysis of a flexible rotor system with multi-span bearing supports
Authors: Lu Y J , Zhang Y F , Dai R , Liu H , Yu L , Hei D , Wang Y
Published: March 2008

The current article deals with the non-linear dynamic behaviours of a flexible rotor system with multi-span bearing supports. The shaft is modelled by using the finite-element method that can take the effects of inertia and shear into consideration. A modified modal synthesis technique with free interface is proposed to reduce the degrees of freedom of the model of a flexible rotor system. In order to keep the accuracy of non-linear analysis and save computational cost, a truncated modal transformation is used to reduce the linear degrees of freedom of the system, whereas non-linear oil-film forces and non-linear degrees of freedom of the system are retained in the physical space. Thus, the non-linear excitation and unbalance force can be easily added to the system equation and the reduced system keeps the non-linearity. In accordance with the physical character of oil film, a variational constraint approach is proposed to revise continuously the variational form of the Reynolds equation at every step of the dynamic iterative procedure. Non-linear oil film forces and their Jacobians are calculated simultaneously without an increase in computing costs and compatible accuracy is obtained. The numerical example shows that the proposed methods not only save computing costs but also have good precision.
Surface roughness effects on the static and dynamic behaviour of squeeze film lubrication of short journal bearings with micropolar fluids
Authors: Naduvinamani N B , Kashinath B
Published: March 2008

The theoretical study of the effect of surface roughness on the squeeze film lubrication of short journal bearings with no journal rotation under fluctuating loads with micropolar fluids is made. A more general form of surface roughness is mathematically modelled by a stochastic random variable with non-zero mean, variance, and skewness. The generalized average Reynolds type equation is derived for the squeeze film lubrication of rough journal bearings with micropolar fluids as lubricant. The closed form expressions for the bearing characteristics are obtained. The cases of a constant applied load and an alternating applied load are analysed. Under a cyclic load the micropolar fluids provide a reduction in the journal centre velocity. Further, it is observed that, the presence of microstructure additives and the negatively skewed surface roughness on the bearing surface increases the load carrying capacity and decreases the journal centre velocity.
Effect of viscosity variation on the squeeze film performance of a narrow hydrodynamic journal bearing operating with couple stress fluids
Authors: Jaya Chandra Reddy G , Eswara Reddy C , Rama Krishna Prasad K
Published: March 2008

In the current paper, a theoretical study of the effect of the viscosity variation on the squeeze film performance of a short bearing operating with couple stress fluids is presented. The modified Reynolds equation accounting for the couple stresses and viscosity variation is mathematically derived. To obtain a closed form solution, the short bearing approximation under constant load is considered. The modified Reynolds equation is solved for the fluid film pressure and then the bearing characteristics, such as the load carrying capacity and the squeeze time for the fluid film are obtained. According to the results evaluated, the couple stress fluid as a lubricant improves the squeeze film characteristics and results in a longer bearing life. Whereas the viscosity variation factor decreases the load carrying capacity and squeeze film time. The results are compared with the Newtonian fluid.
Effects of electrokinetic slip flow on lubrication theory
Authors: Li W‐L , Jin Z
Published: March 2008

A lubrication theory that includes the coupled effects of electric double layer (EDL) and boundary slip is developed. The consideration of EDL (electro-viscous effect) and boundary slip near the solid surface increases and decreases apparent viscosity, respectively. Both effects are important for flow within microscales and lubrication problems. Under the usual assumptions of lubrication and Debye—Hückel approximation for low surface potential, the Navier—Stokes equation with body force due to the electrical potential, as well as the Navier slip boundary conditions, is utilized to derive the velocity distributions, apparent viscosity, and modified Reynolds equation. The apparent viscosity is expressed explicitly as functions of the Debye length, the electro-viscosity, and the slip length. The coupled effects of EDL and boundary slip on the apparent viscosity and one-dimensional slider-bearing performance are analysed and discussed. Results show that the load capacity increases as a decrease in inverse Debye length ( K), a decrease in slip lengths ( B), or an increase in electro-viscosity.
Reliability modelling for biological ageing
Authors: Finkelstein M S
Published: March 2008

Some stochastic approaches to modelling biological ageing are studied. The assumption is made that a random resource is acquired by an organism at birth. Failure (death) occurs when the accumulated wear exceeds this initial resource, modelled by discrete or continuous random variables. Deterioration in repairable objects is also considered. Two models are discussed. The first one is an imperfect repair model. It is shown that under certain assumptions the accumulated damage in this model is bounded. The second model is based on the shot noise process and takes into account the ‘healing effect’, when an increment of damage after each shock is decreasing with time.
A combined Monte Carlo and cellular automata approach to the unreliability analysis of binary network systems
Authors: Zio E , Librizzi M , Sansavini G
Published: March 2008

In the present work, cellular automata are combined with Monte Carlo sampling to solve two critical problems related to the unreliability assessment of complex networks composed of nodes interconnected by binary arcs: the identification of the minimal cut sets of the network and the computation of the Fussell—Vesely importance measures assessing the criticality of each arc with respect to the network unreliability. The effectiveness of the method is tested on two literature case studies.
A framework of indicators for the potential influence of Air Navigation Services on air traffic safety in Europe
Authors: de Jong H H , Preti F , van Es G W H
Published: March 2008

This paper outlines a proposal for a framework of indicators developed with the aim to improve European safety performance monitoring of Air Navigation Services. The extension of scope from the usual choice of Air Traffic Management to Air Navigation Services has been made to address the complication that Air Traffic Management is a different service from Communication, Navigation, and Surveillance, but intimately connected with it. The framework considers the potential influence of Air Navigation Services on air traffic safety, and it uses accidents, their causal/contributing factors, and incidents related to these services as source data for the indicators. Those occurrence categories are considered for which Air Navigation Services have the potential to improve risk. This approach is independent of the notion of a service's contribution to occurrences, which is normally used, but which suffers from a considerable degree of subjectivity. In the data flows from air traffic operations to safety performance indicators, weak links are human incident reporting, varying proportions of incidents actually investigated sufficiently well plus different ways to perform the investigations, and differences in interpretation in providing overviews of the resulting safety data on the level of States. In view of these weaknesses, conditions are developed to prevent data of insufficient quality from being used. The paper mentions a number of aspects to consider when using the indicators. Before drawing conclusions, statistical significance and the existence of reporting bias need to be assessed. The paper finishes with a discussion of the relation of the framework with existing targets and indicates how the framework could support deriving appropriate targets and performance of safety assessments.
A model-based approach for systematic risk analysis
Authors: Flaus J-M
Published: March 2008

A modelling approach based on a mixed structural/functional graph that allows the simultaneous representation of the structural and the functional aspects of a system is presented. This model provides a framework to formalize risk analysis while being as simple as possible. The focus of the proposed approach is to achieve in a common analysis a functional failure analysis and the identification of physical damage, these being the two complementary parts of a full risk analysis. The resulting failure propagation graph is useful for model-based reasoning for fault diagnosis, the detection of dangerous situations, and the prediction of critical events. In addition, the approach is modular and reusable. The approach is illustrated by its use on an example.
Impact of Carvedilol on the Serum Lipid Profile
Authors: Sharp Randall P , Sirajuddin Riaz , Sharief Imran M
Published: March 2008

OBJECTIVE:

To examine the evidence regarding the impact of carvedilol on the serum lipid profile.

DATA SOURCES:

Searches in MEDLINE and International Pharmaceutical Abstracts (1966–December 2007) were conducted. Search terms included carvedilol, cholesterol, lipids, hyperlipidemia, and β-blockers.

STUDY SELECTION AND DATA EXTRACTION:

Published studies and case reports that evaluated the impact of carvedilol on the lipid profile were reviewed. One study was excluded because it evaluated carvedilol for an off-label use and was a small Phase 2 pilot study that evaluated the results of only 10 patients.

DATA SYNTHESIS:

Twelve studies were available for review; 6 of these compared carvedilol with β1-selective antagonists. Three studies compared carvedilol with other antihypertensive medications; 2 of those studies evaluated total cholesterol only. Carvedilol alone was evaluated for its effects on lipids in 3 small single-group studies. In 4 of the 12 studies, carvedilol independently improved the lipid profile significantly, while the drug had a nonsignificant, neutral effect on the lipid profile in 3 studies. Furthermore, in 4 of the 12 studies, carvedilol was compared with other antihypertensive medications. In 3 of these 4 studies, the other drugs worsened the lipid profile significantly compared with carvedilol, while carvedilol significantly improved the lipid profile in the other study. Finally, carvedilol had a potentially negative effect on high-density lipoprotein cholesterol in a single-group study, but p values were not reported.

CONCLUSIONS:

It is clear that β1-selective antagonists worsen the lipid profile compared with carvedilol. However, it is unclear whether carvedilol independently makes an improvement or has a neutral effect on the lipid profile. Carvedilol should be an important treatment consideration in patients with heart failure and/or hypertension with dyslipidemia. However, many questions remain regarding this issue.
Evaluation of Feeding Intolerance in Patients with Pentobarbital-Induced Coma
Authors: Stevens Alison M , Then Janine E , Frock Karen M , Crookes Bruce A , Commichau Christopher , Marden Brian T , Beynnon Bonnie J , Rebuck Jill A
Published: March 2008

BACKGROUND:

There is considerable debate regarding the appropriateness of feeding patients by the enteral route in conjunction with pentobarbital coma therapy.

OBJECTIVE:

To determine the incidence of feeding intolerance (FI) in patients receiving pentobarbital in conjunction with enteral nutrition (EN).

METHODS:

A retrospective, observational evaluation of patients (>14 y of age) who received a therapeutic pentobarbital coma in combination with EN was conducted. Patients were divided into groups, based on the occurrence of FI defined as aspiration of gastric residuals greater than 75 mL for 2 consecutive measurements.

RESULTS:

Forty-eight percent (29 of 61) of patients experienced FI based on our definition. The median pentobarbital infusion rate did not differ significantly between patients who experienced FI versus those who did not (median [intraquartile range, IQR] 1.8 mg/kg/h [1.4, 2.1] vs 1.7 mg/kg/h [1.4, 2.5]; p = 0.680). The total pentobarbital bolus dose during the first 24 hours of therapy was lower in patients who experienced FI (700 mg [225, 980] vs 1000 mg [600, 1475]; p = 0.029). Median duration of pentobarbital therapy was comparable between groups (141.0 h [93.3, 217.3] vs 116.3 h [64.0, 174.8]; p = 0.115). Other factors with the potential to influence FI, such as catecholamines, neuromuscular blockade, and hyperglycemia, were similar between groups. The higher narcotic doses and greater percentage of patients receiving benzodiazepines in the FI group warrants further study.

CONCLUSIONS:

Pentobarbital therapy did not preclude use of EN in the entire study population. In addition, FI did not occur at a greater frequency in patients who received a higher dosage, a longer duration, or an earlier initiation of pentobarbital therapy.
Effectiveness and Safety of Dorzolamide – Timolol Alone or Combined with Latanoprost in Open-Angle Glaucoma or Ocular Hypertension
Authors: Lesk Mark R , Koulis Theodoro , Sampalis Fotini , Sampalis John S , Bastien Natacha R
Published: March 2008

BACKGROUND:

Treatment of glaucoma is aimed at reducing intraocular pressure (IOP) to prevent further damage to the optic nerve. For patients who do not respond to monotherapy, combination treatment may be effective in achieving therapeutic reduction or target IOP.

OBJECTIVE:

To evaluate the effectiveness and safety of dorzolamide 2% with timolol 0.5% alone or combined with latanoprost in reducing IOP in a real-world setting.

METHODS:

A prospective, open-label, multicenter, nonrandomized interventional study was designed. Three hundred fifty patients with primary open-angle glaucoma or ocular hypertension and uncontrolled IOP after latanoprost monotherapy for 4 or more weeks were treated with combination dorzolamide–timolol twice daily added to their existing latanoprost therapy (D/T-Add-On; n = 280) or dorzolamide–timolol twice daily monotherapy (D/T-Switch; n = 70). The primary effectiveness outcome measure was the change in IOP after 6 and 12 weeks of treatment.

RESULTS:

Of the total population, 313 patients completed this trial (248 D/T-Add-On; 65 D/T-Switch). After 12 weeks, the mean ± SD IOP decrease was −6.3 ± 3.6 mm Hg (–28.1%) and −5.8 ± 4.9 mm Hg (–23.5%) in the D/T-Add-On and D/T-Switch groups, respectively (both p < 0.001). Therapeutic response rates (defined as IOP reduction >20%) after 12 weeks of treatment for the D/T-Add-On and the D/T-Switch groups were 66.4% (186/280) and 52.9% (37/70), respectively. There were 116 predominantly mild, nonserious adverse events attributed to the study drugs, reported by 86 (24.6%) patients. The most frequent adverse events were eye irritation (n = 42; 12.0%) and taste perversion (n = 15; 4.3%). No serious adverse events related to the study medications were reported.

CONCLUSIONS:

In patients with primary open-angle glaucoma or ocular hypertension and elevated IOP while on monotherapy with latanoprost, switching to dorzolamide–timolol or combining dorzolamide–timolol with latanoprost are effective and safe treatment options for reducing IOP and achieving therapeutic response.
Rapidly Developing Hyperglycemia During Treatment with Olanzapine
Authors: Kohen Izchak , Gampel Mordechai , Reddy Lakshmi , Manu Peter
Published: March 2008

OBJECTIVE:

To report a case of rapidly occurring hyperglycemia that occurred in a geriatric patient 3 days after treatment with olanzapine.

CASE SUMMARY:

An 89-year-old man was admitted for dementia with behavioral disturbance and psychosis and was started on olanzapine 2.5 mg twice daily. Due to paranoia and agitation, the dose was increased to 5 mg twice daily after 2 days. Subsequently, he developed hyperglycemia (fasting blood glucose 138 mg/dL) that resolved when olanzapine was stopped and recurred (fasting blood glucose 150 mg/dL) after 2 days of rechallenge with olanzapine 2.5 mg twice daily. In addition, his overall medical status worsened, as he developed concurrent acute renal failure and became more confused and lethargic. The hyperglycemia once again resolved with discontinuation of the drug.

DISCUSSION:

We postulate that the rapid onset of hyperglycemia and the resulting medical sequelae were due to olanzapine. An objective causality assessment revealed that the adverse drug event was probable. There have been numerous case reports of hyperglycemia with olanzapine in the literature, but none reported hyperglycemia within days of initiation of the medication. Although weight gain often coincides with hyperglycemia in patients taking atypical antipsychotics, it does not seem to be a necessary causal factor. Recent data in animal studies have indicated that olanzapine and clozapine rapidly impair whole-body insulin sensitivity in a dose-dependent manner.

CONCLUSIONS:

Clinicians treating elderly patients with olanzapine should be aware of the potential for rapidly developing hyperglycemia and monitor such patients accordingly.
A Comprehensive Negative Regulatory Program Controlled by Brn3b to Ensure Ganglion Cell Specification from Multipotential Retinal Precursors
Authors: Qiu Feng , Jiang Haisong , Xiang Mengqing
Published: March 2008

The retinal ganglion cells (RGCs) are the sole output neurons in the retina that form the optic nerve and convey light signals detected by photoreceptors to the higher visual system. Their degeneration and damage caused by glaucoma and injury can lead to blindness. During retinogenesis, RGCs are specified from a population of multipotential precursors capable of generating RGC, amacrine, horizontal, and cone cells. How the RGC fate is selected from these multiple neuron fates is unknown at present. Here we show that the previously unsuspected POU domain transcription factor Brn3b (brain-specific homeobox/POU domain protein 3b) plays such a critical role. Loss ofBrn3bfunction in mice leads to misspecification of early RGC precursors as late-born RGC, amacrine, and horizontal cells, whereas misexpressed Brn3b suppresses non-RGC cell fates but promotes the RGC fate. Microarray profiling and other molecular analyses reveal that, in RGC precursors, Brn3b normally represses the expression of a network of retinogenic factor genes involved in fate commitment and differentiation of late-born RGC, amacrine, horizontal, and cone cells. Our data suggest that Brn3b specifies the RGC fate from multipotential precursors not only by promoting RGC differentiation but also by suppressing non-RGC differentiation programs as a safeguard mechanism.
Telencephalic Neurons Monosynaptically Link Brainstem and Forebrain Premotor Networks Necessary for Song
Authors: Roberts Todd F. , Klein Marguerita E. , Kubke M. Fabiana , Wild J. Martin , Mooney Richard
Published: March 2008

Birdsong, like human speech, is a series of learned vocal gestures resulting from the coordination of vocal and respiratory brainstem networks under the control of the telencephalon. The song motor circuit includes premotor and motor cortical analogs, known as HVC (used as a proper name) and RA (the robust nucleus of the arcopallium), respectively. Previous studies showed that HVC projects to RA and that RA projection neurons (PNs) topographically innervate brainstem vocal-motor and respiratory networks. The idea that singing-related activity flows between HVC and RA in a strictly feedforward manner is a central component of all models of song production. In contrast to this prevailing view of song motor circuit organization, we show that RA sends a reciprocal projection directly to HVC. Lentiviral labeling of RA PN axons and transgene tagging of RA PN synaptic terminals reveal a direct projection from RA to HVC. Retrograde tracing from HVC demonstrates that this projection originates exclusively from neurons in dorsocaudal regions of RA. Using dual retrograde tracer injections, we further show that many of these RAHVCneurons also innervate the brainstem nucleus retroambigualis, which is premotor to expiratory motoneurons, thereby identifying a population of RA PNs positioned to coordinate activity at higher and lower levels of the song motor circuit. In combination, our findings identify a previously unknown pathway that may enable a subset of RA neurons to provide song-related signals to the respiratory brainstem but also transmit a copy of this information to song patterning networks in HVC.
Requirement of an Allosteric Kinetics of NMDA Receptors for Spike Timing-Dependent Plasticity
Authors: Urakubo Hidetoshi , Honda Minoru , Froemke Robert C. , Kuroda Shinya
Published: March 2008

Spike timing-dependent synaptic plasticity (STDP) plays an important role in neural development and information processing in the brain; however, the mechanism by which spike timing information is encoded into STDP remains unclear. Here, we show that a novel allosteric kinetics of NMDA receptors (NMDARs) is required for STDP. We developed a detailed biophysical model of STDP and found that the model required spike timing-dependent distinct suppression of NMDARs by Ca2+-calmodulin. This led us to predict an allosteric kinetics of NMDARs: a slow and rapid suppression of NMDARs by Ca2+-calmodulin with prespiking → postspiking and postspiking → prespiking, respectively. We found that the allosteric kinetics, but not the conventional kinetics, is consistent with specific features of amplitudes and peak time of NMDAR-mediated EPSPs in experiments. We found that the allosteric kinetics of NMDARs was also valid for synaptic plasticity induced by more complex spike trains in layer II/III of visual cortex. We extracted an essential synaptic learning rule by reduction of the allosteric STDP model and found that spike timing-dependent bidirectional role of postspiking in synaptic modification, which depends on the allosteric kinetics, is the essential principle in STDP. Thus, we propose a simple hypothesis of the allosteric kinetics of NMDARs that can coherently explain critical features of spike timing-dependent NMDAR-mediated EPSPs and synaptic plasticity.
Effective and Structural Connectivity in the Human Auditory Cortex
Authors: Upadhyay Jaymin , Silver Andrew , Knaus Tracey A. , Lindgren Kristen A. , Ducros Mathieu , Kim Dae-Shik , Tager-Flusberg Helen
Published: March 2008

Language processing involves multiple neuronal structures in the human auditory cortex. Although a variety of neuroimaging and mapping techniques have been implemented to better understand language processing at the level of the auditory cortex, much is unknown regarding how and by what pathways these structures interact during essential tasks such as sentence comprehension. In this study, the effective and structural connectivity at the level of the auditory cortex were investigated. First, blood oxygenation level-dependent (BOLD) responses were measured with time-resolved functional magnetic resonance imaging (fMRI) during audition of short sentences. Once BOLD activation maps were obtained, the effective connectivity between primary auditory cortex and the surrounding auditory regions on the supratemporal plane and superior temporal gyrus (STG) were investigated using Granger causality mapping (GCM). Effective connectivity was observed between the primary auditory cortex and (1) the lateral planum polare and anterior STG, and (2) the lateral planum temporale and posterior STG. By using diffusion tensor probabilistic mapping (DTPM), rostral and caudal fiber pathways were detected between regions depicting effective connectivity. The effective and structural connectivity results of the present study provide further insight as to how auditory stimuli (i.e., human language) is processed at the level of the auditory cortex. Furthermore, combining BOLD fMRI-based GCM and DTPM analysis could provide a novel means to study effective and structural connectivity not only in the auditory cortex, but also in other cortical regions.
Loss of Astrocytic Domain Organization in the Epileptic Brain
Authors: Oberheim Nancy Ann , Tian Guo-Feng , Han Xiaoning , Peng Weiguo , Takano Takahiro , Ransom Bruce , Nedergaard Maiken
Published: March 2008

Gliosis is a pathological hallmark of posttraumatic epileptic foci, but little is known about these reactive astrocytes beyond their high glial fibrillary acidic protein (GFAP) expression. Using diolistic labeling, we show that cortical astrocytes lost their nonoverlapping domain organization in three mouse models of epilepsy: posttraumatic injury, genetic susceptibility, and systemic kainate exposure. Neighboring astrocytes in epileptic mice showed a 10-fold increase in overlap of processes. Concurrently, spine density was increased on dendrites of excitatory neurons. Suppression of seizures by the common antiepileptic, valproate, reduced the overlap of astrocytic processes. Astrocytic domain organization was also preserved in APP transgenic mice expressing a mutant variant of human amyloid precursor protein despite a marked upregulation of GFAP. Our data suggest that loss of astrocytic domains was not universally associated with gliosis, but restricted to seizure pathologies. Reorganization of astrocytes may, in concert with dendritic sprouting and new synapse formation, form the structural basis for recurrent excitation in the epileptic brain.
Biomechanics of the Vibrissa Motor Plant in Rat: Rhythmic Whisking Consists of Triphasic Neuromuscular Activity
Authors: Hill Dan N. , Bermejo Roberto , Zeigler H. Philip , Kleinfeld David
Published: March 2008

The biomechanics of a motor plant constrain the behavioral strategies that an animal has available to extract information from its environment. We used the rat vibrissa system as a model for active sensing and determined the pattern of muscle activity that drives rhythmic exploratory whisking. Our approach made use of electromyography to measure the activation of all relevant muscles in both head-fixed and unrestrained rats and two-dimensional imaging to monitor the position of the vibrissae in head-fixed rats. Our essential finding is that the periodic motion of the vibrissae and mystacial pad during whisking results from three phases of muscle activity. First, the vibrissae are thrust forward as the rostral extrinsic muscle, musculus (m.) nasalis, contracts to pull the pad and initiate protraction. Second, late in protraction, the intrinsic muscles pivot the vibrissae farther forward. Third, retraction involves the cessation of m. nasalis and intrinsic muscle activity and the contraction of the caudal extrinsic muscles m. nasolabialis and m. maxillolabialis to pull the pad and the vibrissae backward. We developed a biomechanical model of the whisking motor plant that incorporates the measured muscular mechanics along with movement vectors observed from direct muscle stimulation in anesthetized rats. The results of simulations of the model quantify how the combination of extrinsic and intrinsic muscle activity leads to an enhanced range of vibrissa motion than would be available from the intrinsic muscles alone.
Regional Differences in the Decay Kinetics of GABAAReceptor-Mediated Miniature IPSCs in the Dorsal Horn of the Rat Spinal Cord Are Determined by Mitochondrial Transport of Cholesterol
Authors: Inquimbert Perrine , Rodeau Jean-Luc , Schlichter Rémy
Published: March 2008

We examined the possibility of a differential spatial control in the endogenous production of 3α5α-reduced steroids and its consequences on GABAAreceptor-mediated miniature IPSCs (mIPSCs) in laminas II and III–IV of the rat spinal cord dorsal horn (DH). Early in postnatal development [younger than postnatal day 8 (P8)], mIPSCs displayed slow decay kinetics in laminas II and III–IV resulting from a continuous local production of 3α5α-reduced steroids. This was mediated by the tonic activity of the translocator protein of 18 kDa (TSPO), which controls neurosteroid synthesis by regulating the transport of cholesterol across the mitochondrial membrane system. TSPO activity disappeared in laminas III–IV after P8 and was functionally downregulated in lamina II after P15, resulting in a marked reduction of mIPSC duration in these laminas. TSPO-mediated synthesis of 3α5α-reduced steroids was spatially restricted, because, at P9–P15, when their production was maximal in lamina II, no sign of spillover to laminas III–IV was apparent. Interestingly, after P8, the enzymes necessary for the synthesis of 3α5α-reduced steroids remained functional in laminas III–IV and could produce such steroids from various precursors or after a single subcutaneous injection of progesterone. Moreover, induction of an acute peripheral inflammation by intraplantar injection of carrageenan, restored a maximal TSPO-mediated neurosteroidogenesis in laminas III–IV. Our results indicate that the decay kinetics of GABAAreceptor-mediated mIPSCs in the DH of the spinal cord are primarily controlled by 3α5α-reduced steroids, which can be produced from circulating steroid precursors and/or in a spatially restricted manner by the modulation of the activity of TSPO.
The Role of Nerve- versus Muscle-Derived Factors in Mammalian Neuromuscular Junction Formation
Authors: Lin Shuo , Landmann Lukas , Ruegg Markus A. , Brenner Hans Rudolf
Published: March 2008

Neuromuscular junctions (NMJs) normally form in the central region of developing muscle. In this process, agrin released from motor neurons has been considered to initiate the formation of synaptic acetylcholine receptor (AChR) clusters (neurocentric model). However, in muscle developing in the absence of nerves and thus of agrin, AChR clusters still form in the muscle center. This raises the possibility that the region of NMJ formation is determined by muscle-derived cues that spatially restrict the nerve to form synapses from aneural AChR clusters, e.g., by patterned expression of the agrin receptor MuSK (muscle-specific kinase) (myocentric model). Here we examine at initial stages of synaptogenesis whether the responsiveness of myotubes to agrin is spatially restricted, whether the regions of NMJ formation in wild-type muscle and of aneural AChR cluster formation in agrin-deficient animals correlate, and whether AChR cluster growth depends on the presence of agrin. We show that primary myotubes form AChR clusters in response to exogenous agrin in their central region only, a pattern that can spatially restrict NMJ formation. However, the nerve also makes synapses in regions in which aneural AChR clusters do not form, and agrin promotes synaptic cluster growth from the first stages of neuromuscular contact formation. These data indicate that aneural AChR clusters per se are not required for NMJ formation. A model is proposed that explains either the neurocentric or the myocentric mode of NMJ formation depending on a balance between the levels of MuSK expression and the availability of nerve-released agrin.
Structural Mechanisms Underlying Benzodiazepine Modulation of the GABAAReceptor
Authors: Hanson Susan M. , Czajkowski Cynthia
Published: March 2008

Many clinically important drugs target ligand-gated ion channels; however, the mechanisms by which these drugs modulate channel function remain elusive. Benzodiazepines (BZDs), anesthetics, and barbiturates exert their CNS actions by binding to GABAAreceptors and modulating their function. The structural mechanisms by which BZD binding is transduced to potentiation or inhibition of GABA-induced current (IGABA) are essentially unknown. Here, we explored the role of the γ2Q182-R197 region (Loop F/9) in the modulation ofIGABAby positive (flurazepam, zolpidem) and negative [3-carbomethoxy-4-ethyl-6,7-dimethoxy-β-carboline (DMCM)] BZD ligands. Each residue was individually mutated to cysteine, coexpressed with wild-type α1and β2subunits inXenopusoocytes, and analyzed using two-electrode voltage clamp. Individual mutations differentially affected BZD modulation ofIGABA. Mutations affecting positive modulation span the length of this region, whereas γ2W183C at the beginning of Loop F was the only mutation that adversely affected DMCM inhibition. Radioligand binding experiments demonstrate that mutations in this region do not alter BZD binding, indicating that the observed changes in modulation result from changes in BZD efficacy. Flurazepam and zolpidem significantly slowed covalent modification of γ2R197C, whereas DMCM, GABA, and the allosteric modulator pentobarbital had no effects, demonstrating that γ2Loop F is a specific transducer of positive BZD modulator binding. Therefore, γ2Loop F plays a key role in defining BZD efficacy and is part of the allosteric pathway allowing positive BZD modulator-induced structural changes at the BZD binding site to propagate through the protein to the channel domain.
Ronco habitual e apnéia obstrutiva observada em adultos: estudo de base populacional, Pelotas, RS
Authors: Noal Ricardo B , Menezes Ana M B , Canani Simone F , Siqueira Fernando V
Published: March 2008

OBJETIVO: Estimar a prevalência de ronco habitual e apnéia obstrutiva observada e fatores associados. MÉTODOS: Estudo transversal com amostra representativa de 3.136 adultos, com 20 anos ou mais, residentes em Pelotas, Rio Grande do Sul, em 2005. Informações sobre os desfechos e variáveis demográficas, socioeconômicas, comportamentais e antropométricas foram coletadas por meio de questionário. A análise estatística bruta e ajustada foi realizada utilizando-se teste exato de Fisher ou qui-quadrado de tendência linear e regressão de Poisson, respectivamente. RESULTADOS: A prevalência encontrada de ronco habitual foi de 50,5% (IC 95%: 48,1;52,8) e de apnéia obstrutiva de 9,9% (IC 95%: 8,7;11,2). Na análise ajustada, o relato de ronco foi maior nos homens (Razão de Prevalências - RP=1,25; IC 95%: 1,16;1,34), nos idosos (RP=1,62; IC 95%: 1,46;1,80), nos tabagistas (RP=1,15; IC 95%: 1,07;1,25), nos alcoolistas (RP=1,17; IC 95%: 1,03;1,31) e nos obesos (RP 1,71, IC95% 1,55;1,88). O relato de apnéia obstrutiva foi maior nos homens (RP=2,05; IC 95%: 1,67;2,52), nos idosos (RP=2,23; IC 95%: 1,64;3,03), nos tabagistas (RP=1,60; IC 95%: 1,25;2,05) e nos obesos (RP=2,61; IC 95%: 1,97;3,47). CONCLUSÕES: Ronco habitual e apnéia obstrutiva foram sintomas comuns na população estudada. Fatores de risco conhecidos como sexo masculino e idade entre quarta e quinta décadas de vida não são modificáveis. Entretanto, tabagismo, alcoolismo e obesidade também associados aos desfechos, devem ser identificados e tratados na população geral.