bluuebunny/crossref_metadata_2025 huggingface dataset:
‘What counts is what works’? New Labour and partnerships in public health
Authors: Perkins Neil , Smith Katherine , Hunter David J. , Bambra Clare , Joyce Kerry
Published: February 2010

Partnership working has been a central feature of New Labour's approach to the delivery of health and social policy since 1997. A number of partnership-based initiatives have centred on reducing health inequalities and improving health. This article reports on the findings from a systematic review of the impact of partnership working on public health, and considers whether these partnerships have delivered better health outcomes for local/target populations. It finds that there is little evidence that partnerships have produced better health outcomes for local/target populations or reduced health inequalities.
Hypokalemia Following Polyethylene Glycol–Based Bowel Preparation for Colonoscopy in Older Hospitalized Patients with Significant Comorbidities
Authors: Ho Joanne Man-Wai , Juurlink David Nelson , Cavalcanti Rodrigo Brandao
Published: February 2010

Background:

Polyethylene glycol–based bowel preparations (PEGBPs) are widely perceived as safe and effective alternatives to oral sodium phosphate for bowel cleansing prior to colonoscopy. Most studies supporting this belief involve young patients with few comorbidities.

Objective:

To characterize the incidence of electrolyte disturbances following PEGBPs administered prior to colonoscopy among elderly inpatients and hypothesize that PEGBP would be associated with hypokalemia in this setting.

Methods:

This retrospective chart review, conducted at 3 tertiary care teaching hospitals in Toronto, Canada, from 2005 to 2007, included 96 consecutive patients aged 65 or older who were admitted to the hospital and given PEGBP prior to their first inpatient colonoscopy. Patients were excluded if they received additional cathartics, underwent colonoscopy while admitted to a critical care unit, or were admitted for a complication arising from an outpatient colonoscopy. The primary outcome was hypokalemia (serum potassium ≤3.2 mEq/L) within 48 hours of PEGBP.

Results:

Of 96 patients, 73 had serum electrolytes measured at baseline and within 48 hours following PEGBP administration. Hypokalemia was identified in 4 patients (5.5%) prior to PEGBP and in 15 patients (20.5%) after PEGBP (p < 0.001). The incidence of significant hypokalemia, defined as serum potassium ≤3.0 mEq/L, in this group was 9.6% (p = 0.008). We found consistent results among patients with and without concomitant diuretic treatment.

Conclusions:

Among older patients, administration of PEGBP is commonly complicated by the development of hypokalemia, which is occasionally severe. Monitoring of electrolytes may be necessary following colonoscopy, particularly in patients with cardiac or renal disease.
Effectiveness and Safety of Proton Pump Inhibitors in Infantile Gastroesophageal Reflux Disease
Authors: Higginbotham Tanner W
Published: February 2010

Objective:

To evaluate the efficacy and safety of proton pump inhibitors (PPIs) in the treatment of gastroesophageal reflux disease (GERD) in infants <1 year of age.

Data Sources:

A literature search was conducted through PubMed (up to December 2009), International Pharmaceutical Abstracts (1970–December 2009), and The Cochrane Library (up to December 2009) using combinations of the following key search terms: proton pump inhibitor, GERD, infant, children, pediatric, omeprazole, rabeprazole, lansoprazole, esomeprazole, and pantoprazole. Reference citations from identified articles were also reviewed.

Study Selection And Data Extraction:

All double-blind, placebc-controlled trials published in English that evaluated the safety and efficacy of PPIs in infants with GERD were included in this review. Trials involving children older than 12 months were not included.

Data Synthesis:

GERD is a source of pain and discomfort in adults; yet, in infants, symptoms that are thought to be indicative of painful stimuli have no clear cause-and-effect relationship with infant GERD. PPIs are beneficial in relieving symptoms of GERD in the adult population, but their usefulness in decreasing GERD-associated behaviors in infants is still questionable, despite a large increase in PPI prescribing for children <1 year of age. In all studies reviewed, infants treated with PPIs did not experience a significant decrease in behaviors perceived to be caused by GERD. The largest placebo-controlled trial to date found that rates of adverse events were increased in the PPI group compared with the placebo group, whereas the other trials reviewed reported no difference in adverse effects with the use of PPIs.

Conclusions:

Clinical trials reveal that PPI therapy is not an effective treatment for common infant GERD-associated symptoms. Evidence supporting safety of PPI use in infants is conflicting, and more large-scale, randomized, placebo-controlled trials are necessary to better establish the role of PPIs in infant GERD.
Evidence-Based, Multidisciplinary Approach to the Development of a Crotalidae Polyvalent Antivenin (CroFab) Protocol at a University Hospital
Authors: Weant Kyle A , Johnson Peter N , Bowers Rebecca C , Armitstead John A
Published: February 2010

Background:

Several thousand people are bitten annually by venomous snakes in the US. While the development of ovine Crotalidae polyvalent immune Fab antivenin (FabAV) for Crotalinae snakebite envenomations has greatly changed the way this clinical presentation is treated, multiple issues complicate its use. From patient assessment and evaluation, to medication preparation and administration, to the management of adverse drug reactions, the use of this antidote carries with it multiple points of possible medication variances. The inappropriate use of this agent can result in adverse patient consequences and a significant financial burden for both the hospital and the patient.

Objective:

To describe an evidence-based, multidisciplinary approach that was taken to ensure optimal, safe, and cost-effective treatment of patients with FabAV.

Methods:

Following an analysis of the available literature, a multidisciplinary committee was formed to construct a protocol for use of FabAV. This group included clinical pharmacists, pharmacy administrators, emergency medicine physicians who specialized in wilderness medicine and pharmacy residents.

Results:

A multidisciplinary FabAV usage protocol was constructed and implemented to ensure appropriate patient evaluation, FabAV use and preparation, monitoring, and follow-up. This protocol was based on the available literature and the expert opinion of the committee. Through the use of a 24-hour in-house pharmacy resident on-call system, clinical pharmacy services were provided to ensure a multidisciplinary approach to the care of these patients emergently. Although limited, initial data show that this approach is effective and may result in substantial cost savings.

Conclusions:

Initial results from implementation of a protocol for use of FabAV have limited inappropriate use, reduced medication wastage, and decreased costs.
Efficacy and Safety of Ticagrelor: A Reversible P2Y12 Receptor Antagonist
Authors: Anderson Shawn D , Shah Niren K , Yim Juwon , Epstein Benjamin J
Published: February 2010

Objective:

To summarize the pharmacokinetic and pharmacodynamic properties of ticagrelor, a selective P2Y12 receptor antagonist, and evaluate its role in the treatment of patients with acute coronary syndromes (ACS).

Data Sources:

A literature search was conducted in MEDLINE (1966–November 2009), International Pharmaceutical Abstracts (1970–November 2009), and EMBASE (1990–November 2009) using the MeSH terms and key words AZD6140, ticagrelor, P2Y12 receptor antagonist, cardiovascular disease, ACS, atherothrombosis, and platelets.

Study Selection And Data Extraction:

Selected studies evaluated the pharmacology, pharmacokinetics, pharmacodynamics, safety, and efficacy of ticagrelor for the treatment of ACS.

Data Synthesis:

Ticagrelor selectively and reversibly blocks the P2Y12 receptor, inhibiting platelet aggregation and preventing amplification of platelet activation. Optimal dosing strategy as determined by ticagrelor's pharmacokinetic and pharmacodynamic profile is a loading dose of 180 mg followed by 90 mg by mouth twice daily. At these doses, greater platelet inhibition is observed with ticagrelor as compared to clopidogrel 75 mg once daily in both clopidogrel-experienced and -naïve patients. Studies in patients experiencing ACS concluded that ticagrelor reduced the rate of cardiovascular death, nonfatal myocardial infarction, stent thrombosis, and overall mortality compared to clopidogrel without increasing major bleeding when administered with standard therapy for ACS. There was no significant difference in the risk of stroke with ticagrelor compared to clopidogrel; however, intracranial bleeding was more common with ticagrelor. Ticagrelor is well tolerated; however, minor bleeding, dyspnea, hypotension, nausea, and ventricular pauses were reported more frequently than with clopidogrel. Reversible inhibition with ticagrelor may allow for more rapid surgical intervention after discontinuation, suggesting greater flexibility in treatment of ACS.

Conclusions:

Ticagrelor's improved pharmacokinetic and pharmacodynamic profile builds upon the limitations of currently available P2Y12 receptor antagonists. Ticagrelor represents a promising approach for the prevention of cardiovascular events in patients with ACS.
I want it and I want it now: Using a temporal discounting paradigm to examine predictors of consumer impulsivity
Authors: Dittmar Helga. , Bond Rod.
Published: February 2010

This paper proposes a new model of consumer impulsivity, using type of good, a person's endorsement of materialistic values, and identity deficits as predictors. Traditional decision making and psychological accounts see impulsive behaviour as a general overweighing of short‐term gratification (I want that dress now) relative to longer‐term concerns, irrespective of consumer good. Our proposal is that consumers' impulsivity (a) differs according to type of good and (b) is linked systematically to a combination of materialistic values and high identity deficits. Beginning with Study 1, three experiments, using a temporal discounting paradigm, show consistently that discount rates are higher for goods that are seen as highly expressive of identity (e.g., clothes) than goods not expressive of identity (e.g., basic body care products). For materialistic consumers, identity deficits predict discount rates for identity‐expressive goods (Study 2), and discount rates change for materialistic individuals when their identity deficits are made salient (Study 3). These findings support a conceptualization of consumer impulsivity as identity‐seeking behaviour.
MAP3K1 functionally interacts with Axin1 in the canonical Wnt signalling pathway
Authors: Sue Ng Ser , Mahmoudi Tokameh , Li Vivian S.W. , Hatzis Pantelis , Boersema Paul J. , Mohammed Shabaz , Heck Albert J. , Clevers Hans
Published: February 2010

A central point of regulation in the Wnt/β-catenin signalling pathway is the formation of the β-catenin destruction complex. Axin1, an essential negative regulator of Wnt signalling, serves as a scaffold within this complex and is critical for rapid turnover of β-catenin. To examine the mechanism by which Wnt signalling disables the destruction complex, we used an immunoprecipitation-coupled proteomics approach to identify novel endogenous binding partners of Axin1. We found mitogen-activated protein kinase kinase kinase 1 (MAP3K1) as an Axin1 interactor in Ls174T colorectal cancer (CRC) cells. Importantly, confirmation of this interaction in HEK293T cells indicated that the Axin1-MAP3K1 interaction is induced and modulated by Wnt stimulation. siRNA depletion of MAP3K1 specifically abrogated TCF/LEF-driven transcription and Wnt3A-driven endogenous gene expression in both HEK293T as well as DLD-1 CRC. Expression of ubiquitin ligase mutants of MAP3K1 abrogated TCF/LEF transcription, whereas kinase mutants had no effect in TCF-driven activity, highlighting the essential role of the MAP3K1 E3 ubiquitin ligase activity in regulation of the Wnt/β-catenin pathway. These results suggest that MAP3K1, previously reported as an Axin1 inter-actor in c-Jun NH2-terminal kinase pathway, is also involved in the canonical Wnt signalling pathway and positively regulates expression of Wnt target genes.
Identification of novel peptide inhibitors for human trypsins
Authors: Wu Ping , Weisell Janne , Pakkala Miikka , Peräkylä Mikael , Zhu Lei , Koistinen Riitta , Koivunen Erkki , Stenman Ulf-Håkan , Närvänen Ale , Koistinen Hannu
Published: February 2010

Human trypsin isoenzymes share extensive sequence similarity, but certain differences in their activity and susceptibility to inhibitors have been observed. Using phage display technology, we identified seven different peptides that bind to and inhibit the activity of trypsin-3, a minor trypsin isoform expressed in pancreas and brain. All of the peptides contain at least two of the amino acids tryptophan, alanine and arginine, whereas proline was found closer to the N-terminus in all but one peptide. All peptides contain two or more cysteines, suggesting a cyclic structure. However, we were able to make synthetic linear variants of these peptides without losing bioactivity. Alanine replacement experiments for one of the peptides suggest that the IPXXWFR motif is important for activity. By molecular modeling the same amino acids were found to interact with trypsin-3. The peptides also inhibit trypsin-1, but only weakly, if at all, trypsin-2 and -C. As trypsin is a highly active enzyme which can activate protease-activated receptors and enzymes that participate in proteolytic cascades involved in tumor invasion and metastasis, these peptides might be useful lead molecules for the development of drugs for diseases associated with increased trypsin activity.
Glycome profiling using modern glycomics technology: technical aspects and applications
Authors: Vanderschaeghe Dieter , Festjens Nele , Delanghe Joris , Callewaert Nico
Published: February 2010

Glycomics research has become indispensable in many research fields such as immunity, signal transduction and development. Moreover, changes in the glycosylation of proteins and lipids have been reported in several diseases including cancer. The analysis of a complex post-translational modification such as glycosylation depends on the availability or development of appropriate analytical technologies. The research goal determines the sensitivity, resolution and throughput requirements and guides the choice of a particular technology. This review highlights the evolution of glycan profiling tools in the past 5 years. We focus on capillary electrophoresis, liquid chromatography, mass spectrometry and lectin microarrays.
A Geosynthetic Modular Block Connection Creep Test Apparatus, Methodology, and Interpretation
Authors: Bathurst Richard J. , Huang Bingquan
Published: February 2010

A test protocol for the quantification of creep between modular block (segmental) facing units and geosynthetic reinforcement can be found in a Federal Highway Administration guidance document first published in 2001. However, to date the utility of the proposed method has not been examined in a systematic manner nor have test results been reported in the research literature. The paper describes a test apparatus and reports the results of a series of connection creep tests that demonstrate details of the proposed methodology and lessons learned. Important recommendations for data interpretation are presented for the first time. An additional practical result of this study is a consistent method to calculate the connection creep reduction factor required for design using the results of conventional short-term connection test results and connection creep-rupture curves.
Vibrissa-Based Object Localization in Head-Fixed Mice
Authors: O'Connor Daniel H. , Clack Nathan G. , Huber Daniel , Komiyama Takaki , Myers Eugene W. , Svoboda Karel
Published: February 2010

Linking activity in specific cell types with perception, cognition, and action, requires quantitative behavioral experiments in genetic model systems such as the mouse. In head-fixed primates, the combination of precise stimulus control, monitoring of motor output, and physiological recordings over large numbers of trials are the foundation on which many conceptually rich and quantitative studies have been built. Choice-based, quantitative behavioral paradigms for head-fixed mice have not been described previously. Here, we report a somatosensory absolute object localization task for head-fixed mice. Mice actively used their mystacial vibrissae (whiskers) to sense the location of a vertical pole presented to one side of the head and reported with licking whether the pole was in a target (go) or a distracter (no-go) location. Mice performed hundreds of trials with high performance (>90% correct) and localized to <0.95 mm (<6° of azimuthal angle). Learning occurred over 1–2 weeks and was observed both within and across sessions. Mice could perform object localization with single whiskers. Silencing barrel cortex abolished performance to chance levels. We measured whisker movement and shape for thousands of trials. Mice moved their whiskers in a highly directed, asymmetric manner, focusing on the target location. Translation of the base of the whiskers along the face contributed substantially to whisker movements. Mice tended to maximize contact with the go (rewarded) stimulus while minimizing contact with the no-go stimulus. We conjecture that this may amplify differences in evoked neural activity between trial types.
Expression of COUP-TFII Nuclear Receptor in Restricted GABAergic Neuronal Populations in the Adult Rat Hippocampus
Authors: Fuentealba Pablo , Klausberger Thomas , Karayannis Theofanis , Suen Wai Yee , Huck Jojanneke , Tomioka Ryohei , Rockland Kathleen , Capogna Marco , Studer Michèle , Morales Marisela , Somogyi Peter
Published: February 2010

The COUP-TFII nuclear receptor, also known as NR2F2, is expressed in the developing ventral telencephalon and modulates the tangential migration of a set of subpallial neuronal progenitors during forebrain development. Little information is available about its expression patterns in the adult brain. We have identified the cell populations expressing COUP-TFII and the contribution of some of them to network activityin vivo. Expression of COUP-TFII by hippocampal pyramidal and dentate granule cells, as well as neurons in the neocortex, formed a gradient increasing from undetectable in the dorsal to very strong in the ventral sectors. In the dorsal hippocampal CA1 area, COUP-TFII was restricted to GABAergic interneurons and expressed in several, largely nonoverlapping neuronal populations. Immunoreactivity was present in calretinin-, neuronal nitric oxide synthase-, and reelin-expressing cells, as well as in subsets of cholecystokinin- or calbindin-expressing or radiatum-retrohippocampally projecting GABAergic cells, but not in parvalbumin- and/or somatostatin-expressing interneurons.In vivorecording and juxtacellular labeling of COUP-TFII-expressing cells revealed neurogliaform cells, basket cells in stratum radiatum and tachykinin-expressing radiatum dentate innervating interneurons, identified by their axodendritic distributions. They showed cell type-selective phase-locked firing to the theta rhythm but no activation during sharp wave/ripple oscillations. These basket cells in stratum radiatum and neurogliaform cells fired at the peak of theta oscillations detected extracellularly in stratum pyramidale, unlike previously reported ivy cells, which fired at the trough. The characterization of COUP-TFII-expressing neurons suggests that this developmentally important transcription factor plays cell type-specific role(s) in the adult hippocampus.
Corticofugal Control of Vibrissa-Sensitive Neurons in the Interpolaris Nucleus of the Trigeminal Complex
Authors: Furuta Takahiro , Urbain Nadia , Kaneko Takeshi , Deschênes Martin
Published: February 2010

Trigeminal sensory nuclei that give rise to ascending pathways of vibrissal information are heavily linked by intersubnuclear connections. This is the case, for instance, of the principal trigeminal nucleus, which receives strong inhibitory input from the caudal sector of the interpolaris subnucleus. Because this inhibitory input can gate the relay of sensory messages through the lemniscal pathway, a central issue in vibrissal physiology is how brain regions that project to the interpolaris control the activity of inhibitory cells. In the present study, we examined how corticotrigeminal neurons of the primary and second somatosensory cortical areas control the excitability of interpolaris cells. Results show that these two cortical areas exert a differential control over the excitability of projection cells and intersubnuclear interneurons, and that this control also involves the recruitment of inhibitory cells in the caudalis subnucleus. These results provide a basic circuitry for a mechanism of disinhibition through which the cerebral cortex can control the relay of sensory messages in the lemniscal pathway. It is proposed that top–down control of brainstem circuits is prompted by motor strategies, expectations, and motivational states of the animal.
Anti-Glucocorticoid Gene Therapy Reverses the Impairing Effects of Elevated Corticosterone on Spatial Memory, Hippocampal Neuronal Excitability, and Synaptic Plasticity
Authors: Dumas Theodore C. , Gillette Todd , Ferguson Deveroux , Hamilton Kelly , Sapolsky Robert M.
Published: February 2010

Moderate release of the major stress hormones, glucocorticoids (GCs), improves hippocampal function and memory. In contrast, excessive or prolonged elevations produce impairments. Enzymatic degradation and reformation of GCs help to maintain optimal levels within target tissues, including the brain. We hypothesized that expressing a GC-degrading enzyme in hippocampal neurons would attenuate the negative impact of an excessive elevation in GC levels on synaptic physiology and spatial memory. We tested this by expressing 11-β-hydroxysteroid dehydrogenase (type II) in dentate gyrus granule cells during a 3 d GC treatment followed by examination of synaptic responses in hippocampal slices or spatial performance in the Morris water maze. In adrenalectomized rats with basal GC replacement, additional GC treatments for 3 d reduced synaptic strength and promoted the expression of long-term depression at medial perforant path synapses, increased granule cell and CA1 pyramidal cell excitability, and impaired spatial reference memory (without influencing learning). Expression of 11-β-hydroxysteroid dehydrogenase (type II), mostly in mature dentate gyrus granule cells, reversed the effects of high GC levels on granule cell and pyramidal cell excitability, perforant path synaptic plasticity, and spatial memory. These data demonstrate the ability of neuroprotective gene expression limited to a specific cell population to both locally and trans-synaptically offset neurophysiological disruptions produced by prolonged increases in circulating stress hormones. This report supplies the first physiological explanation for previously demonstrated cognitive sparing by anti-stress gene therapy approaches and lends additional insight into the hippocampal processes that are important for memory.
BMPR1a and BMPR1b Signaling Exert Opposing Effects on Gliosis after Spinal Cord Injury
Authors: Sahni Vibhu , Mukhopadhyay Abhishek , Tysseling Vicki , Hebert Amy , Birch Derin , Mcguire Tammy L. , Stupp Samuel I. , Kessler John A.
Published: February 2010

Astrogliosis following spinal cord injury (SCI) involves an early hypertrophic response that is beneficial and a subsequent formation of a dense scar. We investigated the role of bone morphogenetic protein (BMP) signaling in gliosis after SCI and find that BMPR1a and BMPR1b signaling exerts opposing effects on hypertrophy. Conditional ablation of BMPR1a from glial fibrillary acidic protein (GFAP)-expressing cells leads to defective astrocytic hypertrophy, increased infiltration by inflammatory cells, and reduced axon density. BMPR1b-null mice conversely develop “hyperactive” reactive astrocytes and consequently have smaller lesion volumes. The effects of ablation of either receptor are reversed in the double knock-out animals. These findings indicate that BMPR1a and BMPR1b exert directly opposing effects on the initial reactive astrocytic hypertrophy. Also, BMPR1b knock-out mice have an attenuated glial scar in the chronic stages following injury, suggesting that it has a greater role in glial scar progression. To elucidate the differing roles of the two receptors in astrocytes, we examined the effects of ablation of either receptor in serum-derived astrocytesin vitro. We find that the two receptors exert opposing effects on the posttranscriptional regulation of astrocytic microRNA-21. Further, overexpression of microRNA-21 in wild-type serum-derived astrocytes causes a dramatic reduction in cell size accompanied by reduction in GFAP levels. Hence, regulation of microRNA-21 by BMP signaling provides a novel mechanism for regulation of astrocytic size. Targeting specific BMPR subunits for therapeutic purposes may thus provide an approach for manipulating gliosis and enhancing functional outcomes after SCI.
In the Developing Rat Hippocampus, Endogenous Activation of Presynaptic Kainate Receptors Reduces GABA Release from Mossy Fiber Terminals
Authors: Caiati Maddalena D. , Sivakumaran Sudhir , Cherubini Enrico
Published: February 2010

Presynaptic kainate receptors regulate synaptic transmission in several brain areas but are not known to have this action at immature mossy fiber (MF) terminals, which during the first week of postnatal life release GABA, which exerts into targeted cells a depolarizing and excitatory action. Here, we report that, during the first week of postnatal life, endogenous activation of GluK1 receptors by glutamate present in the extracellular space severely depresses MF-mediated GABAergic currents [GABAA-mediated postsynaptic currents (GPSCs)]. Activation of GluK1 receptors was prevented by treating the slices with enzymatic glutamate scavengers that enhanced the clearance of glutamate from the extracellular space. The depressant effect of GluK1 on MF-GPSCs was mediated by a metabotropic process sensitive to pertussis toxin. In the presence of U73122 (1-[6-[[(17b)-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione), a selective inhibitor of phospholipase C, along the transduction pathway downstream to G-protein, GluK1 activation increased the probability of GABA release, thus unveiling the ionotropic action of this receptor. In line with this type of action, we found that GluK1 enhanced MF excitability by directly depolarizing MF terminals via calcium-permeable cation channels. Furthermore, GluK1 dynamically regulated the direction of spike time-dependent plasticity occurring by pairing MF stimulation with postsynaptic spiking and switched spike time-dependent potentiation into depression. The GluK1-induced depression of MF-GPSCs would prevent excessive activation of the CA3 associative network by the excitatory action of GABA and the emergence of seizures in the immature brain.
Presynaptic Mitochondria in Functionally Different Motor Neurons Exhibit Similar Affinities for Ca2+But Exert Little Influence as Ca2+Buffers at Nerve Firing RatesIn Situ
Authors: Chouhan Amit K. , Zhang Jinhui , Zinsmaier Konrad E. , Macleod Gregory T.
Published: February 2010

Mitochondria accumulate within nerve terminals and support synaptic function, most notably through ATP production. They can also sequester Ca2+during nerve stimulation, but it is unknown whether this limits presynaptic Ca2+levels at physiological nerve firing rates. Similarly, it is unclear whether mitochondrial Ca2+sequestration differs between functionally different nerve terminals. We addressed these questions using a combination of synthetic and genetically encoded Ca2+indicators to examine cytosolic and mitochondrial Ca2+levels in presynaptic terminals of tonic (MN13-Ib) and phasic (MNSNb/d-Is) motor neurons inDrosophila, which, as we determined, fire during fictive locomotion at ∼42 Hz and ∼8 Hz, respectively. Mitochondrial Ca2+sequestration starts in both terminals at ∼250 nm, exhibits a similar Ca2+-uptake affinity (∼410 nm), and does not require Ca2+release from the endoplasmic reticulum. Nonetheless, mitochondrial Ca2+uptake in type Is terminals is more responsive to low-frequency nerve stimulation and this is due to higher cytosolic Ca2+levels. Since type Ib terminals have a higher mitochondrial density than Is terminals, it seemed possible that greater mitochondrial Ca2+sequestration may be responsible for the lower cytosolic Ca2+levels in Ib terminals. However, genetic and pharmacological manipulations of mitochondrial Ca2+uptake did not significantly alter nerve-stimulated elevations in cytosolic Ca2+levels in either terminal type within physiologically relevant rates of stimulation. Our findings indicate that presynaptic mitochondria have a similar affinity for Ca2+in functionally different nerve terminals, but do not limit cytosolic Ca2+levels within the range of motor neuron firing ratesin situ.
Network Dynamics during Development of Pharmacologically Induced Epileptic Seizures in RatsIn Vivo
Authors: Cymerblit-Sabba Adi , Schiller Yitzhak
Published: February 2010

In epilepsy, the cortical network fluctuates between the asymptomatic interictal state and the symptomatic ictal state of seizures. Despite their importance, the network dynamics responsible for the transition between the interictal and ictal states are largely unknown. Here we used multielectrode single-unit recordings from the hippocampus to investigate the network dynamics during the development of seizures evoked by various chemoconvulsantsin vivo. In these experiments, we detected a typical network dynamics signature that preceded seizure initiation. The preictal state preceding pilocarpine-, kainate-, and picrotoxin-induced seizures was characterized by biphasic network dynamics composed of an early desynchronization phase in which the tendency of neurons to fire correlated action potentials decreased, followed by a late resynchronization phase in which the activity and synchronization of the network gradually increased. This biphasic network dynamics preceded the initiation both of the initial seizure and of recurrent spontaneous seizures that followed. During seizures, firing of individual neurons and interneuronal synchronization further increased. These findings advance our understanding of the network dynamics leading to seizure initiation and may in future help in the development of novel seizure prediction algorithms.
The Cerebellum Harbors a Circadian Oscillator Involved in Food Anticipation
Authors: Mendoza Jorge , Pévet Paul , Felder-Schmittbuhl Marie-Paule , Bailly Yannick , Challet Etienne
Published: February 2010

The cerebellum participates in motor coordination as well as in numerous cerebral processes, including temporal discrimination. Animals can predict daily timing of food availability, as manifested by food-anticipatory activity under restricted feeding. By studyingex vivoclock gene expression byin situhybridization and recordingin vitro Per1-luciferasebioluminescence, we report that the cerebellum contains a circadian oscillator sensitive to feeding cues (i.e., whose clock gene oscillations are shifted in response to restricted feeding). Food-anticipatory activity was markedly reduced in mice injected intracerebroventricularly with an immunotoxin that depletes Purkinje cells (i.e., OX7-saporin). Mice bearing the hotfoot mutation (i.e.,Grid2ho/ho) have impaired cerebellar circuitry and mild ataxic phenotype.Grid2ho/homice fedad libitumshowed regular behavioral rhythms and day–night variations of clock gene expression in the hypothalamus and cerebellum. When challenged with restricted feeding, however,Grid2ho/homice did not show any food-anticipatory rhythms, nor timed feeding-induced changes in cerebellar clock gene expression. In hypothalamic arcuate and dorsomedial nuclei, however, shifts inPer1expression in response to restricted feeding were similar in cerebellar mutant and wild-type mice. Furthermore, plasma corticosterone and metabolites before mealtime did not differ between cerebellar mutant and wild-type mice. Together, these data define a role for the cerebellum in the circadian timing network and indicate that the cerebellar oscillator is required for anticipation of mealtime.
Fehlertolerante Regelung bei aktuatorähnlichen Fehlern mittels AbleitungsschätzungFault Tolerant Control in the case of Actuator Type of Faults based on Derivative Estimation
Authors: Mai Philipp , Hillermeier Claus
Published: February 2010

In diesem Beitrag wird eine Architektur zur fehlertoleranten Regelung vorgestellt, bei der aktuatorähnliche Fehler online diagnostiziert und durch den Regler kompensiert werden. Die Verwendung von Least-Squares-Ableitungsschätzern zur Fehleridentifikation führt Totzeiten in den Regelkreis ein. Im Rahmen einer Stabilitätsanalyse werden zulässige Totzeiten bestimmt, aus denen sich zulässige Einstellwerte der Verfahrensparameter ableiten lassen. Als Anwendungsfall wird ein Dreitanksystem untersucht.
The Addition Circuit of Zuse´s Z3 ComputerDer Addierer in Zuses Z3 Rechner
Authors: Heyne Georg , Darius Frank
Published: February 2010

This paper provides an overview of the addition circuits of the Z3 computing machine built by Konrad Zuse in 1941. The addition unit of the Z3 is interesting from a historical point of view because it had a binary architecture and used a carry-look-ahead technique similar to that used in modern processors. We built a portable replica of the addition circuits for display in museums. We show diagrams of the architecture and the layout of the reproduction.
Synthese reversibler LogikSynthesizing Reversible Logic
Authors: Wille Robert , Drechsler Rolf
Published: February 2010

Traditionelle Technologien (z. B. CMOS) stoßen durch die stetig steigende Miniaturisierung sowie das exponentielle Wachstum der Anzahl an Komponenten immer mehr an ihre Grenzen. Daher werden in Zukunft Alternativen, welche traditionelle Computerchips ersetzen oder zumindest ergänzen, benötigt. Reversible Logik mit ihren Anwendungen z. B. im Gebiet der Quantencomputer, des Low-Power Designs, des Optical Computing, des DNA Computing oder in der Nanotechnologie stellt eine solche Alternative dar und hat sich daher in den vergangenen Jahren zu einem intensiv untersuchten Forschungsgebiet entwickelt. Allerdings unterscheidet sich die Synthese von reversiblen Schaltkreisen deutlich von der traditionellen Logiksynthese. So sind insbesondere Verzweigungen (Fanouts) und Rückkopplungen (Feedback durch FlipFlops) nicht möglich, sodass reversible Schaltkreise aus Kaskaden von reversiblen Gattern bestehen. Dies erfordert komplett neue Syntheseansätze. Die vorliegende Arbeit gibt eine Einführung in das Thema und stellt ausgewählte Syntheseverfahren für reversible Logik im Überblick vor. Dabei werden reversible Funktionen und Schaltkreise zuerst eingeführt, wobei insbesondere der Aspekt der Einbettung von irreversiblen Funktionen detailliert betrachtet wird. Anschließend wird beschrieben, wie sich solche Funktionen (gegeben in Form einer Wahrheitstabelle) mit Hilfe von exakten und heuristischen Verfahren synthetisieren lassen. Da die Beschreibung in Form einer Wahrheitstabelle generell nur für kleine Funktionen anwendbar ist, wird schließlich noch ein Syntheseansatz beschrieben, welcher binäre Entscheidungsdiagramme (engl.: BDDs) verwendet und damit die Synthese deutlich größerer Funktionen ermöglicht.
Optimierung bioverfahrenstechnischer Prozesse mittels sensorgestütztem MikrobioreaktorOptimization of Biochemical Engineering Processes by Means of a Sensor-Supported Microbioreactor
Authors: Päßler Sandra , Herrmann Sigrun , Bertau Martin , Vonau Winfried
Published: February 2010

Es werden Ergebnisse der Entwicklung und Erprobung eines komplexen Mikroreaktionssystems mit integrierter elektrochemischer Sensorik zur Überwachung und Optimierung biotechnologischer Prozesse vorgestellt. Zur Kontrolle der in einem röhrenförmigen Bioreaktor ablaufenden Reaktionen wurden unterschiedliche prozessrelevante Parameter bei einer Ganzzell-Biotransformation gemessen.
Konzentrationsbestimmung in Wasser-Zucker-Ethanol-Gemischen mittels adiabatischer Kompressibilität und DichteConcentration Determination in Water-Sugar-Ethanol-Mixtures via Adiabatic Compressibility and Density
Authors: Schöck Thomas , Hussein Mohamed , Becker Thomas
Published: February 2010

Bei alkoholischen Hefefermentationsprozessen in der zuckerverarbeitenden Industrie ist es wichtig, die Konzentrationen von Zucker und Ethanol im Fermentationsfluid als Indikatoren für den Reaktionsfortschritt genau zu kennen. Die vorliegende Arbeit beschreibt ein neues Verfahren zur Konzentrationsbestimmung, das sich der physikalischen Parameter adiabatische Kompressibilität und Dichte bedient, die aus den vom einem Ultraschallsensor bei einem Messvorgang simultan gemessenen Größen Schallgeschwindigkeit und akustische Impedanz berechnet werden können. Die Genauigkeit des Verfahrens liegt bei einer Massekonzentration von ca. 0,05 g/100 g.
Acute and 2-week exposure to prednisolone impair different aspects of β-cell function in healthy men
Authors: van Raalte Daniël H , Nofrate Valentina , Bunck Mathijs C , van Iersel Thijs , Elassaiss Schaap Jeroen , Nässander Ulla K , Heine Robert J , Mari Andrea , Dokter Wim H A , Diamant Michaela
Published: February 2010

Objective

Glucocorticoids (GCs), such as prednisolone, are associated with adverse metabolic effects, including glucose intolerance and diabetes. In contrast to the well known GC-induced insulin resistance, the effects of GCs on β-cell function are less well established. We assessed the acute and short-term effects of prednisolone treatment on β-cell function in healthy men.

Research design and methods

A randomised, double-blind, placebo-controlled trial consisting of two protocols was conducted. In protocol 1 (n=6), placebo and a single dose of 75 mg of prednisolone were administered. In protocol 2 (n=23), participants received 30 mg of prednisolone daily or placebo for 15 days. Both empirical and model-based parameters of β-cell function were calculated from glucose, insulin and C-peptide concentrations obtained during standardised meal tests before and during prednisolone treatment (protocols 1 and 2), and 1 day after cessation of treatment (protocol 2).

Results

Seventy-five milligrams of prednisolone acutely increased the area under the postprandial glucose curve (AUCgluc;P=0.005), and inhibited several parameters of β-cell function, including AUCc-pep/AUCglucratio (P=0.004), insulinogenic index (P=0.007), glucose sensitivity (P=0.02) and potentiation factor ratio (PFR;P=0.04). A 15-day treatment with prednisolone increased AUCgluc(P<0.001), despite augmented C-peptide secretion (P=0.05). β-cell function parameters were impaired, including the fasting insulin secretory tone (P=0.02) and PFR (P=0.007).

Conclusions

Acute and short-term exposure to prednisolone impairs different aspects of β-cell function, which contribute to its diabetogenic effects.
From bodily co-regulation to language and thinking
Authors: Cowley Stephen J.
Published: February 2010

Though amenable to formal analysis, unlike a man-made program, language colours experience. Recognising this Michael Tomasello and Derek Melser trace linguistic skills to bodily co-regulation. Applauding this, I contrast their mentalist and antimentalist approaches. While Melser traces language to co-action, Tomasello posits a competence in decoding intentions. While a parsimonious alternative to intention reading, Melser’s actional view fails to explain how children learn to hear words. In Tomasello’s terms, he offers no account of how concrete constructions come to sustain description in terms of (inner) intentions. While Tomasello posits that the problem is solved ‘in the head’, there is a simpler solution. Although conventions matter, children make things up: they learn as they act with expression. Were the problem of concrete constructions resolved, imagination would become crucial to the rise of thinking. Can we fill the gap? Melser separates action from biomechanics and Tomasello reduces language to convention. Both ignore real-time events. By contrast Love (2007) identifies first-order language with on-line sign-making. Using this idea, I link the strengths of Melser and Tomasello’s models. Once co-regulated, semiosis can shape action (including speech) around meanings (and adult goals). Babies orient to what caregivers hear as words. Without intention-reading, neural schema shape acting, speaking and understanding. Concrete constructions arise in the flow of co-action. In becoming a person, a baby makes things up, uses convention and gradually takes responsibility for what she says and thinks.
Old houses, linguistics and literature in schools
Authors: Lin Benedict
Published: February 2010

This article seeks to demonstrate how socially relevant linguistic analysis, using a sufficiently ‘extravagant’ theoretical framework, can provide a founded argument for the value of particular literary texts – and more generally the social, cultural and intellectual worth of literature – in a school curriculum. Through a stylistic analysis using Systemic Functional Grammar of a poem by one of Singapore’s foremost writers, it examines how its language patterns artistically coalesce into a secondary patterning to encode important socio-historical information and thematic issues of relevance to National Education, a key concern of Singapore schools. Thus, it reveals and suggests how literature can be used to meet this concern, as well as another key concern, the stimulation of critical and creative thinking, while simultaneously enhancing awareness of the power of language in the construction of meaning. In so doing, it suggests how literature should have a central place in the school curriculum.
Docetaxel Plus Trastuzumab as Treatment for Her-2 Positive Metastatic Breast Cancer: Review of the Existing Evidence
Authors: Demonty Gaston
Published: February 2010

The aim of this review is to examine the evidence available supporting the use of the docetaxel plus trastuzumab combination for patients with HER-2-positive metastatic breast cancer. The results of trials involving this combination are summarized, with an emphasis on efficacy and cardiotoxicity data. Finally, this article attempts to identify areas of uncertainty where new trials are warranted to improve our knowledge regarding optimal care for patients with HER-2-positive metastatic breast cancer.
Extended-Cycle Oral Contraceptive Pills with 10 μG Ethinyl Estradiol Pills in Place of Placebo Pills
Authors: Nelson Anita L
Published: February 2010

The elimination of monthly withdrawal bleeding with use of extended-cycle (84 pills) monophasic birth-control pills has modernized oral contraceptives. The use of ethinyl estradiol 10 μg pills in place of the seven placebo pills addresses the problems posed by 21/7 formulations of low-dose birth-control pills, which allow early stimulation of ovarian follicles, and of the early 84/7 formulations, which had higher rates of unscheduled bleeding and spotting.
Eliminating Monthly Periods with Combined Hormonal Contraception
Authors: Gerschultz Kelly L , Sucato Gina S
Published: February 2010

Combined hormonal contraceptives have been increasingly marketed and prescribed in extended regimens to manage menstrual-cycle-related complaints and accommodate patients’ preferences. Extended regimens provide less frequent menstruation and may confer better ovarian follicular suppression and, thus, more effective pregnancy prevention. Most healthcare providers prescribe extended regimens and believe that menstrual suppression is safe; many women, when given the choice, would prefer to menstruate less frequently. However, most women will experience breakthrough bleeding, which may limit patient acceptance of an extended regimen. Recent studies have addressed strategies for minimizing unscheduled bleeding, but further research is needed to identify how best to tailor regimens to the medical needs and preferences of individual women.
Liposomal Doxorubicin in Breast Cancer
Authors: Shehata M , Mukherjee A , Sharma R , Chan S
Published: February 2010

Drug-delivery carriers represent an important step in the development of targeted therapy. Encapsulation of drug into liposomes represents such a carrier, and helps to minimize side effects of conventional doxorubicin by improving the tumor-specific biodistribution profile. We review the development of the two liposomal doxorubicin formulations, pegylated liposomal doxorubicin and liposomal-encapsulated doxorubicin citrate from reconstitution and comparative pharmacokinetics to pivotal Phase III trials, with special emphasis in breast cancer. The relative differences in the toxicity profile can be attributed to their differences in the liposomal formulations. Areas of special interest include the reduction in cardiac toxicities and the improved efficacy, such as in the treatment of ovarian cancer. These improvements have also increased the potential of these liposomal formulations of doxorubicin for combination and sequencing with other biological and cytotoxic agents for clinical benefit.
Prediction of Pre-Eclampsia in Early Pregnancy
Authors: Rogers Mike S
Published: February 2010

Pre-eclampsia is a multisystem disorder of pregnancy, usually characterized by the appearance of high blood pressure and the excretion of protein in the urine of a previously healthy woman. Symptoms and signs vary in intensity from woman to woman; from a borderline rise in blood pressure, to convulsions (eclampsia), stroke and death. The disease remits following removal of the placenta and so the mainstay of current treatment is timely delivery. A pathophysiological framework of the disease has been established, beginning with failures in placental development, inducing oxidative stress and release of compounds that lead to endothelial activation, vasoconstriction and glomerular endotheliosis. A combination of epidemiological, biophysical and biochemical tests now allow most patients at-risk to be identified by midpregnancy, whilst minimizing false-positive prediction. It is hoped that earlier classification of patients at-risk of the disease, on the basis of pathophysiological changes, will enable specific therapies to be developed targeting these changes.
Provoked Vestibulodynia
Authors: Pukall Caroline F , Smith Kelly B , Chamberlain Susan M
Published: February 2010

Vulvodynia, or chronic vulvar pain, is a common but poorly understood condition. Affected women report negative impacts in terms of sexual functioning, relationship adjustment, psychological well-being and overall quality of life. Although the etiology of vulvodynia is not well understood, it appears as if different levels of pathophysiology are implicated. Accordingly, therapeutic options are targeted at a variety of mechanisms. Unfortunately, few randomized, controlled trials exist, and few combination therapies have been examined; however, the quality and breadth of the treatment literature is improving. Further studies are needed to more fully investigate the mechanisms involved in the development and maintenance of vulvodynia, and more research in the area of treatment outcome is needed.