bluuebunny/crossref_metadata_2025 huggingface dataset:
Critically Elevated INR in a Patient on Warfarin After Increase in Extended-Release Niacin Dose
Authors: Christopher Amy
Published: October 2011

Objective:

To report a case of a probable interaction between warfarin and extended-release niacin that may have led to synergistic coagulopathy and to inform health care providers of a need for more frequent monitoring of international normalized ratio (INR) in patients taking these drugs concomitantly.

Case Summary:

A 69-year-old white female whose anticoagulation treatment had been stable for 18 months with warfarin 2.5 mg daily (17.5 mg/wk) presented to an anticoagulation clinic with a critically elevated INR of greater than 12.3 after a dose increase in extended-release niacin (Niaspan) from 500 mg to 1000 mg daily the previous week. Extended-release niacin 500 mg daily had not affected the patient's INR for the previous 3 months; the most recent INR before this episode was 2.4. Warfarin was withheld and extended-release niacin was discontinued. The INR 2 days later was 4.8 and, with titration of warfarin to the previous maintenance dose of 2.5 mg daily, the INR was 2.3.

Discussion:

Common drug interaction resources do not consistently list an interaction between warfarin and extended-release niacin. The mechanism of niacin-induced coagulopathy is theorized to be related to diminished coagulation factors, and limited data suggest that this may be more pronounced with extended-release niacin. Because of the described effects of niacin on the coagulation cascade and the possibility for pharmacokinetic interactions, there is a potential for synergistic coagulopathy when combined with warfarin therapy. For patients taking both medications, more frequent INR monitoring than that which drug interaction references suggest may be advised. An objective causality assessment (Horn Drug Interaction Probability Scale) revealed that the interaction was probable.

Conclusions:

An interaction between niacin and warfarin likely elevated the INR in this patient because of synergistic coagulopathy and pharmacokinetic effects of niacin. Increased frequency of INR monitoring may be advised for patients taking these drugs concomitantly.
Implementation of an Enoxaparin Protocol for Venous Thromboembolism Prophylaxis in Obese Surgical Intensive Care Unit Patients
Authors: Ludwig Kyle P , Simons Heidi J , Mone Mary , Barton Richard G , Kimball Edward J
Published: October 2011

Background::

Venous thromboembolism (VTE) is a serious health care issue that affects a large number of people. Few standards exist for delineating the optimal dosing strategy for VTE prevention in obese patients, especially in the setting of major surgery or trauma.

Objective:

To document the efficacy of a surgical intensive care unit (SICU)–specific, weight-based dosing protocol of enoxaparin 0.5 mg/kg given subcutaneously every 12 hours for VTE prophylaxis in morbidly obese (defined as body mass index [BMI] ≥35 kg/m2 or weight ≥150 kg) SICU patients, using peak anti-factor Xa levels to determine therapeutic endpoints.

Methods:

Data were collected retrospectively in an academic, university-based SICU on 23 morbidly obese patients who received weight-based enoxaparin for VTE prophylaxis from December 1, 2008, through June 30, 2010.

Results:

A weight-based dosage range of enoxaparin 50-120 mg twice daily (median 60) was given to 23 patients. The mean BMI was 46.4 kg/m2. The initial mean anti-factor Xa level (measured after the third dose) was 0.34 IU/mL (range 0.20-0.59). Patients received an average of 18 doses. Two cases required an increase or decrease in dosage based on anti-factor Xa levels. Morbidity related to this dosing included a single event of minor endotracheal bleeding and a single deep vein thrombosis that was likely present prior to treatment.

Conclusions:

Weight-based dosing with enoxaparin in morbidly obese SICU patients was effective in achieving anti-factor Xa levels within the appropriate prophylactic range. This regimen reduced the rate of VTE below expected levels and no additional adverse effects were reported.
Atrial Flutter Associated with Carboplatin Administration
Authors: Zakaria Sammy , Lu Kit Yu , Nussenblatt Veronique , Browner Ilene
Published: October 2011

Objective:

To report a novel case of atrial flutter associated with carboplatin administration and review chemotherapy-related cardiac toxicities, focusing on platinum-containing compounds.

Case Report:

A 69-year-old man with extensive small cell lung cancer and asymptomatic cardiovascular and cerebrovascular disease was inconsistently adherent to his medication regimen. While undergoing carboplatin infusion, he developed atrial flutter. He had no other immediate arrhythmogenic causes of atrial flutter and the arrhythmia spontaneously reverted to sinus rhythm after 24 hours. His condition remained stable until he died 8 days later. The cause of death was unknown and the family declined postmortem examination.

Discussion:

Although this patient's cardiac history and nonadherence to his medications may have increased his susceptibility to develop atrial arrhythmias, the Naranjo probability scale reveals a possible relationship between atrial flutter and Infusion of carboplatin. A literature search revealed other adverse cardiac events due to platinum compounds; however, to our knowledge, this case is the first to describe an association with atrial flutter. A definitive causal link cannot be determined, but this may have been the result of a direct arrhythmogenic effect of treatment or to a novel hypersensitivity reaction. Given the potential deleterious impact of drug-induced arrhythmias, we have reported this case to the Food and Drug Administration as a new adverse effect of carboplatin.

Conclusions:

Providers should consider cardiac monitoring during carboplatin infusion in patients with known cardiac disease or at high risk of cardiac complications.
Clinical Experience with Aminoglycosides in Dialysis-Dependent Patients: Risk Factors for Mortality and Reassessment of Current Dosing Practices
Authors: Heintz Brett H , Thompson George R , Dager William E
Published: October 2011

Background::

A resurgence of aminoglycoside use has followed the recent increase of multidrug-resistant gram-negative pathogens and is often needed even in the treatment of dialysis-dependent patients; however, studies evaluating the treatment of gram-negative infections with aminoglycosides, including the optimal dose, in the setting of dialysis are limited.

Objective:

To evaluate the current patterns of aminoglycoside use, including microbiologic and clinical indications, and identify risk factors associated with mortality in dialysis-dependent patients receiving aminoglycosides.

Methods:

Utilization, clinical, and microbiologic data were collected retrospectively over a 2-year period (July 2008-June 2010) for adults with a diagnosis of renal failure requiring dialysis and aminoglycoside therapy. Binary logistic and multivariate regression analyses were performed to identify risk factors for alt-cause 30-day mortality.

Results:

Ninety-five consecutive aminoglycoside courses in 88 patients met inclusion criteria for evaluation. A wide variety of clinical and microbiologic indications were documented. The average duration of aminoglycoside therapy was 5.2 days (range 1-42), the average duration of antimicrobial therapy was 13.5 days (1-60), and the all-cause 30-day mortality rate was 36.5%. Factors associated with all-cause 30-day mortality were gram-negative rod (GNR) bacteremia (OR 28.6; p = 0.035), advanced age (OR 8.5; p = 0.030), recent admission (OR 33.4; p = 0.038). and inadequate empiric therapy (OR 14.9; p = 0.024). Intravenous catheter removal was protective of all-cause 30-day mortality (OR 0.01; p = 0.005). A first pre-dialysis plasma concentration relative to the minimum inhibitory concentration (Cp:MIC) <6 mg/L (gentamicin/tobramycin) was associated with an increased risk of mortality (p = 0.026) upon subgroup analysis of dialysis-dependent patients with GNR bloodstream infections.

Conclusions:

Outcomes among dialysis-dependent patients who received aminoglycosides were below expectations. Various risk factors for mortality were identified, including retention of the catheter, inadequate empiric therapy, and a Cp:MIC <6 mg/L. Improved approaches to dosing of aminoglycosides in dialysis-dependent patients, including more aggressive dosing practices, should be urgently explored in attempts to maximize favorable patient outcomes.
Measuring Attachment Dimensions in Adolescents: Development and Validation of the Experiences in Close Relationships — Revised — General Short Form
Authors: Wilkinson Ross B.
Published: October 2011

The assessment of attachment in adolescence remains problematic, with the most widely used measure, the Inventory of Parent and Peer Attachment (IPPA; Armsden & Greenberg, 1987), argued to have major short-comings. This article reports two studies examining the psychometric properties of a shortened and modified version of the Experiences in Close Relationships — Revised (ECR-R) (Fraley, Waller, & Brennan, 2000), the Experiences in Close Relationships — Revised — General Short Form (ECR-R-GSF), for the assessment of general relationship attachment anxiety and avoidance in adolescents and young adults. Confirmatory factor analyses in two independent samples of high school and university students (TotalN= 1187, 11 to 22 years) demonstrate support for the two-factor model of attachment anxiety and avoidance. The measurement model was supported across data sets and was not significantly different with respect to either age or sex. While the ECR-R-GSF demonstrated appropriate convergent and discriminant validity with the Relationships Questionnaire (RQ (Bartholomew & Horowitz, 1991) it did not converge with specific, parental relationship attachment as assessed by the IPPA. The ECR-R-GSF is argued to be a reliable and psychometrically sound instrument for assessing general attachment dimensions across a wide age range.
Pro-healing effects of morin, a natural antioxidant, on normal and dexamethasone-impaired wounds
Authors: Shenoy Rekha Raghuveer , Sudheendra Arun Theerthahalli , Nayak Pawan Ganesh , Paul Piya , Kutty Nampurath Gopalan , Rao Chamallamudi Mallikarjuna
Published: October 2011

Background: The aim of the study was to investigate the effects of morin on skin breaking strength, hydroxyproline, lysyl oxidase, DNA and RNA content of experimentally inflicted wounds in rats.

Methods: This study was performed on albino rats of either sex at the Central Animal Research Facility (CARF), Manipal University.

Results: Morin showed significant wound contraction on day 7 as compared to control with mean closure of 47.44±6.07% in excision wound model. Granulation tissue breaking strength was significantly increased (p<0.05) in the morin treated group with 180.2±7.94 g when compared to control at 151.2±6.99 g. There was a significant increase in hydroxyproline content with the morin treated group when compared to control with 3.41±0.33 μg/mg of granulation tissue. Similarly, the wound parameters were improved with the morin treated group in dexamethasone delayed healing.

Conclusions: Our results suggest that morin treatment accelerates the healing process delayed by concurrent use of steroids.
Principles of Design and Installation of Below-Grade and Building Deck Waterproofing in 2010
Authors: Rutila Dean A. , Klein Kenneth A. , Normandeau Matthew J.
Published: October 2011

The introduction of new materials, the innovative use of various construction methods, and the popularity of vegetative (green) roofs make it timely to update and expand the 1990 article, “Principles of Design and Installation of Building Deck Waterproofing” [Ruggiero, S. S. and Rutila, D. A., “Principles of Design and Installation of Building Deck Waterproofing,” Building Deck Waterproofing, ASTM STP 1084, L.E. Gish, Ed., ASTM International, West Conshohocken, PA, 1990, p. 5. We review the state of the art for materials and practices, and apply the lessons learned over the past 20 years of below-ground and building deck waterproofing. Of particular importance are the following: Performance and durability advancements in fluid-applied systems have resulted in increased use. New chemical formulations as well as recognition of settled technologies that work allow some fluid-applied membranes to demonstrate proven durability equal to sheet membrane systems. Sodium bentonite-polymer composite systems resolve many past performance questions and often provide advantages over other options. Blind-side and other foundation waterproofing systems are increasingly driven by foundation forming and concrete placement, and support of excavation designs. Vegetative (green) roofing has created challenges not completely addressed by “plaza waterproofing” designs, but key principles of deck waterproofing must still be applied to vegetative roofing.
Where fMRI and Electrophysiology Agree to Disagree: Corticothalamic and Striatal Activity Patterns in the WAG/Rij Rat
Authors: Mishra Asht Mangal , Ellens Damien J. , Schridde Ulrich , Motelow Joshua E. , Purcaro Michael J. , DeSalvo Matthew N. , Enev Miro , Sanganahalli Basavaraju G. , Hyder Fahmeed , Blumenfeld Hal
Published: October 2011

The relationship between neuronal activity and hemodynamic changes plays a central role in functional neuroimaging. Under normal conditions and in neurological disorders such as epilepsy, it is commonly assumed that increased functional magnetic resonance imaging (fMRI) signals reflect increased neuronal activity and that fMRI decreases represent neuronal activity decreases. Recent work suggests that these assumptions usually hold true in the cerebral cortex. However, less is known about the basis of fMRI signals from subcortical structures such as the thalamus and basal ganglia. We used WAG/Rij rats (Wistar albino Glaxo rats of Rijswijk), an established animal model of human absence epilepsy, to perform fMRI studies with blood oxygen level-dependent and cerebral blood volume (CBV) contrasts at 9.4 tesla, as well as laser Doppler cerebral blood flow (CBF), local field potential (LFP), and multiunit activity (MUA) recordings. We found that, during spike-wave discharges, the somatosensory cortex and thalamus showed increased fMRI, CBV, CBF, LFP, and MUA signals. However, the caudate–putamen showed fMRI, CBV, and CBF decreases despite increases in LFP and MUA signals. Similarly, during normal whisker stimulation, the cortex and thalamus showed increases in CBF and MUA, whereas the caudate–putamen showed decreased CBF with increased MUA. These findings suggest that neuroimaging-related signals and electrophysiology tend to agree in the cortex and thalamus but disagree in the caudate–putamen. These opposite changes in vascular and electrical activity indicate that caution should be applied when interpreting fMRI signals in both health and disease from the caudate–putamen, as well as possibly from other subcortical structures.
Oligomeric-Induced Activity by Thienyl Pyrimidine Compounds Traps Prion Infectivity
Authors: Ayrolles-Torro Adeline , Imberdis Thibaut , Torrent Joan , Toupet Karine , Baskakov Ilia V. , Poncet-Montange Guillaume , Grégoire Catherine , Roquet-Baneres Françoise , Lehmann Sylvain , Rognan Didier , Pugnière Martine , Verdier Jean-Michel , Perrier Véronique
Published: October 2011

Accumulation of PrPSc, an abnormal form of cellular prion protein (PrP), in the brain of animals and humans leads to fatal neurodegenerative disorders known as prion diseases. Limited protease digestion of PrPScproduces a truncated form called PrP(27–30) that retains prion infectivity and is the main marker of disease targeted in most diagnostic tests. In the search for new anti-prion molecules, drug-screening assays on prion-infected murine cells have been oriented toward decreasing levels of PrP(27–30). In contrast, we screened for drugs promoting multimers of PrP(27–30), illustrating a possible stabilization of mouse PrPScspecies, because recent studies aiming to characterize the conformational stability of various prion strains showed that stable recombinant amyloids produced more stable prion strain, leading to longest incubation time. We identified a family of thienyl pyrimidine derivatives that induce SDS-resistant dimers and trimers of PrP(27–30). Bioassays performed on mice brain homogenates treated with these compounds showed that these thienyl pyrimidine derivatives diminished prion infectivityin vivo. Oligomeric-induced activity by thienyl pyrimidine compounds is a promising approach not only to understanding the pathogenesis of prions but also for prion diagnostics. This approach could be extended to other neurodegenerative “prionopathies,” such as Alzheimer's, Huntington, or Parkinson's diseases.
Blood-Borne Angiotensin II Acts in the Brain to Influence Behavioral and Endocrine Responses to Psychogenic Stress
Authors: Krause Eric G. , de Kloet Annette D. , Scott Karen A. , Flak Jonathan N. , Jones Kenneth , Smeltzer Michael D. , Ulrich-Lai Yvonne M. , Woods Stephen C. , Wilson Steven P. , Reagan Lawrence P. , Herman James P. , Sakai Randall R.
Published: October 2011

This study elucidates the neural circuits by which circulating angiotensin II (ANGII) acts in the brain to influence humoral and behavioral responses to psychological stressors. To test the hypothesis that systemic ANGII mediates stress responding via the subfornical organ (SFO), we first found that the timing of increased systemic ANGII in response to 60 min restraint coincides with increasedc-fosmRNA expression in the SFO. Next, we administered an anterograde neuronal tract tracer into the SFO and found that fibers originating there make appositions onto neurons in the paraventricular nucleus of the hypothalamus that are alsoc-fospositive following restraint stress. To determine whether circulating ANGII stimulates the release of stress hormones via activation of angiotensin type 1 receptors (AT1R) within the SFO, we delivered lentivirus to knockdown AT1R expression locally in the SFO. Inhibition of AT1R specifically within the SFO blunted the release of adrenocorticotrophin-releasing hormone and corticosterone in response to restraint stress and caused rats to spend more time in the open arms of an elevated-plus maze than controls, indicating that inhibition of AT1R within the SFO is anxiolytic. Collectively, these results suggest that circulating ANGII acts on AT1R in the SFO to influence responding to psychological stressors.
Intact Bilateral Resting-State Networks in the Absence of the Corpus Callosum
Authors: Tyszka J. Michael , Kennedy Daniel P. , Adolphs Ralph , Paul Lynn K.
Published: October 2011

Temporal correlations between different brain regions in the resting-state BOLD signal are thought to reflect intrinsic functional brain connectivity (Biswal et al., 1995; Greicius et al., 2003; Fox et al., 2007). The functional networks identified are typically bilaterally distributed across the cerebral hemispheres, show similarity to known white matter connections (Greicius et al., 2009), and are seen even in anesthetized monkeys (Vincent et al., 2007). Yet it remains unclear how they arise. Here we tested two distinct possibilities: (1) functional networks arise largely from structural connectivity constraints, and generally require direct interactions between functionally coupled regions mediated by white-matter tracts; and (2) functional networks emerge flexibly with the development of normal cognition and behavior and can be realized in multiple structural architectures. We conducted resting-state fMRI in eight adult humans with complete agenesis of the corpus callosum (AgCC) and normal intelligence, and compared their data to those from eight healthy matched controls. We performed three main analyses: anatomical region-of-interest-based correlations to test homotopic functional connectivity, independent component analysis (ICA) to reveal functional networks with a data-driven approach, and ICA-based interhemispheric correlation analysis. Both groups showed equivalently strong homotopic BOLD correlation. Surprisingly, almost all of the group-level independent components identified in controls were observed in AgCC and were predominantly bilaterally symmetric. The results argue that a normal complement of resting-state networks and intact functional coupling between the hemispheres can emerge in the absence of the corpus callosum, favoring the second over the first possibility listed above.
An Olfactory Circuit Increases the Fidelity of Visual Behavior
Authors: Chow Dawnis M. , Theobald Jamie C. , Frye Mark A.
Published: October 2011

Multimodal integration allows neural circuits to be activated in a behaviorally context-specific manner. In the case of odor plume tracking byDrosophila, an attractive odorant increases the influence of yaw-optic flow on steering behavior in flight, which enhances visual stability reflexes, resulting in straighter flight trajectories within an odor plume. However, it is not well understood whether context-specific changes in optomotor behavior are the result of an increased sensitivity to motion inputs (e.g., through increased visual attention) or direct scaling of motor outputs (i.e., increased steering gain). We address this question by examining the optomotor behavior ofDrosophila melanogasterin a tethered flight assay and demonstrate that whereas olfactory cues decrease the gain of the optomotor response to sideslip optic flow, they concomitantly increase the gain of the yaw optomotor response by enhancing the animal's ability to follow transient visual perturbations. Furthermore, ablating the mushroom bodies (MBs) of the fly brain via larval hydroxyurea (HU) treatment results in a loss of olfaction-dependent increase in yaw optomotor fidelity. By expressing either tetanus toxin light chain or diphtheria toxin in gal4-defined neural circuits, we were able to replicate the loss of function observed in the HU treatment within the lines expressing broadly in the mushroom bodies, but not within specific mushroom body lobes. Finally, we were able to genetically separate the yaw responses and sideslip responses in our behavioral assay. Together, our results implicate the MBs in a fast-acting, memory-independent olfactory modification of a visual reflex that is critical for flight control.
Stathmin is Required for Stability of theDrosophilaNeuromuscular Junction
Authors: Graf Ethan R. , Heerssen Heather M. , Wright Christina M. , Davis Graeme W. , DiAntonio Aaron
Published: October 2011

Synaptic connections can be stably maintained for prolonged periods, yet can be rapidly disassembled during the developmental refinement of neural circuitry and following cytological insults that lead to neurodegeneration. To date, the molecular mechanisms that determine whether a synapse will persist versus being remodeled or eliminated remain poorly understood. Mutations inDrosophila stathminwere isolated in two independent genetic screens that sought mutations leading to impaired synapse stability at theDrosophilaneuromuscular junction (NMJ). Here we demonstrate that Stathmin, a protein that associates with microtubules and can function as a point of signaling integration, is necessary to maintain the stability of theDrosophilaNMJ. We show that Stathmin protein is widely distributed within motoneurons and that loss of Stathmin causes impaired NMJ growth and stability. In addition, we show thatstathminmutants display evidence of defective axonal transport, a common feature associated with neuronal degeneration and altered synapse stability. The disassembly of the NMJ instathminincludes a predictable sequence of cytological events, suggesting that a common program of synapse disassembly is induced following the loss of Stathmin protein. These data define a required function for Stathmin during synapse maintenance in a model system in which there is only a singlestathmingene, enabling future genetic investigation of Stathmin function with potential relevance to the cause and progression of neuromuscular degenerative disease.
Properties of Slow Oscillation during Slow-Wave Sleep and Anesthesia in Cats
Authors: Chauvette Sylvain , Crochet Sylvain , Volgushev Maxim , Timofeev Igor
Published: October 2011

Deep anesthesia is commonly used as a model of slow-wave sleep (SWS). Ketamine–xylazine anesthesia reproduces the main features of sleep slow oscillation: slow, large-amplitude waves in field potential, which are generated by the alternation of hyperpolarized and depolarized states of cortical neurons. However, direct quantitative comparison of field potential and membrane potential fluctuations during natural sleep and anesthesia is lacking, so it remains unclear how well the properties of sleep slow oscillation are reproduced by the ketamine–xylazine anesthesia model. Here, we used field potential and intracellular recordings in different cortical areas in the cat to directly compare properties of slow oscillation during natural sleep and ketamine–xylazine anesthesia. During SWS cortical activity showed higher power in the slow/delta (0.1–4 Hz) and spindle (8–14 Hz) frequency range, whereas under anesthesia the power in the gamma band (30–100 Hz) was higher. During anesthesia, slow waves were more rhythmic and more synchronous across the cortex. Intracellular recordings revealed that silent states were longer and the amplitude of membrane potential around transition between active and silent states was bigger under anesthesia. Slow waves were mostly uniform across cortical areas under anesthesia, but in SWS, they were most pronounced in associative and visual areas but smaller and less regular in somatosensory and motor cortices. We conclude that, although the main features of the slow oscillation in sleep and anesthesia appear similar, multiple cellular and network features are differently expressed during natural SWS compared with ketamine–xylazine anesthesia.
Resolving TRPV1- and TNF-α-Mediated Spinal Cord Synaptic Plasticity and Inflammatory Pain with Neuroprotectin D1
Authors: Park Chul-Kyu , Lü Ning , Xu Zhen-Zhong , Liu Tong , Serhan Charles N. , Ji Ru-Rong
Published: October 2011

Mechanisms of inflammatory pain are not fully understood. We investigated the role of TRPV1 (transient receptor potential subtype V1) and TNF-α, two critical mediators for inflammatory pain, in regulating spinal cord synaptic transmission. We found in mice lackingTrpv1the frequency but not the amplitude of spontaneous EPSCs (sEPSCs) in lamina II neurons of spinal cord slices is reduced. Further, C-fiber-induced spinal long-term potentiation (LTP)in vivois abolished inTrpv1knock-out mice. TNF-α also increases sEPSC frequency but not amplitude in spinal outer lamina II (lamina IIo) neurons, and this increase is abolished inTrpv1knock-out mice. Single-cell PCR analysis revealed that TNF-α-responding neurons in lamina IIo are exclusively excitatory (vGluT2+) neurons. Notably, neuroprotectin-1 (NPD1), an anti-inflammatory lipid mediator derived from ω-3 polyunsaturated fatty acid (docosahexaenoic acid), blocks TNF-α- and capsaicin-evoked sEPSC frequency increases but has no effect on basal synaptic transmission. Strikingly, NPD1 potently inhibits capsaicin-induced TRPV1 current (IC50= 0.4 nm) in dissociated dorsal root ganglion neurons, and this IC50is ≈500 times lower than that of AMG9810, a commonly used TRPV1 antagonist. NPD1 inhibition of TRPV1 is mediated by GPCRs, since the effects were blocked by pertussis toxin. In contrast, NPD1 had no effect on mustard oil-induced TRPA1 currents. Spinal injection of NPD1, at very low doses (0.1–10 ng), blocks spinal LTP and reduces TRPV1-dependent inflammatory pain, without affecting baseline pain. NPD1 also reduces TRPV1-independent but TNF-α-dependent pain hypersensitivity. Our findings demonstrate a novel role of NPD1 in regulating TRPV1/TNF-α-mediated spinal synaptic plasticity and identify NPD1 as a novel analgesic for treating inflammatory pain.
Onset of Cholinergic Efferent Synaptic Function in Sensory Hair Cells of the Rat Cochlea
Authors: Roux Isabelle , Wersinger Eric , McIntosh J. Michael , Fuchs Paul A. , Glowatzki Elisabeth
Published: October 2011

In the developing mammalian cochlea, the sensory hair cells receive efferent innervation originating in the superior olivary complex. This input is mediated by α9/α10 nicotinic acetylcholine receptors (nAChRs) and is inhibitory due to the subsequent activation of calcium-dependent SK2 potassium channels. We examined the acquisition of this cholinergic efferent input using whole-cell voltage-clamp recordings from inner hair cells (IHCs) in acutely excised apical turns of the rat cochlea from embryonic day 21 to postnatal day 8 (P8). Responses to 1 mmacetylcholine (ACh) were detected from P0 on in almost every IHC. The ACh-activated current amplitude increased with age and demonstrated the same pharmacology as α9-containing nAChRs. Interestingly, at P0, the ACh response was not coupled to SK2 channels, so that the initial cholinergic response was excitatory and could trigger action potentials in IHCs. Coupling to SK current was detected earliest at P1 in a subset of IHCs and by P3 in every IHC studied. Clustered nAChRs and SK2 channels were found on IHCs from P1 on using Alexa Fluor 488 conjugated α-bungarotoxin and SK2 immunohistochemistry. The number of nAChRs clusters increased with age to 16 per IHC at P8. Cholinergic efferent synaptic currents first appeared in a subset of IHCs at P1 and by P3 in every IHC studied, contemporaneously with ACh-evoked SK currents, suggesting that SK2 channels may be necessary at onset of synaptic function. An analogous pattern of development was observed for the efferent synapses that form later (P6–P8) on outer hair cells in the basal cochlea.
Substrate-Induced Internalization of the High-Affinity Choline Transporter
Authors: Okuda Takashi , Konishi Asami , Misawa Hidemi , Haga Tatsuya
Published: October 2011

Cholinergic neurons are endowed with a high-affinity choline uptake system for efficient synthesis of acetylcholine at the presynaptic terminals. The high-affinity choline transporter CHT1 is responsible for choline uptake, the rate-limiting step in acetylcholine synthesis. However, endogenous physiological factors that affect CHT1 expression or function and consequently regulate the acetylcholine synthesis rate are essentially unknown. Here we demonstrate that extracellular substrate decreases the cell-surface expression of CHT1 in rat brain synaptosomes, primary cultures from the basal forebrain, and mammalian cell lines transfected with CHT1. Extracellular choline rapidly decreases cell-surface CHT1 expression by accelerating its internalization, a process that is mediated by a dynamin-dependent endocytosis pathway in HEK293 cells. Specific inhibitor hemicholinium-3 decreases the constitutive internalization rate and thereby increases cell-surface CHT1 expression. We also demonstrate that the constitutive internalization of CHT1 depends on extracellular pH in cultured cells. Our results collectively suggest that the internalization of CHT1 is induced by extracellular substrate, providing a novel feedback mechanism for the regulation of acetylcholine synthesis at the cholinergic presynaptic terminals.
A Role for Nociceptive, Myelinated Nerve Fibers in Itch Sensation
Authors: Ringkamp Matthias , Schepers Raf J. , Shimada Steven G. , Johanek Lisa M. , Hartke Timothy V. , Borzan Jasenka , Shim Beom , LaMotte Robert H. , Meyer Richard A.
Published: October 2011

Despite its clinical importance, the underlying neural mechanisms of itch sensation are poorly understood. In many diseases, pruritus is not effectively treated with antihistamines, indicating the involvement of nonhistaminergic mechanisms. To investigate the role of small myelinated afferents in nonhistaminergic itch, we tested, in psychophysical studies in humans, the effect of a differential nerve block on itch produced by intradermal insertion of spicules from the pods of a cowhage plant (Mucuna pruriens). Electrophysiological experiments in anesthetized monkey were used to investigate the responsiveness of cutaneous, nociceptive, myelinated afferents to different chemical stimuli (cowhage spicules, histamine, capsaicin). Our results provide several lines of evidence for an important role of myelinated fibers in cowhage-induced itch: (1) a selective conduction block in myelinated fibers substantially reduces itch in a subgroup of subjects with A-fiber-dominated itch, (2) the time course of itch sensation differs between subjects with A-fiber- versus C-fiber-dominated itch, (3) cowhage activates a subpopulation of myelinated and unmyelinated afferents in monkey, (4) the time course of the response to cowhage is different in myelinated and unmyelinated fibers, (5) the time of peak itch sensation for subjects with A-fiber-dominated itch matches the time for peak response in myelinated fibers, and (6) the time for peak itch sensation for subjects with C-fiber-dominated itch matches the time for the peak response in unmyelinated fibers. These findings demonstrate that activity in nociceptive, myelinated afferents contributes to cowhage-induced sensations, and that nonhistaminergic itch is mediated through activity in both unmyelinated and myelinated afferents.
α7-Containing and Non-α7-Containing Nicotinic Receptors Respond Differently to Spillover of Acetylcholine
Authors: Stanchev Doychin , Sargent Peter B.
Published: October 2011

We explored whether nicotinic acetylcholine receptors (nAChRs) might participate in paracrine transmission by asking if they respond to spillover of ACh at a model synapse in the chick ciliary ganglion, where ACh activates diffusely distributed α7- and α3-containing nAChRs (α7-nAChRs and α3*-nAChRs). Elevating quantal content lengthened EPSC decay time and prolonged both the fast (α7-nAChR-mediated) and slow (α3*-nAChR-mediated) components of decay, even in the presence of acetylcholinesterase. Increasing quantal content also prolonged decay times of pharmacologically isolated α7-nAChR- and α3*-nAChR-EPSCs. The effect upon EPSC decay time of changing quantal content was 5–10 times more pronounced for α3*-nAChR- than α7-nAChR-mediated currents and operated over a considerably longer time window: ∼20 vs ∼2 ms. Control experiments rule out a presynaptic source for the effect. We suggest that α3*-nAChR currents are prolonged at higher quantal content because of ACh spillover and postsynaptic potentiation (Hartzell et al., 1975), while α7-nAChR currents are prolonged probably for other reasons, e.g., increased occupancy of long channel open states. α3*-nAChRs report more spillover when α7-nAChRs are competitively blocked than under native conditions; this could be explained if α7-nAChRs buffer ACh and regulate its availability to activate α3*-nAChRs. Our results suggest that non-α7-nAChRs such as α3*-nAChRs may be suitable for paracrine nicotinic signaling but that α7-nAChRs may not be suitable. Our results further suggest that α7-nAChRs may buffer ACh and regulate its bioavailability.
Chemical Effects at the Reaction Front in Corroding Spent Nuclear Fuel
Authors: Fortner Jeffrey A. , Kropf A. Jeremy , Jerden James L. , Cunnane James C.
Published: October 2011

Performance assessment models of the U. S. repository at Yucca Mountain, Nevada suggest that neptunium from spent nuclear fuel is a potentially important dose contributor. A scientific understanding of how the UO2 matrix of spent nuclear fuel impacts the oxidative dissolution and reductive precipitation of Np is needed to predict the behavior of Np at the fuel surface during aqueous corrosion. Neptunium would most likely be transported as aqueous Np(V) species, but for this to occur it must first be oxidized from the Np(IV) state found within the parent spent nuclear fuel. In this paper we present synchrotron x-ray absorption spectroscopy and microscopy findings that illuminate the resultant local chemistry of neptunium and plutonium within uranium oxide spent nuclear fuel before and after corrosive alteration in an air-saturated aqueous environment. We find the Pu and Np in unaltered spent fuel to have a +4 oxidation state and an environment consistent with solid-solution in the UO2 matrix. During corrosion in an air-saturated aqueous environment, the uranium matrix is converted to uranyl (UO22+) mineral assemblage that is depleted in Np and Pu relative to the parent fuel. The transition from U(IV) in the fuel to a fully U(VI) character across the corrosion front is not sharp, but occurs over a transition zone of ∼ 50 micrometers. We find evidence of a thin (∼ 20 micrometer) layer that is enriched in Pu and Np within a predominantly U(IV) environment on the fuel side of the transition zone. These experimental observations are consistent with available data for the standard reduction potentials for NpO2+/Np4+ and UO22+/U4+ couples, which indicate that Np(IV) may not be effectively oxidized to Np(V) at the corrosion potential of uranium dioxide spent nuclear fuel in air-saturated aqueous solutions.
The BRAG and GM2003 Models for Glass Dissolution
Authors: Aertsens Marc
Published: October 2011

The GM2003 model extends the r(t) glass dissolution model with water diffusion through the diffusion layer. Boron and alkali diffusion through the diffusion layer is described by introducing a retention factor Kd,i between boron/alkali and water in the diffusion layer. Introducing a boron/alkali diffusion coefficient, the BRAG model describes boron/alkali diffusion in the diffusion layer as well. It is shown that both models are consistent with each other and an expression is derived for the boron/alkali diffusion coefficient (BRAG) as a function of both parameters of GM2003: the retention factor Kd,i and the water diffusion coefficient DH2O in the diffusion layer. From dissolution data only, it is possible to fit the value for the boron/alkali diffusion coefficient in the diffusion layer but due to correlations the individual values of both parameters Kd,i and DH2O of GM2003 cannot be determined. From theoretical considerations follows that the Kd,i value for boron/alkali should be slightly larger than 0.1 kg/liter. A user friendly code for the BRAG model allows automatic fits of glass dissolution data in water.
Microstructural Characterization of U Coprecipitated Phases Formed in Bentonic-Granitic Groundwater and under Anoxic Conditions
Authors: Quinones Javier , Iglesias Eduardo , Cobo Jose M. , Martinez Esparza Aurora , Gomez de Salazar Jose Maria
Published: October 2011

For improving the accuracy of the performance assessment studies related to the spent fuel safety under storage conditions it is necessary to develop a new matrix alteration model. These models must be based on laboratory experiences and they should be capable to extrapolate to storing environmental conditions. Most of recently models developed included the oxidation and dissolution process of the spent fuel matrix, but the influence of a possible process of secondary phase formation over the spent fuel surface is not taken into account yet. This is a key process that could produce a reduction of the matrix dissolution rate, radiation shielding behaviour; however, the surface precipitation of the secondary phase could induce a localized corrosion process, which in this case dissolution rate of the spent fuel would be increased. This paper is focussed on microstructural characterization of secondary phases formed in coprecipitation experiments performed under anoxic conditions in granitic-bentonitic simulated groundwater. In order to simulate the influence of the container material, the coprecipitation experiments were performed in absence and presence of iron powder. The solid phases formed were characterized using the following techniques: XRD; SEM-EDX and TEM-EDX. The XRD diffraction pattern showed that under anoxic conditions a mixture of phases were obtained (sodium and potassium uranate and schoepite), whereas uranate phases were detected when only iron was present. The characterization study indicates that the U secondary phase formed (under reducing conditions and presence of iron powder) growth from iron surface. The crystal size of the secondary phase is independent of the presence of iron powder (and it is always less than 3 μm). Furthermore, the microstructural study showed the growing of U phases over iron powder.
Development of a Phosphate Ceramic as a Host for Halide-contaminated Plutonium Pyrochemical Reprocessing Wastes
Authors: Metcalfe Brian , Fong Shirley , Gerrard Lee , Donald Ian , Strachan Denis , Scheele Randall
Published: October 2011

The presence of halide anions in four types of wastes arising from the pyrochemical reprocessing of plutonium required an immobilization process to be developed in which not only the actinide cations but also the halide anions were immobilized in a durable, leach resistant form. AWE has developed such a process using Ca3(PO4)2 as the host material. Successful trials of the process using actinide-doped Type I waste (essentially a chloride-based waste) were carried out at PNNL where the immobilization of the waste in a form resistant to aqueous leaching was confirmed. Normalized mass losses determined using a modified MCC-1 test at 40°C/28 days were 12 x 10-6 g.m-2 and 2.7 x 10-3 g.m-2 for Pu and Cl, respectively. Accelerated radiation-induced damage effects are being determined with specimens containing 238Pu. No changes in the crystalline lattice have been detected with XRD after the 239Pu equivalent of 400 years ageing. Confirmation of the process for Type II waste (an oxyhydroxide-based waste) is currently underway at PNNL.

Differences in the ionic state of plutonium in the four types of waste have required different surrogates to be used. Samarium chloride was used successfully as a surrogate for both Pu(III) and Am(III) chlorides. Early investigations into the use of HfO2 as the surrogate for Pu(IV) oxide in Type II waste showed some apparent differences in the phase assemblages of the surrogate and actinide-based products. However XRD examination of the products at higher resolution has demonstrated there is no significant difference and that for this work HfO2 is a suitable surrogate for PUO2.
Modeling of Spent Fuel Oxidation at Low Temperature
Authors: Poulesquen Arnaud , Desgranges Lionel , FERRY Cécile
Published: October 2011

During dry storage, the oxidation of the spent fuel in case of cladding and container failure (accidental scenario) could be detrimental for further handling of the spent fuel rod and for the safety of the facilities. Depending on whether the uranium dioxide is under the form of powder or pellet, irradiated or unirradiated, the weight gain curves do not present the same shape. To account for these different behaviours, two models have been developed. Firstly, the oxidation of unirradiated powders has been modelled based on the coexistence, during the oxidation, of two intermediate products, U4O9 and U3O7. The comparison between the calculation and the literature data is good in terms of weight gain curves and chemical diffusion coefficient of oxygen within the two phases. Secondly, the oxidation of spent fuel fragments is approached by a convolution procedure between a grain oxidation model and an empirical parameter which represents the linear oxidation speed of grain boundary or an average distance able to cover the entire spent fuel fragment. This procedure of calculation allows in one hand to account for the incubation period noticed on unirradiated pellets or spent fuel and in another hand to link the empirical parameter to physical as porosity, cracks or linear power, or operational parameters such as fission gas release (FGR) respectively. A comparison of this new modelling with experimental data will be proposed.
EELS Spectrum Imaging and Tomography Studies of Simulated Nuclear Waste Glasses
Authors: Yang Guang , Saghi Zineb , Xu Xiaojing , Hand Russell , Möbus Günter
Published: October 2011

Electron energy loss spectroscopy (EELS) has been widely used in analysis of ceramic, minerals and semiconductors. It can provide the unique advantage of sensitivity to composition, coordination and valency, while providing nano-scale spatial resolution. Due to the electron irradiation sensitivity, EELS studies on glass are quite rare. However, using special care in glass-composition selection and by recording time series of EELS-spectra to monitor any structural changes, EELS then becomes a very useful technique to study glass-chemistry and glass structure with the highest spatial resolution of all chemically sensitive techniques. Alkali borosilicate glasses (ABS) doped with Cr2O3 (2 mol%), CeO2 (4 mol%) and ZrO4 (4 mol%) were melted, cooled and annealed in the context of simulating radionuclide immobilisation glasses. Precipitates with diameter in the range of ∼20 nm to ∼200 nm were found homogeneously distributed in the glass. In preliminary studies we measured the oxidation state in the glass and in precipitates via evaluation of the Ce-M-edge double white line ratio, confirming the crystals as Ce(IV) oxide. We also found Boron K-edge ELNES spectra as a sensitive signal to boron coordination (N4 = BO4/(BO3+BO4)), which is found at N4 ratios of around 35-45%.

In the present study we have extended this work to the acquisition of dense line scans (spectrum imaging) across an area of interest on our composite glass with emphasis on three questions:

(i) Change of cerium valence upon transition from the glass to the precipitates?

(ii) Possible oscillation of boron N4-ratio in the glass within a line scan as a consequence of random medium-order related glass fluctations when scanning the <5nm probe across a seemingly homogeneous area?

(iii) N4-changes in the immediate glass layer surrounding the precipitates?

Our ongoing research has produced results which prove a systematic change of the Ce oxidation state from precipitates (+IV) to glass (mixed +III/+IV). It is found that boron coordination is constant within the sensitivity given by signal-to-noise in the glass matrix. A change of the Boron K-edge fine structure upon crossing a nanoparticle during one particular linescan has been observed, which could hint to a coordination change of the glass layer surrounding the particle. Other linescan measurements have not shown any change and acquisition of an enlarged better statistic is work in progress.

The ABS-glass with distributed nanoparticles provides an ideal example of a 3D nanocomposite. The only proven technique for the three-dimensional reconstruction of such materials on the nanoscale is electron tomography. We present the first results of a 3D reconstructed nuclear waste glass by using a tilt series of ADF STEM images covering a glass fragment of 2000nm field of view containing several tens of nanoparticles distributed around its volume.
Tc and Re Behavior in Borosilicate Waste Glass Vapor Hydration Tests
Authors: McKeown David A. , Buechele Andrew C. , Lukens Wayne W. , Shuh David K. , Pegg Ian L.
Published: October 2011

Technetium (Tc), found in some nuclear wastes, is of particular concern with regard to long-term storage, because of its long-lived radioactivity and high mobility in the environment. Tc and rhenium (Re), commonly used as a non-radioactive surrogate for Tc, were studied to assess their behavior in borosilicate glass under hydrothermal conditions in the Vapor Hydration Test (VHT). X-ray absorption spectroscopy (XAS) and scanning electron microscopy (SEM) measurements were made on the original Tc- and Re-containing glasses and their corresponding VHT samples, and show different behavior for Tc and Re under VHT conditions. XAS indicates that, despite starting with different Tc(IV) and Tc(VII) distributions in each glass, the VHT samples have 100% Tc(IV)O6 environments. SEM shows complete alteration of the original glass, Tc enrichment near the sample surface, and Tc depletion in the center. Perrhenate (Re(VII)O4−) is dominant in both Re-containing samples before and after the VHT, where Re is depleted near the VHT sample surface and more concentrated toward the center.