bluuebunny/crossref_metadata_2025 huggingface dataset:
Aminoglycosides in Intermittent Hemodialysis: Pharmacokinetics with Individual Dosing
Authors: Dager William E , King Jeff H
Published: December 2005

Background:

Data are limited on aminoglycoside pharmacokinetic differences between acute renal failure (ARF) and chronic kidney disease (CKD) or infection survival when maintaining peak and pre-hemodialysis serum concentrations between 7 and 10 and 3.5 and 5 mg/L, respectively.

Objective:

To report aminoglycoside pharmacokinetic observations in a consecutive series of patients receiving intermittent hemodialysis (IHD), including treatment impact of patient-specific dosing regimens.

Methods:

In this prospective study, all calculated pharmacokinetic parameters used concentrations drawn more than 12 hours after the initial dose and peak concentrations at least 2 hours after the dose. Analysis included pharmacokinetic parameters in stage 5 CKD, ARF, impact of the dialysis prescription, and treatment results of individualized dosing regimens lasting more than 4 days.

Results:

Consecutive patients with IHD (N = 167) receiving 216 courses of aminoglycosides were evaluated. The mean ± SD volume of distribution was 0.39 ± 0.15 L/kg ideal body weight, and elimination half-life during dialysis was 4.2 ± 2.3 hours. The elimination half-life off IHD was 30% shorter in ARF (31.9 ± 20.8 h) versus 45.7 ± 24.2 hours in CKD (p < 0.001). Mean extrapolated peak concentrations and pre-IHD levels were 7.7 ± 1.6 and 3.9 ± 1.2 mg/L, respectively. A 91% treatment success rate was observed in 117 individualized treatment courses in 100 patients receiving greater than or equal to 5 days of aminoglycoside therapy.

Conclusions:

A large variability in aminoglycoside pharmacokinetic parameters in IHD exists, with aminoglycoside elimination off IHD significantly faster in ARF. Individualized regimens using serum concentrations drawn in patients requiring treatment (non-synergistic) targeting peak concentrations of 7–10 mg/L and pre-hemodialysis serum concentrations of 3.5–5 mg/L appears successful for eradicating infections.
Parsing Molecular and Behavioral Effects of Cocaine in Mitogen- and Stress-Activated Protein Kinase-1-Deficient Mice
Authors: Brami-Cherrier Karen , Valjent Emmanuel , Hervé Denis , Darragh Joanne , Corvol Jean-Christophe , Pages Christiane , Simon Arthur J. , Girault Jean-Antoine , Caboche Jocelyne
Published: December 2005

Although the induction of persistent behavioral alterations by drugs of abuse requires the regulation of gene transcription, the precise intracellular signaling pathways that are involved remain mainly unknown. Extracellular signal-regulated kinase (ERK) is critical for the expression of immediate-early genes in the striatum in response to cocaine and Δ9-tetrahydrocannabinol and for the rewarding properties of these drugs. Here we show that in mice a single injection of cocaine (10 mg/kg) activates mitogen- and stress-activated protein kinase 1 (MSK1) in dorsal striatum and nucleus accumbens. Cocaine-induced phosphorylation of MSK1 threonine 581 and cAMP response element-binding protein (CREB) serine 133 (Ser133) were blocked by SL327, a drug that prevents ERK activation. Cocaine increased the acetylation of histone H4 lysine 5 and phosphorylation of histone H3 Ser10, demonstrating the existence of drug-induced chromatin remodelingin vivo. In MSK1 knock-out (KO) mice CREB and H3 phosphorylation in response to cocaine (10 mg/kg) were blocked, and induction of c-Fos and dynorphin was prevented, whereas the induction of Egr-1 (early growth response-1)/zif268/Krox24 was unaltered. MSK1-KO mice had no obvious neurological defect but displayed a contrasted behavioral phenotype in response to cocaine. Acute effects of cocaine and dopamine D1or D2agonists were unaltered. Sensitivity to low doses, but not high doses, of cocaine was increased in the conditioned place preference paradigm, whereas locomotor sensitization to repeated injections of cocaine was decreased markedly. Our results show that MSK1 is a major striatal kinase, downstream from ERK, responsible for the phosphorylation of CREB and H3 and is required specifically for the induction of c-Fos and dynorphin as well as for locomotor sensitization.
Contribution of 5-HT2Receptor Subtypes to Sleep–Wakefulness and Respiratory Control, and Functional Adaptations in Knock-Out Mice Lacking 5-HT2AReceptors
Authors: Popa Daniela , Léna Clément , Fabre Véronique , Prenat Caroline , Gingrich Jay , Escourrou Pierre , Hamon Michel , Adrien Joëlle
Published: December 2005

Serotonin (5-hydroxytryptamine; 5-HT) plays key roles in sleep–wakefulness regulation. Evidence indicates that 5-HT2receptors are involved mainly in non-rapid eye movement sleep (NREMS) regulation and respiratory control. Here, we investigated the relative contribution of 5-HT2A, 5-HT2B, and 5-HT2Creceptor subtypes to NREMS and breathing during sleep, using 5-HT2subtype-selective ligands in wild-type (5-HT2A+/+) and knock-out (5-HT2A–/–) mice that do not express 5-HT2Areceptors. Acute blockade of 5-HT2Areceptors induced an increase in NREMS in 5-HT2A+/+ mice, but not 5-HT2A–/– mutants, which spontaneously expressed less NREMS than wild-type animals. In 5-HT2A+/+ mice, 5-HT2Breceptor blockade produced a reduction of NREMS, whereas receptor activation induced an increase in this sleep stage. These effects were less pronounced in 5-HT2A–/– mice, indicating a lower sensitivity of 5-HT2Breceptors in mutants, with no change in 5-HT2BmRNA. Blockade of 5-HT2Creceptors had no effect on NREMS in both strains. In addition, an increase in EEG power density after sleep deprivation was observed in 5-HT2A+/+ mice but not in 5-HT2A–/– mice. Whole-body plethysmographic recordings indicated that 5-HT2Areceptor blockade in 5-HT2A+/+ mice reduced NREMS apneas and bradypneas that occurred after sighs. In contrast, in 5-HT2A–/– mutants, NREMS apneas were not modified, and bradypnea after sighs were more pronounced. Our results demonstrate that 5-HT exerts a 5-HT2B-mediated facilitation of NREMS, and an influence respectively inhibitory on NREMS and facilitatory on sleep apnea generation, via 5-HT2Areceptors. Moreover, 5-HT2Agene knock-out leads to functional compensations yielding adaptive changes opposite to those caused by pharmacological blockade of 5-HT2Areceptors in 5-HT2A+/+ mice.
Recognition of Familiar Individuals in Golden Hamsters: A New Method and Functional Neuroanatomy
Authors: Lai Wen-Sung , Ramiro Leora-Leigh R. , Yu Helena A. , Johnston Robert E.
Published: December 2005

The ability to recognize individuals is essential for many aspects of social interaction and social organization, yet we know relatively little about the neural mechanisms underlying this ability. Most laboratory studies of individual recognition in rodents have studied differential responses to familiar versus unfamiliar individuals rather than differential responses to equally well known individuals having different significance for the subject. In experiment 1, we use a new method for studying true individual recognition in which male hamsters first had different experiences with two stimulus males (exposures to one male across a wire-mesh barrier and fights with another male). One day later, losers of fights were tested in a Y-maze for reactions to one of the two familiar males. Subjects tested with the familiar winner avoided this stimulus male, but subjects tested with the familiar, neutral male were attracted to him. Immunohistochemistry for c-Fos and Egr-1 implicate several areas of the brain in individual recognition, particularly the anterior piriform cortex, the CA1 and CA3 regions of anterior dorsal hippocampus, anterior and posterior dentate gyrus, and perirhinal cortex. In experiment 2, temporary inactivation of the CA1 region of anterior dorsal hippocampus by microinfusion of lidocaine eliminated the avoidance of the familiar winner, but a saline control injection had no effect. These results are the first to use a rodent model to characterize neural circuits involved in the recognition of equally well known individuals and the corresponding emotional responses to them.
Prolonged Reciprocal Signaling via NMDA and GABA Receptors at a Retinal Ribbon Synapse
Authors: Vigh Jozsef , von Gersdorff Henrique
Published: December 2005

AMPA and GABAAreceptors mediate most of the fast signaling in the CNS. However, the retina must, in addition, also convey slow and sustained signals. Given that AMPA and GABAAreceptors desensitize quickly in the continuous presence of agonist, how are sustained excitatory and inhibitory signals transmitted reliably across retinal synapses? Reciprocal synapses between bipolar and amacrine cells in the retina are thought to play a fundamental role in tuning the bipolar cell output to the dynamic range of ganglion cells. Here, we report that glutamate release from goldfish bipolar cell terminals activates first AMPA receptors, followed by fast and transient GABAA-mediated feedback. Subsequently, prolonged NMDA receptor activation triggers GABAAand a slow, sustained GABAC-mediated reciprocal inhibition. The synaptic delay of the NMDA/GABAC-mediated feedback showed stronger dependence on the depolarization of the bipolar cell terminal than the fast AMPA/GABAA-mediated response. Although the initial depolarization mediated by AMPA receptors was important to prime the NMDA action, NMDA receptors could trigger feedback by themselves in most of the bipolar terminals tested. This AMPA-independent feedback (delay ≈ 10 ms) was eliminated in 2 mmexternal Mg2+and reduced in some terminals, but not eliminated, by TTX. NMDA receptors on amacrine cells with depolarized resting membrane potentials therefore can mediate the late reciprocal feedback triggered by continuous glutamate release. Our findings suggest that the characteristics of NMDA receptors (high agonist affinity, slow desensitization, and activation/deactivation kinetics) are well suited to match the properties of GABACreceptors, which thus provide part of the prolonged inhibition to bipolar cell terminals.
Noradrenaline Triggers Multivesicular Release at Glutamatergic Synapses in the Hypothalamus
Authors: Gordon Grant R. J. , Bains Jaideep S.
Published: December 2005

The origin of large-amplitude miniature EPSCs (mEPSCs) at central synapses remains to be firmly established. Here, we show that at excitatory synapses onto magnocellular neurosecretory cells in the hypothalamus, noradrenaline induces a rapid and robust increase in mEPSC amplitude that requires α1-adrenoceptor activation but is impervious to postsynaptic manipulations that block the putative insertion of AMPA receptors. In response to noradrenaline, mEPSCs exhibit a putative multimodal amplitude histogram distribution that is not attibutable to random temporal summation, the unveiling of a quiescent synapse, or the release of large vesicles. Large-amplitude mEPSCs are sensitive to a high dose of ryanodine and are associated with an enhanced glutamate cleft concentration. Together, these data are consistent with the hypothesis that large-amplitude mEPSCs result from the synchronous release of multiple vesicles via rapid presynaptic calcium expulsion from intracellular stores.
Central Oxytocin, Vasopressin, and Corticotropin-Releasing Factor Receptor Densities in the Basal Forebrain Predict Isolation Potentiated Startle in Rats
Authors: Nair Hemanth P. , Gutman Alisa R. , Davis Michael , Young Larry J.
Published: December 2005

Individual differences in resiliency to particular stressors may be mediated by specific neuropeptide receptor patterns in the brain. Here, we explored this issue by using a multivariate approach to identify brain sites in which oxytocin (OTR), vasopressin (V1aR), and corticotropin-releasing factor type 1 (CRF1) or type 2 receptor binding covaried with a measure of isolation-induced anxiety: isolation potentiated startle (IPS). Partial least squares (PLS) analysis identified three binding sites, the shell of the nucleus accumbens (AccSh), lateral bed nucleus of the stria terminalis, and intermediate zone of the lateral septum, in which CRF1, V1aR, and OTR receptors, respectively, covaried with IPS. Multiple regression analysis demonstrated that the three binding sites accounted for more of the variation in IPS as a linear combination than when considered individually. Using the same multiple regression model, the linear combination of the same three binding sites/peptide receptors measured in a new group of animals successfully predicted their IPS values. There were no differences in binding between grouped and isolated animals, suggesting that the patterns are trait effects rather than a consequence of isolation. Based on the finding that CRF1 receptors in the AccSh were positively correlated with IPS, we infused CRF directly into the AccSh and found that it significantly potentiated startle after a short isolation period but not under grouped conditions. This result directly supported the predictions made by the combined PLS/regression approach. These results suggest that the integrated activity of neuropeptide systems mediating both social behavior and anxiety underlie IPS.
Neural Mechanisms Underlying Probabilistic Category Learning in Normal Aging
Authors: Fera Francesco , Weickert Thomas W. , Goldberg Terry E. , Tessitore Alessandro , Hariri Ahmad , Das Sumitra , Lee Sam , Zoltick Brad , Meeter Martijn , Myers Catherine E. , Gluck Mark A. , Weinberger Daniel R. , Mattay Venkata S.
Published: December 2005

Probabilistic category learning engages neural circuitry that includes the prefrontal cortex and caudate nucleus, two regions that show prominent changes with normal aging. However, the specific contributions of these brain regions are uncertain, and the effects of normal aging have not been examined previously in probabilistic category learning. In the present study, using a blood oxygenation level-dependent functional magnetic resonance imaging block design, 18 healthy young adults (mean age, 25.5 ± 2.6 years) and 15 older adults (mean age, 67.1 ± 5.3 years) were assessed on the probabilistic category learning “weather prediction” test. Whole-brain functional images acquired using a 1.5T scanner (General Electric, Milwaukee, WI) with gradient echo, echo planar imaging (3/1 mm; repetition time, 3000 ms; echo time, 50 ms) were analyzed using second-level random-effects procedures [SPM99 (Statistical Parametric Mapping)]. Young and older adults displayed equivalent probabilistic category learning curves, used similar strategies, and activated analogous neural networks, including the prefrontal and parietal cortices and the caudate nucleus. However, the extent of caudate and prefrontal activation was less and parietal activation was greater in older participants. The percentage correct and reaction time were mainly positively correlated with caudate and prefrontal activation in young individuals but positively correlated with prefrontal and parietal cortices in older individuals. Differential activation within a circumscribed neural network in the context of equivalent learning suggests that some brain regions, such as the parietal cortices, may provide a compensatory mechanism for healthy older adults in the context of deficient prefrontal cortex and caudate nuclei responses.
Downregulation of Transient Receptor Potential Melastatin 8 by Protein Kinase C-Mediated Dephosphorylation
Authors: Premkumar Louis S. , Raisinghani Manish , Pingle Sandeep C. , Long Cheng , Pimentel Fátima
Published: December 2005

Transient receptor potential melastatin 8 (TRPM8) and transient receptor potential vanilloid 1 (TRPV1) are ion channels that detect cold and hot sensations, respectively. Their activation depolarizes the peripheral nerve terminals resulting in action potentials that propagate to brain via the spinal cord. These receptors also play a significant role in synaptic transmission between dorsal root ganglion (DRG) and dorsal horn (DH) neurons. Here, we show that TRPM8 is functionally downregulated by activation of protein kinase C (PKC) resulting in inhibition of membrane currents and increases in intracellular Ca2+compared with upregulation of TRPV1 in cloned and native receptors. Bradykinin significantly downregulates TRPM8 via activation of PKC in DRG neurons. Activation of TRPM8 or TRPV1 at first sensory synapse between DRG and DH neurons leads to a robust increase in frequency of spontaneous/miniature EPSCs. PKC activation blunts TRPM8- and facilitates TRPV1-mediated synaptic transmission. Significantly, downregulation is attributable to PKC-mediated dephosphorylation of TRPM8 that could be reversed by phosphatase inhibitors. These findings suggest that inflammatory thermal hyperalgesia mediated by TRPV1 may be further aggravated by downregulation of TRPM8, because the latter could mediate the much needed cool/soothing sensation.
Decreased Neuronal Death in Na+/H+Exchanger Isoform 1-Null Mice afterIn VitroandIn VivoIschemia
Authors: Luo Jing , Chen Hai , Kintner Douglas B. , Shull Gary E. , Sun Dandan
Published: December 2005

Na+/H+exchanger isoform 1 (NHE1) is a major acid extrusion mechanism after intracellular acidosis. We hypothesized that stimulation of NHE1 after cerebral ischemia contributes to the disruption of Na+homeostasis and neuronal death. In the present study, expression of NHE1 was detected in cultured mouse cortical neurons. Three hours of oxygen and glucose deprivation (OGD) followed by 21 h of reoxygenation (REOX) led to 68 ± 10% cell death. Inhibition of NHE1 with the potent inhibitor cariporide (HOE 642) or genetic ablation of NHE1 reduced OGD-induced cell death by ∼40–50% (p< 0.05). In NHE1+/+neurons, OGD caused a twofold increase in [Na+]i, and 60 min REOX triggered a sevenfold increase. Genetic ablation of NHE1 or HOE 642 treatment had no effects on the OGD-mediated initial Na+irise but reduced the second phase of Na+irise by ∼40–50%. In addition, 60 min REOX evoked a 1.5-fold increase in [Ca2+]iin NHE1+/+neurons, which was abolished by inhibition of either NHE1 or reverse-mode operation of Na+/Ca2+exchange. OGD/REOX-mediated mitochondrial Ca2+accumulation and cytochromecrelease were attenuated by inhibition of NHE1 activity. In anin vivofocal ischemic model, 2 h of left middle cerebral artery occlusion followed by 24 h of reperfusion induced 84.8 ± 8.0 mm3infarction in NHE1+/+mice. NHE1+/+mice treated with HOE 642 or NHE1 heterozygous mice exhibited a ∼33% decrease in infarct size (p< 0.05). These results imply that NHE1 activity disrupts Na+and Ca2+homeostasis and contributes to ischemic neuronal damage.
Activation of Gonadotropin-Releasing Hormone Neurons by Kisspeptin as a Neuroendocrine Switch for the Onset of Puberty
Authors: Han Seong-Kyu , Gottsch Michelle L. , Lee Kathy J. , Popa Simina M. , Smith Jeremy T. , Jakawich Sonya K. , Clifton Donald K. , Steiner Robert A. , Herbison Allan E.
Published: December 2005

We examined the role of kisspeptin and its receptor, the G-protein-coupled receptor GPR54, in governing the onset of puberty in the mouse. In the adult male and female mouse, kisspeptin (10–100 nm) evoked a remarkably potent, long-lasting depolarization of >90% of gonadotropin-releasing hormone (GnRH)–green fluorescent protein neuronsin situ. In contrast, in juvenile [postnatal day 8 (P8) to P19] and prepubertal (P26–P33) male mice, kisspeptin activated only 27 and 44% of GnRH neurons, respectively. This developmental recruitment of GnRH neurons into a kisspeptin-responsive pool was paralleled by an increase in the ability of centrally administered kisspeptin to evoke luteinizing hormone secretionin vivo. To learn more about the mechanisms through which kisspeptin–GPR54 signaling at the GnRH neuron may change over postnatal development, we performed quantitativein situhybridization for kisspeptin and GPR54 transcripts. Approximately 90% of GnRH neurons were found to express GPR54 mRNA in both juvenile and adult mice, without a detectable difference in the mRNA content between the age groups. In contrast, the expression of KiSS-1 mRNA increased dramatically across the transition from juvenile to adult life in the anteroventral periventricular nucleus (AVPV;p< 0.001). These results demonstrate that kisspeptin exerts a potent depolarizing effect on the excitability of almost all adult GnRH neurons and that the responsiveness of GnRH neurons to kisspeptin increases over postnatal development. Together, these observations suggest that activation of GnRH neurons by kisspeptin at puberty reflects a dual process involving an increase in kisspeptin input from the AVPV and a post-transcriptional change in GPR54 signaling within the GnRH neuron.
Molecular and Cellular Diversity of Neuronal G-Protein-Gated Potassium Channels
Authors: Koyrakh Lev , Luján Rafael , Colón Jose , Karschin Christine , Kurachi Yoshihisa , Karschin Andreas , Wickman Kevin
Published: December 2005

Neuronal G-protein-gated potassium (GIRK) channels mediate the inhibitory effects of many neurotransmitters. Although the overlapping distribution of GIRK subunits suggests that channel composition varies in the CNS, little direct evidence supports the existence of structural or functional diversity in the neuronal GIRK channel repertoire. Here we show that the GIRK channels linked to GABABreceptors differed in two neuron populations. In the substantia nigra, GIRK2 was the principal subunit, and it was found primarily in dendrites of neurons in the substantia nigra pars compacta (SNc). Baclofen evoked prominent barium-sensitive outward current in dopamine neurons of the SNc from wild-type mice, but this current was completely absent in neurons from GIRK2 knock-out mice. In the hippocampus, all three neuronal GIRK subunits were detected. The loss of GIRK1 or GIRK2 was correlated with equivalent, dramatic reductions in baclofen-evoked current in CA1 neurons. Virtually all of the barium-sensitive component of the baclofen-evoked current was eliminated with the ablation of both GIRK2 and GIRK3, indicating that channels containing GIRK3 contribute to the postsynaptic inhibitory effect of GABABreceptor activation. The impact of GIRK subunit ablation on baclofen-evoked current was consistent with observations that GIRK1, GIRK2, and GABABreceptors were enriched in lipid rafts isolated from mouse brain, whereas GIRK3 was found primarily in higher-density membrane fractions. Altogether, our data show that different GIRK channel subtypes can couple to GABABreceptorsin vivo. Furthermore, subunit composition appears to specify interactions between GIRK channels and organizational elements involved in channel distribution and efficient receptor coupling.
Neuronal Sensitivity to Microsecond Time Disparities in the Electrosensory System ofGymnarchus niloticus
Authors: Matsushita Atsuko , Kawasaki Masashi
Published: December 2005

To perform the jamming avoidance response (JAR), the weakly electric fishGymnarchusdetects time disparities on the order of microseconds between electrosensory signals received by electroreceptors in different parts of the body surface. This paper describes time-disparity thresholds of output neurons of the electrosensory lateral line lobe (ELL), where the representation of timing information is converted from a time code to a firing-rate code. We recorded extracellular single-unit responses from pyramidal cells in the ELL to sinusoidally modulated time disparity with various depths (0-200 μs). Threshold sensitivity to time disparities measured in 123 units ranged from 0.5 to 100 μs and was ≤5 μs in 60% of the units. The units from pyramidal cells in the inner and outer cell layers of the ELL responded equally well to small time disparities. The neuronal thresholds to time disparities found in the ELL are comparable with those demonstrated in behavioral performance of the JAR. The sensitivity of ELL units to small time disparities was unaffected when the center of the cyclic time-disparity modulation was shifted over a wide range (up to 250 μs), indicating an adaptation mechanism for steady-state time disparities that preserves the sensitivity to small dynamic changes in time disparities. Phase-locked input neurons, which provide time information to the ELL by phase-locked firing of action potentials, did not adapt to steady-state time shifts of sensory signals. This suggests that the adaptation emerges within the ELL.
Tandem Subunits Effectively Constrain GABAAReceptor Stoichiometry and Recapitulate Receptor Kinetics But Are Insensitive to GABAAReceptor-Associated Protein
Authors: Boileau Andrew J. , Pearce Robert A. , Czajkowski Cynthia
Published: December 2005

GABAergic synapses likely contain multiple GABAAreceptor subtypes, making postsynaptic currents difficult to dissect. However, even in heterologous expression systems, analysis of receptors composed of α, β, and γ subunits can be confounded by receptors expressed from α and β subunits alone. To produce recombinant GABAAreceptors containing fixed subunit stoichiometry, we coexpressed individual subunits with a “tandem” α1 subunit linked to a β2 subunit. Cotransfection of the γ2 subunit with αβ-tandem subunits in human embryonic kidney 293 cells produced currents that were similar in their macroscopic kinetics, single-channel amplitudes, and pharmacology to overexpression of the γ subunit with nonlinked α1 and β2 subunits. Similarly, expression of α subunits together with αβ-tandem subunits produced receptors having physiological and pharmacological characteristics that closely matched cotransfection of α with β subunits. In this first description of tandem GABAAsubunits measured with patch-clamp and rapid agonist application techniques, we conclude that incorporation of αβ-tandem subunits can be used to fix stoichiometry and to establish the intrinsic kinetic properties of α1β2 and α1β2γ2 receptors. We used this method to test whether the accessory protein GABAAreceptor-associated protein (GABARAP) alters GABAAreceptor properties directly or influences subunit composition. In recombinant receptors with fixed stoichiometry, coexpression of GABARAP-enhanced green fluorescent protein (EGFP) fusion protein had no effect on desensitization, deactivation, or diazepam potentiation of GABA-mediated currents. However, in α1β2γ2S transfections in which stoichiometry was not fixed, GABARAP-EGFP altered desensitization, deactivation, and diazepam potentiation of GABA-mediated currents. The data suggest that GABARAP does not alter receptor kinetics directly but by facilitating surface expression of αβγ receptors.
Competitive Stimulus Interactions within Single Response Fields of Superior Colliculus Neurons
Authors: Li Xiaobing , Basso Michele A.
Published: December 2005

In addition to its role in saccade generation, the superior colliculus (SC) is involved in target selection, saccade selection, and shifting the focus of spatial attention. Here, we investigated the influence of saccade selection on sensory interactions within single response fields (RFs) of SC neurons. One or two differently shaped stimuli were presented within single RFs of SC neurons, and the shape of a centrally located cue indicated whether and where to make a saccade (Go-Go) or whether to make or withhold a saccade (Go/No-Go). We found that, when two stimuli appeared at different locations within a single RF, SC neuronal activity was reduced compared with when a single stimulus appeared in isolation within the center of the RF in both the Go-Go and Go/No-Go tasks. In both tasks, a subsequent cue indicating one stimulus as a saccade target reduced the influence of the second stimulus located within the RF. We found that the time course of the suppression resulting from the two stimuli was ∼130 ms, a time close to that seen in cortex. Finally, we found that the influence of two stimuli within single RFs of SC neurons changed over time in both the Go-Go and the Go/No-Go tasks. Initially, the neurons averaged the influence of two stimuli. As the trial progressed, the SC neurons signaled only the saccade vector that was produced. We conclude that cues to shift gaze, like attention, modulate the influence of sensory interactions, providing additional support for the linkage between attention and saccade selection.
Oxytocin Modulates Neural Circuitry for Social Cognition and Fear in Humans
Authors: Kirsch Peter , Esslinger Christine , Chen Qiang , Mier Daniela , Lis Stefanie , Siddhanti Sarina , Gruppe Harald , Mattay Venkata S. , Gallhofer Bernd , Meyer-Lindenberg Andreas
Published: December 2005

In non-human mammals, the neuropeptide oxytocin is a key mediator of complex emotional and social behaviors, including attachment, social recognition, and aggression. Oxytocin reduces anxiety and impacts on fear conditioning and extinction. Recently, oxytocin administration in humans was shown to increase trust, suggesting involvement of the amygdala, a central component of the neurocircuitry of fear and social cognition that has been linked to trust and highly expresses oxytocin receptors in many mammals. However, no human data on the effects of this peptide on brain function were available. Here, we show that human amygdala function is strongly modulated by oxytocin. We used functional magnetic resonance imaging to image amygdala activation by fear-inducing visual stimuli in 15 healthy males after double-blind crossover intranasal application of placebo or oxytocin. Compared with placebo, oxytocin potently reduced activation of the amygdala and reduced coupling of the amygdala to brainstem regions implicated in autonomic and behavioral manifestations of fear. Our results indicate a neural mechanism for the effects of oxytocin in social cognition in the human brain and provide a methodology and rationale for exploring therapeutic strategies in disorders in which abnormal amygdala function has been implicated, such as social phobia or autism.
Multiple Receptors Coupled to Phospholipase C Gate Long-Term Depression in Visual Cortex
Authors: Choi Se-Young , Chang Jeff , Jiang Bin , Seol Geun-Hee , Min Sun-Seek , Han Jung-Soo , Shin Hee-Sup , Gallagher Michela , Kirkwood Alfredo
Published: December 2005

Long-term depression (LTD) in sensory cortices depends on the activation of NMDA receptors. Here, we report that in visual cortical slices, the induction of LTD (but not long-term potentiation) also requires the activation of receptors coupled to the phospholipase C (PLC) pathway. Using immunolesions in combination with agonists and antagonists, we selectively manipulated the activation of α1 adrenergic, M1 muscarinic, and mGluR5 glutamatergic receptors. Inactivation of these PLC-coupled receptors prevents the induction of LTD, but only when the three receptors were inactivated together. LTD is fully restored by activating any one of them or by supplying intracellulard-myo-inositol-1,4,5-triphosphate (IP3). LTD was also impaired by intracellular application of PLC or IP3receptor blockers, and it was absent in mice lacking PLCβ1, the predominant PLC isoform in the forebrain. We propose that visual cortical LTD requires a minimum of PLC activity that can be supplied independently by at least three neurotransmitter systems. This essential requirement places PLC-linked receptors in a unique position to control the induction of LTD and provides a mechanism for gating visual cortical plasticity via extra-retinal inputs in the intact organism.
Bidirectional Activity-Dependent Plasticity at Corticostriatal Synapses
Authors: Fino Elodie , Glowinski Jacques , Venance Laurent
Published: December 2005

Corticostriatal projections originate from the entire cerebral cortex and provide the major source of glutamatergic inputs to the basal ganglia. Despite the importance of corticostriatal connections in sensorimotor learning and cognitive functions, plasticity forms at these synapses remain strongly debated. Using a corticostriatal slice preserving the connections between the somatosensory cortex and the target striatal cells, we report the induction of both non-Hebbian and Hebbian forms of long-term potentiation (LTP) and long-term depression (LTD) on striatal output neurons (SONs). LTP and LTD can be induced selectively by different stimulation patterns (high-frequency trains vs low-frequency pulses) and were evoked with similar efficiency in non-Hebbian and Hebbian modes. Combination of LTP–LTD and LTD–LTP sequences revealed that bidirectional plasticity occurs at the same SONs and provides efficient homeostatic mechanisms leading to a resetting of corticostriatal synapses avoiding synaptic saturation. The effect of temporal relationship between cortical stimulation and SON activity was assessed using spike-timing-dependent plasticity (STDP) protocols. An LTP was observed when an action potential was triggered in the striatal neuron before the cortical stimulus, and, conversely, an LTD was induced when the striatal neuron discharge was triggered after the cortical stimulation. Such STDP was reversed when compared with those described so far in other mammalian brain structures. This mechanism may be essential for the role of the striatum in learning of motor sequences in which sensory and motor events are associated in a precise time sequence.
Uptake and distribution of tritium-labeled polysulfated glycosaminoglycan in serum, urine, and superficial digital flexor tendon of rabbits after intramuscular administration
Authors: Walesby H. Ame , Rosenbusch Ricardo , Booth Larry C. , Riley Christopher B.
Published: December 2005

Objective—To determine concentrations of tritiated
polysulfated glycosaminoglycans (3H-PSGAG) in
serum, urine, and the superficial digital flexor tendon
(SDFT) of rabbits after IM administration and molecular
weight of 3H-PSGAG recovered from the SDFT.

Animals—Twenty-five 12-week-old New Zealand
White rabbits.

Procedure—Rabbits were given a single dose of
3H-PSGAG (1.1 mg/kg [70 mCi of specific activity/kg]
of body weight) IM. At each of 5 sample times (2, 24,
48, 96, and 192 hours), 5 rabbits were randomly
selected and sedated, and blood and urine samples
were collected. Rabbits were then euthanatized, and
the SDFT were immediately harvested from the hind
limbs. Scintillation spectrometry was used to detect
concentration of 3H-PSGAG in fluid and tissue samples.
Gel-filtration chromatography was used to determine
molecular weight of recovered 3H-PSGAG.

Results—Mean concentrations of 3H-PSGAG in
SDFT, serum, and urine were greatest 2 hours after
administration. Tritiated PSGAG could be detected in
all samples collected 192 hours after administration.
Gel-filtration chromatography confirmed that 3HPSGAG
detected in SDFT samples was high molecular
weight PSGAG.

Conclusions and Clinical Relevance—Results indicate
that PSGAG is distributed to the SDFT, serum,
and urine after IM administration in rabbits. Further
study is needed to determine whether the same is
true in horses and to determine what effect, if any,
PSGAG has on inflammation of the SDFT. (Am J Vet
Res 2000;61:20–23)
Association of 3-methyleneindolenine, a toxic metabolite of 3-methylindole, with acute interstitial pneumonia in feedlot cattle
Authors: Loneragan Guy H. , Gould Daniel H. , Mason Gary L. , Garry Franklyn B. , Yost Garold S. , Lanza Diane L. , Miles Delbert G. , Hoffman Bruce W. , Mills Leon J.
Published: December 2005

Objective—To compare concentrations of 3-methyleneindolenine (3MEIN) in lung tissues obtained from feedlot cattle that died as a result of acute interstitial pneumonia (AIP) and cattle that died as a result of other causes and to compare blood concentrations of 3MEIN in healthy feedlot cattle and feedlot cattle with AIP.

Study Population—Blood samples and lung tissues collected from 186 cattle housed in 14 feedlots in the western United States.

Procedure—Samples of lung tissues were collected during routine postmortem examination and submitted for histologic, microbiologic, and toxicologic examination. Blood samples were collected from cattle with clinical manifestations of AIP and healthy penmates. Histologic diagnoses were categorized as AIP, bronchopneumonia (BP), control samples, and other disorders. Concentrations of 3MEIN were determined in lung tissues and blood samples, using an ELISA.

Results—Concentrations of 3MEIN in lung tissues were significantly greater in AIP and BP samples, compared with control samples. Absorbance per microgram of protein did not differ between BP and AIP samples. Blood concentrations of 3MEIN were significantly greater in cattle with AIP, compared with healthy cattle or cattle with BP. Odds of an animal with AIP being a heifer was 3.1 times greater than the odds of that animal being a steer.

Conclusion and Clinical Relevance—Increased pulmonary production of 3MEIN may be an important etiologic factor in feedlot-associated AIP. (Am J Vet Res2001;62:1525–1530)
Effect of orally administered cimetidine and ranitidine on abomasal luminal pH in clinically normal milk-fed calves
Authors: Ahmed Ahmed F. , Constable Peter D. , Misk Nabil A.
Published: December 2005

Objective—To characterize the change of pH in the abomasal lumen throughout a 24-hour period, to determine whether pH of the abomasal body differs from pH of the pyloric antrum, and to determine whether oral administration of cimetidine and ranitidine alters pH of the abomasal lumen in milk-fed calves.

Animals—5 male dairy calves (4 Holsteins-Friesian, 1 Ayrshire), 5 to 15 days old.

Procedure—Cannulas were surgically positioned in the abomasal body and pyloric antrum of each calf. Calves received the following treatments in a randomized crossover design: milk replacer (60 ml/kg of body weight, q 12 h [untreated control calves]), milk replacer and cimetidine (50 or 100 mg/kg, q 8 h), or milk replacer and ranitidine (10 or 50 mg/kg, q 8 h). The pH of the abomasal body and pyloric antrum was measured for 24 hours, using miniature glass pH electrodes.

Results—Suckling of milk replacer immediately increased abomasal luminal pH from 1.4 to 6.0, followed by a gradual decrease to preprandial values by 6 hours. Preprandial and postprandial pH values were not significantly different between the abomasal body and pyloric antrum, indicating lack of pH compartmentalization in the abomasum of milk-fed calves. Administration of cimetidine and ranitidine caused a significant dose-dependent increase in mean 24-hour abomasal luminal pH.

Conclusion and Clinical Relevance—Abomasal acid secretion in milk-fed calves is mediated in part by histamine type-2 receptors. Cimetidine and ranitidine may be efficacious in the treatment of abomasal ulcers in milk-fed calves. (Am J Vet Res2001;62:1531–1538)
Telomere length and telomerase activity in canine mammary gland tumors
Authors: Yazawa Mitsuhiro , Okuda Masaru , Setoguchi Asuka , Iwabuchi Shigehito , Nishimura Ryohei , Sasaki Nobuo , Masuda Kenichi , Ohno Koichi , Tsujimoto Hajime
Published: December 2005

Objective—To measure telomere length and telomerase activity in naturally occurring canine mammary gland tumors.

Sample Population—27 mammary gland tumor specimens obtained during resection or necropsy and 12 mammary gland tissue specimens obtained from healthy (control) dogs.

Procedure—Telomere length in tissue specimens was measured by use of restriction endonuclease digestion and Southern blot analysis. Telomerase activity was measured by use of a telomeric repeat amplification protocol assay.

Results—Telomere length in mammary gland tumors ranged from 11.0 to 21.6 kilobase pairs (kbp; mean ± SEM, 14.5 ± 0.5 kbp) but did not differ among tumor types. Telomeres in mammary gland tumors were slightly shorter than in normal tissue specimens, but telomere length could not be directly compared between groups, because mean age of dogs was significantly different between groups. Age was negatively correlated with telomere length in control dogs but was not significantly correlated with length in affected dogs. Telomerase activity was detected in 26 of 27 mammary gland tumors and in 4 of 12 normal tissue specimens. However, telomerase activity and telomere length were not correlated in tumor specimens.

Conclusion and Clinical Relevance—Telomere length is maintained in canine mammary gland tumors regardless of the age of the affected dog. Measurement of telomere length may be a useful tool for monitoring the in vivo effects of telomerase inhibitors in dogs with tumors. (Am J Vet Res2001; 62:1539–1543)
Effects of exogenous insulin on glucose tolerance in alpacas
Authors: Cebra Christopher K. , McKane Shaun A. , Tornquist Susan J.
Published: December 2005

Objective—To evaluate the effects of exogenous
insulin on clearance of exogenous glucose in alpacas.

Animals—7 adult castrated male alpacas.

Procedure—Prior to each of 2 trials, food was withheld
for 8 hours. Glucose (0.5 g/kg of body weight)
was then administered by rapid IV infusion. During 1
of the trials, regular insulin (0.2 U/kg, IV) was also
administered 15 minutes later. Blood was collected
immediately before (0 minutes) and 15, 20, 25, 30,
45, 60, 90, 120, 180, and 240 minutes after glucose
administration. Plasma concentrations of glucose and
lactate were determined, and glucose fractional
turnover rate and plasma half-life were calculated.

Results—Insulin treatment caused a significant
increase in fractional turnover rate of glucose and
plasma lactate concentration. Plasma glucose concentrations
were less in insulin-treated alpacas from
30 minutes after glucose administration (15 minutes
after insulin administration) until the conclusion of
each trial, compared with nontreated alpacas. In addition,
plasma glucose concentration in insulin-treated
alpacas returned to baseline values 1 hour sooner
than in the nontreated group.

Conclusion and Clinical Relevance—Glucose
uptake in alpacas improves after insulin treatment,
suggesting that administration of exogenous insulin
will increase the therapeutic and decrease the pathologic
effects of exogenous glucose administered to
hypoglycemic alpacas. However, alpacas and other
New World camelids should be monitored carefully
during treatment with glucose or insulin, because
these species appear to be partially insulin resistant.
(Am J Vet Res 2001;62:1544–1547)
Telomerase activity as a marker for malignancy in feline tissues
Authors: Cadile Casey D. , Kitchell Barbara E. , Biller Barbara J. , Hetler Elizabeth R. , Balkin Rebecca G.
Published: December 2005

Objective—To establish the diagnostic significance of the telomeric repeat amplification protocol (TRAP) assay in detecting feline malignancies.

Sample Population—Solid tissue specimens collected from 33 client-owned cats undergoing diagnostic or therapeutic procedures at the University of Illinois Veterinary Medical Teaching Hospital between July 1997 and September 1999 and an additional 20 tissue samples were collected from 3 clinically normal control cats euthanatized at the conclusion of an unrelated study.

Procedure—The TRAP assay was used for detection of telomerase activity. Each result was compared to its respective histopathologic diagnosis.

Results—Twenty-nine of 31 malignant and 1 of 22 benign or normal tissue samples had telomerase activity, indicating 94% sensitivity and 95% specificity of the TRAP assay in our laboratory.

Conclusion and Clinical Relevance—The diagnostic significance of telomerase activity has been demonstrated in humans and recently in dogs by our laboratory. We tested feline samples to determine whether similar patterns of telomerase activity exist. On the basis of our results, the TRAP assay may be clinically useful in providing a rapid diagnosis of malignancy in cats. The telomerase enzyme may also serve as a therapeutic target in feline tumors. (Am J Vet Res2001;62:1578–1581)
Model formulation and determination of in vitro parameters of a noninvasive method to calculate flexor tendon forces in the equine forelimb
Authors: Meershoek Liduin S. , Bogert Anton J. van den , Schamhardt Henk C.
Published: December 2005

Objective—To describe a method to calculate flexor tendon forces on the basis of inverse dynamic analysis and an in vitro model of the equine forelimb and to quantify parameters for the model.

Sample Population—38 forelimbs of 23 horses that each had an estimated body mass of ≥ 500 kg.

Procedure—Longitudinal limb sections were used to determine the lines of action of the tendons. Additionally, limb and tendon loading experiments were performed to determine mechanical properties of the flexor tendons.

Results—The study quantified the parameters for a pulley model to describe the lines of action. Furthermore, relationships between force and strain of the flexor tendons and between fetlock joint angle and suspensory ligament strain were determined, and the ultimate strength of the tendons was measured.

Conclusion and Clinical Relevance—The model enables noninvasive determination of forces in the suspensory ligament, superficial digital flexor tendon, and distal part of the deep digital flexor (DDF) tendon. In addition, it provides a noninvasive measure of loading of the accessory ligament of the DDF tendon for within-subject comparisons. However, before application, the method should be validated. The model could become an important tool for use in research of the cause, prevention, and treatment of tendon injuries in horses. (Am J Vet Res2001;62:1585–1593)
Spatial distribution of seropositivity to the causative agent of granulocytic ehrlichiosis in dogs in California
Authors: Foley Janet E. , Foley Patrick , Madigan John E.
Published: December 2005

Objective—To assess spatial and temporal patterns of seroprevalence among dogs in California to the causative agent of granulocytic ehrlichiosis (GE).

Sample Population—Sera of 1,082 clinically normal dogs from 54 of 59 counties in California in 1997 to 1998.

Procedure—Serum-specific IgG reactivity toEhrlichia equiwas assessed by use of an immunofluorescent antibody assay, usingE equi-infected horse neutrophils as substrate. Data were analyzed, using a geographic information system. Spatial analysis of seroprevalence included first order Bayesian analysis of seroprevalence and second order analysis of clustering by K-function and Cuzick-Edwards tests. Monthly seroprevalence among dogs was examined by use of regression on monthly densities ofIxodes pacificusadults and nymphs .

Results—Seroprevalence among dogs toE equiwas 8.68%. Data were seasonally bimodal with highest prevalence in winter (when adult ticks were abundant) and a secondary peak in late spring (corresponding to nymphal ticks). Humboldt County had the highest seroprevalence (47.3%), and other northern coast range counties had seroprevalence from 15 to 30%.

Conclusion and Clinical Relevance—The patchy distribution of exposure toEhrlichiaorganisms is a subset of the distribution of the tick vector. This may reflect enzootic cycles or climatic or historical factors that limited the range of the disease. Dogs, horses, and humans from north coast range counties in California are at increased risk of GE. These data provide a background for assessing risk of infection in horses and dogs, depending on geographic location. Dogs may be sentinels for assessing risk of GE in humans. (Am J Vet Res2001;62:1599–1605)