bluuebunny/crossref_metadata_2025 huggingface dataset:
Spastic Long-Lasting Reflexes of the Chronic Spinal Rat Studied In Vitro
Authors: Li Y. , Harvey P. J. , Li X. , Bennett D. J.
Published: April 2004

Over the months following sacral spinal cord transection in adult rats, a pronounced spasticity syndrome emerges in the affected tail musculature, where long-lasting muscle spasms can be evoked by low-threshold afferent stimulation (termed long-lasting reflex). To develop an in vitro preparation to examine the neuronal mechanisms underlying spasticity, we removed the whole sacrocaudal spinal cord of these spastic chronic spinal rats (>1 mo after S2 sacral spinal transection) and maintained it in artificial cerebral spinal fluid in a recording chamber. The ventral roots were mounted on monopolar recording electrodes in grease, and the reflex responses to dorsal root stimulation were recorded and compared with the reflexes seen in the awake chronic spinal rat. When the dorsal roots were stimulated with a single pulse, a long-lasting reflex occurred in the ventral roots, with identical characteristics to the long-lasting reflex in the awake spastic rat tail. The reflex response was low threshold ( T), short latency, long duration (∼2 s), and enhanced by repeated stimulation. Brief high-frequency stimulation trains (0.5 s, 100 Hz, 1.5 × T) evoked even longer duration responses (5–10 s), with repeated bursts of activity that were similar to the repeated muscle spasms evoked in awake rats with stimulation trains or manual skin stimulation. Stimulation of a given dorsal root evoked long-lasting reflexes in both the ipsilateral and contralateral ventral roots. Long-lasting reflexes did not occur in the sacrocaudal spinal cord of acute spinal rats (S2 transection), which is similar to the areflexia seen in awake acute spinal rats. However, long-lasting reflexes could be made to occur in the acute spinal rat by altering K+ (7 mM) or Mg2+ (0 mM) concentrations, or by application of high doses of the neuromodulators norepinephrine (NE, >20 μM) or serotonin (5-HT, >20 μM). In chronic spinal rats, much lower doses of these neuromodulators (0.1 μM) enhanced the long-lasting reflexes, suggesting a denervation supersensitivity to 5-HT and NE following injury. Higher doses of NE or 5-HT produced a paradoxical inhibition of the long-lasting reflexes. The high dose inhibition by NE was mimicked by the α2-adrenergic receptor agonist clonidine but not the α1-adrenergic receptor agonist methoxamine. In summary, the sacral spinal in vitro preparation offers a new approach to the study of spinal cord injury and analysis of antispastic drugs.
Small-Conductance Ca2+-Dependent K+ Channels Are the Target of Spike-Induced Ca2+ Release in a Feedback Regulation of Pyramidal Cell Excitability
Authors: Yamada Shin-Ichiro , Takechi Hajime , Kanchiku Izumi , Kita Toru , Kato Nobuo
Published: April 2004

Cooperative regulation of inosiol-1,4,5-trisphosphate receptors (IP3Rs) by Ca2+ and IP3 has been increasingly recognized, although its functional significance is not clear. The present experiments first confirmed that depolarization-induced Ca2+ influx triggers an outward current in visual cortex pyramidal cells in normal medium, which was mediated by apamin-sensitive, small-conductance Ca2+-dependent K+ channels (SK channels). With IP3-mobilizing neurotransmitters bath-applied, a delayed outward current was evoked in addition to the initial outward current and was mediated again by SK channels. Calcium turnover underlying this biphasic SK channel activation was investigated. By voltage-clamp recording, Ca2+ influx through voltage-dependent Ca2+ channels (VDCCs) was shown to be responsible for activating the initial SK current, whereas the IP3R blocker heparin abolished the delayed component. High-speed Ca2+ imaging revealed that a biphasic Ca2+ elevation indeed underlays this dual activation of SK channels. The first Ca2+ elevation originated from VDCCs, whereas the delayed phase was attributed to calcium release from IP3Rs. Such enhanced SK currents, activated dually by incoming and released calcium, were shown to intensify spike-frequency adaptation. We propose that spike-induced calcium release from IP3Rs leads to SK channel activation, thereby fine tuning membrane excitability in central neurons.
Sensitization of Mechanosensitive Gastric Vagal Afferent Fibers in the Rat by Thermal and Chemical Stimuli and Gastric Ulcers
Authors: Kang Yu-Ming , Bielefeldt Klaus , Gebhart G. F.
Published: April 2004

In the present study we examined the effects of acute thermal and chemical stimuli and gastric ulceration on mechanosensitive gastric vagal afferent fibers. Single-fiber recordings were made from the cervical vagus nerve. Mechanosensitive afferent fibers were identified by response to gastric distension (GD). Intragastric pressure was maintained below 3 mmHg during intragastric instillation of saline, heated saline, HCl, or glycocholic acid. Responses to graded GD (5–60 mmHg, 20 s, 4-min interval) were determined before and after 30-min exposure to thermal or chemical stimuli. All mechanosensitive fibers studied were C-fibers (mean CV: 1.07 ± 0.07 m/s). Saline (37°C) did not affect resting activity or alter responses to GD, but exposure to heated saline (46°C) significantly increased resting activity and sensitized responses to GD. The decrease in resting activity was hydrochloric acid concentration dependent (0.025–0.2 N), but responses to GD were sensitized after 30-min exposure to 0.1 N HCl ( n = 7). The bile acid glycocholic acid significantly increased resting activity and desensitized responses to GD at an intragastric pH of 7, and similarly increased resting activity but sensitized responses to GD ( n = 6) at an intragastric pH of 1.2. Vagal afferents recorded in rats with gastric ulcers had significantly greater resting activity and responses to GD than sham ulcer rats; intragastric instillation of glycocholic acid (pH 1.2) further increased afferent fiber excitability. These findings indicate that acute gastric thermal and chemical stimuli alter the response characteristics of mechanosensitive vagal afferents in the absence of inflammation or structural damage. Accordingly, acute sensitization of gastric afferents through different stimulus modalities may contribute to the development of dyspeptic symptoms. In the presence of gastric inflammation, mechanosensitive vagal afferents exhibit a further increase in excitability.
CO2/pH Chemosensory Signaling in Co-Cultures of Rat Carotid Body Receptors and Petrosal Neurons: Role of ATP and ACh
Authors: Zhang Min , Nurse Colin A.
Published: April 2004

The neurotransmitter mechanisms that process acid hypercapnia in the mammalian carotid body (CB) are poorly understood. Using a co-culture model containing rat CB chemoreceptor (type 1 cell) clusters and petrosal neurons (PN), we tested the hypothesis that co-released ACh and ATP was an important mechanism. Sensory transmission from type I clusters to PN in co-culture occurred at chemical synapses via co-release of ATP and ACh because isohydric hypercapnia depolarized and/or increased firing in co-cultured PN, but not in PN cultured alone; PN chemoexcitatory responses were inhibited by decreasing the extracellular Ca2+: Mg2+ ratio; partial inhibition of these responses occurred during separate perfusion of cholinergic (hexamethonium or mecamylamine) and P2X (suramin) receptor blockers, although inhibition was often complete with both blockers present; and rapid chemoexcitatory responses to hypercapnia were inhibited by acetazolamide (10 μM), an inhibitor of carbonic anhydrase, localized in type I cells. Acidosis (pH = 7.0, 7.2) enhanced the ATP-induced whole cell current in functional PN relative to that at physiologic pH (7.4), suggesting that increased sensitivity of postsynaptic P2X receptors may contribute to acid chemotransmission. Type I cells in CB tissue sections expressed vesicular acetylcholine transporter (VAChT), a cholinergic marker, as revealed by confocal immunofluorescence. Thus co-release of ACh and ATP is an important neurotransmitter mechanism for processing isohydric and acidic hypercapnia in the rat carotid body.
Afferent Synaptic Transmission in a Hair Cell Organ: Pharmacological and Physiological Analysis of the Role of the Extended Refractory Period
Authors: Dawkins Rosie , Sewell William F.
Published: April 2004

One feature of neuronal discharge proposed to play a role in coding temporal information is the relative refractory period that follows each action potential. In neurons innervating hair cells, there is an extended refractory period that can last ≤100 ms. We have taken a pharmacological approach to examine the extended refractory period in the Xenopus lateral line organ. We show that each action potential in the afferent fiber, whether generated spontaneously or through an antidromic electrical pulse, decreases the probability of subsequent afferent discharge for a period of ≤100 ms. We show that the extended refractory period can be modulated with drugs that alter glutamatergic transmission between the hair cell and the afferent fiber. The extended refractory period can be enhanced by perfusion with agents that reduce synaptic activity. These agents include blockers of voltage-dependent transmitter release, such as cobalt, as well as glutamate receptor antagonists, such as CNQX and kynurenic acid. Conversely, perfusion with agents that increase synaptic activity through activation of the glutamate receptors, such as AMPA or kainate, reduces the magnitude of suppression during the extended refractory period. The extended refractory period is greatly reduced by iberiotoxin and tetraethylammonium (TEA), indicating it may be mediated in large part by a calcium-dependent potassium channel. The ability to modulate the extended refractory period with changes in synaptic input suggests a simple, dynamic mechanism by which strong input (i.e., large or frequent excitatory postsynaptic potentials) can be strengthened and weak inputs weakened.
Effect of the Anesthetic Tricaine (MS-222) on Nerve Activity in the Anterior Lateral Line of the Oyster Toadfish,Opsanus tau
Authors: Palmer Lucy M. , Mensinger Allen F.
Published: April 2004

Inductive neural telemetry was used to record from microwire electrodes chronically implanted into the anterior lateral line nerve of the toadfish, Opsanus tau. Spontaneous neural activity and the response of lateral line fibers to water current were continually monitored from 17 primary afferent fibers before, during, and after the administration of the anesthetic tricaine (MS-222). Significant decrease in spontaneous and evoked activity and increase in interspike interval was noted when anesthetic concentrations were ≥0.010%. Neural activity returned to control levels within ∼90 min of anesthetic withdrawal. Decreasing the pH of the solution without the anesthetic caused transient heightened sensitivity, indicating that tricaine and not the concurrent drop in pH was responsible for the decrease in sensitivity during anesthesia. During a secondary challenge with the anesthetic 24 h after the first, fibers initially showed faster recovery however overall recovery kinetics were similar. Although high tricaine concentration was correlated with decreased neural sensitivity, the concentrations normally used to maintain anesthesia in the toadfish did not have significant effect on the evoked firing rate. Thus given sufficient time to recover from the induction of surgical anesthesia, it may be possible to maintain the animal under light anesthesia while minimizing the physiological effects of tricaine.
Variations in Motor Patterns During Fictive Rostral Scratching in the Turtle: Knee-Related Deletions
Authors: Stein Paul S. G. , Daniels-McQueen Susan
Published: April 2004

Agonist motor neurons usually alternate between activity and quiescence during normal rhythmic behavior; antagonist motor neurons are usually active during agonist motor neuron quiescence. During an antagonist deletion, a naturally occurring motor-pattern variation, there is no antagonist activity and no quiescence between successive bursts of agonist activity. Motor neuron recordings of normal fictive rostral scratching in the turtle displayed rhythmic alternation between activity and quiescence for hip flexors, knee flexors, and knee extensors. Knee-flexor activity occurred during knee-extensor quiescence. During a hip-extensor deletion, a variation of rostral scratching, rhythmic hip-flexor bursts occurred without intervening hip-flexor quiescence. There were 3 distinct patterns of knee motor activity during the cycle before or after a hip-extensor deletion. In most cycles, there was knee flexor-extensor rhythmic alternation. In some cycles, termed knee-flexor deletions, there was no knee-flexor activity and rhythmic knee-extensor bursts occurred without intervening knee-extensor quiescence. In other cycles, termed knee-extensor deletions, there was no knee-extensor activity and rhythmic knee-flexor bursts occurred without intervening knee-flexor quiescence. The concept of a module refers to a population of motor neurons and interneurons with similar activity patterns; interneurons in a module coordinate agonist and antagonist motor neuron activities, either with excitation of agonist motor neurons and interneurons, or with inhibition of antagonist motor neurons and interneurons. Previous studies of hip-extensor deletions support the concept of a rhythmogenic hip-flexor module. The knee-related deletions described here support the concept of rhythmogenic knee-flexor and knee-extensor modules linked by reciprocal inhibition.
Stimulus-Induced Intercolumnar Synchronization of Neuronal Activity in Rat Barrel Cortex: A Laminar Analysis
Authors: Zhang Mengliang , Alloway Kevin D.
Published: April 2004

We used cross-correlation analysis to characterize the coordination of stimulus-induced neuronal activity in the primary somatosensory barrel cortex of isoflurane-anesthetized rats. On each trial, multiple whiskers were simultaneously deflected at frequencies that corresponded to 2, 5, 8, or 11 Hz. Among 476 neuron pairs that we examined, 342 (71.8%) displayed significant peaks of synchronized activity that exceeded the 99.9% confidence limits. The incidence and strength of these functional associations varied across different cortical layers. Only 52.9% of neuron pairs in layer IV displayed synchronized responses, whereas 84.1% of the infragranular neuron pairs were synchronized during whisker stimulation. Neuronal synchronization was strongest in the infragranular layers, weakest in layer IV, and varied according to the columnar configuration of the neuron pairs. Thus correlation coefficients were largest for neuron pairs in the same whisker barrel row but were smallest for neurons in different rows and arcs. Spontaneous activity in the infragranular layers was also synchronized to a greater degree than in the other layers. Although infragranular neuron pairs displayed similar amounts of synchronization in response to each stimulus frequency, granular and supragranular neurons were synchronized mainly during stimulation at 2 or 5 Hz. These results are consistent with previous studies indicating that infragranular neurons have intrinsic properties that facilitate synchronized activity, and they suggest that neuronal synchronization plays an important role in transmitting sensory information to other cortical or subcortical brain regions.
Progression of Coronary Artery Calcium and Risk of First Myocardial Infarction in Patients Receiving Cholesterol-Lowering Therapy
Authors: Raggi Paolo , Callister Tracy Q. , Shaw Leslee J.
Published: April 2004

Objective—

Statins reduce cardiovascular risk and slow progression of coronary artery calcium (CAC). We investigated whether CAC progression and low-density lipoprotein (LDL) reduction have a complementary prognostic impact.

Methods and Results—

We measured the change in CAC in 495 asymptomatic subjects submitted to sequential electron-beam tomography (EBT) scanning. Statins were started after the initial EBT scan. Myocardial infarction (MI) was recorded in 41 subjects during a follow-up of 3.2±0.7 years. Mean LDL level did not differ between groups (118±25 mg/dL versus 122±30 mg/dL, MI versus no MI). On average, MI subjects demonstrated a CAC change of 42%±23% yearly; event-free subjects showed a 17%±25% yearly change (
P
=0.0001). Relative risk of having an MI in the presence of CAC progression was 17.2-fold (95% CI: 4.1 to 71.2) higher than without CAC progression (
P
<0.0001). In a Cox proportional hazard model, the follow-up score (
P
=0.034) as well as a score change >15% per year (
P
<0.001) were independent predictors of time to MI.

Conclusions—

Progression of CAC was significantly greater in patients receiving statins who had an MI compared with event-free subjects despite similar LDL control. Continued expansion of CAC may indicate failure of some patients to benefit from statin therapy and an increased risk of having cardiovascular events.
Enhanced Inhibition of Neointimal Hyperplasia by Genetically Engineered Endothelial Progenitor Cells
Authors: Kong Deling , Melo Luis G. , Mangi Abeel A. , Zhang Lunan , Lopez-Ilasaca Marco , Perrella Mark A. , Liew Chong C. , Pratt Richard E. , Dzau Victor J.
Published: April 2004

Background—

Circulating endothelial progenitor cells (EPCs) have been reported previously. In this study, we examined the hypothesis that overexpression of vasculoprotective gene endothelial nitric oxide synthase (eNOS) and heme oxygenase-1 (HO-1) in EPCs enhances their ability to inhibit neointimal hyperplasia.

Methods and Results—

EPCs were isolated from rabbit peripheral blood, expanded in culture, and transduced with pseudotyped retroviral vectors expressing human eNOS (eNOS-EPCs), HO-1 (HO-1-EPCs), or green fluorescent protein (GFP-EPCs). Transduction efficiency of EPCs ex vivo was >90%. Four groups of rabbits (n=5 to 6 per group) were subjected to balloon angioplasty of the common carotid artery. Immediately after injury, ≈5×10
6
autologous eNOS-EPCs or HO-1-EPCs were transplanted into the injured vessel. Control animals received an equivalent number of GFP-EPCs or Ringer’s saline. Two weeks after transplantation, eNOS and HO-1 transgene transcripts and proteins were detected in the transduced rabbit vessels. Endothelialization was enhanced in the EPC-transplanted vessels independently of gene transfer. Neointimal thickening was significantly reduced in the GFP-EPC-treated vessels relative to the saline control. Neointima size was further reduced in vessels treated with eNOS-EPCs. Surprisingly, no additional reduction was seen in vessels treated with HO-1-EPCs relative to GFP-EPCs. Thrombosis occurred in ≈50% of the saline-treated vessels but was virtually absent in all EPC-transplanted vessels.

Conclusions—

We conclude that transplantation of autologous EPCs overexpressing eNOS in injured vessels enhances the vasculoprotective properties of the reconstituted endothelium, leading to inhibition of neointimal hyperplasia. This cell-based gene therapy strategy may be useful in treatment of vascular disease.
Microvolt T-Wave Alternans as a Predictor of Ventricular Tachyarrhythmias
Authors: Tanno Kaoru , Ryu Syunsho , Watanabe Norikazu , Minoura Yoshino , Kawamura Mitsuharu , Asano Taku , Kobayashi Youichi , Katagiri Takashi
Published: April 2004

Background—

Microvolt T-wave alternans (TWA) is reported to be closely associated with sudden cardiac death (SCD) and ventricular tachycardia (VT). Animal experiments revealed that microvolt TWA is highly dependent on heart rate. The purpose of this study was to determine whether patients with TWA at relatively low heart rates have increased vulnerability to ventricular tachyarrhythmias.

Methods and Results—

Subjects were 248 consecutive patients (158 men, 90 women; mean age, 59±17 years) who underwent electrophysiological study from 1997 to 2000. TWA recording was made in sinus rhythm and at atrial pacing rates of 90, 100, 110, and 120 bpm with the Cambridge Heart CH2000 system. Alternans voltage (V
alt
) was measured when the alternans ratio was >3 for a period of >1 minute in VM, X, Y, Z, or 2 adjacent precordial leads. Study end point was the first appearance of VT, ventricular fibrillation (VF), appropriate implantable cardioverter-defibrillator therapy with pacing or shocks, or SCD. During the 37±12-month follow-up period, 22 patients had sustained VT, and 5 patients died of SCD. In patients with >1.9-μV V
alt
at rates of 90, 100, and 110 bpm, the incidence of VT/VF/SCD was 56%, 28%, and 18%, respectively. V
alt
of >2.9 μV at a heart rate of 90 bpm had a 70% positive predictive value for VT/VF/SCD. However, when V
alt
was <0.9 μV at a rate of 120 bpm, negative predictive value was 100%.

Conclusions—

Patients with TWA at relatively low heart rates are susceptible to ventricular tachyarrhythmias.
Procalcitonin and the Early Diagnosis of Infective Endocarditis
Authors: Mueller Christian , Huber Peter , Laifer Gerd , Mueller Beat , Perruchoud André P.
Published: April 2004

Background—

Variability in the clinical presentation of infective endocarditis (IE) makes the diagnosis a clinical challenge. We hypothesized that serum procalcitonin, a marker of systemic bacterial infection, might be helpful in its diagnosis.

Methods and Results—

We conducted a prospective cohort study in 67 consecutive patients admitted to the hospital with the suspicion of IE or in whom the suspicion arose during the hospital course. IE was diagnosed by an interdisciplinary team that included an infectious disease specialist and a cardiologist who applied the Duke criteria. IE was confirmed in 21 patients. Procalcitonin was significantly higher in patients with IE (median 6.56 ng/mL) than in those with other final diagnoses (median 0.44 ng/mL,
P
<0.001). The area under the receiver operating characteristic curve that used procalcitonin to predict IE was 0.856 (95% CI 0.750 to 0.962), compared with 0.657 (95% CI 0.511 to 0.802) for C-reactive protein. The optimum concentration of procalcitonin for the calculation of positive and negative predictive accuracy as obtained from the receiver operating characteristic curve was 2.3 ng/mL. With this cutoff, the test characteristics of procalcitonin were as follows: sensitivity 81%, specificity 85%, negative predictive value 92%, and positive predictive value 72%. Multiple logistic regression analysis revealed that procalcitonin was the only significant independent predictor of IE on admission (OR 1.52, 95% CI 1.07 to 2.15,
P
=0.018).

Conclusions—

Procalcitonin may be a valuable additional diagnostic marker in patients with suspected IE.
Water Potentiates the Pressor Effect of Ephedra Alkaloids
Authors: Jordan Jens , Shannon John R. , Diedrich André , Black Bonnie , Robertson David , Biaggioni Italo
Published: April 2004

Background—

The use of ephedra alkaloids in over-the-counter preparations has been associated with potentially serious cerebrovascular events. Because of its potential association with hemorrhagic strokes, phenylpropanolamine has been largely substituted for by pseudoephedrine, but it is not clear whether this is indeed a safer alternative. It would be important to understand the cardiovascular effects of ephedra alkaloids, but these are normally masked by baroreflex buffering mechanisms. We therefore investigated the effects of ephedra alkaloids in patients with autonomic impairment and explored their potential interaction with water ingestion.

Methods and Results—

The cardiovascular effects of phenylpropanolamine or pseudoephedrine, alone and in combination with water, were determined in 13 subjects with impairment of baroreflex function due to autonomic failure. Phenylpropanolamine, 12.5 to 25 mg PO, increased systolic blood pressure (SBP) by 21±14 mm Hg after 90 minutes. However, when ingested with 16 oz of room temperature tap water, phenylpropanolamine increased SBP by 82±2 mm Hg. Pseudoephedrine, 30 mg PO, increased SBP on average 52±9 mm Hg when taken with 16 oz of water and by as much as 88 mm Hg.

Conclusions—

Ephedra alkaloids increase blood pressure significantly in individuals with impaired baroreflex function. Concomitant ingestion of ephedra alkaloids and water produced a greater increase in blood pressure. If used cautiously, this interaction can be beneficial in the treatment of orthostatic hypotension. On the other hand, it could contribute to the cardiovascular complications associated with the use of ephedra alkaloids, given that baroreflex function varies widely in normal individuals and is impaired in several medical conditions.
Abciximab-Supported Infarct Artery Stent Implantation for Acute Myocardial Infarction and Long-Term Survival
Authors: Antoniucci David , Migliorini Angela , Parodi Guido , Valenti Renato , Rodriguez Alfredo , Hempel Albrecht , Memisha Gentian , Santoro Giovanni Maria
Published: April 2004

Background—

The impact on survival of routine use of abciximab as adjunctive treatment to routine infarct artery stenting for acute myocardial infarction is not defined. We sought to determine the effect of abciximab on 1-year survival and other major adverse cardiac events of patients with acute myocardial infarction undergoing routine infarct artery stenting.

Methods and Results—

The Abciximab and Carbostent Evaluation (ACE) Trial is an unblinded, randomized, controlled trial that compared abciximab with placebo in patients undergoing routine infarct artery stent implantation for acute myocardial infarction. At 1 year, the survival rate was 95±2% in the abciximab group and 88±2% in the stent-alone group (
P
=0.017). The reinfarction rate was 1% in the abciximab group and 6.0% in the stent-alone group, whereas there were no differences between groups in target vessel revascularization rate (16.5% in the abciximab group, 17.5% in the stent-alone group).

Conclusions—

Abciximab as adjunctive treatment to routine infarct artery stenting for acute myocardial infarction resulted in improved 1-year survival and lower reinfarction rates.
Inhibition of Phosphodiesterase Type 5 by the Activator of Nitric Oxide–Sensitive Guanylyl Cyclase BAY 41-2272
Authors: Mullershausen Florian , Russwurm Michael , Friebe Andreas , Koesling Doris
Published: April 2004

Background—

By the formation of cGMP, nitric oxide (NO)–sensitive guanylyl cyclase (GC) acts as the effector for the signaling molecule NO and mediates the relaxation of vascular smooth muscle and the inhibition of platelet aggregation. The compounds YC-1 and BAY 41-2272 are regarded as NO-independent activators and sensitizers of NO-sensitive GC. In vivo effects, for example, lowering blood pressure and prolonging tail-bleeding times, turn the compounds into promising candidates for the therapy of cardiovascular diseases. However, YC-1 has also been shown to inhibit the major cGMP-degrading enzyme phosphodiesterase type 5 (PDE5). The synergistic properties of YC-1 on cGMP formation and degradation lead to an excessive NO-induced cGMP accumulation in cells, explaining the observed physiological effects. We assessed a potential inhibition of PDE5 by the new GC activator BAY 41-2272.

Methods and Results—

The effects of BAY 41-2272 on NO-sensitive GC and PDE5 activities were tested in vitro. BAY 41-2272 not only sensitized NO-sensitive GC toward activation by NO but also, with comparable potency, inhibited cGMP degradation by PDE5. In intact platelets, BAY 41-2272 greatly potentiated the NO-induced cGMP response that was caused by a synergistic effect of BAY 41-2272 on cGMP formation and degradation.

Conclusions—

The physiological effects of BAY 41-2272, which are commonly ascribed to the NO-independent activation of NO-sensitive GC, are rather due to the synergism of sensitization of NO-sensitive GC and inhibition of PDE5.
Transient Mitochondrial Permeability Transition Pore Opening Mediates Preconditioning-Induced Protection
Authors: Hausenloy Derek , Wynne Abigail , Duchen Michael , Yellon Derek
Published: April 2004

Background—

Transient (low-conductance) opening of the mitochondrial permeability transition pore (mPTP) may limit mitochondrial calcium load and mediate mitochondrial reactive oxygen species (ROS) signaling. We hypothesize that transient mPTP opening and ROS mediate the protection associated with myocardial preconditioning and mitochondrial uncoupling.

Methods and Results—

Isolated perfused rat hearts were subjected to 35 minutes of ischemia/120 minutes of reperfusion, and the infarct-risk-volume ratio was determined by tetrazolium staining. Inhibiting mPTP opening during the preconditioning phase with cyclosporine-A (CsA, 0.2 μmol/L) or sanglifehrin-A (SfA, 1.0 μmol/L) abolished the protection associated with ischemic preconditioning (IPC) (20.2±3.6% versus 45.9±2.5% with CsA, 49.0±7.1% with SfA;
P
<0.001); and pharmacological preconditioning with diazoxide (Dzx, 30 μmol/L) (22.1±2.7% versus 46.3±3.0% with CsA, 48.4±5.5% with SfA;
P
<0.001), CCPA (the adenosine A1-receptor agonist, 200 nmol/L) (24.9±4.5% versus 54.4±6.6% with CsA, 42.6±9.0% with SfA;
P
<0.001), or 2,4-dinitrophenol (DNP, the mitochondrial uncoupler, 50 μmol/L) (15.7±2.7% versus 40.8±5.5% with CsA, 34.3±3.1% with SfA;
P
<0.001), suggesting that mPTP opening during the preconditioning phase is required to mediate protection in these settings. Inhibiting ROS during the preconditioning protocols with
N
-mercaptopropionylglycine (MPG, 1 mmol/L) also abolished the protection associated with IPC (20.2±3.6% versus 47.1±3.8% with MPG;
P
<0.001), diazoxide (22.1±2.7% versus 56.3±3.8% with MPG;
P
<0.001), and DNP (15.7±2.7% versus 50.7±6.6% with MPG;
P
<0.001) but not CCPA (24.9±4.5% versus 26.5±8.4% with MPG;
P
=NS). Further experiments in adult rat myocytes demonstrated that diazoxide induced CsA-sensitive, low-conductance transient mPTP opening (represented by a 28±3% reduction in mitochondrial calcein fluorescence compared with control;
P
<0.01).

Conclusions—

We report that the protection associated with IPC, diazoxide, and mitochondrial uncoupling requires transient mPTP opening and ROS.
Hyperventilation-Induced Hypotension During Cardiopulmonary Resuscitation
Authors: Aufderheide Tom P. , Sigurdsson Gardar , Pirrallo Ronald G. , Yannopoulos Demetris , McKnite Scott , von Briesen Chris , Sparks Christopher W. , Conrad Craig J. , Provo Terry A. , Lurie Keith G.
Published: April 2004

Background—

A clinical observational study revealed that rescuers consistently hyperventilated patients during out-of-hospital cardiopulmonary resuscitation (CPR). The objective of this study was to quantify the degree of excessive ventilation in humans and determine if comparable excessive ventilation rates during CPR in animals significantly decrease coronary perfusion pressure and survival.

Methods and Results—

In humans, ventilation rate and duration during CPR was electronically recorded by professional rescuers. In 13 consecutive adults (average age, 63±5.8 years) receiving CPR (7 men), average ventilation rate was 30±3.2 per minute (range, 15 to 49). Average duration per breath was 1.0±0.07 per second. No patient survived. Hemodynamics were studied in 9 pigs in cardiac arrest ventilated in random order with 12, 20, or 30 breaths per minute. Survival rates were then studied in 3 groups of 7 pigs in cardiac arrest that were ventilated at 12 breaths per minute (100% O
2
), 30 breaths per minute (100% O
2
), or 30 breaths per minute (5% CO
2
/95% O
2
). In animals treated with 12, 20, and 30 breaths per minute, the mean intrathoracic pressure (mm Hg/min) and coronary perfusion pressure (mm Hg) were 7.1±0.7, 11.6±0.7, 17.5±1.0 (
P
<0.0001), and 23.4±1.0, 19.5±1.8, and 16.9±1.8 (
P
=0.03), respectively. Survival rates were 6/7, 1/7, and 1/7 with 12, 30, and 30+ CO
2
breaths per minute, respectively (
P
=0.006).

Conclusions—

Professional rescuers were observed to excessively ventilate patients during out-of-hospital CPR. Subsequent animal studies demonstrated that similar excessive ventilation rates resulted in significantly increased intrathoracic pressure and markedly decreased coronary perfusion pressures and survival rates.
Effects of Diet and Exercise on Obesity-Related Vascular Dysfunction in Children
Authors: Woo Kam S. , Chook Ping , Yu Chung W. , Sung Rita Y.T. , Qiao Mu , Leung Sophie S.F. , Lam Christopher W.K. , Metreweli Con , Celermajer David S.
Published: April 2004

Background—

The prevalence of obesity in both adults and children is increasing rapidly. Obesity in children is independently associated with arterial endothelial dysfunction and wall thickening, key early events in atherogenesis that precede plaque formation.

Methods and Results—

To evaluate the reversibility of obesity-related arterial dysfunction and carotid intima-media thickening by dietary and/or exercise intervention programs, 82 overweight children (body mass index, 25±3), 9 to 12 years of age, were randomly assigned to dietary modification only or diet plus a supervised structured exercise program for 6 weeks and subsequently for 1 year. The prospectively defined primary end points were ultrasound-derived arterial endothelial function (endothelium-dependent dilation) of the brachial artery and intima-media thickness of common carotid artery. At 6 weeks, both interventions were associated with decreased waist-hip ratio (
P
<0.02) and cholesterol level (
P
<0.05) as well as improved arterial endothelial function. Diet and exercise together were associated with a significantly greater improvement in endothelial function than diet alone (
P
=0.01). At 1 year, there was significantly less thickening of the carotid wall (
P
<0.001) as well as persistent improvements in body fat content and lipid profiles in the group continuing an exercise program. Vascular function was significantly better in those children continuing exercise (n=22) compared with children who withdrew from the exercise program (n=19) (
P
<0.05).

Conclusions—

Obesity-related vascular dysfunction in otherwise healthy young children is partially reversible with diet alone or particularly diet combined with exercise training at 6 weeks, with sustained improvements at 1 year in those persisting with diet plus regular exercise.
Rapid Regulation of Platelet Activation In Vivo by Nitric Oxide
Authors: Schäfer Andreas , Wiesmann Frank , Neubauer Stefan , Eigenthaler Martin , Bauersachs Johann , Channon Keith M.
Published: April 2004

Background—

Platelet activation is a feature of many cardiovascular diseases characterized by endothelial dysfunction. The mechanistic relationship between impaired systemic nitric oxide (NO) bioavailability and platelet activation in vivo remains unclear. We investigated whether acute inhibition of NO production in humans modulates platelet activation in vivo and whether exogenous NO would counteract such an effect.

Methods and Results—

Intravenous injection of the NO synthase inhibitor
N
G
-monomethyl-
l
-arginine in healthy volunteers resulted in NO synthase inhibition as detected by increased blood pressure and by significantly reduced phosphorylation of platelet vasodilator-stimulated phosphoprotein, an indicator of NO signaling. NO synthase inhibition increased platelet activation as determined by enhanced platelet binding of fibrinogen and surface expression of P-selectin, glycoprotein 53, and CD40 ligand, demonstrating tonic inhibition of platelet activation by NO production in vivo. Sublingual administration of the NO donor glyceryl trinitrate normalized platelet VASP phosphorylation and restored markers of platelet activation to baseline levels.

Conclusions—

Acute inhibition of endogenous NO production in humans causes rapid platelet activation in vivo, which is reversed by exogenous NO, demonstrating that platelet function in vivo is rapidly regulated by NO bioavailability.
Serotonin-Induced Smooth Muscle Hyperplasia in Various Forms of Human Pulmonary Hypertension
Authors: Marcos Elisabeth , Fadel Elie , Sanchez Olivier , Humbert Marc , Dartevelle Philippe , Simonneau Gerald , Hamon Michel , Adnot Serge , Eddahibi Saadia
Published: April 2004

Hyperplasia of pulmonary artery smooth muscle cells (PA-SMCs) is a hallmark pathological feature of pulmonary hypertension (PH). Serotonin (5-HT) is involved in the hyperplasia through its interactions with specific receptors and internalization by a specific plasma membrane transporter. We investigated the expression and role of the 5-HT transporter (5-HTT) and 5-HT
1B
, 5-HT
2A
, and 5-HT
2B
receptors in lungs and isolated PA-SMCs from patients with primary PH (n=14), pulmonary veno-occlusive disease (n=4), or secondary PH (SPH, n=8) and nonpulmonary hypertensive control subjects. Whereas strong immunostaining for the three receptor types and 5-HTT was seen in remodeled pulmonary vessels from patients in all PH categories, only 5-HTT expression was increased in lungs and cultured PA-SMCs from patients versus controls. The increased growth response of PA-SMCs from patients with primary PH, pulmonary veno-occlusive disease, or SPH to 5-HT or serum was entirely attributable to 5-HTT overexpression, because 5-HTT inhibitors but not 5-HT receptor antagonists abolished 5-HT mitogenic activity and reduced the serum-induced growth response to similar levels in patients as in controls. The L-allelic variant of the 5-HTT gene promoter, which is associated with 5-HTT overexpression, was present homozygously in 14 of 25 (56%) lung transplantation patients with SPH but in only 27% of controls. Polymorphism of the 5-HTT gene promoter was only partly responsible for the increased 5-HTT expression in PH, because PA-SMCs from patients exhibited higher 5-HTT levels than same-genotype cells from controls and no additional promoter sequence alterations were found. We conclude that 5-HTT overexpression is a common pathogenic mechanism in various forms of PH.
Multicenter Comparison of Processes of Care Between Stroke Units and Conventional Care Wards in Australia
Authors: Cadilhac Dominique A. , Ibrahim Joeseph , Pearce Dora C. , Ogden Kathryn J. , McNeill John , Davis Stephen M. , Donnan Geoffrey A.
Published: April 2004

Background and Purpose—

Approximately 23% of Australian hospitals provide Stroke Units (SUs). Evidence suggests that clinical outcomes are better in SUs than with conventional care. Reasons may include greater adherence to processes of care (PoC). The primary hypothesis was that adherence to selected PoC is greater in SUs than in other acute care models.

Methods—

Prospective, multicenter, single-blinded design. Models of care investigated: SUs, mobile services, and conventional care. Selected PoC were related to care models and participant outcomes. Data were collected at acute hospitalization (median 9 days) and at medians of 8 and 28 weeks after stroke.

Results—

1701 patients were screened from 8 hospitals, 823 were eligible, and 468 participated. Response rate was 96% at final follow-up. Mean age was 73 years (SD 14). Overall PoC adherence rates for individual care models were SU 75%, mobile service 65%, and conventional care 52% (
P
<0.001). The adjusted odds of participants being alive at discharge if adhering to all or all but 1 PoC was significant (aOR 3.63; 95% CI: 1.04 to 12.66;
P
=0.043). Important trends at 28 weeks were found for being at home (aOR 3.09; 95% CI: 0.96 to 9.87;
P
=0.058) and independent (aOR 2.61; 95% CI: 0.96 to 7.10;
P
=0.061), with complete PoC adherence.

Conclusion—

Adherence to key PoC was higher in SUs than in other models. For all patients, adherence to PoC was associated with improved mortality at discharge and trends found with independence at home, providing support for the need to increase access to stroke units.
Delayed Treatment of Ischemia/Reperfusion Brain Injury
Authors: Williams Anthony J. , Berti Rossana , Dave Jitendra R. , Elliot Peter J. , Adams Julian , Tortella Frank C.
Published: April 2004

Background and Purpose—

Clinical development of novel neuroprotection therapies for the treatment of brain injury has been unsuccessful. One critical limitation is the lack of a viable therapeutic treatment window (TW). In this study, we evaluated the neuroprotection TW for the proteosome inhibitor MLN519 after ischemia/reperfusion brain injury in rats as related to its antiinflammatory mechanism.

Methods—

Male Sprague-Dawley rats were subjected to 2 hours of middle cerebral artery occlusion (MCAo), followed by 70 hours of reperfusion and recovery. MLN519 was administered after injury (starting 6 to 12 hours after MCAo) to evaluate the full TW. Brain infarction, neuronal degeneration, neurological recovery, leukocyte infiltration, and inflammatory gene mRNA levels were assessed.

Results—

Core infarct volume in vehicle-treated rats (216±25 mm
3
) was reduced with delayed MLN519 treatments of 6, 8, or 10 hours after injury (45±13, 86±28, and 150±27 mm
3
, respectively,
P
<0.05) and was associated with reductions in neuronal and axonal degeneration. MLN519-treated rats had reduced brain mRNA levels of TNF-α (46%,
P
<0.05), ICAM-1 (58%,
P
<0.05), IL-6 (58%,
P
<0.05), and E-selectin (72%,
P
<0.05) at 24 hours after injury. Furthermore, MLN519 treatment reduced leukocyte infiltration by 32% to 80% (
P
<0.05) in ischemic brain regions.

Conclusions—

Neuroprotection treatment with MLN519 provides an extended TW of up to 10 hours after ischemia/reperfusion brain injury, in part by attenuating the inflammatory response. As such, the delayed onset of brain inflammation after an ischemic injury offers a prime target for extending the neuroprotective TW with compounds such as MLN519, used either alone or possibly as an adjunctive therapy with thrombolytic agents.
Matrix Metalloproteinase-9 and Myeloperoxidase Expression
Authors: Maier Carolina M. , Hsieh Lily , Yu Fengshan , Bracci Paige , Chan Pak H.
Published: April 2004

Background and Purpose—

Expression of matrix metalloproteinases (MMPs), proteolytic enzymes that degrade extracellular proteins, is altered after ischemia/reperfusion injury and may contribute to blood–brain barrier (BBB) breakdown. Neutrophils, a source of reactive oxygen species and MMP-9, infiltrate damaged tissue 6 to 24 hours after ischemia and have also been implicated in delayed secondary tissue damage. Here we examined the spatial–temporal relation between MMP-9 expression and neutrophil infiltration after stroke.

Methods—

Knockout mice containing 50% manganese superoxide dismutase activity (SOD2-KOs), which are more susceptible to ischemic damage than wild-type (WT) littermates, underwent quantitative antigen (MMP-9, myeloperoxidase) immunohistochemistry (24 and 72 hours) analysis and protein expression by Western blotting (6, 12, 24, 48, and 72 hours) after transient focal cerebral ischemia. BBB breakdown was determined by Evans blue extravasation.

Results—

There was a clear spatial relation between MMP-9 expression and Evans blue extravasation. MMP-9–positive cell and vessel counts for SOD2-KOs (72 hours) were significantly different from SOD2-KO (24 hours,
P
=0.004), WT (24 hours,
P
=0.01), and WT (72 hours,
P
=0.007) mice. In contrast, MMP-9–positive neutrophil counts were comparatively low and did not differ by time or animal type. MMP-9 expression was biphasic in SOD2-KOs but not in WT littermates, with a significant increase observed 6 to 12 hours after ischemic insult and again at 48 to 72 hours. SOD2-KOs showed increased MMP-9 expression compared with WT littermates at all time points studied (
P
≤0.05).

Conclusions—

In this model, neutrophils are not the primary source of MMP-9 protein and thus are unlikely the key contributor to BBB breakdown observed in SOD2-KOs.
European Immigration to America's Great Basin, 1850–1870
Authors: Carson Scott Alan
Published: April 2004

Nineteenth-century European immigrants bound for America's Great Basin evinced considerable variation in occupational mobility. White-collar and skilled workers frequently abandoned their European human capital to work in agriculture, and European planters remained farmers. Unskilled laborers who entered agriculture in the Great Basin, however, experienced substantial up-ward occupational mobility from their original economic status.
Trust in Renaissance Electoral Politics
Authors: Jurdjevic Mark
Published: April 2004

Medieval Italian political culture was founded on a general mistrust of the candidates for public office. Officials attempted to counteract what they perceived as a natural tendency toward corruption by instituting complex voting strategies designed to make chance the deciding factor in elections. This point has important ramifications for recent theories concerning the origins of social capital and civic society.
Processing Words with Emotional Connotation: An fMRI Study of Time Course and Laterality in Rostral Frontal and Retrosplenial Cortices
Authors: Cato M. Allison , Crosson Bruce , Gökçay Didem , Soltysik David , Wierenga Christina , Gopinath Kaundinya , Himes Nathan , Belanger Heather , Bauer Russell M. , Fischler Ira S. , Gonzalez-Rothi Leslie , Briggs Richard W.
Published: April 2004

Responses of rostral frontal and retrosplenial cortices to the emotional significance of words were measured using functional magnetic resonance imaging (fMRI). Twenty-six strongly righthanded participants engaged in a language task that alternated between silent word generation to categories with positive, negative, or neutral emotional connotation and a baseline task of silent repetition of emotionally neutral words. Activation uniquely associated with word generation to categories with positive or negative versus neutral emotional connotation occurred bilaterally in rostral frontal and retrosplenial cortices. Furthermore, the time courses of activity in these areas differed, indicating that they subserve different functions in processing the emotional connotation of words. Namely, the retrosplenial cortex appears to be involved in evaluating the emotional salience of information from external sources, whereas the rostral frontal cortex also plays a role in internal generation of words with emotional connotation. In both areas, activity associated with positive or negative emotional connotation was more extensive in the left hemisphere than the right, regardless of valence, presumably due to the language demands of word generation. The present findings localize specific areas in the brain that are involved in processing emotional meaning of words within the brain's distributed semantic system. In addition, time course analysis reveals diverging mechanisms in anterior and posterior cortical areas during processing of words with emotional significance.
Eye Movements during Task Switching: Reflexive, Symbolic, and Affective Contributions to Response Selection
Authors: Hodgson Timothy Lewis , Golding Charlotte , Molyva Dimitra , Rosenthal Clive R. , Kennard Christopher
Published: April 2004

Active vision is a dynamic process involving the flexible coordination of different gaze strategies to achieve behavioral goals. Although many complex behaviors rely on an ability to efficiently switch between gaze-control strategies, few studies to date have examined mechanisms of task level oculomotor control in detail. Here, we report five experiments in which subjects alternated between conflicting stimulus-saccade mappings within a block of trials. The first experiment showed that there is no performance cost associated with switching between pro and anti saccades. However, follow-up experiments demonstrate that whenever subjects alternate between arbitrary stimulus-saccade mappings, latency costs are apparent on the first trial after a task change. More detailed analysis of switch costs showed that latencies were particularly elevated for saccades directed toward the same location that had been the target for a saccade on the preceeding trial. This saccade “inhibition of return” effect was most marked when unexpected error feedbacks cued task switches, suggesting that saccade selection processes are modulated by reward. We conclude that there are two systems for saccade control that differ in their characteristics following a task switch. The “reflexive” control system can be enabled/disabled in advance of saccade execution without incurring any performance cost. Switch costs are only observed when two or more arbitrary stimulus-saccade mappings have to be coordinated by a “symbolic” control system.