bluuebunny/crossref_metadata_2025 huggingface dataset:
Receptive Fields and Response Properties of Neurons in Layer 4 of Ferret Visual Cortex
Authors: Usrey W. Martin , Sceniak Michael P. , Chapman Barbara
Published: May 2006

The ferret has become a model animal for studies exploring the development of the visual system. However, little is known about the receptive-field structure and response properties of neurons in the adult visual cortex of the ferret. We performed single-unit recordings from neurons in layer 4 of adult ferret primary visual cortex to determine the receptive-field structure and visual-response properties of individual neurons. In particular, we asked what is the spatiotemporal structure of receptive fields of layer 4 neurons and what is the orientation selectivity of layer 4 neurons? Receptive fields of layer 4 neurons were mapped using a white-noise stimulus; orientation selectivity was determined using drifting, sine-wave gratings. Our results show that most neurons (84%) within layer 4 are simple cells with elongated, spatially segregated,on and off subregions. These neurons are also selective for stimulus orientation; peaks in orientation-tuning curves have, on average, a half-width at half-maximum response of 21.5 ± 1.2° (mean ± SD). The remaining neurons in layer 4 (16%) lack orientation selectivity and have center/surround receptive fields. Although the organization of geniculate inputs to layer 4 differs substantially between ferret and cat, our results demonstrate that, like in the cat, most neurons in ferret layer 4 are orientation-selective simple cells.
Combined Influence of Vergence and Eye Position on Three-Dimensional Vestibulo-Ocular Reflex in the Monkey
Authors: Misslisch H. , Hess B.J.M.
Published: May 2006

This study examined two kinematical features of the rotational vestibulo-ocular reflex (VOR) of the monkey in near vision. First, is there an effect of eye position on the axes of eye rotation during yaw, pitch and roll head rotations when the eyes are converged to fixate near targets? Second, do the three-dimensional positions of the left and right eye during yaw and roll head rotations obey the binocular extension of Listing's law (L2), showing eye position planes that rotate temporally by a quarter as far as the angle of horizontal vergence? Animals fixated near visual targets requiring 17 or 8.5° vergence and placed at straight ahead, 20° up, down, left, or right during yaw, pitch, and roll head rotations at 1 Hz. The 17° vergence experiments were performed both with and without a structured visual background, the 8.5° vergence experiments with a visual background only. A 40° horizontal change in eye position never influenced the axis of eye rotation produced by the VOR during pitch head rotation. Eye position did not affect the VOR eye rotation axes, which stayed aligned with the yaw and roll head rotation axes, when torsional gain was high. If torsional gain was low, eccentric eye positions produced yaw and roll VOR eye rotation axes that tilted somewhat in the directions predicted by Listing's law, i.e., with or opposite to gaze during yaw or roll. These findings were seen in both visual conditions and in both vergence experiments. During yaw and roll head rotations with a 40° vertical change in gaze, torsional eye position followed on average the prediction of L2: the left eye showed counterclockwise (ex-) torsion in down gaze and clockwise (in-) torsion in up gaze and vice versa for the right eye. In other words, the left and right eye's position plane rotated temporally by about a quarter of the horizontal vergence angle. Our results indicate that torsional gain is the central mechanism by which the brain adjusts the retinal image stabilizing function of the VOR both in far and near vision and the three dimensional eye positions during yaw and roll head rotations in near vision follow on average the predictions of L2, a kinematic pattern that is maintained by the saccadic/quick phase system.
Neuromagnetic Correlates of Perceived Contrast in Primary Visual Cortex
Authors: Haynes J. D. , Roth G. , Stadler M. , Heinze H. J.
Published: May 2006

When a target grating is flashed into a larger, surrounding grating, its contrast is perceived to be lower when both gratings are oriented collinearly rather than orthogonally. This effect can be used to dissociate the perceived contrast from the physical contrast of a target grating. We recorded the transient electric potentials and magnetic fields evoked by flashed target gratings and compared them with psychophysical judgments of perceived contrast. Both early (100 ms) and late (150 ms) transients were reduced in amplitude when targets were flashed into a collinear rather than orthogonal surround, thus paralleling the reduction in perceived contrast. Although targets in orthogonal backgrounds required 40% lower physical contrast to match the perceived contrast of collinear targets, the amplitudes of electrophysiological transients of matching stimuli were almost identical. Thus the responses correlated better with perceived than with physical target contrast. This holds especially for the late transient response. Source localization indicated that the transients in question may originate in primary visual cortex. Our results therefore identify the activity of primary visual cortex as one possible neural correlate of perceived contrast.
GABAC Receptors in the Rat Superior Colliculus and Pretectum Participate in Synaptic Neurotransmission
Authors: Boller Mathias , Schmidt Matthias
Published: May 2006

In mammals, GABAC receptors seem to be specifically expressed in the retina and the subcortical visual system, with highest extraretinal expression levels in the superior colliculus (SC). Although its presence in the superficial SC has been demonstrated physiologically, a direct involvement of this receptor type in fast synaptic neurotransmission still awaits verification. We addressed the question of a possible synaptic localization of GABACreceptors by performing in vitro whole-cell patch-clamp recordings of inhibitory postsynaptic currents (IPSCs) in single neurons of the rat SC and the neighboring pretectal nuclear complex, where GABAC receptors are also expressed at significant levels. To increase the likelihood to record IPSCs we induced spontaneous activity by application of the potassium channel blocker 4-aminopyridine (4-AP) and blocked glutamate-mediated excitatory neurotransmission with kynurenic acid. All 4-AP–induced postsynaptic currents were of synaptic origin because they were completely suppressed by lidocaine or by substitution of extracellular calcium with cobalt. In 40% of the SC cells and in 60% of the pretectal neurons, IPSCs in the presence of 4-AP and kynurenic acid were only partly blocked by the selective GABAA receptor antagonist bicuculline. Inhibitory currents that were insensitive to bicuculline, however, could be blocked by coapplication of either the specific GABAC receptor antagonist 1,2,5,6-tetrahydropyridine-4-yl)methylphosphinic acid or picrotoxin, an unselective GABAA and GABACreceptor antagonist. We conclude that GABAC receptors are, at least partially, located synaptically in SC and pretectal neurons in the rat, which indicates a direct function of this receptor type for synaptic processing in both structures.
Substance P Depresses Excitatory Synaptic Transmission in the Nucleus Accumbens Through Dopaminergic and Purinergic Mechanisms
Authors: Kombian Samuel B. , Ananthalakshmi Kethireddy V. V. , Parvathy Subramanian S. , Matowe Wandikayi C.
Published: May 2006

Substance P (SP) is an undecapeptide that is co-localized with conventional transmitters in the nucleus accumbens (NAc). Its neurochemical and behavioral effects resemble those of cocaine and amphetamine. How SP accomplishes these effects is not known, partly because its cellular and synaptic effects are not well characterized. Using whole cell and nystatin-perforated patch recording in rat forebrain slices, we show here that SP, an excitatory neuropeptide, depresses evoked excitatory postsynaptic currents (EPSCs) and potentials (EPSPs) in NAc through intermediate neuromodulators. SP caused a partially reversible, dose-dependent decrease in evoked EPSCs. This effect was mimicked by a neurokinin-1 (NK1) receptor-selective agonist, [Sar9, Met (O2)11]-SP and blocked by a NK1 receptor-selective antagonist, L 732 138. Both the SP- and [Sar9, Met (O2)11]-SP-induced synaptic depressions were accompanied by increases in paired pulse ratio (PPR), effects that were also blocked by L 732 138. In contrast to its effect on PPR, SP did not produce significant changes in the holding current, input resistance, EPSC decay rate (τ), and steady-state I-V curves of the recorded cells. The SP-induced synaptic depressions were prevented by dopamine receptor blockade using SCH23390 and haloperidol, but not by sulpiride. In addition, the SP-induced synaptic depression was blocked by an adenosine A1 receptor blocker 8-cyclopentyltheophylline (8-CPT) but not the N-methyl-d-aspartate (NMDA) receptor antagonist d-APV. These data show that SP, by activating presynaptic NK1 receptors, depresses excitatory synaptic transmission indirectly by enhancing extracellular dopamine and adenosine levels. Since the cellular and synaptic effects of SP resemble those of cocaine and amphetamine, it may serve as an endogenous psychogenic peptide.
Spatiotemporal Patterns of Excitation and Inhibition Evoked by the Horizontal Network in Layer 2/3 of Ferret Visual Cortex
Authors: Tucker Thomas R. , Katz Lawrence C.
Published: May 2006

The horizontal network in visual cortex layer 2/3 is implicated in numerous psychophysical and physiological properties. To investigate the spatial and temporal distribution of excitation and inhibition evoked by this network, we used voltage-sensitive dyes to image the responses to focal electrical stimulation in tangential slices of ferret visual cortex layer 2/3. The resulting optical patterns included a diffuse zone of activation near the stimulation site and numerous ovoid domains throughout the slice. In contrast to the fixed anatomy of the horizontal connections, substantial shifts in both space and time were evident in the distribution of population-based neuronal activity during stimulus trains. Both of these shifts relied on inhibitory synaptic potentials, suggesting that inhibition driven by horizontal connections sculpts the distribution of activity in this cortical network.
Impairment of Synaptic Vesicle Exocytosis and Recycling During Neuromuscular Weakness Produced in Mice by 2,4-Dithiobiuret
Authors: Xu You-Fen , Autio Dawn , Rheuben Mary B. , Atchison William D.
Published: May 2006

Chronic treatment of rodents with 2,4-dithiobiuret (DTB) induces a neuromuscular syndrome of flaccid muscle weakness that mimics signs seen in several human neuromuscular disorders such as congenital myasthenic syndromes, botulism, and neuroaxonal dystrophy. DTB-induced muscle weakness results from a reduction of acetylcholine (ACh) release by mechanisms that are not yet clear. The objective of this study was to determine if altered release of ACh during DTB-induced muscle weakness was due to impairments of synaptic vesicle exocytosis, endocytosis, or internal vesicular processing. We examined motor nerve terminals in the triangularis sterni muscles of DTB-treated mice at the onset of muscle weakness. Uptake of FM1-43, a fluorescent marker for endocytosis, was reduced to approximately 60% of normal after either high-frequency nerve stimulation or K+depolarization. Terminals ranged from those with nearly normal fluorescence (“bright terminals”) to terminals that were poorly labeled (“dim terminals”). Ultrastructurally, the number of synaptic vesicles that were labeled with horseradish peroxidase (HRP) was also reduced by DTB to approximately 60%; labeling among terminals was similarly variable. A subset of DTB-treated terminals having abnormal tubulovesicular profiles in their centers did not respond to stimulation with increased uptake of HRP and may correspond to dim terminals. Two findings suggest that posttetanic “slow endocytosis” remained qualitatively normal: the rate of this type of endocytosis as measured with FM1-43 did not differ from normal, and HRP was observed in organelles associated with this pathway- coated vesicles, cisternae, as well as synaptic vesicles but not in the tubulovesicular profiles. In DTB-treated bright terminals, end-plate potential (EPP) amplitudes were decreased, and synaptic depression in response to 15-Hz stimulation was increased compared with those of untreated mice; in dim terminals, EPPs were not observed during block withd-tubocurarine. Nerve-stimulation-induced unloading of FM1-43 was slower and less complete than normal in bright terminals, did not occur in dim terminals, and was not enhanced by α-latrotoxin. Collectively, these results indicate that the size of the recycling vesicle pool is reduced in nerve terminals during DTB-induced muscle weakness. The mechanisms by which this reduction occurs are not certain, but accumulated evidence suggests that they may include defects in either or both exocytosis and internal vesicular processing.
Effect of Semicircular Canal Stimulation on the Perception of the Visual Vertical
Authors: Pavlou Marousa , Wijnberg Nicole , Faldon Mary E. , Bronstein Adolfo M.
Published: May 2006

The subjective visual vertical (SVV) is usually considered a measure of otolith function. Herewith we investigate the influence of semicircular canal (SCC) stimulation on the SVV by rotating normal subjects in yaw about an earth-vertical axis, with velocity steps of ± 90°/s, for 60 s. SVV was assessed by setting an illuminated line to perceived earth vertical in darkness, during a per- and postrotary period. Four head positions were tested: upright, 30° backward (chin up) or forward, and ∼40° forward from upright. During head upright/backward conditions, a significant SVV tilt ( P < 0.01) in the direction opposite to rotation was found that reversed during postrotary responses. The rotationally induced SVV tilt had a time constant of decay of ∼30 s. Rotation with the head 30° forward did not affect SVV, whereas the 40° forward tilt caused a direction reversal of SVV responses compared with head upright/backward. Spearman correlation values (Rho) between individual SCC efficiencies in different head positions and mean SVV tilts were 0.79 for posterior, 0.34 for anterior, and – 0.80 for horizontal SCCs. Three-dimensional video-oculography showed that SVV and torsional eye position measurements were highly correlated (0.83) and in the direction opposite to the slow phase torsional vestibuloocular reflex. In conclusion: 1) during yaw axis rotation without reorientation of the head with respect to gravity, the SVV is influenced by SCC stimulation; 2) this effect is mediated by the vertical SCCs, particularly the posterior SCCs; 3) rotationally induced SVV changes are due to torsional ocular tilt; 4) SVV and ocular tilts occur in the “anticompensatory,” fast phase direction of the torsional nystagmus; and 5) clinically, abnormal SVV tilts cannot be considered a specific indication of otolith system dysfunction.
Dynamics of Orientation Tuning in Macaque V1: The Role of Global and Tuned Suppression
Authors: Ringach Dario L. , Hawken Michael J. , Shapley Robert
Published: May 2006

The temporal development of neural selectivity to physical attributes of a visual stimulus, such as its orientation and spatial frequency, can provide important clues about mechanisms of cortical tuning. We measured the dynamics of orientation tuning in macaque primary visual cortex (V1) and found several dynamical features in the data: changes in global enhancement and suppression, narrowing of orientation bandwidth, small but significant shifts in preferred orientation, and “Mexican-hat” tuning curves. The dynamics data were analyzed with a model that sums two fixed, tuned components (enhancement and suppression) and one global (untuned) component. The analysis suggests that there is early global enhancement followed by global and tuned suppression. Tuned suppression accounts for the dynamical reduction of orientation bandwidth and for the generation of Mexican-hat tuning profiles. Our findings imply that global and tuned suppression are important factors that determine the selectivity and dynamics of V1 responses to orientation.
Endocannabinoids Mediate Rapid Retrograde Signaling At Interneuron → Pyramidal Neuron Synapses of the Neocortex
Authors: Trettel Joseph , Levine Eric S.
Published: May 2006

In the neocortex, inhibitory interneurons tightly regulate the firing patterns and integrative properties of pyramidal neurons (PNs). The endocannabinoid system of the neocortex may play an important role in the activity-dependent regulation of inhibitory (i.e., GABAergic) inputs received by PNs. In the present study, using whole cell recordings from layer 2/3 PNs in slices of mouse sensory cortex, we have identified a role for PN-derived endocannabinoids in the control of afferent inhibitory strength. Pairing evoked inhibitory currents with repeated epochs of postsynaptic depolarization led to a transient suppression of inhibition that was induced by a rise in postsynaptic Ca2+ and was expressed as a reduction in presynaptic GABA release. An antagonist (AM251) of the type-1 cannabinoid receptor blocked the depolarization-induced suppression of evoked inhibitory postsynaptic currents (eIPSCs), and the cannabinoid WIN55,212-2 reduced eIPSC amplitude and occluded suppression. The degree of WIN55,212-2-mediated inhibition of eIPSCs was strongly correlated with the magnitude of depolarization-induced suppression of the eIPSCs, suggesting that the WIN-sensitive afferents are suppressed by PN depolarization. Moreover, blocking endocannabinoid uptake with AM404 strongly modulated the kinetics and magnitude of eIPSC suppression. We conclude that the release of endocannabinoids from PNs allows for the postsynaptic control of presynaptic inhibition and could have profound consequences for the integrative properties of neocortical PNs.
Morphological and Physiological Characterization of Layer VI Corticofugal Neurons of Mouse Primary Visual Cortex
Authors: Brumberg Joshua C. , Hamzei-Sichani Farid , Yuste Rafael
Published: May 2006

Layer VI is the origin of the massive feedback connection from the cortex to the thalamus, yet its complement of cell types and their connections is poorly understood. The physiological and morphological properties of corticofugal neurons of layer VI of mouse primary visual cortex were investigated in slices loaded with the Ca2+indicator fura-2AM. To identify corticofugal neurons, electrical stimulation of the white matter (WM) was done in conjunction with calcium imaging to detect neurons that responded with changes in intracellular Ca2+ concentrations in response to the stimulation. Subsequent whole cell recordings confirmed that they discharged antidromic action potentials after WM stimulation. Antidromically activated neurons were more excitable and had different spiking properties than neighboring nonantidromic neurons, although both groups had similar input resistances. Furthermore, antidromic neurons possessed narrower action potentials and smaller afterhyperpolarizations. Additionally, three-dimensional reconstructions indicated that antidromically activated neurons had a distinct morphology with longer apical dendrites and fewer nonprimary dendrites than nonantidromic cells. To identify the antidromic neurons, rhodamine microspheres were injected into the dorsal lateral geniculate nucleus of the thalamus and allowed to retrogradely transport back to the somata of the layer VI cortico-geniculate neurons. Physiological and anatomical analysis indicated that most antidromic neurons were likely to be cortico-geniculate neurons. Our results show that cortico-thalamic neurons represent a specific functional and morphological class of layer VI neurons.
Electrical Stimulation of the Supplementary Eye Fields in the Head-Free Macaque Evokes Kinematically Normal Gaze Shifts
Authors: Martinez-Trujillo Julio C. , Wang Hongying , Crawford J. Douglas
Published: May 2006

The supplementary eye fields (SEFs), located on the dorsomedial surface of the frontal cortex, are involved in high-level aspects of saccade generation. Some reports suggest that the same area could also be involved in the generation of motor commands for the head. If so, it is important to establish whether this structure encodes eye and head commands separately or gaze commands that give rise to coordinated eye-head movements. Here we systematically stimulated (50 μA, 300 Hz, 200 ms) the SEF of two head-free (head unrestrained) macaques while recording three-dimensional eye and head rotations. A total of 55 sites were found to consistently elicit saccade-like gaze movements, always in the contralateral direction with variable vertical components, and ranging in average amplitude from 5 to 60°. These movements were always a combination of eye-in-head saccades and head-in-space movements. We then performed a comparison between these movements and natural gaze shifts. The kinematics of the elicited movements (i.e., their temporal structure, their velocity-amplitude relationships, and the relative contributions of the eye and the head as a function of movement amplitude) were indistinguishable from those of natural gaze shifts. Additionally, they obeyed the same three-dimensional constraints as natural gaze shifts (i.e., eye-in-head movements obeyed Listing's law, whereas head- and eye-in-space movements obeyed Donders' law). In summary, gaze movements evoked by stimulating the SEF were indistinguishable from natural coordinated eye-head gaze shifts. Based on this we conclude that the SEF explicitly encodes gaze and that the kinematics aspects of eye-head coordination are implicitly specified by mechanisms downstream from the SEF.
Neuromuscular Modulation inAplysia.II. Modulation of the Neuromuscular Transform in Behavior
Authors: Brezina Vladimir , Orekhova Irina V. , Weiss Klaudiusz R.
Published: May 2006

In this work we use mathematical modeling and complementary experiments to study the dynamics of modulation in the accessory radula closer (ARC) neuromuscular system of Aplysia. Here we join a dynamic model of the modulation from the preceding paper to a model of the basal neuromuscular transform (NMT). The resulting complete model of the NMT allows us to predict, test, and analyze the actual modulated contraction shapes in different types of feeding behavior, through entire quasi-realistic meals. The model reproduces a variety of published and new experimental observations. We find that components of the modulatory network act in interdependency and mutual complementarity, one or another playing a key role depending on the behavior and its past history. The history is remembered by slow dynamical components whose persistence prepares the system for future behavior of the same kind. The persistence becomes counterproductive, however, when the behavior suddenly changes. Superposition of fast dynamical components alleviates the problem under most, but not all, circumstances. In the quasi-realistic meals, the modulation improves functional performance on average, but degrades it after certain behavioral switches, when the model predicts sharp contraction transients. These are indeed seen in the real muscle. We propose that the real system does not switch the underlying motor neuron firing patterns abruptly, but relaxes them gradually, matching the relaxation of the peripheral modulatory state, through such behavioral transitions. We model food-induced arousal, a known phenomenon of this kind. The peripheral dynamics of the modulated NMT thus constrain the motor commands of the CNS.
Effects of Noise on the Spike Timing Precision of Retinal Ganglion Cells
Authors: van Rossum M.C.W. , O'Brien B. J. , Smith R. G.
Published: May 2006

Information in a spike train is limited by variability in the spike timing. This variability is caused by noise from several sources including synapses and membrane channels; but how deleterious each noise source is and how they affect spike train coding is unknown. Combining physiology and a multicompartment model, we studied the effect of synaptic input noise and voltage-gated channel noise on spike train reliability for a mammalian ganglion cell. For tonic stimuli, the SD of the interspike intervals increased supralinearly with increasing interspike interval. When the cell was driven by current injection, voltage-gated channel noise and background synaptic noise caused fluctuations in the interspike interval of comparable amplitude. Spikes initiated on the dendrites could cause additional spike timing fluctuations. For transient stimuli, synaptic noise was dominant and spontaneous background activity strongly increased fluctuations in spike timing but decreased the latency of the first spike.
Unitary EPSCs of Corticogeniculate Fibers in the Rat Dorsal Lateral Geniculate Nucleus In Vitro
Authors: Granseth Björn , Lindström Sivert
Published: May 2006

To investigate unitary corticogeniculate excitatory postsynaptic currents (EPSCs), whole cell patch-clamp recordings were obtained from 20 principal cells in slices of the dorsal lateral geniculate nucleus (dLGN) of DA-HAN rats. EPSCs, evoked by electrical stimulation of corticogeniculate axons, had size distributions with one or more quantal peaks. Gaussian curves fitted to such distributions gave a mean quantal size ( q) of -5.0 ± 0.7 (SD) pA for the EPSCs. Paired-pulse ratio (EPSC2/EPSC1) was 3.3 ± 0.9 for stimuli separated by 40 ms. The mean quantal size was similar for facilitated EPSCs (-5.2 ± 0.8 pA), implying an increase in mean quantal content ( m). Most corticogeniculate axons were capable of releasing only one or two quanta onto individual principal cells. Mean resting release probability ( p) was low, 0.09 ± 0.04. Binomial models, with the same n but increased p, could account for both the basal and facilitated EPSC size distributions in 6/8 cells. It is suggested that the low resting efficacy of corticogeniculate synapses serves to stabilize this excitatory feedback system. The pronounced facilitation in conjunction with large convergence from many corticogeniculate cells would provide a transient, potent excitation of dLGN cells, compliant with the idea of a visually driven neuronal amplifier.
Aspirin Use and Outcomes in a Community-Based Cohort of 7352 Patients Discharged After First Hospitalization for Heart Failure
Authors: McAlister Finlay A. , Ghali William A. , Gong Yanyan , Fang Jiming , Armstrong Paul W. , Tu Jack V.
Published: May 2006

Background—

The safety of aspirin in heart failure (HF) has been called into question, particularly in those patients (1) without coronary disease, (2) with renal dysfunction, or (3) treated with low-dose angiotensin-converting enzyme (ACE) inhibitors and high-dose aspirin.

Methods and Results—

We examined prescription patterns and outcomes (all-cause mortality and/or HF readmission) in patients discharged from 103 Canadian hospitals between April 1999 and March 2001 after a first hospitalization for HF. Of 7352 patients with HF (mean age, 75 years; 44% without coronary disease and 29% with renal dysfunction), 2785 (38%) died or required HF readmission within the first year. Compared with nonusers, aspirin users were no more likely to die or require HF readmission (hazard ratio [HR], 1.02 [0.91 to 1.16]), even in patients without coronary disease (HR, 0.98 [0.78 to 1.22]) or patients with renal dysfunction (HR, 1.13 [0.94 to 1.36]). On the other hand, users of ACE inhibitors were less likely to die or require HF readmission (HR, 0.87 [0.79 to 0.96]), even if they were using aspirin (HR, 0.86 [0.77 to 0.95]). There were no dose-dependent interactions between aspirin and ACE inhibitors.

Conclusions—

In this observational study, aspirin use was not associated with an increase in mortality rates or HF readmission rates, and aspirin did not attenuate the benefits of ACE inhibitors, even in patients without coronary disease, patients with renal dysfunction, or patients treated with high-dose aspirin and low-dose ACE inhibitors.
Risk Factors for Progression of Peripheral Arterial Disease in Large and Small Vessels
Authors: Aboyans Victor , Criqui Michael H. , Denenberg Julie O. , Knoke James D. , Ridker Paul M , Fronek Arnost
Published: May 2006

Background—

Data on the natural history of peripheral arterial disease (PAD) are scarce and are focused primarily on clinical symptoms. Using noninvasive tests, we assessed the role of traditional and novel risk factors on PAD progression. We hypothesized that the risk factors for large-vessel PAD (LV-PAD) progression might differ from small-vessel PAD (SV-PAD).

Methods and Results—

Between 1990 and 1994, patients seen during the prior 10 years in our vascular laboratories were invited for a new vascular examination. The first assessment provided baseline data, with follow-up data obtained at this study. The highest decile of decline was considered major progression, which was a −0.30 ankle brachial index decrease for LV-PAD and a −0.27 toe brachial index decrease for SV-PAD progression. In addition to traditional risk factors, the roles of high-sensitivity C-reactive protein, serum amyloid-A, lipoprotein(a), and homocysteine were assessed. Over the average follow-up interval of 4.6±2.5 years, the 403 patients showed a significant ankle brachial index and toe brachial index deterioration. In multivariable analysis, current smoking, ratio of total to HDL cholesterol, lipoprotein(a), and high-sensitivity C-reactive protein were related to LV-PAD progression, whereas only diabetes was associated with SV-PAD progression.

Conclusions—

Risk factors contribute differentially to the progression of LV-PAD and SV-PAD. Cigarette smoking, lipids, and inflammation contribute to LV-PAD progression, whereas diabetes was the only significant predictor of SV-PAD progression.
Epigenetic acquisition of inducibility of type III cytotoxicity in P. aeruginosa
Authors: Filopon Didier , Mérieau Annabelle , Bernot Gilles , Comet Jean-Paul , LeBerre Rozenne , Guery Benoit , Polack Benoit , Guespin-Michel Janine
Published: May 2006

Background

Pseudomonas aeruginosa, an opportunistic pathogen, is often encountered in chronic lung diseases such as cystic fibrosis or chronic obstructive pneumonia, as well as acute settings like mechanical ventilation acquired pneumonia or neutropenic patients. It is a major cause of mortality and morbidity in these diseases. In lungs, P. aeruginosa settles in a biofilm mode of growth with the secretion of exopolysaccharides in which it is encapsulated, enhancing its antibiotic resistance and contributing to the respiratory deficiency of patients. However, bacteria must first multiply to a high density and display a cytotoxic phenotype to avoid the host's defences. A virulence determinant implicated in this step of infection is the type III secretion system (TTSS), allowing toxin injection directly into host cells. At the beginning of the infection, most strains isolated from patients' lungs possess an inducible TTSS allowing toxins injection or secretion upon in vivo or in vitro activation signals. As the infection persists most of the bacteria permanently loose this capacity, although no mutations have been evidenced. We name "non inducible" this phenotype. As suggested by the presence of a positive feedback circuit in the regulatory network controlling TTSS expression, it may be due to an epigenetic switch allowing heritable phenotypic modifications without genotype's mutations.

Results

Using the generalised logical method, we designed a minimal model of the TTSS regulatory network that could support the epigenetic hypothesis, and studied its dynamics which helped to define a discriminating experimental scenario sufficient to validate the epigenetic hypothesis. A mathematical framework based on formal methods from computer science allowed a rigorous validation and certification of parameters of this model leading to epigenetic behaviour. Then, we demonstrated that a non inducible strain of P. aeruginosa can stably acquire the capacity to be induced by calcium depletion for the TTSS after a short pulse of a regulatory protein. Finally, the increased cytotoxicity of a strain after this epigenetic switch was demonstrated in vivo in an acute pulmonary infection model.

Conclusion

These results may offer new perspectives for therapeutic strategies to prevent lethal infections by P. aeruginosa by reverting the epigenetic inducibility of type III cytotoxicity.
Responding to the Kerr/Haslam Inquiry
Authors: Subotsky Fiona
Published: May 2006

In 2004 I was asked by the College first to respond to the Inquiry's questions and later to attend a ‘stakeholders' meeting’. This was not so much in my capacity as Treasurer but as an officer with an interest in the issue of risk and professional difficulties for psychiatrists. A review of the public reports from the General Medical Council (GMC) of their determinations in the Professional Conduct Committee had made it evident that sexual misconduct was probably the single greatest cause of a finding of serious professional misconduct against a psychiatrist. In addition, I had contributed to an earlier debate on sexual safety for women in psychiatric hospitals (Subotsky, 1991, 1993).
Should Patients with Apparently Sporadic Pheochromocytomas or Paragangliomas be Screened for Hereditary Syndromes?
Authors: Jiménez Camilo , Cote Gilbert , Arnold Andrew , Gagel Robert F.
Published: May 2006

Context: The recent identification of germline mutations of the mitochondrial complex II genes in variants of paraganglioma/pheochromocytoma syndrome has enlarged the number of known causative genes for hereditary pheochromocytoma. A question confronting clinicians is whether they should screen patients with apparently sporadic pheochromocytomas for unsuspected germline mutations of some or all of the seven genes known to cause hereditary paraganglioma or pheochromocytoma (NF1, VHL, RET, MEN1, SDHD, SDHC, and SDHB). A positive answer was suggested by a report that placed the estimate of hereditary disease in apparently sporadic pheochromocytoma as high as 24%.

Evidence Acquisition: We applied clinically useful criteria to a review of the literature, defining cases of apparently sporadic pheochromocytoma as those without a suspicious personal or family history, with a focal, unilateral pheochromocytoma, and presenting at age less than 50 yr.

Evidence Synthesis: We reduced the overall estimate of unsuspected hereditary pheochromocytoma patients with apparently sporadic pheochromocytoma to approximately 17%. Mutations in only three genes (VHL, SDHB, and SDHD) accounted for almost this entire minority, and unsuspected RET mutation was rare. Costs, coverage by insurance, the potential effect on insurability, and deficient information for populations outside of referral centers should be considered before recommending genetic testing in patients with apparently sporadic presentations of pheochromocytomas.

Conclusion: We recommend genetic testing for patients with an apparently sporadic pheochromocytoma under the age of 20 yr with family history or features suggestive of hereditary pheochromocytoma or for patients with sympathetic paragangliomas. For individuals who do not meet these criteria, genetic testing is optional.
Order Assignment and Scheduling in a Supply Chain
Authors: Chen Zhi-Long , Pundoor Guruprasad
Published: May 2006

We consider the supply chain of a manufacturer who produces time-sensitive products that have a large variety, a short life cycle, and are sold in a very short selling season. The supply chain consists of multiple overseas plants and a domestic distribution center (DC). Retail orders are first processed at the plants and then shipped from the plants to the DC for distribution to domestic retailers. Due to variations in productivity and labor costs at different plants, the processing time and cost of an order are dependent on the plant to which it is assigned. We study the following static and deterministic order assignment and scheduling problem faced by the manufacturer before every selling season: Given a set of orders, determine which orders are to be assigned to each plant, find a schedule for processing the assigned orders at each plant, and find a schedule for shipping the completed orders from each plant to the DC, such that a certain performance measure is optimized. We consider four different performance measures, all of which take into account both delivery lead time and the total production and distribution cost. A problem corresponding to each performance measure is studied separately. We analyze the computational complexity of various cases of the problems by either proving that a problem is intractable or providing an efficient exact algorithm for the problem. We propose several fast heuristics for the intractable problems. We analyze the worst-case and asymptotic performance of the heuristics and also computationally evaluate their performance using randomly generated test instances. Our results show that the heuristics are capable of generating near-optimal solutions quickly.
Effect of Bauschinger-Modified Autofrettage Residual Stresses on Cannon Fatigue Life
Authors: Underwood JH , Parker AP , Troiano E
Published: May 2006

Fatigue modeling of autofrettaged cannons is described, including design modifications for steel vessels with 1170 MPa strength. A similar Ni-Cr-Mo-V steel but with 1360 MPa strength is planned to reduce weight. A new design must include modeling of the hoop compressive residual stress at the inner diameter, that has significant control of both the yield pressure and fatigue life. Results shows good agreement between measured lives from full-size cannon tests and calculated Paris lives including a Bauschinger-reduced material strength. Paris life calculations show effects of three important pressure vessel variables: initial crack size, extent of autofrettage, and outer-to-inner radius ratio.
Glutamate Acting on AMPA But Not NMDA Receptors Modulates the Migration of Hippocampal Interneurons
Authors: Manent Jean-Bernard , Jorquera Isabel , Ben-Ari Yehezkel , Aniksztejn Laurent , Represa Alfonso
Published: May 2006

Paracrine GABA and glutamate acting, respectively, on GABAAand NMDA receptors modulate the migration of hippocampal pyramidal cells. Using corticohippocampal organotypic explants from glutamic acid decarboxylase (GAD) 67–enhanced green fluorescent protein (EGFP) knock-in embryos, we now report that, in contrast to pyramidal neurons, the blockade of AMPA but not NMDA receptors exerts important actions on the migration of GABAergic interneurons. In addition, the blockade of GABAAreceptors fails to modify the migration rates of GABAergic interneurons. Immunohistochemical analyses of GAD67–EGFP embryos (from embryonic day 14 to birth) reveal that interneurons colonize the hippocampal primordium by embryonic day 15. At that stage, the hippocampal primordium is already composed of pioneer glutamatergic neurons, including (1) Cajal-Retzius cells, immunopositive to calretinin and reelin, and (2) other presumptive pioneer pyramidal cells that are immunopositive to βIII-tubulin and vesicular glutamate transporter 3 and immunonegative to GABA or GAD67. Therefore, the migrations of pyramidal neurons and GABAergic interneurons are cross-modulated: glutamate released from pioneer glutamatergic neurons facilitates the migration of GABAergic interneurons, which in turn would release GABA, facilitating the migration of glutamatergic neuroblasts. This general sequence may provide a retroactive positive loop needed to construct the hippocampal network. It might constitute a primitive homeostatic mechanism in the developing brain that acts to balance GABA–glutamate contributions to network construction and activity.
Tau Aggregation and Progressive Neuronal Degeneration in the Absence of Changes in Spine Density and Morphology after Targeted Expression of Alzheimer's Disease-Relevant Tau Constructs in Organotypic Hippocampal Slices
Authors: Shahani Neelam , Subramaniam Srinivasa , Wolf Tobias , Tackenberg Christian , Brandt Roland
Published: May 2006

Alzheimer's disease (AD) is characterized by progressive loss of neurons in selected brain regions, extracellular accumulations of amyloid β, and intracellular fibrils containing hyperphosphorylated tau. Tau mutations in familial tauopathies confirmed a central role of tau pathology; however, the role of tau alteration and the sequence of tau-dependent neurodegeneration in AD remain elusive. Using Sindbis virus-mediated expression of AD-relevant tau constructs in hippocampal slices, we show that disease-like tau modifications affect tau phosphorylation at selected sites, induce Alz50/MC1-reactive pathological tau conformation, cause accumulation of insoluble tau, and induce region-specific neurodegeneration. Live imaging demonstrates that tau-dependent degeneration is associated with the development of a “ballooned” phenotype, a distinct feature of cell death. Spine density and morphology is not altered as judged from algorithm-based evaluation of dendritic spines, suggesting that synaptic integrity is remarkably stable against tau-dependent degeneration. The data provide evidence that tau-induced cell death involves apoptotic as well as nonapoptotic mechanisms. Furthermore, they demonstrate that targeted expression of tau in hippocampal slices provides a novel model to analyze tau modification and spatiotemporal dynamics of tau-dependent neurodegeneration in an authentic CNS environment.
The Stop Signal Revised: Immature Cerebellar Granule Neurons in the External Germinal Layer Arrest Pontine Mossy Fiber Growth
Authors: Manzini M. Chiara , Ward M. Stanton , Zhang Qin , Lieberman Michael D. , Mason Carol A.
Published: May 2006

During the formation of neuronal circuits, afferent axons often enter target regions before their target cells are mature and then make temporary contacts with nonspecific targets before forming synapses on specific target cells. The regulation of these different steps of afferent-target interactions is poorly understood.

The cerebellum is a good model for addressing these aspects, because cerebellar development is well defined and identified neurons in the circuitry can be purified and combinedin vitro. Previous reports from our laboratory showed that cultured granule neurons specifically arrest the extension of their pontine mossy fiber afferents, leading us to propose that granule cells arrested growth of their afferents as a prelude to synaptogenesis. However, we knew little about the differentiation state of the cultured granule cells that mediate afferent arrest.

In this study, we better define the purified granule cell fraction by marker expression and morphology, and demonstrate that only freshly plated granule cells in the precursor and premigratory state arrest mossy fiber outgrowth. Mature granule cells, in contrast, support extension, defasciculation, and synapse formation, asin vivo. In addition, axonal tracingin vivoduring the first postnatal week indicates that immature mossy fibers extend into the Purkinje cell layer but never into the external germinal layer (EGL), where precursors of granule cell targets reside. We found that the stop-growing signals are dependent on heparin-binding factors, and we propose that such signals in the EGL restrict the extension of mossy fiber afferents and prevent invasion of proliferative regions.
Teaching Public Health Through a Pedagogy of Collegiality
Authors: Chávez Vivian , Turalba Ruby-Asuncion N. , Malik Savita
Published: May 2006

Curriculum development in masters of public health programs that effectively meets the complex challenges of the 21st century is an important part of public health education and requires purposeful thinking. Current approaches to training the public health work-force do not adequately prepare professionals to be culturally competent in addressing health disparities. Principles of community-based participatory research highlight the importance of building relationships of mutual accountability and emphasize collegial teaching.

We present background and theoretical foundations for a pedagogy of collegiality and describe specific teaching methods, classroom activities, and key assignments organized around 4 essential features: principles of community organizing, building community and valuing diversity, engaging the senses, and writing across the curriculum.
Unauthorized Border Crossings and Migrant Deaths: Arizona, New Mexico, and El Paso, Texas, 2002–2003
Authors: Sapkota Sanjeeb , Kohl Harold W. , Gilchrist Julie , McAuliffe Jay , Parks Bruce , England Bob , Flood Tim , Sewell C. Mack , Perrotta Dennis , Escobedo Miguel , Stern Corrine E. , Zane David , Nolte Kurt B.
Published: May 2006

Objectives. We examined the major causes of and risk factors for death among migrants who died while making unauthorized border crossings into the United States from Mexico.

Methods. Decedents were included in the study if (1) their remains were found between January 1, 2002, and December 31, 2003, in any US county along the 650-mi (1040-km) section of the US–Mexican border from Yuma, Ariz, to El Paso, Tex; (2) their immigration status was unauthorized; and (3) they were believed to have died during transit from Mexico to the United States. Characteristics of the decedents and causes of and risk factors for their deaths were examined.

Results. Among the 409 decedents meeting our inclusion criteria, environmental heat exposure (n=250; 61.1%) was the leading cause of death, followed by vehicle crashes (n=33; 8.1%) and drownings (n=24; 5.9%). Male decedents (n= 298; 72.8%) outnumbered female decedents (n = 105; 25.6%) nearly 3 to 1. More than half of the decedents were known to be Mexican nationals (n=235; 57.5%) and were aged 20 to 39 years (n=213; 52.0%); the nationality of 148 (36.2%) decedents was undetermined.

Conclusions. Deaths among migrants making unauthorized crossings of the US–Mexican border are due to causes that are largely preventable. Prevention strategies should target young Mexican men, and focus on preventing them from conceiving plans to cross the border, discouraging them from using dangerous routes as crossing points, and providing search-and-rescue teams to locate lost or injured migrant crossers.
The ratio of circulating osteoprotegerin to RANKL in early rheumatoid arthritis predicts later joint destruction
Authors: Geusens P. P. , Landewé R. B. M. , Garnero P. , Chen D. , Dunstan C. R. , Lems W. F. , Stinissen P. , van der Heijde D. M. F. M. , van der Linden S. , Boers M.
Published: May 2006

Objective

Rheumatoid arthritis (RA) is a chronic inflammatory disease that may result in debilitating joint deformities with destruction of bone and cartilage. Inflammation is still considered the pivotal inducer of both components of joint damage. Results of recent animal studies suggested a prominent contribution of osteoclastic bone resorption that could be dissociated from inflammation. RANKL and its natural decoy receptor, osteoprotegerin (OPG), play key roles in osteoclast activation. In a group of patients with early RA not treated with disease‐modifying drugs, we tested the hypothesis that osteoclast activation, reflected by the serum OPG:RANKL ratio at baseline, is negatively associated with progression of bone damage, independent of inflammation.

Methods

OPG and RANKL levels, together with a parameter of inflammation (first‐year time‐averaged erythrocyte sedimentation rate [tESR]), were measured in 92 patients with newly diagnosed early active RA who were participants in a randomized study. The tESR and the OPG:RANKL ratio were evaluated for the ability to predict 5‐year radiographic progression of joint damage.

Results

The first‐year tESR and the OPG:RANKL ratio, as measured at baseline, independently predicted 5‐year radiographic progression of joint damage (bothP≤ 0.001). Progression of radiographic damage was greatest in patients with a high tESR and a low OPG:RANKL ratio and was lowest in patients with a low tESR and a high OPG:RANKL ratio.

Conclusion

This study in patients with early untreated RA is the first to confirm the findings in animal models of arthritis, that radiographic progression of the bone component of joint destruction is dependent on both inflammation (tESR) and osteoclast activation (the OPG:RANKL ratio).