bluuebunny/crossref_metadata_2025 huggingface dataset:
A perceptual learning investigation of the pitch elicited by amplitude-modulated noise
Authors: Fitzgerald Matthew B. , Wright Beverly A.
Published: December 2005

Noise that is amplitude modulated at rates ranging from 40 to 850 Hz can elicit a sensation of pitch. Here, the processing of this temporally based pitch was investigated using a perceptual-learning paradigm. Nine listeners were trained (1 hour per day for 6–8 days) to discriminate a standard rate of sinusoidal amplitude modulation (SAM) from a faster rate in a single condition (150 Hz SAM rate, 5 kHz low-pass carrier). All trained listeners improved significantly on that condition. These trained listeners subsequently showed no more improvement than nine untrained controls on pure-tone and rippled-noise discrimination with the same pitch, and on SAM-rate discrimination with a 30 Hz rate, although they did show some improvement with a 300 Hz rate. In addition, most trained, but not control, listeners were worse at detecting SAM at 150 Hz after, compared to before training. These results indicate that listeners can learn to improve their ability to discriminate SAM rate with multiple-hour training and that the mechanism that is modified by learning encodes (1) the pitch of SAM noise but not that of pure tones and rippled noise, (2) different SAM rates separately, and (3) differences in SAM rate more effectively than cues for SAM detection.
Simplified expansions for radiation from a baffled circular piston
Authors: Douglas Mast T. , Yu Feng
Published: December 2005

Computation of acoustic radiation from a baffled circular piston continues be an active area of investigation, both as a canonical problem and because of numerous practical applications. For time-harmonic radiation, exact series expansions are an attractive approach because they do not require numerical integration or limiting approximations. Here, series expansions due to Hasegawa, Inoue, and Matsuzawa [J. Acoust. Soc. Am. 74, 1044–1047 (1983); 75, 1048–1051 (1984)] are shown to reduce to simpler expressions suitable for numerical computations of piston fields in lossless and attenuative fluid media. For the region r⩾a, where a is the piston radius and r is the distance from the piston center, an exact solution is given by an series of spherical Hankel functions and Legendre polynomials with explicit, closed-form, position-independent coefficients. For the paraxial region w⩽a, where w is the distance from the piston axis, a second exact series expansion is valid for all axial distances z and reduces to the known analytic solution for w=0. These two expansions allow the radiated field to be computed at any point, with rapid convergence except for points near the circle bounding the piston. Example numerical results illustrate application of this method to ultrasonic sources.
Superresolution ultrasound imaging using back-projected reconstruction
Authors: Clement G. T. , Huttunen J. , Hynynen K.
Published: December 2005

An ultrasound technique for imaging objects significantly smaller than the source wavelength is investigated. Signals from a focused beam are recorded over an image plane in the acoustic farfield and backprojected in the wave-vector domain to the focal plane. A superresolution image recovery method is then used to analyze the Fourier spatial frequency spectrum of the signal in an attempt to deduce the location and size of objects in this plane. The physical foundation for the method is rooted in the fact that high spatial frequencies introduced by the object in fact affect the lower (nonevanescent) spatial frequencies of the overall signal. The technique achieves this by using a priori measurements of the ultrasound focus in water, which gives full spectral information about the image source. A guess is then made regarding the size and location of the object that distorted the field, and this is convolved with the a priori measurement, thus creating a candidate image. A large number of candidates are generated and the one whose spectrum best matches the uncorrected image is accepted. The method is demonstrated using 0.34- and 0.60-mm wires with a focused 1.05-MHz ultrasound signal and then a human hair (∼0.03mm) with a 4.7-MHz signal.
The mean and variance of diffuse field correlations in finite bodies
Authors: Weaver Richard L. , Lobkis Oleg I.
Published: December 2005

A model consisting of uniformly distributed concentrated transient sources in closed reverberant systems is used to construct predictions for the diffuse field correlation function and its variance. Such correlations are useful for passive imaging. It is found that the variance is small compared with the square of the mean if estimates are based on a sufficient number of sources, and if a sufficiently long data record is taken from each source. Requirements are predicted to be most onerous at high frequency. Laboratory measurements support this theory. They furthermore indicate that the fidelity of the passively obtained correlation function to an actively obtained waveform depends, not only on having sufficient passive data, but also on an informed compensation for source spectrum and receiver characteristics. It is anticipated that these arguments will be relevant to convergence rates and fidelity for passive imaging in open systems such as are found in seismology and ocean acoustics.
Effect of a downstream ventilated gas cavity on turbulent boundary layer wall pressure fluctuation spectra
Authors: Young Steven D. , Brungart Timothy A. , Lauchle Gerald C. , Howe Michael S.
Published: December 2005

An analytical and experimental investigation is made of the effect of a 2-D ventilated gas cavity on the spectrum of turbulent boundary layer wall pressure fluctuations upstream of a gas cavity on a plane rigid surface. The analytical model predicts the ratio of the wall pressure spectrum in the presence of the cavity to the blocked wall pressure spectrum that would exist if the cavity were absent. The ratio is found to oscillate in amplitude with upstream distance (−x) from the edge of the cavity. It approaches unity as −ωx∕Uc→∞, where ω is the radian frequency and Uc is the upstream turbulence convection velocity. To validate these predictions an experiment was performed in a water tunnel over a range of mean flow velocities. Dynamic wall pressure sensors were flush mounted to a flat plate at various distances upstream from a backward facing step. The cavity was formed downstream of the step by injecting carbon dioxide gas. The water tunnel measurements confirm the predicted oscillatory behavior of the spectral ratio, as well as its relaxation to unity as −ωx∕Uc→∞. For −ωx∕Uc>7 the cavity has a negligible influence on the upstream wall pressure fluctuations.
The development of a Component Mode Synthesis (CMS) model for three-dimensional fluid–structure interaction
Authors: Magalhaes M. D. C. , Ferguson N. S.
Published: December 2005

Our main aim in this paper is to develop analytically the three-dimensional Component Mode Synthesis method and to use it on fluid–structure interaction problems, such as sound transmission between coupled volumes. This will be shown for simple volume geometries, but, in principle, the same procedure can be applied when the component modes are obtained from numerical techniques, such as the Finite Element Model (FEM) or Boundary Element Method (BEM). The modal behavior of acoustic volumes and a partition is implemented in two steps. The first extension here is based on a one-dimensional model where the transverse acoustic modes of the volumes are incorporated into the formulation. The second extension, which is more general, considers not only the transverse acoustic modes of the volumes, but also structural modes of the partition. A comparison is made with predictions based on a modal model using the normal modes of rigid walled enclosures separated by a simply supported partition. For the latter modal model, particle velocity continuity was not incorporated in the formulation.
Debye-series analysis of the transmission coefficient of a water-saturated porous plate obeying Biot’s theory
Authors: Derible Serge
Published: December 2005

We derive the Debye-series expansion of the normal transmitted plane wave through a water-saturated porous plate. By using relations from Biot’s theory, the theoretical transmission coefficient of the plate is related to a limited number of unknown parameters (velocity, attenuation coefficient of the fast and slow wave, reflection coefficients at the interfaces of the plate). They are determined via a comparison with the experimental transmission coefficient. The measurements show that the attenuation of the dilatational waves scales as the second power of frequency.
A model for the dynamics of gas bubbles in soft tissue
Authors: Yang Xinmai , Church Charles C.
Published: December 2005

Understanding the behavior of cavitation bubbles driven by ultrasonic fields is an important problem in biomedical acoustics. Keller-Miksis equation, which can account for the large amplitude oscillations of bubbles, is rederived in this paper and combined with a viscoelastic model to account for the strain-stress relation. The viscoelastic model used in this study is the Voigt model. It is shown that only the viscous damping term in the original equation needs to be modified to account for the effect of elasticity. With experiment determined viscoelastic properties, the effects of elasticity on bubble oscillations are studied. Specifically, the inertial cavitation thresholds are determined using Rmax∕R0, and subharmonic signals from the emission of an oscillating bubble are estimated. The results show that the presence of the elasticity increases the threshold pressure for a bubble to oscillate inertially, and subharmonic signals may only be detectable in certain ranges of radius and pressure amplitude. These results should be easy to verify experimentally, and they may also be useful in cavitation detection and bubble-enhanced imaging.
Underwater and in-air sounds from a small hovercraft
Authors: Blackwell Susanna B. , Greene Charles R.
Published: December 2005

Underwater and in-air recordings were made from a boat anchored near Prudhoe Bay, Alaska, while a Griffon 2000TD hovercraft drove by at or near full power on four passes. At the closest point of approach (CPA, 6.5m), underwater broadband (10–10000Hz) levels reached 133 and 131dB re: 1μPa at depths of 1 and 7m, respectively. In-air unweighted and A-weighted broadband (10–10000Hz) levels reached 104 and 97dB re: 20μPa, respectively. The hovercraft produced sound at a wide range of frequencies. Both underwater and in air, the largest spectral peak was near 87Hz, which corresponded to the blade rate of the thrust propeller. In addition, the spectral composition included several harmonics of this frequency. The shaft or blade rate of the lift fan was barely detectable underwater despite its proximity to the water. The hovercraft was considerably quieter underwater than similar-sized conventional vessels and may be an attractive alternative when there is concern over underwater sounds.
Effect of voltage-dependent membrane properties on active force generation in cochlear outer hair cell
Authors: Liao Zhijie , Popel Aleksander S. , Brownell William E. , Spector Alexander A.
Published: December 2005

A computational model is proposed to analyze the active force production in an individual outer hair cell (OHC) under high-frequency conditions. The model takes into account important biophysical properties of the cell as well as constraints imposed by the surrounding environment. The biophysical properties include the elastic, piezoelectric, and viscous characteristics of the cell wall. The effect of the environment is associated with the stiffness of the constraint and the drag forces acting on the cell due to the interaction with the external and internal viscous fluids. The study concentrated on a combined effect of the transmembrane potential, frequency, and stiffness of the constraints. The effect of the voltage-dependent stiffness of the cell was particularly investigated and it was found to be twofold. First, it results in higher sensitivity and nonlinearity of the OHC active force production in the physiological range. Second, it determines smaller active forces in the hyperpolarization range. The resonant properties of the active force as functions of voltage and the constraint stiffness were also analyzed. The obtained results can be important for a better understanding of the OHC active force production and the contribution of cell electromotility to the cochlear amplification, sensitivity, and nonlinearity.
Perception of the envelope-beat frequency of inharmonic complex temporal envelopes
Authors: Füllgrabe Christian , Lorenzi Christian
Published: December 2005

Listeners can hear slow sinusoidal variations in the depth of sinusoidally amplitude-modulated (SAM) stimuli. Here, the SAM stimulus of frequency fm acts as the carrier, and the slow variation in depth of frequency fm′ (referred to as “second-order” amplitude modulation) corresponds to a beat in the temporal envelope. Recent studies have suggested that second-order amplitude modulation perception is based on a modulation-distortion component or the “venelope” (the Hilbert envelope of the ac-coupled Hilbert envelope), both occurring at the envelope-beat frequency fm′. This was tested by transposing to the modulation domain the matching paradigm used by Schouten et al. [J. Acoust. Soc. Am. 34, 1418–1424 (1962)]. Listeners estimated the envelope-beat frequency evoked by a 5-Hz, second-order SAM white noise with fm either an integer multiple of fm′ or shifted in frequency to make the complex envelope inharmonic. The results indicate that the perception of the envelope-beat frequency was affected by these shifts when fm⩽20Hz. This suggests that, at least at low modulation frequencies, the perceived envelope beat is not determined by a modulation-distortion or venelope component, but rather relies on the time intervals between the main peaks of the first-order envelope.
A three-dimensional sound intensity measurement system for sound source identification and sound power determination by ln models
Authors: Nagata Shiho , Furihata Kenji , Wada Tomohiro , Asano David K. , Yanagisawa Takesaburo
Published: December 2005

This paper describes a full vector intensity probe which advances the field of sound intensity and sound source direction estimation using six matched rotating and variable directional microphones. The probe has three pairs of microphones at an equal spacing of 30 mm that are set up in each of the x, y, and z directions and share the same observation point. The calibration method using the rotating microphone system is effective to correct position errors in the y- and z-axes microphone pairs. Sound intensity measurements using the variable directional microphone method can locate with accuracy a sound source, i.e., the structure parts radiating most acoustic energy. The system can find the maximum sound intensity level and beamwidth of the major lobe, and the peak sound intensity levels of the minor lobes. Therefore, a procedure for sound power determination based on minimum measurement data is theoretically and experimentally discussed. Consequently, it is possible to reconstruct only parts of the system emitting the most noise and measure efficiently the sound power level.
Click production during breathing in a sperm whale (Physeter macrocephalus)
Authors: Wahlberg Magnus , Frantzis Alexandros , Alexiadou Paraskevi , Madsen Peter T. , Møhl Bertel
Published: December 2005

A sperm whale (Physeter macrocephalus) was observed at the surface with above- and underwater video and synchronized underwater sound recordings. During seven instances the whale ventilated its lungs while clicking. From this observation it is inferred that click production is achieved by pressurizing air in the right nasal passage, pneumatically disconnected from the lungs and the left nasal passage, and that air flows anterior through the phonic lips into the distal air sac. The capability of breathing and clicking at the same time is unique among studied odontocetes and relates to the extreme asymmetry of the sperm whale sound-producing forehead.
Sound propagation through and scattering by internal gravity waves in a stably stratified atmosphere
Authors: Ostashev Vladimir E. , Chunchuzov Igor P. , Wilson D. Keith
Published: December 2005

A stably stratified atmosphere supports propagation of internal gravity waves (IGW). These waves result in highly anisotropic fluctuations in temperature and wind velocity that are stretched in a horizontal direction. As a result, IGW can significantly affect propagation of sound waves in nighttime boundary layers and infrasound waves in the stratosphere. In this paper, a theory of sound propagation through, and scattering by, IGW is developed. First, 3D spectra of temperature and wind velocity fluctuations due to IGW, which were recently derived in the literature for the case of large wave numbers, are generalized to account for small wave numbers. The generalized 3D spectra are then used to calculate the sound scattering cross section in an atmosphere with IGW. The dependencies of the obtained scattering cross section on the sound frequency, scattering angle, and other parameters of the problem are qualitatively different from those for the case of sound scattering by isotropic turbulence with the von Kármán spectra of temperature and wind velocity fluctuations. Furthermore, the generalized 3D spectra are used to calculate the mean sound field and the transverse coherence function of a plane sound wave propagating through IGW. The results obtained also significantly differ from those for the case of sound propagation through isotropic turbulence.
Measuring the phase of vibration of spheres in a viscoelastic medium as an image contrast modality
Authors: Urban Matthew W. , Kinnick Randall R. , Greenleaf James F.
Published: December 2005

Detection of calcifications in breast is an important problem in the diagnosis of breast cancer. Vibro-acoustography is a recently developed method that uses the radiation force of ultrasound to create images of the mechanical response of an object at a low frequency using the magnitude or phase of the response. Small spheres are used to explore the use of the phase of vibration as a contrast modality for use in detection and identification of calcifications in breast tissue. An experiment is presented to measure the magnitude and phase of vibration at different frequencies. The theoretical and experimental results are compared for spheres of two different sizes. Phase images are shown in which five spheres of different density can be clearly distinguished from each other. With phase measurements and images, it is demonstrated that predictable image contrast exists for spheres of different density embedded in a viscoelastic medium.
Two-dimensional numerical simulation of acoustic wave phase conjugation in magnetostrictive elastic media
Authors: Voinovich Peter , Merlen Alain
Published: December 2005

The effect of parametric wave phase conjugation (WPC) in application to ultrasound or acoustic waves in magnetostrictive solids has been addressed numerically by Ben Khelil et al. [J. Acoust. Soc. Am. 109, 75–83 (2001)] using 1-D unsteady formulation. Here the numerical method presented by Voinovich et al. [Shock waves 13(3), 221–230 (2003)] extends the analysis to the 2-D effects. The employed model describes universally elastic solids and liquids. A source term similar to Ben Khelil et al.’s accounts for the coupling between deformation and magnetostriction due to external periodic magnetic field. The compatibility between the isotropic constitutive law of the medium and the model of magnetostriction has been considered. Supplementary to the 1-D simulations, the present model involves longitudinal/transversal mode conversion at the sample boundaries and separate magnetic field coupling with dilatation and shear stress. The influence of those factors in a 2-D geometry on the potential output of a magneto-elastic wave phase conjugator is analyzed in this paper. The process under study includes propagation of a wave burst of a given frequency from a point source in a liquid into the active solid, amplification of the waves due to parametric resonance, and formation of time-reversed waves, their radiation into liquid, and focusing. The considered subject is particularly important for ultrasonic applications in acoustic imaging, nondestructive testing, or medical diagnostics and therapy.
Focused nonlinear phase-conjugate waves generated by a solid parametric amplifier
Authors: Brysev Andrew P. , Bunkin Fedor V. , Krutyansky Leonid M. , Yan Xiang , Hamilton Mark F.
Published: December 2005

An experimental and numerical study is reported on focused, phase-conjugated sound beams of finite amplitude produced in water by a solid-state parametric amplifier, referred to as the conjugator. The sound beams incident on the conjugator were radiated by a focused circular source. Field distributions were measured along the beam axis and in the focal plane of the source. Both linear and nonlinear propagation were investigated. Apertures of different diameters were placed in front of the conjugator to demonstrate diffraction effects associated with size of the active surface of the conjugator. Peak-to-peak acoustic pressures of 8MPa and strongly distorted, asymmetric waveforms were measured at the focus of conjugate beams having a fundamental frequency of 5MHz. Numerical simulations of harmonic generation in the conjugate beams are in agreement with the measurements. The study reveals that the conjugate beams accurately reproduce the focal region of the incident beams when a sufficiently large aperture is used, even when substantial waveform distortion due to nonlinear propagation effects are observed in the conjugate beams.
Adrenergic receptor agonists prevent bile duct injury induced by adrenergic denervation by increased cAMP levels and activation of Akt
Authors: Glaser Shannon , Alvaro Domenico , Francis Heather , Ueno Yoshiyuki , Marucci Luca , Benedetti Antonio , Morrow Sharon De , Marzioni Marco , Mancino Maria Grazia , Phinizy Jo Lynne , Reichenbach Ramona , Fava Giammarco , Summers Ryun , Venter Julie , Alpini Gianfranco
Published: December 2005

Loss of parasympathetic innervation after vagotomy impairs cholangiocyte proliferation, which is associated with depressed cAMP levels, impaired ductal secretion, and enhanced apoptosis. Agonists that elevate cAMP levels prevent cholangiocyte apoptosis and restore cholangiocyte proliferation and ductal secretion. No information exists regarding the role of adrenergic innervation in the regulation of cholangiocyte function. In the present studies, we investigated the role of adrenergic innervation on cholangiocyte proliferative and secretory responses to bile duct ligation (BDL). Adrenergic denervation by treatment with 6-hydroxydopamine (6-OHDA) during BDL decreased cholangiocyte proliferation and secretin-stimulated ductal secretion with concomitant increased apoptosis, which was associated with depressed cholangiocyte cAMP levels. Chronic administration of forskolin (an adenylyl cyclase activator) or β1- and β2-adrenergic receptor agonists (clenbuterol or dobutamine) prevented the decrease in cholangiocyte cAMP levels, maintained cholangiocyte secretory and proliferative activities, and decreased cholangiocyte apoptosis resulting from adrenergic denervation. This was associated with enhanced phosphorylation of Akt. The protective effects of clenbuterol, dobutamine, and forskolin on 6-OHDA-induced changes in cholangiocyte apoptosis and proliferation were partially blocked by chronic in vivo administration of wortmannin. In conclusion, we propose that adrenergic innervation plays a role in the regulation of biliary mass and cholangiocyte functions during BDL by modulating intracellular cAMP levels.
Anatomic modifications in the enteric nervous system of piebald mice and physiological consequences to colonic motor activity
Authors: Ro Seungil , Hwang Sung Jin , Muto Melodie , Jewett William Keith , Spencer Nick J.
Published: December 2005

It has been assumed that in piebald lethal mice that develop megacolon, impaired colonic motor activity is restricted to the aganglionic distal colon. Peristaltic mechanical recordings, immunohistochemistry, and quantitative PCR were used to investigate whether regions of the colon, other than the aganglionic segment, may also show anatomical modifications and dysfunctional colonic motor activity. Contrary to expectations, colonic migrating motor complexes (MMCs) were absent along the whole colon of piebald lethal homozygote mice and severely impaired in heterozygote siblings. Aganglionosis was detected not only in the distal colon of piebald homozygote lethal mice (mean length: 20.4 ± 2.1 mm) but also surprisingly in their heterozygote siblings (mean length: 12.4 ± 1.1 mm). Unlike homozygote lethal mice, piebald heterozygotes showed no signs of megacolon. Interestingly, mRNA expression for PGP 9.5 was also dramatically reduced (by 71–99%) throughout the entire small and large bowel in both homozygote lethal and heterozygous littermates (by 67–87%). Histochemical staining confirmed a significant reduction in myenteric ganglia along the whole colon. In summary, the piebald mutation in homozygote lethal and heterozygote siblings is associated with dramatic reductions in myenteric ganglia throughout the entire colon and not limited to the distal colon as originally thought. Functionally, this results in an absence or severe impairment of colonic MMC activity in both piebald homozygote lethal and heterozygote siblings, respectively. The observation that piebald heterozygotes have an aganglionic distal colon (mean length: 12 mm) but live a normal murine life span without megacolon suggests that aganglionosis >12 mm and the complete absence of colonic MMCs may be required before any symptoms of megacolon arise.
Basal and evoked levels of bioassayable growth hormone are altered by hindlimb unloading
Authors: Bigbee A. J. , Grindeland R. E. , Roy R. R. , Zhong H. , Gosselink K. L. , Arnaud S. , Edgerton V. R.
Published: December 2005

Bioassayable growth hormone (BGH) in rats is released in large quantities from the pituitary in response to the activation of large, proprioceptive afferent fibers from fast and mixed fiber-type hindlimb musculature. We hypothesized that hindlimb unloading (HU) of adult male rats would 1) reduce the basal levels of plasma BGH, and 2) abolish stimulus-induced BGH release. Rats were exposed to HU for 1, 4, or 8 wk. Plasma and pituitaries were collected under isoflurane anesthesia for hormone analyses. Additionally, at 4 and 8 wk, a subset of rats underwent an in situ electrical stimulation (Stim) of tibial nerve proprioceptive afferents. Basal plasma BGH levels were significantly reduced (−51 and −23%) after 1 and 8 wk of HU compared with ambulatory controls (Amb). Although Amb-Stim rats exhibited increased plasma BGH levels (88 and 143%) and decreased pituitary BGH levels (−27 and −22%) at 4 and 8 wk, respectively, stimulation in HU rats had the opposite effect, reducing plasma BGH (−25 and −33%) and increasing pituitary BGH levels (47 and 10%) relative to HU alone at 4 and 8 wk. The 22-kDa form of GH measured by immunoassay and the plasma corticosterone, T3, T4, and testosterone levels were unchanged by HU or Stim at all time points. These data suggest that BGH synthesis and release from the pituitary are sensitive both to chronically reduced neuromuscular loading and to acute changes in neuromuscular activation, independent of changes in other circulating hormones. Thus BGH may play a role in muscle, bone, and metabolic adaptations that occur in response to chronically unloaded states.
Precooling leg muscle improves intermittent sprint exercise performance in hot, humid conditions
Authors: Castle Paul C. , Macdonald Adam L. , Philp Andrew , Webborn Anthony , Watt Peter W. , Maxwell Neil S.
Published: December 2005

We used three techniques of precooling to test the hypothesis that heat strain would be alleviated, muscle temperature (Tmu) would be reduced, and as a result there would be delayed decrements in peak power output (PPO) during exercise in hot, humid conditions. Twelve male team-sport players completed four cycling intermittent sprint protocols (CISP). Each CISP consisted of twenty 2-min periods, each including 10 s of passive rest, 5 s of maximal sprint against a resistance of 7.5% body mass, and 105 s of active recovery. The CISP, preceded by 20 min of no cooling (Control), precooling via an ice vest (Vest), cold water immersion (Water), and ice packs covering the upper legs (Packs), was performed in hot, humid conditions (mean ± SE; 33.7 ± 0.3°C, 51.6 ± 2.2% relative humidity) in a randomized order. The rate of heat strain increase during the CISP was faster in Control than Water and Packs ( P < 0.01), but it was similar to Vest. Packs and Water blunted the rise of Tmuuntil minute 16 and for the duration of the CISP (40 min), respectively ( P < 0.01). Reductions in PPO occurred from minute 32 onward in Control, and an increase in PPO by ∼4% due to Packs was observed (main effect; P < 0.05). The method of precooling determined the extent to which heat strain was reduced during intermittent sprint cycling, with leg precooling offering the greater ergogenic effect on PPO than either upper body or whole body cooling.
Infliximab Treatment in a Patient with Systemic Sclerosis Associated with Lung Fibrosis and Pulmonary Hypertension
Authors: Bargagli Elena , Galeazzi Mauro , Bellisai Francesca , Volterrani Luca , Rottoli Paola
Published: December 2005

This is the first report of the efficacy of anti-TNFα treatment in a patient with lung fibrosis and pulmonary hypertension associated with advanced systemic sclerosis, refractory to conventional therapies. The patient was treated with infliximab (5 mg/kg) and methotrexate (10 mg/week) for 1 year. After 6 months of therapy, the echocardiogram showed a reduction in pulmonary pressure, confirmed after 1 year. During treatment, the patient’s quality of life improved significantly and high-resolution computed tomography of the chest, lung function tests and blood gas analysis remained stable. After 1 year, the patient decided to stop infliximab therapy (for family reasons related to the distance to our hospital). Lung function tests, pulmonary arterial pressures and blood gas analysis progressively worsened and the patient died 11 months later. Few open-label studies have been conducted on the efficacy of anti-TNFα therapy in patients with systemic sclerosis. Here we report our experience in a case of systemic sclerosis complicated by pulmonary fibrosis and hypertension. Infliximab treatment seemed effective, suggesting that controlled randomized trials to evaluate infliximab efficacy in these patients and to compare infliximab with other anti-TNFα treatments would be worthwhile.
Development of ELISAs Measuring the Extent of TAFI Activation
Authors: Ceresa Erik , Brouwers Els , Peeters Miet , Jern Christina , Declerck Paul J. , Gils Ann
Published: December 2005

Objectives—

To date, quantitation of TAFI antigen levels has been mainly focused on “total” antigen levels and has been shown to yield ambiguous results because of the existence of different isoforms and various degrees of activation. Our objective was to develop assays that allow measuring the extent of TAFI activation.

Methods and Results—

A variety of enzyme-linked immunosorbent assays (ELISAs) were evaluated for their preferential reactivity toward TAFI before and after activation, and toward the recombinantly expressed activation peptide. Three ELISAs with distinct reactivities were selected: recognizing either exclusively nonactivated TAFI, the released activation peptide, or exclusively TAFIa (activated TAFI). Evaluation of TAFI activation during clot lysis revealed that decreases of TAFI levels are associated with increases of the released activation peptide and TAFIa levels. In addition, antigenic measurement of TAFIa parallels activity measured by chromogenic assay. Analyzing plasma samples revealed that subjects with hyperlipidemia had significantly higher plasma levels of both the activation peptide (109.2 versus 95.5;
P
<0.001) and TAFIa (112.1 versus 103.3;
P
=0.03), and not of TAFI antigen (92.5 versus 87.9;
P
=0.07) (results in % of plasma pooled from normolipidemic subjects).

Conclusion—

ELISAs that allow to measure the extent of TAFI activation were developed. These ELISAs constitute more sensitive markers in studies on the relationship between TAFI and cardiovascular diseases.
Role of the Estrogen and Progestin in Hormonal Replacement Therapy on Apolipoprotein A-I Kinetics in Postmenopausal Women
Authors: Lamon-Fava Stefania , Postfai Borbala , Diffenderfer Margaret , DeLuca Carl , O’Connor John , Welty Francine K. , Dolnikowski Gregory G. , Barrett P. Hugh R. , Schaefer Ernst J.
Published: December 2005

Objective—

Plasma high-density lipoprotein (HDL) cholesterol levels are inversely correlated with the risk of developing coronary heart disease. Hormonal replacement therapy (HRT) affects plasma HDL cholesterol levels, with estrogen increasing HDL cholesterol levels and progestins blunting this effect. This study was designed to assess the mechanism responsible for these effects.

Materials and Methods—

HDL apolipoprotein A-I (apoA-I) kinetics were studied in 8 healthy postmenopausal women participating in a double-blind, randomized, crossover study comprising 3 phases: placebo, conjugated equine estrogen (CEE) (0.625 mg/d), and CEE plus medroxyprogesterone acetate (MPA) (2.5 mg/d). Compared with placebo, treatment with CEE resulted in an increase in apoA-I pool size (+20%,
P
<0.01) because of a significant increase in apoA-I production rate (+47%,
P
<0.05) and no significant changes in apoA-I fractional catabolic rate. Compared with the CEE alone phase, treatment with the CEE plus MPA resulted in an 8% (
P
<0.02) reduction in apoA-I pool size and a significant reduction in apoA-I production rate (−13%,
P
<0.04), without changes in apoA-I fractional catabolic rate.

Conclusion—

Postmenopausal estrogen replacement increases apoA-I levels and production rate. When progestin is added to estrogen, it opposes these effects by reducing the production of apoA-I.
Smoking, Metalloproteinases, and Vascular Disease
Authors: Perlstein Todd S. , Lee Richard T.
Published: December 2005

Smoking causes up to 11% of total global cardiovascular deaths. Smoking has numerous effects that may promote atherosclerosis through vascular inflammation and oxidative stress, but the pathogenesis of smoking-related cardiovascular disease remains incompletely understood. The matrix metalloproteinases, a family of endopeptidases that can degrade extracellular matrix components in both physiological and pathophysiological states, play an important role in smoking-associated chronic obstructive pulmonary disease, the second leading cause of smoking attributable mortality. Emerging evidence indicates that the matrix metalloproteinases may also contribute to smoking-related vascular disease. Here we discuss the potential relationship between smoking, matrix metalloproteinases, and acceleration of vascular disease.
Phenotypic Modulation of Intima and Media Smooth Muscle Cells in Fatal Cases of Coronary Artery Lesion
Authors: Hao Hiroyuki , Gabbiani Giulio , Camenzind Edoardo , Bacchetta Marc , Virmani Renu , Bochaton-Piallat Marie-Luce
Published: December 2005

Objectives—Characterize the phenotypic features of media and intima coronary artery smooth muscle cells (SMCs) in mildly stenotic plaques, erosions, stable plaques, and in-stent restenosis.

Methods and Results—Expression of α-smooth muscle actin (α-SMA), smooth muscle myosin heavy chains (SMMHCs), and smoothelin was investigated by immunohistochemistry followed by morphometric quantification. The cross-sectional area and the expression of cytoskeletal proteins in the media were lower in restenotic lesions and, to a lesser extent, in stable plaques compared with mildly stenotic plaques and erosions. An important expression of α-SMA was detected in the intima of the different lesions; moreover, α-SMA staining was significantly larger in erosions compared with all other conditions. In the same location, a striking decrease of SMMHCs and a disappearance of smoothelin were observed in all situations.

Conclusions—Medial atrophy is prevalent in restenotic lesions and stable plaques compared with mildly stenotic plaques and erosions. Intimal SMCs of all situations exhibit a phenotypic profile, suggesting that they have modulated into myofibroblasts (MFs). The high accumulation of α-SMA–positive MFs in erosions compared with stable plaques correlates with the higher appearance of thrombotic complications in this situation.
High-Density Lipoprotein Promotes Endothelial Cell Migration and Reendothelialization via Scavenger Receptor-B Type I
Authors: Seetharam Divya , Mineo Chieko , Gormley Andrew K. , Gibson Linda L. , Vongpatanasin Wanpen , Chambliss Ken L. , Hahner Lisa D. , Cummings Melissa L. , Kitchens Richard L. , Marcel Yves L. , Rader Daniel J. , Shaul Philip W.
Published: December 2005

Vascular disease risk is inversely related to circulating levels of high-density lipoprotein (HDL) cholesterol. However, the mechanisms by which HDL provides vascular protection are unclear. The disruption of endothelial monolayer integrity is an important contributing factor in multiple vascular disorders, and vascular lesion severity is tempered by enhanced endothelial repair. Here, we show that HDL stimulates endothelial cell migration in vitro in a nitric oxide-independent manner via scavenger receptor B type I (SR-BI)-mediated activation of Rac GTPase. This process does not require HDL cargo molecules, and it is dependent on the activation of Src kinases, phosphatidylinositol 3-kinase, and p44/42 mitogen-activated protein kinases. Rapid initial stimulation of lamellipodia formation by HDL via SR-BI, Src kinases, and Rac is also demonstrable. Paralleling the in vitro findings, carotid artery reendothelialization after perivascular electric injury is blunted in apolipoprotein A-I
−/−
mice, and reconstitution of apolipoprotein A-I expression rescues normal reendothelialization. Furthermore, reendothelialization is impaired in SR-BI
−/−
mice. Thus, HDL stimulates endothelial cell migration via SR-BI-initiated signaling, and these mechanisms promote endothelial monolayer integrity in vivo.
Arrhythmogenic Mutation-Linked Defects in Ryanodine Receptor Autoregulation Reveal a Novel Mechanism of Ca
2+
Release Channel Dysfunction
Authors: George Christopher H. , Jundi Hala , Walters Nicola , Thomas N. Lowri , West Robert R. , Lai F. Anthony
Published: December 2005

Arrhythmogenic cardiac ryanodine receptor (RyR2) mutations are associated with stress-induced malignant tachycardia, frequently leading to sudden cardiac death (SCD). The causative mechanisms of RyR2 Ca
2+
release dysregulation are complex and remain controversial. We investigated the functional impact of clinically-severe RyR2 mutations occurring in the central domain, and the C-terminal I domain, a key locus of RyR2 autoregulation, on interdomain interactions and Ca
2+
release in living cells. Using high-resolution confocal microscopy and fluorescence resonance energy transfer (FRET) analysis of interaction between fusion proteins corresponding to amino- (N-) and carboxyl- (C-) terminal RyR2 domains, we determined that in resting cells, RyR2 interdomain interaction remained unaltered after introduction of SCD-linked mutations and normal Ca
2+
regulation was maintained. In contrast, after channel activation, the abnormal Ca
2+
release via mutant RyR2 was intrinsically linked to altered interdomain interaction that was equivalent with all mutations and exhibited threshold characteristics (caffeine >2.5 mmol/L; Ca
2+
>150 nmol/L). Noise analysis revealed that I domain mutations introduced a distinct pattern of conformational instability in Ca
2+
handling and interdomain interaction after channel activation that was absent in signals obtained from the central domain mutation. I domain–linked channel instability also occurred in intact RyR2 expressed in CHO cells and in HL-1 cardiomyocytes. These new insights highlight a critical role for mutation-linked defects in channel autoregulation, and may contribute to a molecular explanation for the augmented Ca
2+
release following RyR2 channel activation. Our findings also suggest that the mutational locus may be an important mechanistic determinant of Ca
2+
release channel dysfunction in arrhythmia and SCD.
Evidence of Structural Remodeling in the Dyssynchronous Failing Heart
Authors: Helm Patrick A. , Younes Laurent , Beg Mirza F. , Ennis Daniel B. , Leclercq Christophe , Faris Owen P. , McVeigh Elliot , Kass David , Miller Michael I. , Winslow Raimond L.
Published: December 2005

Ventricular remodeling of both geometry and fiber structure is a prominent feature of several cardiac pathologies. Advances in MRI and analytical methods now make it possible to measure changes of cardiac geometry, fiber, and sheet orientation at high spatial resolution. In this report, we use diffusion tensor imaging to measure the geometry, fiber, and sheet architecture of eight normal and five dyssynchronous failing canine hearts, which were explanted and fixed in an unloaded state. We apply novel computational methods to identify statistically significant changes of cardiac anatomic structure in the failing and control heart populations. The results demonstrate significant regional differences in geometric remodeling in the dyssynchronous failing heart versus control. Ventricular chamber dilatation and reduction in wall thickness in septal and some posterior and anterior regions are observed. Primary fiber orientation showed no significant change. However, this result coupled with the local wall thinning in the septum implies an altered transmural fiber gradient. Further, we observe that orientation of laminar sheets become more vertical in the early-activated septum, with no significant change of sheet orientation in the late-activated lateral wall. Measured changes in both fiber gradient and sheet structure will affect both the heterogeneity of passive myocardial properties as well as electrical activation of the ventricles.
Dietary Intake of Calcium in Relation to Mortality From Cardiovascular Disease
Authors: Umesawa Mitsumasa , Iso Hiroyasu , Date Chigusa , Yamamoto Akio , Toyoshima Hideaki , Watanabe Yoshiyuki , Kikuchi Shogo , Koizumi Akio , Kondo Takaaki , Inaba Yutaka , Tanabe Naohito , Tamakoshi Akiko ,   JACC Study Group
Published: December 2005

Background and Purpose—

No prospective studies have examined the association between calcium intake and the risk of cardiovascular disease in Japanese populations with a low mean calcium intake.

Methods—

Between 1988 and 1990, 110 792 Japanese subjects (46 465 men and 64 327 women) 40 to 79 years of age without a history of stroke, coronary heart disease, or cancer, completed a lifestyle questionnaire including food intake frequency under the Japan Collaborative Cohort (JACC) Study for Evaluation of Cancer Risk Sponsored by Monbusho. By the end of 1999, after 515 029 person years of follow-up, 566 deaths from stroke (101 subarachnoid hemorrhages, 140 intraparenchymal hemorrhages, and 273 ischemic strokes) and 234 deaths from coronary heart disease had been documented.

Results—

The intake of total calcium tended to be inversely associated with mortality from total stroke but not from coronary heart disease or total cardiovascular disease for men and women. The inverse association with dairy calcium intake was apparent for total stroke, both hemorrhagic and ischemic. The multivariate relative risk for men with highest versus lowest quintiles of dairy calcium intake was 0.53 (95% CI, 0.34 to 0.81) for total stroke, 0.46 (0.23 to 0.91) for hemorrhagic stroke, and 0.53 (0.29 to 0.99) for ischemic stroke; corresponding relative risks for women were 0.57 (0.38 to 0.86), 0.51 (0.28 to 0.94), and 0.50 (0.27 to 0.95).

Conclusions—

Dietary calcium intake from dairy products was associated with reduced mortality from stroke for Japanese men and women.
Midlife Pulse Pressure and Incidence of Dementia
Authors: Freitag Michael H. , Peila Rita , Masaki Kamal , Petrovitch Helen , Ross G. Webster , White Lon R. , Launer Lenore J.
Published: December 2005

Background and Purpose—

Previous studies have shown that midlife systolic blood pressure (SBP) predicts late-life cognitive decline and incident dementia. This study explores whether this association is attributable to the pulsatile, ie, pulse pressure (PP), or the nonpulsatile component of blood pressure (BP).

Methods—

Data are from the Honolulu-Asia Aging Study, a community-based study of Japanese American men. Midlife BP was measured in 1971 to 1974 and dementia assessment was conducted in late-life. The 2505 men who were dementia free in 1991 and had complete follow-up data were re-examined for incident dementia in 1994 to 1996 and 1997 to 1999. Their age ranged from 71 to 93 years. Survival analysis with age as the time scale was performed to estimate the risk (hazard ratio [HR] and 95% CI) for incident dementia associated with mid- and late-life tertiles of PP and mean arterial BP, as well as SBP and diastolic BP categories.

Results—

Over a mean of 5.1 years of follow-up, 189 cases (7.5%) of incident Alzheimer disease or vascular dementia were identified. After adjustment for cerebrovascular risk factors, dementia was significantly associated with SBP (HR 1.77; 95% CI, 1.10 to 2.84, for SBP ≥140 mm Hg compared with SBP <120 mm Hg), but not with PP tertiles. Limiting the analysis to those never treated with antihypertensives, high levels of all 4 BP components were significantly associated with dementia. In models with 2 BP components, only SBP remained significant in both the total sample and the never-treated subgroup (HR 2.29; 95% CI, 1.23 to 4.25, for SBP ≥140 mm Hg in total sample), whereas PP was not significantly associated with the risk for dementia.

Conclusions—

Midlife PP is not independently associated with dementia incidence. Midlife SBP is the strongest BP component predicting incident dementia.
Time Is Brain—Quantified
Authors: Saver Jeffrey L.
Published: December 2005

Background and Purpose—

The phrase “time is brain” emphasizes that human nervous tissue is rapidly lost as stroke progresses and emergent evaluation and therapy are required. Recent advances in quantitative neurostereology and stroke neuroimaging permit calculation of just how much brain is lost per unit time in acute ischemic stroke.

Methods—

Systematic literature-review identified consensus estimates of number of neurons, synapses, and myelinated fibers in the human forebrain; volume of large vessel, supratentorial ischemic stroke; and interval from onset to completion of large vessel, supratentorial ischemic stroke.

Results—

The typical final volume of large vessel, supratentorial ischemic stroke is 54 mL (varied in sensitivity analysis from 19 to 100 mL). The average duration of nonlacunar stroke evolution is 10 hours (range 6 to 18 hours), and the average number of neurons in the human forebrain is 22 billion. In patients experiencing a typical large vessel acute ischemic stroke, 120 million neurons, 830 billion synapses, and 714 km (447 miles) of myelinated fibers are lost each hour. In each minute, 1.9 million neurons, 14 billion synapses, and 12 km (7.5 miles) of myelinated fibers are destroyed. Compared with the normal rate of neuron loss in brain aging, the ischemic brain ages 3.6 years each hour without treatment. Altering single input variables in sensitivity analyses modestly affected the estimated point values but not order of magnitude.

Conclusions—

Quantitative estimates of the pace of neural circuitry loss in human ischemic stroke emphasize the time urgency of stroke care. The typical patient loses 1.9 million neurons each minute in which stroke is untreated.