bluuebunny/crossref_metadata_2025 huggingface dataset:
QUANTIFYING STOCHASTIC RESONANCE IN A SINGLE THRESHOLD DETECTOR FOR RANDOM APERIODIC SIGNALS
Authors: DAS ARUNEEMA , STOCKS N. G. , NIKITIN A. , HINES E. L.
Published: June 2004

We explore stochastic resonance (SR) effects in a single comparator (threshold detector) driven by either a Gaussian or exponentially distributed aperiodic signal. The behaviour of different performance measures, namely the cross-correlation coefficient (CCC), signal-to-noise ratio (SNR) and mutual information, I, has been investigated. The signals were added to Gaussian noise before being passed through the threshold detector. For the two signals tested, we observe the perhaps surprising result that the SNR never displays SR. However, SR is displayed by both the CCC and I for Gaussian signals. For exponential signals SR is not displayed by any of the measures. By generating signals whose probability distributions have the generalized Gaussian form Ae-|βx|n it is possible to demonstrate that SR ceases to occur if n<1.7. We conclude that SR is only observable in threshold based systems for certain types of aperiodic signal. Specifically, SR is not expected to occur for signals whose probability density functions have long, slowly decaying, tails. We discuss the implication of these results for the role of SR in biological sensory systems.
APPLICATION OF NON-STATIONARY TECHNIQUES IN THE ANALYSIS OF ELECTROCHEMICAL NOISE
Authors: DAROWICKI K. , ZIELIŃSKI A.
Published: June 2004

Approaches to the electrochemical noise (EN) analysis are generally based on the assumption of its stationarity. In spite of usability of such methodology, occurrences of non-stationary signals are rather frequent in the practice. The methods of overcoming this drawback are presented in the paper. Applications of short-time Fourier transformation are discussed. It utilizes the concept of time-localized analyzing functions generated by appropriately chosen sliding time-domain window. Such technique, applied in discrete time measurement regime yields time-dependent frequency EN decomposition. Additionally, the authors introduce the concept of time dependent spectral noise response and spectral noise resistance.
RESONANT ACTIVATION DRIVEN BY STRONGLY NON-GAUSSIAN NOISES
Authors: DYBIEC BARTŁOMIEJ , GUDOWSKA-NOWAK EWA
Published: June 2004

The constructive role of non-Gaussian random fluctuations is studied in the context of the passage over the dichotomously switching potential barrier. Our attention focuses on the interplay of the effects of independent sources of fluctuations: an additive stable noise representing non-equilibrium external random force acting on the system and a fluctuating barrier. In particular, the influence of the structure of stable noises on the mean escape time and on the phenomenon of resonant activation (RA) is investigated. By use of the numerical Monte Carlo method it is documented that the suitable choice of the barrier switching rate and random external fields may produce resonant phenomenon leading to the enhancement of the kinetics and the shortest, most efficient reaction time.
THE INCREASING IMPORTANCE OF 1/f-NOISES AS MODELS OF ECOLOGICAL VARIABILITY
Authors: HALLEY JOHN M. , INCHAUSTI PABLO
Published: June 2004

The features of 1/f-noise processes offer important new insights into the field of population biology, greatly helping our quest for understanding and for prediction of ecological processes. 1/f-noises account quite satisfactorily for the observed nature of ecological fluctuations. This article reviews the application of 1/f-noise processes to ecology. After a discussion of the basic problems of population ecology that makes such an innovation necessary, we review the features of 1/f-noises concentrating especially on those aspects that make these processes attractive as a solution. We also present a discussion of the analysis of real ecological data, which confirms that there are good empirical as well as good theoretical reasons to establish a leading role for pink 1/f noise. We then discuss the consequences of such a model for our understanding of ecology. The article finishes with a number of observations about some aspects of ecological data and applications that are likely to drive research in a different direction from that associated with engineering and the physical sciences.
BRAIN TEMPERATURE CALCULATIONS FOR SWINE USING EXPERIMENTAL MEASUREMENTS OF CEREBRAL BLOOD FLOW
Authors: LEY O. , BAYAZITOGLU Y. , LAPTOOK ABBOT R.
Published: June 2004

In this study, numerical simulations are performed to analyze the brain temperature reduction in swine during selective head cooling, whole body cooling or while the animals experience ischemia. Brain temperature is calculated using a time dependent thermal model that incorporates available experimental measurements of the rectal temperature, the cerebral blood flow and the cerebral metabolic rate of oxygen consumption.

The calculated temperature distribution is validated against the in vivo temperature measurements recorded during the different experiments. These comparisons help to better understand the relations between brain temperature, blood flow and metabolic activity, which are essential to successfully apply hypothermia in the treatment of brain injury.

The calculations presented here reproduce the temperature behavior observed in all the experiments considered. It is observed that the arterial temperature and the cerebral metabolic rate are important parameters that affect the deep tissue temperature. It is also concluded that the accurate knowledge of parameters such as the skin and bone thermal conductivity are necessary for effective modeling.
HEARTBEAT SOUND ANALYSIS WITH THE WAVELET TRANSFORM
Authors: DEBBAL S. M. , BEREKSI-REGUIG F.
Published: June 2004

This paper is concerned with a synthesis study of the continuous wavelet transform (CWT) in analyzing the phonocardiogram (PCG). It is shown that the CWT provides enough features of the PCG signals that will help physicians to obtain qualitative and quantitative measurements of the time and the time-frequency PCG signal characteristics, and consequently aid to diagnosis.
EEG SIGNAL COMPRESSION USING RADIAL BASIS NEURAL NETWORKS
Authors: SRIRAAM N. , ESWARAN C.
Published: June 2004

This paper describes a two-stage lossless compression scheme for electroencephalographic (EEG) signals using radial basis neural network predictors. Two variants of the radial basis network, namely, the radial basis function network and the generalized regression neural network are used in the first stage and their performances are evaluated in terms of compression ratio. The training is imparted to the network by using two training schemes, namely, single block scheme and block adaptive scheme. The compression ratios achieved by these networks when used along with arithmetic encoders in a two-stage compression scheme are obtained for different EEG test files. It is found that the generalized regression neural network performs better than other neural network models such as multilayer perceptrons and Elman network and linear predictor such as FIR.
ANALYSIS OF STRESS AND PRESSURE IN THE HUMAN ALVEOLAR WALL BEFORE BURSTING
Authors: CHAUDHRY H. R. , BUKIET B. , KIRSHBLUM S.
Published: June 2004

A strain energy function for the human alveolar wall in vivo is developed based on its length-tension properties. Using large deformation theory, this function is employed to determine the relationship between circumferential stress and stretch ratio as well as between alveolar pressure and stretch ratio. We find that both the circumferential stress and the pressure in the alveolar wall rise very rapidly if the wall is stretched even slightly more than that which occurs at the pressures attained during mechanical in-exsufflation (MI-E). MI-E involves producing a high inspiratory air pressure and then quickly switching to a large negative air pressure in order to remove mucus from the airways.
THREE-DIMENSIONAL SHAPE OPTIMIZATION OF FEMORAL COMPONENT OF HIP PROSTHESES WITH NONLINEAR FRICTIONAL INTERFACE
Authors: KATOOZIAN HAMID , DAVY DWIGHT T.
Published: June 2004

A numerical procedure was implemented for the three-dimensional shape optimization of femoral component of total hip replacements. An algorithm was developed for defining the component geometry in terms of longitudinal and cross-sectional shape variables. The three-dimensional design model was combined with a non-linear 3-D finite element analysis and a numerical optimization procedure. An idealized femoral geometry and a frictional contact were used for bone-implant interfaces. The design objective was to reduce the shear stresses and the relative motion between implant and the surrounding bone along the interface region. The general trend in all design optimization was to produce a somewhat bulky implant with a more rectangular cross section. The outcome was more strongly affected by interface condition than choice of objective function.
ANALYSIS OF LEFT VENTRICULAR MYOCARDIAL PROPERTIES
Authors: JEGATHESE REGINALD C. , NG EDDIE Y. K. , GHISTA DHANJOO N.
Published: June 2004

This work centers around the analysis and quantification of myocardial perfusion, in which the cardiac parameters have been identified to quantify Myocardial Perfusion Index (MPI). The fundamental poroelastic behaviour has been analysed within the physiological range of cardiac parameters. An in-depth investigation of the myocardium behaviour is essential, and two factors that are desirable but complicate the analysis are: the myocardial structure element (fibrous soft tissue), undergoes cyclic deformation during each cardiac cycle and the myocardial fluid component (blood), undergoes variable rate of perfusion through the myocardial soft tissue.
DISTRIBUTED FLOW LEAKAGE IN VISCOELASTIC TUBES: AN EXPERIMENTAL STUDY
Authors: HOFF CRAIG J. , YANG WEN JEI
Published: June 2004

Models of the arterial system often consider only the major arteries in the body; smaller arteries are neglected. Along the aorta are many small branches that create, what is in effect, a distributed flow leakage. Distributed flow leakage is known to significantly attenuate pressure and flow waves in rigid tubes. The purpose of this study was to determine the effects of distributed flow leakage on the transmission of pressure and flow waves in viscoelastic tubes. This was accomplished by conducting a series of experiments using latex tubes. The results of the study indicate that distributed flow leakage has a negligible effect on wave transmission in compliant tubes, hence it is reasonable to neglect distributed flow leakage in models of the arterial system.
BRAIN TEMPERATURE DISTRIBUTION DURING DEEP HYPOTHERMIC CIRCULATORY ARREST IN HUMANS
Authors: LEY O. , BAYAZITOGLU Y.
Published: June 2004

This paper analyzes the effect of different cooling and rewarming strategies on the brain temperature distribution before and after circulatory arrest in adults and children. The temperature variations during systemic cooling, circulatory arrest, and rewarming are calculated using a thermal model that incorporates physiological parameters. The calculations presented here explain why sometimes hypothermia does not show the expected neuroprotective effect.

This work shows the importance of departing from a steady temperature distribution when using deep hypothermic circulatory arrest. In the calculations, the external cooling conditions of the head are varied, and it is observed that hypothermic cardiopulmonary bypass (CPB) together with external head cooling help reduce the temperature gradients within the head during periods of reduced blood flow, and reduces the temperature increase in the deep tissue produced by the residual cerebral metabolic activity. The results presented here agree with previous experimental observations1–3regarding the duration of systemic cooling using CPB.
RELIABILITY AND VALIDITY OF A DEVICE TO MEASURE MUSCLE HARDNESS
Authors: KATO GOHEI , ANDREW PAUL D. , SATO HARUHIKO
Published: June 2004

Although clinicians judge muscle tenseness by palpation, methods to quantify this have not become established. We examined the reliability and validity of a commercially available myotonometer to assess the biceps brachii and brachioradialis. Torques ranging from 0–72% of maximum effort were isometrically resisted in five men and five women, all healthy and 21–23 years of age. Root-mean-square of surface electromyographic response was also measured. Intraclass correlations were 0.80 or higher within sessions but decreased to 0.57 between sessions except for myotonometry of the biceps brachii. Correlation with isometric load was 0.79 or higher for both myotonometry and electromyography, but these relations were consistently curvilinear. The myotonometer is more useful for fleshy muscles like the biceps brachii than for thin muscles like the brachioradialis. Because hardness has a curvilinear relation with tension in the muscle, hardness cannot be considered strictly equivalent to tension.
Characterization of a human colonic cDNA encoding a structurally novel urea transporter, hUT-A6
Authors: Smith Craig P. , Potter Elizabeth A. , Fenton Robert A. , Stewart Gavin S.
Published: June 2004

Two closely related genes, UT-A ( Slc14a2) and UT-B ( Slc14a1), encode specialized transporter proteins that modulate the movement of urea across cell membranes. In this article, we report the characterization of a cDNA isolated from human colonic mucosa encoding a novel UT-A urea transporter, hUT-A6. The encoded protein is 235 amino acids (aa) in length, making it the smallest UT-A member characterized. On the basis of previous structural predictions, hUT-A6 is structurally unique in that it consists of a single hydrophobic core flanked by hydrophilic NH2- and COOH-terminal domains. The transcript encoding hUT-A6 contains a novel 129-bp exon, exon 5a, which, as a result of alternative splicing, introduces a unique 19-aa segment and a stop codon. Functionally, the protein transports urea, and this activity is inhibited by phloretin. Interestingly, despite the lack of a protein kinase A (PKA) consensus site {[RK]( 2 )-X-[ST]}, transport of urea by hUT-A6 is stimulated by PKA agonists. Deletion of the two PKA consensus sites from murine UT-A3 (mUT-A3) did not affect the stimulatory response of PKA agonists, which, together with the lack of PKA consensus sites in hUT-A6, indicates that regulation of hUT-A6 and mUT-A3 is not mediated through a classic PKA phosphorylation consensus.
Granule neurons in cerebellum express distinct splice variants of the inositol trisphosphate receptor that are modulated by calcium
Authors: Choi Joseph Y. , Beaman-Hall Carol M. , Vallano Mary L.
Published: June 2004

Primary cultures of granule cells (GC) from rat cerebellar cortex were used to determine whether bioelectric activity, via a Ca2+/calmodulin-dependent kinase (CaMK) signaling cascade, modulates expression and exon selection in the inositol trisphosphate receptor type 1 (IP3R1). IP3R1 contains or lacks three exons (S1, S2, and S3) that are regulated in a regionally and temporally specific manner. The neuronal, or long, form of IP3R1 is distinguished from peripheral tissues by inclusion of the S2 exon. Although previous studies indicated that IP3R1 are undetectable in the cerebellar granular layer in vivo, receptor protein and mRNA are induced in cultured GC grown in medium supplemented with 25 mM KCl or NMDA, two trophic agents that promote long-term survival, compared with GC grown in 5 mM KCl. IP3R1 induction in response to 25 mM KCl or NMDA is attenuated by coaddition of voltage-sensitive calcium channel or NMDA receptor antagonists, respectively. Actinomycin D, CaMK, and calcineurin antagonists likewise suppress induction. Unlike the major variants of IP3R1 in Purkinje neurons, which lack S1 and S3, GC grown with trophic agents express mRNA containing these exons. Both neuronal types contain S2. Evidence obtained using mutant mice with Purkinje cell lesions, laser-microdissected GC neurons from slices, and explant cultures indicates that GC predominantly express the S1-containing variant of IP3R1 in vivo.
Regulation of plasma long-chain fatty acid oxidation in relation to uptake in human skeletal muscle during exercise
Authors: Roepstorff Carsten , Vistisen Bodil , Roepstorff Kirstine , Kiens Bente
Published: June 2004

In the present study, we investigated possible sites of regulation of long-chain fatty acid (LCFA) oxidation in contracting human skeletal muscle. Leg plasma LCFA kinetics were determined in eight healthy men during bicycling (60 min, 65% peak oxygen uptake) with either high (H-FOX) or low (L-FOX) leg fat oxidation (H-FOX: 1,098 ± 140; L-FOX: 494 ± 84 μmol FA/min, P < 0.001), which was achieved by manipulating preexercise muscle glycogen (H-FOX: 197 ± 21; L-FOX: 504 ± 25 mmol/kg dry wt, P < 0.001). Several blood metabolites and hormones were kept nearly similar between trials by allocating a preexercise meal and infusing glucose intravenously during exercise. During exercise, leg plasma LCFA fractional extraction was identical between trials (H-FOX: 17.8 ± 1.6; L-FOX: 18.2 ± 1.8%, not significant), suggesting similar LCFA transport capacity in muscle. On the contrary, leg plasma LCFA oxidation was 99% higher in H-FOX than in L-FOX (421 ± 47 vs. 212 ± 37 μmol/min, P < 0.001). Probably due to the slightly higher ( P < 0.01) plasma LCFA concentration in H-FOX than in L-FOX, leg plasma LCFA uptake was nonsignificantly ( P = 0.17) higher (25%) in H-FOX than in L-FOX, yet the fraction of plasma LCFA uptake oxidized was 61% higher ( P < 0.05) in H-FOX than in L-FOX. Accordingly, the muscle content of several lipid-binding proteins did not differ significantly between trials, although fatty acid translocase/CD36 and caveolin-1 were elevated ( P < 0.05) by the high-intensity exercise and dietary manipulation allocated on the day before the experimental trial. The present data suggest that, in contracting human skeletal muscle with different fat oxidation rates achieved by manipulating preexercise glycogen content, transsarcolemmal transport is not limiting plasma LCFA oxidation. Rather, the latter seems to be limited by intracellular regulatory mechanisms.
Endogenous ACTH concentration-dependent drive of pulsatile cortisol secretion in the human
Authors: Keenan Daniel M. , Roelfsema Ferdinand , Veldhuis Johannes D.
Published: June 2004

According to current regulatory concepts, pulsatile ACTH concentrations (CON) stimulate time-lagged cortisol secretion rates (SEC) via an implicit CON-SEC dose-response relationship. The present analyses reconstruct nonlinear properties of this in vivo agonist-response interface noninvasively in order to investigate pulse-by-pulse coupling consistency and to obviate the need to infuse isotopes or exogenous effectors, which may disrupt pathway interactions. This approach required an ensemble strategy of 1) measuring ACTH and cortisol CON in plasma sampled every 10 min for 24 h in 32 healthy adults, and 2) estimating simultaneously a) variable-waveform ACTH and cortisol SEC bursts superimposed upon fixed basal SEC; b) biexponential kinetics of ACTH and cortisol disappearance; c) nonequilibrium exchange of cortisol among free and cortisol-binding globulin (CBG)- and albumin-bound moieties; d) two SEC-burst shapes demarcated by a statistically defined day/night boundary; e) feedforward efficacy, potency, and sensitivity; and f) stochastic variability in feedforward measures over time. Thereby, we estimate 1) ACTH SEC (μg·l−1·day−1) of 0.27 ± 0.04 basal and 0.87 ± 0.07 pulsatile (means ± SE); 2) cortisol SEC (μmol·l−1·day−1) of 0.10 ± 0.01 basal and 3.5 ± 0.20 pulsatile; 3) free cortisol half-lives (min) of 1.8 ± 0.20 (diffusion/advection) and 4.1 ± 0.30 (elimination) and a half-life of total cortisol of 49 ± 2.4 and of ACTH of 20 ± 1.3; 4) ACTH potency (EC50, ng/l) of 26 ± 2.4, efficacy (nmol·l−1·min−1) 10 ± 1.8, and sensitivity (slope units) 0.65 ± 0.09; 5) night/day augmentation of ACTH and cortisol SEC-burst mass by 2.1- and 1.7-fold (median); 6) abbreviation of the modal time to maximal ACTH and cortisol SEC rates by 4.4- and 4.3-fold, respectively, after a change point clock time of 0205 (median); 7) in vivo percentage distribution of cortisol as 6% free, 14% albumin bound, and 80% CBG bound with an absolute free cortisol CON (nmol/l) 11.5 ± 0.54; and 8) significant (mean CV) stochastic variability in feedforward efficacy (140%), potency (38%), and sensitivity (56%) within the succession of paired ACTH/cortisol pulses of any given subject. In conclusion, the present composite formulation illustrates a platform for dissecting mechanisms of in vivo regulation of effector-response properties noninvasively in the corticotropic axis of the uninfused individual.
Chronic administration of nitric oxide reduces angiotensin II receptor type 1 expression and aldosterone synthesis in zona glomerulosa cells
Authors: Nithipatikom Kasem , Holmes Blythe B. , McCoy Michael J. , Hillard Cecilia J. , Campbell William B.
Published: June 2004

Acute nitric oxide (NO) inhibits angiotensin II (ANG II)-stimulated aldosterone synthesis in zona glomerulosa (ZG) cells. In this study, we investigated the effects of chronic administration of NO on the ANG II receptor type 1 (AT1) expression and aldosterone synthesis. ZG cells were treated daily with DETA NONOate (10−4 M), an NO donor, for 0, 12, 24, 48, 72, and 96 h. Chinese hamster ovary (CHO) cells, stably transfected with the AT1B receptor, were used as a positive control. Western blot analysis indicated that AT1 receptor expression was decreased as a function of time of NO administration in both CHO and ZG cells. ANG II binding to its receptors was determined by radioligand binding. NO treatment of ZG cells for 96 h resulted in a decrease in ANG II binding compared with control. The receptor density was decreased to 1,864 ± 129 fmol/mg protein from 3,157 ± 220 fmol/mg protein ( P < 0.005), but the affinity was not changed (1.95 ± 0.22 vs. 1.88 ± 0.21 nM). Confocal Raman microspectroscopy and immunocytochemistry both confirmed that the expression of AT1 receptors in ZG cells decreased with chronic NO administration. In addition, chronic NO administration also decreased the expression of cholesterol side-chain cleavage enzyme in ZG cells and inhibited ANG II- and 25-hydroxycholesterol-stimulated aldosterone synthesis in ZG cells. This study demonstrates that chronic administration of NO inhibits aldosterone synthesis in ZG cells by downregulation of the expression of both AT1 receptors and cholesterol side-chain cleavage enzyme.
Tissue-specific gene expression of prolactin receptor in the acute-phase response induced by lipopolysaccharides
Authors: Corbacho Ana M. , Valacchi Giuseppe , Kubala Lukas , Olano-Martín Estibaliz , Schock Bettina C. , Kenny Thomas P. , Cross Carroll E.
Published: June 2004

Acute inflammation can elicit a defense reaction known as the acute-phase response (APR) that is crucial for reestablishing homeostasis in the host. The role for prolactin (PRL) as an immunomodulatory factor maintaining homeostasis under conditions of stress has been proposed; however, its function during the APR remains unclear. Previously, it was shown that proinflammatory cytokines characteristic of the APR (TNF-α, IL-1β, and IFNγ) induced the expression of the PRL receptor (PRLR) by pulmonary fibroblasts in vitro. Here, we investigated the in vivo expression of PRLR during lipopolysaccharide (LPS)-induced APR in various tissues of the mouse. We show that PRLR mRNA and protein levels were downregulated in hepatic tissues after intraperitoneal LPS injection. Downregulation of PRLR in the liver was confirmed by immunohistochemistry. A suppressive effect on mRNA expression was also observed in prostate, seminal vesicle, kidney, heart, and lung tissues. However, PRLR mRNA levels were increased in the thymus, and no changes were observed in the spleen. The proportion of transcripts for the different receptor isoforms (long, S1, S2, and S3) in liver and thymus was not altered by LPS injection. These findings suggest a complex tissue-specific regulation of PRLR expression in the context of the APR.
Selective activation of central NPY Y1 vs. Y5 receptor elicits hyperinsulinemia via distinct mechanisms
Authors: Gao Jun , Ghibaudi Lorraine , Hwa Joyce J.
Published: June 2004

Central administration of neuropeptide Y (NPY) stimulates hyperphagia and hyperinsulinemia. Recent evidence has suggested that the Y1 and Y5 receptor subtypes may both mediate NPY-stimulated feeding. The present study attempts to further characterize the role of central NPY receptor subtypes involved in hyperinsulinemia. NPY and peptide analogs of NPY that selectively activated the NPY Y1 or Y5 receptor subtype induced feeding and hyperinsulinemia in satiated Long Evans rats, whereas NPY analogs that selectively activated the NPY Y2 or Y4 receptor subtype did not. To determine whether NPY-induced hyperinsulinemia is secondary to its hyperphagic effect, we compared the plasma insulin levels in the presence and absence of food after a 1-min central infusion of NPY and its analogs at 15, 60, and 120 min postinfusion. Our data suggest that selective activation of central NPY Y1 receptor subtype induced hyperinsulinemia independent of food ingestion, whereas the NPY Y5 receptor-induced hyperinsulinemia was dependent on food ingestion. Central administration of the selective Y1 receptor agonist d-Arg25 NPY eventually decreased plasma glucose levels 2 h postinfusion in Long Evans rats.
Osteoprotegerin production by human intestinal epithelial cells: a potential regulator of mucosal immune responses
Authors: Vidal Karine , Serrant Patrick , Schlosser Brigitte , van den Broek Peter , Lorget Florence , Donnet-Hughes Anne
Published: June 2004

Receptor activator of NF-κB (RANK) and its ligand (RANKL) are important members of the TNF receptor (TNFR) and TNF superfamilies, respectively. RANK is expressed on osteoclasts, T-lymphocytes, and dendritic cells, and its ligation with RANKL leads to cellular activation. However, another member of the TNFR family, osteoprotegerin (OPG), acts as a decoy receptor, binding to RANKL and preventing its interaction with RANK. Furthermore, OPG also binds TNF-related apoptosis-inducing ligand (TRAIL), an important regulator of cell survival. OPG is therefore an important regulator of bone metabolism and immune responses. Although intestinal epithelial cells (IEC) express some members of the TNF/TNFR superfamilies, the roles of OPG and RANKL in the intestinal mucosa has not been investigated. Here, we report that various human IEC lines constitutively express OPG mRNA and protein as well as mRNA for RANKL. Furthermore, human colonic epithelium constitutively expressed OPG, and this expression was increased in inflamed tissue. All of the IEC lines tested released OPG into the culture supernatant under standard culture conditions. Whereas TNF-α increased OPG protein secretion by HT29 cells, the cytokines IL-1β and IFN-γ had little, if any, effect. Furthermore, the culture supernatant from untreated HT29 cells abrogated TRAIL-induced inhibition of Jurkat T-cell proliferation and inhibited osteoclast activity in an in vitro model of bone resorption. Taken together, our data indicate that OPG is constitutively produced by IEC, could be upregulated by TNF-α, and is biologically active. Thus IEC-derived OPG may represent an important mucosal immunoregulatory factor and may be involved in bone physiology.
Microvascular Po2during extreme hemodilution with hemoglobin site specifically PEGylated at Cys-93(β) in hamster window chamber
Authors: Cabrales Pedro , Kanika Nirmala Devi , Manjula Belur N. , Tsai Amy G. , Acharya Seetharama A. , Intaglietta Marcos
Published: June 2004

The oxygen transport capacity of nonhypertensive polyethylene glycol (PEG)-conjugated hemoglobin solutions were investigated in the hamster chamber window model. Microvascular measurements were made to determine oxygen delivery in conditions of extreme hemodilution [hematocrit (Hct) 11%]. Two isovolemic hemodilution steps were performed with a 6% Dextran 70 (70-kDa molecular mass) plasma expander until Hct was 35% of control. Isovolemic blood volume exchange was continued using two surface-modified PEGylated hemoglobins (P5K2, P50= 8.6, and P10K2, P50= 8.3; P50is the hemoglobin Po2corresponding to its 50% oxygen saturation) until Hct was 11%. P5K2 and P10K2 are PEG-conjugated hemoglobins that maintain most of the hemoglobin allosteric properties and have a cooperativity index of n = 2.2. The effects of these molecular solutions were compared with those obtained in a previous study using MP4, a PEG-modified hemoglobin whose P50was 5.4 and cooperativity was 1.2 (Tsai et al., Am J Physiol Heart Circ Physiol 285: H1411–H1419, 2003). Tissue oxygen levels were higher after P5K2 (7.0 ± 2.5 mmHg) and P10K2 (6.3 ± 2.3 mmHg) versus MP4 (1.7 ± 0.5 mmHg) or the nonoxygen carrier Dextran 70 (1.3 ± 1.2 mmHg). Microvascular oxygen delivery was higher after P5K2 and P10K2 (2.22 and 2.34 ml O2/dl blood) compared with MP4 (1.41 ml O2/dl blood) or Dextran 70 (0.90 ml O2/dl blood); however, all these values were lower than control (7.42 ml O2/dl blood). The total hemoglobin in blood was similar in all cases; therefore, the improvement in tissue Po2and oxygen delivery appears to be due to the increased cooperativity of the new molecules.
Effects of mechanical uncouplers, diacetyl monoxime, and cytochalasin-D on the electrophysiology of perfused mouse hearts
Authors: Baker Linda C. , Wolk Robert , Choi Bum-Rak , Watkins Simon , Plan Patricia , Shah Anisha , Salama Guy
Published: June 2004

Chemical uncouplers diacetyl monoxime (DAM) and cytochalasin D (cyto-D) are used to abolish cardiac contractions in optical studies, yet alter intracellular Ca2+ concentration ([Ca2+]i) handling and vulnerability to arrhythmias in a species-dependent manner. The effects of uncouplers were investigated in perfused mouse hearts labeled with rhod-2/AM or 4-[β-[2-(di- n-butylamino)-6-naphthyl]vinyl]pyridinium (di-4-ANEPPS) to map [Ca2+]i transients (emission wavelength = 585 ± 20 nm) and action potentials (APs) (emission wavelength > 610 nm; excitation wavelength = 530 ± 20 nm). Confocal images showed that rhod-2 is primarily in the cytosol. DAM (15 mM) and cyto-D (5 μM) increased AP durations (APD75 = 20.0 ± 3 to 46.6 ± 5 ms and 39.9 ± 8 ms, respectively, n = 4) and refractory periods (45.14 ± 12.1 to 82.5 ± 3.5 ms and 78 ± 4.24 ms, respectively). Cyto-D reduced conduction velocity by 20% within 5 min and DAM by 10% gradually in 1 h ( n = 5 each). Uncouplers did not alter the direction and gradient of repolarization, which progressed from apex to base in 15 ± 3 ms. Peak systolic [Ca2+]i increased with cyto-D from 743 ± 47 ( n = 8) to 944 ± 17 nM ( n = 3, P = 0.01) but decreased with DAM to 398 ± 44 nM ( n = 3, P < 0.01). Diastolic [Ca2+]i was higher with cyto-D (544 ± 80 nM, n = 3) and lower with DAM (224 ± 31, n = 3) compared with controls (257 ± 30 nM, n = 3). DAM prolonged [Ca2+]i transients at 75% recovery (54.3 ± 5 to 83.6 ± 1.9 ms), whereas cyto-D had no effect (58.6 ± 1.2 ms; n = 3). Burst pacing routinely elicited long-lasting ventricular tachycardia but not fibrillation. Uncouplers flattened the slope of AP restitution kinetic curves and blocked ventricular tachycardia induced by burst pacing.
Influence of increased central venous pressure on baroreflex control of sympathetic activity in humans
Authors: Charkoudian N. , Martin E. A. , Dinenno F. A. , Eisenach J. H. , Dietz N. M. , Joyner M. J.
Published: June 2004

Volume expansion often ameliorates symptoms of orthostatic intolerance; however, the influence of this increased volume on integrated baroreflex control of vascular sympathetic activity is unknown. We tested whether acute increases in central venous pressure (CVP) diminished subsequent responsiveness of muscle sympathetic nerve activity (MSNA) to rapid changes in arterial pressure. We studied healthy humans under three separate conditions: control, acute 10° head-down tilt (HDT), and saline infusion (SAL). In each condition, heart rate, arterial pressure, CVP, and peroneal MSNA were measured during 5 min of rest and then during rapid changes in arterial pressure induced by sequential boluses of nitroprusside and phenylephrine (modified Oxford technique). Sensitivities of integrated baroreflex control of MSNA and heart rate were assessed as the slopes of the linear portions of the MSNA-diastolic blood pressure and R-R interval-systolic pressure relations, respectively. CVP increased ∼2 mmHg in both SAL and HDT conditions. Resting heart rate and mean arterial pressure were not different among trials. Sensitivity of baroreflex control of MSNA was decreased in both SAL and HDT condition, respectively: −3.1 ± 0.6 and −3.3 ± 1.0 versus −5.0 ± 0.6 units·beat−1·mmHg−1 ( P < 0.05 for SAL and HDT vs. control). Sensitivity of baroreflex control of the heart was not different among conditions. Our results indicate that small increases in CVP decrease the sensitivity of integrated baroreflex control of sympathetic nerve activity in healthy humans.
Oxygen distribution in microcirculation after arginine vasopressin-induced arteriolar vasoconstriction
Authors: Friesenecker B. , Tsai A. G. , Dünser M. W. , Mayr A. J. , Martini J. , Knotzer H. , Hasibeder W. , Intaglietta M.
Published: June 2004

The microvascular distribution of oxygen was studied in the arterioles and venules of the awake hamster window chamber preparation to determine the contribution of vascular smooth muscle contraction to oxygen consumption of the microvascular wall during arginine vasopressin (AVP)-induced vasoconstriction. AVP was infused intravenously at the clinical dosage (0.0001 IU·kg−1·min−1) and caused a significant arteriolar constriction, decreased microvascular flow and functional capillary density, and a substantial rise in arteriolar vessel wall transmural Po2 difference. AVP caused tissue Po2 to be significantly lowered from 25.4 ± 7.4 to 7.2 ± 5.8 mmHg; however, total oxygen extraction by the microcirculation increased by 25%. The increased extraction, lowered tissue Po2, and increased wall oxygen concentration gradient are compatible with the hypothesis that vasoconstriction significantly increases vessel wall oxygen consumption, which in this model appears to constitute an important oxygen-consuming compartment. This conclusion was supported by the finding that the small percentage of the vessels that dilated in these experiments had a vessel wall oxygen gradient that was smaller than control and which was not determined by changes in tissue Po2. These findings show that AVP administration, which reduces oxygen supply by vasoconstriction, may further impair tissue oxygenation by the additional oxygen consumption of the microcirculation.
Hypotension and bradycardia during caloric restriction in mice are independent of salt balance and do not require ANP receptor
Authors: Hunt Lisa M. , Hogeland Emily W. , Henry Maria K. , Swoap Steven J.
Published: June 2004

We hypothesized that caloric restriction (CR)-induced hypotension would correlate with increased sodium excretion through an atrial natriuretic peptide (ANP)-dependent mechanism. To test this hypothesis, the cardiovascular parameters of c57/Bl mice were measured with radiotelemetry while urine was collected. The 23-h mean blood pressure (BP) dropped from 108.6 ± 1.8 to 92.7 ± 2.4 mmHg, and 23-h heart rate dropped from 624 ± 5 to 426 ± 13 beats/min over 7 days of CR at 29°C. Contrary to our hypothesis, urine sodium excretion decreased by 55% by day 7 of CR. Consistent with decreased sodium excretion was the drop in plasma ANP (from 82.4 ± 4.3 to 68.0 ± 5.8 pg/ml). To explore the possibility that CR lowers BP through an ANP receptor-dependent mechanism that is independent of its effect on sodium retention, we measured the cardiovascular parameters of mice deficient in the ANP receptor (NPR1−/−) or the ANP clearance receptor (NPR3−/−). Mean BP fell from 117.1 ± 3.9 to 108.0 ± 4.7 mmHg in the NPR1−/− mice and from 87.0 ± 2.4 to 78.4 ± 1.7 mmHg in the NPR3−/− mice during CR. These data indicate that the hypotension induced by CR does not depend on increased sodium excretion. Rather, it appears that the mouse responds to the low BP induced by CR with an increase in sodium reabsorption. Furthermore, circulating ANP levels and data from NPR1−/− and NPR3−/− mice suggest that the ANP pathway may not be involved in the cardiovascular response to CR.
Bmx, a member of the Tec family of nonreceptor tyrosine kinases, is a novel participant in pharmacological cardioprotection
Authors: Zhang Jun , Ping Peipei , Wang Guang-Wu , Lu Ming , Pantaleon Dawn , Tang Xian-Liang , Bolli Roberto , Vondriska Thomas M.
Published: June 2004

Previous studies have indicated that PKC-ε is a central regulator of protective signal transduction in the heart. However, the signaling modules through which PKC-ε exerts its protective effects have only begun to be understood. We have identified a novel participant in the PKC-ε signaling system in cardioprotection, the nonreceptor tyrosine kinase Bmx. Functional proteomic analyses of PKC-ε signaling complexes identified Bmx as a member of these complexes. Subsequent studies in rabbits have indicated that Bmx is activated by nitric oxide (NO) in the heart, concomitant with the late phase of NO donor-induced protection, and provide the first analysis of Bmx expression/distribution in the setting of cardioprotection. In addition, increased expression of Bmx induced by NO donors was blocked by the same mechanism that blocked cardioprotection: inhibition of PKC with chelerythrine. These findings indicate that a novel type of PKC-tyrosine kinase module (involving Bmx) is formed in the heart and may be involved in pharmacological cardioprotection by NO donors.
Physiological significance of troponin T binding domains in striated muscle tropomyosin
Authors: Jagatheesan Ganapathy , Rajan Sudarsan , Petrashevskaya Natalia , Schwartz Arnold , Boivin Greg , Arteaga Grace , de Tombe Pieter P. , Solaro R. John , Wieczorek David F.
Published: June 2004

Striated muscle tropomyosin (TM) plays an essential role in sarcomeric contraction and relaxation through its regulated movement on the thin filament. Previous work in our laboratory established that α- and β-TM isoforms elicit physiological differences in sarcomeric performance. To address the significance of isoform-specific troponin T binding regions in TM, in this present work we replaced α-TM amino acids 175–190 and 258–284 with the β-TM regions and expressed this chimeric protein in the hearts of transgenic mice. Hearts that express this chimeric protein exhibit significant decreases in rates of contraction and relaxation when assessed by ex vivo work-performing cardiac analyses. There are increases in time to peak pressure and in half-time to relaxation. These hearts respond appropriately to β-adrenergic stimulation but do not attain control rates of contraction or relaxation. With increased expression of the transgene, 70% of the mice die by 5 mo of age without exhibiting gross pathological changes in the heart. Myofilaments from these mice have no differences in Ca2+sensitivity of percent maximum force, but there is a decrease in maximum tension development. Our data are the first to demonstrate that the troponin T binding regions of specific TM isoforms can alter sarcomeric performance without changing the Ca2+sensitivity of the myofilaments.
Regulation of myocardial function by histidine-rich, calcium-binding protein
Authors: Fan Guo-Chang , Gregory Kimberly N. , Zhao Wen , Park Woo Jin , Kranias Evangelia G.
Published: June 2004

Impaired sarcoplasmic reticulum (SR) Ca release has been suggested to contribute to the depressed cardiac function in heart failure. The release of Ca from the SR may be regulated by the ryanodine receptor, triadin, junctin, calsequestrin, and a histidine-rich, Ca-binding protein (HRC). We observed that the levels of HRC were reduced in animal models and human heart failure. To gain insight into the physiological function of HRC, we infected adult rat cardiac myocytes with a recombinant adenovirus that contains the full-length mouse HRC cDNA. Overexpression (1.7-fold) of HRC in adult rat cardiomyocytes was associated with increased SR Ca load (28%) but decreased SR Ca-induced Ca release (37%), resulting in impaired Ca cycling and depressed fractional shortening (36%) as well as depressed rates of shortening (38%) and relengthening (33%). Furthermore, the depressed basal contractile and Ca kinetic parameters in the HRC-infected myocytes remained significantly depressed even after maximal isoproterenol stimulation. Interestingly, HRC overexpresssion was accompanied by increased protein levels of junctin (1.4-fold) and triadin (1.8-fold), whereas the protein levels of ryanodine receptor, calsequestrin, phospholamban, and sarco(endo)plasmic reticulum Ca-ATPase remained unaltered. Collectively, these data indicate that alterations in expression levels of HRC are associated with impaired cardiac SR Ca homeostasis and contractile function.
Wnt-responsive element controls Lef-1 promoter expression during submucosal gland morphogenesis
Authors: Driskell Ryan R. , Liu Xiaoming , Luo Meihui , Filali Mohammed , Zhou Weihong , Abbott Duane , Cheng Ningli , Moothart Chris , Sigmund Curt D. , Engelhardt John F.
Published: June 2004

Regulated expression of lymphoid enhancer factor 1 (Lef-1) plays an obligatory role in the transcriptional control of epithelial bud formation during airway submucosal gland and mammary gland development. However, regions of the Lef-1 promoter required for spatial and temporal regulation during glandular development have yet to be defined. We hypothesized that a previously reported 110-bp Wnt-responsive element (WRE) in the Lef-1 promoter, which can be induced by Wnt-3a/β-catenin signals, may also play a role in regulating Lef-1 expression during airway and mammary gland development. Here we show that the Lef-1 promoter is also responsive to Wnt-1 signals in both airway and mammary epithelial cell lines. To better understand the importance of the WRE in dynamically regulating Lef-1 promoter activation in these two types of epithelia in vivo, we utilized LacZ reporter transgenic mice to evaluate the significance of Wnt-responsive sequences in the Lef-1 promoter during glandular bud formation. A 2.5-kb Lef-1 promoter fragment partially reproduced endogenous Lef-1 expression patterns in a subset of cell types involved in both mammary gland and submucosal glandular bud development. Interestingly, removal of the 110-bp WRE from the Lef-1 promoter ablated expression in nasal and tracheal submucosal glandular buds while having no significant effect on developmental expression in mammary glandular buds. These findings suggest that Wnt regulation of the Lef-1 promoter at the WRE may play an important role during airway submucosal glandular bud formation.
Substance P and neutral endopeptidase in development of acute respiratory distress syndrome following fire smoke inhalation
Authors: Wong Simon S. , Sun Nina N. , Lantz R. Clark , Witten Mark L.
Published: June 2004

To characterize the tachykininergic effects in fire smoke (FS)-induced acute respiratory distress syndrome (ARDS), we designed a series of studies in rats. Initially, 20 min of FS inhalation induced a significant increase of substance P (SP) in bronchoalveolar lavage fluid (BALF) at 1 h and persisted for 24 h after insult. Conversely, FS disrupted 51.4, 55.6, 46.3, and 43.0% enzymatic activity of neutral endopeptidase (NEP, a primary hydrolyzing enzyme for SP) 1, 6, 12, and 24 h after insult, respectively. Immunolabeling density of NEP in the airway epithelium largely disappeared 1 h after insult due to acute cell damage and shedding. These changes were also accompanied by extensive influx of albumin and granulocytes/lymphocytes in BALF. Furthermore, levels of BALF SP and tissue NEP activity dose dependently increased and decreased, respectively, following 0, low (10 min), and high (20 min) levels of FS inhalation. However, neither the time-course nor the dose-response study observed a significant change in the highest affinity neurokinin-1 receptor (NK-1R) for SP. Finally, treatment (10 mg/kg im) with SR-140333B, an NK-1R antagonist, significantly prevented 20-min FS-induced hypoxemia and pulmonary edema 24 h after insult. Further examination indicated that SR-140333B (1.0 or 10.0 mg/kg im) fully abolished early (1 h) plasma extravasation following FS. Collectively, these findings suggest that a combination of sustained SP and NEP inactivity induces an exaggerated neurogenic inflammation mediated by NK-1R, which may lead to an uncontrolled influx of protein-rich edema fluid and cells into the alveoli as a consequence of increased vascular permeability.
Regenerative capacity of the dystrophic (mdx) diaphragm after induced injury
Authors: Matecki Stefan , Guibinga Ghiabe H. , Petrof Basil J.
Published: June 2004

Duchenne muscular dystrophy is characterized by myofiber necrosis, muscle replacement by connective tissue, and crippling weakness. Although the mdx mouse also lacks dystrophin, most muscles show little myofiber loss or functional impairment. An exception is the mdx diaphragm, which is phenotypically similar to the human disease. Here we tested the hypothesis that the mdx diaphragm has a defective regenerative response to necrotic injury, which could account for its severe phenotype. Massive necrosis was induced in mdx and wild-type (C57BL10) mouse diaphragms in vivo by topical application of notexin, which destroys mature myofibers while leaving myogenic precursor satellite cells intact. At 4 h after acute exposure to notexin, >90% of diaphragm myofibers in both wild-type and mdx mice demonstrated pathological sarcolemmal leakiness, and there was a complete loss of isometric force-generating capacity. Both groups of mice showed strong expression of embryonic myosin within the diaphragm at 5 days, which was largely extinguished by 20 days after injury. At 60 days postinjury, wild-type diaphragms exhibited a persistent loss (∼25%) of isometric force-generating capacity, associated with a trend toward increased connective tissue infiltration. In contrast, mdx diaphragms achieved complete functional recovery of force generation to noninjured values, and there was no increase in muscle connective tissue over baseline. These data argue against any loss of intrinsic regenerative capacity within the mdx diaphragm, despite characteristic features of major dystrophic pathology being present. Our findings support the concept that significant latent regenerative capacity resides within dystrophic muscles, which could potentially be exploited for therapeutic purposes.
Top-down control analysis of the effect of temperature on ectotherm oxidative phosphorylation
Authors: Chamberlin M. E.
Published: June 2004

Top-down control and elasticity analysis was conducted on mitochondria isolated from the midgut of the tobacco hornworm ( Manduca sexta) to assess how temperature affects oxidative phosphorylation in a eurythermic ectotherm. Oxygen consumption and protonmotive force (measured as membrane potential in the presence of nigericin) were monitored at 15, 25, and 35°C. State 4 respiration displayed a Q10of 2.4–2.7 when measured over two temperature ranges (15–25°C and 25–35°C). In state 3, the Q10s for respiration were 2.0 and 1.7 for the lower and higher temperature ranges, respectively. The kinetic responses (oxygen consumption) of the substrate oxidation system, proton leak, and phosphorylation system increased as temperature rose, although the proton leak and substrate oxidation system showed the greatest thermal sensitivity. Whereas there were temperature-induced changes in the activities of the oxidative phosphorylation subsystems, there was no change in the state 4 membrane potential and little change in the state 3 membrane potential. Top-down control analysis revealed that control over respiration did not change with temperature. In state 4, control of respiration was shared nearly equally by the proton leak and the substrate oxidation system, whereas in state 3 the substrate oxidation system exerted over 90% of the control over respiration. The proton leak and phosphorylation system account for <10% of the temperature-induced change in the state 3 respiration rate. Therefore, when the temperature is changed, the state 3 respiration rate is altered primarily because of temperature's effect on the substrate oxidation system.