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PubMed1995

Characterization of the functional muscarinic receptors in the rat urinary bladder.

1. Muscarinic receptors mediating contraction of the rat urinary bladder were characterized functionally in vitro by use of atropine, 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP methiodide), 4-diphenylacetoxy-N-(2-chloroethyl)-piperidine hydrochloride (4-DAMP mustard), hexahydro-sila-diphenidol hydrochloride (HHSiD), the p-fluoro analogue of hexahydro-sila-diphenidol hydrochloride (p-F-HHSiD), methoctramine, and pirenzepine. 2. (+)-cis-Dioxolane contracted bladder strips in a concentration-dependent manner with an EC50 of 0.169 +/- 0.018 microM and an Emax of 7.84 +/- 0.67 g. 3. Concentration-effect curves to (+)-cis-dioxolane were shifted to the right in the presence of the antagonists in a concentration-dependent manner. The rank order of antagonist affinities against the (+)-cis-dioxolane response was (pA2 values in the parentheses) atropine (9.28) > or = 4-DAMP methiodide (9.04) > HHSiD (8.01) > p-F-HHSiD (7.28) = pirenzepine (7.12) > or = methoctramine (6.77, 7.25). The profile resembles that associated with the M3 receptor subtype. 4. Atropine, 4-DAMP methiodide, pirenzepine, and methoctramine had no effects on the contractile response to 120 mM KCl. However, HHSiD and p-F-HHSiD decreased the response to KCl, and 4-DAMP mustard increased it. 5. Contractile responses to electrical field stimulation (1-32 Hz, 0.05 ms pulse duration) were biphasic in nature. The tonic response was suppressed more than the phasic response by all antagonists except methoctramine. The suppression was not always concentration-dependent, and did not seem to be related to antagonism of any one receptor subtype. 6. Our findings are consistent with the minority M3 receptors mediating the contractile response to muscarinic stimulation by (+)-cis-dioxolane in the rat bladder.

Animals↗

PubMed2004

Experimental determination of dynamic characteristics of the VentrAssist implantable rotary blood pump.

The VentrAssist implantable rotary blood pump, intended for long-term ventricular assist, is under development and is currently being tested for its rotor-dynamic stability. The pump consists of a shaftless impeller, which also acts as the rotor of the brushless DC motor. The impeller remains passively suspended in the pump cavity by hydrodynamic forces, which result from the small clearances between the outside surfaces of the impeller and the pump cavity. These small clearances range from approximately 50 microm to 230 microm in size in the version of pump reported here. This article presents experimental investigation into the dynamic characteristics of the impeller-bearing-pump housing system of the rotary blood pump for increasing pump speeds at different flow rates. The pump was mounted on a suspension system consisting of a platform and springs, where the natural frequency and damping ratio for the suspension system were determined. Real-time measurements of the impeller's displacement were performed using Hall effect sensors. A vertical disturbance force was exerted onto the pump housing, causing the impeller to be displaced in vertical direction from its dynamic equilibrium position within the pump cavity. The impeller displacement was represented by a decaying sine wave, which indicated the impeller restoring to its equilibrium position. From the decaying sine wave the natural frequency and stiffness coefficient of the system were determined. Furthermore, the logarithmic decrement method was used to determine the damping ratio and eventually the damping coefficient of the system. Results indicate that stiffness and damping coefficients increased as flow rate and pump speed increased, representing an increase in stability with these changing conditions. However, pump speed had a greater influence on the stiffness and damping coefficients than flow rate did, which was evident through dynamic analysis. Overall the experimental method presented in this article was successful in determining the dynamic characteristics of the system.

Blood Flow Velocity↗

PubMed2002

Development of new treatments for congenital nystagmus.

The use of ocular motor data as the basis for the development of both nonsurgical and surgical therapies for congenital nystagmus (CN) has been underway since the mid-1960s. This paper presents three nonsurgical therapies (composite prisms, soft contact lenses, and afferent stimulation) and a new surgical therapy (four-muscle tenotomy) hypothesized from analysis of ocular motor data. The expanded nystagmus acuity function test was developed to both predict and measure the effectiveness of CN therapies and for intersubject comparisons. Base-out prisms may be used to damp CN during distance fixation in patients whose CN damps during near fixation and who are binocular (i.e., they have no strabismus). Soft contact lenses may be used in those whose CN damps with afferent stimulation of the ophthalmic division of the trigeminal nerve. Cutaneous afferent stimulation (rubbing, vibration, or electricity) of the forehead or neck damps CN in some individuals. Finally, as first demonstrated in an achiasmic Belgian sheepdog and later in humans, tenotomy of the four horizontal rectus muscles and reattachment at their original sites may also damp CN. Taken together, these findings suggest the existence of one or more proprioceptive feedback loops acting to change the small-signal gain of the extraocular plant. Four-muscle tenotomy provides a needed therapeutic option for the many individuals with CN for whom other surgical therapies are contraindicated. Tenotomy may also prove useful in see-saw nystagmus (it abolished it in the aforementioned canine) or other types of nystagmus; further studies of the latter are required.

Animals↗

PubMed2002

Broadband transmission noise reduction of smart panels featuring piezoelectric shunt circuits and sound-absorbing material.

The possibility of a broadband noise reduction of piezoelectric smart panels is experimentally studied. A piezoelectric smart panel is basically a plate structure on which piezoelectric patches with electrical shunt circuits are mounted and sound-absorbing material is bonded on the surface of the structure. Sound-absorbing material can absorb the sound transmitted at the midfrequency region effectively while the use of piezoelectric shunt damping can reduce the transmission at resonance frequencies of the panel structure. To be able to reduce the sound transmission at low panel resonance frequencies, piezoelectric damping using the measured electrical impedance model is adopted. A resonant shunt circuit for piezoelectric shunt damping is composed of resistor and inductor in series, and they are determined by maximizing the dissipated energy through the circuit. The transmitted noise-reduction performance of smart panels is tested in an acoustic tunnel. The tunnel is a square cross-sectional tube and a loudspeaker is mounted at one side of the tube as a sound source. Panels are mounted in the middle of the tunnel and the transmitted sound pressure across panels is measured. When an absorbing material is bonded on a single plate, a remarkable transmitted noise reduction in the midfrequency region is observed except for the fundamental resonance frequency of the plate. By enabling the piezoelectric shunt damping, noise reduction is achieved at the resonance frequency as well. Piezoelectric smart panels incorporating passive absorbing material and piezoelectric shunt damping is a promising technology for noise reduction over a broadband of frequencies.

Acoustics↗

PubMed1994

Modeling the fine structure of the 2f1-f2 acoustic distortion product. II. Model evaluation.

In a previous article, a vector sum model was developed that successfully reproduces the ADP rippling pattern when a nonuniformity is introduced in the active damping factor, a parameter that is inversely related to the energy gain contribution of the outer hair cells [OHCs, Sun et al., J. Acoust. Soc. Am. 96, 2166-2174 (1994)]. Here, the mean of the damping factor is increased nonlinearly with input level, mimicking the saturation of the active feedback of the OHCs. The passive damping factor in the transmission line model was also nonlinearly increased with input level to reproduce the frequency shift of the peak of the traveling wave observed in experimental data. The resulting model simulates an ADP that is compatible with data from human subjects wherein the ADP fine structure does not saturate with level. Moreover, the model suggests that the shifting of the ADP pattern with level is a direct result of the peak shift of the traveling wave, thus implicating the nonlinear damping factors as the underlying basis of this phenomenon. The input/output (I/O) functions of the simulated ADP emissions at specific frequencies were also examined. The resulting functions show a variety of shapes, depending on the pattern of ADP fine structure around the I/O frequency, and the way the fine structure shifts as primary levels increase. These I/O functions are also similar to those observed in human subjects, even with regard to overall slopes which approximate one. Thus the model illustrates how cubic distortion generators coupled with damping on linearities can yield I/O function slopes on the order of one, rather than the expected three.(ABSTRACT TRUNCATED AT 250 WORDS)

Basilar Membrane↗

PubMed1994

Cloning of Genes Involved in the Synthesis of Pyrrolnitrin from Pseudomonas fluorescens and Role of Pyrrolnitrin Synthesis in Biological Control of Plant Disease.

A soil isolate of Pseudomonas fluorescens (BL915) was shown to be an effective antagonist of Rhizoctonia solani-induced damping-off of cotton. Investigation of the biological basis of this antagonism revealed that the strain produces pyrrolnitrin, a secondary metabolite known to inhibit R. solani and other fungi. Mutants of strain BL915 that did not produce pyrrolnitrin and did not suppress damping-off of cotton by R. solani were generated by exposure to N-methyl-N' -nitro-N-nitrosoguanidine. A gene region that was capable of restoring pyrrolnitrin production to the non-pyrrolnitrin-producing mutants and of conferring this ability upon two other P. fluorescens strains not otherwise known to produce this compound or to be capable of suppressing damping-off caused by R. solani was isolated from strain BL915. The non-pyrrolnitrin-producing strains (mutants of BL915 and the other two P. fluorescens strains) which synthesized pyrrolnitrin after the introduction of the gene region from strain BL915 were also shown to be equal to strain BL915 in their ability to suppress R. solani-induced damping-off of cotton. These results indicate that we have isolated from P. fluorescens BL915 a gene(s) that has a role in the synthesis of pyrrolnitrin and that the production of this compound has a role in the ability of this strain to control damping-off of cotton by R. solani.

Journal Article↗

PubMed2003

Deficits in attention, motor control, and perception: a brief review.

The concept of DAMP (deficits in attention, motor control, and perception) has been in clinical use in Scandinavia for about 20 years. DAMP is diagnosed on the basis of concomitant attention deficit/hyperactivity disorder and developmental coordination disorder in children who do not have severe learning disability or cerebral palsy. In clinically severe form it affects about 1.5% of the general population of school age children; another few per cent are affected by more moderate variants. Boys are overrepresented; girls are currently probably underdiagnosed. There are many comorbid problems/overlapping conditions, including conduct disorder, depression/anxiety, and academic failure. There is a strong link with autism spectrum disorders in severe DAMP. Familial factors and pre- and perinatal risk factors account for much of the variance. Psychosocial risk factors appear to increase the risk of marked psychiatric abnormality in DAMP. Outcome in early adult age was psychosocially poor in one study in almost 60% of unmedicated cases. There are effective interventions available for many of the problems encountered in DAMP.

Attention Deficit Disorder with Hyperactivity↗

PubMed1987

Housing conditions and ill health.

Lack of empirical evidence that living in damp houses has detrimental effects on health may partly be due to inadequate research. A preliminary study was therefore carried out of a random sample of council owned residences in a deprived area of Edinburgh, a respondent from consenting households being interviewed to obtain a profile of the physical and mental health of all adults and children. In addition, information was gathered about other factors that might be important, particularly smoking and selective bias in the allocation of tenants to houses. Independent measures of dampness were made by environmental health officers. No conclusive effects of damp on the health of adults were identified. Nevertheless, children living in damp houses, especially where fungal mould was present, had higher rates of respiratory symptoms, which were unrelated to smoking in the household, and higher rates of symptoms of infection and stress. Housing should remain an important public health issue, and the effects of damp warrant further investigation.

Disease↗

PubMed2004

Regional rheological differences in locomoting neutrophils.

Intracellular rheology is a useful probe of the mechanisms underlying spontaneous or chemotactic locomotion and transcellular migration of leukocytes. We characterized regional rheological differences between the leading, body, and trailing regions of isolated, adherent, and spontaneously locomoting human neutrophils. We optically trapped intracellular granules and measured their displacement for 500 ms after a 100-nm step change in the trap position. Results were analyzed in terms of simple viscoelasticity and with the use of structural damping (stress relaxation follows a power law in time). Structural damping fit the data better than did viscoelasticity. Regional viscoelastic stiffness and viscosity or structural damping storage and loss moduli were all significantly lower in leading regions than in pooled body and/or trailing regions (the latter were not significantly different). Structural damping showed similar levels of elastic and dissipative stresses in body and/or trailing regions; leading regions were significantly more fluidlike (increased power law exponent). Cytoskeletal disruption with cytochalasin D or nocodazole made body and/or trailing regions approximately 50% less elastic and less viscous. Cytochalasin D completely suppressed pseudopodial formation and locomotion; nocodazole had no effect on leading regions. Neither drug changed the dissipation-storage energy ratio. These results differ from those of studies of neutrophils and other cell types probed at the cell membrane via beta(2)-integrin receptors, which suggests a distinct role for the cell cortex or focal adhesion complexes. We conclude that 1) structural damping well describes intracellular rheology, and 2) while not conclusive, the significantly more fluidlike behavior of the leading edge supports the idea that intracellular pressure may be the origin of motive force in neutrophil locomotion.

Antineoplastic Agents↗

PubMed1986

Effect of selective muscarinic antagonists on peristaltic contractions in opossum smooth muscle.

In this study we examined the role of M1- and M2-muscarinic receptors in the mediation of circular smooth muscle esophageal contractions elicited by pharmacological cholinergic stimulation and during peristalsis in anesthetized opossums. Esophageal-body contractions were induced by bethanechol administration, whereas peristalsis was elicited by pharyngeal stroking or cervical vagal stimulation. Contractions were measured by a low-compliance manometric recording system. The incidence and amplitude of bethanechol-induced contractions were antagonized by 4-diphenylacetoxy-n-methylpiperidine (4-DAMP) and atropine but not pirenzepine. 4-DAMP and atropine caused an increased velocity, decreased amplitude, and preferential reduction of the incidence of primary peristaltic contractions in the proximal smooth muscle esophagus. During long-train vagal stimulation, intra-stimulus A-waves had a velocity similar to primary peristalsis, whereas poststimulus B-waves showed a velocity considerably faster than primary peristalsis. Short-train vagal stimulation produced a contraction sequence, termed an "S-wave," that had a velocity similar to that of the A-wave. At low doses 4-DAMP increased the velocity and decreased the amplitude of A-wave and S-wave contractions, and at high doses 4-DAMP abolished both the A-wave and S-wave contractions. B-wave contractions were minimally affected by 4-DAMP. Pirenzepine had no effect on contractions induced by swallows or vagal stimulation. We conclude that M2-muscarinic receptors mediate esophageal contractions in the circular smooth muscle during primary peristalsis and during A-waves and S-waves induced by vagal stimulation, and M1-receptors do not have any important role in the excitatory neural pathway to the esophagus.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1986

Muscarinic receptor subtypes on rat pancreatic acini: secretion and binding studies.

Characterization of muscarinic receptor subtypes on rat pancreatic acinar cells was examined by using specific muscarinic receptor antagonists to study amylase secretion and binding of [N-methyl-3H]scopolamine ([3H]NMS). Rat pancreatic acini were dispersed in HEPES-Ringer buffer and incubated with acetylcholine +/- 4-diphenylacetoxy-N-methylpiperadine-methiodide (4-DAMP, a specific M2 muscarinic receptor antagonist) or +/- pirenzepine (a specific M1 muscarinic receptor antagonist). 4-DAMP (10(-9) to 10(-6) M) caused a progressive parallel rightward shift in the acetylcholine dose-response curve without a change in maximal amylase release. Only high concentrations of pirenzepine (10(-6) to 10(-4) M) caused a rightward shift in the dose-response curve to acetylcholine. Schild analysis of the data indicated an inhibitory constant (Ki) of 200 pM for 4-DAMP and 183 nM for pirenzepine. The slope of the Schild regression lines was not different from unity, suggesting competitive inhibition. Binding of 50 pM [3H]NMS was specific, rapid, and saturable. [3H]NMS binding was displaced by increasing concentrations of 4-DAMP or pirenzepine with apparent Ki's of 102 pM and 330 nM, respectively, and similar maximal binding levels of 60 fmol/mg prot. We have demonstrated that 4-DAMP has an approximately 1,000-fold greater potency than pirenzepine to inhibit amylase release and binding, indicating that cholinergic-stimulated amylase release from pancreatic acini is mediated by M2 muscarinic receptors.

Acetylcholine↗

PubMed2001

Sympathetic restraint of respiratory sinus arrhythmia: implications for vagal-cardiac tone assessment in humans.

Clinicians and experimentalists routinely estimate vagal-cardiac nerve traffic from respiratory sinus arrhythmia. However, evidence suggests that sympathetic mechanisms may also modulate respiratory sinus arrhythmia. Our study examined modulation of respiratory sinus arrhythmia by sympathetic outflow. We measured R-R interval spectral power in 10 volunteers that breathed sequentially at 13 frequencies, from 15 to 3 breaths/min, before and after beta-adrenergic blockade. We fitted changes of respiratory frequency R-R interval spectral power with a damped oscillator model: frequency-dependent oscillations with a resonant frequency, generated by driving forces and modified by damping influences. beta-Adrenergic blockade enhanced respiratory sinus arrhythmia at all frequencies (at some, fourfold). The damped oscillator model fit experimental data well (39 of 40 ramps; r = 0.86 +/- 0.02). beta-Adrenergic blockade increased respiratory sinus arrhythmia by amplifying respiration-related driving forces (P < 0.05), without altering resonant frequency or damping influences. Both spectral power data and the damped oscillator model indicate that cardiac sympathetic outflow markedly reduces heart period oscillations at all frequencies. This challenges the notion that respiratory sinus arrhythmia is mediated simply by vagal-cardiac nerve activity. These results have important implications for clinical and experimental estimation of human vagal cardiac tone.

Adrenergic beta-Antagonists↗

PubMed1992

Muscarinic receptor subtypes in feline tracheal submucosal gland secretion.

To determine what muscarinic receptor subtype regulates [Ca2+]i mediating airway submucosal gland secretion, we examined the effects of atropine (Atr), pirenzepine (PZ), 11([2-(diethylamino)methyl-1-piperidinyl] acetyl)-5,11-dihydro-6H-pyrido (2,3-b)(1,4)-benzo-diazepin-6-one (AF-DX116) and 4-diphenylacetoxy-N-methyl-piperidine methiodide (4-DAMP) on methacholine (MCh)-evoked [Ca2+]i rise in acinar cells, and compared this with mucus glycoprotein (MGP) and electrolyte secretion evoked by MCh from submucosal glands isolated from feline trachea. [Ca2+]i was measured with the Ca(2+)-sensitive fluorescent dye, fura 2. We determined MGP secretion by measuring TCA-precipitable 3H-labeled glycoconjugates and electrolyte secretion by the change in the rate constant of 22Na-efflux from isolated glands. Half-maximal inhibitory concentrations (IC50) of PZ, AF-DX116, 4-DAMP, and Atr against MCh-evoked [Ca2+]i rise were 10(-7) M, 6 x 10(-6) M, 8 x 10(-9) M, and 6 x 10(-9) M, respectively. IC50 of PZ, AF-DX116, 4-DAMP, and Atr against MCh-evoked MGP secretion were 10(-6) M, 2 x 10(-5) M, 8 x 10(-9) M, and 6 x 10(-9) M, respectively. MCh (10(-5) M)-evoked 22Na efflux was significantly inhibited by 10(-7) M 4-DAMP and 10(-7) M Atr (P less than 0.01, each) but not by 10(-7) M PZ. Receptor binding assays with [3H]quinuclidinyl benzilate showed that the Ki values for PZ, AF-D x 116, 4-DAMP and Atr were 2.2 x 10(-8) M, 6.6 x 10(-7) M, 6.2 x 10(-10) M, and 2.9 x 10(-10) M, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1989

Immunocytochemical localization of intracellular acidic compartments: rat proximal nephron.

There is evidence that components of the endosomal-lysosomal system of most cells have an acidic interior. The weak base, N-(3-[(2,4-dinitrophenyl)amino]propyl)-N-(3-aminopropyl)methylamine dihydrochloride (DAMP) has been shown to accumulate in acidic compartments in cultured cells and in isolated perfused proximal tubules. We infused DAMP intravascularly in vivo and used colloidal gold immunocytochemistry to identify acidic compartments in cells of the rat glomerulus and proximal tubule. Sprague-Dawley rats were infused intra-arterially with DAMP. The kidneys were fixed by intravascular perfusion with 1% glutaraldehyde and embedded in Lowicryl K4M. Sections were exposed to a mouse anti-dinitrophenol (DNP) monoclonal antibody that cross-reacts with DAMP, followed by gold-conjugated goat anti-mouse immunoglobulin G. Transmission electron microscopy revealed positive labeling of the lysosome-like structures of the various cells of the glomerulus and lysosomes, endosomes, and numerous endocytic vesicles of all segments of the proximal tubule. We conclude that 1) DAMP can be used in vivo to identify acidic compartments in the kidney and 2) lysosomes, endosomes, and many endocytic vesicles of the rat proximal tubule as well as lysosome-like structures in cells of the glomerulus have an acidic interior.

Acids↗

PubMed1988

Temporal coding of resonances by low-frequency auditory nerve fibers: single-fiber responses and a population model.

1. We recorded responses of low-frequency auditory nerve fibers (characteristic frequency (CF) less than 3 kHz) in the cat to resonant stimuli with varied natural frequencies, damping coefficients, and sound pressure levels. Responses to resonances were synchronized to frequencies lying between the peak frequency of the stimulus spectrum and a frequency near the fiber's CF. The frequency of the dominant synchrony in the response varied systematically as a function of the stimulus parameters. 2. More lightly damped resonances, which have sharp spectral peaks, elicited synchrony closer to the peak frequency, whereas the broader peaks of more highly damped resonances elicited synchrony closer to the fiber's CF. Thus as the stimulus was varied from an undamped tone to a highly damped transient, the dominant component of the synchronized response moved from the peak frequency of the stimulus toward the CF of the fiber. The trajectory of the dominant component varied as a function of stimulus level, with higher levels resulting in synchrony biased toward the peak of the stimulus spectrum over a wider range of damping. 3. The frequency tuning and synchronization characteristics of a fiber, along with the stimulus parameters, determined the temporal properties of its response to complex stimuli. Using reverse correlation (revcor) filters to characterize the tuning and synchronization of auditory nerve fibers, we were able to predict the temporal properties of responses to resonant stimuli. 4. A parametric model was fit to measured revcor functions derived from responses of auditory nerve fibers to wideband noise. In this way, a bank of model revcor filters was developed based on our population of measured filters. 5. The filter bank was used to model the response of a population of auditory nerve fibers to resonances. Temporal patterns present in the response of a population of fibers encoded the parameters of resonant stimuli. 6. The model revcor filter bank provided a means of studying temporal response patterns of the population of fibers to other complex sounds. 7. The output of the population model is a representation of the temporal information provided by the auditory periphery to the central nervous system; thus it provides a potentially useful tool for testing hypotheses concerning the processing of temporal information by the central auditory system.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2002

Sensorimotor integration in human postural control.

It is generally accepted that human bipedal upright stance is achieved by feedback mechanisms that generate an appropriate corrective torque based on body-sway motion detected primarily by visual, vestibular, and proprioceptive sensory systems. Because orientation information from the various senses is not always available (eyes closed) or accurate (compliant support surface), the postural control system must somehow adjust to maintain stance in a wide variety of environmental conditions. This is the sensorimotor integration problem that we investigated by evoking anterior-posterior (AP) body sway using pseudorandom rotation of the visual surround and/or support surface (amplitudes 0.5-8 degrees ) in both normal subjects and subjects with severe bilateral vestibular loss (VL). AP rotation of body center-of-mass (COM) was measured in response to six conditions offering different combinations of available sensory information. Stimulus-response data were analyzed using spectral analysis to compute transfer functions and coherence functions over a frequency range from 0.017 to 2.23 Hz. Stimulus-response data were quite linear for any given condition and amplitude. However, overall behavior in normal subjects was nonlinear because gain decreased and phase functions sometimes changed with increasing stimulus amplitude. "Sensory channel reweighting" could account for this nonlinear behavior with subjects showing increasing reliance on vestibular cues as stimulus amplitudes increased. VL subjects could not perform this reweighting, and their stimulus-response behavior remained quite linear. Transfer function curve fits based on a simple feedback control model provided estimates of postural stiffness, damping, and feedback time delay. There were only small changes in these parameters with increasing visual stimulus amplitude. However, stiffness increased as much as 60% with increasing support surface amplitude. To maintain postural stability and avoid resonant behavior, an increase in stiffness should be accompanied by a corresponding increase in damping. Increased damping was achieved primarily by decreasing the apparent time delay of feedback control rather than by changing the damping coefficient (i.e., corrective torque related to body-sway velocity). In normal subjects, stiffness and damping were highly correlated with body mass and moment of inertia, with stiffness always about 1/3 larger than necessary to resist the destabilizing torque due to gravity. The stiffness parameter in some VL subjects was larger compared with normal subjects, suggesting that they may use increased stiffness to help compensate for their loss. Overall results show that the simple act of standing quietly depends on a remarkably complex sensorimotor control system.

Adaptation, Physiological↗

PubMed1992

A minority of muscarinic receptors mediate rabbit tracheal smooth muscle contraction.

To enhance our understanding of cholinergic mechanisms and muscarinic receptors in bronchoconstriction, we have characterized the muscarinic receptor subtypes in rabbit tracheal smooth muscle using radioligand binding and functional assays. The Kd for [3H]quinuclidinyl benzilate ([3H](-)QNB) binding determined from saturation isotherms was 12.6 x/divided by 1.1 pM (geometric mean x/divided by SEM), and the Bmax was 269 +/- 7 fmol/mg protein (arithmetic mean +/- SEM). Competitive inhibition studies with the muscarinic antagonists pirenzepine (PZ), 11[[2-[(diethylamino)-methyl]1-piperidinyl]acetyl]-5,11-dihydro-6H- pyrido[2,3-b][1,4]benzodiazepine-6-one (AF-DX116), 4-diphenylacetoxy-N-methylpiperidine methobromide (4-DAMP), and hexahydrosiladifenidol (HHSiD) demonstrated heterogeneity of muscarinic receptor subtypes in rabbit tracheal smooth muscle. PZ bound with low affinity to a single receptor site, indicative of an absence of M1 receptors. AF-DX116 (M2 selective) bound with high affinity to approximately 83% of muscarinic binding sites, and 4-DAMP and HHSiD (M3 antagonists) bound with high affinity to approximately 24 and 28% of muscarinic binding sites, respectively. Additionally, direct binding studies with [3H]4-DAMP demonstrated high-affinity binding with 23% of muscarinic binding sites. Thus, the majority of muscarinic receptors in rabbit tracheal smooth muscle bound with high affinity to an M2-selective antagonist, and the remaining receptor sites bound with high affinity to M3 antagonists. The inhibitory effects of atropine, PZ, AF-DX116, and 4-DAMP on methacholine-induced contraction of rabbit tracheal rings were compared. 4-DAMP was a potent inhibitor of methacholine-induced contraction, but PZ and AF-DX116 demonstrated low potency.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2024

Inflammatory and tissue injury marker dynamics in pediatric acute respiratory distress syndrome.

BACKGROUNDThe molecular signature of pediatric acute respiratory distress syndrome (ARDS) is poorly described, and the degree to which hyperinflammation or specific tissue injury contributes to outcomes is unknown. Therefore, we profiled inflammation and tissue injury dynamics over the first 7 days of ARDS, and associated specific biomarkers with mortality, persistent ARDS, and persistent multiple organ dysfunction syndrome (MODS).METHODSIn a single-center prospective cohort of intubated pediatric patients with ARDS, we collected plasma on days 0, 3, and 7. Nineteen biomarkers reflecting inflammation, tissue injury, and damage-associated molecular patterns (DAMPs) were measured. We assessed the relationship between biomarkers and trajectories with mortality, persistent ARDS, or persistent MODS using multivariable mixed effect models.RESULTSIn 279 patients (64 [23%] nonsurvivors), hyperinflammatory cytokines, tissue injury markers, and DAMPs were higher in nonsurvivors. Survivors and nonsurvivors showed different biomarker trajectories. IL-1α, soluble tumor necrosis factor receptor 1, angiopoietin 2 (ANG2), and surfactant protein D increased in nonsurvivors, while DAMPs remained persistently elevated. ANG2 and procollagen type III N-terminal peptide were associated with persistent ARDS, whereas multiple cytokines, tissue injury markers, and DAMPs were associated with persistent MODS. Corticosteroid use did not impact the association of biomarker levels or trajectory with mortality.CONCLUSIONSPediatric ARDS survivors and nonsurvivors had distinct biomarker trajectories, with cytokines, endothelial and alveolar epithelial injury, and DAMPs elevated in nonsurvivors. Mortality markers overlapped with markers associated with persistent MODS, rather than persistent ARDS.FUNDINGNIH (K23HL-136688, R01-HL148054).

Humans↗