bluuebunny/crossref_metadata_2025 huggingface dataset:
A three-dimensional model of the human pulmonary acinus
Authors: Kitaoka Hiroko , Tamura Shinichi , Takaki Ryuji
Published: December 2017

A three-dimensional (3-D) model of the human pulmonary acinus, a gas exchange unit, is constructed with a labyrinthine algorithm generating branching ducts that fill a given space completely. Branching down to the third respiratory bronchioles is generated with the proposed algorithm. A subacinus, a region supplied by the last respiratory bronchiole, is approximated to be a set of cubic cells with a side dimension of 0.5 mm. The labyrinthine algorithm is used to determine a pathway through all cells only once, except at branching points with the smallest path lengths. In choosing each step of a pathway, random variables are used. Resulting labyrinths have equal mean path lengths and equal surface areas of inner walls. An alveolus can be generated by attaching alveolar septa, 0.25 mm long and 0.1 mm wide, to the inner walls. Total alveolar surface area and numbers of alveolar ducts, alveolar sacs, and alveoli in our 3-D acinar model are in good accordance with those reported in the literature.
Muscimol dialysis in the retrotrapezoid nucleus region inhibits breathing in the awake rat
Authors: Nattie Eugene , Li Aihua
Published: December 2017

Under anesthesia, inactivation of the retrotrapezoid nucleus (RTN) region markedly inhibits breathing and chemoreception. In conscious rats, we dialyzed muscimol for 30 min to inhibit neurons of the RTN region reversibly. Dialysis of artificial cerebrospinal fluid had no effect. Muscimol (1 or 10 mM) significantly decreased tidal volume (Vt) (by 16–17%) within 15 min. Vt remained decreased for 50 min or more, with recovery by 90 min. Ventilation (V˙e) decreased significantly (by 15–20%) within 15 min and then returned to baseline within 40 min as a result of an increase in frequency. This, we suggest, is a compensatory physiological response to the reduced Vt. Oxygen consumption was unchanged. In response to 7% CO2 in the 1 mM group, absolute V˙e and change in V˙e were significantly reduced (by 19–22%). In the 10 mM group, the response to dialysis included a time-related increase in frequency and decrease in body temperature, which may reflect greater spread of muscimol. In the awake rat, the RTN region provides a portion of the tonic drive to breathe, as well as a portion of the response to hypercapnia.
Effect of the mechanical ventilatory cycle on thermodilution right ventricular volumes and cardiac output
Authors: Groeneveld A. B. Johan , Berendsen Remco R. , Schneider Anton J. , Pneumatikos Ioannis A. , Stokkel Leo A. , Thijs Lambertus G.
Published: December 2017

The purpose of this study was to evaluate right ventricular (RV) loading and cardiac output changes, by using the thermodilution technique, during the mechanical ventilatory cycle. Fifteen critically ill patients on mechanical ventilation, with 5 cmH2O of positive end-expiratory pressure, mean respiratory frequency of 18 breaths/min, and mean tidal volume of 708 ml, were studied with help of a rapid-response thermistor RV ejection fraction pulmonary artery catheter, allowing 5-ml room-temperature 5% isotonic dextrose thermodilution measurements of cardiac index (CI), stroke volume (SV) index, RV ejection fraction (RVEF), RV end-diastolic volume (RVEDV), and RV end-systolic volume (RVESV) indexes at 10% intervals of the mechanical ventilatory cycle. The ventilatory modulation of CI and RV volumes varied from patient to patient, and the interindividual variability was greater for the latter variables. Within patients also, RV volumes were modulated more by the ventilatory cycle than CI and SV index. Around a mean value of 3.95 ± 1.18 l · min−1 · m−2 (= 100%), CI varied from 87.3 ± 5.2 (minimum) to 114.3 ± 5.1% (maximum), and RVESV index varied between 61.5 ± 17.8 and 149.3 ± 34.1% of mean 55.1 ± 17.9 ml/m2 during the ventilatory cycle. The variations in the cycle exceeded the measurement error even though the latter was greater for RVEF and volumes than for CI and SV index. For mean values, there was an inspiratory decrease in RVEF and increase in RVESV, whereas a rise in RVEDV largely prevented a fall in SV index. We conclude that cyclic RV afterloading necessitates multiple thermodilution measurements equally spaced in the ventilatory cycle for reliable assessment of RV performance during mechanical ventilation of patients.
Differential cardiorespiratory control elicited by activation of ventral medullary sites in mice
Authors: Tolentino-Silva F. P. , Haxhiu M. A. , Ernsberger P. , Waldbaum S. , Dreshaj I. A.
Published: December 2017

We studied the respiratory and blood pressure responses to chemical stimulation of two regions of the ventral brainstem in mice: the rostral and caudal ventrolateral medulla (RVLM and CVLM, respectively). Stimulation of the RVLM by microinjections of the excitatory amino acid l-glutamate induced increases in diaphragm activity and breathing frequency, elevation of blood pressure (BP), and a slight increase in heart rate (HR). However, activation of the CVLM induced a decrease in breathing frequency, mainly due to prolongation of expiratory time (Te), and hypotension associated with a slight slowing of HR. Because adrenergic mechanisms are known to participate in the control of respiratory timing, we examined the role of α2-adrenergic receptors in the RVLM region in mediating these inhibitory effects. The findings demonstrated that blockade of the α2-adrenergic receptors within the RVLM by prior microinjection of SKF-86466 (an α2-adrenergic receptor blocker) significantly reduced changes in Te induced by CVLM stimulation but had little effect on BP responses. These results indicate that, in mice, activation of the RVLM increases respiratory drive associated with an elevation of BP, but stimulation of CVLM induces prolongation of Te via an α2-adrenergic signal transduction pathway.
Transcriptional and translational regulation of heat shock proteins in leukocytes of endurance runners
Authors: Fehrenbach Elvira , Niess Andreas Michael , Schlotz Elke , Passek Frank , Dickhuth Hans-Herrmann , Northoff Hinnak
Published: December 2017

Heat shock proteins (HSP) represent cell-protective and antioxidant systems that may be induced by reactive oxygen species, cytokines, and hyperthermia. In the present study, we evaluated the influence of heavy endurance exercise and training on HSP27 and HSP70 in peripheral leukocytes of 12 athletes (before and at 0, 3, and 24 h after a half-marathon) and 12 untrained controls on protein and mRNA levels by flow cytometry and RT/PCR, respectively. HSP transcripts increased significantly immediately after acute exertion accompanied by elevated levels of corresponding proteins. HSP protein expression remained high until 24 h postexercise. Significant increases of plasma interleukin-8, myeloperoxidase, and creatine kinase occurred after exercise. Basal HSP expression was usually lower in trained compared with untrained subjects. Applying in vitro heat shock to resting blood samples of all subjects significantly stimulated HSP mRNA, showing higher increases in trained individuals. The exercise-induced alterations indicate that immunocompetent cells became activated. In addition to heat stress, other exercise-associated stress agents (oxidants, cytokines) may have also participated in stimulation of HSP expression in leukocytes. The expression pattern of HSP due to training status may be attributed to adaptive mechanisms.
Gender- and height-related limits of muscle strength in world weightlifting champions
Authors: Ford Lincoln E. , Detterline Alvin J. , Ho Kevin K. , Cao Wenyuan
Published: December 2017

To assess factors that limit human muscle strength and growth, we examined the relationship between performance and body dimensions in the world weightlifting champions of 1993–1997. Weight lifted varied almost exactly with height squared (Ht2.16), suggesting that muscle mass scaled almost exactly with height cubed (Ht3.16) and that muscle cross-sectional area was closely correlated with body height, possibly because height and the numbers of muscle fibers in cross section are determined by a common factor during maturation. Further height limitations of muscle strength were shown by only one male champion ≥183 cm and no female champions ≥175 cm. The ratio of weight lifted to mean body cross-sectional area was approximately constant for body-weight classes ≤83 kg for men and ≤64 kg for women and decreased abruptly for higher weight classes. These findings suggest a nearly constant fraction of body mass devoted to muscle in lighter lifters and a lesser fraction in heavier lifters. Analysis also suggests that contractile tissue comprises ∼30% less body mass in female champions.
Glucose kinetics and substrate oxidation during exercise in the follicular and luteal phases
Authors: Zderic Ted W. , Coggan Andrew R. , Ruby Brent C.
Published: December 2017

The purpose of this investigation was to determine whether plasma glucose kinetics and substrate oxidation during exercise are dependent on the phase of the menstrual cycle. Once during the follicular (F) and luteal (L) phases, moderately trained subjects [peak O2 uptake (V˙o 2) = 48.2 ± 1.1 ml · min−1 · kg−1; n = 6] cycled for 25 min at ∼70% of theV˙o 2 at their respective lactate threshold (70%LT), followed immediately by 25 min at 90%LT. Rates of plasma glucose appearance (Ra) and disappearance (Rd) were determined with a primed constant infusion of [6,6-2H]glucose, and total carbohydrate (CHO) and fat oxidation were determined with indirect calorimetry. At rest and during exercise at 70%LT, there were no differences in glucose Raor Rd between phases. CHO and fat oxidation were not different between phases at 70%LT. At 90%LT, glucose Ra(28.8 ± 4.8 vs. 33.7 ± 4.5 μmol · min−1 · kg−1; P < 0.05) and Rd (28.4 ± 4.8 vs. 34.0 ± 4.1 μmol · min−1 · kg−1; P < 0.05) were lower during the L phase. In addition, at 90%LT, CHO oxidation was lower during the L compared with the F phase (82.0 ± 12.3 vs. 93.8 ± 9.7 μmol · min−1 · kg−1; P < 0.05). Conversely, total fat oxidation was greater during the L phase at 90%LT (7.46 ± 1.01 vs. 6.05 ± 0.89 μmol · min−1 · kg−1; P < 0.05). Plasma lactate concentration was also lower during the L phase at 90%LT concentrations (2.48 ± 0.41 vs. 3.08 ± 0.39 mmol/l; P < 0.05). The lower CHO utilization during the L phase was associated with an elevated resting estradiol ( P < 0.05). These results indicate that plasma glucose kinetics and CHO oxidation during moderate-intensity exercise are lower during the L compared with the F phase in women. These differences may have been due to differences in circulating estradiol.
Decreased CSF pH at ventral brain stem induces widespread c-Fos immunoreactivity in rat brain neurons
Authors: Douglas R. M. , Trouth C. O. , James S. D. , Sexcius L. M. , Kc P. , Dehkordi O. , Valladares E. R. , McKenzie J. C.
Published: December 2017

Physiological evidence has indicated that central respiratory chemosensitivity may be ascribed to neurons located at the ventral medullary surface (VMS); however, in recent years, multiple sites have been proposed. Because c-Fos immunoreactivity is presumed to identify primary cells as well as second- and third-order cells that are activated by a particular stimulus, we hypothesized that activation of VMS cells using a known adequate respiratory stimulus, H+, would induce production of c-Fos in cells that participate in the central pH-sensitive respiratory chemoreflex loop. In this study, stimulation of rostral and caudal VMS respiratory chemosensitive sites in chloralose-urethane-anesthetized rats with acidic (pH 7.2) mock cerebrospinal fluid induced c-Fos protein immunoreactivity in widespread brain sites, such as VMS, ventral pontine surface, retrotrapezoid, medial and lateral parabrachial, lateral reticular nuclei, cranial nerves VII and X nuclei, A1 and C1 areas, area postrema, locus coeruleus, and paragigantocellular nuclei. At the hypothalamus, the c-Fos reaction product was seen in the dorsomedial, lateral hypothalamic, supraoptic, and periventricular nuclei. These results suggest that 1) multiple c-Fos-positive brain stem and hypothalamic structures may represent part of a neuronal network responsive to cerebrospinal fluid pH changes at the VMS, and 2) VMS pH-sensitive neurons project to widespread regions in the brain stem and hypothalamus that include respiratory and cardiovascular control sites.
Physiological and mechanical adaptation of periarticular cancellous bone after joint ligament injury
Authors: Shymkiw Roxane C. , Bray Robert C. , Boyd Steven K. , Kantzas Apostolos , Zernicke Ronald F.
Published: December 2017

The relation between blood flow and bone mineral density (BMD) of periarticular bone was examined in an in vivo model of joint instability. Eighty mature New Zealand White rabbits were randomly assigned to experimental [anterior cruciate ligament transection (ACLX)], sham-operated control, or age-matched normal control groups. Experimental rabbits underwent unilateral transection of the right anterior cruciate ligament, and the nonoperated left [contralateral (Cntra)] limb was a within-animal control. BMD and blood flow to the periarticular bone in the femoral condyles were assessed in each group at 2, 4, 6, 14, and 48 wk postsurgery, using quantitative computed tomography scanning and entrapment of colored microspheres. BMD was significantly lower (5%) in the ACLX compared with Cntra limbs. Periarticular bone blood flow in the ACLX limbs was significantly greater than in the Cntra limb (29%) in the early stages (6 wk) after injury. Up to 48 wk post-ACLX, a significant correlation was found between increased blood flow and decreased BMD in the periarticular bone of the femoral condyles in the ACLX limbs. This correlation suggested that heightened blood flow may be linked to mechanisms of bone adaptation in joints after ligament injury.
Short-term exercise training increases ACh-induced relaxation and eNOS protein in porcine pulmonary arteries
Authors: Johnson Lynelle R. , Rush James W. E. , Turk James R. , Price Elmer M. , Laughlin M. Harold
Published: December 2017

We tested the hypothesis that short-term exercise (STEx) training and the associated increase in pulmonary blood flow during bouts of exercise cause enhanced endothelium-dependent vasorelaxation in porcine pulmonary arteries and increased expression of endothelial cell nitric oxide synthase (eNOS) and superoxide dismutase-1 (SOD-1) protein. Mature, female Yucatan miniature swine exercised 1 h twice daily on a motorized treadmill for 1 wk (STEx group, n = 7); control pigs (Sed, n = 6) were kept in pens. Pulmonary arteries were isolated from the left caudal lung lobe, and vasomotor responses were determined in vitro. Arterial tissue from the distal portion of this pulmonary artery was processed for immunoblot analysis. Maximal endothelium-dependent (ACh-stimulated) relaxation was greater in STEx (71 ± 5%) than in Sed (44 ± 6%) arteries ( P < 0.05), and endothelium-independent (sodium nitroprusside-mediated) responses did not differ. Sensitivity to ACh was not altered by STEx training. Immunoblot analysis indicated a 3.9-fold increase in eNOS protein in pulmonary artery tissue from STEx pigs ( P < 0.05) with no change in SOD-1 or glyceraldehyde-3-phosphate dehydrogenase protein levels. We conclude that STEx training enhances ACh-stimulated vasorelaxation in pulmonary arterial tissue and that this adaptation is associated with increased expression of eNOS protein.
Redox modulation of maximum force production of fast-and slow-twitch skeletal muscles of rats and mice
Authors: Plant David R. , Gregorevic Paul , Williams David A. , Lynch Gordon S.
Published: December 2017

We used intact fast-twitch extensor digitorum longus (EDL) and slow-twitch soleus muscles from rats and mice to test the hypothesis that exogenous application of an oxidant would increase maximum isometric force production (Po) of slow-twitch muscles to a greater extent than fast-twitch skeletal muscles. Exposure to an oxidant, hydrogen peroxide (H2O2; 100 μM to 5 mM, 30 min), affected Po of rat muscles in a time- and dose-dependent manner. Po of rat soleus muscles was increased by 8 ± 1 (SE) and 14 ± 1% ( P < 0.01) after incubation with 1 and 5 mM H2O2, respectively, whereas in mouse soleus muscles Po was only increased after incubation with 500 μM H2O2. Po of rat EDL muscles was affected by H2O2 biphasically; initially there was a small increase (3 ± 1%), but then Po diminished significantly after 30 min of treatment. In contrast, all concentrations of H2O2 tested decreased Po of mouse EDL muscles. A reductant, dithiothreitol (DTT; rat = 10 mM, mouse = 1 mM), was added to quench H2O2, and it reversed the potentiation in Po in rat soleus but not in rat EDL muscles or in any H2O2-treated mouse muscles. After prolonged equilibration (30 min) with 5 mM H2O2 without prior activation, Po was potentiated in rat soleus but not EDL muscles, demonstrating that the effect of oxidation in the soleus muscles was also dependent on the activation history of the muscle. The results of these experiments demonstrate that Po of both slow- and fast-twitch muscles from rats and mice is modified by redox modulation, indicating that maximum Po of mammalian skeletal muscles is dependent on oxidation.
Lung tissue mechanics and extracellular matrix composition in a murine model of silicosis
Authors: Faffe Débora S. , Silva Gabriela H. , Kurtz Pedro M. P. , Negri Elnara M. , Capelozzi Vera L. , Rocco Patricia R. M. , Zin Walter A.
Published: December 2017

The dynamic mechanical properties of lung tissue and its contents of collagen and elastic fibers were studied in strips prepared from mice instilled intratracheally with saline (C) or silica [15 (S15) and 30 days (S30) after instillation]. Resistance, elastance, and hysteresivity were studied during oscillations at different frequencies on S15 and S30. Elastance increased from C to silica groups but was similar between S15 and S30. Resistance was augmented from C to S15 and S30 and was greater in S30 than in S15 at higher frequencies. Hysteresivity was higher in S30 than in C and S15. Silica groups presented a greater amount of collagen than did C. Elastic fiber content increased progressively along time. This increment was related to the higher amount of oxytalan fibers at 15 and 30 days, whereas elaunin and fully developed elastic fibers were augmented only at 30 days. Silicosis led not only to pulmonary fibrosis but also to fibroelastosis, thus assigning a major role to the elastic system in the silicotic lung.
Oxygen measurements in brain stem slices exposed to normobaric hyperoxia and hyperbaric oxygen
Authors: Mulkey Daniel K. , Henderson Richard A. , Olson James E. , Putnam Robert W. , Dean Jay B.
Published: December 2017

We previously reported ( J Appl Physiol 89: 807–822, 2000) that ≤10 min of hyperbaric oxygen (HBO2; ≤2,468 Torr) stimulates solitary complex neurons. To better define the hyperoxic stimulus, we measured Po 2 in the solitary complex of 300-μm-thick rat medullary slices, using polarographic carbon fiber microelectrodes, during perfusion with media having Po 2 values ranging from 156 to 2,468 Torr. Under control conditions, slices equilibrated with 95% O2at barometric pressure of 1 atmospheres absolute had minimum Po 2 values at their centers (291 ± 20 Torr) that were ∼10-fold greater than Po 2values measured in the intact central nervous system (10–34 Torr). During HBO2, Po 2 increased at the center of the slice from 616 ± 16 to 1,517 ± 15 Torr. Tissue oxygen consumption tended to decrease at medium Po 2 ≥ 1,675 Torr to levels not different from values measured at Po 2 found in all media in metabolically poisoned slices (2-deoxy-d-glucose and antimycin A). We conclude that control medium used in most brain slice studies is hyperoxic at normobaric pressure. During HBO2, slice Po 2 increases to levels that appear to reduce metabolism.
Etiology and modification of gait instability in older adults: a randomized controlled trial of exercise
Authors: Hausdorff Jeffrey M. , Nelson Miriam E. , Kaliton David , Layne Jennifer E. , Bernstein Melissa J. , Nuernberger Andrea , Singh Maria A. Fiatarone
Published: December 2017

Increased gait instability is common in older adults, even in the absence of overt disease. The goal of the present study was to quantitatively investigate the factors that contribute to gait instability and its potential reversibility in functionally impaired older adults. We studied 67 older men and women with functional impairment before and after they participated in a randomized placebo-controlled, 6-mo multimodal exercise trial. We found that 1) gait instability is multifactorial; 2) stride time variability is strongly associated with functional status and performance-based measures of function that have previously been shown to predict significant clinical outcomes such as morbidity and nursing home admission; 3) neuropsychological status and health-related quality of life play important, independent roles in gait instability; and 4) improvement in physiological capacity is associated with reduced gait instability. Although the etiology of gait instability in older persons with mild-moderate functional impairment is multifactorial, interventions designed to reduce gait instability may be effective in bringing about a more consistent and more stable walking pattern.
Continuous measurement of breathlessness during exercise: validity, reliability, and responsiveness
Authors: Mahler Donald A. , Mejia-Alfaro Roberto , Ward Joseph , Baird John C.
Published: December 2017

A continuous method for recording changes in breathlessness (dyspnea) during exercise is introduced and compared with the traditional discrete method. In study 1, a category-rating scale was presented on a computer screen, and 14 healthy, young female subjects exercised on a cycle ergometer until exhaustion. Two approaches were used to obtain ratings of breathlessness: a discrete method, in which subjects gave single judgments every minute, and a continuous method, in which subjects throughout exercise moved the mouse so that a bar on the screen extended to the desired location along the scale. Psychophysical results relating measures of breathlessness and the variables of work, oxygen consumption, and minute ventilation were statistically indistinguishable with the two methods, and both methods were highly reliable across test sessions. In study 2, both measurement methods were employed, and the subjects were 14 healthy, young males. In each of two sessions (discrete or continuous method), subjects first rated their breathlessness during an incremental test in which the workload was increased over time and levels of work, and minute ventilation were recorded. Subjects then exercised for 10 min at 60% of the maximal oxygen consumption achieved during the incremental test. At two points during steady-state exercise, a respiratory load was introduced that lasted for 1 min. It was possible to determine the responsiveness of subjects to onset and offset of the respiratory load for the continuous method but not for the discrete method. In study 3, patients with chronic obstuctive pulmonary disease employed both methods, and it was found that the continuous method was better at determining whether subjects showed a significant positive slope of the regression line between breathlessness ratings and physiological variables.
Midodrine prevents orthostatic intolerance associated with simulated spaceflight
Authors: Ramsdell Craig D. , Mullen Thomas J. , Sundby Grete H. , Rostoft Siri , Sheynberg Natalie , Aljuri Nikolai , Maa Ming , Mukkamala Ramakrishna , Sherman Derin , Toska Karin , Yelle Janice , Bloomfield Daniel , Williams Gordon H. , Cohen Richard J.
Published: December 2017

Many astronauts after being weightless in space become hypotensive and presyncopal when they assume an upright position. This phenomenon, known as orthostatic intolerance, may interfere with astronaut function during reentry and after spaceflight and may limit the ability of an astronaut to exit a landed spacecraft unaided during an emergency. Orthostatic intolerance is more pronounced after long-term spaceflight and is a major concern with respect to the extended flights expected aboard the International Space Station and for interplanetary exploration class missions, such as a human mission to Mars. Fully effective countermeasures to this problem have not yet been developed. To test the hypothesis that α-adrenergic stimulation might provide an effective countermeasure, we conducted a 16-day head-down-tilt bed-rest study (an analog of weightlessness) using normal human volunteers and administered the α1-agonist drug midodrine at the end of the bed-rest period. Midodrine was found to significantly ameliorate excessive decreases in blood pressure and presyncope during a provocative tilt test. We conclude that midodrine may be an effective countermeasure for the prevention of orthostatic intolerance following spaceflight.
Relationship between myosin phosphorylation and contractile capability of canine airway smooth muscle
Authors: Mitchell Richard W. , Seow Chun Y. , Burdyga Theodor , Maass-Moreno Roberto , Pratusevich Victor R. , Ragozzino Joseph , Ford Lincoln E.
Published: December 2017

To better understand excitation-contraction coupling in smooth muscle, myosin phosphorylation and force-velocity properties of canine tracheal muscle were compared during the rise and early plateau of force in electrically stimulated tetani. Velocity reached a peak of ∼1.5 times plateau value when force had risen to ∼45% of its maximum value and then declined progressively. Except early in the tetanus, when phosphorylation rose rapidly, maximum power and phosphorylation had nearly parallel time courses, reaching peaks of 1.2–1.3 times reference at 6–8 s before declining to the plateau level at ∼12 s. Force, velocity, maximum power, and phosphorylation fell somewhat during the plateau, with the closest correlation between phosphorylation and power. These results suggest that 1) early velocity slowing is not associated with light chain dephosphorylation and 2) maximum power, which we use to signal changes in activation, is closely correlated with the degree of light chain phosphorylation, at least when phosphorylation level is not changing rapidly. Dissociation of these two properties would be expected early in the tetanus if phosphorylation precedes mechanical activity.
Selected Contribution: Osteocytes upregulate HIF-1α in response to acute disuse and oxygen deprivation
Authors: Gross Ted S. , Akeno Nagako , Clemens Thomas L. , Komarova Svetlana , Srinivasan Sundar , Weimer David A. , Mayorov Sergey
Published: December 2017

Loss of mechanical loading, or disuse, rapidly precipitates locally mediated bone resorption. However, the pathway by which this process is initiated and mediated is poorly understood. In this study, we used a complementary in vivo and in vitro approach to determine whether disuse-induced osteocyte hypoxia resulted in upregulation of the hypoxia-dependent transcription factor HIF-1α. We found that acute disuse (1–5 days) resulted in a significant increase in the percentage of osteocytes staining positive for HIF-1α vs. normal bone (30.9 ± 6.1 vs. 14.1 ± 3.8%) and that this response was uniform around the cortex. In addition, we found that acute oxygen deprivation (4–12 h of 2% O2) resulted in a 2.1- to 3.7-fold upregulation of HIF-1α protein expression in MLO-Y4 osteocyte-like cells compared with cells cultured in parallel under normal oxygen conditions. Given known HIF-1α targets genes, we suggest that osteocyte hypoxia and subsequent upregulation of hypoxia-dependent pathways may serve to initiate and mediate disuse-induced bone resorption.
Gender alters impact of hypobaric hypoxia on adductor pollicis muscle performance
Authors: Fulco Charles S. , Rock Paul B. , Muza Stephen R. , Lammi Eric , Braun Barry , Cymerman Allen , Moore Lorna G. , Lewis Steven F.
Published: December 2017

Recently, we reported that, at similar voluntary force development during static submaximal intermittent contractions of the adductor pollicis muscle, fatigue developed more slowly in women than in men under conditions of normobaric normoxia (NN) ( Acta Physiol Scand 167: 233–239, 1999). We postulated that the slower fatigue of women was due, in part, to a greater capacity for muscle oxidative phosphorylation. The present study examined whether a gender difference in adductor pollicis muscle performance also exists during acute exposure to hypobaric hypoxia (HH; 4,300-m altitude). Healthy young men ( n = 12) and women ( n= 21) performed repeated static contractions at 50% of maximal voluntary contraction (MVC) force of rested muscle for 5 s followed by 5 s of rest until exhaustion. MVC force was measured before and at the end of each minute of exercise and at exhaustion. Exhaustion was defined as an MVC force decline to 50% of that of rested muscle. For each gender, MVC force of rested muscle in HH was not significantly different from that in NN. MVC force tended to decline at a faster rate in HH than in NN for men but not for women. In both environments, MVC force declined faster ( P < 0.01) for men than for women. For men, endurance time to exhaustion was shorter ( P < 0.01) in HH than in NN [6.08 ± 0.7 vs. 8.00 ± 0.7 (SE) min]. However, for women, endurance time to exhaustion was similar (not significant) in HH (12.86 ± 1.2 min) and NN (13.95 ± 1.0 min). In both environments, endurance time to exhaustion was longer for women than for men ( P < 0.01). Gender differences in the impact of HH on adductor pollicis muscle endurance persisted in a smaller number of men and women matched ( n = 4 pairs) for MVC force of rested muscle and thus on submaximal absolute force and, by inference, ATP demand in both environments. In contrast to gender differences in the impact of HH on small-muscle (adductor pollicis) exercise performance, peak O2uptake during large-muscle exercise was lower in HH than in NN by a similar ( P > 0.05) percentage for men and women (−27.6 ± 2 and −25.1 ± 2%, respectively). Our findings are consistent with the postulate of a higher adductor pollicis muscle oxidative capacity in women than in men and imply that isolated performance of muscle with a higher oxidative capacity may be less impaired when the muscle is exposed to HH.
Chamber properties from transmitral flow: prediction of average and passive left ventricular diastolic stiffness
Authors: Lisauskas Jennifer B. , Singh Jasvindar , Bowman Andrew W. , Kovács Sándor J.
Published: December 2017

A chamber stiffness ( KLV)-transmitral flow (E-wave) deceleration time relation has been invasively validated in dogs with the use of average stiffness [(ΔP/ΔV)avg]. KLVis equivalent to kE, the (E-wave) stiffness of the parameterized diastolic filling model. Prediction and validation of 1) (ΔP/ΔV)avgin terms of kE, 2) early rapid-filling stiffness [(ΔP/ΔV)E] in terms of kE, and 3) passive (postdiastasis) chamber stiffness [(ΔP/ΔV)PD] from A waves in terms of the stiffness parameter for the Doppler A wave ( kA) have not been achieved. Simultaneous micromanometric left ventricular (LV) pressure (LVP) and transmitral flow from 131 subjects were analyzed. (ΔP)avgand (ΔV)avgutilized the minimum LVP-LV end-diastolic pressure interval. (ΔP/ΔV)Eutilized ΔP and ΔV from minimum LVP to E-wave termination. (ΔP/ΔV)PDutilized atrial systolic ΔP and ΔV. E- and A-wave analysis generated kEand kA. For all subjects, noninvasive-invasive relations yielded the following equations: kE= 1,401 · (ΔP/ΔV)avg+ 59.2 ( r = 0.84) and kE= 229.0 · (ΔP/ΔV)E+ 112 ( r= 0.80). For subjects with diastasis ( n = 113), kA= 1,640 · (ΔP/ΔV)PD− 8.40 ( r = 0.89). As predicted, kAshowed excellent correlation with (ΔP/ΔV)PD; kEcorrelated highly with (ΔP/ΔV)avg. In vivo validation of average, early, and passive chamber stiffness facilitates quantitative, noninvasive diastolic function assessment from transmitral flow.
Exercise training increases the Ca2+sensitivity of tension in rat cardiac myocytes
Authors: Diffee Gary M. , Seversen Eric A. , Titus Marci M.
Published: December 2017

The heart is known to respond to a program of chronic exercise in ways that enhance cardiac function. However, the cellular mechanisms involved in training-induced improvements in the contractile function of the myocardium are not known. In this study we tested the hypothesis that increased contractility of the myocardium associated with exercise training is due, in part, to increases in the Ca2+ sensitivity of steady-state tension. Female Sprague-Dawley rats were randomly divided into sedentary control (C) and exercise-trained (T) groups. The T rats underwent 11 wk of progressive treadmill exercise (1 h/day, 5 days/wk, 26 m/min, 20% grade). Evidence of training effect included a 5.9% increase in heart mass, increases in heart weight-to-body weight ratio, and a 60% increase in skeletal muscle citrate synthase activity in T rats compared with C rats. After the training program, cardiac myocytes were isolated from T and C hearts. Myocytes were chemically skinned (i.e., the sarcolemma was removed) and attached to a force transducer, and steady-state tension was determined in solutions of various Ca2+ concentrations ([Ca2+]). Myocytes isolated from the hearts of T rats showed a significantly ( P < 0.01) increased sensitivity of tension to [Ca2+]. The [Ca2+] giving 50% of maximal tension (pCa50) was 5.90 ± 0.033 and 5.82 ± 0.023 (SD) in T and C myocytes, respectively ( n = 70 myocytes/group). This result suggests that exercise training affects the myofibrillar proteins, such that Ca2+ sensitivity is increased, and that this may be the mechanism that underlies, at least in part, the effect of training to increase myocardial contractility.
Mechanical properties of alveolar epithelial cells in culture
Authors: Berrios Jorge C. , Schroeder Mark A. , Hubmayr Rolf D.
Published: December 2017

With the use of magnetic twisting cytometry, we characterized the mechanical properties of rat type II alveolar epithelial (ATII) cells in primary culture and examined whether the cells' state of differentiation and the application of deforming stresses influence their resistance to shape change. Cells were harvested from rat lungs as previously described (Dobbs LG. Am J Physiol Lung Cell Mol Physiol 258: L134–L147, 1990) and plated at a density of 1 × 106cells/cm2in fibronectin-coated 96 Remova wells, and their mechanical properties were measured 2–9 days later. We show 1) that ATII cells form much stronger bonds with RGD-coated beads than they do with albumin- or acetylated low-density lipoprotein-coated beads, 2) that RGD-mediated bonds seemingly “mature” during the first 60 min of bead contact, 3) that the apparent stiffness of ATII cells increases with days in culture, 4) that stiffness falls when the RGD-coated beads are intermittently oscillated at 0.3 Hz, and 5) that this fall cannot be attributed to exocytosis-related remodeling of the subcortical cytoskeleton. Although the mechanisms of force transfer between basement membrane, cytoskeleton, and plasma membrane of ATII cells remain to be resolved, such analyses undoubtedly require definition of the cell's mechanical properties. To our knowledge, the results presented here provide the first data on this topic.
Adenosine A1receptors mediate plasma exudation from the oral mucosa
Authors: Rubinstein Israel , Chandilawa Rinku , Dagar Sumeet , Hong Dennis , Gao Xiao-Pei
Published: December 2017

The purpose of this study was to pharmacologically characterize the adenosine receptor subtype(s) that mediates adenosine-induced increases in macromolecular efflux from the intact hamster cheek pouch. Using intravital microscopy, we found that 1,3-dipropyl-8-(2-amino-4-chlorophenyl)-xanthine (PACPX), a selective adenosine receptor-1 antagonist, but not 3,7-dimethyl-1-propargylxanthine (DMPX), a selective adenosine receptor-2 antagonist, significantly attenuated adenosine-induced leaky site formation and increased clearance of fluorescein isothiocyanate-labeled dextran (molecular mass, 70 kDa) from the intact hamster cheek pouch ( P < 0.05). Both compounds had no significant effects on bradykinin-induced responses. Nanomolar concentrations of R(−)- N6-(2-phenylisopropyl)-adenosine [R(−)-PIA], a selective adenosine A1agonist, evoked significant, concentration-dependent increases in macromolecular efflux. This response was significantly attenuated by PACPX but not by DMPX. In contrast, CGS-21680, a selective adenosine A2agonist, increased macromolecular efflux but only at micromolar concentrations. This response was significantly attenuated by DMPX but not by PACPX. Suffusion of nitroglycerin had no significant effects on R(−)-PIA- and CGS-21680-induced responses. In addition, suffusion of NG-nitro-l-arginine methyl ester, a nitric oxide synthase inhibitor, had no significant effects on adenosine-induced responses. Indomethacin had no significant effects on adenosine-, R(−)-PIA-, and CGS-21680-induced increases in macromolecular efflux. Collectively, these data indicate that adenosine increases macromolecular efflux from the intact hamster cheek pouch by stimulating high-affinity adenosine A1receptors in a specific, nitric oxide- and prostaglandin-independent fashion.
Cardiovascular responses to three simple, provocative tests of autonomic activity in sleeping infants
Authors: Harrington C. , Kirjavainen T. , Teng A. , Sullivan C. E.
Published: December 2017

Whereas defective cardiovascular autonomic control has been implicated in the sudden infant death syndrome, relatively little is known about the normal development of autonomic control, due to the inability to measure blood pressure in infants noninvasively. We studied 12 normal infants [age: 13 ± 2 (SD) wk] using a noninvasive method of continuous blood pressure recording and examined the cardiovascular responses to 45° head-up tilting, a modified cold face test, and a loud noise. In head-up tilting, in both slow-wave sleep and rapid eye movement sleep, all infants displayed a rapid biphasic heart rate response (mean increase of 16% and mean decrease of 21%) and blood pressure response (mean increase of 16% and mean decrease of 16%), with a return to pretest values within 20 s. Both ice and noise caused a less pronounced biphasic response. In conclusion, at 3 mo, infants show the adult pattern of response to postural challenge. The short latency of the response suggests that neural inputs, apart from baroreceptors, are involved in the initial phase of the response.
Multiple rostral medullary nuclei can influence breathing in awake goats
Authors: Wenninger J. M. , Pan L. G. , Martino P. , Geiger L. , Hodges M. , Serra A. , Feroah T. R. , Forster H. V.
Published: December 2017

The purpose of this study was to determine the effect on breathing of neuronal dysfunction in the retrotrapezoid (RTN), facial (FN), gigantocellularis reticularis (RGN), or vestibular (VN) nuclei of adult awake goats. Microtubules were chronically implanted to induce neuronal dysfunction by microinjection of an excitatory amino acid (EAA) receptor antagonist or a neurotoxin. The EAA receptor antagonist had minimal effect on eupneic breathing, but 8–10 days after injection of the neurotoxin, 7 of 10 goats hypoventilated (arterial Pco 2 increased 3.2 ± 0.7 Torr). Overall there were no significant ( P > 0.10) effects of the EAA receptor antagonist on CO2 sensitivity. However, for all nuclei, ≥66% of the antagonist injections altered CO2sensitivity by more than the normal 12.7 ± 1.6% day-to-day variation. These changes were not uniform, inasmuch as the antagonist increased (RTN, n = 2; FN, n = 7; RGN, n = 6; VN, n = 1) or decreased (RTN, n = 2; RGN, n = 3; VN, n = 2) CO2 sensitivity. Ten days after injection of the neurotoxin into the FN ( n = 3) or RGN ( n = 5), CO2 sensitivity was also reduced. Neuronal dysfunction also did not have a uniform effect on the exercise arterial Pco 2 response, and there was no correlation between effects on CO2 sensitivity and the exercise hyperpnea. We conclude that there is a heterogeneous population of neurons in these rostral medullary nuclei (or adjacent tissue) that can affect breathing in the awake state, possibly through chemoreception or chemoreceptor-related mechanisms.
Sequential hyperglycemic-euglycemic clamp to assess β-cell and peripheral tissue: studies in female athletes
Authors: Ryan Alice S. , Muller Denis C. , Elahi Dariush
Published: December 2017

Insulin secretion and rate of utilization (Rd) of glucose were tested during a newly developed sequential clamp in 42 highly trained female athletes (A; 18–69 yr old) and 14 sedentary control women (C; 18–50 yr old; body mass index <25 kg/m2). The A women were categorized into four age groups: 18–29, 30–39, 40–49, and 50–69 yr old. The C women were also grouped by age (18–29 and 40–50 yr old). During the three-step clamp (hyperglycemia, return to euglycemia, and hyperinsulinemia), glucose turnover was assessed with [3-3H]glucose. Among the A, the youngest group had the largest first- and second-phase insulin response, which was significantly different from the oldest A ( P < 0.05). Among the two C groups, first-phase response of both groups and second-phase response of the older group was higher than respective age-matched A ( P < 0.05). During the hyperglycemic period, glucose Rdwas similar among A groups and between A and C. Despite similar levels of insulin between groups during the hyperinsulinemic period (∼400 pmol/l), A utilized 36% more glucose than C ( P < 0.001). Glucose Rdwas not different across the age groups of A. This newly developed sequential clamp procedure allows assessment of both β-cell sensitivity to glucose and peripheral tissue sensitivity to insulin in a single session. We have shown that physical activity improves β-cell efficiency across the age span in women and ameliorates the effect of age on the decline of peripheral tissue sensitivity to insulin.
Selected Contribution: Tryptase-induced PAR-2-mediated Ca2+signaling in human airway smooth muscle cells
Authors: Berger Patrick , Tunon-De-Lara J. Manuel , Savineau Jean-Pierre , Marthan Roger
Published: December 2017

Tryptase, the major mast cell product, is considered to play an important role in airway inflammation and hyperresponsiveness. Tryptase produces different, sometimes opposite, effects on airway responsiveness (bronchoprotection and/or airway contraction). This study was designed to examine the effect of human lung tryptase and activation of protease-activated receptor (PAR)-2 by synthetic activated peptide (AP) SLIGKV-NH2on Ca2+signaling in human airway smooth muscle (HASM) cells. Immunocytochemistry revealed that PAR-2 was expressed by HASM cells. Tryptase (7.5–30 mU/ml) induced a concentration-dependent transient relative rise in cytoplasmic Ca2+concentration ([Ca2+]i) that reached 207 ± 32 nM ( n = 10) measured by indo 1 spectrofluorometry. The protease inhibitors leupeptin or benzamidine (100 μM) abolished tryptase-induced [Ca2+]iincrease. Activation of PAR-2 by AP (1–100 μM) also induced a concentration-dependent transient rise in [Ca2+]i, whereas the reverse peptide produced no effect. There was a homologous desensitization of the [Ca2+]iresponse on repeated stimulation with tryptase or AP. U-73122, a specific phospholipase C (PLC) antagonist, xestospongin, an inositol trisphosphate (IP3)-receptor antagonist, or thapsigargin, a sarcoplamic Ca2+-ATPase inhibitor, abolished tryptase-induced [Ca2+]iresponse, whereas Ca2+removal, in the additional presence of EGTA, had no effect. Calphostin C, a protein kinase C inhibitor, increased PAR-2 [Ca2+]iresponse. Our results indicate that tryptase activates a [Ca2+]iresponse, which appears as PAR-2 mediated in HASM cells. Signal transduction implicates the intracellular Ca2+store via PLC activation and thus via the IP3pathway. This study provides evidence that tryptase, which is increasingly recognized as an important mediator in airway inflammation and hyperresponsiveness, is also a potent direct agonist at the site of airway smooth muscle.
Inflammatory and mechanical factors of allergen-induced bronchoconstriction in mild asthma and rhinitis
Authors: Crimi Emanuele , Milanese Manlio , Oddera Susanna , Mereu Carlo , Rossi Giovanni A. , Riccio Annamaria , Canonica G. Walter , Brusasco Vito
Published: December 2017

We studied whether different bronchial responses to allergen in asthma and rhinitis are associated with different bronchial inflammation and remodeling or airway mechanics. Nine subjects with mild asthma and eight with rhinitis alone underwent methacholine and allergen inhalation challenges. The latter was preceded and followed by bronchoalveolar lavage and bronchial biopsy. The response to methacholine was positive in all asthmatic but in only two rhinitic subjects. The response to allergen was positive in all asthmatic and most, i.e., five, rhinitic subjects. No significant differences between groups were found in airway inflammatory cells or basement membrane thickness either at baseline or after allergen. The ability of deep inhalation to dilate methacholine-constricted airways was greater in rhinitis than in asthma, but it was progressively reduced in rhinitis during allergen challenge. We conclude that 1) rhinitic subjects may develop similar airway inflammation and remodeling as the asthmatic subjects do and 2) the difference in bronchial response to allergen between asthma and rhinitis is associated with different airway mechanics.
“Living high-training low” altitude training improves sea level performance in male and female elite runners
Authors: Stray-Gundersen James , Chapman Robert F. , Levine Benjamin D.
Published: December 2017

Acclimatization to moderate high altitude accompanied by training at low altitude (living high-training low) has been shown to improve sea level endurance performance in accomplished, but not elite, runners. Whether elite athletes, who may be closer to the maximal structural and functional adaptive capacity of the respiratory (i.e., oxygen transport from environment to mitochondria) system, may achieve similar performance gains is unclear. To answer this question, we studied 14 elite men and 8 elite women before and after 27 days of living at 2,500 m while performing high-intensity training at 1,250 m. The altitude sojourn began 1 wk after the USA Track and Field National Championships, when the athletes were close to their season's fitness peak. Sea level 3,000-m time trial performance was significantly improved by 1.1% (95% confidence limits 0.3–1.9%). One-third of the athletes achieved personal best times for the distance after the altitude training camp. The improvement in running performance was accompanied by a 3% improvement in maximal oxygen uptake (72.1 ± 1.5 to 74.4 ± 1.5 ml · kg−1· min−1). Circulating erythropoietin levels were near double initial sea level values 20 h after ascent (8.5 ± 0.5 to 16.2 ± 1.0 IU/ml). Soluble transferrin receptor levels were significantly elevated on the 19th day at altitude, confirming a stimulation of erythropoiesis (2.1 ± 0.7 to 2.5 ± 0.6 μg/ml). Hb concentration measured at sea level increased 1 g/dl over the course of the camp (13.3 ± 0.2 to 14.3 ± 0.2 g/dl). We conclude that 4 wk of acclimatization to moderate altitude, accompanied by high-intensity training at low altitude, improves sea level endurance performance even in elite runners. Both the mechanism and magnitude of the effect appear similar to that observed in less accomplished runners, even for athletes who may have achieved near maximal oxygen transport capacity for humans.