Reassessment of the interruption technique for measuring flow resistance in humans

We have previously produced evidence that, in patients with obstructive lung disease, compliance of extrathoracic airways is responsible for lack of mouth-to-alveolar pressure equilibration during respiratory efforts against a closed airway. The flow interruption method for measuring respiratory resistance (Rint) is potentially faced with the same problems. We reassessed the merits of the interruption technique by rendering the extrathoracic airways more rigid and by using a rapid shutter. We measured airway resistance (Raw) with whole body plethysmography during panting (at 2 Hz) and Rint during quiet breathing. Rint and Raw were expressed as specific airway (sGaw) and interruptive conductance (sGint), respectively. In nine healthy subjects (cheeks supported), sGint (0.140 +/- 0.050 s-1.cmH2O-1) was lower (P less than 0.02) than sGaw (0.182 +/- 0.043 s-1.cmH2O-1). By contrast, in 12 patients with severe obstructive lung disease (forced expiratory volume in 1 s/vital capacity = 41.0 +/- 19.8%), sGint (0.058 +/- 0.012 s-1.cmH2O-1) was higher (P less than 0.05) than sGaw (0.047 +/- 0.007 s-1.cmH2O-1), when the cheeks were supported. When the mouth floor was also supported, average values of sGaw (0.048 +/- 0.008 s-1.cmH2O-1) and sGint (0.049 +/- 0.014 s-1.cmH2O-1) became similar. In conclusion, we confirm previous findings in healthy subjects of higher values of Rint, with respect to Raw, probably because of differences in glottis opening between quiet breathing and panting. In airflow obstruction, supporting both the cheeks and the mouth floor decreased sGint, which became similar to sGaw.     

Inhibition of mucin secretion with MARCKS-related peptide improves airway obstruction in a mouse model of asthma.

Allergic asthma is associated with airway epithelial cell mucous metaplasia and mucin hypersecretion, but the consequences of mucin hypersecretion on airway function are unclear. Recently, a peptide derived from the myristoylated alanine-rich C kinase substrate protein NH(2)-terminal sequence (MANS) was shown to inhibit methacholine (MCh)-induced mucin secretion from airway mucous cells by >90%. We studied the effect of intranasal pretreatment with this peptide on specific airway conductance (sGaw) during challenge with MCh in mice with allergen-induced mucous cell metaplasia. sGaw was noninvasively measured in spontaneously breathing restrained mice, using a double-chamber plethysmograph. Pretreatment with MANS peptide, but not a control peptide [random NH(2)-terminal sequence (RNS)], resulted in partial inhibition of the fall in sGaw induced by 60 mM MCh (mean +/- SE; baseline 1.15 +/- 0.06; MANS/MCh 0.82 +/- 0.05; RNS/MCh 0.55 +/- 0.05 cmH(2)O/s). The protective effect of MANS was also seen in mice challenged with allergen for 3 consecutive days to increase airway hyperresponsiveness, although the degree of protection was less (baseline 1.1 +/- 0.08; MANS/MCh, 0.65 +/- 0.06; RNS/MCh 0.47 +/- 0.03 cmH(2)O/s). Because routine sGaw measurement in mice includes nasal airways, the effectiveness of MANS was also confirmed in mice breathing through their mouths after nasal occlusion (baseline 0.92 +/- 0.05; MANS/MCh 0.83 +/- 0.06; RNS/MCh 0.61 +/- 0.03 cmH(2)O/s). In all instances, sGaw in the MANS-pretreated group was approximately 35% higher than in RNS-treated controls, and mucous obstruction accounted for approximately 50% of the MCh-induced fall in sGaw. In summary, mucin secretion has a significant role in airway obstruction in a mouse model of allergic asthma, and strategies to inhibit mucin secretion merit further investigation.     

Control of panting in the desert iguana: roles for peripheral temperatures and the effect of dehydration

Although it is generally held that panting is a physiological mechanism for the regulation of brain temperature during heat stress, a number of studies have pointed to the importance of peripheral input for the initiation of the panting response in a variety of animals. By presenting ambient heat loads of 47 degrees, 54 degrees, 58 degrees, and 65 degrees C, and measuring skin, ear and core temperatures of the desert iguana, Dipsosaurus dorsalis, at the onset of panting, we found that the skin temperature at panting onset was independent of ambient heat load. This suggests that skin (peripheral) temperature is the body temperature on which the central thermoregulatory center cues to initiate thermal panting. Peripheral temperature control of panting was retained when the plasma osmolality of the desert iguana was increased by 100 mOsm/kg H2O to simulate dehydration. Dehydration to 80% initial body weight (IBW) resulted in a progressive increase in panting threshold (skin) from 42 degrees C for untreated lizards to 42.5 degrees C at 90% IBW to 43.3 degrees C at 80% IBW. Injection of 80% IBW lizards with a volume of 10 mM NaCl equivalent to weight loss resulted in a decrease in panting threshold to 40.8 degrees C. Injection with 1% body weight 3000 mM NaCl produced a dramatic increase in panting threshold to 45.9 degrees C. These data suggest that the desert iguana responds to dehydration by elevating panting threshold, thus promoting water conservation. These data also suggest that changes in plasma osmolality may be involved in the "setting" of panting threshold.     

Effects of induced bronchoconstriction on pulmonary blood flow

Allergic bronchoconstriction may be associated with hemodynamic alterations due to changes in respiratory mechanics (or the associated changes in arterial blood gas composition) or the cardiovascular effects of chemical mediators. In an attempt to differentiate between these two possible mechanisms, we obtained measurements of hemodynamics, respiratory mechanics, and O2 consumption (VO2) in nine asymptomatic adult ragweed asthmatics before and after inhalation challenge with either ragweed extract or methacholine. We measured specific airway conductance (sGaw) by body plethysmography, pleural pressure with an esophageal balloon catheter, pulmonary blood flow (Q) and VO2 by a rebreathing technique, and heart rate. For a similar degree of bronchoconstriction after the two types of challenge (mean +/- SD sGaw 0.06 +/- 0.03 and 0.05 +/- 0.02 cmH2O-1 . s-1, P = NS), mean Q increased by 29 and 29%, and mean VO2 by 33 and 37% 15-20 min after ragweed and methacholine, respectively. Since heart rate did not change, there was a concomitant increase in mean stroke volume by 25 and 35%, respectively (P less than 0.05). The respiratory pleural pressure swings during quiet breathing and the rebreathing maneuver and the work of breathing during rebreathing also increased to a similar degree after the two types of challenge. These observations suggest that, if chemical mediators are released into the circulation during antigen-induced bronchoconstriction, their blood concentrations are too low for appreciable cardiovascular effects. The increase in rebreathing cardiac output during allergic and nonallergic bronchoconstriction is probably due to increases in intrathoracic pressure swings and in the work of breathing.     

Absence of selective brain cooling in pyrogen-induced fever in rabbits

In 9 rabbits the effect of intravenous administration of E. coli pyrogen 0.5 microgram/kg on the reaction of selective brain cooling was studied at ambient temperatures of 20, 30 and 40 degrees C. In the freely moving animals the temperatures of the brain, carotid artery and nuchal muscles were measured with an accuracy down to 0.05 degree C and the temperatures of the ear pinna and nasal mucosa were measured accurate to 0.5 degree C. The respiratory rate was measured as well. It was found that the spontaneous febrile reaction without the component of passive hyperthermia failed to cause selective brain cooling, even if its temperature reached higher values than in case of brain temperature rise caused only by high ambient temperature. On the other hand, when the high ambient temperature caused thermal panting, pyrogen administration at an ambient temperature of 30 degrees C could reduce panting, while at an ambient temperature of 40 degrees C intense panting initiated prior to the appearance of the febrile reaction and was associated with the fever and outlasted it.     

Effect of age on changes in flow rates and airway conductance after a deep breath

The effects of aging on changes in maximal expiratory flow rates and specific airway conductance after a deep breath were evaluated in 64 normal subjects. Flow rates (Vp) on partial expiratory flow-volume curves (PEFV), initiated from 60-70% of the vital capacity (VC), were compared with those (Vc) on maximal flow-volume curves (MEFV), initiated from total lung capacity (TLC), at a lung volume corresponding to 25% of VC on the MEFV curves. Specific airway conductance was measured before (sGaw) and after a deep inspiration (sGawDI). Bronchodilation after inspiration to TLC was inferred by Vp/Vc less than 1 and sGaw/sGawDI less than 1. The mean Vp was less than Vc. However, the ratio Vp/Vc increased significantly with age (r = 0.75, P less than 0.001). Specific conductance also increased after a deep inspiration (sGaw less than sGawDI). The ratio sGaw/sGawDIj increased slightly but significantly with age (r = 0.28, P less than 0.02). Measurement of lung elastic recoil pressures before and after a deep breath in a subgroup of patients (n = 14) suggested that the age-related increase in Vp/Vc was secondary to a decrement in the ability of a deep breath to decrease the upstream airway resistance. These findings suggest that even though changes in airway size after a deep breath as measured by sGaw/sGawDI have minimal age dependence, aging diminishes expiratory flow rates of MEFV curves relative to PEFV curves because of a decrease in the ability of a deep breath to increase the size of the peripheral airways.     

Time dependence of airways and lung parenchymal recoil hysteresis

Hysteresis of airways and lung parenchymal recoil was examined in normal subjects by measuring specific conductance (sGaw) and lung elastic recoil (Pst,L) before and 5, 10, 15, and 30 s after deep inspiration (DI). Routine lung function tests were normal before and after inhaled metaproterenol. sGaw increased significantly for 10 s after DI. Also, sGaw(DI) was greater than sGaw in 11 of 12, 8 of 12, 7 of 12, and 6 of 12 subjects at 5, 10, 15, and 30 s, respectively, after DI. The response of sGaw to DI and metaproterenol correlated significantly with each other (r = 0.82, P less than 0.001). However, after metaproterenol, sGaw(DI) did not exceed sGaw. Pst,L decreased significantly for 15 s after DI, with the lowest measured Pst,L(DI) values occurring 5 s after DI (P less than 0.01-0.001). Both sGaw(DI) and Pst,L(DI) values returned to base line (preinspiration) in a time-dependent exponential manner, with time constants of 9.2 +/- 4.9 and 11.3 +/- 6.1 s, respectively; these time constants were not significantly different from each other. We conclude that airways hysteresis is the predominant finding in normal subjects (even without prior pharmacological bronchoconstriction) before but not after metaproterenol; Pst,L decreases after DI and, in normal individuals, returns to base line in a time-dependent manner; and the time-dependent behavior of airways and lung parenchymal hysteresis have opposite (and unequal) effects on airway caliber.     

Evaluation of phase correction and low gas density to improve thoracic gas volume measurement

We investigated two methods of decreasing the error on plethysmographic determinations of thoracic gas volume (TGV) related to cheeks movements during panting maneuvers: lowering gas density in the airways with an 80% He-20% O2 mixture and computing TGV from the in-phase component of the plethysmographic signal (TGVr). The methods were tested by measuring how TGV estimates varied when panting frequency was raised from 0.8 to 2.5 Hz during the same occlusion. The measurements were performed in 6 normal subjects and 12 patients with chronic bronchitis with and without cheeks support and when the airway was connected to an external device simulating an increased cheeks compliance. A small negative frequency dependence of TGV (delta TGV/delta f = -1.2 +/- 0.8%/Hz with cheeks support), most probably unrelated to upper airway walls, was found in normal subjects. Delta TGV/delta f was positive and algebraically larger in patients than in normals, reaching 2.2 +/- 3.4%/Hz without cheeks support and 11.8 +/- 8.0%/Hz with the additional cheeks. The latter value was only 20% smaller when computed on the basis of TGVr, demonstrating the limited usefulness of the phase-based correction. In contrast, breathing He-O2 decreased delta TGV/delta f to approximately 50% of its air value (P less than 0.01) and appears as an effective way to diminish the error in obstructive patients.     

Gas exchange across avian eggshells oscillates in phase with heartbeat

Rahn et al. (J. Appl. Physiol. 69: 1546-1548, 1990) showed that the gas pressure in a plethysmograph containing an intact egg oscillates in phase with electrocardiogram (ECG) and that this pressure variation could be used as a noninvasive way to determine the heart rate of an avian embryo. One possible mechanism to account for the pressure oscillation is the mechanical movement of the embryonic heart, which leads to volume shifts of gas within the plethysmograph. Another possibility is that the oscillation of gas pressure with heartbeat is pulsatile gas exchange resulting from pulsatile blood flow. If gas exchange were transiently stopped, a pressure signal dependent on gas exchange should disappear, while a pressure signal dependent on cardiovascular motion should persist. Using a number of late-age hen eggs (at days 15-20 of incubation), we tested these hypotheses by suddenly changing the gas composition surrounding an egg and measuring the effect of the pressure oscillation. We found that 1) after 5% CO2-95% N2 was flushed into the plethysmograph (presumably halting gas exchange), pressure oscillations went almost to zero and the ECG signal remained; after air was flushed back to the plethysmograph, the pressure signal returned to control level; 2) after 20% CO2-20% O2-60% N2 was flushed into the plethysmograph (presumably increasing net gas exchange), the pressure signal increased 2.5-fold compared with that in air; and 3) after 1% CO2-99% N2 was flushed into the plethysmograph (presumably reversing gas exchange), the oscillation pressure decreased to one-fourth of that in air and the phase of pressure relative to ECG reversed compared with the phase in air.(ABSTRACT TRUNCATED AT 250 WORDS)     

Elevation of the panting threshold of the desert iguana,Dipsosaurus dorsalis,during dehydration: Potential roles of changes in plasma osmolality and body fluid volume

Summary Dehydration of the desert iguana,Dipsosaurus dorsalis, resulted in a progressive elevation in the magnitude of the skin temperature necessary to elicit thermal panting (i.e., the panting threshold). Panting threshold increased from 43.4±0.8 °C at 100% initial body weight (IBW) to 45.4±1.2 °C at 90% IBW to 45.7±0.9 °C at 80% IBW. Plasma osmolality showed no significant change with dehydration to 80% IBW. Changes in plasma osmolality, whether induced by NaCl or non-ionic sucrose loading, had a significant impact on panting threshold. Increasing plasma osmolality resulted in an elevation of panting threshold while decreasing plasma osmolality resulted in lower panting thresholds. Decreasing body fluid volume by exsanguination of 1 ml whole blood/100 g body weight resulted in a mean increase in panting threshold by 0.7±0.2 °C. Volume loading with 160 mM NaCl (approximately isosmotic) had no significant effect on panting threshold. These data suggest that plasma osmolality and decreases in body fluid volume may be potent modulators of panting threshold during periods of water deprivation. However, at least in desert iguanas, increases in plasma osmolality would not appear to be an important factor in the elevation of panting threshold during dehydration to 80% IBW.     

Eosinophils in the bronchial mucosa in relation to methacholine dose-response curves in atopic asthma.

Asthma is characterized by both local infiltration of eosinophils in the bronchial mucosa and bronchial hyperreactivity (BHR). A detailed characterization of BHR implies analysis of a histamine or methacholine dose-response curve yielding not only the dose at 20% fall of baseline forced expiratory volume in 1 s (FEV1), but also a plateau (P) representing the maximal narrowing response in terms of percent change in FEV1 and reactivity as the steepest slope at 50% of P (%FEV1/doubling dose). In the baseline condition, the specific airway conductance (sGaw) may be considered closely related to airway lumen diameter. In 20 nonsmoking asthmatic patients, methacholine dose-response curves were obtained, and a sigmoid model fit yielded the BHR indexes. Immunohistochemistry with the monoclonal antibodies (EG1 and EG2) was used to recognize the total number of eosinophils and activated eosinophils, respectively. The number of activated eosinophils was significantly correlated to both P (r = 0.62; P < 0.05) and sGaw (r = -0.52; P < 0.05), whereas weaker and nonsignificant correlations were found for dose at 20% fall of baseline FEV1 and the total number of eosinophils. We conclude that the number of activated eosinophils can be considered a marker of the inflammation-induced decrease of airway lumen diameter as represented by the plateau index and sGaw.     

Glottal aperture during panting with voluntary limitation of tidal volume.

A disadvantage of the forced oscillatory technique for measuring total respiratory resistance (namely, that it is usually done during quiet breathing or breathing holding--breathing patterns where the glottic aperture may be highly variable) was overcome by making the measurement during panting. The imposed forced oscillations (Hz) were distinguished from the spontaneous quiet breathing and panting frequencies by ensemble averaging. However, when panting was voluntary restricted so as to standardize the quiet breathing and panting flow amplitudes, resistance values frequently increased. The suggestion that partial glottal closure occurred during voluntarily restricted panting was confirmed by simultaneous inspection of the glottis with a fiberoptic bronchoscope. Thus, maximal opening of the glottis is assured only during unrestricted panting.     

Panting in reindeer (Rangifer tarandus)

Two winter-insulated Norwegian reindeer (Rangifer tarandus tarandus) were exposed to air temperatures of 10, 20, 30, and 38 degrees C while standing at rest in a climatic chamber. The direction of airflow through nose and mouth, and the total and the nasal minute volumes, respectively, were determined during both closed- and open-mouth panting. The animals alternated between closed- and open-mouth panting, but the proportion of open-mouth panting increased with increasing heat load. The shifts from closed- to open-mouth panting were abrupt and always associated with a rise in respiratory frequency and respiratory minute volume. During open-mouth panting, the direction of airflow was bidirectional in both nose and mouth, but only 2.4 +/- (SD) 1.1% of the air was routed through the nose. Estimates suggest that the potential for selective brain cooling is markedly reduced during open-mouth panting in reindeer as a consequence of this airflow pattern.     

Panting and acid-base regulation in heat stressed birds

1. Studies in respiratory physiology and acid-base balance of panting birds exposed to high Tas show that flying as well as nonflying birds can use the respiratory system simultaneously for gas exchange and evaporative cooling. 2. The present study proves that well acclimated hand-reared birds can effectively regulate a normal CO2 level and acid-base status in arterial blood, when exposed to extremely high temperatures (50-60 degrees C). 3. In many birds practising simple or "flush-out" panting, the dead space can be reduced to a volume which is estimated to be approx 15% the volume of the respiratory tract. 4. These two modes of ventilation, shallow and high-rate, restricted to the nonrespiratory surfaces, may ensure the avoidance of CO2-washout and limit lung ventilation to the volumes needed for oxygen consumption. 5. This view supports earlier theories, suggesting the existence of physiological shunt mechanisms which operate during thermal panting in birds.     

Cardiac responses to the Valsalva manoeuvre in different body positions

A standardized Valsalva manoeuvre (VM) with a 15-s straining period was repeated in each of four postures by six male subjects. The postures were supine (SUP), sitting leaning back (LB), sitting leaning forward (LF) and standing (ST). During straining, the increase in heart rate (fc) was different between LB and LF (+50% and +23%, respectively P less than 0.05). The decrease in stroke volume (SV), which was monitored by means of impedance cardiography, was different (63%, 68%, 39%, and 72%, P less than 0.001) as well as the decrease in cardiac output (CO) (55%, 53%, 26%, and 61%, P less than 0.001) in SUP, LB, LF, and ST, respectively. Accordingly, after pressure release the smallest changes of SV, fc and CO were found in LF. In conclusion, cardiovascular stability during straining was increased during LF. Consequently, this posture would appear to be superior to other postures during unavoidable VM (weight lifting and defaecation). To perform tests on autonomic function LB would appear to be superior to the other postures because of the large autonomic responses, combined with minimum risk for the subject. The impedance method provided simple and reproducible determinations of SV changes during VM.     

Assessment of the performance of a fed-batch cultivation from the preculture quality using an electronic nose

An electronic nose, a gas-phase multisensor system, was used to monitor precultivations of a recombinant tryptophan-producing Escherichia coli strain. The electronic nose signals showed a high correlation toward the main stages of the precultivations, namely, exponential growth, oxygen-limited growth, and glucose depletion. Principal component analysis (PCA) of the electronic nose signals was performed and shown to be useful for monitoring preculture progression. More importantly, PCA also allowed a qualitative assessment of the preculture performance during subsequent fed-batch cultivations. The electronic nose signals from the precultures showed, furthermore, a high correlation to the time of phosphate limitation and the tryptophan yield coefficient of the subsequent fed-batch cultivations, which allowed an accurate prediction of these process variables using partial least squares (PLS). The results demonstrate on data from 12 cultivations how the electronic nose can be a useful tool for the assessment of inoculum quality, thereby providing means of reducing batch-to-batch variation and increasing the productivity of bioprocesses.     

Neuron selection by relative importance for neural decoding of dexterous finger prosthesis control application

Future generations of upper limb prosthesis will have dexterous hand with individual fingers and will be controlled directly by neural signals. Neurons from the primary motor (M1) cortex code for finger movements and provide the source for neural control of dexterous prosthesis. Each neuron's activation can be quantified by the change in firing rate before and after finger movement, and the quantified value is then represented by the neural activity over each trial for the intended movement. Since this neural activity varies with the intended movement, we define the relative importance of each neuron independent of specific intended movements. The relative importance of each neuron is determined by the inter-movement variance of the neural activities for respective intended movements. Neurons are ranked by the relative importance and then a subpopulation of rank-ordered neurons is selected for the neural decoding. The use of the proposed neuron selection method in individual finger movements improved decoding accuracy by 21.5% in the case of decoding with only 5 neurons and by 9.2% in the case of decoding with only 10 neurons. With only 15 highly ranked neurons, a decoding accuracy of 99.5% was achieved. The performance improvement is still maintained when combined movements of two fingers were included though the decoding accuracy fell to 95.7%. Since the proposed neuron selection method can achieve the targeting accuracy of decoding algorithms with less number of input neurons, it can be significant for developing brain–machine interfaces for direct neural control of hand prostheses.     

Modified Box-Cox transform for modulating the dynamic range of flow cytometry data

We describe an algorithm, Vout = Integer ([2(12)-1/2(12 lambda)-1] V lambda in-1) + 1; lambda greater than 0 based upon Box-Cox transformations as an alternative to nonlinear electronic amplifiers to expand or compress high- or low-amplitude flow cytometer-derived signals. If the indexing parameter lambda less than 1, input channels in the high-amplitude input range are compressed in the output range as occurs when an electronic logarithmic amplifier is used. However, if lambda greater than 1, input channels in the low-amplitude input range are compressed in the output range as occurs when an electronic power amplifier is used. Our modified Box-Cox transform can be implemented either during data collection or off-line for the transformation of previously collected raw data. The transform is the equivalent of an infinite class of nonlinear amplifiers. As the transform is implemented in software, it does not suffer from many of the disadvantages of nonlinear electronic amplifiers.     

Use of Electronic Loggers to Measure Changes in the Rates of Hand Washing with Soap in Low-Income Urban Households in India

We evaluated the utility of electronic loggers to measure the effects of a simple intervention designed to influence the rates of hand washing with soap within enclosed toilets and bathrooms in low-income urban households in Kerala, India. 58 households were given three items with embedded electronic loggers for a period of 2-5 days. Two logged soaps tracked hand and body washing in the bathroom. The third logged item was a water vessel used for flushing the toilet and for post-defecation anal cleansing; this served as a marker of toilet use. In addition, 28 households in a Soap by toilet arm were given an additional logged soap, to be kept by the toilet, and used for hand washing. Compared with the Soap in bathroom arm, the loggers in the Soap by toilet households recorded 73% greater daily use of soaps designated for hand washing (t(36)=2.92, p<0.01) and 172% greater use within 2 minutes of the use of the water vessel (t(36)=3.51, p = 0.001). We conclude that the loggers were capable of detecting changes in the rates of hand washing with soap and changes in hand washing with soap after use of the toilet. Further adoption of logger technologies would enable more insightful studies of hand washing within urban environments.