We report heterozygous mutations in the genes encoding either type I or type II transforming growth factor β receptor in ten families with a newly described human phenotype that includes widespread ...perturbations in cardiovascular, craniofacial, neurocognitive and skeletal development. Despite evidence that receptors derived from selected mutated alleles cannot support TGFβ signal propagation, cells derived from individuals heterozygous with respect to these mutations did not show altered kinetics of the acute phase response to administered ligand. Furthermore, tissues derived from affected individuals showed increased expression of both collagen and connective tissue growth factor, as well as nuclear enrichment of phosphorylated Smad2, indicative of increased TGFβ signaling. These data definitively implicate perturbation of TGFβ signaling in many common human phenotypes, including craniosynostosis, cleft palate, arterial aneurysms, congenital heart disease and mental retardation, and suggest that comprehensive mechanistic insight will require consideration of both primary and compensatory events.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The modified Campbell diagram provides one of the most comprehensive assessments of the work of breathing (Wb) during exercise, wherein the resistive and elastic work of inspiration and expiration ...are quantified. Importantly, a necessary step in constructing the modified Campbell diagram is to obtain a value for chest wall compliance (C
). To date, it remains unknown whether estimating or directly measuring C
impacts the Wb, as determined by the modified Campbell diagram. Therefore, the purpose of this study was to evaluate whether the components of the Wb differ when the modified Campbell diagram is constructed using an estimated versus measured value of C
. Forty-two participants (
= 26 men, 16 women) performed graded exercise to volitional exhaustion on a cycle ergometer. C
was measured directly at rest via quasistatic relaxation. Estimated values of C
were taken from prior literature. The measured value of C
was greater than that obtained via estimation (214 ± 52 mL/cmH
O vs. 189 ± 18 mL/cmH
O;
< 0.05). At modest-to-high minute ventilations (i.e., 50-200 L/min), the inspiratory elastic Wb was greater and expiratory resistive Wb was lower, when modified Campbell diagrams were constructed using estimated compared with measured values of C
(
= 0.001). These differences were however small and never exceeded ±5%. Thus, although our findings demonstrate that estimating C
has a measurable impact on the determination of the Wb, its effect appears relatively small within a cohort of healthy adults during graded exercise.
The measurement of the work of breathing (Wb) during exercise provides us with deep insights into respiratory (patho)physiology, and sheds light on the putative factors which lead to respiratory ...muscle fatigue. There are 4 popular methods available to determine the Wb. Our study demonstrates that no two of these methods produce identical values of Wb during exercise. This paper also discusses the practical and theoretical limitations of each method.
The mechanical work of breathing (Wb) is an insightful tool used to assess respiratory mechanics during exercise. There are several different methods used to calculate the Wb, however, each approach having its own distinct advantages/disadvantages. To date, a comprehensive assessment of the differences in the components of Wb between these methods is lacking. We therefore sought to compare the values of Wb during graded exercise as determined via the four most popular methods: 1) pressure-volume integration; 2) the Hedstrand diagram; 3) the Otis diagram; and the 4) modified Campbell diagram. Forty-two participants (30 ± 15 yr; 16 women) performed graded cycling to volitional exhaustion. Esophageal pressure-volume loops were obtained throughout exercise. These data were used to calculate the total Wb and, where possible, its subcomponents of inspiratory and expiratory, resistive and elastic Wb, using each of the four methods. Our results demonstrate that the components of Wb were indeed different between methods across the minute ventilations engendered by graded exercise. Importantly, however, no systematic pattern in these differences could be observed. Our findings indicate that the values of Wb obtained during exercise are uniquely determined by the specific method chosen to compute its value—no two methods yield identical results. Because there is currently no “gold-standard” for measuring the Wb, it is emphasized that future investigators be cognizant of the limitations incurred by their chosen method, such that observations made by others may be interpreted with greater context, and transparency.
NEW & NOTEWORTHY The measurement of the work of breathing (Wb) during exercise provides us with deep insights into respiratory (patho)physiology, and sheds light on the putative factors which lead to respiratory muscle fatigue. There are 4 popular methods available to determine the Wb. Our study demonstrates that no two of these methods produce identical values of Wb during exercise. This paper also discusses the practical and theoretical limitations of each method.
We report the outcomes of the discussion initiated at the workshop entitled A 3D Cellular Context for the Macromolecular World and propose how data from emerging three-dimensional (3D) cellular ...imaging techniques-such as electron tomography, 3D scanning electron microscopy and soft X-ray tomography-should be archived, curated, validated and disseminated, to enable their interpretation and reuse by the biomedical community.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Intrapleural pressure during a forced vital capacity (VC) maneuver is often in excess of that required to generate maximal expiratory airflow. This excess pressure compresses alveolar gas (i.e., ...thoracic gas compression TGC), resulting in underestimated forced expiratory flows (FEFs) at a given lung volume. It is unknown if TGC is influenced by sex; however, because men have larger lungs and stronger respiratory muscles, we hypothesized that men would have greater TGC. We examined TGC across the “effort‐dependent” region of VC in healthy young men (n = 11) and women (n = 12). Subjects performed VC maneuvers at varying efforts while airflow, volume, and esophageal pressure (POES) were measured. Quasistatic expiratory deflation curves were used to obtain lung recoil (PLUNG) and alveolar pressures (i.e., PALV = POES–PLUNG). The raw maximal expiratory flow–volume (MEFVraw) curve was obtained from the “maximum effort” VC maneuver. The TGC‐corrected curve was obtained by constructing a “maximal perimeter” curve from all VC efforts (MEFVcorr). TGC was examined via differences between curves in FEFs (∆FEF), area under the expiratory curves (∆AEX), and estimated compressed gas volume (∆VGC) across the VC range. Men displayed greater total ∆AEX (5.4 ± 2.0 vs. 2.0 ± 1.5 L2·s−1; p < .001). ∆FEF was greater in men at 25% of exhaled volume only (p < .05), whereas ∆VGC was systematically greater in men across the entire VC (main effect; p < .05). PALV was also greater in men throughout forced expiration (p < .01). Taken together, these findings demonstrate that men display more TGC, occurring early in forced expiration, likely due to greater expiratory pressures throughout the forced VC maneuver.
We sought to examine whether sex influences the degree to which thoracic gas compression (TGC) underestimates forced expiratory flows at a given lung volume during forced expiration. Men displayed greater TGC than women, particularly at 25% of the forced expired volume. This greater TGC was likely due to greater expiratory pressures generated by men throughout the maneuver. Failure to appropriately account for TGC results in a greater underestimation of expiratory airflow in men, primarily during the early phase of forced expiration.
Matrix-diffusion parameters deduced from an infiltration tracer test at Idaho National Laboratory (INL), USA, are combined with other site information in an analysis involving two dimensionless ...lumped parameters to assess the effects of matrix diffusion on contaminant transport at the INL over longer distance and time scales than were evaluated in the test. Matrix diffusion was interrogated in the test by comparing, in three different observation wells, the breakthrough curves of two simultaneously injected nonsorbing solutes that have different diffusion coefficients. The matrix-diffusion parameters deduced from the different breakthrough curves were in good agreement, suggesting that the parameters may be broadly applicable at the INL. With this in mind, the uncertainties in the individual parameters that make up the two lumped parameters were estimated, and the resulting ranges of parameter values were used to assess matrix diffusion over larger scales. Assessments of the effects of flow transients, spatial heterogeneity in transport parameters, and sorption on solute transport in the shallow subsurface flow system were also conducted. The methods presented here should be generally applicable to other settings for making bounding assessments of the effects of matrix diffusion while honoring the information obtained from tracer tests and other supporting data.
Abstract only
The respiratory muscle pressure (P
mus
) waveform lends insight into the patterns of net inspiratory
v
expiratory muscle recruitment under a wide variety of conditions, including ...mechanical ventilation, spontaneous breathing, and during exercise. On this last point, inspection of the P
mus
waveform during incremental and constant work rate cycling reveals that inspiratory and expiratory muscle recruitment systematically increase with rising minute ventilations, and that the duration of post‐inspiratory inspiratory activity (PIIA) gradually disappears from low to high levels of respiratory motor output. In recent years, it has become increasingly evident that the work of breathing is systematically higher for women compared with men at a given minute ventilation during exercise. Yet, no study has examined the potential sex differences in the evolution of P
mus
(and its components; e.g., PIIA) during exercise. Thus, a comprehensive assessment of the P
mus
waveform during exercise between sexes is warranted.
Purpose
To compare the evolution of inspiratory and expiratory P
mus
between men and women during incremental cycling.
Methods
Thirteen men (21 ± yrs; 181 ± 5 cm; 82 ± 11 kg) and 10 women (21 ± 1 yrs; 165 ± 6 cm; 62 ± 6 kg) visited the laboratory on two separate occasions. The first occasion was used to obtain informed consent and to screen participants for normal pulmonary function (>85% age‐predicted). On the second visit, participants were instrumented with an esophageal balloon catheter to estimate variations in pleural pressure (P
pl
). Quasi‐static relaxation curves were obtained to measure chest wall recoil pressure (P
cw
). Participants then completed an incremental cycling protocol until volitional exhaustion. P
mus
was calculated at given minute ventilations during the exercise protocol as follows: P
mus
= P
cw
– P
pl
.
Results
The peak inspiratory P
mus
were significantly greater in females compared with men at a given minute ventilation during incremental cycling (
P
< 0.05), yet peak expiratory P
mus
was similar between sexes. The average rates of change (slope) in P
mus
during inspiration & expiration were significantly faster in females than males at a given minute ventilation (
P
< 0.05). Finally, the duration of PIIA (expressed as a fraction of expiratory time) gradually decreased with increasing minute ventilation during exercise (
P
< 0.05). This reduction in PIIA was however similar between men and women.
Conclusion
The primary finding of this study was that the pattern of respiratory muscle recruitment was different between sexes during incremental cycling, insofar as women displayed systematically larger inspiratory P
mus
, and faster rates of net inspiratory & expiratory pressure‐development compared with men at matched ventilations. However, no differences in PIIA between sexes were observed.
Support or Funding Information
This research was funded by preliminary data funds provided by Northern Arizona University (JWD). TJC was supported by the Irene Diamond Fund/American Federation for Aging Research Postdoctoral Transition Award during the time of this study.
Abstract only
The equal pressure point (EPP) states that expiratory flow limitation occurs at the precise location along the tracheobronchial tree where intraluminal and peribronchial pressures are ...equal (i.e., where the local transmural pressure is 0 cmH
2
O). The EPP may be determined numerically via the expiratory isovolume pressure flow (IVPF) curve. For instance, using data from a given isovolume curve, the EPP is determined as the point along the x‐axis at which pressure‐flow data fails to conform to Rohrer’s equation: driving pressure = k
1
(flow) + k
2
(flow
2
). The probability of incurring expiratory flow‐limitation can be greatly determined by the EPP such that a lower EPP at a given lung volume requires only minimal pressure development to create a flow‐limiting segment during expiration. The EPP is affected by two principal factors: lung elastic recoil (P
LUNG
) & airway geometry. Given recent evidence suggesting that airway geometry is different between men & women, we sought to determine whether the EPP is likewise affected by sex in healthy adults.
Purpose
Determine whether or not there is an effect of sex on the magnitude of the EPP.
Methods
To address this question, 11 men (23.1 ± 4.8 years) and 12 women (21.2 ± 1.0 years) completed a study requiring two visits to the laboratory. On the initial visit, we obtained written informed consent and conducted spirometry to ensure subjects met the inclusion criteria of normal (>85% of predicted) lung function. During the second visit, a balloon catheter was passed intranasally to the lower one‐third of the esophagus and remained there for the duration of the visit to measure esophageal pressure (P
ES
). Subjects then performed a minimum of 10–15 graded vital capacity maneuvers from 100‐5% of maximal effort. Data were imported into Matlab and, using custom‐written code, multiple calculations were performed. First, the lowest effort vital capacity efforts were taken as quasi‐static expiratory deflations of the lung and the negative sign of P
ES
was taken to equal P
LUNG
. Second, alveolar pressure (P
ALV
) was taken to equal P
ES
+ P
LUNG
. Finally, the EPP was determined by iteratively fitting Rohrer’s equation to pressure‐flow data at a given iso‐volume. The pressure at which Rohrer’s equation no longer adequately fit the data (>5% error) was termed the EPP. To test for an effect of sex and lung volume, a two‐way ANOVA was computed. Pairwise comparisons were adjusted for multiple comparisons using the Tukey‐Sidak
post hoc
test.
Results
There was no effect of sex on P
LUNG
, but P
ALV
was greater in men than women throughout the entire VC range. EPP was significantly greater in men than women during the initial half of VC (95‐55% of VC) (p < 0.05), but not the remaining half (p > 0.05).
Conclusion
Because P
LUNG
did not differ between men and women, the differing location of EPP was the result of a greater P
ES
in men. This suggests that the larger airways present in men are more resistant to compression than those of women.
PDF
