Type B atrial receptor discharge increases on opening a nonhypotensive arteriovenous shunt in the dog

A vagovagal cardioacceleratory reflex is activated when an arteriovenous (a-v) shunt is opened in the dog. However, the receptors which initiate this reflex have not been localized. Type B atrial receptor excitation was considered to be a major component of this reflex. The effect of opening a femoral nonhypotensive a-v shunt (i.e., shunt open plus infusion of blood to compensate for the resultant fall in mean arterial and pulse pressure) on type B atrial receptor discharge and heart rate was therefore studied in seven anesthetized, artifically ventilated dogs with beta-adrenergic blockade. Right atrial and aortic blood pressures, heart rate, and type B atrial receptor discharge was studied before and after opening a femoral a-v shunt. On opening the a-v shunt there was a significant increase (44%) in the average activity of type B atrial receptors and a small, but significant (6.8%) increase in heart rate. A significant linear positive correlation was observed between the change in activity of type B atrial receptors and the shunt flow. The results suggest that type B atrial receptors may be one of the receptor groups that initiate this vagovagal reflex.     

Salt Appetite Is Reduced by a Single Experience of Drinking Hypertonic Saline in the Adult Rat

Salt appetite, the primordial instinct to favorably ingest salty substances, represents a vital evolutionary important drive to successfully maintain body fluid and electrolyte homeostasis. This innate instinct was shown here in Sprague-Dawley rats by increased ingestion of isotonic saline (IS) over water in fluid intake tests. However, this appetitive stimulus was fundamentally transformed into a powerfully aversive one by increasing the salt content of drinking fluid from IS to hypertonic saline (2% w/v NaCl, HS) in intake tests. Rats ingested HS similar to IS when given no choice in one-bottle tests and previous studies have indicated that this may modify salt appetite. We thus investigated if a single 24 h experience of ingesting IS or HS, dehydration (DH) or 4% high salt food (HSD) altered salt preference. Here we show that 24 h of ingesting IS and HS solutions, but not DH or HSD, robustly transformed salt appetite in rats when tested 7 days and 35 days later. Using two-bottle tests rats previously exposed to IS preferred neither IS or water, whereas rats exposed to HS showed aversion to IS. Responses to sweet solutions (1% sucrose) were not different in two-bottle tests with water, suggesting that salt was the primary aversive taste pathway recruited in this model. Inducing thirst by subcutaneous administration of angiotensin II did not overcome this salt aversion. We hypothesised that this behavior results from altered gene expression in brain structures important in thirst and salt appetite. Thus we also report here lasting changes in mRNAs for markers of neuronal activity, peptide hormones and neuronal plasticity in supraoptic and paraventricular nuclei of the hypothalamus following rehydration after both DH and HS. These results indicate that a single experience of drinking HS is a memorable one, with long-term changes in gene expression accompanying this aversion to salty solutions.     

Effect of acute increases in pulmonary vascular pressures on exercise pulmonary gas exchange.

The purpose of this study was to determine the effect of acute increases in pulmonary vascular pressures, caused by the application of lower-body positive pressure (LBPP), on exercise alveolar-to-arterial PO2 difference (A-aDO2), anatomical intrapulmonary (IP) shunt recruitment, and ventilation. Eight healthy men performed graded upright cycling to 90% maximal oxygen uptake under normal conditions and with 52 Torr (1 psi) of LBPP. Pulmonary arterial (PAP) and pulmonary artery wedge pressures (PAWP) were measured with a Swan-Ganz catheter. Arterial blood samples were obtained from a radial artery catheter, cardiac output was calculated by the direct Fick method, and anatomical IP shunt was determined by administering agitated saline during continuous two-dimensional echocardiography. LBPP increased both PAP and PAWP while upright at rest, and at all points during exercise (mean increase in PAP and PAWP 3.7 and 4.0 mmHg, respectively, P<0.05). There were no differences in exercise oxygen uptake or cardiac output between control and LBPP. Despite the increased PAP and PAWP with LBPP, A-aDO2 was not affected. In the upright resting position, there was no evidence of shunt in the control condition, whereas LBPP caused shunt in one subject. At the lowest exercise workload (75 W), shunt occurred in three subjects during control and in four subjects with LBPP. LBPP did not affect IP shunt recruitment during subsequent higher workloads. Minute ventilation and arterial PcO2 were not consistently affected by LBPP. Therefore, small acute increases in pulmonary vascular pressures do not widen exercise A-aDO2 or consistently affect IP shunt recruitment or ventilation.     

Pulmonary vascular K+ channel expression and vasoreactivity in a model of congenital heart disease

K+ channels play an important role in mediating pulmonary vasodilation caused by increased oxygen tension, nitric oxide, alkalosis, and shear stress. To test the hypothesis that lung K+ channel gene expression may be altered by chronic increases in pulmonary blood flow, we measured gene and protein expression of calcium-sensitive (K Ca ) and voltage-gated (Kv2.1) K+ channels, and a pH-sensitive K+ channel (TASK), in distal lung from fetal lambs in which an aortopulmonary shunt was placed at 139 days gestation. Under baseline conditions, animals with an aortopulmonary shunt showed elevated pulmonary artery pressure and pulmonary blood flow compared with twin controls. Hypoxia caused a greater increase in pulmonary vascular tone in shunt animals compared with controls. Alkalosis caused pulmonary vasodilation in control but not shunt animals. To determine lung K+ channel mRNA levels, we performed quantitative RT-PCR. In comparison with control animals, lung K Ca channel mRNA content was increased in shunt animals, whereas TASK mRNA levels were decreased. There was no difference in Kv2.1 mRNA levels. Channel protein expression was consistent with these findings. We conclude that, in the presence of elevated pulmonary blood flow, K Ca channel expression is increased and TASK is decreased.     

Hydrogen sulfide acts as an inflammatory mediator in cecal ligation and puncture-induced sepsis in mice by upregulating the production of cytokines and chemokines via NF-kappaB

Increasing data suggest that oxidative stress, due to an increased production of reactive oxygen species and/or a decrease in antioxidants, is involved in the pathophysiology of pulmonary hypertension. Several antioxidant systems regulate the presence of oxidant species in vivo, and of primary interest are the superoxide dismutases (SOD) and catalase. However, little is known about the expression of antioxidant enzymes during the development of pulmonary hypertension. This study uses our lamb model of increased postnatal pulmonary blood flow, secondary to in utero aortopulmonary graft placement (shunt lambs), to investigate the expression patterns as well as activities of antioxidant enzymes during the early development of pulmonary hypertension. Protein levels of catalase, SOD1, SOD2, and SOD3 were evaluated by Western blot, and the activities of catalase and SOD were also quantified. In control lambs, protein expression and activities of catalase and SOD2 increased postnatally (P < 0.05). However, SOD1 and SOD3 protein levels did not change. In shunt lambs, catalase, SOD1, and SOD2 protein levels all increased over the first 8 wk of life (P < 0.05). However, SOD3 did not change. This was associated with an increase in the activities of catalase and SOD2 (P < 0.05). Compared with control lambs, catalase and SOD2 protein levels were decreased in 2-wk-old shunt lambs and this was associated with increased levels of hydrogen peroxide (H(2)O(2)) and superoxide (P < 0.05). Developmentally superoxide but not H(2)O(2) levels significantly increased in both shunt and control lambs with levels being significantly higher in shunt compared with control lambs at 2 and 4 but not 8 wk. These data suggest that the antioxidant enzyme systems are dynamically regulated postnatally, and this regulation is altered during the development of pulmonary hypertension secondary to increased pulmonary blood flow. An increased understanding of these alterations may have important therapeutic implications for the treatment of pulmonary hypertension secondary to increased pulmonary blood flow.     

Impacts of a national strategy to reduce population salt intake in England: serial cross sectional study

Background

The UK introduced an ambitious national strategy to reduce population levels of salt intake in 2003. The aim of this study was to evaluate the impact of this strategy on salt intake in England, including potential effects on health inequalities.

Methods

Secondary analysis of data from the Health Survey for England. Our main outcome measure was trends in estimated daily salt intake from 2003–2007, as measured by spot urine. Secondary outcome measures were knowledge of government guidance and voluntary use of salt in food preparation over this time period.

Results

There were significant reductions in salt intake between 2003 and 2007 (−0.175grams per day per year, p<0.001). Intake decreased uniformly across all other groups but remained significantly higher in younger persons, men, ethnic minorities and lower social class groups and those without hypertension in 2007. Awareness of government guidance on salt use was lowest in those groups with the highest intake (semi-skilled manual v professional; 64.9% v 71.0% AOR 0.76 95% CI 0.58–0.99). Self reported use of salt added at the table reduced significantly during the study period (56.5% to 40.2% p<0.001). Respondents from ethnic minority groups remained significantly more likely to add salt during cooking (white 42.8%, black 74.1%, south Asian 88.3%) and those from lower social class groups (unskilled manual 46.6%, professional 35.2%) were more likely to add salt at the table.

Conclusions

The introduction a national salt reduction strategy was associated with uniform but modest reductions in salt intake in England, although it is not clear precisely which aspects of the strategy contributed to this. Knowledge of government guidance was lower and voluntary salt use and total salt intake was higher among occupational and ethnic groups at greatest risk of cardiovascular disease.     

Quantitation of conductance pathways in antral gastric mucosa

The magnitude of cellular and shunt conductance of Necturus gastric antral mucosa was studied by (a) comparing the cellular PD response to transepithelial PD response during changes of ionic activity in the serosal bathing solution and (b) by measurement of current spread within the epithelial sheet. Using constant product KCl changes cellular resistance was 6,788 omegacm2 and shunt resistance was 1,803 omegacm2. Deletion of HCO3- from the serosal solution produced similar but quantitatively smaller changes in PD. Using HCO3- deletion cellular resistance was 7,338 omegacm2 and shunt resistance was 1,973 omegacm2. Measurement of current spead within the mucosa avoids changing ionic gradients yet gave very similar results; cellular resistance was 8,967 omegacm2 and shunt resistance was 2,947 omegacm2. The shunt contribution to transepithelial conductance ranged from 75.2 to 79.0%. Shunt selectivity was assessed using KCl dilution potentials, where mucosal dilution gave a small change in tissue PD compatible with an anion/cation selectivity ratio of 1.16 across the shunt, whereas serosal dilution effect was dominated by a PD change across the serosal membrane of the cell.     

Role of a short open reading frame in ribosome shunt on the cauliflower mosaic virus RNA leader

The pregenomic 35 S RNA of cauliflower mosaic virus (CaMV) belongs to the growing number of mRNAs known to have a complex leader sequence. The 612-nucleotide leader contains several short open reading frames (sORFs) and forms an extended hairpin structure. Downstream translation of 35 S RNA is nevertheless possible due to the ribosome shunt mechanism, by which ribosomes are directly transferred from a take-off site near the capped 5' end of the leader to a landing site near its 3' end. There they resume scanning and reach the first long open reading frame. We investigated in detail how the multiple sORFs influence ribosome migration either via shunting or linear scanning along the CaMV leader. The sORFs together constituted a major barrier for the linear ribosome migration, whereas the most 5'-proximal sORF, sORF A, in combination with sORFs B and C, played a positive role in translation downstream of the leader by diverting scanning ribosomes to the shunt route. A simplified, shunt-competent leader was constructed with the most part of the hairpin including all the sORFs except sORF A replaced by a scanning-inhibiting structure. In this leader as well as in the wild type leader, proper translation and termination of sORF A was required for efficient shunt and also for the level of shunt enhancement by a CaMV-encoded translation transactivator. sORF A could be replaced by heterologous sORFs, but a one-codon (start/stop) sORF was not functional. The results implicate that in CaMV, shunt-mediated translation requires reinitiation. The efficiency of the shunt process is influenced by translational properties of the sORF.     

Salt tolerance analysis of <Emphasis Type="Italic">Arabidopsis thaliana</Emphasis> NOK2 accession under saline conditions and potassium supply

The response to salt treatment and K⁺ provision of two Arabidopsis thaliana accessions grown for 17 days in the presence of 50 mM NaCl was investigated. Leaf and root dry weight deposition was restricted by salt, more in Col accession than in NOK2 accession. In both accessions, the growth inhibition induced by salinity was associated with a decrease in total leaf surface area, which resulted from diminished leaf number, but not from restriction of individual leaf surface area. Comparing the effects of salt on dry matter production and total leaf surface area revealed large difference between Col and NOK2 for net assimilation rate (the amount of whole plant biomass produced per unit leaf surface area), which was augmented by salt and K⁺ in NOK2 but not in Col. This result, which suggested a better capacity of NOK2 to preserve its photosynthetic machinery against salt stress, was in agreement with the effect of NaCl on photosynthetic pigments. Indeed, salt significantly reduced chlorophyll and carotenoid content in Col leaves but had no impact on NOK2 leaf pigment content. Since K⁺ provision had only marginal effects on these responses to salt stress, leaf mineral unbalance was unlikely. Guaiacol peroxidase activity was augmented by salt treatment in leaves and roots of both accessions. Salinity decreased the catalase activity in Col leaves and in roots, and increased this activity in NOK2 organs. In conclusion, when aggressed by salt, NOK2 was able (1) to produce more leaves than Col, and (2) to efficiently protect its photosynthetic apparatus, perhaps by developing more efficient antioxidative defense through increased catalase and peroxidase activities. Consequently, the overall photosynthetic activity was higher and more robust to salt aggression in NOK2 than in Col.     

Selection of operation in patients with bleeding esophageal varices.

The results of surgical treatment of bleeding esophageal varices over an 8-year period in 155 patients are reviewed. Primary treatment of bleeding was conservative, with intravenous administration of vasopressin and balloon tamponade. Emergency operations were carried out after 48 hours in persons with persistent bleeding who were surgical candidates. Operative mortality was higher in this group (40%) than in those undergoing elective or urgent operations (each 10%). Postoperative encephalopathy occurred in 35% of patients and was correlated closely to late death after establishment of a shunt. The mesocaval shunt is no better than the portacaval but appears to be a good alternative in an emergency. In a controlled trial the distal splenorenal shunt was found to be associated with a lower rate of postoperative encephalopathy than the portacaval shunt, but thus far the long-term survival rates have not differed.     

Improved 2D nano-LC/MS for proteomics applications: a comparative analysis using yeast proteome.

The most commonly used method for protein identification with two-dimensional (2D) online liquid chromatography-mass spectrometry (LC/MS) involves the elution of digest peptides from a strong cation exchange column by an injected salt step gradient of increasing salt concentration followed by reversed phase separation. However, in this approach ion exchange chromatography does not perform to its fullest extent, primarily because the injected volume of salt solution is not optimized to the SCX column. To improve the performance of strong cation exchange chromatography, we developed a new method for 2D online nano-LC/MS that replaces the injected salt step gradient with an optimized semicontinuous pumped salt gradient. The viability of this method is demonstrated in the results of a comparative analysis of a complex tryptic digest of the yeast proteome using the injected salt solution method and the semicontinuous pump salt method. The semicontinuous pump salt method compares favorably with the commonly used injection method and also with an offline 2D-LC method.     

Saltwater spray as an agent of natural selection: no evidence of local adaptation within a coastal population of Triplasis purpurea (Poaceae)

An ability to tolerate airborne saltwater spray is critical for plant populations in coastal environments. The opportunity for continued microevolution for improved salt tolerance can exist if there is variation in the response of genetic families to saltwater spray. Our objective was to determine whether or not there was differentiation among subpopulations near (15 m) and far (80 m) from shore and among families within subpopulations in relation to the effects of salt spray on life history traits in a population of the dunegrass Triplasis purpurea. In this annual, most seeds are matured in cleistogamous spikelets on axillary, leaf-sheath enclosed panicles and show poor dispersal capacity. Plants were reared in the greenhouse from seeds of 13 and 11 families from the near and far subpopulations, respectively. Fifty percent of plants in a family were subjected to 6 seawater sprays/wk, resulting in weekly salt deposition of 213 μg/cm(2); the others were sprayed with distilled water. Data were recorded on life span, tiller numbers, root and shoot dry mass, and seed production. There was no effect of subpopulation on any measured trait and, hence, no evidence for local adaptation to salt spray. Final tiller numbers, but not dry mass or seed production, were reduced by salt spray. However, for most traits there were significant family (within subpopulation) effects, indicating genetic substructuring. Life span and mean seed mass showed a significant family by treatment interaction, indicating genetic variation in phenotypic responses to salt spray. Life span and mean seed mass were reduced by salt spray in some, but not all, families. Path analysis revealed that an increase in life span or tiller number indirectly increased seed production via direct effects on vegetative mass. For this relatively salt-tolerant T. purpurea population on the south shore of Staten Island, New York, USA, salt sprays may not be a significant agent of natural selection. However, there are pronounced phenotypic differences among inbred family groups and opportunity for genetic substructuring within these subpopulations. Variable effects of salt spray among families could result in microevolutionary changes in life span and mean seed mass, both of which impact annual fitness in this dunegrass.     

The role of nitric oxide synthase-derived reactive oxygen species in the altered relaxation of pulmonary arteries from lambs with increased pulmonary blood flow

Congenital cardiac defects associated with increased pulmonary blood flow (Q(p)) produce pulmonary hypertension. We have previously reported attenuated endothelium-dependent relaxations in pulmonary arteries (PA) isolated from lambs with increased Q(p) and pulmonary hypertension. To better characterize the vascular alterations in the nitric oxide-superoxide system, 12 fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt). Twin lambs served as controls. PA were isolated from these lambs at 4-6 wk of age. Electron paramagnetic resonance spectroscopy on fourth-generation PA showed significantly increased superoxide anion generation in shunt PA that were decreased to control levels following inhibition of nitric oxide synthase (NOS) with 2-ethyl-2-thiopseudourea. Preconstricted fifth-generation PA rings were relaxed with a NOS agonist (A-23187), a nitric oxide donor [S-nitrosyl amino penicillamine (SNAP)], polyethylene glycol-conjugated superoxide dismutase (PEG-SOD), or H(2)O(2). A-23187-, PEG-SOD-, and H(2)O(2)-mediated relaxations were impaired in shunt PA compared with controls. Pretreatment with PEG-SOD significantly enhanced the relaxation response to A-23187 and SNAP in shunt but not control PA. Inhibition of NOS with nitro-L-arginine or scavenging superoxide anions with tiron enhanced relaxation to SNAP and inhibited relaxation to PEG-SOD in shunt PA. Pretreatment with catalase inhibited relaxation of shunt PA to A-23187, SOD, and H(2)O(2). We conclude that NOS catalyzes the production of superoxide anions in shunt PA. PEG-SOD relaxes shunt PA by converting these anions to H(2)O(2), a pulmonary vasodilator. The redox environment, influenced by the balance between production and scavenging of ROS, may have important consequences on pulmonary vascular reactivity in the setting of increased Q(p).     

Pulmonary hemodynamics and gas exchange properties during progressive edema

In this investigation we have studied the effect of increments of pulmonary edema on pulmonary hemodynamics, and physiological and hemodynamic shunt in an isolated lung preparation. Hemodynamic shunt was defined by the slope of the relationship between pulmonary arterial and airway pressures; when the slope decreases, there is a greater degree of shunt. Cardiovascular changes were analyzed using a Starling resistor model of the pulmonary circulation where the effective downstream pressure to flow as seen from the pulmonary artery exceeds the pulmonary venous outflow pressure. This effective downstream pressure is referred to as the critical pressure (Pc), and at low lung inflation the locus of this critical pressure is in extra-alveolar vessels. With 3-4 h of progressive edema to an average of 185% initial lobe weight we found a progressive rise in pulmonary arterial pressure (Ppa) from 12.1 to 21.5 cmH2O. About one-third of this increase in Ppa resulted from an increased Pc and the remainder resulted from an increased resistance upstream from the locus of Pc. These results are consistent with the hypothesis that the interstitial accumulation of fluid creates enough of an increase in interstitial pressure to compress extra-alveolar vessels. There was no significant correlation between the amount of edema and the measured physiologic shunt, but the hemodynamic shunt showed a highly significant correlation. The hemodynamic shunt theoretically measures the extent of obstructed airways and may be a useful index of the degree of pulmonary edema.     

Characterization of a large form of DNA polymerase delta from HeLa cells that is insensitive to proliferating cell nuclear antigen

A large form of DNA polymerase delta from HeLa cells was recently purified in this laboratory as a factor required for conservative DNA synthesis in a reconstituted system utilizing UV-irradiated permeabilized human diploid fibroblasts (Nishida, C., Reinhard, P., and Linn, S. (1988) J. Biol. Chem. 263, 501-510). We have now purified this form of the enzyme utilizing its polymerase activity and further characterized it. The enzyme activity sediments at 11.1 S in low salt and 6.8 S in high salt. In both cases, activity cosediments with the major visible peptide displayed by sodium dodecyl sulfate-polyacrylamide gels which has an Mr of 215,000. This value is consistent with the molecular mass calculated from the sedimentation coefficient and gel filtration behavior in high salt. In low salt the apparent molecular mass was approximately double. The enzyme prefers poly(dA).oligo(dT) as template/primer in low salt, with which it has a processivity of several thousand nucleotides in 1 mM MgCl2. At isotonic KCl or potassium phosphate concentrations, the preferred template/primer is activated DNA. Proliferating cell nuclear antigen, also characterized as a DNA polymerase delta auxiliary protein, does not increase the activity of this preparation of the enzyme. An antibody to the proliferating cell nuclear antigen has no inhibitory effect, nor is it able to recognize any peptides in immunoblots of purified enzyme fractions. Under polymerizing conditions, the enzyme removes mismatched, but not matched nucleotides from the 3' terminus of oligo(dT) annealed to poly(dA) suggesting a proofreading function. The properties of this form of DNA polymerase delta distinguish it from other preparations reported in the literature.     

MicroRNA-208a Increases Myocardial Fibrosis via Endoglin in Volume Overloading Heart

MicroRNA-208a (mir-208a) is essential for cardiac hypertrophy and fibrosis. Endoglin, a co-receptor of transforming growth factor-β is also essential for cardiac fibrosis. Endoglin has been shown to be a target of mir-208a in the in vitro mechanical stress model. Volume overload can lead to heart failure and cardiac fibrosis. The role of mir-208a and endoglin in volume overload heart failure is well known. We sought to investigate the mechanism of regulation of mir-208a and endoglin in volume overload-induced heart failure. Aorta-caval (AV) shunt was performed in adult Sprague-Dawley rats to induce volume overload. Heart weight and heart weight/body weight ratio significantly increased in AV shunt animals. AV shunt significantly increased left ventricular end-diastolic dimension as compared to sham group. Mir-208a was significantly induced by AV shunt from 3 to 14 days. Endoglin, myosin heavy chain-β and brain natriuretic peptide were significantly induced by AV shunt from 3 to 14 days. Overexpression of mir-208a in the sham group without AV shunt significantly increased endoglin expression similar to the AV shunt group. Antagomir-208a attenuated the endoglin expression induced by AV shunt. Pretreatment with atorvastatin also attenuated the endoglin expression induced by AV shunt. AV shunt significantly increased myocardial fibrosis as compared to sham group. Overexpression of mir-208a in the sham group significantly increased myocardial fibrosis. Antagomir-208a and atorvastatin significantly attenuated the myocardial fibrosis induced by AV shunt. In conclusion, mir-208a increased endoglin expression to induce myocardial fibrosis in volume overloaded heart failure. Treatment with atorvastatin can attenuate the myocardial fibrosis induced by volume overload through inhibition of endoglin expression.     

Effect of a patent foramen ovale on pulmonary gas exchange efficiency at rest and during exercise

The prevalence of a patent foramen ovale (PFO) is ~30%, and this source of right-to-left shunt could result in greater pulmonary gas exchange impairment at rest and during exercise. The aim of this work was to determine if individuals with an asymptomatic PFO (PFO+) have greater pulmonary gas exchange inefficiency at rest and during exercise than subjects without a PFO (PFO-). Separated by 1 h of rest, 8 PFO+ and 8 PFO- subjects performed two incremental cycle ergometer exercise tests to voluntary exhaustion while breathing either room air or hypoxic gas [fraction of inspired O(2) (FI(O(2))) = 0.12]. Using echocardiography, we detected small, intermittent boluses of saline contrast bubbles entering directly into the left atrium within 3 heart beats at rest and during both exercise conditions in PFO+. These findings suggest a qualitatively small intracardiac shunt at rest and during exercise in PFO+. The alveolar-to-arterial oxygen difference (AaDo(2)) was significantly (P < 0.05) different between PFO+ and PFO- in normoxia (5.9 ± 5.1 vs. 0.5 ± 3.5 mmHg) and hypoxia (10.1 ± 5.9 vs. 4.1 ± 3.1 mmHg) at rest, but not during exercise. However, arterial oxygen saturation was significantly different between PFO+ and PFO- at peak exercise in normoxia (94.3 ± 0.9 vs. 95.8 ± 1.0%) as a result of a significant difference in esophageal temperature (38.4 ± 0.3 vs. 38.0 ± 0.3°C). An asymptomatic PFO contributes to pulmonary gas exchange inefficiency at rest but not during exercise in healthy humans and therefore does not explain intersubject variability in the AaDO(2) at maximal exercise.