Modeling Long-Term Facilitation of Respiration During Interval Exercise in Humans.

Long-term facilitation (LTF) of respiration has been mainly initiated by intermittent hypoxia and resultant chemoreceptor stimulation in humans. Comparable levels of chemoreceptor stimulation can occur in combined exercise and carbon dioxide (CO2) inhalation and lead to LTF. This possibility was supported by data collected during combined interval exercise and 3% inhaled CO2 in seven normal subjects. These data were further analyzed based on the dynamics involved using mathematical models in this study. Previously estimated peripheral chemoreceptor sensitivity during light exercise (40 W) with air or 3% inhaled CO2 approximately doubled resting sensitivity. Ventilation after a delay increased by 17.0 ± 2.48 L/min (p < 0.001) during recovery following 45% maximal oxygen uptake ([Formula: see text] ) exercise consistent with LTF which exceeded what can be achieved with intermittent hypoxia. Model fitting of the dynamic responses was used to separate neural from chemoreceptor-mediated CO2 responses. Exercise of 45% [Formula: see text] was followed by ventilation augmentation following initial recovery. Augmentation of LTF developed slowly according to second-order dynamics in accordance with plasticity involving a balance between self-excitatory and self-inhibitory neuronal pools.

Stoichiometry validation of supramolecular complexes with a hydrocarbon cage host by van 't Hoff analyses.

Defining chemical processes with equations is the first important step in characterizing equilibria for the assembly of supramolecular complexes, and the stoichiometry of the assembled components must be defined to generate the equation. Recently, this subject has attracted renewed interest, and statistical and/or information-theoretic measures were introduced to examine the validities of the equilibrium models used during curve fitting analyses of titration. The present study shows that these measures may not always be appropriate for credibility examinations and that further reformation of the protocols used to determine the overall stoichiometry is necessary. Hydrocarbon cage hosts and their chloroform complexes formed via weak CH-π hydrogen bonds were studied, which allowed us to introduce van 't Hoff analyses for effective validation of the stoichiometries of supramolecular complexes. This study shows that the stoichiometries of supramolecular complexes should be carefully examined by adopting multiple measures with different origins.

Associations between Comorbidities and Acute Exacerbation of Interstitial Lung Disease after Primary Lung Cancer Surgery.

Acute exacerbation (AE) of interstitial lung disease (ILD) is a severe complication of lung resection in lung cancer patients with ILD (LC-ILD). This study aimed to assess the predictive value of comorbidities other than ILD for postoperative AE in patients with LC-ILD. We retrospectively evaluated 68 patients with LC-ILD who had undergone lung resection. We classified them into two groups: those who had developed postoperative AE within 30 days after resection and those who had not. We analyzed patient characteristics, high-resolution computed tomography findings, clinical data, pulmonary function, and intraoperative data. The incidence of postoperative AEs was 11.8%. In univariate analysis, performance status (PS), honeycombing, forced vital capacity (FVC), and high hemoglobin A1c (HbA1c) levels without comorbidities were significantly associated with postoperative AE. Patients were divided into two groups according to cutoff levels of those four variables as determined by receiver operating characteristic curves, revealing that the rates of patients without postoperative AE differed significantly between groups. The present results suggested that preoperative comorbidities other than ILD were not risk factors for postoperative AE in patients with LC-ILD. However, a high preoperative HbA1c level, poor PS, low FVC, and honeycombing may be associated with postoperative AE of LC-ILD.

A minimal cage of a diamond twin with chirality.

A network of tetrahedral vertices can fill three-dimensional (3D) spaces in a beautiful and isotropic manner, which is found as diamonds with sp3-hybridized carbon atoms. Although a network of trigonal vertices (i.e., another form of carbon atoms with sp2-hybridization) naturally results in a lower-dimensional two-dimensional network of graphenes, an isotropic 3D arrangement of trigonal vertices has been of theoretical and mathematical interest, which has materialized as a proposal of a "diamond twin." We herein report the synthesis and optical resolution of a minimal cage of a chiral diamond-twin network. With triangular phenine units at 14 vertices, triply fused decagonal rings were assembled by forming 15 biaryl edges via coupling. A unique chirality of the network has been disclosed with the minimal cage, which may stimulate explorations of chiral carbonaceous materials.

Altered chemosensitivity to CO2 during exercise.

The effect of exercise on chemosensitivity to carbon dioxide (CO2 ) has been controversial. Most studies have been based on rebreathing to alter inspired CO2 which is poorly tolerated in exercise. Instead, inhaling a fixed 3% CO2 from rest to moderate exercise was found to be well tolerated by seven normal subjects enabling CO2 chemosensitivity to be studied with minimal negative reaction. Results showed that chemosensitivity to CO2 following 5-6 min of stimulation was significantly enhanced during mild exercise (p < 0.01). This motivated exploring how much of the dynamic ventilatory response to mild exercise breathing air could be predicted by a model with central and peripheral chemosensitivity. Chemoreceptor stimulation combined with hypercapnia has been associated with long-term facilitation of ventilation (LTF). 3% CO2 inhalation during moderate exercise led to ventilation augmentation consistent with LTF following 6 min of exercise in seven normal human subjects (p < 0.01). Increased ventilation could not be attributed to hypercapnia or metabolic changes. Moderate exercise breathing air resulted in significantly less augmentation. In conclusion, both peripheral and central chemosensitivity to CO2 increased in exercise with the peripheral chemoreceptors playing a dominant role. This separation of central and peripheral contributions was not previously reported. This chemoreceptor stimulation can lead to augmented ventilation consistent with LTF.

[Malignant Pleural Mesothelioma with High Serum Granulocyte Coronary Stimulating Factor].

A 38-year-old man was admitted to our hospital because of right chest pain and high fever. Chest X-ray and computed tomography scan revealed right pleural effusion and pleural thickness. Diagnosis of malignant mesothelioma was established by pleural biopsy. Serum level of granulocyte colony stimulating factor (G-CSF) was high. We performed extrapleural pneumonectomy which improved high fever and inflammation, however the patient died three months after surgery.

Modeling cerebral blood flow and ventilation instability due to CO2.

A minimal model of cerebral blood flow and respiratory control was developed to describe hypocapnic and hypercapnic responses. Important nonlinear properties such as cerebral blood flow changes with arterial partial pressure of carbon dioxide ([Formula: see text]) and associated time-dependent circulatory time delays were included. It was also necessary to vary cerebral metabolic rate as a function of [Formula: see text]. The cerebral blood flow model was added to a previously developed respiratory control model to simulate central and peripheral controller dynamics for humans. Model validation was based on previously collected data. The variable time delay due to brain blood flow changes in hypercapnia was an important determinant of predicted instability due to nonlinear interaction in addition to linear loop gain considerations. Peripheral chemoreceptor gains above a critical level, but within normal limits, were necessary to produce instability. Instability was observed in recovery from hypercapnia and hypocapnia. The 20-s breath-hold test appears to be a simple test of brain blood flow-mediated instability in hypercapnia. Brain blood flow was predicted to play an important role with nonlinear properties. There is an important interaction predicted by the current model between central and peripheral control mechanisms related to instability in hypercapnia recovery. Posthyperventilation breathing pattern can also reveal instability tied to brain blood flow. Previous data collected in patients with chronic obstructive lung disease were closely fitted with the current model and instability predicted. Brain vascular volume was proposed as a potential cause of instability despite cerebral autoregulation promoting constant brain flow.NEW & NOTEWORTHY Prior models of brain blood flow and respiratory control have not focused on instability. Time varying time delay resulting from brain blood flow changes due to carbon dioxide (CO2) and peripheral chemoreceptor gain were predicted to be important determinants of instability due to nonlinear interaction in addition to linear control loop gain. Time delay was assumed to be set by the ratio of brain arterial vascular volume and blood flow. This vascular volume was predicted to also significantly change with CO2.

Effect of 3% CO2 inhalation on respiratory exchange ratio and cardiac output during constant work-rate exercise.

BACKGROUND: The aim of this study was to examine whether the decrease in respiratory exchange ratio (RER) during constant work-rate exercise (CWE) with 3% carbon dioxide (CO2) inhalation could be caused by the combination of the decrease in CO2 output (V̇CO2) and the increase in oxygen uptake (V̇O2). In addition, we investigated the effect of 3% CO2 inhalation on cardiac output (Q̇) during CWE. METHODS: Seven males (V̇O2max: 44.1±6.4 mL/min/kg) carried out transitions from low-load cycling (baseline; 40w) to light intensity exercise (45% V̇O2 max; 89.3±12.5 W) and heavy intensity exercise (80% V̇O2max; 186.5±20.2 W) while inhaling normal air (Air) or an enriched CO2 gas (3% CO2, 21% O2, balance N2). Each exercise session was 6 min, and respiratory responses by Douglas bag technique and cardiac responses by thoracic bio-impedance method were measured during the experiment. RESULTS: Ventilation for 3% CO2 was higher than for air through the experiment (P<0.05). Steady and non-steady state RER and V̇CO2 for 3% CO2 were less than for air in both light and heavy intensities (P<0.05), but V̇O2 and Q̇ did not differ between the two conditions. CONCLUSIONS: 3% CO2 inhalation induced the decrease in RER during CWE at light and heavy intensities, which was due to the decrease in V̇CO2. The promoted ventilation with 3% CO2 did not lead to the increase in V̇O2. Moreover, 3% CO2 inhalation did not affect Q̇ during CWE at light and heavy intensities.

Prediction of Spirometric Indices Using Forced Oscillometric Indices in Patients with Asthma, COPD, and Interstitial Lung Disease.

Background and Objective: Spirometry is sometimes difficult to perform in elderly patients and patients with cognitive impairment. Forced oscillometry (FOT) is a simple, noninvasive technique used for measuring respiratory impedance. The aim of this study was to develop regression equations to estimate vital capacity (VC), forced vital capacity (FVC), and forced expiratory volume in 1 s (FEV1.0) on the basis of FOT indices and to evaluate the accuracy of these equations in patients with asthma, chronic obstructive pulmonary disease (COPD), and interstitial lung disease (ILD). Materials and Methods: We retrospectively included data on 683 consecutive patients with asthma (388), COPD (128), or ILD (167) in this study. We generated regression equations for VC, FVC, and FEV1.0 by multivariate linear regression analysis and used them to estimate the corresponding values. We determined whether the estimated data reflected spirometric indices. Results: Actual and estimated VC, FVC, and FEV1.0 values showed significant correlations (all r > 0.8 and P < 0.001) in all groups. Biases between the actual data and estimated data for VC, FVC, and FEV1.0 in the asthma group were -0.073 L, -0.069 L, and 0.017 L, respectively. The corresponding values were -0.064 L, 0.027 L, and 0.069 L, respectively, in the COPD group and -0.040 L, -0.071 L, and -0.002 L, respectively, in the ILD group. The estimated data in the present study did not completely correspond to the actual data. In addition, sensitivity for an FEV1.0/FVC ratio of <0.7 and the diagnostic accuracy for the classification of COPD grade using estimated data were low. Conclusion: These results suggest that our method is not highly accurate. Further studies are needed to generate more accurate regression equations for estimating spirometric indices based on FOT measurements.

[Influence of Inversion Time of Fat Suppression Methods on Measurement of Apparent Diffusion Coefficient].

Recently, tumor differentiation in various tissues has been performed by using the apparent diffusion coefficient (ADC) value. However, the influence of ADC value due to the different inversion time (TI) of fat suppression methods has not been reported yet. Therefore, the purpose of our study was to verify the influence of the different TI of fat suppression methods on the ADC value. ADC values were compared for diffusion-weighted imaging (DWI), using the short-TI inversion recovery (STIR) method and the spectral attenuated inversion recovery (SPAIR) method. For the STIR method, when TI was closed to the null point of each phantom, signal intensity decreased, and the ADC value thereby decreased. However, by the SPAIR method, signal intensity and ADC value were not affected by the inversion time. When using the STIR method, signal intensity decreased when the null point for each phantom was approached, which was thought to decrease the ADC value. In conclusion, when using STIR-DWI after contrast agent administration, the ADC value might have been affected by the TI.

[Pneumonia and Streptococcal Toxic Shock Syndrome Due to Group A Streptococci: A Case Report].

A 71-year-old woman who was undergoing immunosuppressive therapy presented with a 7-day history of productive cough and 2-day history of fever. She was diagnosed with severe pneumonia and septic shock. Meropenem, azithromycin, large amounts of fluids, and noradrenaline were administered, and high-flow nasal cannula oxygen therapy was provided. The gross appearance of the aspirated sputum was ginger-like, and the gram-positive cocci in chains were identified as group A beta-hemolytic streptococci (GAS), Streptococcus pyogenes. The blood sample culture test revealed negative results. Based on Stevens' criteria, the patient was finally diagnosed as having streptococcal toxic shock syndrome (STSS). Antibiotics were switched to ampicillin/sulbactam and clindamycin as an antitoxin treatment, and the patient was discharged on day 33. Serotypes of GAS were T1, M1, and emm1. Superantigens spe A, spe B, and spe F were present, and spe C was absent. These observations were compatible with the clinical features of hypotension. GAS is an uncommon cause of community-acquired pneumonia, which when potentially complicated with STSS can lead to a high mortality rate, and the rapid progression is particularly a striking feature. We should be aware that GAS can cause pneumonia, and antitoxin treatment can play a key role in STSS management.

Nonparametric Model of Smooth Muscle Force Production During Electrical Stimulation.

A nonparametric model of smooth muscle tension response to electrical stimulation was estimated using the Laguerre expansion technique of nonlinear system kernel estimation. The experimental data consisted of force responses of smooth muscle to energy-matched alternating single pulse and burst current stimuli. The burst stimuli led to at least a 10-fold increase in peak force in smooth muscle from Mytilus edulis, despite the constant energy constraint. A linear model did not fit the data. However, a second-order model fit the data accurately, so the higher-order models were not required to fit the data. Results showed that smooth muscle force response is not linearly related to the stimulation power.

A case of EGFR mutant lung adenocarcinoma that acquired resistance to EGFR-tyrosine kinase inhibitors with MET amplification and epithelial-to-mesenchymal transition.

EGFR mutant lung cancer responds to EGFR tyrosine kinase inhibitors (TKIs), but all patients eventually develop resistance to EGFR-TKIs. Herein we report a case of EGFR mutant lung adenocarcinoma that acquired resistance to EGFR-TKI with MET amplification and epithelial-to-mesenchymal transition (EMT). A 73-year-old woman was diagnosed with adenocarcinoma harboring an EGFR exon 19 deletion. She received gefitinib as second-line therapy. Tumors were reduced 1 month after gefitinib therapy. However, only a few months later, chest computed tomography results indicated cancer progression. Gefitinib therapy was stopped and docetaxel therapy started. However, she died 13 days after admission. Microscopic examination of postmortem specimens revealed a diffuse proliferation of atypical giant cells in primary and metastatic lesions, but no adenocarcinomatous components as in the antemortem specimens. Immunohistochemical analyses showed that antemortem tumor specimens were positive for CDH1 but negative for VIM. In contrast, postmortem tumor specimens were positive for VIM but negative for CDH1. Genetic analyses revealed MET amplification. We concluded that resistance to EGFR-TKI might be caused by MET amplification and EMT. To our knowledge, no clinical studies have reported that MET amplification and EMT together may be associated with acquired resistance to EGFR-TKI. Second biopsy after the development of EGFR-TKI resistance may be recommended to determine the best therapeutic strategy.

Modeling rate sensitivity of exercise transient responses to limb motion.

Transient responses of ventilation (V̇e) to limb motion can exhibit predictive characteristics. In response to a change in limb motion, a rapid change in V̇e is commonly observed with characteristics different than during a change in workload. This rapid change has been attributed to a feed-forward or adaptive response. Rate sensitivity was explored as a specific hypothesis to explain predictive V̇e responses to limb motion. A simple model assuming an additive feed-forward summation of V̇e proportional to the rate of change of limb motion was studied. This model was able to successfully account for the adaptive phase correction observed during human sinusoidal changes in limb motion. Adaptation of rate sensitivity might also explain the reduction of the fast component of V̇e responses previously reported following sudden exercise termination. Adaptation of the fast component of V̇e response could occur by reduction of rate sensitivity. Rate sensitivity of limb motion was predicted by the model to reduce the phase delay between limb motion and V̇e response without changing the steady-state response to exercise load. In this way, V̇e can respond more quickly to an exercise change without interfering with overall feedback control. The asymmetry between responses to an incremental and decremental ramp change in exercise can also be accounted for by the proposed model. Rate sensitivity leads to predicted behavior, which resembles responses observed in exercise tied to expiratory reserve volume.

Effect of hypercapnia on changes in blood pH, plasma lactate and ammonia due to exercise.

The present study examined the effects of hypercapnia on changes in blood pH, plasma lactate and ammonia due to exhaustive exercise. Six male subjects underwent exercise of increasing intensity until exhaustion: (1) breathing air = MAX (maximal exercise), or (2) under hypercapnia (HC: 21% O(2), 6% CO(2)) that had been maintained from 60 min before to 30 min after exercise = HC; and (3) exercise of the same intensity as HC in air = SUB (submaximal exercise). Arterialized blood was drawn from a superficial vein. Blood pH in HC was significantly lower than in MAX or SUB at rest, at the end of exercise and throughout recovery (P<0.05). Plasma lactate and ammonia concentration in HC was significantly lower than in MAX (P<0.05), and similar to that in SUB at the end of exercise and throughout recovery. Respiratory acidosis resulting from hypercapnia shifted the linear lactate to blood pH relationship during exhaustive exercise below that at normocapnia (P<0.001). The reduced slope of linear blood pH to ammonia relationship under hypercapnia (P<0.001) is attributed to lactic acidosis that is less, due to the lesser work intensity at the end of exhaustion, than that of normocapnia. From these results we conclude that (1) hypercapnia-induced respiratory acidosis promoted the decrease in blood pH due to lactate production throughout recovery; (2) plasma lactate concentration at maximal exercise was lowered under hypercapnia; (3) plasma ammonia concentration at maximal exercise was reduced, probably due to a less intense lactic acidosis.

Effect of low oxygen inhalation on changes in blood pH, lactate, and ammonia due to exercise.

The present study examined the effect of hypoxia-induced respiratory alkalosis on exercise-induced metabolic acidosis and increases in plasma lactate and ammonia levels. Six male subjects underwent exercise of increasing intensity until exhaustion: (1) in normoxia (20.9% O(2)) (=MAX), (2) in hypoxia (12% O(2)) (=HP) in which hypoxic condition had been maintained from 60 min before to 30 min after exercise, and (3) the same intensity of exercise as HP in normoxia (=SUB). Arterialized blood was drawn from a superficial vein. Post-exercise blood pH was significantly higher in HP than in MAX ( P<0.05), although plasma lactate was at the same level. For hypoxia as compared to normoxia, regression analysis confirmed a parallel shift of plasma lactate to higher pH levels indicating the effect of respiratory alkalosis ( P<0.01). After exercise plasma levels of ammonia were lower in HP than in MAX ( P<0.05). Regression analysis between ammonia and pH revealed nearly identical changes in hypoxia and normoxia at low pH. From these results, we conclude that: (1) hypoxia-induced respiratory alkalosis attenuated exhaustive exercise-induced metabolic acidosis, (2) plasma lactate concentration was determined by the relative exercise intensity, (3) the maximum plasma ammonia concentration under exhaustive exercise was reduced at hypoxia because of respiratory alkalosis.