Relationship between disturbances of CO2 homeostasis and force output characteristics during isometric knee extension.

To determine whether disturbances of CO2 homeostasis alter force output characteristics of lower limb muscles, participants performed four isometric knee extension trials (MVC30 %, 10 s each with 20-s rest intervals) in three CO2 conditions (normocapnia [NORM], hypercapnia [HYPER], and hypocapnia [HYPO]). Respiratory frequency and tidal volume were matched between CO2 conditions. In each MVC30 %, the participants exerted a constant force (30 % of maximum voluntary contraction [MVC]). The force coefficient of variation (Fcv) during each MVC30 % and MVC before and after the four MVC30 % trials were measured. For the means of the four trials, Fcv was significantly lower in HYPER than in HYPO. However, within HYPER, a significant positive correlation was found between the increase in end-tidal CO2 partial pressure and the increase in Fcv. MVCs in NORM and HYPO decreased significantly over the four trials, while no such reduction was observed in HYPER. These results suggest that perturbed CO2 homeostasis influences the force output characteristics independently of breathing pattern variables.

Enhancement of self-sustained muscle activity through external dead space ventilation appears to be associated with hypercapnia.

We reported that external dead space ventilation (EDSV) enhanced self-sustained muscle activity (SSMA) of the human soleus muscle, which is an indirect observation of plateau potentials. However, the main factor for EDSV to enhance SSMA remains unclear. The purpose of the present study was to examine the effects of EDSV-induced hypercapnia, hypoxia, and hyperventilation on SSMA. In Experiment 1 (n = 11; normal breathing [NB], EDSV, hypoxia, and voluntary hyperventilation conditions) and Experiment 2 (n = 9; NB and normoxic hypercapnia [NH] conditions), SSMA was evoked by electrical train stimulations of the right tibial nerve and measured using surface electromyography under each respiratory condition. In Experiment 1, SSMA was significantly higher than that in the NB condition only in the EDSV condition (P < 0.05). In Experiment 2, SSMA was higher in the NH condition than in the NB condition (P < 0.05). These results suggest that the EDSV-enhanced SSMA is due to hypercapnia, not hypoxia or increased ventilation.

Effects of sustained unilateral handgrip on corticomotor excitability in both knee extensor muscles.

PURPOSE: Repetitive or sustained simple muscle contractions have been shown to alter corticomotor excitability. The present study investigated the effects of a sustained handgrip contraction with the right hand on motor-evoked potentials (MEPs) in task-unrelated knee extensor muscles and determined whether the effects are influenced by intensity of the handgrip contraction. METHODS: Subjects performed a 120-s sustained handgrip contraction at 10% or 50% maximal voluntary contraction (MVC) using the right hand. MEPs in vastus lateral (VL) muscles elicited by transcranial magnetic stimulation were measured before, during, and after the handgrip contraction. RESULTS: Both the handgrip contractions at 10 and 50% MVC induced significant greater MEPs in the left VL muscle (121.5 ± 25.7%) than in the right VL muscle (97.9 ± 17.4%) from 10 min after the handgrip contraction (P < 0.05). MEPs in both the right and left VL muscles were significantly increased by the handgrip contractions at 10% MVC (124.8 ± 45.2%, P < 0.05), but were not increased by the handgrip contractions at 50% MVC. CONCLUSION: The results of the present study indicate that a unilateral sustained handgrip contraction can differentially alter corticomotor excitability in knee extensor muscles ipsilateral and contralateral to the exercised hand after the handgrip and that the intensity of the handgrip contraction influences corticomotor excitability in both knee extensor muscles after the handgrip.

Morning Mastication Enhances Postprandial Glucose Metabolism in Healthy Young Subjects.

Postprandial glucose concentration is dependent on the time of day and its concentration in the morning is lower than in the evening. However, whether it is dependent on mastication at different times of the day has not been studied before. We hypothesized that mastication affects insulin-mediated glucose metabolism differently in the morning and evening in healthy individuals. Firstly, nine healthy male volunteers (22.0 ± 0.7 SEM years, body mass index 22.0 ± 1.0 kg/m2) performed a 75-g oral glucose tolerance test (OGTT). One week after the OGTT, they participated in a high-carbohydrate food (rice) consumption test with 10 or 40 chews per mouthful. Each experiment was conducted in the morning (0800 h) and evening (2000 h) on the same day. Blood samples were collected before and at 30-min intervals for 120 min after glucose or rice consumption. The incremental area under the curve (iAUC) for glucose in the OGTT was significantly lower in the morning than in the evening, whereas the iAUC for insulin was similar at both times. In participants who chewed 40 times, the iAUC for glucose after rice consumption was significantly lower in the morning than in the evening but was similar at both times in individuals who chewed 10 times. Chewing 40 times in the morning (but not the evening) significantly increased insulin secretion at 30 min. This suggests that morning mastication improves early-phase insulin secretion after rice consumption. This novel finding may aid in reducing the incidence of obesity and type 2 diabetes mellitus.

Cathepsin S, a new serum biomarker of sarcoidosis discovered by transcriptome analysis of alveolar macrophages.

BACKGROUND: Development of reliable new biomarkers remains crucial to improve diagnosis and assessing disease activity in sarcoidosis. The objective of this study was to seek such markers from the gene expression signature of alveolar macrophages by transcriptome analysis. METHODS: Pooled RNA extracted from alveolar macrophages from patients with active sarcoidosis and control patients was subjected to transcriptome analysis using microarrays. Expressed gene intensity in sarcoidosis relative to that in control was calculated. We measured serum cathepsin S (CTSS) concentrations in 89 healthy volunteers, 107 patients with sarcoidosis, 26 with interstitial pneumonia, 150 with pneumoconiosis, and 76 with pulmonary mycobacteriosis by the enzyme-linked immunosorbent assay. RESULTS: Among 12 genes with ratios higher than that of a housekeeping gene, we selected CTSS for scrutinizing protein expression in serum because of the feasibility of the protein assay. CTSS concentrations were significantly increased in sarcoidosis compared with not only controls but also all the other lung diseases. Receiver operating characteristics curve for sarcoidosis and parenchymal lung diseases revealed an area under the curve of 0.800 (95% confidence interval, 0.751-0.850; p=1.4 x 10-18) with 70% sensitivity and 78% specificity at a CTSS concentration of 15.5 ng/ml. A significant trend was identified between CTSS concentrations and the number of affected organs. Serum CTSS concentrations varied in parallel with clinical courses both spontaneously and in response to corticosteroid therapy. Epithelioid cells in granulomas were positive for immunohistochemical staining with CTSS. CONCLUSIONS: CTSS has the potential to be a useful biomarker in sarcoidosis.

Computed tomography findings of arc-welders' pneumoconiosis: Comparison with silicosis.

OBJECTIVE: Arc-welders' pneumoconiosis (AWP) is a less fibrogenic pneumoconiosis with radiographic shadows that can improve after isolation from dusty environments. Therefore, early diagnosis is important. However, the exact role of chest radiograph and computed tomography (CT) for diagnosing AWP is not fully understood. This study was performed to assess the CT appearance of AWP using semi-quantitative methods and to compare the findings with those of silicosis. The profusion of pulmonary abnormality on chest radiograph were also compared with the semi-quantitative CT score. MATERIALS AND METHODS: Sixty-six patients with clinically diagnosed AWP were included and compared with 33 patients with silicosis. The CT images were interpreted according to the International Classification of HRCT for Occupational and Environmental Respiratory Diseases (ICOERD). Data on the profusion score by chest radiograph were also compared with CT score. RESULTS: Ill-defined centrilobular nodules, ground-glass opacity (GGO) and centrilobular branching opacity were more frequently observed (p = 0.0031) in AWP, whereas well-defined rounded opacity (p < 0.0001), progressive massive fibrosis (p < 0.0001), and mediastinal lymphadenopathy (p < 0.0001) were more frequently observed in silicosis. Regarding lung nodules, there was a high correlation between the ICOERD and CXR profusion scores in silicosis, but CXR underestimated AWP. CONCLUSION: Ill-defined centrilobular nodules, GGO and centrilobular branching opacity were more frequently observed in AWP than silicosis. Because these findings are difficult to detect by chest radiograph, CT should be considered for the assessment of patients with suspected AWP.

Effect of hypercapnia on self-sustained muscle activity.

The aim of the present study was to determine the effect of hypercapnia on motor neuromuscular activity of the human triceps surae muscle. Nine subjects participated in trials in a normal breathing condition and a CO2 rebreathing condition. In both conditions, in order to provoke self-sustained muscle activity, percutaneous electrical train stimulation was applied to the tibial nerve while each subject lay on a bed. Self-sustained muscle activity, which is an indirect observation of plateau potentials in spinal motoneurons, was measured for 30 s after the train stimulation by using surface electromyography. The sustained muscle activity was increased by CO2 rebreathing (P < 0.05). This finding suggests that motor neuromuscular activity may be linked to the respiratory system that is activated during hypercapnia.

Clinical significance of serum anti-GM-CSF autoantibody levels in autoimmune pulmonary alveolar proteinosis.

AIM: Precise clinical significance of antigranulocyte-macrophage colony stimulating factor (GM-CSF) autoantibody levels in autoimmune pulmonary alveolar proteinosis (aPAP) has not been well studied. METHODS: We obtained sera from 50 healthy controls, 46 aPAP patients, 50 with sarcoidosis, 52 with idiopathic interstitial pneumonia and 75 with pneumoconiosis. The clinical course of aPAP patients was assessed by scoring computed tomography images in 19 patients. RESULTS: The cut-off level of anti-GM-CSF IgG for discrimination between aPAP and other diffuse lung diseases was 2.8 µg/ml with 100% sensitivity and 98% specificity. Antibody levels at baseline were significantly lower in the improved group than in the unimproved group (p = 0.008). CONCLUSION: Our results indicate the existence of threshold levels of serum anti-GM-CSF IgG for the development and persistence of aPAP.

Relationship between motor corticospinal excitability and ventilatory response during intense exercise.

PURPOSE: Effort sense has been suggested to be involved in the hyperventilatory response during intense exercise (IE). However, the mechanism by which effort sense induces an increase in ventilation during IE has not been fully elucidated. The aim of this study was to determine the relationship between effort-mediated ventilatory response and corticospinal excitability of lower limb muscle during IE. METHODS: Eight subjects performed 3 min of cycling exercise at 75-85 % of maximum workload twice (IE1st and IE2nd). IE2nd was performed after 60 min of resting recovery following 45 min of submaximal cycling exercise at the workload corresponding to ventilatory threshold. Vastus lateralis muscle response to transcranial magnetic stimulation of the motor cortex (motor evoked potentials, MEPs), effort sense of legs (ESL, Borg 0-10 scale), and ventilatory response were measured during the two IEs. RESULTS: The slope of ventilation (l/min) against CO2 output (l/min) during IE2nd (28.0 ± 5.6) was significantly greater than that (25.1 ± 5.5) during IE1st. Mean ESL during IE was significantly higher in IE2nd (5.25 ± 0.89) than in IE1st (4.67 ± 0.62). Mean MEP (normalized to maximal M-wave) during IE was significantly lower in IE2nd (66 ± 22 %) than in IE1st (77 ± 24 %). The difference in mean ESL between the two IEs was significantly (p < 0.05, r = -0.82) correlated with the difference in mean MEP between the two IEs. CONCLUSIONS: The findings suggest that effort-mediated hyperventilatory response to IE may be associated with a decrease in corticospinal excitability of exercising muscle.

Association between Smoking Status and Obesity in a Nationwide Survey of Japanese Adults.

OBJECTIVE: A positive association between the number of cigarettes smoked per day and obesity has been reported, whereas how other smoking-related indices, such as pack-years and duration of smoking, are related with obesity has been less investigated. We analyzed the age-adjusted cross-sectional association between smoking and obesity in a general Japanese population. METHODS: We used data from a nationwide epidemiological study of Japanese adults (N = 23,106). We compared the prevalence of obesity (defined as body mass index ≥ 25kg/m2) among groups classified by smoking behavior, pack-years, number of cigarettes per day, duration of smoking, and duration and time of smoking cessation. RESULTS: In men, current smokers had a lower odds ratio (OR) for obesity of 0.80 (95% confidence interval (CI): 0.72-0.88) compared to non-smokers, whereas past smokers had a higher OR of 1.23 (95% CI: 1.09-1.37) compared to current smokers. In women, there were no differences in obesity between the three groups classified by smoking behavior. However, in both sexes, the prevalence of obesity tended to increase with pack-years and the number of cigarettes per day, but not with duration of smoking in current and past smokers. Further, in male smokers, the risks for obesity were markedly higher in short-term heavy smokers compared with long-term light smokers, even with the same number of pack-years. Regarding the impact of smoking cessation, female past smokers who quit smoking at an age > 55-years had an elevated OR of 1.60 (95% CI:1.05-2.38) for obesity. CONCLUSIONS: In a general Japanese population, obesity is progressively associated with pack-years and number of cigarettes per day, but not with the duration of smoking. When investigating the association between obesity and cigarette smoking, the daily smoking burden and the duration of smoking require to be independently considered.

Voluntary breathing increases corticospinal excitability of lower limb muscle during isometric contraction.

The aim of the present study was to determine the effects of voluntary breathing on corticospinal excitability of a leg muscle during isometric contraction. Seven subjects performed 5-s isometric knee extension at the intensity of 10% of maximal voluntary contraction (10% MVC). During the 10% MVC, the subjects were instructed to breath normally (NORM) or to inhale (IN) or exhale (OUT) once as fast as possible. Motor-evoked potentials (MEPs) induced by transcranialmagnetic stimulation in the right vastus lateralis (VL) during the 10% MVC were recorded and compared during the three breathing tasks. MEPs in IN and OUT were significantly higher than that in NORM. Effort sense of breathing was significantly higher in IN and OUT than in NORM. There was a significant positive correlation between MEP and effort sense of breathing. These results suggest that activation of the breathing-associated cortical areas with voluntary breathing is involved in the increase in corticospinal excitability of the VL during isometric contraction.

Blood viscometer applying electromagnetically spinning method.

Viscosity is an important parameter which affects hemodynamics during extracorporeal circulation and long-term cardiac support. In this study, we have aimed to develop a novel viscometer with which we can easily measure blood viscosity by applying the electromagnetically spinning (EMS) method. In the EMS method, we can rotate an aluminum ball 2 mm in diameter indirectly in a test tube with 0.3 ml sample of a liquid by utilizing the moment caused by the Lorentz force as well as separate the test tube from the viscometer body. First, we calibrated the EMS viscometer by means of liquid samples with known viscosities and computational fluid dynamics. Then, when we measured the viscosity of 9.4 mPa s silicone oil in order to evaluate the performance of the EMS viscometer, the mean viscosity was found to be 9.55 ± 0.10 mPa s at available shear rates from 10 to 240 s(-1). Finally, we measured the viscosity of bovine blood. We prepared four blood samples whose hematocrit levels were adjusted to 23, 45, 50, and 70% and a plasma sample without hemocyte components. As a result, the measurements of blood viscosities showed obedience to Casson's equation. We found that the viscosity was approximately constant in Newtonian silicone oil, whereas the viscosity decreased with increasing shear rate in non-Newtonian bovine blood. These results suggest that the EMS viscometer will be useful to measure blood viscosity at the clinical site.

Progression of pneumoconiosis in coal miners after cessation of dust exposure: a longitudinal study based on periodic chest X-ray examinations in Hokkaido, Japan.

BACKGROUND: The progression rate of pneumoconiosis in retired coal miners over ten years has not been studied in Japan. METHODS: A retrospective longitudinal study was undertaken using chest X-rays of 1091 pneumoconiosis subjects in Hokkaido, Japan between 1985 and 2005. RESULTS: The final numbers of subjects were 207 (19% of the entry) after 1 decade and 85 (8%) after 2 decades. Sixty-two percent of 207 subjects after 1 decade and 29% of 85 showed progression in 2 decades. Thirty-one percent of ILO category 1 and 55% of category 2 subjects showed progression to complicated pneumoconiosis after 1 decade, and 6% (4 of 64) of category 1 and 6% (5 of 77) of category 2 subjects progressed to complicated pneumoconiosis during 2 decades. CONCLUSION: The progression of pneumoconiosis was observed after the cessation of dust exposure, especially during the first 10 years.

Knockdown of macrophage migration inhibitory factor disrupts adipogenesis in 3T3-L1 cells.

Obesity is a condition in which adipose tissue mass is expanded. Increases in both adipocyte size and number contribute to enlargement of adipose tissue. The increase in cell number is thought to be caused by proliferation and differentiation of preadipocytes. Macrophage migration inhibitory factor (MIF) is expressed in adipocytes, and intracellular MIF content is increased during adipogenesis. Therefore, we hypothesized that MIF is associated with adipocyte biology during adipogenesis and focused on the influence of MIF on adipogenesis. To examine the effects of MIF on adipocytes, MIF expression in 3T3-L1 preadipocytes was inhibited by RNA interference, and cell differentiation was induced by standard procedures. The triglyceride content of MIF small interfering RNA (siRNA)-transfected 3T3-L1 cells was smaller than that of nonspecific siRNA-transfected cells. In addition, MIF knockdown apparently abrogated increases in adiponectin mRNA levels during differentiation. Gene expression of peroxisome proliferator-activated receptor (PPAR)gamma, CCAAT/enhancer binding protein (C/EBP)alpha, and C/EBPdelta decreased with MIF siRNA transfection, but C/EBPbeta expression increased. Cell number and incorporation of 5-bromo-2-deoxyuridine into cells decreased from 1-3 d and from 14-20 h, respectively, after induction of differentiation in MIF siRNA-transfected cells, thus suggesting that MIF siRNA inhibits mitotic clonal expansion. Taken together, these results indicated that MIF regulates differentiation of 3T3-L1 preadipocytes, at least partially, through inhibition of mitotic clonal expansion and/or C/EBPdelta expression.

Mannose-binding lectin gene polymorphisms and the development of coal workers' pneumoconiosis in Japan.

BACKGROUND: Infection, immunity and genetic factors play roles in the development of coal worker's pneumoconiosis (CWP) and progressive massive fibrosis (PMF). We investigate whether the genetic polymorphisms of mannose-binding lectin (MBL), one of the key molecules of innate immunity, is associated with the susceptibility to CWP. METHOD: MBL2 polymorphisms (codon54, promoter -221, and -550) were assessed for 197 patients with CWP (119 with nodular CWP and 78 with PMF) and 153 unexposed regional controls. Serum MBL concentrations were measured in 119 CWP patients. RESULTS: Three polymorphisms were in linkage disequilibrium for all study populations. The MBL2 genotype and haplotypes were associated with lower serum MBL levels. The frequency of such MBL2 genotype and haplotypes were significantly higher in patients with CWP compared to controls, whereas these distributions were not different between patients with nodular CWP and those with PMF. CONCLUSION: MBL2 polymorphisms and haplotypes may be one of the genetic determinants for the susceptibility of CWP.

Autoantibody to alanyl-tRNA synthetase in patients with idiopathic pulmonary fibrosis.

BACKGROUND AND OBJECTIVES: The pathogenesis of IPF is unknown and it is hypothesized that immunological responses are involved. The purpose of this study was to detect autoantibodies in IPF patients and to identify the relevant antigens. METHODS: Sera from 37 healthy subjects and 22 IPF patients who had no clinical symptoms of collagen vascular disease were examined for immunostaining of A549 human type II cells and human lung tissue. Immunoprecipitation and proteome analysis were performed to identify the antigen. RESULTS: Fifty per cent of the patient sera and none of the control sera exhibited positive staining. Sera from 10 of the 22 IPF patients showed positive immunohistochemistry and immunoprecipitated a 110-kDa protein from the A549 cell lysate. Sera from only two of 41 patients with collagen vascular disease showed positive immunoreactivity. Proteome analysis using tandem mass spectrometry revealed that the protein was alanyl-tRNA synthetase. Transfection of cDNA of this enzyme into CHO-K1 cells conferred positive staining on these cells with the patients' IgG. The 135-kDa fusion protein consisting of 108-kDa enzyme protein and 27-kDa YFP from the cell lysate of the transfected cells was immunoprecipitated by the patient IgG. In addition, sera from IPF patients significantly inhibited the enzyme activity of alanyl-tRNA synthetase. CONCLUSION: A significant number of IPF patients possess circulating autoantibodies against alanyl-tRNA synthetase, suggesting the involvement of an autoimmune background in the pathogenesis of IPF.

Estimation of beta-cell function from the data of the oral glucose tolerance test.

Although a hyperbolic relationship between insulin secretion and insulin sensitivity has been shown, the relationship has been often questioned. We examined the relationship using oral glucose tolerance test (OGTT)-derived indexes. A total of 374 Japanese subjects who had never been given a diagnosis of diabetes underwent a 75-g OGTT. In subjects with normal glucose tolerance (NGT), the ln [insulinogenic index (IGI)] was described by a linear function of ln (x) (x, insulin sensitivity index) in regression analysis when the reciprocal of the insulin resistance index in homeostasis model assessment, Matsuda's index, and oral glucose insulin sensitivity index were used as x. Because the 95% confidence interval of the slope of the regression line did not necessarily include -1, the relationships between IGI and x were not always hyperbolic, but power functions IGI x x(alpha) = a constant. We thought that IGI x x(alpha) was an appropriate beta-cell function estimate adjusted by insulin sensitivity and referred to it as beta-cell function index (BI). When Matsuda's index was employed as x, the BI values were decreased in subjects without NGT. Log BI had a better correlation with fasting plasma glucose (PG; FPG) and 2-h PG in non-NGT subjects than in NGT subjects. In subjects with any glucose tolerance, log BI was linearly correlated with 1-h PG and glucose spike (the difference between maximum PG and FPG). In conclusion, the relationship between insulin secretion and insulin sensitivity was not always hyperbolic. The BI is a useful tool in the estimation of beta-cell function with a mathematical basis.

[A case of lung tuberculosis showing no chest radiograph findings with recurrent hemoptysis].

A 59-year-old male was referred to our hospital because of hemoptysis. A chest X-ray film and 7 mm-slice CT scan showed no abnormal finding. Bronchoscopy revealed hemorrhage in the right upper bronchus (B1a) Bronchial lavage of the lesion was performed, but Mycobacterium tuberculosis was not detected. Because of repeated hemoptysis, he was admitted to our hospital. Right bronchial artery angiograph showed vascular hyperplasia in the peripheral part of the upper lobal branch, and this lesion was suggested to be a bleeding point. There were no vascular malformations. Thin slice (0.5 mm-thick) CT scan showed mild infiltrative shadow in the right upper lobe. After admission, sputa smear for mycobacteria and PCR for M. tuberculosis became positive, and he was diagnosed as pulmonary tuberculosis. After starting antituberculous chemotherapy, hemoptysis disappeared, and sputa smear and culture for mycobacteria converted to negative. This case suggests that lung tuberculosis should be suspected in patients having hemoptysis, even though they had no chest X-ray film abnormality.

[A case of advanced double cancer of the lung and stomach responding to combination chemotherapy of cisplatin and TS-1].

A 76-year-old male patient was diagnosed with advanced double cancer of the lung and stomach. He had also been suffering from interstitial pneumonitis for several years. He was treated with combination of cisplatin and TS-1. TS-1 (120 mg/body/day) was administered for 21 days from day 1, and cisplatin (60 mg/m(2)) was given on day 8 followed by a 14-days interval. After two courses of chemotherapy,the dose of cisplatin was reduced to 48 mg/m(2) because of grade 1 serum creatinine elevation. The lesions of the lung and stomach were improved significantly without exacerbation of the interstitial pneumonitis.