Role of transient receptor potential vanilloid 4 in therapeutic antifibrotic effects of pirfenidone.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fatal lung disorder characterized by aberrant extracellular matrix deposition in the interstitium. Pirfenidone is an antifibrotic agent used to treat patients with IPF. Pirfenidone shows a pleiotropic mode of action, but its underlying antifibrotic mechanism is unclear. Transient receptor potential vanilloid 4 (TRPV4), which is a mechanosensitive calcium channel, was recently shown to be related to pulmonary fibrosis. To clarify the antifibrotic mechanisms of pirfenidone, we investigated whether TRPV4 blockade has a pharmacological effect in a murine model of pulmonary fibrosis and whether pirfenidone contributes to suppression of TRPV4. Our synthetic TRPV4 antagonist and pirfenidone treatment attenuated lung injury in the bleomycin mouse model. TRPV4-mediated increases in intracellular calcium were inhibited by pirfenidone. In addition, TRPV4-stimulated interleukin-8 release from cells was reduced and a delay in cell migration was abolished by pirfenidone. Furthermore, pirfenidone decreased TRPV4 endogenous ligands in bleomycin-administered mouse lungs and their production by microsomes of human lungs. We found TRPV4 expression in the bronchiolar and alveolar epithelium and activated fibroblasts of the lungs in patients with IPF. Finally, we showed that changes in forced vital capacity of patients with IPF treated with pirfenidone were significantly correlated with metabolite levels of TRPV4 endogenous ligands in bronchoalveolar lavage fluid. These results suggest that the antifibrotic action of pirfenidone is partly mediated by TRPV4 and that TRPV4 endogenous ligands in bronchoalveolar lavage fluid may be biomarkers for distinguishing responders to pirfenidone.

Achilles Tendon Length Is Not Related to 100-m Sprint Time in Sprinters.

This study examined the relationship between Achilles tendon (AT) length and 100-m sprint time in sprinters. The AT lengths at 3 different portions of the triceps surae muscle in 48 well-trained sprinters were measured using magnetic resonance imaging. The 3 AT lengths were calculated as the distance from the calcaneal tuberosity to the muscle-tendon junction of the soleus, gastrocnemius medialis, and gastrocnemius lateralis, respectively. The absolute 3 AT lengths did not correlate significantly with personal best 100-m sprint time (r = -.023 to .064, all Ps > .05). Furthermore, to minimize the differences in the leg length among participants, the 3 AT lengths were normalized to the shank length, and the relative 3 AT lengths did not correlate significantly with personal best 100-m sprint time (r = .023 to .102, all Ps > .05). Additionally, no significant correlations were observed between the absolute and relative (normalized to body mass) cross-sectional areas of the AT and personal best 100-m sprint time (r = .012 and .084, respectively, both Ps > .05). These findings suggest that the AT morphological variables, including the length, may not be related to superior 100-m sprint time in sprinters.

Correction to: Surfactant protein A as a biomarker of outcomes of anti-fibrotic drug therapy in patients with idiopathic pulmonary fibrosis.

Following publication of the original article [1], the authors have flagged that there is an error in Fig. 3.

Surfactant protein A as a biomarker of outcomes of anti-fibrotic drug therapy in patients with idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive and fibrosing lung disease with poor prognosis. Pirfenidone and nintedanib are anti-fibrotic drugs used for patients with IPF. These drugs reduce the rate of decline in forced vital capacity (FVC). Serum surfactant protein (SP)-A, SP-D, and Krebs von den Lungen-6 (KL-6) are monitoring and prognostic biomarkers in patients with IPF; however, their relationship with the therapeutic outcomes of anti-fibrotic drugs has not been investigated. We aim to clarify whether serum SP-A, SP-D, and KL-6 reflect therapeutic outcomes of pirfenidone and nintedanib administration in patients with IPF. METHODS: We retrospectively investigated patients with IPF who were initiated on pirfenidone or nintedanib administration between January 2014 and June 2018 at our hospital. Changes in clinical parameters and serum SP-A, SP-D, and KL-6 levels were evaluated. Patients with ≥10% decline in FVC or ≥ 15% decline in diffusing capacity of the lung for carbon monoxide (DLco) from baseline to 6 months were classified as progression group, while the other patients were classified as stable group. RESULTS: Forty-nine patients were included (pirfenidone, 23; nintedanib, 26). Stable group comprised 32 patients, while progression group comprised 17 patients. In the stable group, changes in SP-A and KL-6 from baseline to 3 and 6 months significantly decreased compared with the progression group (SP-A: 3 months - 6.0% vs 16.7%, 6 months - 10.2% vs 20.2%, KL-6: 3 months - 9.2% vs 6.7%, 6 months - 15.0% vs 12.1%, p < 0.05). Changes in SP-A and SP-D levels showed significant negative correlations with the change in %FVC (r = - 0.46 and r = - 0.39, p < 0.01, respectively) and %DLco (r = - 0.67 and r = - 0.54, p < 0.01, respectively). Similar results were also seen in subgroup analysis for both pirfenidone and nintedanib groups. On logistic regression analysis, decrease in SP-A from baseline to 3 months and 6 months was found to predict the outcomes at 6 months (odds ratios: 0.89 and 0.88, respectively). CONCLUSIONS: Changes in serum SP-A reflected the outcomes of anti-fibrotic drug therapy. Serum SP-A has a potential as a biomarker of therapeutic outcomes of anti-fibrotic drugs.

Insufficient serum L-ficolin is associated with disease presence and extent of pulmonary Mycobacterium avium complex disease.

BACKGROUND: The incidence of infectious disease caused by nontuberculous mycobacteria is increasing worldwide. Pulmonary Mycobacterium avium complex (MAC) disease is difficult to treat with chemotherapy, and its mechanism of infection, infection route, disease onset, and severity remain unknown. Ficolins are oligomeric defense lectins. L-ficolin plays an important role in innate immunity. This study's aim was to identify L-ficolin's role in patients with pulmonary MAC disease. METHODS: Between April 2011 and September 2017, 61 Japanese patients with pulmonary MAC disease were seen at our hospital. A control group, comprising 30 healthy individuals, without respiratory disease were enrolled in our study. The relationship between serum L-ficolin levels and disease severity was assessed, and L-ficolin's antibacterial role was examined. RESULTS: Serum L-ficolin levels were significantly lower in patients with pulmonary MAC disease than in healthy subjects (1.69 ± 1.27 µg/ml vs. 3.96 ± 1.42 µg/ml; p < 0.001). The cut-off value, based on receiver operating characteristic (ROC) analysis results, was 2.48 µg/ml (area under the curve (AUC) 0.90, sensitivity and specificity 83.6 and 86.7%, respectively). Serum L-ficolin levels were significantly lower in the patients with nodular bronchiectatic type disease compared with the patients with fibrocavitary type disease and were lower in the high-resolution computed tomography high-scoring group compared with low-scoring group. An in vitro analysis showed that purified recombinant L-ficolin bound to M. avium and its major cell wall component, lipoarabinomannan, in a concentration-dependent manner. In addition, recombinant L-ficolin suppressed M. avium growth in a concentration-dependent manner. CONCLUSIONS: Insufficient serum L-ficolin is associated with disease progression in pulmonary MAC disease, and the level of serum L-ficolin is a possible biomarker. TRIAL REGISTRATION: This study is registered with UMIN ( UMIN000022392 ).

Risk factors for acute exacerbation of idiopathic interstitial pneumonia in patients undergoing lung cancer treatment.

OBJECTIVE: Identifying risk factors for cancer treatment-related acute exacerbations (AEs) of idiopathic interstitial pneumonia (IIP) in patients with lung cancer. METHODS: We retrospectively reviewed clinical records of 98 patients with concurrent lung cancer and IIPs diagnosed and treated at the Sapporo Medical University Hospital from January 2010 to December 2014. RESULTS: Of the 98 patients with concurrent lung cancer and IIPs, 14 patients (14.3%) had AEs. A total of 10 patients died. The univariate analysis revealed that the patients with idiopathic pulmonary fibrosis (IPF) or usual interstitial pneumonia (UIP) patterns on chest computed tomography (CT) had significantly higher rates of AE than those with non-IPF or non-UIP patterns, respectively. Further, those with a reduced percentage of forced vital capacity (%FVC) predictive values or elevated Krebs von den Lungen-6 (KL-6) presented significantly higher rates of AE. Our multivariate analysis identified that UIP pattern on chest CT and each 10% decrease in %FVC were significant independent risk factors for AEs. Of the 14 patients who experienced AEs, 10 cases were associated with cancer treatment. The treatment-specific incidences were 3/40 (7.5%) for surgery, 5/50 (10.0%) for chemotherapy, and 2/26 (7.7%) for radiation therapy. After comparing the AE incidences in 55 cases receiving one treatment (monotherapy group) and in 29 cases receiving two types of treatment or more (multitherapy group), we found no significant differences. CONCLUSIONS: Chest CT UIP patterns and reduced %FVC are independent risk factors for AE. Moreover, AE incidence did not increase in the multitherapy group compared with the monotherapy group.

Feasibility of rapid on-site cytological evaluation of lung cancer by a trained pulmonologist during bronchoscopy examination.

OBJECTIVE: Rapid on-site cytological evaluation (ROSE) in bronchoscopy is a useful ancillary technique. ROSE is usually performed by a cytopathologist or cytotechnologist. However, because of staff shortages and reduced availability, ROSE cannot be performed in every hospital. We aimed to evaluate the accuracy of ROSE when performed by a trained pulmonologist, comparing the diagnosis results with the final diagnosis of cytopathologists. METHODS: We performed a retrospective cohort study on 125 patients who underwent bronchoscopy with endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and endobronchial ultrasonography with a guide sheath (EBUS-GS) for peripheral pulmonary lesions by conventional bronchoscopy at Sapporo Medical University Hospital between March 2012 and September 2018. ROSE was performed by a pulmonologist who was trained by a cytotechnologist for a total of 1 month. DiffQuik® staining for ROSE was used to prepare cytology slides. The results of ROSE were compared with the final diagnosis obtained using Papanicolaou staining by cytopathologists. RESULTS: In all procedures, the sensitivity, specificity and diagnostic accuracy of ROSE were 88.5%, 83.0% and 86.4%, respectively. There was no significant difference in the sensitivity, specificity, positive predictive value, negative predictive value or accuracy between EBUS-TBNA and EBUS-GS. CONCLUSIONS: ROSE of lung cancer by a trained pulmonologist can be highly accurate and deemed as feasible and useful for not only EBUS-TBNA but also EBUS-GS.

Bilateral deficit of spring-like behaviour during hopping in sprinters.

PURPOSE: Unilateral leg stiffness is a key contributor to sprint running speed, thereby great bilateral deficit (BLD) of leg stiffness would be expected to be observed in sprinters. However, it remains clear only BLD of leg stiffness at the preferred hopping frequency in non-sprinters. The purpose of this study was to clarify the BLD of spring-like behaviour in hopping at various frequencies and the effect of chronic adaptation via sprint running experience on BLD during the hopping. METHODS: Fifteen male experienced sprinters and 12 male novices participated in this study. They were instructed to hop in place at three frequencies (2.0, 2.5, and 3.0 Hz), and to perform hopping with maximal effort. Ground reaction forces (GRF) of both legs during the hopping were recorded using two force plates. RESULTS: At higher hopping frequencies during the unilateral and bilateral hopping, smaller peak value of vertical GRF (F max) and greater leg stiffness (K leg) were significantly observed. The BLD index of F max and the BLD index of K leg were significantly smaller at higher hopping frequencies. No significant differences of BLD index of F max and BLD index of K leg were observed between sprinters and novices. CONCLUSION: Our results demonstrate that neuromuscular inhibition in the contralateral leg changes during the hopping based on hopping frequency. This suggests that plyometric training in the beginning of rehabilitation should involve bilateral jumping at a high frequency. In experienced sprinters, detailed mechanics of chronic neuromuscular adaptation via unilateral facilitation of spring-like behaviour should be assessed by measuring electromyographic activity.

Non-linear growth trends of toe flexor muscle strength among children, adolescents, and young adults: a cross-sectional study.

PURPOSE: There are only a few studies on the muscular strength of the foot in children and adolescents; thus, the developmental pattern and normative data of these populations during growth are unclear. We sought to elucidate the developmental pattern of the foot muscle strength among children, adolescents, and young adults compared with that of the hand. METHODS: A total of 747 children, adolescents, and young adults participated in this study, and their maximum isometric toe flexor strength (TFS), hand grip strength (HGS), and foot length were measured. RESULTS: TFS was correlated with HGS (r = 0.785), age (r = 0.659), height (r = 0.757), body mass (r = 0.737), and foot length (r = 0.594). Multiple regression analyses revealed that TFS was correlated with age (ß = 0.243 in boys; ß = 0.461 in girls), squared value of age (age2; ß = - 0.296 in boys; ß = - 0.260 in girls), and body mass (ß = 0.256 in boys; ß = 0.311 in girls) in both sexes, indicating a non-linear relationship between age and TFS development. In a regression model for HGS, age was a significant variable, but not age2. HGS increased linearly from childhood until young adulthood, whereas TFS increased from childhood until adolescence and then levelled off. CONCLUSION: Our results demonstrate that TFS has a different developmental pattern compared with HGS.

Hip Flexor and Knee Extensor Muscularity Are Associated With Sprint Performance in Sprint-Trained Preadolescent Boys.

PURPOSE: We attempted to determine the relationships between the cross-sectional area (CSA) of the trunk and lower limb muscles and sprint performance in male preadolescent sprinters. METHODS: Fifteen sprint-trained preadolescent boys (age 11.6 ± 0.4 y) participated in this study. The CSAs of the participants' trunk and lower limb muscles were measured using magnetic resonance imaging, and these muscles were normalized with free-fat mass. To assess participants' sprint performance, sprint time and variables during the 50-m sprint test were measured. The sprint variables were expressed as their indices by normalizing with body height. RESULTS: The relative CSAs of psoas major, adductors, and quadriceps femoris were significantly correlated with sprint time (r = -.802, -.643, and -.639). Moreover, the relative CSAs of these muscles were significantly correlated with indices of sprint velocity (r = .694, .612, and .630) and step frequency (r = .687, .740, and .590) but not with that of step length. CONCLUSIONS: These findings suggest that greater hip flexor and knee extensor muscularity in male preadolescent sprinters may help achieve superior sprint performance by potentially enhancing their moments, which may be induced by increased step frequency rather than step length during sprinting.

Fibroblastic foci, covered with alveolar epithelia exhibiting epithelial-mesenchymal transition, destroy alveolar septa by disrupting blood flow in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease of unknown cause. IPF has a distinct histopathological pattern of usual interstitial pneumonia in which fibroblastic foci (FF) represent the leading edge of fibrotic destruction of the lung. Currently there are three major hypotheses for how FF are generated: (1) from resident fibroblasts, (2) from bone marrow-derived progenitors of fibroblasts, and (3) from alveolar epithelial cells that have undergone epithelial-mesenchymal transition (EMT). We found that FF dissociated capillary vessels from the alveolar epithelia, the basement membranes of which are fused in normal physiological conditions, and pushed the capillaries and elastic fibers down ~100 µm below the alveolar epithelia. Furthermore, the alveolar epithelial cells covering the FF exhibited a partial EMT phenotype. In addition, normal human alveolar epithelial cells in vitro underwent dynamic EMT in response to transforming growth factor-ß signaling within 72 h. Because it seems that resident fibroblasts or bone marrow-derived cells cannot easily infiltrate and form FF between the alveolar epithelia and capillaries in tight contact with each other, FF are more likely to be derived from the epithelial-to-mesenchymal transitioned alveolar epithelia located over them. Moreover, histology and immunohistochemistry suggested that the FF formed in the lung parenchyma disrupt blood flow to the alveolar septa, thus destroying them. Consequently, collapse of the alveolar septa is likely to be the first step toward honeycombing in the lung during late stage IPF. On the basis of these findings, inhibition of transforming growth factor-ß signaling, which can suppress EMT of the alveolar epithelial cells in vitro, is a potential strategy for treating IPF.

Treatment of pulmonary fibrosis with siRNA against a collagen-specific chaperone HSP47 in vitamin A-coupled liposomes.

BACKGROUND: Pulmonary fibrosis is a life-threatening pathological state of progressive interstitial lung diseases, such as idiopathic pulmonary fibrosis. Myofibroblasts are known to play a critical role in the pathogenesis of pulmonary fibrosis. This study aimed to evaluate the inhibitory effect of a small interfering RNA (siRNA) on a collagen-specific chaperone heat shock protein 47 (HSP47). The siRNA was preferentially delivered to myofibroblasts in a bleomycin (BLM)-induced pulmonary fibrosis rat model using siRNA against HSP47, encapsulated in a vitamin A-coupled liposome (VA-lip-siRNA HSP47). METHODS AND RESULTS: Male Sprague-Dawley rats were treated with an intratracheal injection of BLM or phosphate buffered saline followed by an intravenous injection of VA-lip-siRNA HSP47 three times per week under preventive administration schedules from day 1 to day 21 and therapeutic administration schedules from day 15 to day 35. The expression of HSP47 after the treatment was assessed by immunoblotting. The specific delivery of VA-lip-siRNA HSP47 conjugated with 6'-carboxyfluoresce into myofibroblasts was examined by immunofluorescence staining. The effect of VA-lip-siRNA HSP47 on fibrosis was analyzed by morphological and biochemical methods. Preferential delivery of VA-lip-siRNA HSP47 to myofibroblasts in fibrotic areas in BLM-treated rats was verified by immunofluorescence staining. Treatment of VA-lip-siRNA HSP47 clearly suppressed HSP47 expression and induced apoptosis of myofibroblasts in the lung of BLM-treated rats. Hydroxyproline levels and inflammatory cytokines in the lungs, and the number of inflammatory cells in the bronchial alveolar lavage of BLM-treated rats were significantly suppressed by the treatment. Morphological assessment showed that VA-lip-siRNA HSP47 also significantly improved the morphological pulmonary fibrosis of BLM-treated rats in both preventive and therapeutic schedules. CONCLUSIONS: These results suggest that VA-lip-siRNA HSP47 improves pulmonary fibrosis in not only preventive, but also therapeutic schedules, and thus, this drug delivery system should provide a novel therapy for refractory pulmonary fibrosis.

Volatile Organic Compounds in Exhaled Breath of Idiopathic Pulmonary Fibrosis for Discrimination from Healthy Subjects.

Purpose Human breath analysis is proposed with increasing frequency as a useful tool in clinical application. We performed this study to find the characteristic volatile organic compounds (VOCs) in the exhaled breath of patients with idiopathic pulmonary fibrosis (IPF) for discrimination from healthy subjects. Methods VOCs in the exhaled breath of 40 IPF patients and 55 healthy controls were measured using a multi-capillary column and ion mobility spectrometer. The patients were examined by pulmonary function tests, blood gas analysis, and serum biomarkers of interstitial pneumonia. Results We detected 85 VOC peaks in the exhaled breath of IPF patients and controls. IPF patients showed 5 significant VOC peaks; p-cymene, acetoin, isoprene, ethylbenzene, and an unknown compound. The VOC peak of p-cymene was significantly lower (p < 0.001), while the VOC peaks of acetoin, isoprene, ethylbenzene, and the unknown compound were significantly higher (p < 0.001 for all) compared with the peaks of controls. Comparing VOC peaks with clinical parameters, negative correlations with VC (r =-0.393, p = 0.013), %VC (r =-0.569, p < 0.001), FVC (r = -0.440, p = 0.004), %FVC (r =-0.539, p < 0.001), DLco (r =-0.394, p = 0.018), and %DLco (r =-0.413, p = 0.008) and a positive correlation with KL-6 (r = 0.432, p = 0.005) were found for p-cymene. Conclusion We found characteristic 5 VOCs in the exhaled breath of IPF patients. Among them, the VOC peaks of p-cymene were related to the clinical parameters of IPF. These VOCs may be useful biomarkers of IPF.

The knee extensor moment arm is associated with performance in male sprinters.

PURPOSE: Although large knee extensor torque contributes to superior sprint performance, previous findings have indicated that the quadriceps cross-sectional area (CSA), a pivotal morphological regulator of knee extensor torque, is not correlated with performance in sprinters. We hypothesized that the knee extensor moment arm (MA), another main morphological regulator of knee extensor torque, may affect sprint performance. To test this hypothesis, we examined the relationship between knee extensor MA and sprint performance. METHODS: The quadriceps CSA and knee extensor MA in 32 well-trained male sprinters and 32 male non-sprinters were measured using magnetic resonance imaging. RESULTS: Knee extensor MA, but not quadriceps CSA, was greater in sprinters than in non-sprinters (P = 0.013). Moreover, knee extensor MA, but not the quadriceps CSA, was correlated with the personal best time in a 100-m race in sprinters (r = -0.614, P < 0.001). Furthermore, among 24 sprinters who participated in the 60-m sprint test, knee extensor MA was correlated with sprinting velocities in the acceleration (r = 0.717, P < 0.001) and maximum speed (r = 0.697, P < 0.001) phases. CONCLUSION: The present study demonstrates that the knee extensor MA is greater in sprinters than in non-sprinters, and this morphological structure in sprinters is associated with sprint performance. Therefore, for the first time, we provided evidence that a greater knee extensor MA in sprinters may be an advantageous for achieving superior sprint performance.

Surfactant protein D is a useful biomarker for monitoring acute lung injury in rats.

PURPOSE: The purpose of this study is to investigate the serial changes in the SP-D concentrations of serum and bronchoalveolar lavage fluid (BALF) in a bleomycin-induced lung injury rat model and compare them with the levels of conventional biochemical markers. MATERIALS AND METHODS: Male Wister rats were anesthetized and intratracheally administered bleomycin (1.0 mg/kg). We evaluated the histological changes and SP-D expression of their lung tissues. We also measured the concentrations of SP-D, albumin, and lactate dehydrogenase (LDH) and the numbers of various types of cells in BALF, and the serum levels of SP-D and conventional markers, including LDH, high mobility group box 1, monocyte chemoattractant protein-1, and C-reactive protein. RESULTS: The BALF SP-D level increased and peaked on day 3, and then gradually decreased. These variations were significantly correlated with the changes in the BALF albumin level and granulocyte cell count. The serum SP-D level increased from day 5, peaked on day 10, and then gradually decreased until day 28. The changes in the serum SP-D level accurately reflected the extent of the histological changes caused by the lung injury. On the other hand, the serum levels of conventional biomarkers were only elevated for a few days or did not change during the study period. CONCLUSIONS: The SP-D level is the most useful marker of the severity of lung injuries. These results suggest that the measurement of SP-D levels is an additional tool for monitoring acute lung injuries in rats.

Acute Response of Well-Trained Sprinters to a 100-m Race: Higher Sprinting Velocity Achieved With Increased Step Rate Compared With Speed Training.

This study aimed to clarify the contribution of differences in step length and step rate to sprinting velocity in an athletic race compared with speed training. Nineteen well-trained male and female sprinters volunteered to participate in this study. Sprinting motions were recorded for each sprinter during both 100-m races and speed training (60-, 80-, and 100-m dash from a block start) for 14 days before the race. Repeated-measures analysis of covariance was used to compare the step characteristics and sprinting velocity between race and speed training, adjusted for covariates including race-training differences in the coefficients of restitution of the all-weather track, wind speed, air temperature, and sex. The average sprinting velocity to the 50-m mark was significantly greater in the race than in speed training (8.26 ± 0.22 m·s vs. 8.00 ± 0.70 m·s, p < 0.01). Although no significant difference was seen in the average step length to the 50-m mark between the race and speed training (1.81 ± 0.09 m vs. 1.80 ± 0.09 m, p = 0.065), the average step rate was significantly greater in the race than in speed training (4.56 ± 0.17 Hz vs. 4.46 ± 0.13 Hz, p < 0.01). These findings suggest that sprinters achieve higher sprinting velocity and can run with higher exercise intensity and more rapid motion during a race than during speed training, even if speed training was performed at perceived high intensity.

Epidemiologic survey of Japanese patients with idiopathic pulmonary fibrosis and investigation of ethnic differences.

RATIONALE: Idiopathic pulmonary fibrosis (IPF) has an unknown etiology and poor prognosis. Several large-scale epidemiologic studies have been conducted predominantly in Western countries. There are few studies reported from Asian countries. It remains unclear whether ethnic difference exists in IPF. It is important to determine the current IPF status in Asian populations and compare it with that of Western populations. OBJECTIVES: To provide the epidemiologic status of IPF in Japan and to investigate ethnic differences. METHODS: We selected Hokkaido prefecture (population, 5.6 million) as the epidemiologic cohort of IPF among Japanese. On the basis of the clinical records of 553 patients with IPF who were accepted based on the application of the Certificate of Medical Benefit between 2003 and 2007, we conducted a retrospective epidemiologic and prognostic analysis. MEASUREMENTS AND MAIN RESULTS: The prevalence and cumulative incidence of IPF was 10.0 and 2.23 per 100,000 population, respectively, with 72.7% predominance of males and an increase in frequency with age. The median survival time was 35 months, and the most common (40%) cause of death was acute exacerbation. The most important factor influencing IPF prognosis was the percent vital capacity. CONCLUSIONS: The status of IPF in the Japanese population was clarified for the first time through our study. Our results showed that in men, the incidence of death caused by acute exacerbation was higher and that caused by cardiovascular disease was lower in Japan than in Western countries. These results may suggest ethnic differences in IPF.

Distinct compartmentalization of SP-A and SP-D in the vasculature and lungs of patients with idiopathic pulmonary fibrosis.

BACKGROUND: Surfactant proteins SP-A and SP-D are useful biomarkers in diagnosis, monitoring, and prognosis of idiopathic pulmonary fibrosis (IPF). Despite their high structural homology, their serum concentrations often vary in IPF patients. This retrospective study aimed to investigate distinct compartmentalization of SP-A and SP-D in the vasculature and lungs by bronchoalveolar lavage fluid (BALF)/serum analysis, hydrophilicity and immunohistochemistry. METHODS: We included 36 IPF patients, 18 sarcoidosis (SAR) patients and 20 healthy subjects. Low-speed centrifugal supernatants of BALF (Sup-1) were obtained from each subject. Sera were also collected from each patient. Furthermore, we separated Sup-1 of IPF patients into hydrophilic supernatant (Sup-2) and hydrophobic precipitate (Ppt) by high-speed centrifugation. We measured SP-A and SP-D levels of each sample with the sandwich ELISA technique. We analyzed the change of the BALF/serum level ratios of the two proteins in IPF patients and their hydrophilicity in BALF. The distribution in the IPF lungs was also examined by immunohistochemical staining. RESULTS: In BALF, SP-A levels were comparable between the groups; however, SP-D levels were significantly lower in IPF patients than in others. Although IPF reduced the BALF/serum level ratios of the two proteins, the change in concentration of SP-D was more evident than SP-A. This suggests a higher disease impact for SP-D. Regarding hydrophilicity, although more than half of the SP-D remained in hydrophilic fractions (Sup-2), almost all of the SP-A sedimented in the Ppt with phospholipids. Hydrophilicity suggests that SP-D migrates into the blood more easily than SP-A in IPF lungs. Immunohistochemistry revealed that SP-A was confined to thick mucus-filling alveolar space, whereas SP-D was often intravascular. This data also suggests that SP-D easily leaks into the bloodstream, whereas SP-A remains bound to surfactant lipids in the alveolar space. CONCLUSIONS: The current study investigated distinct compartmentalization of SP-A and SP-D in the vasculature and lungs. Our results suggest that serum levels of SP-D could reflect pathological changes of the IPF lungs more incisively than those of SP-A.

Effect of expertise on 3D force application during the starting block phase and subsequent steps in sprint running.

In sprinters with different levels of block acceleration, we investigated differences in their three-dimensional force application in terms of the magnitude, direction, and impulse of the ground reaction force (GRF) during the starting block phase and subsequent two steps. Twenty-nine participants were divided into three groups (well-trained, trained, and nontrained sprinters) based on their mean anteroposterior block acceleration and experience with a block start. The participants sprinted 10 m from a block start with maximum effort. Although the mean net resultant GRF magnitude did not differ between the well-trained and trained sprinters, the net sagittal GRF vector of the well-trained sprinters was leaned significantly further forward than that of the trained and nontrained sprinters during the starting block phase. In contrast, during the starting block phase and the subsequent steps, the transverse GRF vectors which cause the anteroposterior and mediolateral acceleration of the whole-body was directed toward the anterior direction more in the well-trained sprinters as compared with the other sprinters. Therefore, a more forward-leaning GRF vector and a greater anteroposterior GRF may particularly allow well-trained sprinters to generate a greater mean anteroposterior block acceleration than trained and nontrained sprinters.