High-intensity intermittent inspiratory and abdominal muscle combined training in respiratory, swallowing and systemic muscles of healthy adults.

BACKGROUND: Low-intensity continuous inspiratory muscle training improves its strength. The abdominal muscles are the main expiratory muscles, and their training may improve expiratory muscle strength. Respiratory muscle strength regulates coughing effectiveness, which is critical for pneumonia management. In older people, risk factors for the development of pneumonia were respiratory muscle weakness and swallowing impairment. Currently, the impact of high-intensity intermittent inspiratory and abdominal muscle combined training on the respiratory, swallowing, and systemic muscles is unclear. OBJECTIVE: We aimed to explore the effects of high-intensity inspiratory muscle training combined with or without abdominal muscle training on respiratory muscle strength as well as the strength, mass, and performance of swallowing and systemic muscles. METHODS: Twenty-eight healthy adults were divided into two groups. Participants performed high-intensity intermittent inspiratory muscle single or its combination with abdominal muscle training for 4 weeks. Respiratory muscle strength, swallowing muscle strength and mass, systemic muscle strength, mass and performance were measured at baseline, Week 2 and Week 4. RESULTS: Both groups showed greater maximal respiratory pressures at Week 2 and Week 4 than baseline. Both groups showed improved tongue pressure and geniohyoid muscle thickness at Week 4. In addition, the combined training group improved body trunk muscle mass, handgrip strength and five-time chair stand test, whereas the single training group did not. CONCLUSION: This study revealed that high-intensity inspiratory muscle training improved inspiratory muscle strength and swallowing muscle strength and mass. Moreover, inspiratory and abdominal muscle combined training showed an additional benefit of improving systemic muscle strength, mass and performance. CLINICAL TRIAL REGISTRATION NUMBER: UMIN000046724; https://upload.umin.ac.jp/cgi-open-bin/ctr/index.cgi?ctrno=UMIN000046724.

Anatomy and function of the lymphatic vessels in the parietal pleura and their plasticity under inflammation in mice.

Inflammatory pleuritis often causes pleural effusions, which are drained through lymphatic vessels (lymphatics) in the parietal pleura. The distribution of button- and zipper-like endothelial junctions can identify the subtypes of lymphatics, the initial, pre-collecting, and collecting lymphatics. Vascular endothelial growth factor receptor (VEGFR)-3 and its ligands VEGF-C/D are crucial lymphangiogenic factors. Currently, in the pleura covering the chest walls, the anatomy of the lymphatics and connecting networks of blood vessels are incompletely understood. Moreover, their pathological and functional plasticity under inflammation and the effects of VEGFR inhibition are unclear. This study aimed to learn the above-unanswered questions and immunostained mouse chest walls as whole-mount specimens. Confocal microscopic images and their 3-dimensional reconstruction analyzed the vasculatures. Repeated intra-pleural cavity lipopolysaccharide challenge induced pleuritis, which was also treated with VEGFR inhibition. Levels of vascular-related factors were evaluated by quantitative real-time polymerase chain reaction. We observed the initial lymphatics in the intercostals, collecting lymphatics under the ribs, and pre-collecting lymphatics connecting both. Arteries branched into capillaries and gathered into veins from the cranial to the caudal side. Lymphatics and blood vessels were in different layers with an adjacent distribution of the lymphatic layer to the pleural cavity. Inflammatory pleuritis elevated expression levels of VEGF-C/D and angiopoietin-2, induced lymphangiogenesis and blood vessel remodeling, and disorganized the lymphatic structures and subtypes. The disorganized lymphatics showed large sheet-like structures with many branches and holes inside. Such lymphatics were abundant in zipper-like endothelial junctions with some button-like junctions. The blood vessels were tortuous and had various diameters and complex networks. Stratified layers of lymphatics and blood vessels were disorganized, with impaired drainage function. VEGFR inhibition partially maintained their structures and drainage function. These findings demonstrate anatomy and pathological changes of the vasculatures in the parietal pleura and their potential as a novel therapeutic target.

Anatomy and pathology of lymphatic vessels under physiological and inflammatory conditions in the mouse diaphragm.

The lymphatic vessels in the parietal pleura drain fluids. Impaired drainage function and excessive fluid entry in the pleural cavity accumulate effusion. The rat diaphragmatic lymphatics drain fluids from the pleura to the muscle layer. Lymphatic subtypes are characterized by the major distribution of discontinuous button-like endothelial junctions (buttons) in initial lymphatics and continuous zipper-like junctions (zippers) in the collecting lymphatics. Inflammation replaced buttons with zippers in tracheal lymphatics. In the mouse diaphragm, the structural relationship between the lymphatics and blood vessels, the presence of lymphatics in the muscle layer, and the distributions of initial and collecting lymphatics are unclear. Moreover, the endothelial junctional alterations and effects of vascular endothelial growth factor receptor (VEGFR) inhibition under pleural inflammation are unclear. We subjected the whole-mount mouse diaphragms to immunohistochemistry. The lymphatics and blood vessels were distributed in different layers of the pleural membrane. Major lymphatic subtypes were initial lymphatics in the pleura and collecting lymphatics in the muscle layer. Chronic pleural inflammation disorganized the stratified layers of the lymphatics and blood vessels and replaced buttons with zippers in the pleural lymphatics, which impaired drainage function. VEGFR inhibition under inflammation maintained the vascular structures and drainage function. In addition, VEGFR inhibition maintained the lymphatic endothelial junctions and reduced the blood vessel permeability under inflammation. These findings may provide new targets for managing pleural effusions caused by inflammation, such as pleuritis and empyema, which are common pneumonia comorbidities.

Respiratory Muscle Weakness as a Risk Factor for Pneumonia in Older People.

INTRODUCTION: The respiratory muscle strength regulates the effectiveness of coughing, which clears the airways and protects people from pneumonia. Sarcopenia is an aging-related loss of muscle mass and function, the worsening of which is associated with malnutrition. The loss of respiratory and swallowing muscle strength occurs with aging, but its effect on pneumonia is unclear. This study aimed to determine the risks of respiratory muscle weakness on the onset and relapse of pneumonia in older people in conjunction with other muscle-related factors such as malnutrition. METHODS: We conducted a longitudinal study with 47 pneumonia inpatients and 35 non-pneumonia controls aged 70 years and older. We evaluated the strength of respiratory and swallowing muscles, muscle mass, and malnutrition (assessed by serum albumin levels and somatic fat) during admission and confirmed pneumonia relapse within 6 months. The maximal inspiratory and expiratory pressures determined the respiratory muscle strength. Swallowing muscle strength was evaluated by tongue pressure. Bioelectrical impedance analysis was used to evaluate the muscle and fat mass. RESULTS: The respiratory muscle strength, body trunk muscle mass, serum albumin level, somatic fat mass, and tongue pressure were significantly lower in pneumonia patients than in controls. Risk factors for the onset of pneumonia were low inspiratory respiratory muscle strength (odds ratio [OR], 6.85; 95% confidence interval [CI], 1.56-30.11), low body trunk muscle mass divided by height2 (OR, 6.86; 95% CI, 1.49-31.65), and low serum albumin level (OR, 5.46; 95% CI, 1.51-19.79). For the relapse of pneumonia, low somatic fat mass divided by height2 was a risk factor (OR, 20.10; 95% CI, 2.10-192.42). DISCUSSION/CONCLUSIONS: Respiratory muscle weakness, lower body trunk muscle mass, and malnutrition were risk factors for the onset of pneumonia in older people. For the relapse of pneumonia, malnutrition was a risk factor.

Axl kinase drives immune checkpoint and chemokine signalling pathways in lung adenocarcinomas.

Axl receptor tyrosine kinase is involved in the growth and metastasis and is an indicator of poor prognosis in several cancers including lung cancers. Although a mitogen-activated protein kinase (MAPK) pathway and an epithelial-to-mesenchymal transition (EMT) program are critical, molecular mechanisms underlying the Axl-driven cancer progression have not been fully elucidated. We aimed to identify molecules up-regulated by Axl kinase in lung adenocarcinomas. Through the global gene expression analysis and the functional annotation clustering, we found that AXL expression positively correlated with mRNA expressions of immune checkpoint molecules and chemokine receptors in non-small-cell lung cancers. Validation cohorts including our biobank confirmed that the AXL expression significantly correlated with expression of genes encoding programmed death-ligand1 (PD-L1) and CXC chemokine receptor 6 (CXCR6) in lung adenocarcinoma, especially in epidermal growth factor receptor (EGFR) mutation-positive adenocarcinoma. Pharmacological inhibition of Axl kinase activity decreased mRNA expressions of PD-L1 and CXCR6 in EGFR mutation-positive cell lines. Our data indicates the novel role of Axl kinase as a driver of immune checkpoint molecules and chemokine signalling pathways in the progression of lung adenocarcinomas. This study also highlights the necessity of clinical trials in order to test the efficacy of Axl kinase inhibition in the Axl-highly expressing subset of lung adenocarcinomas. .

TLR7 agonist attenuates acetylcholine-induced, Ca2+ -dependent ionic currents in swine tracheal submucosal gland cells.

NEW FINDINGS: What is the central question of this study? Does Toll-like receptor 7 (TLR7) have any direct effects on Ca2+ -dependent physiological function of tracheal submucosal gland cells? What is the main finding and its importance? TLR7 is co-localized with SERCA2 in tracheal submucosal gland cells and causes a rapid attenuation of acetylcholine (ACh)-induced, Ca2+ -dependent ionic currents through the activation of SERCA2-dependent Ca2+ clearance. TLR7 is abundantly expressed in the airways of both swine and healthy human subjects, but is significantly downregulated in chronic obstructive pulmonary disease (COPD) airways. These findings suggest that a dysfunction of TLR7 in COPD removes the brake on ACh-induced serous secretion during viral infections, resulting in prolonged airway hypersecretion, and that it is one of the triggers of COPD exacerbations. ABSTRACT: Airway surface fluids are mainly secreted from submucosal glands (SMGs) and play important roles in the defence of airways via the activation of mucociliary transport. Toll-like receptor 7 (TLR7) recognizes and eliminates single stranded RNA (ssRNA) viruses through the induction of innate immunity. However, there is no obvious connection between TLR7 and mucus secretion, aside from TLR7 recognizing ssRNA viruses, which are often associated with airway hypersecretion in chronic obstructive pulmonary disease (COPD). Here, we investigated whether TLR7 has any direct effects on the Ca2+ -dependent physiological function of tracheal SMG cells. Patch-clamp analyses revealed that TLR7 ligand inhibited the acetylcholine (ACh)-induced ionic currents in isolated tracheal SMG cells. Intracellular calcium assays and pharmacological analyses revealed that TLR7 attenuated the transient rises in the intracellular calcium concentration evoked by ACh by activating sarco/endoplasmic reticulum Ca2+ -ATPase 2 (SERCA2). Immunofluorescence staining and immunohistochemical staining revealed that TLR7 was co-localized with SERCA2. These findings suggest that the activation of TLR7 during viral infections contributes to the rapid attenuation of ACh-induced ionic currents through an increase in SERCA2-dependent Ca2+ clearance in healthy airway SMG cells. Our study also revealed that TLR7 expression was significantly downregulated in COPD airways. Based on these findings, we speculate that a dysfunction of TLR7 may not only have an adverse effect on the elimination of these viruses but also remove the brake on ACh-induced serous secretion, resulting in prolonged hypersecretion and acting as one of the triggers of COPD exacerbations.

Exome sequencing deciphers a germline MET mutation in familial epidermal growth factor receptor-mutant lung cancer.

Lung cancer accompanied by somatic activating mutations in the epidermal growth factor receptor (EGFR) gene, which is associated with a significant clinical response to the targeted therapy, is frequently found in never-smoking Asian women with adenocarcinoma. Although this implies genetic factors underlying the carcinogenesis, the etiology remains unclear. To gain insight into the pathogenic mechanisms, we sequenced the exomes in the peripheral-blood DNA from six siblings, four affected and two unaffected siblings, of a family with familial EGFR-mutant lung adenocarcinoma. We identified a heterozygous missense mutation in MET proto-oncogene, p.Asn375Lys, in all four affected siblings. Combined with somatic loss of heterozygosity for MET, the higher allele frequency in a Japanese sequencing database supports a causative role of the MET mutation in EGFR-mutant lung cancer. Functional assays showed that the mutation reduces the binding affinity of MET for its ligand, hepatocyte growth factor, and damages the subsequent cellular processes, including proliferation, clonogenicity, motility and tumorigenicity. The MET mutation was further observed to abrogate the ERBB3-mediated AKT signal transduction, which is shared downstream by EGFR. These findings provide an etiological view that the MET mutation is involved in the pathogenesis of EGFR-mutant lung cancer because it generates oncogenic stress that induces compensatory EGFR activation. The identification of MET in a family with familial EGFR-mutant lung cancer is insightful to explore the pathogenic mechanism of not only familial, but also sporadic EGFR-mutant lung cancer by underscoring MET-related signaling molecules.

Decrease in an anti-ageing factor, growth differentiation factor 11, in chronic obstructive pulmonary disease.

RATIONALE: Cellular senescence is observed in the lungs of patients with COPD and may contribute to the disease pathogenesis. Growth differentiation factor 11 (GDF11) belongs to the transforming growth factor ß superfamily and was recently reported to be a circulating protein that may have rejuvenating effects in mice. We aimed to investigate the amounts of GDF11 in the plasma and the lungs of patients with COPD and elucidate the possible roles of GDF11 in cellular senescence. METHODS: The plasma levels of GDF11 were investigated in two separate cohorts by western blotting. The localisation and expression of GDF11 in the lungs were investigated by immunohistochemistry and quantitative reverse transcription PCR, respectively. The effects of GDF11 on both cigarette smoke extract (CSE)-induced cellular senescence in vitro and on elastase-induced cellular senescence in vivo were investigated. RESULTS: The levels of plasma GDF11 in the COPD group were decreased compared with the control groups in the two independent cohorts. The levels of plasma GDF11 were significantly positively correlated with pulmonary function data. The mRNA expression of GDF11 in mesenchymal cells from the COPD group was decreased. Chronic exposure to CSE decreased the production of GDF11. Treatment with GDF11 significantly inhibited CSE-induced cellular senescence and upregulation of inflammatory mediators, partly through Smad2/3 signalling in vitro. Daily GDF11 treatment attenuated cellular senescence and airspace enlargement in an elastase-induced mouse model of emphysema. CONCLUSIONS: The decrease in GDF11 may be involved in the cellular senescence observed in COPD.

Production of reactive persulfide species in chronic obstructive pulmonary disease.

BACKGROUND: Oxidative stress is a major aetiological factor driving chronic obstructive pulmonary disease (COPD). Recently recognised as potent antioxidants, reactive persulfide and polysulfide species are biosynthesised by cystathionine ß-synthase and cystathionine γ-lyase. The production of reactive persulfide and polysulfide species in the lungs of patients with COPD remain unknown. OBJECTIVES: The aim of this study was to examine the production of reactive persulfides and polysulfides, such as glutathione persulfide (GSSH), cysteine persulfide (CysSSH) and glutathione trisulfide (GSSSH), in lung-resident cells and epithelial lining fluid (ELF) obtained from patients with mild to moderate COPD. METHODS: Lung tissues, primary lung cells, ELF and sputum were obtained. The amounts of reactive persulfides and polysulfides in the cells and ELF were measured by liquid chromatography-tandem mass spectrometry with ß-(4-hydroxyphenyl) ethyl iodoacetamide as a trapping agent for hydroper/polysulfides. The amounts of synthases in the lung tissues, sputum and primary cells were quantified. RESULTS: The amounts of GSSH, CysSSH and GSSSH were decreased in the lung cells and ELF from patients with COPD. The amounts of reactive persulfides and polysulfides in the lung cells had a positive correlation with the degree of airflow limitation. By contrast, the amounts of the synthases were increased in the lung tissues and sputum cells of patients with COPD. CONCLUSIONS: We have identified a decrease in reactive persulfide and polysulfide species in the lungs of patients with COPD. These data suggest that the newly detected antioxidants reactive persulfides and polysulfides could be associated with the redox balance in the lungs of patients with COPD.

27-Hydroxycholesterol accelerates cellular senescence in human lung resident cells.

Cellular senescence is reportedly involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). We previously showed that 27-hydroxycholesterol (27-OHC) is elevated in the airways of COPD patients compared with those in healthy subjects. The aim of this study was to investigate whether lung fibroblasts of COPD patients are senescent and to determine the effects of 27-OHC on senescence of lung resident cells, including fibroblasts and airway epithelial cells. Localization of senescence-associated proteins and sterol 27-hydroxylase was investigated in the lungs of COPD patients by immunohistochemical staining. To evaluate whether 27-OHC accelerates cellular senescence, lung resident cells were exposed to 27-OHC. Senescence markers and fibroblast-mediated tissue repair were investigated in the 27-OHC-treated cells. Expression of senescence-associated proteins was significantly enhanced in lung fibroblasts of COPD patients. Similarly, expression of sterol 27-hydroxylase was significantly upregulated in lung fibroblasts and alveolar macrophages in these patients. Treatment with the concentration of 27-OHC detected in COPD airways significantly augmented expression of senescence-associated proteins and senescence-associated ß-galactosidase activity, and delayed cell growth through the prostaglandin E2-reactive nitrogen species pathway. The 27-OHC-treated fibroblasts impaired tissue repair function. Fibroblasts from lungs of COPD patients showed accelerated senescence and were more susceptible to 27-OHC-induced cellular senescence compared with those of healthy subjects. In conclusion, 27-OHC accelerates cellular senescence in lung resident cells and may play a pivotal role in cellular senescence in COPD.

Possible role of Krüppel-like factor 5 in the remodeling of small airways and pulmonary vessels in chronic obstructive pulmonary disease.

BACKGROUND: Small airway remodeling is an important cause of the airflow limitation in chronic obstructive pulmonary disease (COPD). A large population of patients with COPD also have pulmonary hypertension. Krüppel-like factor 5 (KLF5) is a zinc-finger transcription factor that contributes to tissue remodeling in cardiovascular diseases. Here, we evaluate the possible involvement of KLF5 in the remodeling of small airways and pulmonary vessels in COPD. METHODS: Lung tissues were obtained from 23 control never-smokers, 17 control ex-smokers and 24 ex-smokers with COPD. The expression of KLF5 in the lung tissues was investigated by immunohistochemistry. We investigated whether oxidative/nitrosative stress, which is a major cause of the pathogenesis in COPD, could augment the production of KLF5. We examined the role of KLF5 in the stress-mediated tissue remodeling responses. We also investigated the susceptibility of KLF5 expression to nitrosative stress using bronchial fibroblasts isolated from the lung tissues. RESULTS: The expression of KLF5 was up-regulated in the small airways and pulmonary vessels of the COPD patients and it was mainly expressed in bronchial fibroblasts and cells of the pulmonary vessels. The extent of the KLF5 expression in the small airway of the COPD group had a significant correlation with the severity of the airflow limitation. Oxidative/nitrosative stress augmented the production of KLF5 in lung fibroblasts as well as the translocation of KLF5 into the nuclei. Silencing of KLF5 suppressed the stress-augmented differentiation into myofibroblasts, the release of collagens and metalloproteinases. Bronchial fibroblasts from the patients with COPD highly expressed KLF5 compared to those from the control subjects under basal condition and were more susceptible to the induction of KLF5 expression by nitrosative stress compared to those from the control subjects. CONCLUSION: We provide the first evidence that the expression of KLF5 is up-regulated in small airways and pulmonary vessels of patients with COPD and may be involved in the tissue remodeling of COPD.

Chronic inflammation, lymphangiogenesis, and effect of an anti-VEGFR therapy in a mouse model and in human patients with aspiration pneumonia.

Chronic inflammation induces lymphangiogenesis and blood vessel remodelling. Since aged pneumonia patients often have repeated episodes of aspiration pneumonia, the pathogenesis may involve chronic inflammation. For lymphangiogenesis, VEGFR-3 and its ligand VEGF-C are key factors. No previous studies have examined chronic inflammation or vascular changes in aspiration pneumonia or its mouse models. In lung inflammation, little is known about the effect of blocking VEGFR-3 on lung lymphangiogenesis and, moreover, its effect on the disease condition. This study aimed to establish a mouse model of aspiration pneumonia, examine the presence of chronic inflammation and vascular changes in the model and in patients, and evaluate the effect of inhibiting VEGFR-3 on the lymphangiogenesis and disease condition in this model. To induce aspiration pneumonia, we repeated inoculation of pepsin at low pH and LPS into mice for 21-28 days, durations in which bronchioalveolar lavage and plasma leakage in the lung suggested the presence of exaggerated inflammation. Conventional and immunohistochemical analysis of tracheal whole mounts suggested the presence of chronic inflammation, lymphangiogenesis, and blood vessel remodelling in the model. Quantitative RT-PCR of the trachea and lung suggested the involvement of lymphangiogenic factor VEGF-C, VEGFR-3, and pro-inflammatory cytokines. In the lung, the aspiration model showed the presence of chronic inflammation and exaggerated lymphangiogenesis. Treatment with the VEGFR inhibitor axitinib or the VEGFR-3 specific inhibitor SAR131675 impaired lymphangiogenesis in the lung and improved oxygen saturation in the aspiration model. Since the lung is the main site of aspiration pneumonia, the changes were intensive in the lung and mild in the trachea. Human lung samples also showed the presence of chronic inflammation and exaggerated lymphangiogenesis, suggesting the relevance of the model to the disease. These results suggest lymphatics in the lung as a new target of analysis and therapy in aspiration pneumonia.

Simultaneous development of sarcoidosis and cutaneous vasculitis in a patient with refractory Crohn's disease during infliximab therapy.

BACKGROUND: Paradoxical inflammations during anti-TNF-α therapy are defined as adverse effects such as psoriasiform skin lesions, uveitis and sarcoidosis-like granulomas induced by immune reactions, not by infectious agents. Here, we report a very rare case of the simultaneous development of sarcoidosis and cutaneous vasculitis in a patient with refractory Crohn's disease during infliximab therapy and both of which resolved spontaneously without the cessation of infliximab. CASE PRESENTATION: In September 2000, 23-year old Japanese male was diagnosed with Crohn's disease. Prednisolone in combination with mesalazine was introduced at first and succeeded for almost one year. In June 2002, since his gastrointestinal symptoms relapsed and were refractory, infliximab (IFX) therapy 5 mg/kg was introduced. In February 2011, because he had repeated arthralgia almost every intravenous IFX administration, IFX was increased to 10 mg/kg under the diagnosis of a secondary failure of IFX. In December 2012, he complained of slight dry cough and an itchy eruption on both lower limbs, and he was referred to our hospital due to the appearance of bilateral hilar lymphadenopathy on chest X-ray examination. Chest computed tomogram revealed bilateral hilar lymphadenopathy and fine reticulonodular shadows on the bilateral upper lungs. Serum calcium, angiotensin-converting enzyme and soluble interleukin 2 receptor levels were not elevated, but the titer of antinuclear antibody was considerably elevated. Mycobacterium infection was carefully excluded. Trans-bronchial lung biopsy showed non-caseating epithelioid cell granulomas compatible with sarcoidosis. The skin biopsy of the right limb was diagnosed as leukocytoclastic vasculitis. The patient was diagnosed as having a series of paradoxical inflammations during anti-TNF-α therapy. Since his paradoxical inflammations were not severe and opportunistic infections were excluded, IFX was cautiously continued for refractory Crohn's disease. Nine months later, not only his intrathoracic lesions but also his cutaneous lesions had spontaneously resolved. CONCLUSION: Physicians caring for patients with anti-TNF-α therapy should know that, based on a careful exclusion of infectious agents and thoughtful assessment of the patient's possible risks and benefits, paradoxical inflammations can be resolved without the cessation of anti-TNF-α therapy.

Muscle-specific inhibition of the classical nuclear factor-κB pathway is protective against diaphragmatic weakness in murine endotoxemia.

OBJECTIVE: Diaphragmatic weakness and acute respiratory failure are common in sepsis. Nuclear factor-κB acts as a general coordinator of the systemic inflammatory response, but its role within the diaphragm itself during sepsis is unknown. We investigated the potential protective effect upon the diaphragm of inhibiting nuclear factor-κB only within muscle fibers during acute endotoxemia. DESIGN: Prospective study in experimental animals. SETTING: University research laboratory. INTERVENTIONS: Wild-type and transgenic (muscle-specific IκBα super-repressor) mice with skeletal muscle-specific inhibition of the classical nuclear factor-κB pathway were subjected to acute endotoxemia. Muscle-specific ubiquitin ligases (muscle RING-finger protein 1 and atrogin-1), caspase-3 activity, inhibitor of apoptosis proteins, proinflammatory cytokines (interleukin-1ß, monocyte chemoattractant protein-1, and tumor necrosis factor-α), and diaphragmatic contractility were evaluated after 24 hours. MEASUREMENTS AND MAIN RESULTS: In wild-type mice, endotoxemia significantly increased proinflammatory cytokines (fold-change messenger RNA: interleukin-1ß = 7.6, monocyte chemoattractant protein-1 = 15.3, and tumor necrosis factor-α = 2.2) and proteolysis effectors (fold-change messenger RNA: muscle RING-finger protein 1 = 5.7, atrogin-1 = 2.8; caspase-3 activity elevated by 28%) in the diaphragm, while reducing its force-generating capacity by 38%. In nonendotoxemic muscle-specific IκBα super-repressor diaphragms, caspase-3 activity was unexpectedly increased by 40% above basal wild-type levels and inhibitors of apoptosis proteins were down-regulated, but force production remained normal. In muscle-specific IκBα super-repressor mice subjected to endotoxemia, proinflammatory cytokines, muscle RING-finger protein 1, and atrogin-1 were not significantly increased above their basal levels, and diaphragmatic weakness and further increases in caspase-3 activity were completely prevented. CONCLUSIONS: These results suggest that nuclear factor-κB signaling within skeletal muscle fibers is a key pathway leading to diaphragmatic weakness during acute endotoxemia, most likely via effects on multiple inflammatory mediators. In addition, inhibition of nuclear factor-κB signaling within diaphragm muscle fibers has complex effects on caspase-3 activation, which could have implications for the treatment of sepsis-induced diaphragmatic dysfunction.

Effects of body postures on respiratory muscle force and coughing in healthy people.

The respiratory muscle force determines the intensity of cough force. A greater cough force for cleaning the airways is essential for preventing and managing pneumonia. Body posture can affect the onset of aspiration pneumonia. However, the effects of body posture on the respiratory muscle and cough forces remain unclear. Thus, we aimed to explore the influence of the four body postures on respiratory muscle force, cough pressure, subjective ease of coughing, and pulmonary function in healthy individuals. Twenty healthy individuals were included in this study. Body postures were 0-degree supine, 30- and 60-degree semi-recumbent, and 90-degree sitting. The maximal inspiratory and expiratory pressures, maximal cough pressure, subjective ease of coughing, and pulmonary function, including peak expiratory flow, were evaluated. We set the measured values in the supine posture to 100% and showed the relative values. The 60-degree posture showed stronger inspiratory (125.1 ± 3.9%, mean ± standard error [SE]) and expiratory (116.4 ± 3.0%) muscle force, cough pressure, more subjective ease of coughing, and greater peak expiratory flow (113.4 ± 3.0%) than the supine posture. The sitting posture also showed greater inspiratory muscle force and peak expiratory flow than the supine posture. The correlation coefficient for the 60-degree posture showed that the maximal inspiratory pressure was moderately correlated with the maximal expiratory pressure (r = 0.512), cough pressure (r = 0.495), and peak expiratory flow (r = 0.558). The above findings suggest the advantage of keeping a 60-degree posture and avoiding the supine posture to generate a greater cough force in the prevention and management of pneumonia.

Establishment of a post-disaster healthcare information booklet for the Turkey-Syrian earthquake, based on past disasters.

The scientific evidence based on experiences with past disasters points to the possibility of the occurrence of future mental health issues among those who were affected by the recent Turkey-Syria earthquake. However, post-disaster care information on factors that could give rise to mental health issues among those affected have yet to be provided. In March 2011, Tohoku University compiled and published a booklet with post-disaster healthcare information based on the experiences with the Great East Japan Earthquake. This study aimed to promote the introduction and use of this booklet for post-disaster care in Turkey and Syria by presenting the results of a satisfaction survey conducted with relevant Japanese organizations about the booklet. A total of 505 Japanese organizations participated in the satisfaction survey of, and evaluated, the booklet. The results indicated the need to consider the ease of understanding for the general public when providing information on post-disaster care through booklets. We hope that this study leads to the appropriate provision of easy-to-understand, post-disaster healthcare information to the victims of the Turkey-Syria earthquake and future disasters.

Impacts of body positions on the geniohyoid muscle contraction and swallowing difficulty in healthy adults.

BACKGROUND: Body positions affect swallowing and gastroesophageal reflux. Swallowing impairment is one of the main causes of aspiration pneumonia. To prevent pneumonia, evaluation of body positions on gastroesophageal reflux recommended 30 degrees or higher semi-recumbent positions. The geniohypoid muscle and tongue play central roles in swallowing. However, the effects of body positions on contracting rates in the geniohyoid muscle and tongue pressure are unclear. Moreover, correlations between geniohyoid muscle contracting rates and subjective swallowing difficulties are unclear. AIMS: This study aimed to identify the proper body positions on contracting rates in the geniohyoid muscle, tongue pressure, and subjective swallowing difficulties. MATERIALS & METHODS: Twenty healthy adults swallowed 15- or 50 ml of water at 90 degrees sitting, 60- and 30 degrees semi-recumbent, and 0 degrees supine positions. We scored the subjective swallowing difficulties and measured the tongue pressure and the number of swallows. An ultrasound evaluated the geniohyoid muscle size and contracting rates. RESULTS: At sitting and 60 degrees semi-recumbent positions, the geniohyoid muscle showed greter contracting rates than at 30 degrees semi-recumbent and supine postions (P < 0.05), which resulted in easier swalloiwng. Greater tongue pressure was weakly correlated with fewer swallows (r = -0.339, P = 0.002), whereas the body positions did not affect. CONCLUSION: Considering swallowing and gastroesophageal reflux together, a trunk angle of 60 degrees or more might be beneficial for reducing the risk of aspiration.

Importance of Skeletal Muscle and Interdisciplinary Team Approach in Managing Pneumonia in Older People.

Pneumonia is the most frequent lower respiratory tract disease and a major cause of morbidity and mortality globally [...].

Geriatric Nutritional Risk Index Predicts High Activities of Daily Living at Discharge in Older Patients with Heart Failure after Cardiac Rehabilitation.

BACKGROUND: Hospitalization often leads to a decline in activities of daily living (ADL) in older patients with heart failure. Although cardiac rehabilitation (CR) improves ADL, it can be difficult to perform CR due to the deconditioning of these patients. This study aimed to examine the factors associated with ADL at discharge in older patients with heart failure who underwent CR. METHODS: A total of 86 of 110 older heart failure patients aged ≥ 75 years (average age, 86.9 ± 5.7 years) transferred to our institution for CR were enrolled and classified into high ADL at discharge (n = 54) and low ADL at discharge (n = 32) groups. Physical characteristics, comorbidities, medications, blood test data, echocardiographic data, and nutritional status (Geriatric Nutritional Risk Index [GNRI]) were retrospectively examined from medical records. ADL were assessed using the Barthel Index (BI) at admission and discharge. Considering multicollinearity, the relationship between high ADL (BI ≥ 60) at discharge and these assessments at admission was analyzed using multiple logistic regression analysis. The receiver operating characteristic curve was analyzed to calculate the cutoff values for the parameters identified by the multiple logistic regression analysis. RESULTS: The GNRI was the only independent factor predicting high ADL at discharge (p = 0.041; odds ratio [OR], 1.125; 95% confidence interval [CI], 1.005-1.260). The area under the receiver operating characteristic curve for the GNRI was 0.770 (95% CI, 0.664-0.876). The cutoff value for the GNRI was 83.4 (sensitivity, 85.2%; specificity, 62.5%). CONCLUSION: These findings suggest that the GNRI score at admission predicts high ADL at discharge in older patients with heart failure who underwent CR.

Association between Low Forced Vital Capacity and High Pneumonia Mortality, and Impact of Muscle Power.

Impaired % predicted value forced vital capacity (% FVC) is related to higher all-cause mortality in aged adults, and strong muscle force may improve this relationship. A muscle disease, sarcopenia, causes higher mortality. We aimed to identify the unknown disease that relates impaired % FVC with higher mortality in aged adults among the three major leading causes of death, and the effect of strong leg force on this relationship. Cox proportional hazard model analyzed the longitudinal Tsurugaya cohort that registered 1048 aged Japanese for 11 years. The primary outcome was the relationship between % FVC and mortality by cancer, cardiovascular disease, or pneumonia. Exposure variables were % FVC or leg force divided by 80% or median values, respectively. The secondary outcome was the effects of leg force on the relationship. Among the diseases, % FVC < 80% was related only to higher pneumonia mortality (hazard ratio [HR], 4.09; 95% CI, 1.90-8.83) relative to the % FVC ≥ 80% group before adjustment. Adding the leg force as an explanatory variable reduced the HR to 3.34 (1.54-7.25). Weak leg force might indicate sarcopenia, and its prevention may improve higher pneumonia mortality risk related to impaired % FVC, which we may advise people in clinical settings.