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A decline in lung function is the basis of the definition of progressive fibrosing interstitial lung disease. This study aimed to evaluate the epidemiology and clinical relevance of lung function decline in sarcoidosis.This retrospective observational study was conducted at a general sarcoidosis clinic. Lung function decline was defined as a relative 24-month decline in the percentage of predicted forced vital capacity (%FVC) of ≥10% or the percentage of predicted diffusion capacity for carbon monoxide (%DLco) of ≥15%. The frequency of lung function decline and its associations with the subsequent 24-month change in lung function and survival time were analyzed.Of the 201 patients, 14 (7.0%) exhibited a 24-month decline in %FVC of ≥10% and 28 (16.6%) exhibited a 24-month decline in %DLco of ≥15%. A 24-month decline in lung function was not associated with a subsequent 24-month lung function decline. Eleven patients died during the median observational time of 148.3 months; 4 of the 11 deaths were associated with sarcoidosis. A 24-month decline in lung function was associated with worse survival even after the adjustment for composite physiological index (CPI) and pulmonary hypertension (PH): 24-month decline in %FVC ≥10%, hazard ratio (HR) adjusted for CPI = 21.8, HR adjusted for PH = 19.3 and 24-month decline in %DLco ≥15%, HR adjusted for PH = 6.74.A 24-month decline in lung function can be a risk factor for mortality in sarcoidosis irrespective of CPI and PH.

STUDY OBJECTIVES: Whether the association between sleep-disordered breathing (SDB) and cardiovascular disease is independent of comorbid risk factors for cardiovascular disease is controversial. The objective of this study was to elucidate whether the association between SDB severity and the surrogate markers of cardiovascular disease events differs in relation to the number of comorbidities. METHODS: This cross-sectional study included 7,731 participants. Severity of SDB was determined by the oxygen desaturation index adjusted by actigraph-measured objective sleep time. Participants were stratified according to SDB severity and the number of comorbidities (hypertension, diabetes, dyslipidemia, and obesity), and the associations between the maximum value of intima-media thickness of the common carotid artery (CCA-IMT-max), brachial-ankle pulse wave velocity, and cardio-ankle vascular index were evaluated. RESULTS: Among participants with no risk factors, CCA-IMT-max increased according to SDB severity (n = 1022, P < .0001). Even after matching the background, the median CCA-IMT-max value was 14% higher in moderate-severe SDB patients than those without SDB (n = 45 in each group, P = .020). The difference was not significant for brachial-ankle pulse wave velocity and cardio-ankle vascular index. On the other hand, a significant difference in CCA-IMT-max was not found in those with multiple comorbidities. Consistently, multiple regression analysis revealed an independent association between CCA-IMT-max and moderate-severe SDB for all study participants (β: 0.0222, 95% confidence interval: 0.0039–0.0405, P = .017), but the association was not significant for stratified participants with multiple comorbidities. CONCLUSIONS: SDB severity is associated with the CCA-IMT-max level, but the independent association becomes weaker for those with multiple comorbidities. CITATION: Nakatsuka Y, Murase K, Matsumoto T, et al. Markers of cardiovascular disease risk in sleep-disordered breathing with or without comorbidities: the Nagahama Study. J Clin Sleep Med. 2021;17(12):2467–2475.

Recently an association between blood glucose dysregulation and sleep disruption was suggested. The association between sleep disordered breathing, most of which is due to obstructive sleep apnea (OSA) in the general population, and diabetic severity, as well as the impact of antidiabetic treatment, remains unclear. This study aimed to investigate these associations as well as age and sex differences. This cross-sectional study evaluated 7,680 community participants as the main cohort (population-based cohort). OSA was assessed by the 3% oxygen desaturation index from pulse oximetry, which was corrected for sleep duration obtained by wrist actigraphy. For arguing the limitations for using pulse oximetry, 597 hospitalised patients, who were assessed by the apnea-hypopnea index from attended polysomnography, were also evaluated as the validation cohort (hospital-based cohort). Moderate-to-severe OSA was more prevalent as haemoglobin A1c (HbA1c) levels increased (5.6%/5.6%-6.5%/6.5%-7.5%/≥7.5%, respectively) in both cohorts (p 0.001), but only in those without antidiabetic treatment. The HbA1c level was an independent factor for moderate-to-severe OSA (population-based cohort, odds ratio [OR] 1.26, 95% confidence interval [CI] 1.10-1.45; hospital-based cohort, OR 1.69, 95% CI 1.22-2.33, per 1% increase). These associations were more prominent in the middle-aged (aged60 years) than in the elderly (aged ≥60 years) and in women than in men in both cohorts. The prevalence of moderate-to-severe OSA in patients with antidiabetic treatment in the hospital-based cohort was ≥75% regardless of HbA1c levels. In conclusion, an association between the prevalence of OSA and HbA1c level even within or over the normal range was found only in patients without antidiabetic treatment and was more prominent in the middle-aged and in women.

A matricellular protein osteopontin (OPN) is considered to exert neuroprotective and healing effects on neurovascular injuries in an acute phase of aneurysmal subarachnoid hemorrhage (SAH). However, the relationships between OPN expression and chronic shunt-dependent hydrocephalus (SDHC) have never been investigated. In 166 SAH patients (derivation and validation cohorts, 110 and 56, respectively), plasma OPN levels were serially measured at days1-3, 4-6, 7-9, and 10-12 after aneurysmal obliteration. The OPN levels and clinical factors were compared between patients with and without subsequent development of chronic SDHC. Plasma OPN levels in the SDHC patients increased from days 1-3 to days 4-6 and remained high thereafter, while those in the non-SDHC patients peaked at days 4-6 and then decreased over time. Plasma OPN levels had no correlation with serum levels of C-reactive protein (CRP), a systemic inflammatory marker. Univariate analyses showed that age, modified Fisher grade, acute hydrocephalus, cerebrospinal fluid drainage, and OPN and CRP levels at days 10-12 were significantly different between patients with and without SDHC. Multivariate analyses revealed that higher plasma OPN levels at days 10-12 were an independent factor associated with the development of SDHC, in addition to a more frequent use of cerebrospinal fluid drainage and higher modified Fisher grade at admission. Plasma OPN levels at days 10-12 maintained similar discrimination power in the validation cohort and had good calibration on the Hosmer-Lemeshow goodness-of-fit test. Prolonged higher expression of OPN may contribute to the development of post-SAH SDHC, possibly by excessive repairing effects promoting fibrosis in the subarachnoid space.

Cortical superficial siderosis (cSS) is a rare condition that is regarded as a potential magnetic resonance marker of cerebral amyloid angiopathy (CAA). We describe the case of a 68-year-old man with cSS and Parkinson's disease (PD) who subsequently exhibited incidental microhemorrhages, which were only detected on magnetic resonance imaging (MRI), at one week after deep brain stimulation (DBS) surgery. cSS is now considered to be a significant risk factor for CAA and future bleeding. Therefore, because DBS surgery is invasive and may increase the risk of intracerebral hemorrhage, the procedure should be performed carefully when managing patients with PD and CAA.

STUDY OBJECTIVES: Since subjective sleep duration (SSD) is considered to be longer than objective sleep duration (OSD), results of SSD minus OSD (SSD−OSD) might always be thought to be positive. Some recent reports showed different results, but exact results have not been obtained. The difference between SSD and OSD may change according to OSD. We investigated this difference and its association with sleep-disordered breathing (SDB) or nonrestorative sleep. METHODS: This cross-sectional study evaluated 6,908 community residents in Nagahama, Japan. SSD was determined by self-administered questionnaire. OSD was measured by wrist actigraphy and sleep diary. SDB was assessed according to the 3% oxygen desaturation index adjusted for OSD. RESULTS: Worthy of notice was that SSD was shorter than OSD for those with SSD longer than 6.98 hours in all participants, 7.36 hours in males, and 6.80 hours in females. However, SSD was longer than OSD (mean ± SD: 6.49 ± 1.07 vs 6.01 ± 0.96; P < .001) overall, as SSD is considered to be longer than OSD. In patients with SDB, the difference between SSD−OSD was greater when OSD was shorter. The difference also depended on SDB severity. The degree of positivity between OSD and SSD was a significant factor in nonrestorative sleep (odds ratio: 2.691; P < .001). CONCLUSIONS: When OSD was slightly less than 7 (6.98) hours, participants reported or perceived SSD > OSD. When OSD was > 6.98 hours, participants reported or perceived SSD < OSD. Patients with SDB reported longer SSD than OSD according to severity of SDB. Evaluating SSD, OSD, and their differences may be useful for managing sleep disturbances, including nonrestorative sleep. CITATION: Takahashi N, Matsumoto T, Nakatsuka Y, et al. Differences between subjective and objective sleep duration according to actual sleep duration and sleep-disordered breathing: the Nagahama Study. J Clin Sleep Med. 2022;18(3):851–859.

Background and objective: Generally, a disease-specific health-related quality of life (HRQOL) measurement is more useful than generic measures in assessing perceived physical and mental health characteristic of a particular disease. The idiopathic pulmonary fibrosis (IPF)-specific version of St. George’s Respiratory Questionnaire (SGRQ-I) has been recently developed for patients with IPF. We proposed to evaluate associations between the SGRQ-I and other clinical indices, as well as its prognostic value in patients with IPF. Methods: Fifty-two patients with IPF were recruited in this prospective cohort study. HRQOL was assessed using the SGRQ-I and the Medical Outcomes Study 36-item Short Form, dyspnea using the modified Medical Research Council (mMRC) dyspnea scale, and psychological status using the Hospital Anxiety and Depression Scale (HADS). We then evaluated the relationship between the SGRQ-I and other clinical measures, as well as one-year clinical deterioration defined as a hospital admission due to respiratory exacerbation or all-cause death. Results: Stepwise multiple-regression analyses revealed that the mMRC dyspnea scale, the HADS anxiety or depression, and minimum oxygen saturation during a six-minute walk test significantly contributed to the Total and three components of the SGRQ-I. In multivariate Cox proportional-hazards analyses, the Total score of SGRQ-I predicted clinical deterioration independent of forced vital capacity, the six-minute walk distance, or partial pressure of arterial oxygen on room air. Conclusions: The SGRQ-I is a multidisciplinary instrument representing physical, functional and psychological impairments in patients with IPF. The SGRQ-I is a significant predictor of short-term disease progression independent of physiological measurements. (Sarcoidosis Vasc Diffuse Lung Dis 2017; 34: 226-235)

Idiopathic pleuroparenchymal fibroelastosis (PPFE) is a rare type of idiopathic interstitial pneumonia, and pathological PPFE is also observed in patients with secondary interstitial pneumonia. This study aimed to evaluate the pathological findings associated with radiological PPFE-like lesions and the clinical and morphological features of patients with pathological PPFE.We retrospectively reviewed the pathology of the explanted lungs from 59 lung transplant recipients with radiological PPFE-like lesions. Pathological PPFE lesions were identified in 14 patients with idiopathic disease and in 12 patients with secondary disease. Pathological PPFE was associated with previous pneumothorax, volume loss in the upper lobes, and a flattened chest. Patients with idiopathic disease and those with secondary disease with pathological PPFE had similar clinical, radiological and pathological findings, whereas fibroblastic foci were more common in patients with idiopathic disease, and patients with secondary disease more frequently showed alveolar septal thickening with elastosis or fibrosis. Post-transplantation survival did not differ between patients with idiopathic and secondary disease with pathological PPFE (log-rank; P = 0.57) and was similar between patients with idiopathic disease with pathological PPFE and those with idiopathic pulmonary fibrosis (IPF) (log-rank; P = 0.62).Not all patients with interstitial pneumonia with radiological PPFE-like lesions have pathological PPFE. Characteristic clinical features can suggest the presence of pathological PPFE, and idiopathic and secondary cases with pathological PPFE are similar except for fibroblastic foci in idiopathic cases and alveolar septal thickening with elastosis or fibrosis in secondary cases. Patients with pathological PPFE have a similar prognosis to those with IPF after transplantation.

Blood eosinophil count is a useful measure in asthma or COPD management. Recent epidemiological studies revealed that body mass index (BMI) is positively associated with eosinophil counts. However, few studies focused on the role of adiposity and fatty acid-related metabolites on eosinophil counts, including the effect of genetic polymorphism. In this community-based study involving 8265 participants (30–74 year old) from Nagahama city, we investigated the relationship between eosinophil counts and serum levels of fatty acid-related metabolites. The role of MDC1, a gene that is related to eosinophil counts in our previous study and encodes a protein that is thought to be involved in the repair of deoxyribonucleic acid damage, was also examined taking into account its interaction with adiposity. Serum levels of linoleic acid (LA) and β-hydroxybutyric acid (BHB) were negatively associated with eosinophil counts after adjustment with various confounders; however, there were positive interactions between serum LA and BMI and between serum BHB and BMI/body fat percentages in terms of eosinophil counts. In never-smokers, there was positive interaction for eosinophil counts between the CC genotype of MDC1 rs4713354 and BMI/body fat percentages. In conclusion, both serum LA and BHB have negative impacts on eosinophil counts, while adiposity shows robust positive effects on eosinophil counts, partly via genetic background in never-smokers.

The treatment for large central disk herniation (LCDH) at upper lumbar spine is often challenging. Previous reports showed various surgical strategies, such as microdiscectomy with posterior fixation, endoscopic surgery, and microdiscectomy through transdural approach. However, there is no consensus regarding which surgical option is better for LCDH at upper lumbar spine. In this report, we describe the novel transdural epiarachnoid approach (TDEA), which uses the corridor of epiarachnoid space for microdiscectomy. Compared with classical transdural approaches, this novel approach may reduce risks of postoperative cerebrospinal fluid leakage and the development of arachnoiditis.A 69-yr-old man presented with progressive bilateral radiating leg pain, intermittent claudication, and low back pain. Magnetic resonance images and computed tomography scans revealed LCDH at L2/3 level. We performed microdiscectomy using the TDEA. Postoperative course was uneventful, and his symptoms were relieved after surgery.The novel TDEA for LCDH at upper lumbar spine is illustrated with a video. This novel approach has an advantage of the preservation of subarachnoid components compared with classical transdural approaches.

Background Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic lung disease that leads to respiratory failure and death. Although there is a greater understanding of the etiology of this disease, accurately predicting the disease course in individual patients is still not possible. This study aimed to evaluate serum cytokines/chemokines as potential biomarkers that can predict outcomes in IPF patients. Methods A multi-institutional prospective two-stage discovery and validation design using two independent cohorts was adopted. For the discovery analysis, serum samples from 100 IPF patients and 32 healthy controls were examined using an unbiased, multiplex immunoassay of 48 cytokines/chemokines. The serum cytokine/chemokine values were compared between IPF patients and controls; the association between multiplex measurements and survival time was evaluated in IPF patients. In the validation analysis, the cytokines/chemokines identified in the discovery analysis were examined in serum samples from another 81 IPF patients to verify the ability of these cytokines/chemokines to predict survival. Immunohistochemical assessment of IPF-derived lung samples was also performed to determine where this novel biomarker is expressed. Results In the discovery cohort, 18 cytokines/chemokines were significantly elevated in sera from IPF patients compared with those from controls. Interleukin-1 receptor alpha (IL-1Rα), interleukin-8 (IL-8), macrophage inflammatory protein 1 alpha (MIP-1α), and cutaneous T-cell-attracting chemokine (CTACK) were associated with survival: IL-1Rα, hazard ratio (HR) = 1.04 per 10 units, 95% confidence interval (95% CI) 1.01–1.07; IL-8, HR = 1.04, 95% CI 1.01–1.08; MIP-1α, HR = 1.19, 95% CI 1.00–1.36; and CTACK, HR = 1.12 per 100 units, 95% CI 1.02–1.21. A replication analysis was performed only for CTACK because others were previously reported to be potential biomarkers of interstitial lung diseases. In the validation cohort, CTACK was associated with survival: HR = 1.14 per 100 units, 95% CI 1.01–1.28. Immunohistochemistry revealed the expression of CTACK and CC chemokine receptor 10 (a ligand of CTACK) in airway and type II alveolar epithelial cells of IPF patients but not in those of controls. Conclusions CTACK is a novel prognostic biomarker of IPF. Trial registration None (because of no healthcare intervention)

Subarachnoid hemorrhage (SAH) is a devastating disease. Neuronal death is an important pathophysiology in the acute phase of SAH, but the histopathological features of dying neurons have been poorly studied. Using several staining methods including terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and microtubule-associated protein 2 (MAP-2) double immunolabeling, we investigated the morphological changes of nucleus and cytoskeleton in neurons and sought susceptible areas to neuronal death in filament perforation SAH mice under light microscope. TUNEL and MAP-2 double immunolabeling clearly showed morphological features of shrunken cytoplasm and sometimes curl-like fibers in dying neurons, besides nuclear abnormalities. More dying neurons were detected in the moderate SAH group than in the mild SAH group, and the temporal base cortex was the most susceptible area to neuronal death with deoxyribonucleic acid (DNA) damage among the cerebral cortices and hippocampus at 24 hr after SAH ( p

Although delayed cerebral ischemia (DCI) is a well-known complication after subarachnoid hemorrhage (SAH), there are no reliable biomarkers to predict DCI development. Matricellular proteins (MCPs) have been reported relevant to DCI and expected to become biomarkers. As machine learning (ML) enables the classification of various input data and the result prediction, the aim of this study was to construct early prediction models of DCI development with clinical variables and MCPs using ML analyses. Early-stage clinical data of 95 SAH patients in a prospective cohort were analyzed and applied to a ML algorithm, random forest, to construct three prediction models: (1) a model with only clinical variables on admission, (2) a model with only plasma levels of MCP (periostin, osteopontin, and galectin-3) at post-onset days 1-3, and (3) a model with both clinical variables on admission and MCP values at days 1-3. The prediction accuracy of the development of DCI, angiographic vasospasm, or cerebral infarction and the importance of each feature were computed. The prediction accuracy of DCI development was 93.9% in model 1, 87.2% in model 2, and 95.1% in model 3, but that of angiographic vasospasm or cerebral infarction was lower. The three most important features in model 3 for DCI were periostin, osteopontin, and galectin-3, followed by aneurysm location. All of the early-stage prediction models of DCI development constructed by ML worked with high accuracy and sensitivity. One-time early-stage measurement of plasma MCPs served for reliable prediction of DCI development, suggesting their potential utility as biomarkers.

Rationale The Sarcoidosis Health Questionnaire (SHQ) is the first sarcoidosis-specific health status questionnaire ever developed. Worse health status, as evaluated by the SHQ, may indicate higher risk for deterioration in the following 5 years. Objectives To evaluate the association between SHQ scores and deterioration defined clinically at 5-year follow-up. Methods 122 patients with biopsy-supported sarcoidosis completed the SHQ and underwent evaluation with respect to organ involvement, chest radiograph, electrocardiogram, serum biomarker measurements, pulmonary function tests, and echocardiogram. Of these 122, 88 (72.1%) were available for pulmonary, cardiac, and non-pulmonary, non-cardiac deterioration assessment during the following 5 years. Measurements and main results Five-year deterioration was observed in 20 patients (23%). The SHQ total score was significantly associated with 5-year deterioration, after adjusting for cardiac involvement at baseline, with adjusted odds ratio (OR) of 0.54 (95% confidence interval [95% CI], 0.29–0.99). The association of the total SHQ with 5-year outcome was not significant when adjusted for left ventricular ejection fraction (LVEF) at baseline (adjusted OR, 0.61 [0.32–1.16]), whereas LVEF was significantly associated with 5-year outcome (adjusted OR, 0.92 [0.86–0.99]). The association between total SHQ score and 5-year deterioration was marginal when adjusted for baseline usage of systemic corticosteroid (CS)/immunosuppressive (IS) agents (adjusted OR, 0.58 [0.31–1.10]), whereas systemic CS/IS usage significantly predicted 5-year deterioration (adjusted odds ratio [OR], 3.46 [1.12–10.7]). There was a marginal correlation between the total SHQ and LVEF (rho = 0.19, p = 0.07) and a weak association between the total SHQ and systemic CS/IS usage (rho = −0.23, p = 0.03). The Physical Functioning domain scores of the SHQ were significantly associated with 5-year deterioration (adjusted OR, 0.45–0.51). Conclusions Worse health status, as assessed by the SHQ score, can be a risk factor for 5-year deterioration of sarcoidosis, although usage of the CS/IS at baseline and lower LVEF at baseline are more predictive of 5-year deterioration.

STUDY OBJECTIVES: It is well known that a family history of diabetes (FHD) is a definitive risk factor for type 2 diabetes. It has not been known whether sleep-disordered breathing (SDB) increases the prevalence of diabetes in those with an FHD. METHODS: We assessed SDB severity in 7,477 study participants by oximetry corrected by objective sleep duration determined by wrist actigraphy. Glycated hemoglobin ≥6.5% and/or current medication for diabetes indicated the presence of diabetes. In addition to the overall prevalence, the prevalence of recent-onset diabetes during the nearly 5 years before the SDB measurements were made was investigated. RESULTS: Of the 7,477 participants (mean age: 57.9; range: 34.2–80.7; SD: 12.1 years; 67.7% females), 1,569 had an FHD. The prevalence of diabetes in FHD participants with moderate-to-severe SDB (MS-SDB) was higher than in those without SDB (MS-SDB vs without SDB: all, 29.3% vs 3.3% [P < .001]; females, 32.6% vs 1.9% [P < .001]; males, 26.2% vs 11.7% [P = .037]). However, multivariate analysis showed that MS-SDB was significantly associated with a higher prevalence of diabetes only in FHD-positive females (odds ratio [95% confidence interval]: females, 7.43 [3.16–17.45]; males, 0.92 [0.37–2.31]). Among the FHD-positive participants, the prevalence of recent-onset diabetes was higher in those with MS-SDB than those without SDB, but only in females (MS-SDB vs without SDB: 21.4% vs 1.1%; P < 0.001). CONCLUSIONS: MS-SDB was associated with diabetes risk in females with an FHD, and future studies are needed on whether treatment of SDB in females with an FHD would prevent the onset of diabetes. CITATION: Minami T, Matsumoto T, Tabara Y, et al. Impact of sleep-disordered breathing on glucose metabolism among individuals with a family history of diabetes: the Nagahama study. J Clin Sleep Med. 2021;17(2):129–140.

Background: While self-reported subjective sleep duration (SSD) usually tends to exceed actual sleep duration (objective sleep duration, OSD), factors related to the differences between SSD and OSD are unknown. It was reported that sleep disordered breathing (SDB) altered the perception of sleep habits. Aims and Objectives: This study aimed to compare SSD with OSD and to examine whether SDB was related to the differences between SSD and OSD. Methods: This cross-sectional study evaluated 6908 community residents in Nagahama city, Japan. SSD was determined by a self-administered questionnaire while OSD was measured by wrist actigraphy and a sleep diary. SDB was assessed according to the 3% oxygen desaturation index modified for OSD obtained by actigraphy. Results: In groups of participants with SSD Conclusions: OSD tended to be longer than SSD in those who reported short SSD, while the opposite occurred in those reporting long SSD; however, this tendency was offset at 5.7 hours. OSD was shorter than SSD as the severity of SDB increased. These data will help to better assess patients’ complaints about sleep duration.

Our previous cross-sectional study showed that periodic limb movements during sleep (PLMS) were frequently found in patients with obstructive sleep apnea (OSA) and that both OSA and PLMS were associated with higher plasma fibrinogen levels. We explored the longitudinal relationships among these factors. Plasma fibrinogen levels were measured in 333 consecutive patients who underwent polysomnography to diagnose OSA. Patients who initiated continuous positive airway pressure (CPAP) underwent follow-up polysomnography after 3 months of CPAP use. They were categorized into groups with good or poor adherence (% days with ≥ 4 h/night of CPAP use ≥ 70% or

Background Pulmonary arterial hypertension (PAH) is frequently complicated by sleep disordered breathing (SDB), and previous studies have largely focused on hypoxemic SDB. Even though nocturnal hypercapnia was shown to exacerbate pulmonary hypertension, the clinical significance of nocturnal hypercapnia among PAH patients has been scarcely investigated. Method Seventeen patients with PAH were identified from 246 consecutive patients referred to Kyoto University Hospital for the evaluation of lung transplant registration from January 2010 to December 2017. Included in this study were 13 patients whose nocturnal transcutaneous carbon dioxide partial pressure (PtcCO2) monitoring data were available. Nocturnal hypercapnia was diagnosed according to the guidelines of the American Academy of Sleep Medicine. Associations of nocturnal PtcCO2 measurements with clinical features, the findings of right heart catheterization and pulmonary function parameters were evaluated. Results Nocturnal hypercapnia was diagnosed in six patients (46.2%), while no patient had daytime hypercapnia. Of note, nocturnal hypercapnia was found for 5 out of 6 patients with idiopathic PAH (83.3%). Mean nocturnal PtcCO2 levels correlated negatively with the percentage of predicted total lung capacity (TLC), and positively with cardiac output and cardiac index. Conclusion Nocturnal hypercapnia was prevalent among advanced PAH patients who were waiting for lung transplantation, and associated with %TLC. Nocturnal hypercapnia was associated with the increase in cardiac output, which might potentially worsen pulmonary hypertension especially during sleep. Further studies are needed to investigate hemodynamics during sleep and to clarify whether nocturnal hypercapnia can be a therapeutic target for PAH patients.

Subarachnoid hemorrhage (SAH) by a rupture of cerebral aneurysms remains the most devastating cerebrovascular disease. Early brain injury (EBI) is increasingly recognized to be the primary determinant for poor outcomes, and also considered to cause delayed cerebral ischemia (DCI) after SAH. Both clinical and experimental literatures emphasize the impact of global cerebral edema in EBI as negative prognostic and direct pathological factors. The nature of the global cerebral edema is a mixture of cytotoxic and vasogenic edema, both of which may be caused by post-SAH induction of tenascin-C (TNC) that is an inducible, non-structural, secreted and multifunctional matricellular protein. Experimental SAH induces TNC in brain parenchyma in rats and mice. TNC knockout suppressed EBI in terms of brain edema, blood-brain barrier disruption, neuronal apoptosis and neuroinflammation, associated with the inhibition of post-SAH activation of mitogen-activated protein kinases and nuclear factor-kappa B in mice. In a clinical setting, more severe SAH increases more TNC in cerebrospinal fluid and peripheral blood, which could be a surrogate marker of EBI and predict DCI development and outcomes. In addition, cilostazol, a selective inhibitor of phosphodiesterase type III that is a clinically available anti-platelet agent and is known to suppress TNC induction, dose-dependently inhibited delayed cerebral infarction and improved outcomes in a pilot clinical study. Thus, further studies may facilitate application of TNC as biomarkers for non-invasive diagnosis or assessment of EBI and DCI, and lead to development of a molecular target drug against TNC, contributing to the improvement of post-SAH outcomes.

Inhaled pathogens including Pseudomonas aeruginosa initially encounter airway epithelial cells (AECs), which are poised to evoke cell-intrinsic innate defense, affecting second tier of hematopoietic cell-mediated immune reaction. However, it is largely unknown how pulmonary immune responses mediated by a variety of immune cells are coordinated. Here we show that Regnase-1, an endoribonuclease expressed in AECs and immune cells, plays an essential role in coordinating innate responses and adaptive immunity against P. aeruginosa infection. Intratracheal treatment of mice with heat-killed P. aeruginosa resulted in prolonged disappearance of Regnase-1 consistent with sustained expression of Regnase-1 target inflammatory genes, whereas the transcription factor NF-κB was only transiently activated. AEC-specific deletion of Regnase-1 not only augmented innate defenses against P. aeruginosa but also enhanced secretion of Pseudomonas-specific IgA and Th17 accumulation in the lung, culminating in conferring significant resistance against P. aeruginosa re-infection in vivo. Although Regnase-1 directly controls distinct sets of genes in each of AECs and T cells, degradation of Regnase-1 in both cell types is beneficial for maximizing acquired immune responses. Collectively, these results demonstrate that Regnase-1 orchestrates AEC-mediated and immune cell-mediated host defense against pulmonary bacterial infection.

Introduction It has been reported that brain tumor resection by craniotomy is a high risk for deep venous thrombosis (DVT), though few data is available in Japanese patients. The aim of this retrospective study was to evaluate the incidence and risk factors for DVT in Japanese adult patients with brain tumor surgery. Materials and methods Medical records of Japanese adult patients with craniotomy for brain tumor were reviewed. In addition to clinical variables including patients' age, sex, body mass index, previous history of DVT, leg paresis, medications, tumor histology, surgical factors, adjuvant therapy, infection, and duration of post-operative immobilization and hospitalization, plasma D-dimer levels were measured at pre-surgery (baseline), on post-operative day (POD) one to 30 and during adjuvant therapy, and were compared between patients with and without DVT. Results Thirteen of 61 patients (21.3%) had DVT after surgery with mechanical prophylaxis. All DVTs were asymptomatic. Multivariate analyses found post-operative infection (odds ratio, 12.15; 95% confidence interval, 1.09–134.98; P = 0.03) to be a sole independent risk factor for DVT. D-dimer levels were not significantly different between patients with and without DVT at baseline and POD 1–30, but were significantly elevated during adjuvant therapy in patients with DVT (P = 0.03). Conclusions Not a few Japanese patients developed DVT after brain tumor surgery with mechanical prophylaxis, and patients with infection should be carefully monitored for post-operative DVT.

Background: The significance of the nutritional status in idiopathic pulmonary fibrosis (IPF) is largely unknown. Temporal body weight (BW) change, a dynamic index of nutrition status, can detect the malnutrition more accurately than the conventional single-point body mass index evaluation. Objective: To investigate how the temporal BW change influences the clinical courses of IPF. Methods: This multicenter study enrolled IPF patients from four referral hospitals of interstitial lung diseases in Japan (the Japanese cohort, the derivation cohort) and the Royal Brompton Hospital (the UK cohort, the validation cohort). The annual rate of BW change from the initial presentation was evaluated. A > 5% decrease of BW was defined as a significant BW loss. Results: Twenty-seven out of 124 patients in the Japanese cohort and 13 out of 86 patients in the UK cohort showed significant BW loss. Patients with BW loss showed significantly worse survival in both cohorts. Multivariate analyses revealed that BW loss was an independent factor for decreased survival (Japanese cohort: p = 0.047, UK cohort: p = 0.013). A 6.1% loss of BW was chosen as the optimal cutoff value to predict the 2-year mortality from the initial presentation. The stratified analysis revealed that a 6.1% or greater BW loss could predict worse survival specifically in cases without a greater than 10% decline in forced vital capacity (FVC). Conclusions: BW loss is independently associated with the survival of IPF patients, particularly when a decline in the FVC was not observed. Further studies are needed to understand the mechanisms underlying BW loss in IPF.

Regnase-1 and Roquin are RNA binding proteins that are essential for degradation of inflammatory mRNAs and maintenance of immune homeostasis. Although deficiency of either of the proteins leads to enhanced T cell activation, their functional relationship in T cells has yet to be clarified because of lethality upon mutation of both Regnase-1 and Roquin. By using a Regnase-1 conditional allele, we show that mutations of both Regnase-1 and Roquin in T cells leads to massive lymphocyte activation. In contrast, mutation of either Regnase-1 or Roquin affected T cell activation to a lesser extent than the double mutation, indicating that Regnase-1 and Roquin function nonredundantly in T cells. Interestingly, Regnase-1 and Roquin double-mutant mice suffered from severe inflammation and early formation of fibrosis, especially in the heart, along with the increased expression of Ifng, but not Il4 or Il17a. Consistently, mutation of both Regnase-1 and Roquin leads to a huge increase in the Th1, but not the Th2 or Th17, population in spleens compared with T cells with a single Regnase-1 or Roquin deficiency. Regnase-1 and Roquin are capable of repressing the expression of a group of mRNAs encoding factors involved in Th1 differentiation, such as Furin and Il12rb1, via their 3′ untranslated regions. Moreover, Regnase-1 is capable of repressing Roquin mRNA. This cross-regulation may contribute to the synergistic control of T cell activation/polarization. Collectively, our results demonstrate that Regnase-1 and Roquin maintain T cell immune homeostasis and regulate Th1 polarization synergistically.

A matricellular protein galectin-3 is involved in tissue injury and inflammation, but the role of galectin-3 remains unclear in aneurysmal subarachnoid hemorrhage (SAH). The purpose of this study was to assess whether acute-stage galectin-3 levels were associated with the subsequent development of neurovascular events and outcome after SAH. This study included 83 consecutive patients diagnosed with aneurysmal SAH of resuscitated World Federation of Neurological Surgeons (WFNS) grades 1-3. Plasma galectin-3 levels were once measured on days 1-3 (the day after clipping or coiling). Fifteen patients had poor outcomes, which were associated with increasing age, female, pre-onset morbidity, worse WFNS grade, modified Fisher computed tomography scale, acute hydrocephalus, and higher galectin-3 levels compared with good outcomes. Multivariate analyses revealed that plasma galectin-3 was an independent determinant for poor outcome (odds ratio, 3.08; 95% confidence interval, 1.58-6.00; p = 0.001). Among post-SAH neurovascular events occurring on day 4 and thereafter, delayed cerebral ischemia and infarction, but not angiographic vasospasm and shunt-dependent hydrocephalus, showed significantly higher plasma galectin-3 levels on days 1-3. The receiver operating characteristic curve indicated that plasma galectin-3 with a cutoff value of 3.30 or 3.48 ng/ml predicted delayed cerebral infarction development or poor outcome (specificity, 62.5%, 70.6%; sensitivity, 90.9%, 73.3%, respectively). The findings suggest that plasma galectin-3 levels on days 1-3 would be a useful biomarker for predicting subsequent development of delayed cerebral infarction and eventual poor outcome and provide a new candidate, which may mediate between post-SAH early brain injury or inflammation and delayed cerebral infarction without vasospasm.

Here, we report a case of vertebral artery aneurysm causing dysphagia in a 56-year-old man who had no remarkable past history. Two months before the first visit, he developed posterior neck pain followed by difficulty swallowing 1 month later. He was referred to our clinic because of gradually worsening dysphagia. Physical examination showed paralysis of cranial nerves IX, X, and XII; therefore, he was hospitalized. Because enhanced CT and MRI showed a partially thrombosed right vertebral artery aneurysm, he was transferred to the care of the Department of Neurosurgery. Parent artery occlusion of the right vertebral artery aneurysm was performed and it improved his symptoms. After regaining his ability to take in liquid food, he was transferred to another hospital for further rehabilitation. In this case, we attributed the dysphagia to aneurysmal compression of the roots of cranial nerves IX, X, and XII. A partially thrombosed cerebral artery aneurysm may often rupture and cause worsening of neurologic symptoms. The prognosis is generally poor because the rupture rate is extremely high especially with large or giant aneurysms. However, this case had a good clinical course owing to treatment by parent artery occlusion.

The clinical significance of serial changes in serum biomarkers in patients with idiopathic pulmonary fibrosis (IPF) remains to be established. This retrospective study was conducted to clarify the associations of serial changes in serum Krebs von den Lungen-6 (KL-6) and surfactant protein-D (SP-D) with changes in physiological indices and overall mortality in IPF. The study subjects were 75 patients with IPF. The 6 month change in serum KL-6 was significantly correlated with changes in the percentage of the predicted forced vital capacity (FVC % pred) and the percentage of the predicted diffusing capacity of the lung for carbon monoxide (% DLCO), while the 6 month change in serum SP-D was correlated only with % DLCO. During the mean follow-up period of 647 days, 22 (29.3%) patients died. An increase in serum KL-6 over a 6 month period was a significant predictor of mortality even after adjustment for %FVC, % DLCO and serum KL-6 at the baseline (hazard ratio 1.10 per 100 U·mL−1, 95% CI 1.01–1.18, p=0.03), whereas the 6 month increase in serum SP-D was not significant. Serial measurements of serum KL-6 may provide additional prognostic information compared to that provided by physiological parameters in patients with IPF., Serial changes in serum KL-6 are associated with changes in physiological variables and can predict survival in IPF http://ow.ly/hCkb30eauLg

Background: The prevalence of chronic kidney disease (CKD) increases with age as with idiopathic pulmonary fibrosis (IPF). Objectives: We assessed the prevalence of CKD (stages 3-5) and investigated the relationship of CKD to clinical features and outcomes in patients with IPF. Methods: This study comprised 123 patients with IPF; 61 subjects with chronic obstructive pulmonary disease (COPD), which was reportedly associated with CKD, were also enrolled as a disease control. CKD (stages 3-5) was defined as an estimated glomerular filtration rate (eGFR) 2. Results: Thirty-seven patients (30%) with IPF and 14 controls (23%) with COPD were diagnosed with CKD, and these frequencies were not significantly different. The patients with IPF and CKD were older (p < 0.01) and had a higher frequency of hypertension (p = 0.048) and ischemic heart disease (p = 0.02) than those with IPF but without CKD. Furthermore, the diffusing capacity of the lung for carbon monoxide (DLCO) and the 6-min walking distance in the patients with CKD were significantly lower (40.0 ± 13.2 vs. 45.9 ± 14.4%, p = 0.04, and 416 ± 129 vs. 474 ± 84 m, p = 0.01, respectively) than in the patients without CKD. The outcome of the patients with CKD showed significantly worse survival compared with the patients without CKD (p = 0.04). Moreover, eGFR remained an independent predictor of survival after adjusting for age and pulmonary function data. Conclusion: A substantial percentage of IPF patients have CKD. CKD with a low eGFR was associated with decreased survival in IPF.

Background: Systemic inflammation can be associated with an accelerated decrease in pulmonary function in the general population. Alpha-1 antitrypsin (AAT) is a major protease inhibitor and its deficiency is one of the most common risk factors for developing early onset emphysema and chronic obstructive pulmonary disease. Recently, AAT has been recognized as a systemic inflammation marker. However, the association between AAT levels and longitudinal forced expiratory volume in one second (FEV1) changes has been unknown in the general population. Aims and Objectives: To examine the association between baseline AAT levels and longitudinal FEV1 changes in a general population-based large-scale cohort study. Methods: This study included 9,053 Japanese participants (male 2,962; female 6,091), in whom 7,525 (male 2,397; female 5,128) were included in the longitudinal analysis. The change in FEV1 was calculated by dividing the difference between the baseline and follow-up by follow-up periods (years). The change in FEV1 was categorized into two groups: rapid decline (change in FEV1 Results: Follow-up period was 1815 ± 135 days. FEV1 decreased by 34.2 ± 0.6 ml/year during the follow-up period. There were 862 (11.5%) participants with the rapid decline in FEV1. The elevation of baseline AAT levels was independently associated with the rapid decline in FEV1 (odds ratio = 1.09; 95% confidence interval = 1.04–1.14; p = 0.0004), although baseline AAT levels were not associated with baseline FEV1. Conclusions: The present findings imply that baseline AAT levels might become a new predicting factor for longitudinal FEV1 decline.

Introduction: Idiopathic pleuroparenchymal fibroelastosis (IPPFE) has been recognized as a distinct entity. Similar PPFE pattern is also seen in secondary interstitial lung diseases (ILDs), which is categorized as secondary PPFE (SPPFE). IPPFE and SPPFE have not been comparatively studied. Aims and Objectives: To evaluate the clinical and pathological features of IPPFE and SPPFE. Methods: Patients with IPPFE and SPPFE were identified from consecutive recipients undergoing cadaveric lung transplantation (LT) at Kyoto University Hospital between 2010 and 2018. IPPFE was diagnosed through post-transplant multidisciplinary consensus. SPPFE was diagnosed when the diagnostic criteria for IPPFE were fulfilled in secondary ILDs. Clinical data and pathological features of explanted lungs were retrospectively evaluated. Results: Of 104 cadaveric LT recipients, nine were diagnosed as IPPFE and seven as SPPFE. Etiologies for SPPFE were late onset non-infectious pulmonary complication after hematopoietic stem-cell transplantation or chemotherapy in six, and dermatomyositis in one. At the time of LT, the median age of patients was 46 years and eleven were managed with long-time oxygen therapy or mechanical ventilation. Distribution of pathological PPFE was similar between IPPFE and SPPFE. Granulomas and peribronchiolar inflammation were more frequently observed with SPPFE than IPPFE, while the frequency of constrictive bronchiolitis obliterans was not significantly different. Estimated three-year survival rate after LT was 79.6% (IPPFE 75.0%, SPPFE 85.7%). Conclusions: IPPFE and SPPFE have similar PPFE lesions and different additional pathological findings.