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AIMS: Megalin, a proximal tubular endocytosis receptor, is excreted in urine in two forms: ectodomain (A-megalin) and full-length (C-megalin). We explored whether urinary megalin levels can be used as independent prognostic biomarkers in the progression of diabetic kidney disease (DKD). METHODS: The associations between baseline urinary A-megalin/creatinine (Cr) and/or C-megalin/Cr levels and the subsequent estimated glomerular filtration rate (eGFR) slope were analyzed using a generalized estimating equation. Patients were categorized into higher or lower groups based on the optimal cutoff values, obtained from a receiver operating characteristic curve, of the two forms of urinary megalin. RESULTS: We retrospectively analyzed 188 patients with type 2 diabetes. The eGFR slopes of the higher A-megalin/Cr and higher C-megalin/Cr groups were - 0.904 and -0.749 ml/min/1.73 m2/year steeper than those of the lower groups, respectively. Moreover, the eGFR slope was -1.888 ml/min/1.73 m2/year steeper in the group with both higher A- and higher C-megalin/Cr than in the other group. These results remained significant when adjusted for known urinary biomarkers (albumin, α1-microglobulin, β2-microglobulin, and N-acetyl-β-d-glucosaminidase). CONCLUSIONS: Urinary A- and C-megalin/Cr levels are likely to be prognostic biomarkers in the progression of DKD independent of other urinary biomarkers.

DOI： 10.1016/j.jdiacomp.2022.108312

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BACKGROUND: Heart failure in elderly people causes physical and cognitive dysfunction and often requires long-term care insurance (LTCI); however, among patients with left ventricular (LV) systolic dysfunction, the incidence and risk factors of future LTCI requirements need to be elucidated.Methods and Results:The study included 1,852 patients aged ≥65 years with an echocardiographic LV ejection fraction (LVEF) ≤50%; we referred to their LTCI data and those of 113,038 community-dwelling elderly people. During a mean 1.7-year period, 332 patients newly required LTCI (incidence 10.7 per 100 person-years); the incidence was significantly higher than that for the community-dwelling people (hazard ratio [HR], 1.47; 95% confidence interval [CI], 1.32-1.64). On multivariate analysis, the risk factors at the time of echocardiography leading to future LTCI requirement were atrial fibrillation (HR, 1.588; 95% CI, 1.279-1.971), history of stroke (HR, 2.02; 95% CI, 1.583-2.576), osteoporosis (HR, 1.738; 95% CI, 1.253-2.41), dementia (HR, 2.804; 95% CI, 2.075-3.789), hypnotics (HR, 1.461; 95% CI, 1.148-1.859), and diuretics (HR, 1.417; 95% CI, 1.132-1.773); however, the LVEF was not a risk factor (HR, 0.997; 95% CI, 0.983-1.011). CONCLUSIONS: In elderly patients with LV systolic dysfunction, the incidence of LTCI requirement was more common than that for community-dwelling people; its risk factors did not include LVEF, but included many other non-cardiac comorbidities and therapies, suggesting the need for interdisciplinary cooperation to prevent disabilities.

DOI： 10.1253/circj.CJ-21-0580

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DOI： 10.1002/osi2.1122

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BACKGROUND: Low-dose droperidol has been reported to suppress the amplitude of transcranial electrical motor-evoked potentials (TCE-MEPs), but no randomized controlled trials have been conducted to assess this. This randomized, double-blinded, placebo-controlled trial aimed to test the hypothesis that low-dose droperidol reduced TCE-MEP amplitudes. METHODS: Twenty female patients with adolescent idiopathic scoliosis, aged between 12 and 20 years, and scheduled to undergo corrective surgery were randomly allocated to receive droperidol (20 µg/kg) or 0.9% saline. After recording baseline TCE-MEPs, the test drug was administered, following which TCE-MEP recordings were carried out every 2 minutes for up to 10 minutes. The primary outcome was the minimum relative TCE-MEP amplitude (peak-to-peak amplitude, percentage of baseline value) recorded in the left tibialis anterior muscle. Secondary outcomes included minimum relative MEP amplitudes recorded from all other muscle groups monitored in the study. Data are expressed as medians (interquartile range). RESULTS: The TCE-MEP amplitude of the left tibialis anterior muscle was significantly reduced following droperidol administration compared with saline (37% [30% to 55%] vs. 76% [58% to 93%], respectively, P<0.01). In the other muscles, the amplitudes were reduced in the droperidol group, except for the bilateral abductor pollicis brevis and the left quadriceps femoris muscles. The relative amplitude of the bilateral F waves recorded from the gastrocnemius was decreased in the droperidol group. CONCLUSIONS: Low-dose droperidol (20 µg/kg) reduced TCE-MEP amplitudes. Anesthesiologists should pay attention to the timing of droperidol administration during intraoperative TCE-MEP recordings, even if used in a low dose.

DOI： 10.1097/ANA.0000000000000784

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INTRODUCTION: The precise blood glucose (BG) profile of hemodialysis patients is unclear, as is the effectiveness of dipeptidyl peptidase-4 (DPP-4) inhibitors in hemodialysis patients with type 2 diabetes. Here, we used continuous glucose monitoring (CGM) to evaluate BG variability in these patients and to assess the efficacy of DPP-4 inhibitors, particularly during hemodialysis sessions and at nighttime (UMIN000012638). METHODS: We examined BG profiles using CGM in 31 maintenance hemodialysis patients with type 2 diabetes. Differences between patients with and without DPP-4 inhibitors (n = 15 and 16, respectively) were analyzed using a linear mixed-effects model to assess changes in glucose levels in 5-min intervals. RESULTS: The model revealed that DPP-4 inhibitor use was significantly associated with suppression of a rapid drop in glucose levels, both with and without adjustment for BG levels at the start of hemodialysis. Moreover, the model revealed that the two groups differed significantly in the pattern of changes in BG levels from 0:00 to 6:55 am. DPP-4 inhibitors suppressed the tendency for subsequent nocturnal hypoglycemia. CONCLUSIONS: This prospective observational exploratory study showed that DPP-4 inhibitors could suppress BG variability during hemodialysis sessions as well as subsequent nocturnal changes in patients with type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov identifier, UMIN000012638.

DOI： 10.1007/s13300-020-00928-5

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INTRODUCTION: Type 2 diabetes (T2DM) is associated with cardiovascular death, including sudden cardiac death due to arrhythmias. Patients with an implantable cardioverter-defibrillator (ICD) are also at high risk of developing a clinically significant ventricular arrhythmia. It has been reported that sodium-glucose cotransporter 2 (SGLT2) inhibitors can reduce cardiovascular deaths; however, the physiological mechanisms of this remain unclear. It is, however, well known that SGLT2 inhibitors increase blood ketone bodies, which have been suggested to have sympatho-suppressive effects. Empagliflozin (EMPA) is an SGLT2 inhibitor. The current clinical trial titled "Placebo-controlled, double-blind study of empagliflozin (EMPA) and implantable cardioverter-defibrillator (EMPA-ICD) in patients with type 2 diabetes (T2DM)" was designed to investigate the antiarrhythmic effects of EMPA. METHODS: The EMPA-ICD study is a prospective, multicenter, placebo-controlled, double-blind, randomized, investigator-initiated clinical trial currently in progress. A total of 210 patients with T2DM (hemoglobin A1c 6.5-10.0%) will be randomized (1:1) to receive once-daily placebo or EMPA, 10 mg, for 24 weeks. The primary endpoint is the number of clinically significant ventricular arrhythmias for 24 weeks before and 24 weeks after study drug administration, as documented by the ICD. The secondary endpoints of the study are the change from baseline concentrations in blood ketone and catecholamine 24 weeks after drug treatment. CONCLUSION: The EMPA-ICD study is the first clinical trial to assess the effect of an SGLT2 inhibitor on clinically significant ventricular arrhythmias in patients with T2DM and an ICD. TRIAL REGISTRATION: Unique trial number, jRCTs031180120 ( https://jrct.niph.go.jp/latest-detail/jRCTs031180120 ).

DOI： 10.1007/s13300-020-00924-9

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Mycobacterium tuberculosis (Mtb) strains of Beijing lineage have caused great concern because of their rapid emergence of drug resistance and worldwide spread. DNA mutation rates that reflect evolutional adaptation to host responses and the appearance of drug resistance have not been elucidated in human-infected Beijing strains. We tracked and obtained an original Mtb isolate of Beijing lineage from the 1999 tuberculosis outbreak in Japan, as well as five other isolates that spread in humans, and two isolates from the patient caused recurrence. Three isolates were from patients who developed TB within one year after infection (rapid-progressor, RP), and the other three isolates were from those who developed TB more than one year after infection (slow-progressor, SP). We sequenced genomes of these isolates and analyzed the propensity and rate of genomic mutations. Generation time versus mutation rate curves were significantly higher for RP. The ratio of oxidative versus non-oxidation damages induced mutations was higher in SP than RP, suggesting that persistent Mtb are exposed to oxidative stress in the latent state. Our data thus demonstrates that higher mutation rates of Mtb Beijing strains during human infection is likely to account for the higher adaptability and an emergence ratio of drug resistance.

DOI： 10.1038/s41598-020-75028-2

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Language：Japanese   Publisher：(一社)日本透析医学会  

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INTRODUCTION/OBJECTIVES: Interstitial lung disease (ILD) is a significant cause of mortality among patients with dermatomyositis (DM) or polymyositis (PM). There are two subtypes of PM and DM often complicated with ILD: those with anti-aminoacyl-tRNA synthetase (anti-ARS) antibodies and those with anti-MDA-5-associated amyopathic DM (ADM). Our aim is to clarify the inflammatory and immunological differences between the disorders. METHODS: We retrospectively collected consecutive patients with anti-ARS-ILD and those with anti-MDA-5 antibody-positive ADM-ILD. The serum concentration of 38 cytokines was measured using a cytokine panel. The relative risks for anti-MDA-5 antibody-positive ADM-ILD were examined with univariate and multivariate logistic regression models. Spearman's rank correlation coefficient was calculated between cytokine levels and clinical parameters in the disease. Levels of cytokines were compared between anti-ARS-ILD and anti-MDA-5-positive ADM-ILD patients (alive or dead) using Dunnett's test. RESULTS: Twenty-three patients with anti-ARS-ILD and the same number of patients with anti-MDA-5-positive ADM-ILD were enrolled. The anti-MDA-5 group had poor survival (p = 0.025). Univariate logistic regression models showed that eotaxin, IL-10, IP-10, and MCP-1 were associated with the diagnosis of anti-MDA-5-positive ADM-ILD. Multivariate logistic regression models revealed that IP-10 was the most significantly associated (p = 0.001). Relationship analyses showed that IL-10 had significant positive correlations with CK (r = 0.5267, p = 0.009) and ferritin (r = 0.4528, p = 0.045). A comparison of the cytokine levels found that IP-10 was elevated in both patients who were alive and patients who had died with ADM-ILD compared with the levels in those with ARS-ILD (p = 0.003 and p = 0.001, respectively). CONCLUSIONS: Anti-MDA-5-positive ADM-ILD had poorer survival than anti-ARS-ILD. IP-10 seems to be most deeply involved in the pathophysiology of anti-MDA-5-associated ADM-ILD.Key Points• To clarify differences in the inflammatory and immunological features of anti-MDA-5-positive ADM-ILD and anti-ARS-ILD, we performed an observational study to measure serum cytokine concentrations before treatment using a multiplex immunoassay system.• Multivariate logistic regression models revealed that IP-10 was associated with the most significant relative risk for ADM-ILD with anti-MDA-5 antibodies.• Levels of IP-10 were elevated considerably in anti-MDA-5-positive survivors and nonsurvivors compared with the levels in anti-ARS patients.• These results suggest that IP-10 is the most deeply involved in the pathophysiology of anti-MDA-5-positive ADM-ILD.

DOI： 10.1007/s10067-020-04984-x

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Recently, attempts to reveal the structures of autoantibodies comprehensively using improved proteogenomics technology, have become popular. This technology identifies peptides in highly purified antibodies by using an Orbitrap device to compare spectra from liquid chromatography-tandem mass spectrometry against a cDNA database obtained through next-generation sequencing. In this study, we first analyzed granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies in a patient with autoimmune pulmonary alveolar proteinosis, using the trapped ion mobility spectrometry coupled with quadrupole time-of-flight (TIMS-TOF) instrument. The TIMS-TOF instrument identified peptides that partially matched sequences in up to 156 out of 162 cDNA clones. Complementarity-determining region 3 (CDR3) was fully and partially detected in nine and 132 clones, respectively. Moreover, we confirmed one unique framework region 4 (FR4) and at least three unique across CDR3 to FR4 peptides via de novo peptide sequencing. This new technology may thus permit the comprehensive identification of autoantibody structure.

DOI： 10.1038/s41598-020-61934-y

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Very recently, a modest but significant efficacy of granulocyte-macrophage colony-stimulating factor (GM-CSF) inhalation therapy for the treatment of mild to moderate autoimmune pulmonary alveolar proteinosis (aPAP) has been reported. As the ability to measure the level of GM-CSF autoantibody (GMAb) in the serum is required to decide the indication for this therapy, we developed a high-performance GMAb testing kit for clinical use. As the kit succeeded in reducing nonspecific IgG binding to the ELISA plate, the predictive performance shown in the training study to discriminate aPAP patients from healthy subjects was perfect, providing a cut-off value of 1.65 U·mL-1 in 78 patients with aPAP and 90 healthy subjects in an operator-blinded manner using logistic regression analysis. As in the validation study, serum samples from another 213 patients with aPAP were also blinded and evaluated in an operator-blinded manner against external 207 samples from patients with other types of PAP and patients exhibiting various ground-glass opacities on chest high-resolution computed tomography that require discrimination from PAP. The logistic regression analysis of these validation data sets revealed values of 97.6% and 100% for specificity and sensitivity, respectively. Thus, this new GMAb testing kit is reliable for the diagnosis of aPAP and differential diagnosis of other lung diseases.

DOI： 10.1183/23120541.00259-2019

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Obesity and related disorders, which are increasing in adults worldwide, are closely linked to childhood diet and are associated with chronic inflammation. Rice endosperm protein (REP) intake during adulthood has been reported to improve lipid metabolism and suppress the progression of diabetic kidney disease in animal models. However, the effects of REP intake during childhood on adulthood health are unclear. Therefore, we used a mouse model to experimentally investigate the preconditioning effects of REP intake during childhood on the development of obesity and related disorders in adulthood. Male C57BL/6J mice were pair-fed a normal-fat diet containing casein or REP during the juvenile period and then a high-fat diet (HFD) containing casein or REP during adulthood. Mice fed REP during the juvenile period showed better body weight, blood pressure, serum lipid profiles, lipopolysaccharide (LPS)-binding protein levels, and glucose tolerance in adulthood than those fed casein during the juvenile period. HFD-induced renal tubulo-glomerular alterations and hepatic microvesicular steatosis were less evident in REP-fed mice than in casein-fed ones. REP intake during the juvenile period improved HFD-induced dysbiosis (i.e., Escherichia genus proliferation and reduced gut microbiota diversity), thereby suppressing endotoxin-related chronic inflammation. Indeed, REP-derived peptides showed antibacterial activity against Escherichia coli, a major producer of LPS. In conclusion, REP supplementation during the juvenile period may regulate the gut microbiota and thus suppress the development of obesity and related disorders in adulthood in mice.

DOI： 10.3390/nu11122919

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BACKGROUND: Pulmonary alveolar proteinosis is a disease characterized by abnormal accumulation of surfactant in the alveoli. Most cases are autoimmune and are associated with an autoantibody against granulocyte-macrophage colony-stimulating factor (GM-CSF) that prevents clearing of pulmonary surfactant by alveolar macrophages. An open-label, phase 2 study showed some therapeutic efficacy of inhaled recombinant human GM-CSF in patients with severe pulmonary alveolar proteinosis; however, the efficacy in patients with mild-to-moderate disease remains unclear. METHODS: We conducted a double-blind, placebo-controlled trial of daily inhaled recombinant human GM-CSF (sargramostim), at a dose of 125 μg twice daily for 7 days, every other week for 24 weeks, or placebo in 64 patients with autoimmune pulmonary alveolar proteinosis who had a partial pressure of arterial oxygen (Pao2) while breathing ambient air of less than 70 mm Hg (or <75 mm Hg in symptomatic patients). Patients with severe pulmonary alveolar proteinosis (Pao2 <50 mm Hg) were excluded to avoid possible exacerbation of the disease in patients who were assigned to receive placebo. The primary end point was the change in the alveolar-arterial oxygen gradient between baseline and week 25. RESULTS: The change in the mean (±SD) alveolar-arterial oxygen gradient was significantly better in the GM-CSF group (33 patients) than in the placebo group (30 patients) (mean change from baseline, -4.50±9.03 mm Hg vs. 0.17±10.50 mm Hg; P = 0.02). The change between baseline and week 25 in the density of the lung field on computed tomography was also better in the GM-CSF group (between-group difference, -36.08 Hounsfield units; 95% confidence interval, -61.58 to -6.99, calculated with the use of the Mann-Whitney U test and the Hodges-Lehmann estimate of confidence intervals for pseudo-medians). Serious adverse events developed in 6 patients in the GM-CSF group and in 3 patients in the placebo group. CONCLUSIONS: In this randomized, controlled trial, inhaled recombinant human GM-CSF was associated with a modest salutary effect on the laboratory outcome of arterial oxygen tension, and no clinical benefits were noted. (Funded by the Japan Agency for Medical Research and Development and the Ministry of Health, Labor, and Welfare of Japan; PAGE ClinicalTrials.gov number, NCT02835742; Japan Medical Association Center for Clinical Trials number, JMA-IIA00205.).

DOI： 10.1056/NEJMoa1816216

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The IgG-type neutralizing GM-CSF autoantibody (GMAb) is known to be the causative agent for autoimmune pulmonary alveolar proteinosis (APAP). Previous studies report that serum levels of IgG-GMAb are approximately 50-fold higher in APAP patients than in healthy subjects (HS). Serum levels of IgM-GMAb are also higher in APAP patients than in HS, but this has been assumed to be an etiological bystander. However, the mechanism for the excessive production of IgG-GMAb in APAP remains unclear. To investigate this, we detected putative GMAb-producing B cells (PGMPB) by inoculated B cells from the peripheral blood of APAP patients, HS, and umbilical cord blood mononuclear cells (UCBMNs) with Epstein-Barr virus. Both ELISA and ELISPOT assays showed that IgM-type GMAb was consistently and frequently present in all three groups, whereas IgG-type GMAb was high only in APAP patients, in whom it was exclusively produced in memory B cells and not in naive B cells. Since PGMPB in UCBMNs produced IgM-GMAb, but not IgG-GMAb, to the same extent as in HS and APAP patients, most IgM-GMAb reacted with GM-CSF in a non-specific manner. The memory B cell pool of APAP patients contain higher frequency of PGMPB than that of healthy subjects.

DOI： 10.1016/j.imlet.2019.05.013

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The incidence and prevalence of autoimmune pulmonary alveolar proteinosis in Japan were previously estimated to be 0.49 and 6.2 per million, respectively. Thereafter, an increase in serological diagnosis forced a re-estimation of the incidence based on more contemporaneous data using more robust methods. Sera of 702 patients were positive for granulocyte-macrophage colony-stimulating factor autoantibody during the 2006-2016 period (group A). Of these patients, 43 were actively surveyed in Niigata prefecture (group B) for estimation of the incidence. To estimate the survival period, 103 patients (group C) were investigated retrospectively for the 1999-2017 period using restricted mean survival time. In group A, the number of patients diagnosed in each prefecture was closely correlated with the corresponding population, indicating no regional integration of onset. In group B, a total of 43 patients were diagnosed, the annual number followed a Poisson distribution and the incidence was thus estimated to be 1.65 per million. In group C, the retrospective cohort study revealed the mean survival period to be 16.1 years. Taken together, the prevalence was estimated to be 26.6 per million, indicating that the previous data for incidence and prevalence was an underestimation.

DOI： 10.1183/23120541.00190-2018

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During a clinical trial of a Saccharomyces cerviciae-derived recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF), sargramostim, in patients with autoimmune pulmonary alveolar proteinosis (aPAP), we conducted a pharmacokinetic study of single-dose sargramostim inhalation. Several problems were encountered whereby sargramostim formed an immune-complex with GM-CSF autoantibodies (GMAbs) immediately after entering the body; thus, we could not measure the concentration of sargramostim using a commercial high sensitivity enzyme-linked immunosorbent assay (ELISA). Moreover, the ELISA could not discriminate inhaled sargramostim from intrinsic GM-CSF. To solve these problems, we developed a novel ELISA system with a capture antibody that is specific for sargramostim and a detection antibody capable of binding with GM-CSF. This system quantified the serum sargramostim concentration, but not E. coli-, CHO-, or HEK293T-derived human recombinant GM-CSF. Using this system, serum pharmacokinetics were estimated in five patients after inhalation of 250 μg sargramostim, with a mean Cmax of 9.7 ± 2.85 pg/ml at a Tmax of 2 ± 1.22 h.

DOI： 10.1016/j.jim.2018.05.012

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PURPOSE: Lymphangioleiomyomatosis is a rare lung disease caused by proliferation of abnormal smooth muscle-like cells and typically occurs in premenopausal women. Sirolimus is now the first-line drug for the treatment of lymphangioleiomyomatosis. Sirolimus-induced stomatitis is the most frequent adverse event experienced during treatment. To identify risk factors, we investigated the association of stomatitis incidence with patient background data and treatment parameters, using data from the multicenter long-term sirolimus trial. METHODS: Subjects received sirolimus for 2 years at doses adjusted to maintain a trough blood level of 5 to 15 ng/mL. The incidence of stomatitis was correlated with baseline demographics, clinical characteristics, and changes in the longitudinal data. Risk factors at baseline were assessed by using univariate and multivariate analyses. RESULTS: The most frequent adverse event was stomatitis, with the cumulative rate reaching 88.9% by 9 months, higher than that reported in postrenal transplant patients. The repetition, the duration, and the severity of stomatitis events were variable among patients. We found that patients with low hemoglobin (Hb) (<14.5 g/dL) showed significantly higher incidence than those with high Hb (≥14.5 g/dL, P < .01). The cumulative rate for stomatitis incidence was significantly associated with a decrease in the mean corpuscular volume, while the Hb level was constant; thus, red blood cell count in patients increased during the study. CONCLUSIONS: Baseline Hb levels and a decrease in mean corpuscular volume during treatment were correlated with the incidence of stomatitis.

DOI： 10.1002/pds.4259

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Persistent endoleaks may lead to adverse events after endovascular aortic repair. We prospectively examined the relationship between intraoperative residual spontaneous echocardiographic contrast (SEC) within the aneurysmal sac and the incidence of postoperative endoleaks in 60 patients undergoing thoracic endovascular aortic repair. Patients with SEC had a higher incidence of postoperative endoleaks than did patients without SEC within a few days postoperatively (60.0% vs 12.5%, respectively; P < .001) and at 6 months postoperatively (40.0% vs 2.5%, respectively; P < .001). Intraoperative confirmation of the absence of SEC may identify patients at low risk for persistent endoleaks after thoracic endovascular aortic repair.

DOI： 10.1213/ANE.0000000000002207

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RATIONALE: Sirolimus has been shown in a randomized, controlled clinical trial to stabilize lung function in patients with lymphangioleiomyomatosis (LAM) treated for a 12-month time period; however the pretreatment decline in lung function after the drug was discontinued indicated that continued exposure is required to suppress disease progression. OBJECTIVES: To elucidate the durability and tolerability of long-term sirolimus treatment in Asian patients with LAM. METHODS: We conducted a single-arm, open-label, investigator-initiated safety and efficacy study of sirolimus in 63 women with LAM at 9 sites in Japan. Subjects received sirolimus for 2 years at doses adjusted to maintain a trough blood level of 5-15 ng/ml. MEASUREMENTS AND MAIN RESULTS: Fifty-two subjects (82.5%) completed the trial with mean drug compliance of more than 80% overall during the study. The number of adverse events was greatest during the initial 6 months of therapy, but they continued to occur with declining frequency throughout the 2-year study period. Of the 1,549 adverse events, 27 were classified as serious, including reversible sirolimus pneumonitis in 3 patients. New hypercholesterolemia occurred in 30 patients (48%); microcytosis in 10 patients; loss of body weight in 33 patients; and increase in blood pressure that required treatment in 5 patients. FEV1, FVC, and quality-of-life parameters were stable in the overall study cohort during the study period, but baseline to 2-year improvements in lung function occurred in the subset of patients with a prior history of chylothorax. CONCLUSIONS: Although long-term sirolimus treatment of Asian patients with LAM was associated with a large number of adverse events, including three episodes of pneumonitis, most patients completed the 2-year course of medication with good drug compliance and stable quality of life and lung function.

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Language：English   Publisher：EUROPEAN RESPIRATORY SOC JOURNALS LTD  

DOI： 10.1183/13993003.congress-2016.PA3873

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Language：English   Publisher：WILEY-BLACKWELL  

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Obesity, an important risk factor for metabolic syndrome (MetS) and cardiovascular disease, is often complicated by CKD, which further increases cardiovascular risk and causes ESRD. To elucidate the mechanism underlying this relationship, we investigated the role of the endocytic receptor megalin in proximal tubule epithelial cells (PTECs). We studied a high-fat diet (HFD)-induced obesity/MetS model using kidney-specific mosaic megalin knockout (KO) mice. Compared with control littermates fed a normal-fat diet, control littermates fed an HFD for 12 weeks showed autolysosomal dysfunction with autophagy impairment and increased expression of hypertrophy, lipid peroxidation, and senescence markers in PTECs of the S2 segment, peritubular capillary rarefaction with localized interstitial fibrosis, and glomerular hypertrophy with mesangial expansion. These were ameliorated in HFD-fed megalin KO mice, even though these mice had the same levels of obesity, dyslipidemia, and hyperglycemia as HFD-fed control mice. Intravital renal imaging of HFD-fed wild-type mice also demonstrated the accumulation of autofluorescent lipofuscin-like substances in PTECs of the S2 segment, accompanied by focal narrowing of tubular lumens and peritubular capillaries. In cultured PTECs, fatty acid-rich albumin induced the increased expression of genes encoding PDGF-B and monocyte chemoattractant protein-1 via megalin, with large (auto)lysosome formation, compared with fatty acid-depleted albumin. Collectively, the megalin-mediated endocytic handling of glomerular-filtered (lipo)toxic substances appears to be involved primarily in hypertrophic and senescent PTEC injury with autophagy impairment, causing peritubular capillary damage and retrograde glomerular alterations in HFD-induced kidney disease. Megalin could be a therapeutic target for obesity/MetS-related CKD, independently of weight, dyslipidemia, and hyperglycemia modification.

DOI： 10.1681/ASN.2015020190

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BACKGROUND: Although no report has demonstrated the efficacy of corticosteroid therapy for autoimmune pulmonary alveolar proteinosis (aPAP), we sometimes encounter patients who have received this therapy for various reasons. However, as corticosteroids can suppress alveolar macrophage function, corticosteroid therapy might worsen disease severity and increase the risk of infections. METHODS: For this retrospective cohort study, we sent a screening form to 165 institutions asking for information on aPAP patients treated with corticosteroids. Of the resulting 45 patients screened, 31 were enrolled in this study. We collected demographic data and information about corticosteroid treatment period, dose, disease severity score (DSS) over the treatment period, and complications. RESULTS: DSS deteriorated during corticosteroid therapy in 23 cases (74.1 %) and the estimated overall cumulative worsening rate was 80.8 % for the total observation period. The worsening rate was significantly higher in patients treated with high-dose prednisolone (>18.9 mg/day, n = 16) than treated with low-dose prednisolone (≤18.9 mg/day, n = 15) divided by median daily dose (p < 0.02). Of patients with worsening, one died of disseminated aspergillosis and another of respiratory failure. Infections newly emerged in 6 cases during corticosteroid therapy (p < 0.05). Median serum granulocyte/macrophage colony-stimulating factor (GM-CSF) autoantibody levels were similar to previously reported data in a large cohort study. CONCLUSION: The results demonstrate that corticosteroid therapy may worsen DSS of aPAP, increasing the risk for infections.

DOI： 10.1186/s12890-015-0085-0

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Whole-lung lavage (WLL) remains the standard therapy for pulmonary alveolar proteinosis (PAP), a process in which accumulated surfactants are washed out of the lung with 0.5-2.0 l of saline aliquots for 10-30 wash cycles. The method has been established empirically. In contrast, the kinetics of protein transfer into the lavage fluid has not been fully evaluated either theoretically or practically. Seventeen lungs from patients with autoimmune PAP underwent WLL. We made accurate timetables for each stage of WLL, namely, instilling, retaining, draining, and preparing. Subsequently, we measured the volumes of both instilled saline and drained lavage fluid, as well as the concentrations of proteins in the drained lavage fluid. We also proposed a mathematical model of protein transfer into the lavage fluid in which time is a single variable as the protein moves in response to the simple diffusion. The measured concentrations of IgG, transferrin, albumin, and β2-microglobulin closely matched the corresponding theoretical values calculated through differential equations. Coefficients for transfer of β2-microglobulin from the blood to the lavage fluid were two orders of magnitude higher than those of IgG, transferrin, and albumin. Simulations using the mathematical model showed that the cumulative amount of eliminated protein was not affected by the duration of each cycle but dependent mostly on the total time of lavage and partially on the volume instilled. Although physicians have paid little attention to the transfer of substances from the lung to lavage fluid, WLL seems to be a procedure that follows a diffusion-based mathematical model.

DOI： 10.1152/ajplung.00239.2014

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To date, the biological activity of granulocyte macrophage-colony stimulating factor (GM-CSF) has been investigated by using mostly Escherichia coli- or yeast cell-derived recombinant human GM-CSF (erhGM-CSF and yrhGM-CSF, respectively). However, Chinese hamster ovary cell-derived recombinant human GM-CSF (crhGM-CSF), as well as natural human GM-CSF, is a distinct molecule that includes modifications by complicated oligosaccharide moieties. In the present study, we reevaluated the bioactivity of crhGM-CSF by comparing it with those of erhGM-CSF and yrhGM-CSF. The effect of short-term stimulation (0.5h) on the activation of neutrophils/monocytes or peripheral blood mononuclear cells (PBMCs) by crhGM-CSF was lower than those with erhGM-CSF or yrhGM-CSF at low concentrations (under 60pM). Intermediate-term stimulation (24h) among the different rhGM-CSFs with respect to its effect on the activation of TF-1 cells, a GM-CSF-dependent cell line, or PBMCs was not significantly different. In contrast, the proliferation/survival of TF-1 cells or PBMCs after long-term stimulation (72-168h) was higher at low concentrations of crhGM-CSF (15-30pM) than that of cells treated with other GM-CSFs. The proportion of apoptotic TF-1 cells after incubation with crhGM-CSF for 72h was lower than that of cells incubated with other rhGM-CSFs. These effects were attenuated by desialylation of crhGM-CSF. Clearance of crhGM-CSF but not desialylated-crhGM-CSF by both TF-1 cells and PBMCs was delayed compared with that of erhGM-CSF or yrhGM-CSF. These results suggest that sialylation of oligosaccharide moieties delayed the clearance of GM-CSF, thus eliciting increased long-term bioactivity in vitro.

DOI： 10.1016/j.cyto.2014.03.009

PubMed

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Language：English   Publishing type：Research paper (scientific journal)  

Previous studies demonstrated that antigranulocyte colony-stimulating factor autoantibody (GMAb) was consistently present in patients with autoimmune pulmonary alveolar proteinosis (aPAP), and, thus, represented candidature as a reliable diagnostic marker. However, our large cohort study suggested that the concentration of this antibody was not correlated with disease severity in patients. We found that the κ/λ ratio of GMAb was significantly correlated with the degree of hypoxemia. The proportion of λ-type GMAb per total λ-type IgG was significantly higher in severely affected patients than those in mildly affected patients, but the proportion of κ-type was unchanged. The κ/λ ratio was significantly correlated with both KL-6 and SP-D, which have been previously reported as disease severity markers. Thus, the light chain isotype usage of GMAb may not only be associated with the severity of aPAP, but may also represent a useful disease severity marker.

DOI： 10.1016/j.clim.2013.10.002

PubMed

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Wasting is known as a prominent feature of tuberculosis (TB). To monitor the disease state, markers of metabolism and inflammation are potentially useful. We thus analyzed two major adipokines, adiponectin and leptin, and two other metabolic markers, fetuin-A and retinol-binding protein 4 (RBP4). METHODS: The plasma levels of these markers were measured using enzyme-linked immunosorbent assays in 84 apparently healthy individuals (=no-symptom group) and 46 patients with active pulmonary TB around the time of treatment, including at the midpoint evaluation (=active-disease group) and compared them with body mass index (BMI), C-reactive protein (CRP), chest radiographs and TB-antigen specific response by interferon-γ release assay (IGRA). RESULTS: In the no-symptom group, adiponectin and leptin showed negative and positive correlation with BMI respectively. In the active-disease group, at the time of diagnosis, leptin, fetuin-A and RBP4 levels were lower than in the no-symptom group [adjusted means 2.01 versus 4.50 ng/ml, P<0.0001; 185.58 versus 252.27 µg/ml, P<0.0001; 23.88 versus 43.79 µg/ml, P<0.0001, respectively]. High adiponectin and low leptin levels were associated with large infiltrates on chest radiographs even after adjustment for BMI and other covariates (P=0.0033 and P=0.0020). During treatment, adiponectin levels increased further and then decreased. Leptin levels remained low. Initial low levels of fetuin-A and RBP4 almost returned to the normal reference range in concert with reduced CRP. CONCLUSIONS: Our data and recent literature suggest that low fat store and underlying inflammation may regulate these metabolic markers in TB in a different way. Decreased leptin, increased adiponectin, or this ratio may be a promising marker for severity of the disease independent of BMI. We should further investigate pathological roles of the balance between these adipokines.

DOI： 10.1371/journal.pone.0038703

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BACKGROUND: Biological parameters are useful tools for understanding and monitoring complicated disease processes. In this study, we attempted to identify proteins associated with active pulmonary tuberculosis (TB) using a proteomic approach. METHODS: To assess TB-associated changes in the composition of human proteins, whole blood supernatants were collected from patients with active TB and healthy control subjects. Two-dimensional difference gel electrophoresis (2D-DIGE) was performed to analyze proteins with high molecular weights (approximately >20 kDa). Baseline protein levels were initially compared between patients with active TB and control subjects. Possible changes of protein patterns in active TB were also compared ex vivo between whole blood samples incubated with Mycobacterium tuberculosis (Mtb)-specific antigens (stimulated condition) and under unstimulated conditions. Immunoblot and enzyme-linked immunosorbent assays (ELISA) were performed to confirm differences in identified proteins. RESULTS: Under the baseline condition, we found that the levels of retinol-binding protein 4 (RBP4), fetuin-A (also called α-HS-glycoprotein), and vitamin D-binding protein differed between patients with active TB and control subjects on 2D gels. Immunoblotting results confirmed differential expression of RBP4 and fetuin-A. ELISA results further confirmed significantly lower levels of these two proteins in samples from patients with active TB than in control subjects (P < 0.0001). Mtb-specific antigen stimulation ex vivo altered clusterin expression in whole blood samples collected from patients with active TB. CONCLUSIONS: We identified TB-associated proteins in whole blood supernatants. The dynamics of protein expression during disease progression may improve our understanding of the pathogenesis of TB.

DOI： 10.1186/1471-2334-11-71

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：(一社)日本病態栄養学会  

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Language：Japanese   Publisher：(一社)日本病態栄養学会  

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Language：Japanese   Publisher：先端医学社  

CiNii Article

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Other Link： http://search.jamas.or.jp/link/ui/2017202282

Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Language：Japanese   Publisher：Japanese Proteomics Society (Japan Human Proteome Organisation)  

DOI： 10.14889/jhupo.2012.0.124.0

CiNii Article

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Language：Japanese   Publisher：日本プロテオーム学会（日本ヒトプロテオーム機構）  

DOI： 10.14889/jhupo.2010.0.110.1

CiNii Article

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Event date： 2015

Language：English  

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Event date： 2015

Language：English  

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Event date： 2014

Language：English  

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Event date： 2010

Language：Japanese  

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