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Background: Non-tuberculous mycobacterial pulmonary disease (NTM-PD) is becoming a significant health burden. Recent advances in analysis techniques have allowed the accurate identification of previously unknown NTM species. Here, we report a case of NTM-PD caused by a newly identified mycobacteria in an immunocompetent patient., Case Presentation: A 44-year-old woman was referred to our hospital due to the frequent aggravation of her chronic respiratory symptoms, with NTM-PD-compatible computed tomography findings. Unidentified mycobacterium was repeatedly isolated from respiratory specimens and we diagnosed her as NTM-PD of unidentified mycobacterium. Subsequent whole-genome analysis revealed that the unidentified mycobacterium was a novel mycobacterium genetically close to Mycolicibacterium mucogenicum. We started combination therapy with clarithromycin, moxifloxacin, amikacin, and imipenem/cilastatin, referring to drug sensitivity test results and observed its effect on M. mucogenicum infection. Her symptoms and radiological findings improved significantly., Conclusion: We report a case of NTM-PD caused by a newly identified mycobacteria, Mycolicibacterium toneyamachuris, genetically close to M. mucogenicum. This pathogenic mycobacterium showed different characteristics from M. mucogenicum about clinical presentation and drug sensitivity. The clinical application of genomic sequencing will advance the identification and classification of pathogenic NTM species, and enhance our understanding of mycobacterial diseases.

Because avidin and biotin molecules exhibit the most specific and strongest non-covalent interaction, avidin-biotin technology is widely used in ELISA (enzyme-linked immunosorbent assay) kits for the detection of different bio-macromolecules linked to different diseases including cancer and influenza. Combining the outstanding electrical conductivity (200,000 cm 2 V -1 s -1 ) of graphene with the unique avidin and biotin interaction, we demonstrate a novel graphene field-effect transistor (GFET) biosensor for the quantitative detection of bio-macromolecules. The GFET consists of six pairs of interdigital Cr/Au electrodes supported on Si/SiO 2 substrate with an avidin immobilized single layer graphene channel as the sensing platform. By monitoring the real time current change upon the addition of biotin solution in bovine serum albumin (BSA) in the silicone pool preformed onto the GFET, the lowest detectable biotin concentration is estimated to be 90 fg/ml (0.37 pM). The specificity of the GFET is confirmed both by controlled and real sample measurements. From the magnitude of current change upon the addition of different concentrations of biotin solutions, the dissociation constant K d is estimated to be 1.6 × 10 -11  M. Since biotin is capable of conjugating with proteins, nucleotides and other bio-macromolecules without altering their properties, the present GFET sensor with its ultra-high sensitivity (0.37 pM) and specificity can be tailored to the rapid point-of-care detection of different types of desired biomolecules at very low concentration level through biotinylation as well as the exogenous biotin in blood serum., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Left ventricular (LV) ejection fraction (EF) and LV volumes were reported to have prognostic efficacy in cardiac diseases. In particular, the end-systolic volume index (LVESVI) has been featured as the most reliable prognostic indicator. However, such efficacy in patients with LVEF ≥ 50% has not been elucidated., Methods: We screened the patients who received cardiac catheterization to evaluate coronary artery disease concomitantly with both left ventriculography and LV pressure recording using a catheter-tipped micromanometer and finally enrolled 355 patients with LVEF ≥ 50% and no history of heart failure (HF) after exclusion of the patients with severe coronary artery stenosis requiring early revascularization. Cardiovascular death or hospitalization for HF was defined as adverse events. The prognostic value of LVESVI was investigated using a Cox proportional hazards model., Results: A univariable analysis demonstrated that age, log BNP level, tau, peak - d P /d t , LVEF, LV end-diastolic volume index (LVEDVI), and LVESVI were associated with adverse events. A correlation analysis revealed that LVESVI was significantly associated with log BNP level ( r  = 0.356, p < 0.001), +d P /d t ( r  = -0.324, p < 0.001), -d P /d t ( r  = 0.391, p < 0.001), and tau ( r  = 0.337, p < 0.001). Multivariable analysis with a stepwise procedure using the variables with statistical significance in the univariable analysis revealed that aging, an increase in BNP level, and enlargement of LVESVI were significant prognostic indicators (age: HR: 1.071, 95% CI: 1.009-1.137, p =0.024; log BNP : HR : 1.533, 95% CI: 1.090-2.156, p =0.014; LVESVI : HR : 1.051, 95% CI: 1.011-1.093, p =0.013, respectively). According to the receiver-operating characteristic curve analysis for adverse events, log BNP level of 3.23 pg/ml (BNP level: 25.3 pg/ml) and an LVESVI of 24.1 ml/m 2 were optimal cutoff values (BNP : AUC : 0.753, p < 0.001, LVESVI : AUC : 0.729, p < 0.001, respectively)., Conclusion: In patients with LVEF ≥ 50%, an increased LVESVI is related to the adverse events. LV contractile performance even in the range of preserved LVEF should be considered as a role of a prognostic indicator., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Marina Kato et al.)

The incidence and prevalence of non-tuberculous mycobacteria (NTM) infections are steadily increasing worldwide, partially due to the increased incidence of immunocompromised conditions, such as the post-transplantation state. The importance of proper diagnosis and management of NTM infection has been recently recognized. Host immunological responses play integral roles in vulnerability to NTM infections, and may contribute to the onset of specific types of NTM infection. Furthermore, distinct NTM species are known to affect and attenuate these host immune responses in unique manners. Therefore, host immune responses must be understood with respect to each causative NTM species. Here, we review innate, cellular-mediated, and humoral immunity to NTM and provide perspectives on novel diagnostic approaches regarding each NTM species.

Background: Lung resection in patients with nontuberculous mycobacterial pulmonary disease (NTM-PD) has been reported to be associated with favorable outcomes. However, little is known regarding the risk and prognostic factors for refractory and recurrent cases. We aimed to evaluate the overall impact and benefit of adjuvant lung surgery by comparing NTM-PD patients who underwent adjuvant lung resection with those treated exclusively with antibiotics. We also investigated the efficacy of serum IgA antibody against glycopeptidolipid (GPL) core antigen (GPL core antibody) to monitor disease activity and predict the recurrence of disease after adjuvant lung resection., Methods: We retrospectively evaluated the clinical characteristics and surgical outcomes of 35 patients surgically treated for NTM-PD. Furthermore, we compared surgically treated patients and control patients treated exclusively with antibiotics who were matched statistically 1:1 using a propensity score calculated from age, sex, body mass index, and radiologic features of disease., Results: In the surgically treated patients, the median age was 58 (interquartile range, 47-65) years and 65.7% were female. Twenty-eight patients had Mycobacterium avium complex. Operations comprised four pneumonectomies, two bilobectomies, one bilobectomy plus segmentectomy, 17 lobectomies, two segmentectomies, and nine lobectomies plus segmentectomies. Postoperative complications occurred in seven patients (20%), there were no operative deaths, and 33 (94.3%) patients achieved negative sputum culture conversion. Refractory and recurrent cases were associated with remnant bronchiectasis, contralateral shadows, and positive acid-fast bacilli staining or culture. Of 28 statistically matched pairs, long-term sustained negative culture conversion was observed in 23 (82.2%) surgical group patients and in 14 (50.0%) non-surgical group patients (0.0438). The mortality rate was lower in the surgical group, but did not reach statistical significance (one in the surgical group and four in the non-surgical group, p = 0.3516). GPL core antibody was correlated with disease activity and recurrence., Conclusions: NTM-PD patients who underwent adjuvant lung resection experienced overall favorable outcomes and achieved sputum culture conversion more frequently. Long-term mortality may have been reduced by this procedure, and the level of GPL core antibody was shown to be a good clinical indicator of disease activity after surgery.

Purpose of Review: Clinical evidence suggesting the beneficial effects of vitamin D on survival of patients with cancer has been accumulating. Recent articles were thoroughly reviewed to determine if there is enough evidence to conclude that vitamin D supplementation improves survival of patients with cancer., Recent Findings: Meta-analyses of observational studies showed that higher blood 25-hydroxyvitamin D levels in patients with cancer at a variety of sites were associated with lower cancer-specific and overall mortalities. Moreover, meta-analyses of randomized clinical trials (RCTs) also suggested that vitamin D supplementation improved the survival of patients with cancer. However, each RCT used in these meta-analyses, as well as very recent RCTs, e.g., the SUNSHINE and the AMATERASU trial, did not show statistical significance in the primary results. For now, compelling evidence that vitamin D supplementation effectively improves survival of patients with cancer is lacking. Thus, confirmatory RCTs are still obligatory for the future.

We report a rapid and safe procedure for the synthesis of black phosphorus (BP) by the chemical transport reaction (CTR) method and a purification procedure for the as-prepared BP. Frequent explosion of glass ampules containing reactants (red P, Sn, and SnI 4 ) during high-temperature annealing in the CTR method is inevitable. We found that any danger from the explosions can be prevented by enclosing the glass ampule in a flange-fitted stainless-steel tube without compromising the yield and the quality of BP. In contrast to prolonged heating at approximately 823 K, the BP crystals can be synthesized by immediately cooling (100 K/h) to 400 K after heating the glass ampule to the desired highest temperature (∼823-873 K) over 2 h. The minimum time required for BP synthesis is estimated to be approximately 5 h. The as-prepared BP predominantly contains Sn and I impurities on the upper layers of the BP flakes. These impurities can be removed by exfoliating the upper layers of the flakes or by combining vacuum annealing at ∼600 K and HCl treatment., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)

Background: Multidrug therapy is essential for preventing respiratory failure in patients with highly progressive Mycobacterium avium complex pulmonary disease (MAC-PD). However, the prognosis and long-term outcome following combination therapy is poorly understood., Methods: We retrospectively evaluated the clinical characteristics and long-term outcomes in patients with chemo-naïve progressive MAC-PD, hospitalized for first-line multidrug therapy., Results: Among 125 patients, 86 (68.8%) received standardized treatment (rifampicin, ethambutol, clarithromycin), 25 (20.0%) received a fluoroquinolone (FQ)-containing regimen, and 53 (42.4%) received aminoglycoside injection. The sputum conversion rate was 80.0%, and was independently associated with standardized treatment. The incidence of refractory disease (45.6%) was independently and negatively associated with standardized regimen and aminoglycoside use. Choice of an FQ-containing regimen was not associated with positive outcome. Clarithromycin resistance occurred in 16.8% and was independently associated with refractory disease. MAC-PD-associated death occurred in 3.3% of patients with non-cavitary nodular bronchiectasis (NB) and 21.3% with cavitary MAC-PD over a median follow-up period of 56.4 months. The rates of MAC-PD-associated death were comparable between cavitary-NB and fibrocavitary disease. Concurrent chronic pulmonary aspergillosis (CPA) occurred in 13 (17.3%) patients with cavitary MAC-PD, and age, diabetes mellitus, and CPA were independent risk factors for mortality., Conclusions: Standardized intensive multidrug treatment reduces disease progression and persistence in progressive MAC-PD. Cavitary NB may differ from, rather than being just an advanced stage of, non-cavitary NB. The high incidence and significant mortality of CPA in cavitary MAC-PD highlight the need for early diagnosis and treatment., Competing Interests: The authors declare competing financial interests. Details are available in the online version of the paper. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

The red swamp crayfish Procambarus clarkii is native to northeastern Mexico and the south-central USA, and it has expanded its distribution worldwide and negatively impacted the ecosystems in the invaded regions. The dynamics of the P. clarkii populations have been studied as the basis for the development of effective control measures against this invasive alien species. Adult males of P. clarkii exhibit a cyclical dimorphism between two sexual morphotypes; reproductive form I has large chelae and non-reproductive form II has small chelae. However, whether P. clarkii females have two sexual morphotypes and exhibit form alternation has not been resolved, and little is known about the degree of intra-sexual dimorphism of the chelae, even among males. We employed allometric growth analysis on the chelae dimensions of P. clarkii females and males that were collected from a small pond in Yokohama, Japan. Our analysis demonstrated the existence of form I, which has larger chelae, and form II, which has smaller chelae, in P. clarkii females and highlighted the intra- and inter-sexual dimorphisms in the chelae of this species. The reproductive cycle of the population was successfully traced by the reproductive status of P. clarkii based on the occurrence patterns of each sexual morphotype; the form I crayfish occurred throughout the sampling period from April to December, while the occurrences of form I females and males were highly correlated, peaking in October. Our results suggested that alternation of sexual forms occurs in P. clarkii females. The ability to discriminate between the sexual morphotypes based on chelae allometric growth would allow us to evaluate the female reproductive status more easily and precisely in invasive P. clarkii populations.

Background: Although cavities are an important finding in Mycobacterium avium complex pulmonary disease (MAC-PD), there is little information regarding the types of cavities that indicate disease progression. This study was performed to identify cavity characteristics that were associated with disease progression in patients with MAC-PD., Methods: This retrospective cohort study included 97 patients presenting with MAC-PD with cavities between December 2006 and June 2016. We compared initial and final computed tomography (CT) findings, classified 52 and 45 patients in the progressive and non-progressive cavity groups, respectively, and examined the progression-related imaging features in initial CT images. A progressive cavity was defined by more than two-fold increase in internal diameter or emergence of a new cavity around the initial cavity., Results: Patients in the progressive group were older (p < 0.001), had a lower body mass index (p = 0.043), and showed higher diabetes complication rates (p = 0.005). The initial CT in the progressive group showed a longer maximum internal diameter of the cavity (p < 0.001) and higher rates of cavities close to the chest wall (p < 0.001), multiple cavities (p = 0.023), consolidation around the cavity (p < 0.001), atelectasis (p = 0.011), and pleural thickening (p < 0.001). Multivariable logistic regression analysis revealed that the maximum internal diameter of the cavity (odds ratio [OR]: 1.11, 95% confidence interval [CI]: 1.02-1.21; p=0.012) and consolidation around the cavity (OR: 16.15, 95% CI: 4.05-64.46; p < 0.001) were significantly associated with progressive cavities. In cavities with a maximum internal diameter of ≥10 mm and simultaneous consolidation, the probability of progression was as high as 96.2%. The 10-year mortality rates in the progressive and non-progressive cavity groups were 46.7 and 9.8% (p < 0.001), respectively, while the 10-year respiratory failure rates were 28.1 and 0%, respectively (p < 0.001)., Conclusions: Large cavity size and consolidation on CT showed strong relationships with disease progression, which led to respiratory failure and high mortality rate.

Background: Bacillus thuringiensis (Bt) is a Gram-positive bacterium that is known worldwide for its entomopathogenic properties. Recent studies indicate that bacteria produces protein inclusions called parasporins (PSs) that have anti-cancer activity against several types of tumor cells., Objective: The present work aimed to select a Bt strain that produces an active PS against MCF-7 breast cancer cells, and to provide an initial quantification of its toxicity and protein concentration., Methods: Two batches of Bt strains were fermented, and the parasporins were produced and isolated. In vitro tests were performed in 96-well plates and analyzed by a spectrophotometer., Results: Most peptides did not have any cytopathic effect, but the A14d2 strain produces a PS with high toxicity to cancer cells. In the MTT test, the A14d2 strain PS was efficient with an LD50 of 14.83 μg/mL and a protein concentration of 520 μg/mL. At the end of the experiments, this PS was added to bacterial cells that produce other biologically active bacterial toxins against MCF-7 cells, which allowed it to be produced by a safe and inert microorganism to humans., Conclusion: PSs represent a potential tool to treat this form of breast cancer by providing peptides that may be useful in therapy.

Purpose: Pharmacological therapy and pulmonary rehabilitation are useful for exertional dyspnoea in patients with chronic obstructive pulmonary disease (COPD); however, several patients have no meaningful improvements. Although acupuncture significantly improves exercise intolerance and dyspnoea, the pathophysiological mechanism of these effects is unknown; therefore, we evaluated this mechanism using cardiopulmonary exercise testing in a single-arm, open experimental study., Patients and Methods: Sixteen patients with COPD underwent acupuncture once a week for 12 weeks. Primary outcomes were exercise performance parameters, including peak oxygen uptake in the incremental exercise tests (IETs) and the time to the limit of tolerance measured in constant work rate exercise tests (CWRETs) at 70% peak work-rate of the IET. IETs and CWRETs were performed at baseline and at weeks 12, 16, and 24., Results: During the time course, there were significant increases in peak oxygen uptake (p = 0.018) and minute ventilation (V̇ E , p = 0.04) in the IETs. At 12 weeks, the endurance time significantly increased (810 ± 470 vs 1125 ± 657 s, p < 0.001) and oxygen uptakes at terminated exercise were significantly lower (771 ± 149 mL/min, p < 0.05) than those at baseline (822 ± 176 mL/min) in CWRETs. The significant decreases in oxygen uptake and minute ventilation and improvements in Borg scale scores were also observed during CWRETs after acupuncture. The decreases at isotime in the Borg scale (r = -0.789, p = 0.0007) and V̇ E (r = -0.6736, p = 0.0042) were significantly correlated with the improvement of endurance time., Conclusion: The positive effects of acupuncture on exertional dyspnoea were associated with increased endurance time influenced by improved oxygen utilisation and reduced ventilation during exercise. Acupuncture may be a new intervention for COPD in addition to conventional maintenance therapies., Competing Interests: The authors report no conflicts of interest in this work., (© 2019 Maekura et al.)

Background: The optimal and practical laboratory diagnostic approach for detection of Clostridioides difficile to aid in the diagnosis of C. difficile infection (CDI) is controversial. A two-step algorithm with initial detection of glutamate dehydrogenase (GDH) or nucleic acid amplification test (NAAT) alone are recommended as a predominant method for C. difficile detection in developed countries. The aim of this study was to compare the performance of enzyme immunoassays (EIA) detecting toxins A and B, NAAT detecting the toxin B gene, and GDH compared to toxigenic culture (TC) for C. difficile as the gold standard, in patients prospectively and actively assessed with clinically significant diarrhea in 12 medical facilities in Japan., Methods: A total of 650 stool specimens were collected from 566 patients with at least three diarrheal bowel movements (Bristol stool grade 6-7) in the preceding 24 h. EIA and GDH were performed at each hospital, and NAAT and toxigenic C. difficile culture with enriched media were performed at the National Institute of Infectious Diseases. All C. difficile isolates recovered were analyzed by PCR-ribotyping., Results: Compared to TC, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of EIA were 41%, 96%, 75% and 84%, respectively, and for NAAT were 74%, 98%, 91%, and 92%, respectively. In 439 specimens tested with GDH, the sensitivity, specificity, PPV, and NPV were 73%, 87%, 65%, and 91%, and for an algorithm (GDH plus toxin EIA, arbitrated by NAAT) were 71%, 96%, 85%, and 91%, respectively. Among 157 isolates recovered, 75% of isolates corresponded to one of PCR-ribotypes (RTs) 002, 014, 018/018", and 369; RT027 was not isolated. No clear differences in the sensitivities of any of EIA, NAAT and GDH for four predominant RTs were found., Conclusion: The analytical sensitivities of NAAT and GDH-algorithm to detect toxigenic C. difficile in this study were lower than most previous reports. This study also found low PPV of EIAs. The optimal method to detect C. difficile or its toxins to assist in the diagnosis of CDI needs further investigation., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Clostridioides (Clostridium) difficile is the leading cause of healthcare-associated infectious diarrhea in the developed world. Retrospective studies have shown a lower incidence of C. difficile infection (CDI) in Japan than in Europe or North America. Prospective studies are needed to determine if this is due lack of testing for C. difficile or a true difference in CDI epidemiology. A prospective cohort study of CDI was conducted from May 2014 to May 2015 at 12 medical facilities (20 wards) in Japan. Patients with at least three diarrheal bowel movements (Bristol stool grade 6-7) in the preceding 24 h were enrolled. CDI was defined by positive result on enzyme immunoassay for toxins A/B, nucleic acid amplification test for the toxin B gene or toxigenic culture. C. difficile isolates were subjected to PCR-ribotyping (RT), slpA-sequence typing (slpA-ST), and antimicrobial susceptibility testing. The overall incidence of CDI was 7.4/10,000 patient-days (PD). The incidence was highest in the five ICU wards (22.2 CDI/10,000 PD; range: 13.9-75.5/10,000 PD). The testing frequency and CDI incidence rate were highly correlated (R 2  = 0.91). Of the 146 isolates, RT018/018″ was dominant (29%), followed by types 014 (23%), 002 (12%), and 369 (11%). Among the 15 non-ICU wards, two had high CDI incidence rates (13.0 and 15.9 CDI/10,000 PD), with clusters of RT018/slpA-ST smz-02 and 018"/smz-01, respectively. Three non-RT027 or 078 binary toxin-positive isolates were found. All RT018/018" isolates were resistant to moxifloxacin, gatifloxacin, clindamycin, and erythromycin. This study identified a higher CDI incidence in Japanese hospitals than previously reported by actively identifying and testing patients with clinically significant diarrhea. This suggests numerous patients with CDI are being overlooked due to inadequate diagnostic testing in Japan., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The aim of this study was to investigate the effect of activated ghrelin with dietary octanoic acids or medium-chain triglyceride (MCT) administration to underweight patient with chronic obstructive pulmonary disease (COPD). Eleven severe and very severe COPD patients received a 5-day treatment with edible MCT. Sequentially, 10 patients received a 3-week combination treatment with MCT and intravenous acyl ghrelin. Five-day MCT treatment increased endogenous acyl ghrelin (p = 0.0049), but the total ghrelin level was unchanged. MCT-ghrelin combination treatment improved the peak oxygen uptake (p = 0.0120) during whole treatment course. This effect was attributed to the resultant improvements in cardiac function by O 2 pulse, and to the difference between inspired and expired oxygen concentration rather than minute ventilation. Addition of dietary MCT to ghrelin treatment improved the aerobic capacity of underweight COPD patients, likely by mechanisms of increased O 2 delivery through improvements in primary cardiocirculatory and muscular crosstalk.

The present study aimed to elucidate the population dynamics of land hermit crabs on the coast of the Boso Peninsula, Chiba Prefecture, Japan, which is the northern limit of their geographical distribution. We conducted monthly field surveys at four sites from April 2012 to December 2014 and visually searched for crabs. Laboratory experiments were also conducted to evaluate the overwintering ability of two species, Coenobita purpureus and C . rugosus , which were detected during the field surveys; adult crabs and laboratory-raised juveniles were exposed to low-temperature conditions that simulated the in situ temperatures during the early overwintering period. Newly landed juveniles first appeared in August. They were identified as either C . purpureus or C . rugosus , with C . purpureus being the dominant species. Early juveniles grew until October. The abundance of early juveniles decreased with decreasing air temperatures, and dead individuals were found during the overwintering period. The low-temperature tolerance ability of C . purpureus was stronger than that of C . rugosus . Some crabs successfully overwintered, and all were identified as C . purpureus . The growth and overwintering success of juveniles varied among the survey sites depending on the local temperature regime. Our results highlight the frontier for expanding the northern geographical distribution of land hermit crab populations by the colonization and overwintering success of C . purpureus .

The diagnosis of Mycobacterium avium complex (MAC) pulmonary disease is occasionally cumbersome and time-consuming because the MAC species is ubiquitous, and therefore its detection is not necessarily indicative of a definitive diagnosis. A serodiagnostic method specific for MAC pulmonary disease that measures the serum anti-glycopeptidolipid core antigen IgA has been developed and is commercially available. Meta-analysis revealed that the test showed a good diagnostic accuracy. The estimated sensitivity and specificity values were 69.6% (95% confidence interval 62.1-76.1) and 90.6% (95% confidence interval 83.6-95.1), respectively. As antibody levels may reflect the disease activity, their serial measurement can also be used in the management of MAC disease. To justify its routine use in clinical practice, further validation in various regions and studies addressing whether serodiagnosis combined with present diagnostic criteria facilitate more rapid accurate diagnosis of MAC pulmonary disease are necessary., (Copyright © 2019 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Impaired glucose metabolism is associated with an increased risk of cardiovascular complications, and coronary artery spasm is thought to underlie the development of coronary artery disease. Intraday glucose variability (GV) accelerates oxidative stress and inflammatory cytokine release, but its impact on coronary artery spasm remains unclear. This study investigated the relationship between intraday GV and coronary artery spasm. The study included 50 patients with dysglycemia and suspected coronary spastic angina. GV was analyzed by 24-h monitoring of the blood glucose concentration using a flash glucose monitoring system. The mean amplitude of glycemic excursion (MAGE) was calculated as an index of GV. Coronary artery spasm was assessed using the intracoronary acetylcholine provocation test. Coronary spasm was defined as acetylcholine-induced total or subtotal coronary occlusion. Changes in vessel diameter in response to acetylcholine were evaluated with quantitative coronary angiography. Coronary artery spasms were observed in 21 patients (42%). MAGE was significantly higher in patients with spasms compared to those without spasms (127.5 ± 33.5 vs. 91.4 ± 37.6, p < 0.01). Regression analysis showed a positive correlation between MAGE levels and coronary diameter changes induced by acetylcholine (r = 0.47, p < 0.01). In multiple regression analysis, MAGE was independently associated with acetylcholine-induced coronary diameter change (β = 0.47, p < 0.01). Intraday GV was associated with coronary artery spasm in patients with dysglycemia.

Radiation-induced graft polymerization was applied to prepare membranes for multilayer immobilization of laccase, which has biodegradation ability for bisphenol A (BPA). Glycidyl methacrylate (GMA) was grafted onto porous polyethylene membranes as the monomer of polymer brushes, and aminoethanol (AE) was introduced to the grafted GMA membrane, creating unfolded polymer brushes that serve as a good support for multilayer immobilization of laccase. The objectives of this study were as follows: adjustment of space velocity (SV) for optimum performance; enhancement of stability in organic media through moisture retention; biodegradation of BPA at continuous operation; and investigation of the effects of redox mediators. Laccase and membrane activities were increased at higher SVs as a result of stronger substrate transport. The 1.85% moisture retention as a result of high-density AE containing polymer brushes demonstrated the improved stability of immobilized laccase over free laccase in methanol-containing solutions. BPA was removed with an activity of 0.11 mol/h/kg-membrane. The effects of three major laccase mediators on BPA oxidation was studied, and only 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) was shown to increase the oxidation of BPA to 100% at low SVs. Improved stability of laccase and high removal rates in the continuous biodegradation of BPA were achieved by the presented method., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Inappropriate activation of the IL-23 signaling pathway causes chronic inflammation through the induction of immunopathological Th17 cells in several tissues including the intestine, whereas adequate Th17 responses are essential for host defense against harmful organisms. In the intestinal lamina propria, IL-23 is primarily produced by innate myeloid cells including dendritic cells (DCs) and macrophages (Mϕs). However, the molecular mechanisms underlying the regulation of IL-23 production by these cells remains poorly understood. In this study, we demonstrated that BATF2 regulates intestinal homeostasis by inhibiting IL-23-driven T-cell responses. Batf2 was highly expressed in intestinal innate myeloid subsets, such as monocytes, CD11b+ CD64+ Mϕs and CD103+ DCs. Batf2-/- mice spontaneously developed colitis and ileitis with altered microbiota composition. In this context, IL-23, but not TNF-α and IL-10, was produced in high quantities by intestinal CD11b+ CD64+ Mϕs from Batf2-/- mice compared with wild-type mice. Moreover, increased numbers of IFN-γ+, IL-17+ and IFN-γ+ IL-17+ CD4+ T cells, but not IL-10+ CD4+ T cells, accumulated in the colons and small intestines of Batf2-/- mice. In addition, RORγt-expressing innate lymphoid cells were increased in Batf2-/- mice. Batf2-/-Rag2-/- mice showed a reduction in intestinal inflammation present in Batf2-/- mice. Furthermore, the high numbers of intestinal IL-17+ and IFN-γ+ IL-17+ CD4+ T cells were markedly reduced in Batf2-/- mice when introducing Il23a deficiency, which was associated with the abrogation of intestinal inflammation. These results indicated that BATF2 in innate myeloid cells is a key molecule for the suppression of IL-23/IL-17 pathway-mediated adaptive intestinal pathology., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Japanese Society for Immunology.)

Human airway trypsin-like protease (HAT) localizes at human bronchial epithelial cells (HBECs). HAT enhanced release of interleukin-8 (IL-8) from HBECs at 10-100 mU/mL and the enhanced release was almost completely abolished by 50 μM leupeptin, a serine protease inhibitor. Previous reports suggested that HAT displays its physiological functions via protease-activated receptor 2 (PAR2). In the present study, we examined the mechanism whereby HAT upregulates IL-8 synthesis in HBECs with a focus on PAR2. Northern blot analysis revealed that HAT enhanced IL-8 mRNA expression at concentrations of 10-100 mU/mL. PAR2 activating peptide (PAR2 AP) also enhanced IL-8 release and IL-8 mRNA expression in HBECs at 50-1,000 μM at similar levels as HAT. Knockdown of PAR2 mRNA by siRNA methods showed that PAR2 mRNA expression was significantly depressed in primary HBECs, and both HAT- and PAR2 AP-induced IL-8 mRNA elevation was significantly depressed in PAR2 siRNA-transfected HBECs. Additionally, HAT cleaved the PAR2 activating site (R 36 -S 37 bond) of synthetic PAR2 N-terminal peptide. These results indicate that HAT stimulates IL-8 synthesis in airway epithelial cells via PAR2 and could help to amplify inflammation in chronic respiratory tract disease., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Release of captively-bred individuals into the wild is one of the most popular tools in fisheries, forestry, and wildlife management, and introgression of hatchery-reared animals into wild populations is of global concern. However, research and monitoring of impacts on wild populations are generally lacking, and the benefit of hatcheries for long-term fisheries and conservation goals is unclear. Using spatio-temporal genetic monitoring and a four-dacade time series of catch data, we quantified the effects on the size and genetic diversity of wild populations of one of the world's largest marine stock enhancement programs-the red sea bream (Pagrus major) in Kagoshima Bay, Japan. Our analyses found that the stock enhancement program reduced genetic diversity of the population, but the genetic effect diminished with increased size of the wild population. Increases to the seaweed communities and reduced fishing efforts were the primary factors associated with the wild population recovery; effects of aquaculture were much smaller. Our results represent crucial evidence that hatcheries for enhancement and conservation of populations cannot be successful over the long term unless sufficient efforts are also made to reduce harvest rates and rehabilitate natural habitats.

One-third of the world's humans has latent tuberculosis infection (LTBI), representing a large pool of potentially active TB. Recent LTBI carries a higher risk of disease progression than remote LTBI. Recent studies suggest important roles of antibodies in TB pathology, prompting us to investigate serum antibody profiles in a cohort with LTBI. In this single-center prospective observational study, we analyzed IgG-antibody concentrations against five major Mycobacterium tuberculosis (Mtb) antigens (including 6 kDa early secretory antigenic target (ESAT6), CFP10, and antigen 85A, which are expressed mainly in the growth phase; and mycobacterial DNA-binding protein 1 (MDP1) and alpha-crystallin like protein (Acr), which are expressed in the dormant phases) in individuals with recent (n=13) or remote (n=12) LTBI, no Mtb infection (n=19), or active TB (n=15). Antibody titers against ESAT6 and MDP1 were significantly higher in individuals with recent LTBI than in those with no Mtb infection or remote LTBI. All pairwise antibody titers against these five major antigens were significantly correlated throughout the stages of Mtb infection. Five individuals with recent LTBI had significantly higher antibody titers against ESAT6 (P = 0.03), Ag85A (P = 0.048), Acr (P = 0.057), and MDP1 (P = 0.0001) than in individuals with remote LTBI; they were also outside the normal range (+2 SDs). One of these individuals was diagnosed with active pulmonary TB at 18-month follow-up examination. These findings indicated that concentrations of antibodies against both multiplying and dormant Mtb are higher in recent LTBI and that individuals with markedly higher antibody titers may be appropriate candidates for prophylactic therapy., (© 2019 The Societies and John Wiley & Sons Australia, Ltd.)

Diffuse pulmonary ossification (DPO) is an uncommon diffuse lung disease characterized by metaplastic bone formation in the lung parenchyma and is rarely diagnosed in life. While DPO usually occurs as a secondary disease, idiopathic cases are extremely rare. We describe three cases of idiopathic DPO, two of which were definitively diagnosed by surgical lung biopsy. One case was observed in a 43-year-old man with a history of recurrent pneumothorax who developed pneumothorax after the surgical biopsy. Few reports have described cases of DPO with recurrent pneumothorax; however, pneumothorax should be considered as a potential complication when such patients are encountered.

Background: Patients with chronic obstructive pulmonary disease (COPD) show varying mechanisms of exertional dyspnea with different exercise capacities. Methods: To investigate the pathophysiologic conditions related to exertional dyspnea, 294 COPD patients were evaluated using cardiopulmonary exercise testing (CPET) with arterial blood analyses, with the patients classified into two groups according to their exercise limitation: the leg fatigue group ( n = 58) and the dyspnea group ( n = 215). The dyspnea group was further subdivided into four groups based on peak oxygen uptake ( V ° O 2 in mL/min/kg): group A (< 11), group B (11 to < 15), group C (15 to < 21), and group D (≥21). Results: In the dyspnea group, group A (n = 28) showed the following findings: (i) the forced expiratory volume in 1 s was not correlated with the peak V ° O 2 ( p = 0.288), (ii) the arterial oxygen tension (PaO 2 ) slope (peak minus resting PaO 2 /Δ V ° O 2 ) was the steepest ( p < 0.0001) among all subgroups, (iii) reduced tidal volume (V T ) was negatively correlated with respiratory frequency at peak exercise ( p < 0.0001), and (iv) a break point in exertional V T curve was determined in 17 (61%) patients in group A. In these patients, there was a significant negative correlation between bicarbonate ion ( HCO 3 - ) levels at peak exercise and V T level when the V T -break point occurred ( p = 0.032). In group D ( n = 46), HCO 3 - levels were negatively correlated with plasma lactate levels ( p < 0.0001). In all subgroups, the HCO 3 - level was negatively correlated with minute ventilation. The dyspnea subgroups showed no significant differences in the overall mean pH [7.363 (SD 0.039)] and Borg scale scores [7.4 (SD, 2.3)] at peak exercise. Conclusions: During exercise, ventilation is stimulated to avoid arterial blood acidosis and hypoxemia, but ventilatory stimulation is restricted in the setting of reduced respiratory system ability. These conditions provoke the exertional dyspnea in COPD. Although symptom levels were similar, the exertional pathophysiologic conditions differed according to residual exercise performance; moreover, COPD patients showed great inter-individual variability. An adequate understanding of individual pathophysiologic conditions using CPET is essential for proper management of COPD patients.

Long-term, low-dose erythromycin monotherapy, based on the anti-inflammatory effects of macrolides, has been reported to have the potential to suppress the exacerbation of Mycobacterium avium complex (MAC) lung disease with less toxicity. It remains unclear whether erythromycin monotherapy induces cross-resistance to clarithromycin, a key drug for MAC. To clarify this point, we conducted a retrospective, single-center, case-series study on patients with MAC lung disease who underwent erythromycin monotherapy for at least 6 months. Drug susceptibility tests, before and after erythromycin treatment initiation, were analyzed. Thirty-three patients were included in our study. All 33 patients showed susceptibility to clarithromycin for MAC both before and after erythromycin monotherapy. There was no significant difference in clarithromycin minimum inhibitory concentrations between before and after erythromycin treatment (median difference = 0 μg/ml; P = .313, Wilcoxon's signed-rank test). We conclude that erythromycin monotherapy for MAC lung disease may not induce cross-resistance to clarithromycin., (Copyright © 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Rationale: Little is known about the applicability of respiratory muscle training based on exertional pathophysiological conditions in patients with chronic obstructive pulmonary disease (COPD). The aim of this study was to investigate the relationship between breathing timing and exertional responses, as well as whether exertional changes in the inspiratory duty cycle (Ti/Ttot) affect pathophysiological conditions, including respiratory muscles., Methods: Forty-five stable COPD patients (mean age: 71.2 years, severe and very severe COPD: 80%) were evaluated based on exertional cardiopulmonary function and respiratory muscle strength. To compare exertional responses and the balance of inspiratory-to-expiratory muscle strength, the patients were divided into two groups according to whether the Ti/Ttot increased (Ti/Ttot-increased group: resting Ti/Ttot ≤ peak Ti/Ttot, n = 21) or decreased during exercise (Ti/Ttot-decreased group: resting Ti/Ttot > peak Ti/Ttot, n = 24)., Results: At peak exercise, the Ti/Ttot was positively correlated with minute ventilation ([Formula: see text] E ), and oxygen uptake ([Formula: see text]) in all patients. No significant differences were seen in breathing frequency, tidal volume, or [Formula: see text] E at peak exercise between the two groups. Compared with the Ti/Ttot-increased group, the Ti/Ttot-decreased group had significantly lower mean values of [Formula: see text] and ΔFO 2 (the inspired minus expired oxygen concentration) at peak exercise, and significantly higher mean values of the absolute ratio of maximal inspiratory pressure/maximal expiratory pressure., Conclusions: The exertional change of breathing timing affected exercise tolerance and the balance of inspiratory-to-expiratory muscle strength; this finding might be helpful in making the contradictory choice of managing COPD patients with inspiratory or expiratory muscle training.

CD163 is preferentially expressed by monocyte/macrophages; however, recent studies using immunohistochemistry (IHC) have reported that some cancer cells also express CD163. In the present IHC study, we investigated CD163 staining of cancer cells and macrophages in clear cell renal cell carcinoma (ccRCC) tissues and determined the relationship between cancer cell CD163 expression and clinical prognosis in patients with ccRCC. IHC for CD163 was performed in ccRCC tissues from 103 patients. CD163-positive cancer cells were detected in 35% of the patients (36/103); however, the positive signals on cancer cells were significantly lower than those on macrophages. CD163-positive cancer cells were preferentially detected in patients with high T classification, and females, and were significantly associated with shortened progression-free survival and a lower overall survival ratio. Notably, a high intensity of CD163-positive macrophage infiltration was detected in the CD163-positive cancer cell-high tumor areas. Although CD163 mRNA was detected in cultured macrophages, no CD163 mRNA was detected in two cultured RCC cell lines. The detailed mechanism by which a positive signal is detected on cancer cells has not been clarified. Detection of the CD163 antigen on cancer cells might be a useful marker for evaluating the clinical course of patients with ccRCC.

Aims: Cardiac function varies in the population of patients with heart failure (HF) with preserved left ventricular ejection fraction (LVEF; HFpEF). This study investigated the heterogeneity of clinical features associated with HF and the prognostic value of BNP levels in patients with HFpEF., Methods and Results: The study enrolled 288 patients with stable HF and serum creatinine <1.5 mg/dL who were part of the original J-MELODIC study cohort. They were categorized as having HF with reduced LVEF (HFrEF; EF ≤ 40%, n = 83) or as having HFpEF (EF > 40%, n = 205). Patients with HFpEF were further categorized as having relatively low LVEF (HFrlEF; EF 40-60%, n = 107) or as having relatively high LVEF (HFrhEF; EF ≥ 60%, n = 98). We defined cardiovascular death and hospitalization for HF as adverse events and evaluated the prognostic value of the BNP levels in each group. There was no significant difference in event-free survival between HFpEF and HFrEF patients or between HFrhEF and HFrlEF patients. A multivariate Cox proportional hazards model revealed that the BNP level was an independent predictor of adverse events in HFrEF patients (hazard ratio: 4.088, 95% confidence interval: 1.178-14.179, P = 0.027) and in HFrlEF patients (hazard ratio: 14.888, 95% confidence interval: 4.969-44.608, P < 0.001) but not in HFrhEF patients (P = 0.767)., Conclusions: The BNP level has prognostic value in HFrlEF but not in HFrhEF. This indicates that HFrhEF and HFrlEF are distinct entities that may require different approaches for the management of HF., (© 2017 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

T-cell immunoglobulin and mucin domain (TIMD) family genes are related to innate immune responses. TIMD4 is a receptor for phosphatidylserine and is involved in the phagocytosis of apoptotic cells by macrophages. In the present study, we found that TIMD4 is expressed on the cancer cells of patients with clear cell renal cell carcinoma (ccRCC). TIMD4 was immunostained in the resected samples of 89 patients diagnosed as ccRCC. High expression of TIMD4 in cancer cells was closely related to short progression free survival time; however, it was not correlated with other clinicopathological factors. Intracellular expression of TIMD4 was observed in the RCC cell line, 786-O. In vitro studies using 786-O cells and shRNA targeting TIMD4 indicated that TIMD4 expression was associated with resistance to sorafenib but not with cell proliferation. TIMD4 might be useful as a prognostic factor and may also be a new target for therapy of ccRCC.

Infection with Trypanosoma cruzi causes Chagas disease. The methods provided here allow for the quantification of T. cruzi in the liver, heart, and blood of intraperitoneally-infected mice and analysis of the killing activity of the cells infected with T. cruzi in vitro ., (Copyright © 2017 The Authors; exclusive licensee Bio-protocol LLC.)

Population structure and demographic history of the Japanese Spanish mackerel Scomberomorus niphonius a highly piscivorous and migratory marine fish, were assessed using mitochondrial DNA control region sequences (n = 720) and microsatellite genotypes at five loci (n = 1331) for samples collected on Japanese coasts from 2001 to 2010. The population structure was panmictic and the haplotype and allele frequencies were temporally stable even during the recent recovery process. Demographic expansion was strongly supported throughout the Pleistocene, suggesting that the oscillating glacial and interglacial climate conditions in the Pleistocene had no substantial impact on the demographic history of S. niphonius., (© 2017 The Fisheries Society of the British Isles.)

An empirical Bayes (EB) pairwise F ST estimator was previously introduced and evaluated for its performance by numerical simulation. In this study, we conducted coalescent simulations and generated genetic population structure mechanistically, and compared the performance of the EBF ST with Nei's G ST , Nei and Chesser's bias-corrected G ST (G ST&#95;NC ), Weir and Cockerham's θ (θ WC ) and θ with finite sample correction (θ WC&#95;F ). We also introduced EB estimators for Hedrick' G' ST and Jost' D. We applied these estimators to publicly available SNP genotypes of Atlantic herring. We also examined the power to detect the environmental factors causing the population structure. Our coalescent simulations revealed that the finite sample correction of θ WC is necessary to assess population structure using pairwise F ST values. For microsatellite markers, EBF ST performed the best among the present estimators regarding both bias and precision under high gene flow scenarios (FST≤0.032). For 300 SNPs, EBF ST had the highest precision in all cases, but the bias was negative and greater than those for G ST&#95;NC and θ WC&#95;F in all cases. G ST&#95;NC and θ WC&#95;F performed very similarly at all levels of F ST . As the number of loci increased up to 10 000, the precision of G ST&#95;NC and θ WC&#95;F became slightly better than for EBF ST for cases with FST≥0.004, even though the size of the bias remained constant. The EB estimators described the fine-scale population structure of the herring and revealed that ~56% of the genetic differentiation was caused by sea surface temperature and salinity. The R package finepop for implementing all estimators used here is available on CRAN., (© 2017 The Authors. Molecular Ecology Resources Published by John Wiley & Sons Ltd.)

Objectives: Ghrelin, a growth hormone-releasing peptide, has shown efficacy in chronic obstructive pulmonary disease (COPD) patients in previous trials. This study was designed to evaluate the effective dose of ghrelin in chronic respiratory failure patients., Methods: In this randomized, double-blind, dose-finding, single-center study, 18 patients, including 16 with COPD, were randomly assigned to receive pulmonary rehabilitation (PR) with intravenous ghrelin at 1 μg/kg or 2 μg/kg, twice daily for 3 weeks. The primary outcome was the change in peak oxygen uptake ( V˙o2). Secondary outcomes included changes in plasma vascular endothelial growth factor (VEGF)-A levels, and exertional cardio-respiratory functions with blood gas analysis., Results: With incremental exercise, there was no significant differences in the mean difference (high-dose ghrelin minus low-dose ghrelin) of peak V˙o2 (1.0 mL/kg/min, 95% CI: -0.6 to 2.6 mL/kg/min, between-group, P = 0.193). However, there were significant differences in the mean difference of (i) O 2 -pulse (0.6 mL/beats, 95% CI: 0.0 to 1.1 mL/beats, between-group, P = 0.035) at iso-time; and ii) PaO 2 (4.2 mmHg, 95% CI: 0.2 to 8.2 mmHg, between-group, P = 0.041) and PaCO 2 (-3.1 mmHg, 95% CI: -6.0 to -0.3 mmHg, between-group, P = 0.034) at peak exercise. The mean difference in the plasma VEGF-A level was significantly inhibited by high dose-ghrelin with PR (-125.4 pg/mL, 95% CI: -235.2 to -15.5 pg/mL, between-group, P = 0.028)., Conclusion: Although the primary outcome of the study was not met, high-dose ghrelin with PR improved exertional cardiac function and blood gas values, and inhibited circulating VEGF-A levels., (© 2015 John Wiley & Sons Ltd.)

Limb bud patterning, outgrowth, and differentiation are precisely regulated in a spatio-temporal manner through integrated networks of transcription factors, signaling molecules, and downstream genes. However, the exact mechanisms that orchestrate morphogenesis of the limb remain to be elucidated. Previously, we have established EMBRYS, a whole-mount in situ hybridization database of transcription factors. Based on the findings from EMBRYS, we focused our expression pattern analysis on a selection of transcription factor genes that exhibit spatially localized and temporally dynamic expression patterns with respect to the anterior-posterior axis in the E9.5-E11.5 limb bud. Among these genes, Irx3 showed a posteriorly expanded expression domain in Shh-/- limb buds and an anteriorly reduced expression domain in Gli3-/- limb buds, suggesting their importance in anterior-posterior patterning. To assess the stepwise EMBRYS-based screening system for anterior regulators, we generated Irx3 transgenic mice in which Irx3 was expressed in the entire limb mesenchyme under the Prrx1 regulatory element. The Irx3 gain-of-function model displayed complex phenotypes in the autopods, including digit loss, radial flexion, and fusion of the metacarpal bones, suggesting that Irx3 may contribute to the regulation of limb patterning, especially in the autopods. Our results demonstrate that gene expression analysis based on EMBRYS could contribute to the identification of genes that play a role in patterning of the limb mesenchyme.

Inappropriate IL-17 responses are implicated in chronic tissue inflammation. IL-23 contributes to Trypanosoma cruzi -specific IL-17 production, but the molecular mechanisms underlying regulation of the IL-23-IL-17 axis during T. cruzi infection are poorly understood. Here, we demonstrate a novel function of BATF2 as a negative regulator of Il23a in innate immune cells. IL-17, but not IFN-γ, was more highly produced by CD4 + T cells from spleens and livers of T. cruzi -infected Batf2 -/- mice than by those of wild-type mice. In this context, Batf2 -/- mice showed severe multiorgan pathology despite reduced parasite burden. T. cruzi -induced IL-23 production was increased in Batf2 -/- innate immune cells. The T. cruzi -induced enhanced Th17 response was abrogated in Batf2 -/- Il23a -/- mice. The interaction of BATF2 with c-JUN prevented c-JUN-ATF-2 complex formation, inhibiting Il23a expression. These results demonstrate that IFN-γ-inducible BATF2 in innate immune cells controls Th17-mediated immunopathology by suppressing IL-23 production during T. cruzi infection., (© 2017 Kitada et al.)

Background: COPD patients undergoing pulmonary rehabilitation (PR) show various responses. The purpose of this study was to investigate the possible mechanisms and predictors of the response to PR in COPD patients., Methods: Thirty-six stable COPD patients underwent PR including a 4-week high-intensity exercise training program, and they were evaluated by cardiopulmonary exercise testing. All patients (mean age 69 years, severe and very severe COPD 94%) were classified into four groups by whether the exercise time (T ex ) or the peak oxygen uptake [Formula: see text] increased after PR: two factors increased (both the T ex and the peak [Formula: see text] increased); two factors decreased; time only increased (the T ex increased, but the peak [Formula: see text] economized); and [Formula: see text] only increased (the T ex decreased, but the peak [Formula: see text] increased). Within all patients, the relationships between baseline variables and the post-to-pre-change ratio of the time-slope, T ex /(peak minus resting [Formula: see text]), were investigated., Results: Compared with the two factors increased group (n=11), in the time only increased group (n=18), the mean differences from pre-PR at peak exercise in 1) minute ventilation [Formula: see text] ( P =0.004), [Formula: see text] ( P <0.0001), and carbon dioxide output [Formula: see text] ( P <0.0001) were lower, 2) [Formula: see text]/ [Formula: see text] ( P =0.034) and [Formula: see text]/ [Formula: see text] ( P =0.006) were higher, and 3) the dead space/tidal volume ratio (V D /V T ) and the dyspnea level were similar. After PR, there was no significant difference in the ratio of the observed peak heart rate (HR) to the predicted peak HR (220 - age [years]) between the two groups. A significant negative correlation with the baseline time-slope ( r =-0.496, P =0.002) and a positive correlation with the baseline body mass index (BMI) ( r =0.496, P =0.002) were obtained., Conclusions: PR in COPD patients improves T ex rather than exercise tolerance, economizing oxygen requirements, resulting in reduced ventilatory requirements without cardiac loads followed by reduced exertional dyspnea. In addition, the time-slope and BMI could be used to predict PR responses beforehand., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

The diagnosis of Mycobacterium avium complex pulmonary disease (MAC-PD) is sometimes complicated and time-consuming. A serodiagnostic kit that measures the serum levels of IgA antibodies against the glycopeptidolipid (GPL) core is commercially available and has good diagnostic accuracy for MAC-PD. However, the significance of measurement of GPL core IgA antibody levels in monitoring for chemotherapy response in patients with MAC-PD was not well investigated. Thirty-four treatment naive MAC-PD patients who were started on multidrug chemotherapy were enrolled. Their antibody levels were prospectively measured at regular intervals. The relationships between their antibody levels and the therapeutic outcomes were examined. The patients were classified into three groups (conversion, recurrence, and nonconversion) based on the bacteriological outcomes after chemotherapy. There were no significant differences in the antibody levels before treatment between the culture conversion ( n = 19), recurrence ( n = 7), and nonconversion ( n = 8) groups ( P = 0.9881). The levels decreased significantly after the chemotherapy ( P < 0.0001). Recurrence and/or worsening of chest radiography findings were observed in cases whose antibody levels subsequently increased after cessation of the chemotherapy. No significant difference in the percent decrease in antibody levels by the chemotherapy was observed between the culture conversion and recurrence groups ( P = 0.9338). The initial antibody levels are not a predictor of therapeutic outcomes, and also the percent decrease in antibody levels is not a sufficient indicator of the cessation of chemotherapy. However, serial measurements of antibody levels may allow objective monitoring of disease activity in individual MAC-PD patients., (Copyright © 2017 American Society for Microbiology.)

We examined the ontogenetic change of body color patterns in the laboratory-raised juveniles of six terrestrial hermit crab species, including Birgus latro, Coenobita brevimanus, C. cavipes, C. purpureus, C. rugosus, and C. violascens, which commonly occur in the southern islands, Japan. The body color patterns of coenobitid juveniles were species-specific. The diagnostic features of body color patterns enable identification of juveniles of coenobitid crab species in the wild, thereby helping to understand the precise habitats of each coenobitid species.

Background: The immune escape or tolerance of cancer cells is considered to be closely involved in cancer progression. Programmed death-1 (PD-1) is an inhibitory receptor expressed on activating T cells, and several types of cancer cells were found to express PD-1 ligand 1 (PD-L1) and ligand 2 (PD-L2)., Methods: In the present study, we investigated PD-L1/2 expression in papillary renal cell carcinoma (pRCC)., Result: We found PD-L1 expression in 29 of 102 cases, but no PD-L2 expression was seen. PD-L1 expression was not significantly correlated with any clinicopathological factor, including progression-free survival and overall survival. The frequency of PD-L1-positive cases was higher in type 2 (36%) than in type 1 (22%) pRCC; however, there was no significant difference in the percentages of score 0 cases (p value = 0.084 in Chi-square test). The frequency of high PD-L1 expression cases was higher in type 2 (23%) than in type 1 (11%), and the frequency of high PD-L1 expression cases was higher in grade 3/4 (21%) than in grade 1/2 (13%). However, no significant association was found between PD-L1 expression and all clinicopathological factors in pRCC., Conclusion: High expression of PD-L1 in cancer cells was potentially associated to highly histological grade of malignancy in pRCC. The evaluation of the PD-L1 protein might still be useful for predicting the efficacy of anti-cancer immunotherapy using immuno-checkpoint inhibitors, however, not be useful for predicting the clinical prognosis.

Purpose: Classification of femoral trochanteric fractures is usually based on plain X-ray findings using the Evans, Jensen, or AO/OTA classification. However, complications such as nonunion and cut out of the lag screw or blade are seen even in stable fracture. This may be due to the difficulty of exact diagnosis of fracture pattern in plain X-ray. Computed tomography (CT) may provide more information about the fracture pattern, but such data are scarce. In the present study, it was performed to propose a classification system for femoral trochanteric fractures using three-dimensional CT (3D-CT) and investigate the relationship between this classification and conventional plain X-ray classification., Methods: Using three-dimensional (3D)-CT, fractures were classified as two, three, or four parts using combinations of the head, greater trochanter, lesser trochanter, and shaft. We identified five subgroups of three-part fractures according to the fracture pattern involving the greater and lesser trochanters. In total, 239 femoral trochanteric fractures (45 men, 194 women; average age, 84.4 years) treated in four hospitals were classified using our 3D-CT classification. The relationship between this 3D-CT classification and the AO/OTA, Evans, and Jensen X-ray classifications was investigated., Results: In the 3D-CT classification, many fractures exhibited a large oblique fragment of the greater trochanter including the lesser trochanter. This fracture type was recognized as unstable in the 3D-CT classification but was often classified as stable in each X-ray classification., Conclusions: It is difficult to evaluate fracture patterns involving the greater trochanter, especially large oblique fragments including the lesser trochanter, using plain X-rays. The 3D-CT shows the fracture line very clearly, making it easy to classify the fracture pattern.

Parasporin-2 (PS2), alternatively named Cry46Aa1, an anticancer protein derived from Bacillus thuringiensis strain A1547, causes specific cell damage via PS2 oligomerization in the cell membrane. Although PS2 requires glycosylphosphatidylinositol (GPI)-anchored proteins for its cytocidal action, their precise role is unknown. Here, we report that the glycan of GPI induces PS2 oligomerization, which causes cell death. Cytotoxicity, cell-binding and oligomerization of the toxin were not observed in GPI-anchored protein-deficient Chinese hamster ovary cells. Expression and protease-treatment analyses showed that the actions of the toxin were dependent on the glycan core, not the polypeptide moiety, of GPI-anchored proteins. However, surface expression of some GPI-anchored proteins is observed in PS2-insensitive cells. These data suggest that GPI-anchored proteins do not determine the target specificity, but instead function as a kind of coreceptor, in the cytocidal action of PS2., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective To investigate the association between arginine vasopressin (AVP) levels and loop diuretic (LD) therapy in patients with heart failure and to determine if AVP levels are a prognostic indicator of treatment failure. Methods Patients with stable heart failure and reduced (< 40%) left ventricular ejection fraction (LVEF) were divided into those treated with (LD) or without LD (NLD). The LD group was separated into subgroups of high (> 6.5 pg/dl) and low (≤ 6.5 pg/dl) AVP levels. The clinical and biochemical characteristics of the two groups were compared and the prognostic value of AVP levels in heart failure evaluated. Results Of the 63 patients enrolled into the study, 41 (65.1%) were in the LD group and 22 (34.9%) were in the NLD group. Despite no differences between groups in LVEF, creatinine clearance, or brain natriuretic peptide, the LD group had significantly higher AVP levels compared with the NLD group. A Cox proportional-hazards model showed that AVP was an independent predictor of adverse events. In addition, the elevation in AVP in the LD group was inversely correlated with an increase in free water clearance but not serum osmolality and was related to poor outcome. Conclusions Elevated AVP levels in patients with heart failure who received LD therapy were associated with a poor prognosis. Loop diuretics may induce non-osmolar AVP release, which can worsen heart failure.

The prevalence of nontuberculous mycobacterial (NTM) pulmonary disease is increasing in Japan and worldwide, and the importance of proper diagnosis and management of the disease has been recently recognized. Mycobacterium aviun complex (MAC) is the most common and important causative agent of pulmonary disease among nontuberculous mycobacteria. I have described the latest epidemiology of NTM lung disease, clinical feature, disease type, disease progression, diagnosis including serodiagnosis, and treatment strategy of MAC lung disease in this report. There are a lot of unsolved problems in the field of NTM lung disease, therefore, further investigations are required.

Cancer stem-like cells (CSC) or cancer-initiating cells are now considered to be an important cell population related to cancer recurrence and the resistance to anti-cancer therapy. Tumor-associated macrophages (TAM) are a main component of stromal cells and are related to cancer progression in clear cell renal cell carcinoma (ccRCC). Because the detailed mechanisms allowing the maintenance of CSC in cancer tissues remain unclear, we investigated the relationship between TAM and CD44-expressing cancer cells in ccRCC. CD44 was used as a marker for CSC, and CD163 and CD204 were used as markers for TAM. CD44-positive cancer cells were detected in 37 of the 103 cases. Although statistical analysis showed no relationship between CD44-positive cancer cells and the clinical course, the distribution of CD44-positive cancer cells was significantly associated with a high density of TAM. Our in vitro study using RCC cell lines and human macrophages demonstrated that CD44 expression was upregulated by direct co-culture with macrophages. Silencing of TNF-alpha on macrophages abrogated the upregulation of CD44 expression in cancer cells. Macrophage-induced CD44 overexpression was also suppressed by NF-κB inhibitors. These results suggest that TNF-alpha derived from TAM is linked to CD44 overexpression via NF-κB signaling in ccRCC., (© 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)