Cross-sectional and prospective study of the association between lung function and prediabetes

Objectives: A growing body of evidence suggests that there is a relationship between impaired lung function and the risk of developing diabetes mellitus (DM). However, it is not known if this reflects a causal effect of lung function on glucose metabolism. To clarify the relationship between lung function and the development of DM, we examined the incidence of newly diagnosed prediabetes (a precursor of DM) among subjects with normal glucose tolerance (NGT) at baseline. Design: Primary analysis of an occupational cohort with both cross-sectional and longitudinal data (follow-up duration mean±SD: 28.4±6.1 months). Setting and participants: Data were analysed from 1058 men in a cross-sectional study and from 560 men with NGT in a longitudinal study. Outcomes and methods: Impaired lung function (per cent predicted value of forced vital capacity (%FVC) or per cent value of forced expiratory volume 1 s/FVC (FEV1/FVC ratio)) in relation to the ratio of prediabetes or DM in a cross-sectional study and development of new prediabetes in a longitudinal study. NGT, prediabetes including impaired glucose tolerance (IGT) and increased fasting glucose (IFG) and DM were diagnosed according to 75 g oral glucose tolerance tests. Measurements and main results: %FVC at baseline, but not FEV1/FVC ratio at baseline, was significantly associated with the incidences of DM and prediabetes. Among prediabetes, IGT but not IFG was associated with %FVC. During follow-up, 102 subjects developed prediabetes among those with NGT. A low %FVC, but not FEV1/FVC ratio, was predictive of an increased risk for development of IGT, but not of IFG. Conclusions: Low lung volume is associated with an increased risk for the development of prediabetes, especially IGT, in Japanese men. Although there is published evidence for an association between chronic obstructive pulmonary disease and DM, prediabetes is not associated with the early stage of COPD.This work was supported in part by a grant-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (No. 23390222 and 24659405), and a grant to the Respiratory Failure Research Group from the Ministry of Health, Labor and Welfare, Japan

Matrix metalloproteinase-1 up-regulation by hepatocyte growth factor in human dermal fibroblasts via ERK signaling pathway involves Ets1 and Fli1

In this study, we clarified the molecular mechanism(s) underlying the regulation of matrix metalloproteinase (MMP)-1 gene by hepatocyte growth factor (HGF) in cultured human dermal fibroblasts. HGF induced MMP-1 protein as well as mRNA at a transcriptional level via extracellular signal-regulated kinase (ERK) signaling pathway. The region in the MMP-1 promoter mediating the inducible responsiveness to HGF, defined by the transient transfection analysis of the serial 5′ deletion constructs, contained an Ets binding site. Mutation of this Ets binding site abrogated the HGF-inducible promoter activity. Ets1 up-regulated the expression of MMP-1 promoter activity, whereas Fli1 had antagonistic effects on them. After HGF treatment, the protein level and the binding activity of Ets1 was increased and those of Fli1 was decreased, which were canceled by PD98059. These results suggest that HGF up-regulates MMP-1 expression via ERK signaling pathway through the balance of Ets1 and Fli1, which may be a novel mechanism of regulating MMP-1 gene expression

Multipotent Neurotrophic Effects of Hepatocyte Growth Factor in Spinal Cord Injury

Spinal cord injury (SCI) results in neural tissue loss and so far untreatable functional impairment. In addition, at the initial injury site, inflammation induces secondary damage, and glial scar formation occurs to limit inflammation-mediated tissue damage. Consequently, it obstructs neural regeneration. Many studies have been conducted in the field of SCI; however, no satisfactory treatment has been established to date. Hepatocyte growth factor (HGF) is one of the neurotrophic growth factors and has been listed as a candidate medicine for SCI treatment. The highlighted effects of HGF on neural regeneration are associated with its anti-inflammatory and anti-fibrotic activities. Moreover, HGF exerts positive effects on transplanted stem cell differentiation into neurons. This paper reviews the mechanisms underlying the therapeutic effects of HGF in SCI recovery, and introduces recent advances in the clinical applications of HGF therapy

A novel, visible light-induced, rapidly cross-linkable gelatin scaffold for osteochondral tissue engineering

Osteochondral injuries remain difficult to repair. We developed a novel photo-cross-linkable furfurylamine-conjugated gelatin (gelatin-FA). Gelatin-FA was rapidly cross-linked by visible light with Rose Bengal, a light sensitizer, and was kept gelled for 3 weeks submerged in saline at 37 degrees C. When bone marrow-derived stromal cells (BMSCs) were suspended in gelatin-FA with 0.05% Rose Bengal, approximately 87% of the cells were viable in the hydrogel at 24 h after photo-cross-linking, and the chondrogenic differentiation of BMSCs was maintained for up to 3 weeks. BMP4 fusion protein with a collagen binding domain (CBD) was retained in the hydrogels at higher levels than unmodified BMP4. Gelatin-FA was subsequently employed as a scaffold for BMSCs and CBD-BMP4 in a rabbit osteochondral defect model. In both cases, the defect was repaired with articular cartilage-like tissue and regenerated subchondral bone. This novel, photo-cross-linkable gelatin appears to be a promising scaffold for the treatment of osteochondral injury

Structural and functional insights into thermally stable cytochrome c' from a thermophile

Thermophilic Hydrogenophilus thermoluteolus cytochrome c0 (PHCP) exhibits higher thermal stability than a mesophilic counterpart, Allochromatium vinosum cytochrome c0 (AVCP), which has a homo-dimeric structure and ligand-binding ability. To understand the thermal stability mechanism and ligand-binding ability of the thermally stable PHCP protein, the crystal structure of PHCP was first determined. It formed a homo-dimeric structure, the main chain root mean square deviation (rmsd) value between PHCP and AVCP being 0.65 A ° . In the PHCP structure, six specific residues appeared to strengthen the heme-related and subunit–subunit interactions, which were not conserved in the AVCP structure. PHCP variants having altered subunit–subunit interactions were more severely destabilized than ones having altered heme-related interactions. The PHCP structure further revealed a ligand-binding channel and a penta-coordinated heme, as observed in the AVCP protein. A spectroscopic study clearly showed that some ligands were bound to the PHCP protein. It is concluded that the dimeric PHCP from the thermophile is effectively stabilized through heme-related and subunit–subunit interactions with conservation of the ligand-binding ability.This work was performed under the Cooperative Research Program of the “Network Joint Research Center for Materials and Devices”

Effects of (−)-epigallocatechin-3-gallate on EGFR- or Fusion Gene-driven Lung Cancer Cells

(−)-Epigallocatechin-3-gallate (EGCG) has been shown to bind to several receptors including epidermal growth factor receptor (EGFR). EGFR tyrosine kinase inhibitors and anaplastic lymphoma kinase (ALK) inhibitors are effective for non-small cell lung cancers harboring activating EGFR mutations and ALK or c-ros oncogene 1 (ROS1) fusion genes, respectively. We investigated the effects of EGCG on EGFR- or fusion gene-driven lung cancer cells such as PC-9, RPC-9, H1975, H2228 and HCC78. The five cell lines had similar sensitivity to EGCG. Phosphorylated (p)EGFR, pAkt and pErk in PC-9, RPC-9 and H1975 cells were suppressed by EGCG (50 or 100 μM). EGCG also inhibited pALK in H2228, pROS1 in HCC78, and pErk and pAkt in both cell lines. All the xenograft tumors established using the 5 cell lines in EGCG-treated groups were significantly smaller than the tumors in the vehicle-treated groups. The numbers of tumor blood vessels of xenograft tissues in EGCG-treated mice were significantly lower than those in vehicle-treated mice. In conclusion, EGCG may be effective for EGFR-driven lung tumors irrespective of the presence of T790M, and for ALK or ROS1 fusion gene-driven lung tumors

Decline in Left Ventricular Ejection Fraction during Follow-up in Patients with Severe Aortic Stenosis

Objectives: The aim of this study was to investigate the prognostic impact of the decline in left ventricular ejection fraction (LVEF) at 1-year follow-up in patients with severe aortic stenosis (AS) managed conservatively. Background: No previous study has explored the association between LVEF decline during follow-up and clinical outcomes in patients with severe AS. Methods: Among 3, 815 patients with severe AS enrolled in the multicenter CURRENT AS (Contemporary Outcomes After Surgery and Medical Treatment in Patients With Severe Aortic Stenosis) registry in Japan, 839 conservatively managed patients who underwent echocardiography at 1-year follow-up were analyzed. The primary outcome measure was a composite of AS-related deaths and hospitalization for heart failure. Results: There were 91 patients (10.8%) with >10% declines in LVEF and 748 patients (89.2%) without declines. Left ventricular dimensions and the prevalence of valve regurgitation and atrial fibrillation or flutter significantly increased in the group with declines in LVEF. The cumulative 3-year incidence of the primary outcome measure was significantly higher in the group with declines in LVEF than in the group with no decline (39.5% vs. 26.5%; p 10% declines in LVEF at 1 year after diagnosis had worse AS-related clinical outcomes than those without declines in LVEF under conservative management. (Contemporary Outcomes After Surgery and Medical Treatment in Patients With Severe Aortic Stenosis Registry; UMIN000012140

Initial Surgical Versus Conservative Strategies in Patients With Asymptomatic Severe Aortic Stenosis

AbstractBackgroundCurrent guidelines generally recommend watchful waiting until symptoms emerge for aortic valve replacement (AVR) in asymptomatic patients with severe aortic stenosis (AS).ObjectivesThe study sought to compare the long-term outcomes of initial AVR versus conservative strategies following the diagnosis of asymptomatic severe AS.MethodsWe used data from a large multicenter registry enrolling 3,815 consecutive patients with severe AS (peak aortic jet velocity >4.0 m/s, or mean aortic pressure gradient >40 mm Hg, or aortic valve area <1.0 cm2) between January 2003 and December 2011. Among 1,808 asymptomatic patients, the initial AVR and conservative strategies were chosen in 291 patients, and 1,517 patients, respectively. Median follow-up was 1,361 days with 90% follow-up rate at 2 years. The propensity score–matched cohort of 582 patients (n = 291 in each group) was developed as the main analysis set for the current report.ResultsBaseline characteristics of the propensity score–matched cohort were largely comparable, except for the slightly younger age and the greater AS severity in the initial AVR group. In the conservative group, AVR was performed in 41% of patients during follow-up. The cumulative 5-year incidences of all-cause death and heart failure hospitalization were significantly lower in the initial AVR group than in the conservative group (15.4% vs. 26.4%, p = 0.009; 3.8% vs. 19.9%, p < 0.001, respectively).ConclusionsThe long-term outcome of asymptomatic patients with severe AS was dismal when managed conservatively in this real-world analysis and might be substantially improved by an initial AVR strategy. (Contemporary Outcomes After Surgery and Medical Treatment in Patients With Severe Aortic Stenosis Registry; UMIN000012140

化学療法施行中のオピオイド使用による便秘に対するルビプロストンの有用性

　当科において2014年10月から2016年２月に入院で化学療法を施行し，がん性疼痛に対して使用したオピオイドにより誘発された便秘に対してルビプロストンを投与した全症例を対象とした．対照群は，当院のルビプロストン採用以前の2012年４月から2014年９月まで，化学療法施行中にオピオイドを使用した患者に緩下薬を使用していた全症例とした．ルビプロストンを追加してからの排便回数と食事量の変化を後方視的に解析した．対照群の排便回数と食事量の変化は，新たな緩下薬（センノシド，ピコスルファートナトリウム，または大建中湯）の追加または酸化マグネシウムを増量した前後を基準とした．ルビプロストン使用群７人，未使用の対照群12人で，オキシコドン換算の使用量中央値（範囲）は対照群で10.0（10.0～62.9）mg，ルビプロストン群で39.3（10.0～125.7）mg であった（P=0.103）．ルビプロストン群ではその投与翌日に７例中６人，対照群においては12例中３例で排便が認められた（P<0.05）．ルビプロストン群においては排便があった翌日の食事摂取量は７例中６例，対照群は12例中３例で改善していた（P<0.05）．化学療法施行中にもオピオイドによる便秘に対するルビプロストンが有用であることが示唆された．　Lubiprostone is a useful treatment for opioid-induced constipation (OIC); however, it is not known whether the treatment is suitable for OIC in patients undergoing cancer chemotherapy. This study evaluated hospitalized patients receiving cancer chemotherapy in whom OIC was treated with lubiprostone between October 2014 and February 2016. The control group consisted of OIC + chemotherapy patients who were hospitalized between April 2012 and September 2014, before lubiprostone was approved for use at our hospital. Frequency of stool and food intake were retrospectively evaluated before and after treatment with lubiprostone (lubiprostone group; n=7) or other laxative agent (control group; n=12). Other laxative agents included sennoside, sodium picosulfate, daikenchuto or magnesia. The lubiprostone and control groups both received oxycodone (median [range]: 39.3 [10.0-125.7] mg vs 10.0 [10.0-62.9] mg; P=0.103). The day following treatment, defecation was observed in 6 of 7 patients in the lubiprostone group and 3 of 12 patients in the control group (P<0.05). Dietary intake also increased in 6 of 7 patients in the lubiprostone group and 3 of 12 patients in the control group (P<0.05). Therefore, lubiprostone may be an effective treatment for OIC during chemotherapy