Prognostic significance of hypertension history and blood pressure on admission in Japanese patients with coronavirus disease 2019: integrative analysis from the Japan COVID-19 Task Force.

The effect of preexisting hypertension on coronavirus disease 2019 (COVID-19) prognosis remains controversial. Additionally, no studies have compared the association between blood pressure (BP) indices on admission and COVID-19 outcomes using preexisting hypertension status. Therefore, this study aimed to investigate the association between preexisting hypertension and COVID-19 outcomes in Japanese patients with COVID-19 and assess the impact of BP indices on admission on clinical outcomes in patients with and without preexisting hypertension. Preexisting hypertension presence was confirmed based on the patient's clinical history. Critical outcomes were defined as high-flow oxygen use, non-invasive and invasive positive-pressure ventilation, extracorporeal membrane oxygenation, or death during hospitalization. Preexisting hypertension was observed in 64.6% of the patients. Multivariable logistic regression analysis of severe COVID-19 risk factors indicated that preexisting hypertension was independently associated with critical outcomes [adjusted odds ratio (OR): 1.35; 95% confidence interval (CI): 1.05-1.73]. Low or high BP and high pulse pressure on admission were associated with critical outcomes in patients without preexisting hypertension [OR for systolic BP < 100 mmHg: 2.13, 95% CI: 1.21-3.75; OR for high BP stage 2 (160-179 systolic and/or 100-109 mmHg diastolic BP): 2.13, 95% CI: 1.27-3.58; OR for pulse pressure ≥60 mmHg: 1.68, 95% CI: 1.14-2.48]. Preexisting hypertension is a risk factor for critical outcomes in Japanese patients with COVID-19. BP indices are useful biomarkers for predicting COVID-19 outcomes, particularly in patients without preexisting hypertension. Thus, hypertension history, systolic BP, and pulse pressure should be assessed to predict severe COVID-19 outcomes.

Comprehensive analysis of long COVID in a Japanese nationwide prospective cohort study.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly since 2019, and the number of reports regarding long COVID has increased. Although the distribution of long COVID depends on patient characteristics, epidemiological data on Japanese patients are limited. Hence, this study aimed to investigate the distribution of long COVID in Japanese patients. This study is the first nationwide Japanese prospective cohort study on long COVID. METHODS: This multicenter, prospective cohort study enrolled hospitalized COVID-19 patients aged ≥18 years at 26 Japanese medical institutions. In total, 1200 patients were enrolled. Clinical information and patient-reported outcomes were collected from medical records, paper questionnaires, and smartphone applications. RESULTS: We collected data from 1066 cases with both medical records and patient-reported outcomes. The proportion of patients with at least one symptom decreased chronologically from 93.9% (947/1009) during hospitalization to 46.3% (433/935), 40.5% (350/865), and 33.0% (239/724) at 3, 6, and 12 months, respectively. Patients with at least one long COVID symptom showed lower quality of life and scored higher on assessments for depression, anxiety, and fear of COVID-19. Female sex, middle age (41-64 years), oxygen requirement, and critical condition during hospitalization were risk factors for long COVID. CONCLUSIONS: This study elucidated the symptom distribution and risks of long COVID in the Japanese population. This study provides reference data for future studies of long COVID in Japan.

Association between ABO blood group/genotype and COVID-19 in a Japanese population.

An association between coronavirus disease 2019 (COVID-19) and the ABO blood group has been reported. However, such an association has not been studied in the Japanese population on a large scale. Little is known about the association between COVID-19 and ABO genotype. This study investigated the association between COVID-19 and ABO blood group/genotype in a large Japanese population. All Japanese patients diagnosed with COVID-19 were recruited through the Japan COVID-19 Task Force between February 2020 and October 2021. We conducted a retrospective cohort study involving 1790 Japanese COVID-19 patients whose DNA was used for a genome-wide association study. We compared the ABO blood group/genotype in a healthy population (n = 611, control) and COVID-19 patients and then analyzed their associations and clinical outcomes. Blood group A was significantly more prevalent (41.6% vs. 36.8%; P = 0.038), and group O was significantly less prevalent (26.2% vs. 30.8%; P = 0.028) in the COVID-19 group than in the control group. Moreover, genotype OO was significantly less common in the COVID-19 group. Furthermore, blood group AB was identified as an independent risk factor for most severe diseases compared with blood group O [aOR (95% CI) = 1.84 (1.00-3.37)]. In ABO genotype analysis, only genotype AB was an independent risk factor for most severe diseases compared with genotype OO. Blood group O is protective, whereas group A is associated with the risk of infection. Moreover, blood group AB is associated with the risk of the "most" severe disease.

Propensity-Score Matched Analysis of the Effectiveness of Baricitinib in Patients With Coronavirus Disease 2019 (COVID-19) Using Nationwide Real-World Data: An Observational Matched Cohort Study From the Japan COVID-19 Task Force.

Background: To determine the effectiveness of baricitinib in patients with coronavirus disease 2019 (COVID-19), investigate whether baricitinib prevents the need for invasive mechanical ventilation and identify patient subgroups that would benefit from baricitinib. Methods: This observational matched-cohort study was conducted by the Japan COVID-19 Task Force, a nationwide multicenter consortium. Patients with COVID-19 aged ≥18 years were identified from 70 hospitals in Japan. Among patients with confirmed COVID-19 from February 2020 to September 2021, those receiving baricitinib were propensity-score matched with controls. Results: Among 3309 patients, 144 propensity score-matched pairs were identified. Thirteen (9.0%) patients in the baricitinib group and 27 (18.8%) in the control group required invasive mechanical ventilation during the disease course (odds ratio, 0.43). Although the baricitinib group had more severe disease, there were no significant differences in the intensive care unit admission rates (odds ratio, 1.16) and mortality rates (odds ratio, 0.74) between groups. In subgroup analyses, baricitinib was associated with a significant reduction in the need for invasive mechanical ventilation in patients requiring oxygen support (odds ratio, 0.28), with rapid shadow spread on chest radiography (odds ratio, 0.11), or treated with remdesivir (odds ratio, 0.27), systemic corticosteroids (odds ratio, 0.31), or anticoagulants (odds ratio, 0.17). Conclusions: Baricitinib is effective at preventing the need for invasive mechanical ventilation in patients with COVID-19.

Differential impacts between fat mass index and fat-free mass index on patients with COPD.

BACKGROUND: Differences in the clinical impacts of fat mass index (FMI) and fat-free mass index (FFMI) remain unclear in patients with chronic obstructive pulmonary disease (COPD). We hypothesized that FMI and FFMI have different impacts on 1) emphysema and 2) pulmonary function and health-related quality of life of COPD patients. METHODS: Patients with COPD (n = 228), enrolled in a multicenter prospective 3-year cohort were classified into four groups based on baseline median FMI and FFMI values. Emphysema assessed as the ratio of low attenuation area to total lung volume (LAA%) on computed tomography, pulmonary function, and health-related quality of life assessed using the St. George's Respiratory Questionnaire (SGRQ) were compared. RESULTS: The four groups had statistically significant differences in LAA%, pulmonary function, and SGRQ scores. The Low FMI Low FFMI group exhibited the highest LAA%, lowest pulmonary function, and worst SGRQ scores among the four groups. In addition, these differences were consistent over 3 years. Multivariate analysis showed that low FMI was associated with high LAA%, low inspiratory capacity/total lung capacity (IC/TLC), and carbon monoxide transfer coefficient (KCO). In contrast, low FFMI was associated with these factors as well as worse SGRQ scores. CONCLUSION: FMI and FFMI have different effects on the clinical manifestations of COPD. Both low fat and muscle mass contributed to severe emphysema, whereas only low muscle mass contributed to worse health-related quality of life in patients with COPD.

Serum KL-6 levels predict clinical outcomes and are associated with MUC1 polymorphism in Japanese patients with COVID-19.

BACKGROUND: Krebs von den Lungen-6 (KL-6) is a known biomarker for diagnosis and monitoring of interstitial lung diseases. However, the role of serum KL-6 and the mucin 1 (MUC1) variant (rs4072037) in COVID-19 outcomes remains to be elucidated. We aimed to evaluate the relationships among serum KL-6 levels, critical outcomes and the MUC1 variant in Japanese patients with COVID-19. METHODS: This is a secondary analysis of a multicentre retrospective study using data from the Japan COVID-19 Task Force collected from February 2020 to November 2021, including 2226 patients with COVID-19 whose serum KL-6 levels were measured. An optimal serum KL-6 level cut-off to predict critical outcomes was determined and used for multivariable logistic regression analysis. Furthermore, the relationship among the allele dosage of the MUC1 variant, calculated from single nucleotide polymorphism typing data of genome-wide association studies using the imputation method, serum KL-6 levels and COVID-19 critical outcomes was evaluated. RESULTS: Serum KL-6 levels were significantly higher in patients with COVID-19 with critical outcomes (511±442 U/mL) than those without (279±204 U/mL) (p<0.001). Serum KL-6 levels ≥304 U/mL independently predicted critical outcomes (adjusted OR (aOR) 3.47, 95% CI 2.44 to 4.95). Moreover, multivariable logistic regression analysis with age and sex indicated that the MUC1 variant was independently associated with increased serum KL-6 levels (aOR 0.24, 95% CI 0.28 to 0.32) but not significantly associated with critical outcomes (aOR 1.11, 95% CI 0.80 to 1.54). CONCLUSION: Serum KL-6 levels predicted critical outcomes in Japanese patients with COVID-19 and were associated with the MUC1 variant. Therefore, serum KL-6 level is a potentially useful biomarker of critical COVID-19 outcomes.

Characteristics and clinical effectiveness of COVID-19 vaccination in hospitalized patients in Omicron-dominated epidemic wave - a nationwide study in Japan.

OBJECTIVES: COVID-19 was severe in the Delta variant-dominated epidemic wave (fifth wave) in Japan. The clinical characteristics and effectiveness of COVID-19 vaccination are not fully understood in the Omicron variant-dominated wave (sixth and seventh waves), especially in hospitalized patients. We investigated the relationship between vaccination and disease severity in the Omicron-dominated wave and compared these variant-dominated waves. METHODS: The nationwide COVID-19 database (Japan COVID-19 Task Force) was used to compare clinical characteristics and critical outcomes in patients hospitalized with Delta (fifth, N = 735) vs Omicron-dominated waves (sixth, N = 495; seventh, N = 128). RESULTS: Patients in the sixth and seventh waves had a lower incidence of critical outcomes and respiratory outcomes, and a higher incidence of bacterial infection, although the mortality rate did not differ significantly between waves. In the sixth and seventh waves, 138 (27.9%) and 29 (22.7%) patients with COVID-19 were unvaccinated, respectively. Multivariable analysis adjusted with previously reported factors revealed that the proportion of (1) critical outcomes and (2) respiratory outcomes decreased in a frequency-dependent manner. Thus, (1) (the number of vaccinations): 1-2 times: adjusted odds ratio (aOR) 0.37 (95% confidence interval [CI]; 0.20-0.69); 3-4 times: aOR 0.25 (95% CI; 0.11-0.58); and (2) 1-2 times: aOR 0.43 (95% CI; 0.27-0.66); 3-4 times: aOR 0.36 (95% CI; 0.21-0.60). CONCLUSIONS: Patients hospitalized with COVID-19 with Omicron infections showed a lower incidence of critical outcomes than those with Delta infections, and COVID-19 vaccination may contribute to preventing respiratory failure.

Golgi-Targeting Anticancer Natural Products.

The Golgi apparatus plays an important role in maintaining cell homeostasis by serving as a biosynthetic center for glycans, lipids and post-translationally modified proteins and as a sorting center for vesicular transport of proteins to specific destinations. Moreover, it provides a signaling hub that facilitates not only membrane trafficking processes but also cellular response pathways to various types of stresses. Altered signaling at the Golgi apparatus has emerged as a key regulator of tumor growth and survival. Among the small molecules that can specifically perturb or modulate Golgi proteins and organization, natural products with anticancer property have been identified as powerful chemical probes in deciphering Golgi-related pathways and, in particular, recently described Golgi stress response pathways. In this review, we highlight a set of Golgi-targeting natural products that enabled the characterization of the Golgi-mediated signaling events leading to cancer cell death and discuss the potential for selectively exploiting these pathways for the development of novel chemotherapeutic agents.

Elucidation of OSW-1-Induced Stress Responses in Neuro2a Cells.

OSW-1, a steroidal saponin isolated from the bulbs of Ornithogalum saundersiae, is a promising compound for an anticancer drug; however, its cytotoxic mechanisms have not been fully elucidated. Therefore, we analyzed the stress responses triggered by OSW-1 in the mouse neuroblastoma cell line Neuro2a by comparing it with brefeldin A (BFA), a Golgi apparatus-disrupting reagent. Among the Golgi stress sensors TFE3/TFEB and CREB3, OSW-1 induced dephosphorylation of TFE3/TFEB but not cleavage of CREB3, and induction of the ER stress-inducible genes GADD153 and GADD34 was slight. On the other hand, the induction of LC3-II, an autophagy marker, was more pronounced than the BFA stimulation. To elucidate OSW-1-induced gene expression, we performed a comprehensive gene analysis using a microarray method and observed changes in numerous genes involved in lipid metabolism, such as cholesterol, and in the regulation of the ER-Golgi apparatus. Abnormalities in ER-Golgi transport were also evident in the examination of secretory activity using NanoLuc-tag genes. Finally, we established Neuro2a cells lacking oxysterol-binding protein (OSBP), which were severely reduced by OSW-1, but found OSBP deficiency had little effect on OSW-1-induced cell death and the LC3-II/LC3-I ratio in Neuro2a cells. Future work to elucidate the relationship between OSW-1-induced atypical Golgi stress responses and autophagy induction may lead to the development of new anticancer agents.

Deciphering the Biological Activities of Antifungal Agents with Chemical Probes.

The growing number of fungal infections caused by pathogens resistant to one or more classes of antifungal drugs emphasizes the threat that these microorganisms pose to animal and human health and global food security. Open questions remain regarding the mechanisms of action of the limited repertoire of antifungal agents, making it challenging to rationally develop more efficacious therapeutics. In recent years, the use of chemical biology approaches has resolved some of these questions and has provided new promising concepts to guide the design of antifungal agents. By focusing on examples from studies carried out in recent years, this minireview describes the key roles that probes based on antifungal agents and their derivatives have played in uncovering details about their activities, in detecting resistance, and in characterizing the interactions between these agents and their targets.

Impact of upper and lower respiratory symptoms on COVID-19 outcomes: a multicenter retrospective cohort study.

BACKGROUND: Respiratory symptoms are associated with coronavirus disease 2019 (COVID-19) outcomes. However, the impacts of upper and lower respiratory symptoms on COVID-19 outcomes in the same population have not been compared. The objective of this study was to characterize upper and lower respiratory symptoms and compare their impacts on outcomes of hospitalized COVID-19 patients. METHODS: This was a multicenter, retrospective cohort study; the database from the Japan COVID-19 Task Force was used. A total of 3314 COVID-19 patients were included in the study, and the data on respiratory symptoms were collected. The participants were classified according to their respiratory symptoms (Group 1: no respiratory symptoms, Group 2: only upper respiratory symptoms, Group 3: only lower respiratory symptoms, and Group 4: both upper and lower respiratory symptoms). The impacts of upper and lower respiratory symptoms on the clinical outcomes were compared. The primary outcome was the percentage of patients with poor clinical outcomes, including the need for oxygen supplementation via high-flow oxygen therapy, mechanical ventilation, and extracorporeal membrane oxygenation or death. RESULTS: Of the 3314 COVID-19 patients, 605, 1331, 1229, and 1149 were classified as Group 1, Group 2, Group 3, and Group 4, respectively. In univariate analysis, patients in Group 2 had the best clinical outcomes among all groups (odds ratio [OR]: 0.21, 95% confidence interval [CI]: 0.11-0.39), while patients in Group 3 had the worst outcomes (OR: 3.27, 95% CI: 2.43-4.40). Group 3 patients had the highest incidence of pneumonia, other complications due to secondary infections, and thrombosis during the clinical course. CONCLUSIONS: Upper and lower respiratory tract symptoms had vastly different impacts on the clinical outcomes of COVID-19.

Short-term intermittent cigarette smoke exposure enhances alveolar type 2 cell stemness via fatty acid oxidation.

BACKGROUND: Cigarette smoke (CS) is associated with chronic obstructive pulmonary disease (COPD) and cancer. However, the underlying pathological mechanisms are not well understood. We recently reported that mice exposed to long-term intermittent CS for 3 months developed more severe emphysema and higher incidence of adenocarcinoma than mice exposed to long-term continuous CS for 3 months and long-term continuous CS exposure activated alveolar stem cell proliferation. However, the influence of variations in the CS exposure pattern in alveolar stem cell in unknown. Here, we exposed mice to 3 weeks of continuous or intermittent CS to identify whether different CS exposure patterns would result in differential effects on stem cells and the mechanisms underlying these potential differences. METHODS: Female mice expressing GFP in alveolar type 2 (AT2) cells, which are stem cells of the alveolar compartment, were exposed to mainstream CS via nasal inhalation. AT2 cells were collected based on their GFP expression by flow cytometry and co-cultured with fibroblasts in stem cell 3D organoid/colony-forming assays. We compared gene expression profiles of continuous and intermittent CS-exposed AT2 cells using microarray analysis and performed a functional assessment of a differentially expressed gene to confirm its involvement in the process using activator and inhibitor studies. RESULTS: AT2 cells sorted from intermittent CS-exposed mice formed significantly more colonies compared to those from continuous CS-exposed mice, and both CS-exposed groups formed significantly more colonies when compared to air-exposed cells. Comparative microarray analysis revealed the upregulation of genes related to fatty acid oxidation (FAO) pathways in AT2 cells from intermittent CS-exposed mice. Treatment of intermittent CS-exposed mice with etomoxir, an inhibitor of the FAO regulator Cpt1a, for 5 weeks resulted in a significant suppression of the efficiency of AT2 cell colony formation. In vitro treatment of naïve AT2 cells with a FAO activator and inhibitor further confirmed the relationship between FAO and AT2 stem cell function. CONCLUSIONS: Alveolar stem cell function was more strongly activated by intermittent CS exposure than by continuous CS exposure. We provide evidence that AT2 stem cells respond to intermittent CS exposure by activating stem cell proliferation via the activation of FAO.

Reactivity Analysis of New Multivalent Electrophilic Probes for Affinity Labeling of Carbohydrate Binding Proteins.

We have designed and synthesized six different multivalent electrophiles as carbohydrate affinity labeling probes. Evaluation of the reactivity of the electrophiles against peanut agglutinin (PNA) and Ricinus communis agglutinin (RCA) showed that p- and m-aryl sulfonyl fluoride are effective protein reactive groups that label carbohydrate binding lectins in a ligand-dependent fashion at a nanomolar probe concentration. Analysis of the selectivity of affinity labeling in the presence of excess BSA as a nonspecific protein indicated that m-arylsulfonyl fluoride is a more selective protein-reactive group, albeit with attenuated reactivity. Further analysis showed that the labeling efficiency of the multivalent electrophilic probes can be improved by employing reaction conditions involving 25 °C instead of typically employed 4 °C. Both isomers of arylsulfonyl fluoride groups together represent promising affinity labels for target identification studies that could serve as more efficient alternatives to photoreactive groups.

Clinical Utility of the Electrocardiographic P-Wave Axis in Patients with Chronic Obstructive Pulmonary Disease.

BACKGROUND: The vertical P-wave axis on electrocardiography (ECG) is a useful criterion for screening patients with chronic obstructive pulmonary disease (COPD). This study aimed to investigate the clinical characteristics of patients with COPD with a vertical P-wave axis as they have not yet been elucidated. METHODS: Keio University and its affiliated hospitals conducted an observational COPD cohort study over 3 years. We analyzed 201 patients using ECG and chest computed tomography. RESULTS: The severity of airflow limitation was higher in patients with a P-wave axis >75° than in those with a P-wave axis ≤75°. Patients with a P-wave axis >75° exhibited significantly higher total COPD assessment test scores and increased St. George's Respiratory Questionnaire total, activity, and impact scores than those with a P-wave axis ≤75°. The incidence of exacerbations over 1 and 3 years was significantly higher in patients with a P-wave axis >75° than in those with a P-wave axis ≤75°. The optimal cutoff for the P-wave axis for a percentage of the predicted forced expiratory volume in 1 s <50% and future exacerbations over 3 years was 70° (the areas under the curve [AUC]: 0.788; sensitivity: 65.3%; specificity: 78.3%) and 79° (AUC: 0.642; sensitivity: 36.7%; specificity: 92.6%). The ratio of the low attenuation area was also significantly higher in patients with a P-wave axis >75° than in those with a P-wave axis ≤75°. However, the ratio of the airway wall area did not differ between the 2 groups. CONCLUSIONS: Patients with COPD with a vertical P-wave axis exhibited severe airflow limitation and emphysema, a worse health status, and more frequent exacerbation than patients without a vertical P-wave. Detection of the vertical P-wave axis by ECG is beneficial for the management of patients with COPD.

Exploration of the Reactivity of Multivalent Electrophiles for Affinity Labeling: Sulfonyl Fluoride as a Highly Efficient and Selective Label.

Here we explored the reactivity of a set of multivalent electrophiles cofunctionalized with a carbohydrate ligand on gold nanoparticles to achieve efficient affinity labeling for target protein analysis. Evaluation of the reactivity and selectivity of the electrophiles against three different cognate binding proteins identified arylsulfonyl fluoride as the most efficient protein-reactive group in this study. We demonstrated that multivalent arylsulfonyl fluoride probe 4 at 50 nm concentration achieved selective affinity labeling and enrichment of a model protein PNA in cell lysate, which was more effective than photoaffinity probe 1 with arylazide group. Labeling site analysis by LC-MS/MS revealed that the nanoparticle-immobilized arylsulfonyl fluoride group can target multiple amino acid residues around the ligand binding site of the target proteins. Our study highlights the utility of arylsulfonyl fluoride as a highly effective multivalent affinity label suitable for covalently capturing unknown target proteins.

Clickable gold-nanoparticles as generic probe precursors for facile photoaffinity labeling application.

Rapid access to appropriately functionalized probes is crucial in chemical labeling approaches to target identification studies. We designed and synthesized clickable gold-nanoparticles as generic probe precursors that enable (1) one-step ligand derivatization by click chemistry, and (2) facile photoaffinity labeling application. Using cholesterol as a model ligand, we successfully demonstrated the utility of the ligand-clicked probe in photoaffinity labeling of endogenously expressed oxysterol-binding protein (OSBP) in cell lysate.

Interactions of OSW-1 with Lipid Bilayers in Comparison with Digitonin and Soyasaponin.

OSW-1, a unique steroidal saponin isolated from the bulbs of Ornithogalum saundersiae, has potent cell-growth inhibition activity. In this study, we conducted fluorescence measurements and microscopic observations using palmitoyloleoylphosphatidylcholine (POPC)-cholesterol (Chol) bilayers to evaluate the membrane-binding affinity of OSW-1 in comparison with another steroidal saponin, digitonin, and the triterpenoid saponin, soyasaponin Bb(I). The membrane activities of these saponins were evaluated using calcein leakage assays and fitted to the binding isotherm by changing the ratios of saponin-lipids. Digitonin showed the highest binding affinity for the POPC-Chol membrane (Kapp = 0.38 µM-1) and the strongest membrane disruptivity in the bound saponin-lipid ratio at the point of 50% calcein leakage (r50 = 0.47) occurrence. OSW-1 showed slightly lower activity (Kapp = 0.31 µM-1; r50 = 0.78), and the soyasaponin was the lowest in the membrane affinity and the calcein leakage activity (Kapp = 0.017 µM-1; r50 = 1.66). The effect of OSW-1 was further assessed using confocal microscopy in an experiment utilizing DiI and rhodamine 6G as the fluorescence probes. The addition of 30 µM OSW-1 induced inward membrane curvature in some giant unilamellar vesicles (GUVs). At the higher OSW-1 concentration (58 µM, r50 = 0.78) where the 50% calcein leakage was observed, the morphology of some GUVs became elongated. With digitonin at the corresponding concentration (35 µM, r50 = 0.47), membrane disruption and formation of large aggregates in aqueous solution were observed, probably due to a detergent-type mechanism. These saponins, including OSW-1, required Chol to exhibit their potent membrane activity although their mechanisms are thought to be different. At the effective concentration, OSW-1 preferably binds to the bilayers without prominent disruption of vesicles and exerts its activity through the formation of saponin-Chol complexes, probably resulting in membrane permeabilization.

Characteristics of Chronic Obstructive Pulmonary Disease Patients with Pulmonary Hypertension Assessed by Echocardiography in a Three-Year Observational Cohort Study.

Background: Pulmonary hypertension (PH) is a major comorbidity of chronic obstructive pulmonary disease (COPD). However, the association of PH detected by echocardiography and COPD-related outcome in longitudinal follow-up has not been elucidated. In this study, we aimed to investigate the relationship between clinical characteristics of COPD patients with PH detected by echocardiography and various outcome parameters such as COPD exacerbation and health status over a three-year observation period. Methods: In this observational study, we analyzed patients with COPD who underwent chest computed tomography and echocardiography at baseline (n = 183). Results: The prevalence of PH was 21.9% (40 patients). The median estimated systolic pulmonary artery pressure in patients with PH was 38.8 mmHg. COPD patients with PH were older, had a lower body mass index, scored worse in the COPD Assessment Test and St. George's Respiratory Questionnaire, and exhibited a lower diffusing capacity of the lung for carbon monoxide in comparison to patients without PH. In computed tomography images, the percentages of low-attenuation areas (LAA%) and interstitial abnormalities were higher in COPD patients with PH than in those without PH. Higher values for LAA% (LAA ≥ 30%) and interstitial abnormalities independently increased the risk of PH. The ratio of main pulmonary diameter to aortic artery diameter was significantly correlated with estimated systolic pulmonary artery pressure. In the follow-up analysis, the frequency of exacerbations in three years was significantly higher in patients with PH compared to patients without PH. Conclusion: In this study, we identified the clinical characteristics of COPD patients with PH detected by echocardiography. The presence of PH assessed by echocardiography was related to future COPD exacerbations and closely related to radiographical emphysema.

Phospholipid-Dependent Functions of a Macrocyclic Analogue of the Ion-Channel-Forming Antibiotic Gramicidin A.

An ion-channel-forming natural peptide, gramicidin A (1), exhibits potent antimicrobial activity against Gram-positive bacteria, although medical applications are limited to topical use due to its mammalian cytotoxicity. We recently reported that the artificial macrocyclic analogue 2 provides a promising starting point for developing new ion-channel-based systemic antibacterial agents because of its low mammalian cytotoxicity compared to that of the parent 1. To dissect the molecular factors involved in the species selectivity of 2, we evaluated the ion transport activities, phospholipid affinities, and conformational properties of 1 and 2 using various compositions of phospholipids. A combination of lipid dot blot assays and circular dichroism (CD) analysis with H+/Na+ exchange assays revealed that the higher H+/Na+ exchange activity of 2 than that of 1 in liposomes containing 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (POPC) or 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (POPG) is attributable to its higher affinity towards the phospholipids than that of 1. Notably, we also discovered that 2 showed weaker H+/Na+ exchange activity in liposomes containing 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylethanolamine (POPE). CD analysis of 2 in liposomes indicated that the weak H+/Na+ exchange activity is induced by disturbance of the ion-conducting ß6.3-helical conformation in the POPE-containing lipid bilayer. These results suggest that the POPE-induced attenuation of the ion-conducting activity of 2 contributes to the alleviation of undesirable mammalian cytotoxicity of 2 compared to that of 1.