Clinical significance of aortic spontaneous echo contrast in patients with nonvalvular atrial fibrillation.

BACKGROUND: Little is known about spontaneous echo contrast (SEC) in the descending aorta (DASEC), occurring with or without SEC in the left atrium (LASEC), in the presence of atrial fibrillation (AF). We examined the clinical significance of DASEC, including its relationship with LASEC, in patients with nonvalvular AF. METHODS: Among 176 patients, 41 (23%) had DASEC and 51 (29%) had LASEC. The patients were divided into four groups based on the presence/absence of LASEC and DASEC, as Group A: no SEC (n = 107); Group B: only LASEC (n = 28); Group C: only DASEC (n = 18); and Group D: both types of SEC (n = 23). Clinical and echocardiographic parameters were compared between groups, and the possible determinants of DASEC were evaluated. RESULTS: Age, sex, and CHA2 DS2 -VASc score were similar in the four groups. Group D was more likely to have an increased LA diameter, decreased left ventricular ejection fraction (LVEF), and low LA appendage velocity compared to Group A. Group C had a smaller LA diameter and a higher appendage velocity than Group B. Multivariate logistic regression analysis, with age ≥75 years, female sex, LASEC, LVEF < 50%, and presence of DA plaques included as covariates, showed that LASEC (OR 4.22, 95% CI 1.92-9.26, p < .001) and LVEF < 50% (OR 2.70, 95% CI 1.12-6.52, p = .027) were significant determinants of DASEC. The prevalence of DASEC increased with increasing LASEC severity in order of none (13%), mild (28%), and dense (50%) (p < .001). CONCLUSIONS: In nonvalvular AF patients, DASEC is common, and it partly originates from LASEC, particularly in the presence of LV systolic dysfunction.

Left Atrial Remodeling Related to Disproportionately Low B-Type Natriuretic Peptide in Acute Heart Failure Patients with Atrial Fibrillation.

The diagnostic performance of B-type natriuretic peptide (BNP) for acute heart failure (HF) is impaired in patients with atrial fibrillation (AF). Increased AF burden in HF is associated with left atrial (LA) remodeling. Recent studies have revealed that LA remodeling may affect LV filling. We hypothesized that LA remodeling affects BNP secretion in acute HF conditions. The study investigated the clinical impact of LA remodeling on admission BNP levels in acute HF patients with and without AF. Consecutive acute HF hospitalized patients (n = 899) were divided into groups with (n = 382) or without AF (n = 507) and subdivided into disproportionately low BNP (LB) (≤200 pg/ml), medium BNP (200 to 600 pg/ml) and high BNP (≥600 pg/ml) subgroups. The AF group had a higher proportion of patients with LB than the non-AF group (23.6% vs 16.6%, p = 0.009). BNP levels in both groups were positively correlated with LV end-diastolic volume and negatively correlated with LV ejection fraction in both groups. In contrast, BNP was positively correlated with LA volume index in the non-AF group, but negatively correlated in the AF group. The survival rates were significantly higher in the LB group than in the other groups in non-AF. Conversely, there were no significant differences across all groups in AF patients. In conclusion, in patients with acute HF and AF, disproportionately low BNP levels are associated with LA structural remodeling and poor prognosis.

Prognostic impact of a reduction in the fibrosis-4 index among patients hospitalized with acute heart failure.

Although the fibrosis-4 index (FIB-4) is associated with right atrial pressure or prognosis in acute heart failure (AHF), the prognostic impact of its reduction during hospitalization remains uncertain. We included 877 patients (age, 74.9 ± 12.0 years; 58% male) hospitalized with AHF. The reduction in FIB-4 was defined as: (FIB-4 on admission-FIB-4 at discharge)/FIB-4 on admission × 100. Patients were divided into low (< 1.0%, n = 293), middle (1.0-27.4%, n = 292), and high (> 27.4%, n = 292) FIB-4 reduction groups. The primary outcome was a composite of all-cause death or heart failure rehospitalization within 180 days. The median FIB-4 reduction was 14.7% (interquartile range - 7.8-34.9%). The primary outcome was observed in 79 (27.0%), 63 (21.6%), and 41 (14.0%) patients in the low, middle, and high FIB-4 reduction groups, respectively (P = 0.001). Adjusted Cox proportional-hazards analysis revealed that the middle and low FIB-4 reduction groups were associated with the primary outcome, independent of the pre-existing risk model including baseline FIB-4 ([high vs. middle] hazard ratio [HR]: 1.70, 95% confidence interval [CI]: 1.10-2,63, P = 0.017; [high vs. low] HR: 2.16, 95% CI 1.41-3.32, P < 0.001). FIB-4 reduction provided additional prognostic value to the baseline model, including well-known prognostic factors ([continuous net reclassification improvement] 0.304; 95% CI 0.139-0.464; P < 0.001; [integrated discrimination improvement] 0.011; 95% CI 0.004-0.017; P = 0.001). Additionally, the combination of the reduction in FIB-4 and brain natriuretic peptide was useful for risk stratification. In conclusion, among patients hospitalized with AHF, a greater FIB-4 reduction during hospitalization was associated with better prognoses.

Prognostic Impact of Multiple Drug Use at Discharge in Patients Hospitalized with Heart Failure.

The association between polypharmacy/multiple drug use (MDU) and prognosis in patients hospitalized with heart failure (HF) is unclear. It is also unknown whether the prognostic values of MDU vary depending on the presence/absence of a previous history of HF and preserved/reduced left ventricular ejection fraction (LVEF). We analyzed consecutive 1,034 patients hospitalized with HF (age, 74.9 ± 11.5 years; 58.7% male). MDU was defined as ≥5 drugs at discharge. The primary endpoint was a composite of all-cause death and HF readmission. MDU was observed in 695 patients (67.2%). Patients with MDU use had higher prevalences of a previous history of HF, reduced LVEF, and comorbidities than those without MDU. Cox proportional hazard analysis showed that MDU was significantly associated with the primary endpoint after adjustment for possible confounders (hazard ratio [HR], 1.36; 95% confidence interval [CI], 1.03-1.79; P = 0.030). There was significant interaction between the presence/absence of a history of HF and the prognostic impact of MDU (HF history [-]: HR, 0.86; 95% CI, 0.54-1.40; P = 0.553; HF history [+]: HR, 1.72; 95% CI, 1.16-2.55; P = 0.007; P for interaction = 0.005). However, there was no significant interaction between preserved/reduced LVEF and the prognostic impact of MDU (P for interaction = 0.274). In conclusion, MDU at discharge is an independent risk factor for the composite of death or HF readmission in patients hospitalized with HF. We observed a significant interaction between the presence of de novo versus recurrent HF and the prognostic value of MDU.

Fibrosis-4 index identifies worsening renal function associated with adverse outcomes in acute heart failure.

AIMS: Worsening renal function (WRF) often develops during heart failure (HF) treatment. However, prognostic implications of WRF in acute HF remain controversial, and risk stratification of WRF is challenging. Although the fibrosis-4 index (FIB-4) was initially established as a liver fibrosis marker, recent studies show that high FIB-4 is associated with venous congestion and poor prognosis in acute HF. This study aimed to evaluate whether FIB-4 could identify prognostically relevant and non-relevant WRF in patients with acute HF. METHODS AND RESULTS: We retrospectively analysed data from a single-centre registry on acute HF at our university hospital between January 2015 and June 2021. This study included patients with acute HF aged ≥20 years who were immediately hospitalized and had brain natriuretic peptide levels ≥100 pg/mL at admission. WRF was defined as increases of ≥0.3 mg/dL and >25% in serum creatinine level from admission to discharge. FIB-4 scores were calculated before discharge. The primary endpoint was all-cause mortality within 1 year of discharge. Based on the presence of WRF and whether FIB-4 scores were above the median, patients were stratified into four groups: no WRF and lower FIB-4 scores, no WRF and higher FIB-4 scores, WRF and lower FIB-4 scores, and WRF and higher FIB-4 scores. The patients were followed up via clinical visits or telephone interviews. Clinical outcomes were collected from the electronic medical records. RESULTS: Of the 969 patients hospitalized for acute HF (76 ± 11 years, 59% men), 118 patients (12%) had WRF at discharge. The median (interquartile range) FIB-4 score at discharge was 2.36 (1.55-3.25). The primary endpoint occurred in 136 patients (14.0%). The 1 year mortality rates were 10.5% in the no WRF and lower FIB-4 scores (≤2.36) group (n = 428), 16.1% in the no WRF and higher FIB-4 scores (>2.36) group (n = 423), 12.5% in the WRF and lower FIB-4 scores group (n = 56), and 25.8% in the WRF and higher FIB-4 scores group (n = 62) (P = 0.005). Kaplan-Meier analysis demonstrated higher all-cause mortality in the WRF and higher FIB-4 group (log-rank P = 0.003). In the Cox regression analysis, only the WRF and higher FIB-4 scores group was associated with an increased risk of mortality compared with the no WRF and lower FIB-4 scores group (hazard ratio = 2.11, 95% confidence interval: 1.07-4.18, P = 0.032), despite adjusting for other confounding factors. CONCLUSIONS: FIB-4 is a valuable risk stratification marker for WRF in patients with acute HF. The underlying mechanism and potential clinical importance of these observations require further investigation.

Prognostic Value of the FAN Score, a Combination of the Fibrosis-4 Index, Albumin-Bilirubin Score and Neutrophil-Lymphocyte Ratio, in Patients Hospitalized with Heart Failure.

The fibrosis-4 index, albumin-bilirubin score and neutrophil-lymphocyte ratio are all prognostic markers in patients with heart failure. Recently, the FAN score, which includes all 3 of these markers, was developed as a useful risk stratification tool in patients with cancer. However, its cut-off values have not been validated for heart failure. We aimed to investigate the optimal cut-off and prognostic values of the FAN score in patients with heart failure. We analyzed 669 consecutive patients hospitalized with heart failure (age, 75.8 ± 11.3 years). Their median values of the fibrosis-4 index, albumin-bilirubin score, and neutrophil-lymphocyte ratio at discharge were 2.12, -2.25, and 2.41, respectively. The FAN score for heart failure (HF-FAN score) was calculated using these median values. The primary outcome was a composite of all-cause death and heart failure rehospitalization. Patients were divided into 4 groups according to HF-FAN scores of 0 (n = 112), 1 (n = 231), 2 (n = 242) and 3 (n = 84). Patients with HF-FAN scores of 3 were older, had higher brain natriuretic peptide levels, and larger inferior vena cava diameters. Kaplan-Meier analysis showed a direct correlation between higher HF-FAN scores and occurrence of the primary endpoint (log-rank P < 0.001). Cox proportional hazard analysis revealed a higher HF-FAN score was significantly associated with a worse prognosis even after adjustment for possible prognostic factors. Changing from the FAN score to HF-FAN score provided significant continuous net reclassification improvement. In conclusion, the HF-FAN score at discharge was useful for risk stratification in patients hospitalized with heart failure. The HF-FAN score might be more suitable for patients with heart failure than the FAN score.

Relationship of warfarin versus DOACs with thrombogenic milieu in the left atrium among patients with nonvalvular atrial fibrillation.

BACKGROUND: Thrombogenic milieu (TM) within the left atrium plays a pivotal role in the pathogenesis of thromboembolic events, for which anticoagulation treatment is indicated typically on the mandatory basis. Little is known, however, about which regimen of anticoagulation, warfarin or direct oral anticoagulants (DOACs), is more likely associated with TM. We evaluated relative relationship of the two treatment options with concurrently-observed TM in patients with nonvalvular atrial fibrillation (AF) who underwent transesophageal echocardiography. METHODS: TM was defined as the presence of either left atrial spontaneous echo contrast (SEC) or thrombus, or both. To determine which regimen was more likely related to TM, we firstly compared the prevalence of TM in 208 patients taking warfarin (Warfarin group) versus 486 patients taking DOACs (DOAC group); and secondly, did the same analysis after propensity score matching. RESULTS: Warfarin group was more likely associated with TM compared with DOAC group (46% vs 29%, p < 0.001). Similar findings were observed for dense SEC (18% vs 7%, p < 0.001) and thrombus (4% vs 1%, p = 0.057). The propensity score matching (198 patients for each group), where several baseline parameters were matched including age, gender, chronicity of AF, estimated glomerular filtration rate and B-type natriuretic peptide as well as the left ventricular ejection fraction, resulted in similar findings to the original groups (TM, 47% vs 32%, p = 0.002; dense SEC, 18% vs 7%, p = 0.001; thrombus, 4% vs 1%, p = 0.047). CONCLUSIONS: This study may strengthen the data on randomized trials that DOACs are superior to warfarin in preventing thromboembolic events in nonvalvular AF patients. Further studies are required to elucidate the details behind this difference.

Prognostic value of the liver fibrosis marker fibrosis-5 index in patients with acute heart failure.

AIMS: Recently, liver fibrosis markers, such as the fibrosis-4 index (FIB-4), have been shown to be associated with prognosis in patients with heart failure. The fibrosis-5 (FIB-5) index, which assesses albumin, alkaline phosphatase, aspartate transaminase, alanine aminotransferase and platelet count, is a simple liver fibrosis marker that was reported to be superior to FIB-4 for differentiation of liver fibrosis. This study aimed to compare the prognostic value of FIB-4 and FIB-5 in patients with heart failure. METHODS AND RESULTS: The FIB-4 and FIB-5 scores were calculated at discharge in 906 patients hospitalized with heart failure. The patients were stratified into three groups based on their FIB-5 scores: low (n = 303), middle (n = 301), and high (n = 302) FIB-5 groups. The primary endpoint was a composite of cardiac death or rehospitalization for heart failure. The low FIB-5 group was older and had larger inferior vena cava diameters and higher brain natriuretic peptide levels than the other two groups. The primary endpoint occurred in 156 (51.5%), 110 (36.5%), and 54 patients (17.9%) in the low, middle, and high FIB-5 groups, respectively (P < 0.001). On Cox proportional hazard analysis, the low FIB-5 was independently associated with the primary endpoint after adjustment for confounding factors. The association was consistent in both patients with preserved and reduced left ventricular ejection fraction (LVEF), and there was no significant interaction between LVEF phenotypes in terms of the prognostic impact of FIB-5 (P for interaction = 0.311). FIB-5 was superior to FIB-4 as a prognostic indicator of the primary endpoint (continuous net reclassification improvement, 0.530; 95% confidence interval [CI], 0.399-0.662; P < 0.001; integrated discrimination improvement, 0.072; 95% CI, 0.057-0.088; P < 0.001). CONCLUSIONS: The FIB-5 is a useful risk stratification marker with better prognostic value than FIB-4 in patients hospitalized with heart failure.

Hypoplastic Left Atrial Appendage: A Case Report and Literature Review.

BACKGROUND The left atrial appendage (LAA) has considerable variations in its size, shape, and spatial relationship with other cardiac structures. Absence of the LAA is a congenital cardiac condition usually identified by an imaging modality intended for other purposes. Absence of the LAA has been described in a total of 19 case reports so far; however, no cases of "hypoplastic" LAA in a real sense have ever been reported. CASE REPORT We herein report a case of hypoplastic, but not truly absent, LAA in a 76-year-old man scheduled for catheter ablation against atrial flutter. Preprocedural transesophageal echocardiography (TEE) performed in this patient to exclude intracardiac thrombosis failed to detect the LAA, although Doppler color-flow mapping revealed a jet signal spewed out into the main LA around where the LAA would be located. The LAA was also not detectable by routinely developed tomographic images from computed tomography (CT) angiography. Eventually, however, the multiplanar reconstruction into 3-dimensional volume rendering via the CT angiography identified a very small LAA. Those findings by TEE and CT led to a diagnosis of hypoplastic LAA. CONCLUSIONS Hypoplastic LAA should be kept in mind when considering LAA interventions as well as anticoagulation treatment. Multiple imaging modalities are necessary to recognize morphological aberration of the LAA.

The effects of cisplatin, an emetic agent, on behavior and plasma cortisol levels in goats.

Ruminants are not considered to experience nausea because they do not possess the emetic reflex. This study examined the effects of administration of cisplatin (cis-diamminedichloro platinum (II): CDDP), a common emetic agent, on the behavior of goats. In Experiment 1, adult Shiba goats received intravenous (IV) administration of CDDP. CDDP-administered goats spent a shorter time feeding (P < 0.01), lied down earlier (P < 0.01), and spent a longer period lying down (P < 0.01) than the saline-administered control goats, and sometimes, they directed their face downward and close their eyes. These behavioral responses were followed by a significant (P < 0.01) increase in plasma cortisol (Cor) levels, which indicated that goats experienced stress. The dose dependency was found in the extent of the CDDP effects. In Experiment 2, the effects of pretreatment of ondansetron (Ond), an antiemetic agent, were examined. Pretreatment of Ond extended the latency of lying (P < 0.01), shortened the time spent lying (P < 0.05), and reduced the extent of the increase in plasma Cor levels (P < 0.01). These results suggested that CDDP administration generated some state of stress in goats via the similar physiological mechanisms as emesis-caused stress in emetic species.

Left Atrial Appendage Ostial Stenosis: A Case Report and Literature Review.

BACKGROUND Left atrial appendage (LAA) ostial stenosis is a rare cardiac condition usually identified by transesophageal echocardiography (TEE). LAA ostial stenosis can be classified into 2 types: one is idiopathic and the other is a complication after incomplete surgical LAA ligation. The former one is even rarer and only 12 cases have previously been reported. CASE REPORT An asymptomatic young woman was found at a medical checkup to have an abnormal jet signal in the left atrium on transthoracic echocardiography. TEE revealed that the abnormal signal originated from a narrowed orifice of the LAA. There were no other cardiac abnormalities in this woman. Unlike the previously reported cases, our case had LAA ostial stenosis detected by transthoracic echocardiography but not by TEE. CONCLUSIONS We describe a case of anatomic narrowing of the LAA orifice in a young woman. This was a first-ever case of idiopathic LAA ostial stenosis that was detected by transthoracic echocardiography. Because of the very small number of such cases reported, it remains unknown whether anticoagulation is required to prevent intra-atrial thrombus formation.

Non-target environmental analysis by liquid chromatography/high-resolution mass spectrometry with a product ion and neutral loss database.

Despite the increasing detection of emerging substances in the environment, the identity of most are left unknown due to the lack of efficient identification methods. We developed a non-target analysis method for identifying unknown substances in the environment by liquid chromatography/high-resolution mass spectrometry (LC/HRMS) with a product ion and neutral loss database (PNDB). The present analysis describes an elucidation method with elemental compositions of the molecules, product ions, and corresponding neutral losses of the unknown substance: (1) with the molecular formula, possible molecular structures are retrieved from two chemical structure databases (PubChem and ChemSpider); then (2) with the elemental compositions of product ions and neutral losses, possible partial structures are retrieved from the PNDB; and finally, (3) molecular structures that match the possible partial structures are listed in order of number of hits. A molecular structure with a higher number of hits is more similar to the structure of the analyzed substance. The performance of the non-target method was evaluated by simulated analysis of 150 LC/HRMS spectra registered in MassBank. First, all substances of the same mass data (41/41) and 68% (39/57) of the mass data of the same substances not registered in the PNDB were elucidated. It was demonstrated that 14% (7/52) and 31% (16/52) of the substances with no mass spectral data registered in the PNDB were obtained at the first and within the fifth place, respectively. Owing to the fact that 10 of the total hits occurred in product ions and neutral losses, almost 50% of the substances evaluated with this method were placed at the top 4 positions in the similarity ranking. Importantly, the proposed method is effective for analyzing mass spectral data that has not been registered in the PNDB and thus is expected to be used for a variety of non-target analyses.

Development of a rapid and comprehensive method for identifying organic micropollutants with high ecological risk to the aquatic environment.

Currently, tens-of-thousands of chemicals are used in Japan, and their presence in and impact on aquatic ecosystems are poorly understood. Because conventional risk evaluation processes using target analysis and biological tests are time-consuming and costly, it is challenging to investigate all substances. Therefore, we aimed to develop a rapid and highly efficient screening scheme for identifying hazardous organic micropollutants (OMPs) in aquatic ecosystems. The scheme is divided into two steps: chemical analysis and risk evaluation. First, a comprehensive screening method (CSM) using gas chromatography (GC)-mass spectrometry (MS) and a database containing nearly 1000 compounds is used to identify known compounds, and nontargeted analysis is carried out using a GC × GC-time-of-flight (TOF)MS to detect compounds not registered in the database. Secondly, the predicted toxicity values obtained by quantitative structure-activity relationship (QSAR) are used to evaluate and rank the ecological risk of each detected OMPs and to identify priority compounds for detailed survey. To assess the proposed scheme, we surveyed representative urban rivers in Japan and ranked the potential toxicity of the identified compounds. The total number of compounds detected in water from each river ranged from 29 to 87, and the total concentrations ranged from 2.3 to 63 µg L-1. Pharmaceuticals and personal care products, such as crotamiton and galaxolide, were identified in the urban rivers and found to have high ecotoxicity rankings. Thus, the scheme combining CSM and risk evaluation using QSAR is a novel screening that can identify candidates with high ecological risk in aquatic environment rapidly and efficiently.

Time-resolved characterization of organic compounds in PM2.5 collected at Oki Island, Japan, affected by transboundary pollution of biomass and non-biomass burning from Northeast China.

To evaluate the transboundary pollution of organic aerosols from Northeast Asia, a highly time-resolved measurement of organic compounds was performed in March 2019 at Oki Island located in Japan, which is a remote site and less affected by local anthropogenic sources. PM2.5, water-soluble organic carbon (WSOC) concentrations, and WSOC fraction in PM2.5 showed high values on March 22-23 (high-WSOC period (HWSOC)) when the air mass passed through the area where many fire spots were detected in Northeast China. Biomass burning tracers showed higher concentration, especially levoglucosan exceeded 1 µg/m3 during the HWSOC than the low-WSOC period (LWSOC). Notably, high time-resolved measurements of biomass burning tracers and back trajectory analysis during HWSOC revealed a difference in the variation of lignin pyrolyzed compounds and anhydrous sugars on 22 and 23 March. The air mass passed to different areas in Northeast China in which fire spots were detected, such as the eastern area on the 22nd and the western area on the 23rd. Almost-organic compounds also showed high concentration and strong correlations with levoglucosan and sulfate during HWSOC. Moreover, low-carbon dicarboxylic acids (e.g., adipic acid) and secondary products from anthropogenic volatile organic compounds (e.g., 2,3-dihydroxy-4-oxopentanoic, phthalic, 5-nitrosalicylic acids), also showed a strong correlation with sulfate ions during the HWSOC and LWSOC, respectively. These higher concentrations and strong correlations with levoglucosan and sulfate during the HWSOC propose that their generation could be enhanced by biomass burning. The ratios of organics (e.g., levoglucosan/mannnosan, pinic/3-methylbutane-1,2,3-tricarboxylic acids) suggest that the high concentrations of PM2.5 and WSOC observed during the HWSOC were caused by aged organic aerosols that originated from the combustion of herbaceous plants transported from Northeast China. Our findings indicate that biomass combustion in Northeast China could significantly affect the chemical compositions and the characterization of organic aerosols in downwind regions of Northeast China.

Reliability and validity of the Japanese version of the Ocular Surface Disease Index for dry eye disease.

OBJECTIVES: The Ocular Surface Disease Index (OSDI) questionnaire is widely used to evaluate subjective symptoms of dry eye disease (DED) as a primary diagnostic criterion. This study aimed to develop a Japanese version of the OSDI (J-OSDI) and assess its reliability and validity. DESIGN AND SETTING: Hospital-based cross-sectional observational study. PARTICIPANTS: A total of 209 patients recruited from the Department of Ophthalmology at Juntendo University Hospital. METHODS: We translated and culturally adapted the OSDI into Japanese. The J-OSDI was then assessed for internal consistency, reliability and validity. We also evaluated the optimal cut-off value to suspect DED using an area under the receiver operating characteristic curve (AUC) analysis. PRIMARY OUTCOME MEASURES: Internal consistency, test-retest reliability and discriminant validity of the J-OSDI as well as the optimal cut-off value to suspect DED. RESULTS: Of the participants, 152 had DED and 57 did not. The J-OSDI total score showed good internal consistency (Cronbach's alpha=0.884), test-retest reliability (interclass correlation coefficient=0.910) and discriminant validity by known-group comparisons (non-DED, 19.4±16.0; DED, 37.7±22.2; p<0.001). Factor validity was used to confirm three subscales within the J-OSDI according to the original version of the questionnaire. Concurrent validity was assessed by Pearson correlation analysis, and the J-OSDI total score showed a strong positive correlation with the Dry Eye-Related Quality-of-Life Score (γ=0.829). The optimal cut-off value of the J-OSDI total score was 36.3 (AUC=0.744). CONCLUSIONS: The J-OSDI was developed and validated in terms of reliability and validity as an effective tool for DED assessment and monitoring in the Japanese population.

Neonicotinoids disrupt aquatic food webs and decrease fishery yields.

Invertebrate declines are widespread in terrestrial ecosystems, and pesticide use is often cited as a causal factor. Here, we report that aquatic systems are threatened by the high toxicity and persistence of neonicotinoid insecticides. These effects cascade to higher trophic levels by altering food web structure and dynamics, affecting higher-level consumers. Using data on zooplankton, water quality, and annual fishery yields of eel and smelt, we show that neonicotinoid application to watersheds since 1993 coincided with an 83% decrease in average zooplankton biomass in spring, causing the smelt harvest to collapse from 240 to 22 tons in Lake Shinji, Shimane Prefecture, Japan. This disruption likely also occurs elsewhere, as neonicotinoids are currently the most widely used class of insecticides globally.

Role for tyrosine phosphorylation of SUV39H1 histone methyltransferase in enhanced trimethylation of histone H3K9 via neuregulin-1/ErbB4 nuclear signaling.

Protein-tyrosine kinases transmit signals by phosphorylating their substrates in diverse cellular events. The receptor-type tyrosine kinase ErbB4, a member of the epidermal growth factor receptor subfamily, is activated and proteolytically cleaved upon ligand stimulation, and the cleaved ErbB4 intracellular domain (4ICD) is released into the cytoplasm and the nucleus. We previously showed that generation of nuclear 4ICD by neuregulin-1 (NRG-1) stimulation enhances the levels of trimethylation of histone H3 at lysine 9 (H3K9me3). However, it remains unclear how nuclear 4ICD enhances H3K9me3 levels. Here we show that the histone H3K9 methyltransferase SUV39H1 associates with NRG-1/ErbB4-mediated H3K9me3. Knockdown of SUV39H1 blocked NRG-1-mediated enhancement of the levels of H3K9me3. Nuclear 4ICD was found to phosphorylate SUV39H1 primarily at Tyr-297, -303, and -308 that are conserved among humans, mice, and flies. Furthermore, knockdown-rescue experiments showed that the unphosphorylatable SUV39H1 mutant (3 YF) was incapable of enhancing the levels of H3K9me3 upon NRG-1 stimulation. These results suggest that nuclear ErbB4 enhances H3K9me3 levels through tyrosine phosphorylation of SUV39H1 in NRG-1/ErbB4 signal-mediated chromatin remodeling.

Linagliptin Has Wide-Ranging Anti-Inflammatory Points of Action in Human Umbilical Vein Endothelial Cells.

BACKGROUND: Because of the potential anti-inflammatory effects, linagliptin, a therapeutic dipeptidyl peptidase-4 inhibitor, is used as an effective drug for diabetic patients for whom inflammation is a prognosis-related factor. We investigated the anti-inflammatory mechanism of linagliptin using seven markers. METHODS: We pretreated human umbilical vein endothelial cells (HUVECs), with linagliptin and lipopolysaccharide (LPS). The cytosolic fractions were evaluated for protein kinase A (PKA), protein kinase B (PKB), protein kinase C (PKC), ratio of reactive oxygen species (ROS) and Cu/Zn superoxide dismutase (SOD), activator protein 1 (AP-1), and adenosine 3',5'-cyclic monophosphate (cAMP). RESULTS: Linagliptin increased the PKA and PKC activities and the cAMP levels in LPS-treated cells. However, it inhibited LPS-induced PKB phosphorylation, ratio of ROS and Cu/Zn SOD, and LPS-stimulated AP-1 nuclear translocation. CONCLUSION: We reaffirmed the anti-inflammatory and antioxidant effects of linagliptin. These effects might be related to the three protein kinases. Our findings suggest that linagliptin has a wide range of anti-inflammatory effects.

Diabetes therapies in hemodialysis patients: Dipeptidase-4 inhibitors.

Although several previous studies have been published on the effects of dipeptidase-4 (DPP-4) inhibitors in diabetic hemodialysis (HD) patients, the findings have yet to be reviewed comprehensively. Eyesight failure caused by diabetic retinopathy and aging-related dementia make multiple daily insulin injections difficult for HD patients. Therefore, we reviewed the effects of DPP-4 inhibitors with a focus on oral antidiabetic drugs as a new treatment strategy in HD patients with diabetes. The following 7 DPP-4 inhibitors are available worldwide: sitagliptin, vildagliptin, alogliptin, linagliptin, teneligliptin, anagliptin, and saxagliptin. All of these are administered once daily with dose adjustments in HD patients. Four types of oral antidiabetic drugs can be administered for combination oral therapy with DPP-4 inhibitors, including sulfonylureas, meglitinide, thiazolidinediones, and alpha-glucosidase inhibitor. Nine studies examined the antidiabetic effects in HD patients. Treatments decreased hemoglobin A1c and glycated albumin levels by 0.3% to 1.3% and 1.7% to 4.9%, respectively. The efficacy of DPP-4 inhibitor treatment is high among HD patients, and no patients exhibited significant severe adverse effects such as hypoglycemia and liver dysfunction. DPP-4 inhibitors are key drugs in new treatment strategies for HD patients with diabetes and with limited choices for diabetes treatment.

Overexpression of zinc-finger protein 777 (ZNF777) inhibits proliferation at low cell density through down-regulation of FAM129A.

Krüppel-associated box-containing zinc finger proteins (KRAB-ZFPs) regulate a wide range of cellular processes. KRAB-ZFPs have a KRAB domain, which binds to transcriptional corepressors, and a zinc finger domain, which binds to DNA to activate or repress gene transcription. Here, we characterize ZNF777, a member of KRAB-ZFPs. We show that ZNF777 localizes to the nucleus and inducible overexpression of ZNF777 inhibits cell proliferation in a manner dependent on its zinc finger domain but independent of its KRAB domain. Intriguingly, ZNF777 overexpression drastically inhibits cell proliferation at low cell density but slightly inhibits cell proliferation at high cell density. Furthermore, ZNF777 overexpression decreases the mRNA level of FAM129A irrespective of cell density. Importantly, the protein level of FAM129A strongly decreases at low cell density, but at high cell density the protein level of FAM129A does not decrease to that observed at low cell density. ZNF777-mediated inhibition of cell proliferation is attenuated by overexpression of FAM129A at low cell density. Furthermore, ZNF777-mediated down-regulation of FAM129A induces moderate levels of the cyclin-dependent kinase inhibitor p21. These results suggest that ZNF777 overexpression inhibits cell proliferation at low cell density and that p21 induction by ZNF777-mediated down-regulation of FAM129A plays a role in inhibition of cell proliferation.