tbuckley/cabot-search huggingface dataset:
Abstract 5925: Temporary Percutaneus Left Ventricular Stimulation in Patients with Cardiogenic Shock and Asynchronous Left Ventricular Contraction
Authors: Charlotte Staab, Christopher Piorkowski, Eik Grebe, Holger Thiele, Arash Arya, Philipp Sommer, Kerstin Bode, Gerhard Hindricks
Journal: Circulation (2008)

Despite modern medical treatment strategies such as early coronary revascularization and intraaortic balloon pump cardiogenic shock is still associated with a high mortality. Cardiac resynchronization therapy (CRT) has shown significant benefits in patients with symptomatic heart failure and asynchronous left ventricular contraction. In the present study CRT was used as a temporary treatment strategy in patients with cardiogenic shock without further treatment options. 11 consecutive patients with cardiogenic shock (6 ICM, 5 DCM) and asynchronous left ventricular contraction (Δ PEP, SPWMD) received a temporary left ventricular (LV) lead, introduced through the right jugular vein and positioned in a posterolateral target vein. 4 patients were pacemaker dependent due to AV-block III, 7 patients were in SR with intrinsic AV conduction and additionally received a temporary right atrial lead for AV synchronous LV stimulation. The leads were externally connected to a re-sterilized single or dual chamber pacemaker. In all 11 patients the external LV lead could be positioned in a posterolateral target vein. Median procedure time was 24 (15;90) min. Median radiation time was 12 (8,25) min. After LV lead placement mean arterial pressure significantly improved in median by 15 (5,30) mmHg. After two days of therapy 8/11 (73%) patients were free from catecholamines. Median duration of temporary LV stimulation was 5 (2,12) days. The 30 day mortality measured 4/11 (36%). 6/7 surviving patients received permanent implantation of a CRT device subsequently. A temporary percutaneus left ventricular stimulation in patients with cardiogenic shock is feasible. In selected patients with terminal cardiogenic shock and lack of further treatment options temporary left ventricular stimulation can significantly improve the patient’s hemodynamic situation.
Abstract 2507: Integrating Functional and Anatomical Information to Guide Cardiac Resynchronization Therapy using a Computed Heart Model
Authors: Francois Tournoux, Raymond C Chan, Robert Manzke, Jorge Solis, Annabel Chen-Tournoux, Olivier Gerard, E Kevin Heist, Pascal Allain, Vivek Y Reddy, Arthur E Weyman, Jeremy N Ruskin, Michael H Picard, Jagmeet P Singh
Journal: Circulation (2007)
子痫前期肾素-血管紧张素-醛固酮水平的研究
Authors: 虞斌, 袁佩, 吴贤, 王秋伟, 周红
Journal: BMJ (2007)

采用放射免疫分析技术(RIA)分别检测34例子痫前期患者分娩前后血浆及脐血中肾素、血管紧张素Ⅱ、醛固酮水平,并与20例正常孕妇比较.结果表明,子痫前期患者分娩后血浆肾素、血管紧张素Ⅱ、醛固酮水平有不同程度的降低,与正常孕妇相似.与正常孕妇比较,分娩前子痫前期孕妇血浆血管紧张素Ⅱ明显升高、醛固酮显著降低,两者有统计学意义(P＜0.05),肾素/醛固酮比值升高1.75倍;分娩后,两组孕妇血浆肾素、血管紧张素Ⅱ、醛固酮水平差异均无统计学意义(P＞0.05).子痫前期患者脐静脉血中醛固酮明显降低。
Abstract 15774: Atrial Fibrillation is a Significant Predictor of Long-term Outcomes in Asymptomatic or Minimally Symptomatic Hypertrophic Cardiomyopathy Patients
Authors: Aditya Bhonsale, Zoran B Popovic, Deborah H Kwon, Nicholas G Smedira, Maran Thamilarasan, Bruce W Lytle, Harry M Lever, Milind Y Desai
Journal: Circulation (2010)

Background:  Atrial fibrillation (AF) is associated with increased morbidity and mortality. Hypertrophic cardiomyopathy (HCM) patients have varying degrees of diastolic dysfunction; and AF in this setting can be potentially detrimental. We sought to assess the effect of AF on long-term outcomes of asymptomatic or minimally symptomatic HCM patients that did not undergo septal reduction therapy or successful invasive therapy for AF.   Methods:  We included 602 HCM patients (mean age 47 ± 13 years, 70 % men, 95 % in functional class I and II), between 18–65 years of age that were referred to a tertiary care center between 1/1997 and 12/2007. The following were excluded: hypertensive heart disease of elderly, SM or alcohol septal ablation prior to or following the initial visit, successful therapy for AF (including electrical cardioversion, percutaneous or surgical ablation) and ejection fraction    Results:  In a mean follow up of 6.3 + 1.6 years, there were 57 composite events. Results of univariable and multivariable Cox proportional hazard analysis are shown in Table. Only degree of septal hypertrophy and history/presence of AF was associated with composite events. AF remained a significant predictor even when stroke was removed from composite events (Chi square 6.9, p = 0.009).   Conclusions:  In asymptomatic or minimally symptomatic HCM patients that did not have septal reduction therapy or definitive/successful AF treatment, AF was a powerful predictor of long term outcomes.
糖尿病诊治新进展——解读美国糖尿病学会《2010版糖尿病诊疗指南》
Authors: 吴菁, 谷卫
Journal: BMJ (2010)

糖尿病是一种困扰全球的慢性代谢性疾病。据WHO数据资料统计，全球已有糖尿病患者1．85亿左右，预测到2025年全世界糖尿病患病人数将达到3．33亿。目前，对该病的诊治仍存在治疗达标率低、并发症风险巨大的现状。2010美国糖尿病学会（ADA）《糖尿病诊疗指南》（简称“指南”）以最新的临床研究证据为基础，提出了一些糖尿病诊断与治疗的新概念。
Abstract #LB-209: The HDAC inhibitor belinostat downregulates survivin in the FET colon cancer cell line by a TGF\#946; signaling dependent mechanism
Authors: Sanjib Chowdhury, Michael Brattain, Gillian Howell
Journal: Cancer Research (2009)

Survivin is a member of the IAP family and is ubiquitously expressed in tumor cells. This \#8220;cancer specific\#8221; gene also functions to promote angiogenesis, cell division and is a marker of poor prognosis. Histone deacetylase inhibitors (HDACi) induce apoptosis and re-expression of epigenetically silenced tumor suppressor genes (TSG) in cancer cells. In association with increased expression of the TSG transforming growth factor \#946; receptor II (TGFsRII) induced by the HDACi belinostat, we have observed decreased survivin expression. HDACi are in clinical trial. Identification of the targets and molecular mechanisms involved in their effects will identify both the therapeutically important HDAC\#8217;s and the most effective combination therapies. Therefore, we are currently investigating the molecular mechanisms involved in survivin downregulation by the HDACi belinostat in the FET colon carcinoma cell line. We have identified two mechanisms involved in the belinostat induced repression of survivin. Firstly, at early time points following belinostat treatment (0-4h), the survivin protein half life is significantly decreased. The proteasome is involved in this increased degradation as determined by the use of MG132 and lactacystin. Significantly, the decrease in survivin half life is delayed in FET cells stably transfected with dominant negative TGFsRII. Secondly, at late time points (24-72h) following treatment with belinostat, the level of survivin mRNA is decreased. The transcriptional activity of the survivin promoter construct p1430-luciferase stably transfected into FET cells is similarly decreased 48h post treatment. This suppression of transcriptional activity by belinostat also demonstrates some dependence on TGF\#946; signaling. At pharmacologically low doses of belinostat, blocking the TGF\#946; pathway by the ALK5i inhibitor or using FET cells stably transfected with dominant negative TGFsRII partially rescued survivin transcription. We also treated FET Smad 2 knockdown cells with belinostat and found that survivin downregulation by belinostat was partially rescued. DNA fragmentation assay revealed that belinostat induced cell death is through the activation of caspase 3 and 9 and blocking the TGF\#946; pathway reduced cell death. Similar results were obtained with the HDACi trichostatin A. Belinostat also induced expression of epigenetically silenced TGFsRII in the MCF7L breast cancer cell line which resulted in TGF\#946; mediated survivin repression. Therefore, induction of TGFsRII with concomitant survivin repression may represent significant mechanisms in the anti-cancer effects of this drug.   Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr LB-209.
Abstract 1371: NCS-1 is a Potential Therapeutic Target for Avoiding Bradycardia and Optimizing Cancer Chemotherapy with Paclitaxel
Authors: Kun Zhang, Felix M Heidrich, Barbara Ehrlich
Journal: Circulation (2007)

We hypothesize that the inositol 1,4,5-trisphosphate receptor (InsP3R) signaling pathway is crucial for the development of cardiac arrhythmia caused by paclitaxel treatment. Paclitaxel, a well established drug used for cancer chemotherapy, constrains tumor growth through a microtubule stabilizing mechanism. However, use of paclitaxel is limited by serious side effects including bradycardia, which cannot be explained by its effect on microtubules. Recently, a new binding partner of paclitaxel was described - neuronal calcium sensor-1 (NCS-1), a protein that modulates the function of the InsP3R and that we found to be expressed in cardiomoycytes. After treating neonatal ventricular cardiomyocytes from rats with a therapeutic dose of paclitaxel for several hours, NCS-1 levels were markedly elevated. The same effect was also detectable in vivo, in hearts extracted from adult mice chronically injected with paclitaxel. Using live cell imaging, we observed an increase in the peak of the intracellular calcium signal and a significant decrease in the spontaneous calcium oscillation frequency in paclitaxel treated cardiomyocytes compared to control. The changes could not be explained by the function of ryanodine receptors (RyR) because there is no functional interaction between NCS-1 and RyR, as previously shown in bilayer experiments, and no paclitaxel-dependent change in RyR expression. However, co-immunoprecipitation confirmed a direct interaction between NCS-1 and InsP3R type 2, the predominant isoform in cardiomyocytes. To test whether this interaction is functionally relevant, we stimulated cardiomyocytes with endothelin, an activator of the InsP3 signaling cascade and found a difference in calcium transients between paclitaxel-treated and untreated cardiomyocytes. NCS-1 knockdown in cardiomyocytes by shRNA validated our findings. Taken together, our results suggest that paclitaxel-induced cardiac arrhythmia in patients is mediated by the interaction of NCS-1 and the InsP3R. This gives us a new understanding of the pathomechanism and provides a new approach for reducing the side effects of paclitaxel treatment and optimizing cancer chemotherapy.
Silencing The Sialyltransferase Gene ST3GAL6 Inhibits Adhesion and Migration Of Myeloma Cells In Vitro and Reduces The Homing and Proliferation Of Tumor Cells In Vivo
Authors: Siobhan Glavey, Salomon Manier, Antonio Sacco, Michaela R Reagan, Yuji Mishima, Yong Zhang, Ilyas Sahin, Yu Zhang, Wenjing Zhang, Laura S Murillo, Catherine Loughrey, Alessandro Natoni, Katarzyna Kazlowska, Lokesh Joshi, Aldo M Roccaro, Irene M. Ghobrial, Michael E O'Dwyer
Journal: Blood (2013)
Drug points: Hepatitis associated with Kava, a herbal remedy for anxiety
Authors: M. Escher
Journal: BMJ (2001)

Kava, the rhizome of the pepper plant Piper methysticum, has been widely used in the South Pacific as a narcotic drink.Lactones, the major constituents of kava, are considered to be pharmacologically active and are sold in Europe and the United States as standardised extracts for anxiety and tension.A 50 year old man presented to his doctor because of jaundice.He had noticed fatigue for a month, a "tanned" skin, and dark urine.The medical history was unremarkable apart from slight anxiety, for which he had been taking three to four capsules of kava extracts daily for two months (maximum recommended dose three capsules) corresponding to a dose of 210-280 mg lactones (Laitain, Schwabe, Switzerland).He took no other drugs and did not consume alcohol.Liver function tests showed a 60-fold and 70-fold increase in aspartate aminotransferase and alanine aminotransferase concentrations, respectively.Alkaline phosphatase concentration was 430 IU/l (normal range 30-125), -glutamyltransferase 691 IU/l (9-35), lactate dehydrogenase 1132 IU/l (125-240), and total and conjugated bilirubin 279.2 mol/l (6.8-25) and 212.3 mol/l (1.7-8.6), respectively.Prothrombin time was 25%.The patient was admitted to hospital.Ultrasonography showed a slight increase in liver size but no ascites or portal vein thrombosis.Blood tests for hepatitis A, B, C, and E, HIV, cytomegalovirus, and Epstein-Barr virus gave negative results.The patient's condition deteriorated within 48 hours.He developed stage IV encephalopathy and had to be intubated.Prothrombin
Aln-CC5, an Investigational RNAi Therapeutic Targeting C5 for Complement Inhibition
Authors: Anna Borodovsky, Kristina Yucius, Andrew Sprague, Nirmal K Banda, V. Michael Holers, Akshay Vaishnaw, Martin Maier, Rajeev Kallanthottathil, Klaus Charisse, Satya Kuchimanchi, Muthiah Manoharan, David J Salant, Kevin Fitzgerald, Rachel Meyers, Benny Sorensen
Journal: Blood (2014)
Abstract 18112: Impact of Exogenous Cholesterol in Newborns on Arterial Stiffness Decades Later: A 25 Year Prospective Follow-Up Study
Authors: Adam J Lewandowski, Merzaka Lazdam, Ilias Kylintireas, Jonathan Diesch, Corinne Trevitt, Atul Singhal, Alan Lucas, Paul Leeson
Journal: Circulation (2010)

Background: In postmortem studies, exposure to high maternal cholesterol levels during prenatal life is related to increased fatty streak formation in the fetal aorta. However, it is unknown whethe...
Abstract 10916: Utility of Serum Concentration of High-Sensitivity Cardiac Troponin T as a Screening Marker of Cardiovascular Risk in Outpatients with Type-2 Diabetes
Authors: Shigeru Matsui, Junnichi Ishii, Atsushi Suzuki, Mitsuyasu Itoh, Tousei Hashimoto, Kousuke Hattori, Hiroyuki Naruse, Sadako Motoyama, Hideo Izawa, Yukio Ozaki
Journal: Circulation (2011)

Background:  Recently, circulating high-sensitivity troponin T (hsTnT) level has been reported to be associated with structural heart diseases and subsequent risk for all-cause mortality in the general population. Thus, we investigated prospectively the utility of hsTnT as a marker to stratify cardiovascular risk in outpatients with type-2 diabetes mellitus (T2DM).   Methods:  We measured serum levels of hsTnT, N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein (hsCRP) and cystatin C and urinary albumin/creatinine ratio in 409 consecutive outpatients with T2DM (median age, 66 yrs; 241 males). A previous history of cardiovascular disease, which was defined as acute coronary syndrome, heart failure or stroke, was present in 89 (22%) patients. Cardiovascular event was defined as cardiovascular death or hospitalization for cardiovascular disease.   Results:  Serum hsTnT was detected (> lower detection limit of 2 pg/mL) in 80% of patients, and was higher than 14 pg/mL (99th percentile in apparently healthy subjects) in 19.3%. Patients with increased hsTnT (> 14 pg/mL) were older, had higher values of NT-proBNP, hsCRP, cystatin C, and urinary albumin/creatinine ratio, had a lower value of estimated glomerular filtration rate (GFR), and had a higher prevalence of cardiovascular disease compared with those without it ( Table ). During mean follow-up period of 11 months, there were 189 (4.4%) cardiovascular events, including 2 cardiovascular deaths. On a stepwise Cox regression analysis including 8 clinical and biochemical variables, increased hsTnT (relative risk 4.08, P = 0.004) and a history of cardiovascular disease (3.62, P = 0.01) were independently associated with cardiovascular events. In the Kaplan-Meier analysis, patients with increased hsTnT had a higher risk of cardiac events than those without it (P    Conclusion:  An hsTnT may be useful as a screening marker of cardiovascular risk in this population.
同时化放疗治疗鳞状细胞癌——已成为新的金标准，适用于任何原发部位
Authors: 张弘纲
Journal: BMJ (2002)

数十年来 ,常见肿瘤的基本治疗主要为根治性外科手术 (如大肠癌、非小细胞肺癌和肾癌 ) ,或根治性放射治疗———用于不能手术的病例或希望保留组织的部位以及对放疗十分敏感的肿瘤 (如头颈部癌 ,特别是喉癌 )。手术和放疗有时是“竞争对手” ,但在某种情况下 (如乳腺癌 ) ,局限性手术和放疗联合应用能够在良好局部控制的同时 ,保存组织和尽可能地保持美观 ,是两全其美的治疗方案。在过去的数年中 ,一场革命一直在悄悄地进行着 ,对相当大部分的实体瘤患者的治疗观点发生了戏剧性的改变。人们越来越清楚地认识到 ,对于大多数发生于常见部位的原发性鳞癌患者而言 ,传统的外科手术、放射治疗或二者联合治疗不再是最
Abstract 6: Intravenous Oxygen Gas-Filled Liposomes Prevent Death From Asphyxia
Authors: John N Kheir, Laurie Scharp, Brian Walsh, Francis X McGowan
Journal: Circulation (2010)

Introduction: Hypoxemia contributes to cellular dysfunction and death in a number of disease states. We investigated the possibility of administering clinically-relevant volumes of oxygen gas to th...
Abstract 1376: The Nadph Oxidase Nox4 Controls Mkp1 Expression and Thereby the Development of White Adipose Tissue
Authors: Katrin Schröder, Judith G Schreiber, Ralf P Brandes
Journal: Circulation (2008)

Obesity is a cardiovascular risk factor. Insulin promotes the formation of adipocytes by promoting fibroblast into adipocyte differentiation. Insulin however also acts as a mitogen for fibroblasts and the balance of insulin-induced proliferation and differentiation is incompletely understood. We hypothesize that the NADPH oxidase Nox4 acts as a central switch between these two processes. In 3T3-fibroblasts Nox4 siRNA reduced the cellular radical formation and attenuated the insulin-stimulated differentiation from fibroblasts into adipocytes. Importantly, insulin-induced proliferation was enhanced by Nox4 siRNA. Accordingly, Nox4 overexpression enhanced differentiation and reduced insulin-stimulated proliferation. We generated Nox4 knockout mice to study the in vivo relevance of this observation: The amount of adipose tissue was reduced in the Nox4−/− animals as compared to their wildtype littermates suggesting indeed an attenuated adipocyte differentiation, whereas fibroblasts obtained from Nox4−/− mice presented with enhanced proliferation. To uncover the underlying mechanism, we focused on the Erk1/2 pathway. Erk1/2 signaling is prevented by dephosphorylation through the dualspecific phosphatase MKP1. Luciferase reportergene assays using the full-length MKP1 promotor revealed that Nox4 siRNA reduced, and overexpression of Nox4 as well as treatment of the cells with H 2 O 2 induced MKP1 promotor activity. Indeed, Nox4 siRNA reduced MKP1 protein expression and thus enhanced basal and insulin-induced activation of Erk1/2 in fibroblasts. Nox4 overexpression had the opposite effect. Importantly, MKP1 expression was also reduced in adipose tissue from Nox4−/− mice. Overexpression of MKP1 in fibroblastes increased insulin-induced differentiation and attenuated proliferation, whereas MKP1 siRNA had the opposite effect. We conclude that Nox4, by regulating MKP1, is essentially involved in adipocyte differentiation and development of obesity.
Abstract 19799: Slowed Activation in Acute Myocardial Infarction: Role of Lateralized Connexin43
Authors: Elena Dolmatova, Deepak Kumaraswamy, Jennifer R Baum, David Gutstein, Heather S Duffy
Journal: Circulation (2010)

Background: In acute myocardial infarction (MI) Connexin43 (Cx43) structural remodeling occurs by 30 min. However functional remodeling during this period has not been explored. We hypothesized tha...
Abstract 15682: High 3-Year-Mortality Rates in Females With Newly Diagnosed Diabetes After Acute STEMI and NSTEMI in Clinical Practice in Germany: Results of the SWEETHEART Registry
Authors: Anselm K Gitt, Andrea Papp, Frank Towae, Evelyn Deeg, Jochen Senges, Ralf Zahn, Diethelm Tschoepe, Sweetheart Study-Group
Journal: Circulation (2011)

Background: Many patients with coronary artery disease suffer from diabetes or its pre-states. Joint guidelines by the ESC and the EASD recommend testing for diabetes using OGTT in patients with es...
Abstract 15431: Pressure Overload Causes PTP1B Activation – a Possible Mechanism for Heart Failure Associated Insulin Resistance
Authors: Michael Schwarzer, Tien D Nguyen, Claudia Hain, Paulo A Amorim, Daniel Blum, Andrea Schrepper, Torsten Doenst
Journal: Circulation (2010)

Cardiac insulin resistance has been suggested as possible cause for contractile dysfunction. We investigated cardiac insulin sensitivity (cIR) in rats developing pressure overload (PO) heart failure and in left ventricles from patients with or without aortic stenosis and preserved or impaired ejection fraction (EF). Methods and Results: Male Sprague-Dawley rats were subjected to PO by transverse aortic constriction for 2, 10 and 20 weeks. PO caused hypertrophy (LVPWD 1,69±0,56 vs. 2,35±0,51mm, p<0,05) with normal systolic function up to 10 weeks (EF 74,7±1,7 vs. 67,5±3,3%; FS 45,6±1,6 vs. 39,7±2,7%, ns) and impaired systolic function at 20 weeks (EF: 68,2±2,0 vs. 47,8±1,6 %; p<0,05; FS: 45,6± vs. 29,4±1,0%; p<0,05). In isolated working hearts, insulin response was normal at 2 weeks of PO (ΔGO 2w: 0,98±0,26 vs. 0,69±0,13 μmol/min/gdry, ns) and significantly reduced after 10 and 20 weeks (ΔGO 10w: 0,88±0,16 vs. 0,29±0,05, 20w: 0,95±0,16 vs.±0,04 μmol/min/gdry; p<0,05), indicating the onset of cIR before imp...
Abstract 3477: Increase in Creatinine and Cardiovascular Risk in Patients with Systolic Dysfunction after Myocardial Infarction
Authors: Powell Jose, Hicham Skali, Nagesh Anavekar, Charles Tomson, Harlan M Krumholz, Jean L Rouleau, Lemuel Moye, Marc A Pfeffer, Scott D Solomon
Journal: Circulation (2006)

Background:  Baseline renal function is a potent independent risk factor for adverse events after acute myocardial infarction (MI). Worsening renal function (WRF) has been shown to influence outcomes in the heart failure population, but its impact on cardiovascular risk in the post-MI period has not been well-defined.   Methods:  To assess the prognostic importance of WRF, we studied 2231 subjects with left ventricular dysfunction enrolled in the Survival and Ventricular Enlargement (SAVE) trial. Subjects were randomized between 3–16 days (average 11 days) after acute MI to receive captopril or placebo; those with a serum creatinine above 2.5mg/dl were excluded from SAVE. WRF was defined as an increase in creatinine greater-than 0.3mg/dl measured from baseline to two weeks after randomization. We examined the predictive value of WRF on cardiovascular morbidity and mortality over 42 months of follow-up.   Results:  Paired serum creatinine measurements at baseline and two weeks were available in 1854 subjects. WRF occurred in 223 subjects (12.0%), and was a stronger predictor of death (HR 1.46, 95%CI 1.05–2.02) than baseline creatinine (HR 1.31, 95%CI 1.01–1.70). WRF also showed increased risk for cardiovascular death (HR 1.62, 95%CI 1.14–2.30) and the composite endpoint (HR 1.32, 95%CI 1.03–1.70). When stratified by treatment, there were 104 (5.7%) and 116 (6.4%) with WRF in the placebo and captopril groups with no significant association between treatment group and WRF (p=0.38). The risk of death associated with WRF was (HR 1.63, 1.05–2.52) in the placebo group compared to (HR 1.33, 0.81–2.21) the captopril group (p for interaction=0.49).   Conclusions:  WRF as early as two weeks after myocardial infarction was not uncommon (12.0%), and was associated with increased mortality in subjects without renal dysfunction at baseline. Patients who received captopril did not demonstrate more WRF than patients receiving placebo. Monitoring serum creatinine in patients during the first few weeks after myocardial infarction may help identify those at highest risk and guide effective long-term therapeutic choices.
Combinations of 4 mutations (FV R506Q, FV H1299R, FV Y1702C, PT 20210G/A) affecting the prothrombinase complex in a thrombophilic family
Authors: Elisabetta Castoldi, Paolo Simioni, Michael Kalafatis, Barbara Lunghi, Daniela Tormene, Domenico Girelli, Antonio Girolami, Francesco Bernardi
Journal: Blood (2000)