tbuckley/cabot-search huggingface dataset:
Abstract 5521: Activation of Farnesoid X Receptor (FXR) Reduces Atherosclerosis in LDLRKO and apoEKO Mice
Authors: Helen B Hartman, Douglas C Harnish, Mark J Evans
Journal: Circulation (2008)

The nuclear hormone receptors farnesoid X Receptor (FXR) and small heterodimer partner (SHP) regulate bile acid synthesis and cholesterol homeostasis in a complex fashion. In regard to atherosclerosis, FXR repression of bile acid synthesis has been proposed to be either detrimental due to reduced elimination of cholesterol or beneficial due to decreased cholesterol absorption. FXRKO mice have failed to resolved this question, with atherosclerotic lesions in FXRKO mice either enhanced (apoE, FXRdKO mice) or reduced (LDLR, FXRdKO mice). Here we demonstrate that the synthetic ligand FXR-450 blocked Western diet-mediated increases in VLDL and LDL cholesterol in both male or female LDLRKO and male or female apoEKO mice. Correspondingly, FXR-450 strongly reduced lesion development in female and male ApoEKO mice fed a Western diet. To determine if FXR-450 reduction of lipids and atherosclerotic lesion size is solely mediated by induction of SHP and repression of bile acid synthesis, LDLRKO/SHPKO and ApoEKO/SHPKO were similarly analyzed. In female LDLRKO/SHPKO or female apoEKO/SHPKO, FXR-450 no longer reduced VLDL or LDL cholesterol. Surprisingly, FXR-450 still reduced VLDL and LDL cholesterol in male LDLRKO/SHPKO and male apoEKO/SHPKO. Further FXR-450 significantly reduced lesion development in male apoEKO/SHPKO mice. These results demonstrate activation of FXR has highly beneficial effects on plasma lipids and lesion formation in multiple mouse atherosclerosis models. Further, while induction of SHP appears to be the predominant protective mechanism of FXR activation in female mice, additional mechanisms may play a role, particularly in male mice.
Abstract 17113: Dietary Supplementation of Hyodeoxycholic Acid and D-Limonene Decreased Atherosclerotic Lesion Formation in LDLR Knockout Mouse
Authors: Diana M Shih, Zory Shaposhnik, Melenie Rosales, Xuping Wang, Yonghong Meng, Judy Wu, Boris Ratiner, Filiberto Zadini, Georgio Zadini, Aldons J Lusis
Journal: Circulation (2011)

In this study, we examined the effects of dietary supplementation of two natural emulsifiers, hyodeoxycholic acid (HDCA) and D-limonene (D-Lim), on atherosclerotic lesion formation in LDLRKO mouse. Female LDLRKO mice were maintained on a western diet for 8 weeks, then divided into 3 groups that received the following diets for 15 weeks before euthanization, chow diet, chow diet + 1.25% HDCA, or chow diet + 5% D-Lim. We found that 1.25% HDCA was able to significantly suppress the development of plaque area throughout the aorta (beyond the root of the aorta) by 47% (p&lt;0.01) over 15 weeks of treatment. 5% D-lim treated mice showed a 25% (p&lt;0.05) reduction in plaque formation. Atherosclerotic lesion size at the innominate artery was decreased by 94% (p&lt;0.0001) and 53% (p&lt;0.05) in the HDCA and D-Lim groups, respectively, as compared to the chow diet group. Plasma VLDL/IDL/LDL cholesterol levels were significantly decreased by 61% (p&lt;0.0001) and 23% (p=0.01) in the HDCA and D-Lim groups, respectively, as compared to the chow diet group. We found that HDCA supplementation decreased cholesterol absorption from gut by 76% (p&lt;0.0001), whereas D-Lim had no effect on cholesterol absorption. Interestingly, hepatic mRNA level of Cyp7a1, a key enzyme in bile acid synthesis, was significantly increased by more than 100% (p&lt;0.05) in D-Lim group, suggesting D-Lim may act as a bile sequestrant in the gut. In addition, HDL isolated from the HDCA and D-Lim groups exhibited significantly increased ability (49% and 45% increase, respectively) to mediate cholesterol efflux from cholesterol loaded RAW 264.7 cells as compared to those of the chow diet group. In summary, our data demonstrated that HDCA supplementation decreased plasma VLDL/IDL/LDL cholesterol levels mainly through its ability to block intestinal cholesterol absorption. D-Lim decreased plasma VLDL/IDL/LDL cholesterol levels probably through decreased bile acid re-absorption in the intestine and increased conversion of cholesterol into bile acid in the liver. HDCA and D-Lim improve the cholesterol efflux ability of HDL as well. These anti-atherogenic effects resulted in significantly decreased atherosclerosis in LDLRKO mice receiving HDCA or D-Lim. HDCA and D-Lim may be new candidates for anti-atherosclerotic drugs.
The Impact of Integration of a Multidetector Computed Tomography Annulus Area Sizing Algorithm on Outcomes of Transcatheter Aortic Valve Replacement
Authors: Ronald K. Binder, John G. Webb, Alexander B. Willson, Marina Urena, Nicolaj C. Hansson, Bjarne L. Norgaard, Philippe Pibarot, Marco Barbanti, Eric Larose, Melanie Freeman, Eric Dumont, Chris Thompson, Miriam Wheeler, Robert R. Moss, Tae-hyun Yang, Sergio Pasian, Cameron J. Hague, Giang Nguyen, Rekha Raju, Stefan Toggweiler, James K. Min, David A. Wood, Josep Rodés-Cabau, Jonathon Leipsic
Journal: Journal of the American College of Cardiology (2013)
Disproportionate suicidality in patients with comorbid major depression and alcoholism
Authors: J R Cornelius, I M Salloum, J Mezzich, M D Cornelius, H Fabrega, J G Ehler, R F Ulrich, M E Thase, J J Mann
Journal: American Journal of Psychiatry (1995)

The two purposes of this study were to provide a comprehensive description of the clinical features of patients who presented to an intake psychiatric setting with major depression and alcohol dependence and to determine which clinical features distinguished this dual-diagnosis group from patients with the two relevant single diagnoses.During a recent 5-year period, a total of 107 patients who came to a psychiatric facility for initial evaluation were diagnosed as having both major depression and alcohol dependence. The clinical profile of this dual-diagnosis group was compared to that of nondepressed alcoholics (N = 497) and nonalcoholic patients with major depression (N = 5,625), assessed at the same facility, on the basis of information from the Initial Evaluation Form, a semistructured instrument containing a standardized symptom inventory that includes ratings of severity.The psychiatric symptom that most strongly distinguished the depressed alcoholics from the two comparison groups was the level of suicidality. The depressed alcoholics differed significantly from the nonalcoholic depressed patients on only two depressive symptoms, suicidality (59% higher) and low self-esteem (22% higher); they were also significantly distinguished from the nonalcoholic depressed patients by factors such as greater impulsivity, functional impairment, and abnormal personal and social history markers.Suicidality was disproportionately greater than other psychiatric symptoms in the depressed alcoholics. The clinical profile of depressed alcoholics suggests that they suffer an additive or synergistic effect of two separate disorders, resulting in a disproportionately high level of acute suicidality upon initial psychiatric evaluation.
Abstract A26: Protein phosphatase 4 (PP4) as a potential therapeutic target gene for BRAF wild type melanoma
Authors: Richard Essner, Ke Wei Gong, David Kaufman, Hsiaowang Chen, Charles Ginther, Judy Dering, Erika von Euw, Bartosz Chmielowski, Richard Finn, Dennis Slamon
Journal: Cancer Research (2015)

Abstract Protein phosphatase 4 (PP4) participates in cell cycle progression and regulation of centrosome maturation. Gene expression of PP4 is elevated in cancerous tissues of various origins and its overexpression in pancreatic cancer is of prognostic importance. Microarray analysis from primary and metastatic melanoma tissues (N=89) showed that PP4 mRNA expression was up-regulated in metastatic melanoma as compared to primary melanoma of any thickness (relative expression: 1.12 ±0.14, p&amp;lt;0.01). Expression levels from thin (&amp;lt;2 mm) were less than thicker primary melanoma (&amp;gt;2 mm), and varied for the site of metastases from lung&amp;gt; intestine&amp;gt; skin and subcutaneous tissue. Human melanoma cell lines also demonstrate PP4 gene expression with variable levels. We hypothesized that PP4 may be a novel target for treatment of metastatic melanoma through a BRAF and MEK independent pathway. We performed western blot analysis of human melanoma cell lines: M275 (BRAF wild-type) that had a high level of PP4 gene expression and demonstrated its resistant to BRAF inhibitor (PLX4032) and MEK inhibitor (MEK162) treatment. M275 were chosen for PP4 siRNA gene silencing because of its high level of PP4 protein expression. PP4 protein level was reduced by 20% and 60%, respectively in this cell line at day 4 and 6, respectively; and PP4 siRNA gene silencing reduced cell proliferation by 19.9% and 63.6%. Flow cytometry demonstrated there was higher percentage of apoptotic cells after PP4 siRNA gene silencing as compared to controls (54.4% vs. 15.5%, p, 0.05). PP4 is overexpressed in melanoma as it advances from the skin primary to metastases, and varies to the site of the metastases. We demonstrated that PP4 gene silencing leads to cell cycle arrest and apoptosis. PP4 may be a novel target for BRAF wild type melanoma. Note: This abstract was not presented at the conference. Citation Format: Richard Essner, Ke Wei Gong, David Kaufman, Hsiaowang Chen, Charles Ginther, Judy Dering, Erika von Euw, Bartosz Chmielowski, Richard Finn, Dennis Slamon. Protein phosphatase 4 (PP4) as a potential therapeutic target gene for BRAF wild type melanoma. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr A26.
Neurocardiogenic Syncope
Authors: Blair P. Grubb
Journal: New England Journal of Medicine (2005)

A 23-year-old nurse presents for evaluation after having five episodes of syncope at work during the previous three months. All the episodes occurred while she was standing and were characterized by a feeling of light-headedness lasting one to two seconds and then an abrupt loss of consciousness. Two of the episodes caused falls that resulted in facial trauma. The syncope was brief and not associated with incontinence; it was followed by severe fatigue but no confusion. How should the patient be evaluated and treated?
A multimodality treatment for malignant pleural mesothelioma patients with or without lymph node metastases.
Authors: K. A. Cengel, A. Fernandes, R. Mick, D. Smith, M. Culligan, J. Stevenson, D. Sterman, E. Glatstein, S. M. Hahn, J. S. Friedberg
Journal: Journal of Clinical Oncology (2010)

7043 Background: Recent surgically based series have reported significantly worse survival for patients with malignant pleural mesothelioma (MPM) and nodal metastases, and suggested that node positive patients may not be good surgical candidates. Based upon our previous experience with photodynamic therapy (PDT) in treating MPM, we designed a multimodal treatment program and elected to include patients with suspected ipsilateral nodal metastases. Methods: 38 patients with localized MPM (ages 27-81) were treated from 2/2004 to 6/2009. 12 patients were treated on a phase II study and 26 additional consecutive patients were treated as per protocol. Therapy included cytoreduction with radical pleurectomy (RP) or extrapleural pneumonectomy (EPP), intraoperative PDT and adjuvant pemetrexed-based chemotherapy ± radiotherapy. RP was employed in more recent years for all patients, regardless of tumor bulk. Results: A macroscopic complete resection was achieved in all 38 patients (14 EPP/24 RP). 30 patients had locally advanced (AJCC stage III/IV) and 10 patients had nonepithelial MPM. There were 3 postoperative deaths (2 EPP/1 RP). 32 patients received chemotherapy (10 preop/22 postop) and 14 patients received postop radiotherapy. With a median follow-up of 15 months, median PFS and OS were 13 months (36±9% at 2 years) and 26.5 months (54 ±9% at 2 years), respectively. 15 have experienced disease progression, with a first site of failure being local in 6, distant in 6 and local + distant in 3. There was no difference in OS (log rank p=0.88) or PFS (log rank p=0.41) for the 20 patients with positive lymph nodes (3 N1, 17 N2) compared to the 18 N0 patients. Conclusions: The 26.5 month median OS compares favorably with other series, particularly since our patients were 79% stage III/IV and 26% nonepithelial histology. With a multimodality approach including intraoperative PDT, the majority of our patients had a lung sparing surgery but the reason for the surprising lack of impact of nodal metastases remains incompletely understood. We conclude that this multimodal approach is deserving of further study and that future studies of this approach should not exclude MPM patients with suspected nodal metastases. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Axcan Pharmaceuticals
Abstract 8935: Differentiation of Left Atrial Volume by Time Measured by Speckle Tracking Echocardiography as a Novel Index of Left Atrial Global and Phasic Function
Authors: Reiko Matsuoka, Ryuhei Tanaka, Koji Ono, Takatomo Watanabe, Maki Nagaya, Noriyuki Onishi, Noriaki Sato, Tomoko Fujii, Takashi Kato, Shintaro Abe, Takashi Yoshizane, Yoshiaki Goto, Fumitaka Tokoro, Syunichiro Warita, Tai Kojima, Makoto Iwama, Takeshi Hirose, Shintaro Tanihata, Toshiyuki Noda, Mami Iida, Sachiro Watanabe, Masanori Kawasaki, Shinya Minatoguchi
Journal: Circulation (2011)

Background: Left atrial (LA) strain rate (SR) is proposed to assess LA relaxation, conduit function and contraction. Differentiation of strain by time (SR) is one dimensional parameter, but differentiation of LA volume by time (dV/dt) is three dimensional parameter. Thus, we hypothesized that LA dV/dt is more useful index of LA global and phasic function. Methods: We examined 138 subjects; normal (n=54, age 69±11 yrs, 30 men), hypertensive pts (HTN) with normal systolic function (n=84, age 71±9 yrs, 48 men). LA peak dV/dt and SR at systole, early diastole and atrial contraction were measured by speckle tracking which can automatically provide dV/dt from time-LA volume curve (Figure). LA peak dV/dt and SR in HTN were compared to normal. Time from onset of R wave on ECG to peak dV/dt at each phase was compared to that to peak SR. Results: Inter and intraobserver correlation coefficient for dV/dt at each phase was 0.97-0.99. There was a good relation between dV/dt and SR (r=0.94, p&lt;0.01). Time to peak dV/dt was comparable to time to peak SR at each phase (208±62 vs. 189±56, 523±50 vs. 527±51, 921±161 vs. 920±162msec, respectively, p&lt;0.01). Peak positive dV/dt and SR at systole in HTN were reduced compared to normal (178±35 vs. 204±47 ml/s, 1.1±0.3 vs. 1.3±0.4 s- 1 , respectively, p&lt;0.05). Peak negative dV/dt and SR at early diastole in HTN were lower (-174±62 vs. -216±92ml/s, -0.9±0.3 vs. -1.4±0.6 s- 1 , respectively, p&lt;0.05), associated with elevated E/e’ (9.0±1.9 vs. 7.2±1.9, p&lt;0.01). Despite no difference in peak SR at atrial contraction between 2 groups, peak negative dV/dt in HTN was higher than normal (-222±67 vs. -147±74 ml/s, p&lt;0.01). Conclusions: LA relaxation assessed by dV/dt and SR was reduced in HTN and conduit function was also reduced in HTN by impaired diastolic function. LA active contraction assessed by dV/dt was increased in HTN to compensate reduced conduit function. Measurement of LA dV/dt may be more promising method to assess LA function with highly acceptable variability.
Abstract 15211: Calcium/Calmodulin-Dependent Protein Kinase Kinase β Plays a Key Role for the Diverse Functions of Endothelial Nitric Oxide Synthases System between Conduit and Resistance Arteries in Mice
Authors: Junko Ohashi, Ayuko Sawada, Aya Takaki, Kazuki Noda, Sota Nakajima, Maki Hosoya, Hiroaki Shimokawa
Journal: Circulation (2010)

Background:  We have previously demonstrated in animals and humans that endothelium-derived hydrogen peroxide (H 2 O 2 ) is an endothelium-derived hyperpolarizing factor (EDHF) and that endothelial NO synthase (eNOS)-derived superoxide anions is a major precursor of EDHF/H 2 O 2 . We also have recently demonstrated in mice deficient of the whole NOSs system that endothelial NOSs system plays diverse roles depending on vessel size, mainly serving as a superoxide generating system to cause EDHF/H 2 O 2  responses in resistance arteries (e.g. mesenteric arteries, MA) while serving as a NO generating system in conduit arteries (e.g. the aorta, Ao). In this study, we aimed to elucidate the mechanisms involved in the diverse roles of endothelial NOSs system in mice.   Methods and Results:  We used male wild-type mice (10–16 weeks-old) (n=4∼6 in all protocols). Isometric tensions were recorded in organ chamber experiments. Since we previously reported that pathological eNOS uncoupling is not the mechanism for the divergent roles of eNOS between Ao and MA, we further examined this point. The extent of eNOS phosphorylation at Ser 1177  (stimulatory site) was significantly greater in Ao than in MA, whereas that at Thr 495  (inhibitory site) was significantly greater in MA than in Ao. STO-609 (5 μM for 1 hour), an inhibitor of calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ) that lies upstream of eNOS Ser 1177  phosphorylation pathway, significantly decreased EDHF-mediated relaxations and hyperpolarizations to acetylcoline (ACh) in MA but not in Ao. STO-609 had no effects on contractions or endothelium-independent relaxations. In response to ACh, eNOS Ser 1177  phosphorylation was enhanced in both MA and Ao, which was inhibited by STO-609 in MA more than in Ao. The extent of eNOS Thr 495  phosphorylation was unchanged by STO-609 in MA or Ao. The AMP-activated protein kinase (AMPK) inhibitor compound C and the phosphoinositide 3-kinase (PI3K) inhibitor wortmannin had no effects on EDHF-mediated relaxations or hyperpolarizations to ACh in MA and Ao.   Conclusions:  These results suggest that eNOS activity is significantly attenuated in MA and that CaMKKβ plays a key role for the diverse functions of endothelial NOSs system between conduit and resistance arteries.
CHOLESTATIC JAUNDICE FROM TOLBUTAMIDE
Authors: R W BAIRD, J G HULL
Journal: Annals of Internal Medicine (1960)

Case Reports1 July 1960CHOLESTATIC JAUNDICE FROM TOLBUTAMIDER. WILLIAM BAIRD, M.D., JOHN G. HULL, M.D.R. WILLIAM BAIRD, M.D.Search for more papers by this author, JOHN G. HULL, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-53-1-194 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptThe list of chemicals capable of producing hepatic injury grows in disturbingly direct proportion to the number of drugs introduced into the pharmacy. The identification of these agents is of importance because the physician needs to balance the risk of any drug against its desired benefit with clearer eye and greater precision. Moreover, the perplexing problem of the differential diagnosis of jaundice is increased with each addition to the list.This report concerns a patient with jaundice induced by tolbutamide. This relationship was demonstrated by the patient himself, quite unknowingly, when he performed a challenge test. As far as we...Bibliography1. WilliamsPollenTannerBarnes RHRHDCRH: Oral antidiabetic therapy, Ann. Int. Med. 51: 1121 (Dec.) 1959. LinkGoogle Scholar2. Steigmann F: The early recognition of drug induced liver disease, M. Clin. North America 44: 183 (Jan.) 1960. CrossrefMedlineGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Houston, Texas*Received for publication February 12, 1960.From the Medical Section, Hermann Hospital, Houston, Texas.Requests for reprints should be addressed to R. William Baird, Jr., 3701 Montrose Boulevard, Houston 6, Texas. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byDrugs and ToxinsProteome profiling of tolbutamide-treated rat primary hepatocytes using nano LC-MS/MS and label-free protein quantitationAdverse Effects of Drugs on the LiverAcute and Chronic Hepatotoxicity: Pathologic AspectsClinical Utilization of Alkaline Phosphatase MeasurementsTolazamide HepatotoxicityZur Pharmakologie und Toxikologie der blutzuckersenkenden SulfonamideTolbutamide gastric analysisDie Wirkung von Tolbutamid auf die Elimination von Bromsulphalein aus dem BlutTHE HISTOPATHOLOGY OF DRUG-INDUCED LIVER DISEASECLINICAL AND LABORATORY MANIFESTATIONS OF HEPATOTOXICITYSerum Alkaline Phosphatase, SGOT and SGPT During Treatment of Diabetic Patients with Tolbutamide and InsulinThe Effect of Tolbutamide on Human Basal Gastric SecretionALEX WEISS, M.D., WILLIAM J. SCIALES, M.D.The liver and Its Diseases 1 July 1960Volume 53, Issue 1Page: 194-196KeywordsDrugs ePublished: 1 December 2008 Issue Published: 1 July 1960 PDF downloadLoading ...
Abstract 18296: Investigation of Hepatic and Vascular Changes Associated with Familial Combined Hypolipidemia
Authors: Marcello Arca, Ilenia Minicocci, Vito Cantisani, Eleonora Poggiogale, Elda favari, Francesca Zimetti, Anna Montali, Giancarlo Labbadia, Giovanni Pigna, Marianna Maranghi, Franco Bernini
Journal: Circulation (2012)

Background . Familial combined hypolipidemia (FHBL2, OMIM #605019), due to mutations in ANGPTL3 gene, is a rare low-cholesterol syndrome characterized by a profound reduction of pro-atherogenic, apoB-containing and anti-atherogenic, apoAI- containing lipoproteins. FHBL2 individuals show reduced hepatic production of very low density lipoprotein, a condition predisposing to fatty liver. However, the impact of FHBL2 on risk of atherosclerosis or hepatic steatosis is unknown. Methods and Results . We assessed in 66 FHBL2 subjects carrying the ANGPTL3 S17X LOF mutation (7 homozygotes and 59 heterozygotes) and 126 age- and sex-matched controls the extent of preclinical atherosclerosis, by measuring carotid intima-media thickness (IMT) and flow-mediated dilatation (FMD), as well as the prevalence of hepatic steatosis by abdominal ultrasonography. Compared with controls, homozygous, but not heterozygous, FHBL2 carriers showed increased average and maximum IMT (P&lt;0.01). Homozygous carriers also showed lower, although not significant, FMD. Compared to controls, ApoB-depleted sera from FHBL2 individuals had a reduced capacity to promote cell cholesterol efflux (4.9 ± 1.8 % vs. 8.5 ± 1.6 %; P&lt;0.01). This was evident with ABCA1-, SR-BI- and ABCG1-mediated pathways and was related to the number of mutated alleles. No difference in the prevalence of hepatic steatosis was found between FHBL2 and controls. Conclusions . Homozygous FHBL2 are at increased risk of developing early vascular atherosclerotic changes and that this might be related to the severely impaired HDL function in these subjects. FHBL2 subjects did not show increased risk of hepatic steatosis, thus supporting the notion that Angplt3 deficiency exerts its metabolic effects not impairing the secretion of TG by the liver.
Impact of Coronary Lesion Complexity on Drug-Eluting Stent Outcomes in Patients With and Without Diabetes Mellitus
Authors: Elvin Kedhi, Philippe Généreux, Tullio Palmerini, Thomas C. McAndrew, Helen Parise, Roxana Mehran, George D. Dangas, Gregg W. Stone
Journal: Journal of the American College of Cardiology (2014)