tbuckley/cabot-search huggingface dataset:
Identification of Anomalous Coronary Arteries and Their Anatomic Course by Magnetic Resonance Coronary Angiography
Authors: Michael V. McConnell, Peter Ganz, Andrew P. Selwyn, Wei Li, Robert R. Edelman, Warren J. Manning
Journal: Circulation (1995)

Anomalous coronary arteries are a rare but recognized cause of myocardial ischemia and sudden death. Identification currently requires x-ray angiography, which may have difficulty defining the three-dimensional course of the anomalous vessel. Magnetic resonance coronary angiography (MRCA) has been shown to image coronary artery anatomy noninvasively. We hypothesize that MRCA may be useful in the identification of anomalous coronary arteries and their anatomic course.Sixteen patients (9 men, 7 women, age 44 to 81 years) with anomalous aortic origins of the coronary arteries by conventional x-ray angiography underwent MRCA. Multiple images of the major epicardial coronary arteries were obtained by use of a breathhold, fat-suppressed, segmented-k space, gradient-echo technique by investigators blinded to all patient data. Anomalous coronary artery pathology, by x-ray angiography, included right-sided left main coronary artery (n = 3), right-sided left circumflex artery (n = 6), separate left-sided left anterior descending and left circumflex arteries (n = 2), left-sided right coronary artery (n = 4), and an anteriorly displaced right coronary artery (n = 1). MRCA correctly identified the anomalous coronary vessel(s) in 14 of 15 patients. In 1 patient, the anomalous vessel was incorrectly identified, and in 2 patients the course of the anomalous vessel was not clearly seen; one of these was a nondominant, anomalous right coronary artery.MRCA is a useful technique for the noninvasive identification of anomalous coronary arteries and their anatomic course.
Diuretic Therapy, the α-Adducin Gene Variant, and the Risk of Myocardial Infarction or Stroke in Persons With Treated Hypertension
Authors: Bruce M. Psaty
Journal: JAMA (2002)

ContextA genetic variant in α-adducin has been associated with renal sodium reabsorption and salt-sensitive hypertension. Whether this genetic variant modifies the effect of diuretic therapy on the incidence of myocardial infarction (MI) and stroke is unknown.ObjectivesTo estimate the interaction between α-adducin and diuretic therapy on the risk of MI or stroke. Specifically, we hypothesized that in participants with treated hypertension, the risk of MI or stroke associated with diuretic use would be lower in carriers of the adducin variant than in carriers of the adducin wild-type genotype.Design, Setting, and ParticipantsPopulation-based case-control study of patients enrolled in a health maintenance organization, treated pharmacologically for hypertension, and genotyped as homozygous carriers of the adducin wild-type genotype or carriers of 1 or 2 copies of the Trp460 variant allele. Cases had a first nonfatal MI (n = 206) or stroke (n = 117) between January 1995 and December 1998. Controls (n = 715) were a stratified random sample of pharmacologically treated hypertensive patients who were matched to MI cases by age, sex, and calendar year.Main Outcome MeasureRisk of the combined outcome of first nonfatal MI or stroke.ResultsThe adducin variant was present in more than one third of the participants. Among the 653 carriers of the adducin wild-type genotype, diuretic therapy was not associated with the risk of MI or stroke (odds ratio [OR], 1.09; 95% confidence interval [CI], 0.78-1.52). Among the 385 carriers of the adducin variant allele, diuretic therapy was associated with a lower risk of the combined outcome of MI and stroke than other antihypertensive therapies (OR, 0.49; 95% CI, 0.32-0.77). The OR in carriers of the adducin variant was less than half of the OR in carriers of the wild-type genotype (P = .005). The case-control synergy index (SI) was 0.45 (95% CI, 0.26-0.79) for the combined outcome of MI and stroke. The point estimates of the diuretic-adducin interaction were similar in separate analyses of MI (SI, 0.41; 95% CI, 0.21-0.80) and stroke (SI, 0.53; 95% CI, 0.24-1.19). The diuretic-adducin interaction was not confounded by traditional cardiovascular risk factors, was specific to diuretic therapy but not present for other major antihypertensive drug classes, and did not differ substantially between subgroups defined by age, sex, race, diabetes, and history of cardiovascular disease.ConclusionsIn carriers of the adducin variant, diuretic therapy was associated with a lower risk of combined MI or stroke than other antihypertensive therapies. If these findings are confirmed in other studies, this large subgroup of the hypertensive population may be especially likely to benefit from low-dose diuretic therapy.
Insertional Mutagenesis Reveals Progression Genes and Checkpoints in <i>MYC/Runx2</i> Lymphomas
Authors: Monica Stewart, Nancy Mackay, Linda Hanlon, Karen Blyth, Linda Scobie, Ewan Cameron, James C. Neil
Journal: Cancer Research (2007)

In this study, we have exploited the power of insertional mutagenesis to elucidate tumor progression pathways in mice carrying two oncogenes (MYC/Runx2) that collaborate to drive early lymphoma development. Neonatal infection of these mice with Moloney murine leukemia virus resulted in accelerated tumor onset with associated increases in clonal complexity and lymphoid dissemination. Large-scale analysis of retroviral integration sites in these tumors revealed a profound bias towards a narrow range of target genes, including Jdp2 (Jundm2), D cyclin, and Pim family genes. Remarkably, direct PCR analysis of integration hotspots revealed that every progressing tumor consisted of multiple clones harboring hits at these loci, giving access to large numbers of independent insertion events and uncovering the contrasting mutagenic mechanisms operating at each target gene. Direct PCR analysis showed that high-frequency targeting occurs only in the tumor environment in vivo and is specific for the progression gene set. These results indicate that early lymphomas in MYC/Runx2 mice remain dependent on exogenous growth signals, and that progression can be achieved by constitutive activation of pathways converging on a cell cycle checkpoint that acts as the major rate-limiting step for lymphoma outgrowth.
A Phase I and Pharmacokinetic Study of TAS-108 in Postmenopausal Female Patients with Locally Advanced, Locally Recurrent Inoperable, or Progressive Metastatic Breast Cancer
Authors: L. Johnetta Blakely, Aman Buzdar, Hsiu-Yin Chang, Debra Frye, Richard Theriault, Vicente Valero, Edgardo Rivera, Daniel Booser, Jun Kuritani, Masuhiro Tsuda
Journal: Clinical Cancer Research (2004)

TAS-108 is a novel steroidal anti-estrogen compound that has a strong binding affinity to the estrogen receptor and, in preclinical studies, has antitumor activity against tamoxifen-resistant breast cancer cell lines. The objective of this study was to investigate the safety and the pharmacokinetics in patients with previously treated advanced breast cancer.TAS-108 was administered orally once daily starting at 40 mg/day, with dose escalations of 60, 80, 120, and 160 mg/day. A minimum of three patients were enrolled in each dose level, and, if no drug-related grade 3 or higher adverse events were seen in the first 14 days, the next cohort of patients was treated at the next level. Pharmacokinetic data were obtained on day 1, 2, 15, and 28 of the first course.A total of 16 patients were enrolled, and most had received six to seven prior therapies. Clinical toxicities included nausea, vomiting, hot flashes, headache, weakness and fatigue; all were grade 1-2. TAS-108 had no effect on endometrial thickness based on trans-vaginal ultrasound evaluation. The average duration of therapy was 17.4 weeks (range, 4-60 weeks). The mean terminal half-life ranged from 8.0 to 10.7 hour in the interval of 12 to 24 hours postdose. The mean C(max) ranged from 2.8 to 21.0 ng/mL and AUC(0-t) from 15.1 to 148.7 ng.h/mL, this showed a linear correlation with the dose.TAS-108 was well tolerated in the doses studied with no maximum tolerated dose. The drug has linear pharmacokinetics, and in this heavily treated patient population, there was evidence of biological antitumor activity. A multi-institutional phase II study is planned.
Glucagon-stimulable adenylyl cyclase in rat liver. The impact of streptozotocin-induced diabetes mellitus.
Authors: R R Dighe, F J Rojas, L Birnbaumer, A J Garber
Journal: Journal of Clinical Investigation (1984)

Glucagon receptor levels, glucagon-stimulated and other forms of adenylyl cyclase activity, and regulatory component activity of adenylyl cyclase were determined in hepatic plasma membranes of rats administered streptozotocin without and with insulin to produce varying degrees of hyperglycemia. Receptor levels were assayed by direct binding of the specific probe [125I-Tyr10]-iodoglucagon; regulatory component activity was assayed by the capacity to reconstitute stimulatory regulation in deficient membranes from cyc- S49 murine lymphoma cells. In rats given 150 mg streptozotocin, glucagon stimulation of adenylyl cyclase as well as basal, sodium fluoride, 5' guanylylimidodiphosphate [GMP-P(NH)P] and Mn-dependent activities were reduced 50%, glucagon receptor levels but not affinity were reduced 67%, and regulatory component activity was decreased 50%. In addition, alpha 1-adrenergic receptors and 5'-nucleotidase were similarly reduced in diabetes. However, specific ouabain-inhibitable Na+, K+, ATPase activity was not altered by streptozotocin treatment. The streptozotocin-induced changes were noted within 24 h and became maximal by 120 h after its administration. All of these decreases were partially reversed by in vivo insulin treatment. DNA, cytochrome c oxidase, glucose-6-phosphatase, and N-acetyl-beta-glucosaminidase content in hepatic plasma membrane preparations were not substantially different in diabetic as compared with control animals. The data demonstrate that glucagon-mediated regulation of cyclic AMP formation is deranged in insulin deficiency owing to a combined decrease in receptors, derangement of the coupling mechanism intervening between receptor and adenylyl cyclase, and possibly, an altered basal effector system. Some of these changes appear to reflect a "desensitization-like" phenomenon which may or may not be attributable to the hyperglucagonemia of diabetes mellitus. There also appears to be a concurrent generalized decrease in several but not all plasma membrane receptor and enzymatic proteins. This may be the result of a number of processes among which is the accelerated proteolysis of uncontrolled diabetes.
Phylogeny and Comparative Substitution Rates of Frogs Inferred from Sequences of Three Nuclear Genes
Authors: S. Hoegg
Journal: Molecular Biology and Evolution (2004)

Phylogenetic relationships among major clades of anuran amphibians were studied using partial sequences of three nuclear protein coding genes, Rag-1, Rag-2, and rhodopsin in 26 frog species from 18 families. The concatenated nuclear data set comprised 2,616 nucleotides and was complemented by sequences of the mitochondrial 12S and 16S rRNA genes for analyses of evolutionary rates. Separate and combined analyses of the nuclear markers supported the monophyly of modern frogs (Neobatrachia), whereas they did not provide support for the monophyly of archaic frog lineages (Archaeobatrachia), contrary to previous studies based on mitochondrial data. The Neobatrachia contain two well supported clades that correspond to the subfamilies Ranoidea (Hyperoliidae, Mantellidae, Microhylidae, Ranidae, and Rhacophoridae) and Hyloidea (Bufonidae, Hylidae, Leptodactylidae, and Pseudidae). Two other families (Heleophrynidae and Sooglossidae) occupied basal positions and probably represent ancient relicts within the Neobatrachia, which had been less clearly indicated by previous mitochondrial analyses. Branch lengths of archaeobatrachians were consistently shorter in all separate analyses, and nonparametric rate smoothing indicated accelerated substitution rates in neobatrachians. However, relative rate tests confirmed this tendency only for mitochondrial genes. In contrast, nuclear gene sequences from our study and from an additional GenBank survey showed no clear phylogenetic trends in terms of differences in rates of molecular evolution. Maximum likelihood trees based on Rag-1 and using only one neobatrachian and one archaeobatrachian sequence, respectively, even had longer archaeobatrachian branches averaged over all pairwise comparisons. More data are necessary to understand the significance of a possibly general assignation of short branches to basal and species-poor taxa by tree-reconstruction algorithms.
Duration of DNA Synthesis in Ehrlich Ascites Cells as Estimated by Double-Labeling With C&lt;sup&gt;14&lt;/sup&gt;- and H&lt;sup&gt;3&lt;/sup&gt;-Thymidine and Autoradiography&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Renato Baserga, M.D., Elizabeth Lisco
Journal: JNCI Journal of the National Cancer Institute (1963)

Ehrlich ascites tumor cells growing in the peritoneal cavity of male mice were labeled with C14-thymidine, and, after a 1-hour interval, with H3-thymidine. In such a population, the ratio of all cells labeled by C14 only, relative to all other labeled cells, is equal to the ratio: interval between the administration of the radioisotopes/length of the deoxyribonucleic acid (DNA) synthesis phase. Knowing the first three terms of these ratios, one can estimate the length of the DNA synthesis phase. Cells labeled by C14-thymidine only and all other labeled cells were identified by two-emulsion autoradiography, and the length of the DNA synthesis phase was estimated at 10.4 hours. In another experiment, tumor-bearing female mice were given two injections of H3-thymidine; each injection was followed by sampling of the tumor. The difference in the percentage of labeled cells between the two samples gives the fraction of cells entering the DNA synthesis phase in the interval between the administration of the two radioisotopes. From it, and from the fraction of cells labeled by the first injection, the length of the DNA synthesis phase can be estimated as above. It lasted in females 12.5 hours. With tritiated thymidine, the limits of accuracy of the autoradiographs were within the counting error, but with C14-thymidine there was a further error due to uncertainties in the identification of cells.
Verocytotoxin-Induced Apoptosis of Human Microvascular Endothelial Cells
Authors: ANTONETTA H. J. M. PIJPERS, PETRA A. VAN SETTEN, LAMBERTUS P. W. J. VAN DEN HEUVEL, KAREL J. M. ASSMANN, HENDRIKUS B. P. M. DIJKMAN, ARIE H. M. PENNINGS, LEO A. H. MONNENS, VICTOR W. M. VAN HINSBERGH
Journal: Journal of the American Society of Nephrology (2001)

Abstract. The pathogenesis of the epidemic form of hemolytic uremic syndrome is characterized by endothelial cell damage. In this study, the role of apoptosis in verocytotoxin (VT)-mediated endothelial cell death in human glomerular microvascular endothelial cells (GMVEC), human umbilical vein endothelial cells, and foreskin microvascular endothelial cells (FMVEC) was investigated. VT induced apoptosis in GMVEC and human umbilical vein endothelial cells when the cells were prestimulated with the inflammatory mediator tumor necrosis factor-α (TNF-α). FMVEC displayed strong binding of VT and high susceptibility to VT under basal conditions, which made them suitable for the study of VT-induced apoptosis without TNF-α interference. On the basis of functional (flow cytometry and immunofluorescence microscopy using FITC-conjugated annexin V and propidium iodide), morphologic (transmission electron microscopy), and molecular (agarose gel electrophoresis of cellular DNA fragments) criteria, it was documented that VT induced programmed cell death in microvascular endothelial cells in a dose- and time-dependent manner. Furthermore, whereas partial inhibition of protein synthesis by VT was associated with a considerable number of apoptotic cells, comparable inhibition of protein synthesis by cycloheximide was not. This suggests that additional pathways, independent of protein synthesis inhibition, may be involved in VT-mediated apoptosis in microvascular endothelial cells. Specific inhibition of caspases by Ac-Asp-Glu-Val-Asp-CHO, but not by Ac-Tyr-Val-Ala-Asp-CHO, was accompanied by inhibition of VT-induced apoptosis in FMVEC and TNF-α-treated GMVEC. These data indicate that VT can induce apoptosis in human microvascular endothelial cells.
Cellular basis for increased sensitivity of vascular smooth muscle in spontaneously hypertensive rats.
Authors: K Hermsmeyer
Journal: Circulation Research (1976)

There is evidence that hypersensitivity of vascular muscle to neurotransmitters contributes to the development of hypertension. Comparison of the caudal arteries of spontaneously hypertensive rats (SHR) and their genetically related Kyoto-Wistar normotensive control rats (KNR) showed that although there is no difference in membrane potential under unstimulated conditions, greater depolarization of the SHR vascular muscle cells by norepinephrine occurs at concentrations which cause greater contraction. The mechanism for the increased depolarization and resulting increase in contraction appears to be a lower intracellular potassium ion activity in SHR vascular muscle cells, which results in a lower contribution of potassium gradient to membrane potential. Experiments to determine the sensitivity of isolated, dispersed chick omphalomesenteric vascular muscle cells to neurotransmitters showed remarkably low thresholds to the neutransmitters norepinephrine, serotonin, and acetylcholine, but not potassium chloride. The high sensitivity of isolated cells to neurotransmitters suggests that factors in the intact vessel may cause thresholds to be high, possibly implying that alterations in a neurotrophic mechanism might be responsible for changes in vascular muscle sensitivity in situ.
Cx43 CT domain influences infarct size and susceptibility to ventricular tachyarrhythmias in acute myocardial infarction
Authors: Karen Maass, Sharon E. Chase, Xianming Lin, Mario Delmar
Journal: Cardiovascular Research (2009)

Aims Hearts of mice expressing K258stop in place of connexin43 (Cx43) protein were subjected to acute myocardial infarction in order to assess the importance of Cx43 regulation on infarct size and arrhythmia susceptibility.This mutation K258stop prevents chemical regulation of Cx43 channels, including by low intracellular pH.Methods and results Langendorff-perfused hearts of mice harbouring one Cx43 knockout (KO) allele and one K258stop or Cx43 allele (K258stop/KO; Cx43/KO as control) were subjected to 1 h of ischaemia and 4 h of reperfusion by reversibly occluding the left anterior descending (LAD) coronary artery.Inducibility of ventricular tachyarrhythmias (VTs) was tested by applying an endocardial burst-pacing protocol during LAD occlusion.Separately, time course and the extent of acidification-induced closure of gap junction channels were tested by dual-voltage clamp.Infarct volume (as per cent of area at risk) was significantly larger in K258stop/KO hearts compared with Cx43/KO controls (42.2 + 3 vs.30.4+ 1.7%, P ¼ 0.004, n ¼ 8 each).During LAD occlusion, K258stop/KO hearts had a higher incidence of pacinginduced VT and a higher frequency of occurrence of spontaneous premature ventricular beats.The occurrence of ventricular arrhythmias was also significantly larger in the K258stop/KO hearts during reperfusion.In separate experiments, we demonstrated reduced sensitivity to acidification-induced uncoupling in cell pairs obtained from K258stop/KO hearts.Conclusion Loss of the regulatory domain of Cx43 leads to an increase in infarct size and increased susceptibility to arrhythmias following acute coronary occlusion.
Let the fog be lifted: screening for hepatitis B virus before biological therapy
Authors: Kevin L Winthrop, Leonard H Calabrese
Journal: Annals of the Rheumatic Diseases (2011)

Hepatitis B virus (HBV) and tuberculosis have much in common. Approximately one-third of the world has been infected with each, and in the world of rheumatology, both represent important causes of infectious morbidity in patients who use biological and other immunosuppressive therapies. Furthermore, unlike most infections encountered in the biological setting, reactivation or progression of both hepatitis B and latent tuberculosis infection is largely preventable. Both infections can be screened for and preventive therapy is available and efficacious when employed correctly. Perhaps most pertinent to this editorial, the similarities do not end there. As for tuberculosis, there is variation in rheumatological practice and sometimes confusion, with optimal screening strategies often obscured by the fog of inadequate data and imperfect tests. The publication by Lan et al 1 (pp. 1719) in this edition of Annals of Rheumatic Diseases helps clear the fog, adds important insights into the screening question, and provides strong data to suggest an optimal algorithm for HBV screening in this setting.

HBV is a DNA virus highly endemic in southeast Asia, Africa and other regions of the world outside of North America and western Europe, whereby most infection is transmitted perinatally (figure 1).2 If overlaid with the map for tuberculosis prevalence, one would be hard-pressed to distinguish the two. Within low prevalence regions, and also similar to tuberculosis, infection is more common among certain subgroups such as persons with HIV, a history of intravenous drug use, or a history of incarceration (box 1). In a substantial majority of HBV-infected patients, generally those infected perinatally, infection is chronic and life-long, frequently resulting in cirrhosis and eventually death.2 The lifetime risk of death among men from endemic regions with HBV approaches 40%, with substantial risk among women noted although several fold lower.3 Worldwide, approximately one million …
Identification of C3 beta chain as the human serum eosinophil cytotoxicity inhibitor.
Authors: M S Minkoff, W W Wong, D S Silberstein
Journal: The Journal of Experimental Medicine (1991)

An eosinophil cytotoxicity inhibitor (ECI) was purified from serum of a human subject with severe allergic dermatitis. Molecular weight of the isolated polypeptide (75,000) and its NH2-terminal amino acid sequence identified it as the beta chain of the C3 complement component (apparently free, but perhaps attached to very small fragments of the alpha chain). Free beta chain, prepared from normal plasma by reduction of C3, inhibited both eosinophil cytotoxicity and neutrophil adherence functions, with half-maximal activity at approximately 250 ng/ml. Apparently free C3 beta chain was detected in certain human biological fluids associated with inflammation; the presence of C3 beta chain correlated with ECI activity. This evidence demonstrates a potential role for free C3 beta chain as a suppressor of eosinophil and neutrophil functions in inflammation.