UMLS:C0018801 - FACTA Search

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Query: UMLS:C0018801 (heart failure)
72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sixty breast cancer patients with hormone-resistant metastatic disease who had progressed after chemotherapy with low-dose cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) or with L-phenylalanine mustard underwent treatment with a low-dose Adriamycin regimen,i.e., 20 mg/m2, intravenously on days 1 and 8 every 28 days. Two percent of patients had complete responses; 25%, partial responses; 38%, stabilization; and 35%, progression. The time to progression for the responders was similar to that of the stabilized patients, while the responders and stabilized patients survived significantly longer than did the progressors. Responses were seen in nodal, hepatic, dermal/subcutaneous, bone, pulmonary, and peritoneal metastases. The toxicity was mild: 18% of patients had leukocyte counts of less than 3,000/mm3; 10% had platelet counts of less than 90,000/mm3, 22% experience vomiting; and 33% had hair loss. No patient experienced local venous/subcutaneous toxicity or heart failure. Since this regimen of low-dose Adriamycin appears to be as effective as, but less toxic than, the secondary standard-dose of Adriamycin at 60--75 mg/m2 every three weeks, a randomized trial of low-dose Adriamycin vs. standard-dose Adriamycin should be conducted in metastatic breast cancer patients who have previously undergone chemotherapy.
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PMID:An effective low-dose adriamycin regimen as secondary chemotherapy for metastatic breast cancer patients. 739 18

Trypanosoma cruzi, a protozoan parasite, is the etiologic agent of American trypanosomiasis or Chagas' disease. Chagas' disease afflicts more than 24 million individuals in South and Central America producing a debilitating life-long disease. It is the leading cause of heart failure in many Latin American countries. Currently, there is no satisfactory treatment for this parasitic infection. Cruzain (also known as cruzipain, gp 57/51), the major cysteine protease present in T. cruzi, is critical for the development and survival of the parasite within the host cells, making this enzyme a target for potential trypanocidal drugs. Here we report the X-ray crystal structure of cruzain complexed with the potent inhibitor Z-Phe-Ala-fluoromethyl ketone. The structure was determined at 2.35 A (Rcryst = 0.15) by molecular replacement using a modified papain as the search model. The refined structure is compared to papain. Features which distinguish cruzain from papain are discussed since they may aid in the design of specificity inhibitors. Fluorescence microscopy shows that a biotinylated form of the bound inhibitor does not effectively reach host proteases in their lysosomal compartment, but is selectively taken up by the parasite. The inhibitor greatly reduces parasitemia in a cell culture system, without adverse effects to mammalian cells. This biological selectivity can be exploited, in conjunction with unique active site features revealed by the crystal structure, to develop chemotherapy for Chagas' disease.
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PMID:The crystal structure of cruzain: a therapeutic target for Chagas' disease. 770 73

Synthesis of angiotensin-converting enzyme is induced during its chronic inhibition. Like angiotensin-converting enzyme, neutral endopeptidase (EC 3.4.24.11) is a plasma membrane peptidase. We studied changes of the two enzymes in lung, kidney and serum in a coronary ligation model of experimental congestive heart failure, and during chronic inhibition of the enzymes. Coronary-ligated rats (n = 19) and sham-operated controls (n = 18) were given SCH 34826 [(S)-N-[N-[1-[[(2,2-dimethyl-1,3-dioxolan-4-yl) methoxy]carbonyl]-2-phenylethyl]-L-phenylalanine]-beta-alanine], a specific neutral endopeptidase inhibitor (n = 13), captopril (n = 12), or vehicle (n = 12) for 4 days, and exsanguinated. Pulmonary angiotensin-converting enzyme was induced both by captopril (52% compared to vehicle) and by SCH 34826 (21%). Serum angiotensin-converting enzyme was induced by captopril (44%). Neutral endopeptidase was induced in lung by captopril (73%), and in kidney by SCH 38426 (32%). Compared to controls, the relative heart weight of rats with heart failure was increased by 29%, and the plasma level of atrial natriuretic peptide elevated by 74%, but enzyme activities were not different. We conclude that, in the rat, separate inhibition of either angiotensin-converting enzyme or neutral endopeptidase induces both enzymes, and that the induction varies in different tissues. Alterations in the substrates of the two enzymes, e.g. in bradykinin, might cause these changes.
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PMID:Inhibition of either angiotensin-converting enzyme or neutral endopeptidase induces both enzymes. 785 75

Baroreflex sensitivity (BRS) conveys useful prognostic information in patients with heart disease, yet methods for its quantification suffer from poor reproducibility and test failure in some patients with heart failure. We set out to compare the short-term reproducibility and success rate of four different methods of assessing BRS in normal subjects and patients with chronic heart failure (CHF). A total of 31 patients with CHF and 18 normal controls underwent BRS testing using four techniques: (1) bolus phenylephrine (BRS(Phe)), (2) alpha-index in both low- and high-frequency bands (BRS(alphaLF) and BRS(alphaHF) respectively), (3) the sequence method (BRS(Seq)), and (4) a new 0.1 Hz controlled-breathing, time-domain analysis method (BRS(Cbr)). Each subject underwent two test episodes with each method on the same day. The average values for BRS in patients and controls respectively were: BRS(Phe), 4.4 (+/-4.4) ms/mmHg and 19.8 (+/-11.5) ms/mmHg; BRS(alphaLF), 5.6 (+/-4.1) ms/mmHg and 15.4 (+/-5.0) ms/mmHg; BRS(alphaHF), 7.1 (+/-7.0) ms/mmHg and 25.1 (+/-8.3) ms/mmHg; BRS(Seq), 7.7 (+/-6.3) ms/mmHg and 22.5 (+/-8.4) ms/mmHg; BRS(Cbr), 6.6 (+/-5.9) ms/mmHg and 22.8 (+/-10.8) ms/mmHg. The coefficients of variation (S.D. of the difference in repeated values divided by mean) in patients and controls respectively were: BRS(Phe), 85.6% and 52.2%; BRS(alphaLF), 65.9% and 33.7%; BRS(alphaHF), 99.7% and 52. 1%; BRS(Seq), 30.7% and 40.4%; BRS(Cbr), 30.7% and 19.6%. The numbers of test failures in patients were: BRS(Phen), 15; BRS(alphaLF), 7; BRS(alphaHF), 5; BRS(Seq), 14; BRS(Cbr), 1. Of the four techniques assessed for measuring BRS, the controlled breathing time-domain method yielded the best reproducibility and lowest failure rate in controls and in patients with CHF.
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PMID:Reproducibility of methods for assessing baroreflex sensitivity in normal controls and in patients with chronic heart failure. 1049 52

We tested an innovative approach for estimating baroreflex sensitivity (BRS) from the gain function between spontaneous oscillations of systolic arterial pressure (SAP) and heart period (HP). The major goal was to assess the practical implications of abandoning the classical coherence criterion (> or =0.5) as regards measurability of BRS, and agreement with values of BRS obtained using the phenylephrine test (Phe-BRS). We studied 19 normal subjects, 44 patients with a history of previous myocardial infarction (MI) and 45 patients with chronic heart failure (CHF). The experimental protocol included recording of SAP and HP for 10 min of supine rest, and evaluation of Phe-BRS. From resting SAP and HP, the gain and coherence functions were computed. The new BRS index was obtained in all subjects by averaging the gain function over the whole low-frequency band (0.04-0.15 Hz) (whole-band average BRS, WBA-BRS). WBA-BRS was 7.4 (5.8-10.8) ms/mmHg [median (25th-75th percentile)] in normal controls, 3.1 (1.4-5.4) ms/mmHg in MI patients (P<0.001 compared with normals) and 5.0 (3.2-6.9) ms/mmHg in CHF patients (P<0.01 compared with normals). Using the coherence criterion, BRS could be measured in only 43% and 49% of MI and CHF patients respectively, and the proportion of the low-frequency band contributing to the measurement was 21% (14-47%) and 29% (16-35%) respectively. The correlation between WBA-BRS and Phe-BRS was 0.47, 0.63 and 0.36 in the normal, MI and CHF groups respectively (all P<0.001). The relative bias of WBA-BRS was -5.2 ms/mmHg (P<0.001) in normals, -1.4 ms/mmHg (P=0.004) in MI patients and -1.0 ms/mmHg (P=0.11) in CHF patients. The limits of agreement were -13 to 2.6, -7.4 to 4.6 and -9.3 to 7.3 ms/mmHg in the normal, MI and CHF groups respectively. Thus the WBA-BRS method standardizes the computation of BRS among subjects, and dramatically increases its measurability in subjects with pathology compared with the classical spectral technique based on the coherence criterion. Compared with Phe-BRS, WBA-BRS tends to give negatively biased results. The correlation and the magnitude of the limits of agreement between the two methods are similar to those observed previously using coherence-based spectral methods.
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PMID:Measuring baroreflex sensitivity from the gain function between arterial pressure and heart period. 1209 9

Heart failure (HF) is a slow progressive syndrome characterized by low cardiac output and peripheral metabolic, biochemical, and histological alterations. Protein loss and reduced protein turnover occur with aging, but the consequences of congestive HF (CHF) superimposed on the normal aging response are unknown. This study has two objectives: 1) to determine whether there was a difference between older age-matched controls and those with stable HF (i.e., ischemic pathology) in whole body protein turnover and 2) to determine whether protein metabolism in liver and skeletal muscle protein turnover is impacted by CHF. We measured the whole body protein synthesis rate with a U-(15)N-labeled algal protein hydrolysate in 10 patients with CHF and in 10 age-matched controls. Muscle fractional synthesis rate of lateral vastus muscle was determined with [U-(13)C]alanine on muscle biopsies obtained by a standard percutaneous needle biopsy technique. Fractional synthesis rates of five plasma proteins of hepatic origin (fibrinogen, complement C-3, ceruloplasmin, transferrin, and very low-density lipoprotein apoliprotein B-100) were determined by using (2)H(5)-labeled l-phenylalanine as tracer. Results showed that whole body protein synthesis rate was reduced in CHF patients (3.09 +/- 0.19 vs. 2.25 +/- 0.71 g protein x kg(-1) x day(-1), P < 0.05) as was muscle fractional synthesis rate (3.02 +/- 0.58 vs. 1.33 +/- 0.71%/day, P < 0.05) and very low-density lipoprotein apoliprotein B-100 (265 +/- 25 vs. 197 +/- 16%/day, P < 0.05). CHF patients were hyperinsulinemic (9.6 +/- 3.1 vs. 47.0 +/- 7.8 microU/ml, P < 0.01). The results were compared with those found with bed rest patients. In conclusion, protein turnover is depressed in CHF patients, and both skeletal muscle and liver are impacted. These results are similar to those found with bed rest, which suggests that inactivity is a factor in depressed protein metabolism.
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PMID:Protein kinetics in stable heart failure patients. 1239 Oct 30

Scorpion human envenoming is a public health hazard in the southwest of Venezuela. Tityus zulianus is one of the scorpion species whose venom causes lung edema and cardiac failure in children. These occasionally deadly manifestations have been attributed to a massive sympathetic discharge. The intraperitoneal administration of T. zulianus venom (20 micrograms/g mouse) to anesthetized mice during subcutaneous microdialysis caused increased secretions, dyspnea, seizures and death between 30 min to 2 h. Seven amino acids were analyzed by capillary electrophoresis with laser induced fluorescence detection (CE-LIFD) in the collected samples before and after the venom administration. We found an increase of arginine (39%), phenylalanine (40%) and glutamate (94%), with no changes in valine, serine and aspartate, changes were significant when the injection of venom and vehicle were compared and before vs after venom injection. Further investigation is needed to know if the observed changes could be related to the molecular mechanisms of the venom or some of its components and therefore with the envenoming symptoms. To our knowledge, this is the first report with subcutaneous microdialysis and CE-LIFD coupling in scorpion envenomation studies in vivo, in mice.
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PMID:[Amino acid changes following intraperitoneal administration of Tityus zulianus scorpion venom in mice. Study with subcutaneous microdialysis and capillary electrophoresis]. 1472 83

The Na+/Ca2+ exchanger (NCX) is an ion transporter that exchanges Na+ and Ca2+ in either Ca2+ efflux or Ca2+ influx mode, depending on membrane potential and transmembrane ion gradients. In myocytes, neurons, and nephron cells, NCX is thought to play an important role in the regulation of intracellular Ca2+ concentration. Recently, the benzyloxyphenyl derivatives KB-R7943, SEA0400, and SN-6 have been developed as selective NCX inhibitors. Currently, SEA0400 is the most potent and selective inhibitor. These inhibitors possess different isoform-selectivities, although they have similar properties, such as Ca2+ influx mode-selectivity and I1 inactivation-dependence. Recent site-directed mutagenesis has revealed that these inhibitors possess some molecular determinants (Phe-213, Val-227, Tyr-228, Gly-833, and Asn-839) for interaction with NCX1. These benzyloxyphenyl derivatives are expected to be useful tools to study the physiological roles of NCX. Moreover, such inhibitors may have therapeutic potential as a new remedy for ischemic disease, arrhythmias, heart failure, and hypertension.
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PMID:Forefront of Na+/Ca2+ exchanger studies: molecular pharmacology of Na+/Ca2+ exchange inhibitors. 1535 84

The cardiac isoform of the ryanodine receptor (RyR2) from dog binds predominantly a 12.6-kDa isoform of the FK506-binding protein (FKBP12.6), whereas RyR2 from other species binds both FKBP12.6 and the closely related isoform FKBP12. The role played by FKBP12.6 in modulating calcium release by RyR2 is unclear at present. We have used cryoelectron microscopy and three-dimensional (3D) reconstruction techniques to determine the binding position of FKBP12.6 on the surface of canine RyR2. Buffer conditions that should favor the "open" state of RyR2 were used. Quantitative comparison of 3D reconstructions of RyR2 in the presence and absence of FKBP12.6 reveals that FKBP12.6 binds along the sides of the square-shaped cytoplasmic region of the receptor, adjacent to domain 9, which forms part of the four clamp (corner-forming) structures. The location of the FKBP12.6 binding site on "open" RyR2 appears similar, but slightly displaced (by 1-2 nm) from that found previously for FKBP12 binding to the skeletal muscle ryanodine receptor that was in the buffer that favors the "closed" state. The conformation of RyR2 containing bound FKBP12.6 differs considerably from that depleted of FKBP12.6, particularly in the transmembrane region and in the clamp structures. The x-ray structure of FKBP12.6 was docked into the region of the 3D reconstruction that is attributable to bound FKBP12.6, to show the relative orientations of amino acid residues (Gln-31, Asn-32, Phe-59) that have been implicated as being critical in interactions with RyR2. A thorough understanding of the structural basis of RyR2-FKBP12.6 interaction should aid in understanding the roles that have been proposed for FKBP12.6 in heart failure and in certain forms of sudden cardiac death.
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PMID:Three-dimensional visualization of FKBP12.6 binding to an open conformation of cardiac ryanodine receptor. 1621 74

Accumulating evidence demonstrates the involvement of oxidative stress in the pathophysiology of cardiovascular diseases. The molecular mechanisms accountable for the increased production of reactive oxygen species remain uncertain. Among others, NADPH oxidase is one of the most important sources of superoxide in vascular cells. Here we investigate the role of NF-kB in the regulation of p22(phox) subunit and NADPH oxidase activity, in human aortic smooth muscle cells. Overexpression of p65/RelA or IKKbeta up-regulated p22(phox) gene promoter activity. Transcription factor pull-down assays demonstrated the physical interaction of p65/RelA protein with predicted NF-kB binding sites. Real time PCR and Western blotting analysis showed that p22(phox) mRNA and protein expression are significantly down-regulated by NF-kB decoy oligodeoxynucleotides and N-alpha-tosyl-l-phenylalanine chloromethyl ketone (TPCK). Lucigenin-enhanced chemiluminescence assay revealed that NF-kB inhibitors reduce the NADPH-dependent superoxide production. Regulation of NADPH oxidase by NF-kB may represent a possible mechanism whereby pro-inflammatory factors induce oxidative stress in atherosclerosis, hypertension, diabetes, stroke or heart failure.
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PMID:Regulation of NADPH oxidase subunit p22(phox) by NF-kB in human aortic smooth muscle cells. 1815 42

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