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2,333,300 |
[Investigation of properties of the thermostable protein complex obtained from the myocardium left ventricles of adult white rats].
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A thermostable protein complex (TSPC) obtained from the myocardium ventricules of adult rats inhibits mitotic and transcriptional activity of cardiomyocytes. At the same time this complex is more active on early stages of the postnatal ontogenesis in rats, aged 1 and 5 days. Following its action on RNA synthesis, the TSPC reveals tissue specificity only in cells with terminal differentiation, and is determined by its nuclear membranes. We continue studies for identifying the molecular weight and chemical nature of the TSPC, and the role of its different fractions in regulation of proliferation processes. Besides, it is planned to produce antibodies against TSPC fractions with the purpose to block its inhibitory effect on myocyte regeneration in the damaged myocardium.
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2,333,301 |
Ancillary subunits and stimulation frequency determine the potency of chromanol 293B block of the KCNQ1 potassium channel.
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KCNQ1 (Kv7.1 or KvLQT1) encodes the alpha-subunit of a voltage-gated potassium channel found in tissues including heart, brain, epithelia and smooth muscle. Tissue-specific characteristics of KCNQ1 current are diverse, due to modification by ancillary subunits. In heart, KCNQ1 associates with KCNE1 (MinK), producing a slowly activating voltage-dependent channel. In epithelia, KCNQ1 co-assembles with KCNE3 (Mirp2) producing a constitutively open channel. Chromanol 293B is a selective KCNQ1 blocker. We studied drug binding and frequency dependence of 293B on KCNQ1 and ancillary subunits expressed in Xenopus oocytes. Ancillary subunits altered 293B potency up to 100-fold (IC(50) for KCNQ1 = 65.4 +/- 1.7 microm; KCNQ1/KCNE1 = 15.1 +/- 3.3 microm; KCNQ1/KCNE3 = 0.54 +/- 0.18 microm). Block of KCNQ1 and KCNQ1/KCNE3 was time independent, but 293B altered KCNQ1/KCNE1 activation. We therefore studied frequency-dependent block of KCNQ1/KCNE1. Repetitive rapid stimulation increased KCNQ1/KCNE1 current biphasically, and 293B abolished the slow component. KCNQ1/KCNE3[V72T] activates slowly with a KCNQ1/KCNE1-like phenotype, but retains the high affinity binding of KCNQ1/KCNE3, demonstrating that subunit-mediated changes in gating can be dissociated from subunit-mediated changes in affinity. This study demonstrates the KCNQ1 pharmacology is significantly altered by ancillary subunits. The response of KCNQ1 to specific blockers will therefore be critically dependent on the electrical stimulation pattern of the target organ. Furthermore, the dissociation between gating and overall affinity suggests that mutations in ancillary subunits can potentially strongly alter drug sensitivity without obvious functional changes in gating behaviour, giving rise to unexpected side-effects such as a predisposition to acquired long QT syndrome.
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2,333,302 |
Long-term and immediate effect of testosterone on single T-type calcium channel in neonatal rat cardiomyocytes.
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In the cardiovascular system, T-type calcium channels play an important role for the intracellular calcium homeostasis and spontaneous pacemaker activity and are involved in the progression of structural heart diseases. Androgens influence the cardiovascular physiology and pathophysiology. However, their effect on native T-type calcium currents (I(Ca,T)) remains unclear. To test the chronic effect of testosterone on the cardiac I(Ca,T), cultured neonatal rat ventricular cardiomyocytes were treated with testosterone (1 nM-10 microM) for 24-30 h. Current measurements were performed after testosterone washout to exclude any acute testosterone effects. Testosterone (100 nm) pretreatment significantly increased whole-cell I(Ca,T) density from 1.26 +/- 0.48 pA/pF (n = 8) to 5.06 +/- 1.75 pA/pF (n = 7; P < 0.05) and accelerated beating rate. This was attributed to both increased expression levels of the pore-forming subunits Ca(v)3.1 and Ca(v)3.2 and increased T-type single-channel activity. On single-channel level, the increase of the ensemble average current by testosterone vs. time-matched controls was due to an increased availability (58.1 +/- 4.2 vs. 21.5 +/- 4.0%, P < 0.01) and open probability (2.78 +/- 0.29 vs. 0.85 +/- 0.23%, P < 0.01). Cotreatment with the selective testosterone receptor antagonist flutamide (10 mum) prevented these chronic testosterone-induced effects. Conversely, acute application of testosterone (10 microM) decreased T-type single-channel activity in testosterone pretreated cells by reducing the open probability (0.78 +/- 0.13 vs. 2.91 +/- 0.38%, P < 0.01), availability (23.6 +/- 3.3 vs. 57.6 +/- 4.5%, P < 0.01), and peak current (-20 +/- 4 vs. -58 +/- 4 fA, P < 0.01). Flutamide (10 microM) did not abolish the testosterone-induced acute block of T-type calcium channels. Our results indicate that long-term testosterone treatment increases, whereas acute testosterone decreases neonatal rat T-type calcium currents. These effects seem to be mediated by a genomic chronic stimulation and a nongenomic acute inhibitory action.
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2,333,303 |
Successful resuscitation of a patient with ropivacaine-induced asystole after axillary plexus block using lipid infusion.
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Ropivacaine 1% 40 ml was mistakenly injected as part of an axillary plexus block in an 84-year-old woman. After 15 min the patient complained of dizziness and drowsiness and developed a generalised tonic-clonic seizure followed by an asystolic cardiac arrest. After 10 min of unsuccessful cardiopulmonary resuscitation, a bolus of 100 ml of Intralipid 20% (2 ml.kg(-1)) was administered followed by a continuous infusion of 10 ml.min(-1). After a total dose of 200 ml of Intralipid 20% had been given spontaneous electrical activity and cardiac output was restored. The patient recovered completely. We believe the cardiovascular collapse was secondary to ropivacaine absorption following the accidental overdose. This case shows that lipid infusion may have a beneficial role in cases of local anaesthetic toxicity when conventional resuscitation has been unsuccessful.
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2,333,304 |
The effect of peribulbar block with ropivacaine on bi-hemispheric cerebral oxygen saturation in aged patients.
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We evaluated the effects of peribulbar block for eye surgery on bi-hemispheric regional cerebral oxygenation (rSO2)) of aged patients. In 66 adult patients, peribulbar block was performed using ropivacaine 10 mg.ml(-1) with hyaluronidase 100 IU.ml(-1). Cerebral oxygenation was monitored using continuous non-invasive, near-infrared spectroscopy. The rSO2 data on the side where the eye block was performed were evaluated as eye block side values, whereas the data recorded on the other side were taken as control values. Mean rSO2 values on the side where regional block was performed were not significantly different from control values (p > 0.05). Nevertheless, in several patients, a slight desaturation in the cerebral hemisphere on the block side was detected. Therefore, in aged patients, peribulbar block with ropivacaine does not significantly modify bi-hemispheric rSO2, but rSO2 monitoring during peribulbar block should be a field of future research in aged patients with brain injury or disease.
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2,333,305 |
Structural basis for platelet collagen responses by the immune-type receptor glycoprotein VI.
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Activation of circulating platelets by exposed vessel wall collagen is a primary step in the pathogenesis of heart attack and stroke, and drugs to block platelet activation have successfully reduced cardiovascular morbidity and mortality. In humans and mice, collagen activation of platelets is mediated by glycoprotein VI (GPVI), a receptor that is homologous to immune receptors but bears little sequence similarity to known matrix protein adhesion receptors. Here we present the crystal structure of the collagen-binding domain of human GPVI and characterize its interaction with a collagen-related peptide. Like related immune receptors, GPVI contains 2 immunoglobulin-like domains arranged in a perpendicular orientation. Significantly, GPVI forms a back-to-back dimer in the crystal, an arrangement that could explain data previously obtained from cell-surface GPVI inhibition studies. Docking algorithms identify 2 parallel grooves on the GPVI dimer surface as collagen-binding sites, and the orientation and spacing of these grooves precisely match the dimensions of an intact collagen fiber. These findings provide a structural basis for the ability of an immune-type receptor to generate signaling responses to collagen and for the development of GPVI inhibitors as new therapies for human cardiovascular disease.
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2,333,306 |
Cell adhesion molecules for targeted drug delivery.
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Rapid advancement of the understanding of the structure and function of cell adhesion molecules (i.e., integrins, cadherins) has impacted the design and development of drugs (i.e., peptide, proteins) with the potential to treat cancer and heart and autoimmune diseases. For example, RGD peptides/peptidomimetics have been marketed as anti-thrombic agents and are being investigated for inhibiting tumor angiogenesis. Other cell adhesion peptides derived from ICAM-1 and LFA-1 sequences were found to block T-cell adhesion to vascular endothelial cells and epithelial cells; these peptides are being investigated for treating autoimmune diseases. Recent findings suggest that cell adhesion receptors such as integrins can internalize their peptide ligands into the intracellular space. Thus, many cell adhesion peptides (i.e., RGD peptide) were used to target drugs, particles, and diagnostic agents to a specific cell that has increased expression of cell adhesion receptors. This review is focused on the utilization of cell adhesion peptides and receptors in specific targeted drug delivery, diagnostics, and tissue engineering. In the future, more information on the mechanism of internalization and intracellular trafficking of cell adhesion molecules will be exploited for delivering drug molecules to a specific type of cell or for diagnosis of cancer and heart and autoimmune diseases.
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2,333,307 |
Contributions of GABAergic and glutamatergic mechanisms to isoflurane-induced suppression of thalamic somatosensory information transfer.
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Indications for a pivotal role of the thalamocortical network in producing the state of anesthesia have come from in vivo animal studies as well as imaging studies in humans. We studied possible synaptic mechanisms of anesthesia-induced suppression of touch perception in the rat's thalamus. Thalamocortical relay neurons (TCNs) receive ascending and descending glutamatergic excitatory inputs via NMDA and non-NMDA receptors (AMPAR) and are subjected to GABA(A)ergic inhibitory input which shapes the sensory information conveyed to the cortex. The involvement of these synaptic receptors in the suppressive effects of the prototypic volatile anesthetic isoflurane was assessed by local iontophoretic administration of receptor agonists/antagonists during extracellular recordings of TCNs of the ventral posteromedial nucleus responding to whisker vibration in rats anesthetized with isoflurane concentrations of approximately 0.9 vol.% (baseline) and approximately 1.9 vol.% (ISO high). ISO high induced a profound suppression of response activity reflected by a conversion of the sustained vibratory responses to ON responses. Administration of NMDA, AMPA, or GABA(A)R antagonists caused a reversal to sustained responses in 88, 94 and 88% of the neurons, respectively, with a recovery to baseline levels of response activity. The data show that the block of thalamocortical transfer of tactile information under ISO high may result from an enhancement of GABA(A)ergic inhibition and/or a reduction of glutamatergic excitation. Furthermore, they show that the ascending vibratory signals still reach the thalamic neurons under the high isoflurane concentration, indicating that this input is resistant to isoflurane while the attenuation of excitation may be brought about at the corticothalamic glutamatergic facilitatory input.
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2,333,308 |
[Effect of serum autoantibodies against the M2 muscarinic acetylcholine receptors from patients with heart failure on L-Type Ca2+ channel activity in guinea pig cardiac myocytes].
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To investigate the effect of serum autoantibodies against the human M(2) muscarinic acetylcholine receptors (M(2)-receptors, Abs) from patients with congestive heart failure on L-Type Ca(2+) channel activity in guinea pig cardiac myocytes.</AbstractText>Using whole cell patch-clamp technique, we quantitatively measured the ionic intensity and density of L-Type Ca(2+) channel (I(Ca-L)).</AbstractText>The M(2)-receptors agonist (carbachol) could decrease the I(Ca-L) peak intensity and density stimulated by isoprenaline from (2111.65 +/- 203.13) pA and (18.83 +/- 1.14) pA/pF to (1230.87 +/- 208.14) pA (P < 0.01) and (10.72 +/- 1.06) pA/pF (P < 0.01). The serum Abs could also decrease I(Ca-L) peak intensity and density [from (1995.21 +/- 195.13) pA and (18.13 +/- 1.03) pA/pF to (636.42 +/- 110.07) pA (P < 0.01) and (5.54 +/- 0.81) pA/pF, P < 0.01]. The M(2)-receptors antagonist, atropine was able to block these effects of carbachol and Abs.</AbstractText>The circulating serum autoantibodies against the M(2)-receptors has similar effect as M(2)-receptors agonist on decreasing the isoprenaline stimulated I(Ca-L) in guinea pig cardiac myocytes and possess negative inotropic effect. These results further suggest that serum autoantibodies against the human M(2) muscarinic acetylcholine receptors may participate in the pathophysiological processes in patients with heart failure.</AbstractText>
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2,333,309 |
[Tolerance of Huso dauricus embryo at its different development stages to low temperature].
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This paper studied the embryo hatching rate and larva survival rate of Huso dauricus when the embryo at its different development stages was exposed to low temperature for different durations. The results showed that the embryo at its yolk plug, narrow-opening, and neural block closing stages could not survive at 2 - 8 degrees C over 24 h. When exposed to 2 - 8 degrees C for 3 days, the hatching rate of embryo at its cleavage, early blastula, and mid gastrula stages was lower than 30%. Both the embryo hatching rate and the larva survival rate were higher than 70% when the embryo at its late blastula, early blastula, optic rudiment, tail bud, heart beating, and tail touching head stages was exposed to 5 - 8 degrees C for 3 days. The death rates of embryo and larva under low temperature were increased with time. There was a negative correlation between the exposure duration at low temperature and the embryo hatching rate (r = - 0.8024) and larva survival rate (r = - 0.8468) of H. dauricus. The embryo at its late blastula, early gastrula, and optic rudiment stages had a stronger tolerance at 5 degrees C for 10 h, with the embryo hatching rate and larva survival rate being higher than 70%. It could be concluded that there was a little difference in embryo hatching rate and larva survival rate of H. dauricus when the embryo at its some development stages was preserved at low temperatures at least for 10 - 15 days and at normal temperature (16 - 17 degrees C).
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2,333,310 |
Sensitization following LVAD implantation using leucodepleted blood is not due to HLA antibodies.
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Implantation of left ventricular assist devices (LVAD) is associated with HLA antibody sensitization. The objective of this study was to determine the specificity of antibodies produced by LVAD recipients using a combination of ELISA, Luminex and microcytotoxicity assays. Fifty-one LVAD patients were studied, from 44 to 838 days post-implantation. No patient developed HLA antibodies, although 24 produced IgG antibodies detectable in both ELISA and Luminex assays. These antibodies manifest as positive reactions with class I and class II wells of the ELISA and also blank wells. In Luminex assays, they produce high MFI readings with the negative control beads. Antibodies were detected 18 to 228 days after implantation. This reactivity was found to be directed against bovine serum albumin (BSA), commonly used to block non-specific binding in ELISA and Luminex assays; absorption of sera with BSA-coated beads completely abrogated reactivity in all solid phase assays, but did not eliminate anti-HLA antibodies in control sera. Ten of the 24 patients have proceeded to transplantation, with a 1-year graft survival of 69%. In conclusion, it appears that implantation of LVADS disrupts immunoregulatory pathways leading to production of anti-albumin antibodies. These can be misinterpreted as anti-HLA antibodies in solid phase assays.
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2,333,311 |
Essential role of ICAM-1/CD18 in mediating EPC recruitment, angiogenesis, and repair to the infarcted myocardium.
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Bone marrow-derived endothelial progenitor cells (EPCs) have the ability to migrate to ischemic organs. However, the signals that mediate trafficking and recruitment of these cells are not well understood. Using a functional genomics strategy, we determined the genes that were upregulated in the ischemic myocardium and might be involved in EPC recruitment. Among them, CD18 and its ligand ICAM-1 are particularly intriguing because CD18 and its heterodimer binding chains CD11a and CD11b were correspondingly expressed in ex vivo-expanded EPCs isolated from rat and murine bone marrows. To further verify the functional role of CD18 in mediating EPC recruitment and repair to the infarcted myocardium, we used neutralizing antibody to block CD18. Blockade of CD18 in EPCs significantly inhibited their attachment capacity in vitro and reduced their recruitment to the ischemic myocardium in vivo by 95%. Moreover, mice receiving EPCs that were treated with control isotype IgG exhibited significantly increased capillary density in the infarct border zone, reduced cardiac dilatation, ventricular wall thinning, and fibrosis when compared with myocardial infarction mice receiving PBS and CD18 blockade reversed the EPC-mediated improvements to the infarcted heart. Thus, our results suggest an essential role of CD18 in mediating EPC recruitment and the subsequent functional effects on the infarcted heart.
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2,333,312 |
Regional cardiac dysfunction is associated with specific alterations in inflammatory cytokines and matrix metalloproteinases after acute myocardial infarction in sheep.
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Cardiac remodeling following myocardial infarction (MI) is a maladaptive process, fundamental to the progression of ischemic heart failure. The extent of remodeling is influenced by mechanical stress, inflammatory response and activation of matrix metalloproteinases (MMPs). This study examined regional association between these parameters in response to acute MI. Coronary ligation was performed in ten sheep. Sonomicrometer transducers measured segmental length in the infarcted, border and non-infarcted region. Regional tissue samples obtained 3 h post MI from six sheep were analysed using RT-PCR, gelatin zymography and Western blot. Six sham-operated sheep served as controls.Region-specific dilation and reduced contraction was associated with corresponding alterations in matrix molecules.IL-6 and MMP-9 mRNA were increased in the infarcted and border regions compared to controls.MMP-2 and TIMP-1 mRNA increased in non-infarcted myocardium and both correlated positively with segmental shortening. IL-6 mRNA levels, in contrast, were negatively associated with segmental shortening. In summary, inflammatory cytokines and MMPs are altered early after MI in a region-specific manner, and these changes correspond to acute regional myocardial dysfunction. Therapies for LV remodeling from the time of reperfusion may benefit from further understanding this portfolio of acute alterations.
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2,333,313 |
A surprising case of sustained antenatal fetal bradycardia.
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Persistent fetal bradycardia noted in the antenatal period can occur secondary to maternal conditions, fetal cardiac structural defects, or from congenital heart block. Fetal bradycardia can be mistaken for maternal pulse and should be confirmed with ultrasound whenever possible. Prompt evaluation of the fetus with bradycardia can lead to early interventions designed to prevent cardiac damage and/or hydrops.
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2,333,314 |
A comparison of effects of alfentanil, fentanyl, and remifentanil on hemodynamic and respiratory parameters during stereotactic brain biopsy.
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The aim of this study was to compare the effects of 3 different sedative-analgesic regimens in patients with intracranial mass lesions undergoing stereotactic brain biopsy. A 135 outpatients with American Society of Anesthesiologists I to II were divided into 3 groups: group A (n = 45) received a loading dose of IV alfentanil 7.5 microg/kg followed by infusion rate of 0.25 microg/kg/min; group F (n = 45) received a bolus dose of 1 microg/kg IV fentanyl and repeated as needed; and group R (n = 45) received infusion of 0.05 microg/kg/min remifentanil. Target level of sedation was 3 to 4 of the Ramsay Sedation Scale. Systolic and diastolic blood pressure, heart rate, respiratory rate, peripheric oxygen saturation (SpO2), and end-tidal carbon dioxide were recorded at different stages of the procedures. The patients in group F had significantly lower mean heart rate than those in groups A and R, but this was not in the limits of the bradycardia. The patients in group A had significantly lower mean SpO2 than those in the other groups, but mean SpO2 values did not drop below 94%. There were no significant differences in end-tidal carbon dioxide and respiratory rate values among the groups. Our results suggest that all 3 regimens have relatively similar hemodynamic and respiratory responses. The use of bolus fentanyl technique caused less hemodynamic stability. The continuous infusion technique of remifentanil or alfentanil provided better control on hemodynamic parameters.
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2,333,315 |
Ultrasonography-guided rectus sheath block in paediatric anaesthesia--a new approach to an old technique.
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The purpose of this study was an anatomical and clinical evaluation of ultrasonography-guided rectus sheath blocks in children.</AbstractText>A total of 30 children were included in the sono-anatomical part of the study. The depth of the anterior and posterior rectus sheath was evaluated with a portable SonSite 180 plus ultrasound machine and a 5-10 MHz linear probe. In total, 20 consecutive children undergoing umbilical hernia repair were included in the clinical part of this study. After induction of general anaesthesia children received a rectus sheath block under real-time ultrasonographic guidance by placing 0.1 ml kg(-1) bilaterally in the space between the posterior aspect of the sheath and the rectus abdominis muscle.</AbstractText>Ultrasonographic visualization of the posterior rectus sheath was possible in all children. The correlation between the depth of the posterior rectus sheath and weight (adjusted r(2)=0.175), height (adjusted r(2)=0.314) and body surface area (adjusted r(2)=0.241) was poor. The ultrasound-guided rectus sheath blockade provided sufficient analgesia in all children with no need for additional analgesia in the perioperative period.</AbstractText>The bilateral placement of levobupivacaine 0.25% 0.1 ml kg(-1) in the space between the posterior aspect of the rectus sheath and the rectus abdominis muscle under real-time ultrasonographic guidance provides sufficient analgesia for umbilical hernia repair. The unpredictable depth of the posterior rectus sheath in children is a good argument for the use of ultrasonography in this regional anaesthetic technique in children.</AbstractText>
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2,333,316 |
[Cardiac manifestations during viral acute hepatitis].
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The authors describe a retrospective study conducted on 46 patients with acute viral hepatitis, searching for cardiac disorders. These disorders appeared in about 43% of cases, only with benign evolution. The most frequent alterations are electrocardiographic disorders, followed by conduction blocks, axis deviations and arrhythmias. Acute pericarditis was also described, associated with HCV infection. The viral agents most frequently involved are HBV and HCV, followed by cytomegalovirus, and Epstein-Barr virus. In conclusion, the incidence of cardiac manifestations during viral acute hepatitis is rather high, but with benign evolution.
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2,333,317 |
Testosterone is required for delayed cardioprotection and enhanced heat shock protein 70 expression induced by preconditioning.
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Ischemic preconditioning fails to confer immediate cardioprotection in the absence of testosterone, indicating that the hormone is required for the process. Here we set out to determine whether testosterone is also necessary for delayed cardioprotection and, if so, how it acts. Male Sprague Dawley rats (7-8 wk) underwent sham operation or gonadectomy without (G) or with testosterone replacement (GT) for 8 wk. Isolated ventricular myocytes were preconditioned either by metabolic inhibition or with U50,488H, a kappa-opioid receptor agonist. In intact rats, U50,488H was administered systemically and 24 h later the hearts were removed. Ventricular myocytes were then subjected to metabolic inhibition and anoxia and isolated hearts to regional ischemia, followed by reperfusion to induce injury. Both types of preconditioning significantly increased the viability and decreased the lactate dehydrogenase release in ventricular myocytes from sham rats. They also activated heat shock transcription factor-1 and increased heat shock protein 70 expression. In contrast, all these effects were absent in myocytes from G rats and were restored by testosterone replacement. Parallel results were found in isolated hearts. In addition, preconditioning improved contractile functions impaired by ischemic insults in sham and rats gonadectomized with testosterone replacement but not G rats. The effects of testosterone replacement in ventricular myocytes were abolished by androgen receptor blockade. In conclusion, preconditioning requires testosterone to increase heat shock protein 70 synthesis, which mediates delayed cardioprotection in the male. These effects of testosterone are mediated by the androgen receptor.
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2,333,318 |
Modeling the calcium gate of cardiac gap junction channel.
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We addressed the question how Ca2+ transients affect gap junction conductance (Gj) during action potential (AP) propagation by constructing a dynamic gap junction model coupled with a cardiac cell model. The kinetics of the Ca2+ gate was determined based on published experimental findings that the Hill coefficient for the [Ca2+]i-Gj relationship ranges from 3 to 4, indicating multiple ion bindings. It is also suggested that the closure of the Ca2+ gate follows a single exponential time course. After adjusting the model parameters, a two-state (open-closed) model, assuming simultaneous ion bindings, well described both the single exponential decay and the [Ca2+]i-Gj relationship. Using this gap junction model, 30 cardiac cell models were electrically connected in a one-dimensional cable. However, Gj decreased in a cumulative manner by the repetitive Ca2+ transients, and a conduction block was observed. We found that a reopening of the Ca2+ gate is possible only by assuming a sequential ion binding with one rate limiting step in a multistate model. In this model, the gating time constant (T) has a bell-shaped dependence on [Ca2+]i, with a peak around the half-maximal concentration of [Ca2+]i. Here we propose a five-state model including four open states and one closed state, which allows normal AP propagation; namely, the Gj is decreased -15% by a single Ca2+ transient, but well recovers to the control level during diastole. Under the Ca(2+)-overload condition, however, the conduction velocity is indeed decreased as demonstrated experimentally. This new gap junction model may also be useful in simulations of the ventricular arrhythmia.
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2,333,319 |
Atypical MRI findings in Kearns-Sayre syndrome: T2 radial stripes.
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Kearns-Sayre syndrome (KSS) is a mitochondrial disorder consisting of external ophthalmoplegia, retinitis pigmentosa, ataxia and heart block. Magnetic resonance imaging (MRI) shows abnormal T2 high signal intensity in the deep gray matter nuclei, the cerebellar and the subcortical white matter. We report an unusual MR pattern of KSS, where the T2 images revealed radially oriented, hypointense stripes in hyperintense white matter, a characteristic MRI pattern of lysosomal disease not previously reported in KSS.
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2,333,320 |
Evaluation of blood pressure changes using vascular transit time.
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Imbalance of the human haemodynamic system can provide a prognosis of syncope, dizziness or hypertension. This can be assessed by monitoring its responses to postural change. Examining variations in blood pressure (BP) is deemed an effective means to identify symptoms of this associated condition. However, conventional methods do not promote prolonged monitoring due to the discomfort caused to patients. Established correlations between BP and pulse wave transmission have shown its usefulness in clinical applications. In this study, photoplethysmography and phonocardiography were used to estimate BP changes via observed variations in delay transmission or vascular transit time (VTT) at the upper limb. Thirty-one healthy adults (21 male) were recruited to perform three test activities, namely the arm held at heart level, fully raised up and held down. Association of the three BP indices and heart rate variations with transit time changes was then computed. The results showed that observed VTT changes were related to systolic BP (R(2) = 0.820; p < 0.05), diastolic BP (R(2) = 0.517; p < 0.05), mean arterial pressure (R(2) = 0.673; p < 0.05) and heart rate (R(2) = 0.000; p > 0.05). As systolic BP had the strongest correlation, a regression equation was formulated to associate the two parameters. The non-invasive measuring nature of VTT can be more accommodating to patients, especially during continual monitoring. Moreover, it has the added advantage that the pre-ejection period is not included in its time-related derivations.
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2,333,321 |
Monoamine uptake inhibitors block alpha7-nAChR-mediated cerebral nitrergic neurogenic vasodilation.
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We have proposed that activation of cerebral perivascular sympathetic alpha7-nicotinic acetylcholine receptors (alpha7-nAChRs) by nicotinic agonists releases norepinephrine, which then acts on parasympathetic nitrergic nerves, resulting in release of nitric oxide and vasodilation. Using patch-clamp electrophysiology, immunohistochemistry, and in vitro tissue bath myography, we tested this axo-axonal interaction hypothesis further by examining whether blocking norepinephrine reuptake enhanced alpha7-nAChR-mediated cerebral nitrergic neurogenic vasodilation. The results indicated that choline- and nicotine-induced alpha7-nAChR-mediated nitrergic neurogenic relaxation in endothelium-denuded isolated porcine basilar artery rings was enhanced by desipramine and imipramine at lower concentrations (0.03-0.1 microM) but inhibited at higher concentrations (0.3-10 microM). In cultured superior cervical ganglion (SCG) neurons of the pig and rat, choline (0.1-30 mM)-evoked inward currents were reversibly blocked by 1-30 microM mecamylamine, 1-30 microM methyllycaconitine, 10-300 nM alpha-bungarotoxin, and 0.1-10 microM desipramine and imipramine, providing electrophysiological evidence for the presence of similar functional alpha7-nAChRs in cerebral perivascular sympathetic neurons of pigs and rats. In alpha7-nAChR-expressing Xenopus oocytes, choline-elicited inward currents were attenuated by alpha-bungarotoxin, imipramine, and desipramine. These monoamine uptake inhibitors appeared to directly block the alpha7-nAChR, resulting in diminished nicotinic agonist-induced cerebral nitrergic vasodilation. The enhanced nitrergic vasodilation by lower concentrations of monoamine uptake inhibitors is likely due to a greater effect on monoamine uptake than on alpha7-nAChR blockade. These results further support the hypothesis of axo-axonal interaction in nitrergic regulation of cerebral vascular tone.
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2,333,322 |
Matrix metalloproteinase-7 affects connexin-43 levels, electrical conduction, and survival after myocardial infarction.
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Matrix metalloproteinases (MMPs) contribute to left ventricular remodeling after myocardial infarction (MI). Specific causative roles of particular MMPs, however, remain unclear. MMP-7 is abundant in cardiomyocytes and macrophages, but MMP-7 function after MI has not been defined.</AbstractText>Wild-type (WT; n=55) and MMP-7-null (MMP-7-/-; n=32) mice underwent permanent coronary artery ligation for 7 days. MI sizes were similar, but survival was greatly improved in MMP-7-/- mice. The survival difference could not be attributed to differences in left ventricular dilation because end-diastolic volumes increased similarly. ECG analysis revealed a prolonged PR interval in WT but not in MMP-7-/- post-MI mice. Post-MI conduction velocity, determined by optically mapping electrical wavefront propagation, decreased to 78+/-6% of control for WT and was normalized in MMP-7-/- mice. In WT mice, slower conduction velocity correlated with a 53% reduction in the gap junction protein connexin-43. Direct binding of MMP-7 to connexin-43, determined by surface plasmon resonance technology, occurred in a dose-dependent manner. Connexin-43 processing by MMP-7 was confirmed by in silico and in vitro substrate analyses and MMP-7 infusion induced arrhythmias in vivo.</AbstractText>MMP-7 deletion results in improved survival and myocardial conduction patterns after MI. This is the first report to implicate MMP-7 in post-MI remodeling and to demonstrate that connexin-43 is a novel MMP-7 substrate.</AbstractText>
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2,333,323 |
Endothelin-1 and PKC induce positive inotropy without affecting pHi in ventricular myocytes.
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It has been proposed that intracellular alkalinization underlies the enhanced contractility of ventricular myocytes exposed to endothelin (ET)-1. The effects of ET-1 on the contractility and intracellular pH (pH(i)) were examined here in cultured adult rat ventricular myocytes by employing the pH-sensitive fluorescent dye SNARF-1. Variable pH(i) changes were observed on ET-1 stimulation. Most myocytes (n = 20 of 32) did not alkalinize, but showed an approximate 60% increase in twitch amplitude in response to ET-1. In the remaining myocytes (12 of 32), ET-1 induced an increase in pH(i) by 0.05 +/- 0.02 pH units with a similar approximate 60% increase in twitch amplitude. Therefore, there was no strong correlation between ET-1-mediated positive inotropy (enhanced contractility) and intracellular alkalinization. To determine whether ET-1 contractile and pH(i) responses were mediated by protein kinase C (PKC), yellow fluorescent protein (YFP)-fused dominant negative (dn) PKC constructs were used as isoform specific inhibitors. In dn-PKC-epsilon-YFP-expressing myocytes, the ET-1-mediated positive inotropic response was greatly diminished to 13 +/- 15%, but alkalinization was still observed. Expression of dn-PKC-delta-YFP also did not block alkalinization, but in this case the positive inotropic response was still observed. In a previous study, we showed that expression of PKC-delta and PKC-epsilon caused a strong positive inotropy on stimulation with phorbol 12,13-dibutyrate (PDBu). Using this system, PDBu failed to affect pH(i) in the majority of PKC expressing myocytes despite increases in twitch amplitudes of >60%. Overall, the poor correlation of positive inotropic responses and alkalinization was observed for ET-1 with and without dn-PKC constructs and for PDBu with and without wild-type PKC constructs. These results suggest that ET-1 produces positive inotropy via PKC-epsilon by mechanisms other than intracellular alkalinization.
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2,333,324 |
Addition of cisatracurium to lidocaine for intravenous regional anesthesia.
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To determine the onset and regression time of motor and sensory block, and the quality of anesthesia and postoperative analgesia by the addition of cisatracurium to local anesthetic solution in small doses in intravenous regional anesthesia.</AbstractText>Prospective, randomized, double-blind study.</AbstractText>University hospital.</AbstractText>40 ASA physical status I and II patients undergoing elective hand surgery.</AbstractText>Intravenous regional anesthesia was achieved using 3 mg/kg lidocaine diluted with saline to a total volume of 40 mL in the control group or 0.01 mg/kg of cisatracurium plus 3 mg/kg lidocaine diluted with saline to a total volume of 40 mL in the cisatracurium group.</AbstractText>The onset and the regression time for sensory and motor block were recorded. Quality of anesthesia, intraoperative, and postoperative analgesic requirements were noted. Mean arterial pressure and heart rate were recorded every 5 minutes.</AbstractText>The onset time of sensory and motor block in the cisatracurium group was shorter than in the control group, and the difference was statistically significant. The quality of anesthesia was better in the cisatracurium group than in the control group, and the difference was statistically significant. There was no difference between the two groups with respect to sensory block regression time. Motor block regression time was statistically longer in the cisatracurium group than in the control group. Analgesic requirement was greater in the control group than in the cisatracurium group.</AbstractText>The addition of cisatracurium to lidocaine in intravenous regional anesthesia shortened the sensory and motor block onset times, improved the quality of anesthesia, and decreased analgesic requirements without causing clinical side effects.</AbstractText>
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2,333,325 |
An evaluation of a polyamine-deficient diet for the treatment of inflammatory pain.
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Polyamines are thought to be involved in the regulation of numerous metabolic and electrophysiological processes in the nervous system. In this study we evaluated the effect of a synthetic polyamine-deficient diet on pain in a carrageenan (Car)-induced inflammatory rat model. Inflammation was induced with a unilateral subcutaneous injection of Car in a plantar hindpaw in rats fed without (control group) or with (deficiency group) a polyamine-deficient diet. Ipsilateral and contralateral hyperalgesia was evaluated using the Randall-Sellito pressure test. Heart rate changes were also recorded under general anesthesia. Then, the effects of a bupivacaine sciatic nerve block and subcutaneous injection of naloxone or ketamine were evaluated for Car-induced hyperalgesia. Data were analyzed using analysis of variance followed by unpaired Student's t-test (significance P < 0.05). Before Car injection, no significant difference was observed in response to mechanical stimuli between the control and the deficiency groups (n = 114 in pooled data). Car injection induced significant ipsilateral and contralateral hyperalgesia in the control groups, whereas a significant analgesic effect appeared in the deficient groups on both the ipsilateral and contralateral hindpaws. This analgesic effect was confirmed by the electrocardiogram recording that showed a significant increase in heart rate in the control group after Car injection compared with the deficiency group that showed a decrease in heart rate under general anesthesia. Bupivacaine sciatic nerve block had no significant effect on hypoalgesia phenomena induced by polyamine deficiency. Naloxone administration had no effect in the control group but reversed the analgesic effect in the deficiency group. Ketamine administration induced a significant analgesic effect in the control group and partly reversed the analgesic effect in the deficiency group. In conclusion, a synthetic polyamine-deficient diet had a significant general analgesic effect on Car-induced mechanical hyperalgesia. The mechanism of analgesic action remains to be elucidated.
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2,333,326 |
Pulse transit time based on piezoelectric technique at the radial artery.
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Pulse transit time (PTT) has shown its potential in relevant cardiovascular and cardiorespiratory studies. However, the use of photoplethysmography (PPG) in PTT measurement can be limited in events of poor peripheral perfusion. Uninterrupted PTT monitoring may also not be achievable when less cooperative patients distribute the PPG probe due to its prominent light source. Hence, there is a need for an alternative method to measure PTT in such incidents.</AbstractText>In this study, the piezoelectric (PIEZO) technique to detect pulsations from a human wrist above the radial artery to estimate PTT is presented. 17 healthy adults (11 male; age range of 21-33 years) were recruited to compare PTT and heart rate (HR) differences between the PPG and PIEZO methods. These time-related derivations were made with respect to an electrocardiogram (ECG).</AbstractText>The timing consistency of the PIEZO transducer shows significant correlations (p < 0.01) to those derived from the ECG and a pulse oximeter. Particularly, there is a high level of agreement of < 1 beat per minute (bpm) difference in HR estimates observed when compared to the two commercial devices in the respective Bland-Altman plots. Comparison of PTT obtained from the PIEZO transducer against the PPG signal shows constantly lower values due to the shorter path length it requires to propagate. A regression equation was formulated to relate the PTT values acquired from both these signals.</AbstractText>Preliminary findings herein suggest that the PIEZO technique can be useful as an alternative for PTT monitoring. This shows promise to be more accommodating for less cooperative patients or those with insufficient peripheral perfusion.</AbstractText>
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2,333,327 |
Analgesic efficacy of two doses of intrathecal midazolam with bupivacaine in patients undergoing cesarean delivery.
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In this prospective, randomized, double-blind, placebo-controlled study, we investigated the postoperative analgesic efficacy of 2 doses of intrathecal midazolam as an adjunct to bupivacaine for spinal anesthesia.</AbstractText>Sixty patients undergoing elective cesarean delivery under spinal anesthesia were allocated randomly to 3 groups: group B, 2 mL hyperbaric bupivicaine 0.5%; group BM1, 2 mL bupivacaine plus midazolam 1 mg (preservative free); and group BM2, 2 mL bupivicaine plus midazolam 2 mg.</AbstractText>The mean duration of postoperative analgesia (determined by request for rescue medication) was 3.8 +/- 0.5 hours in group B compared with 4.3 +/- 0.7 hours in group BM1 (P = .18), and 6.1 +/- 1.0 hours in group BM2 (P = .001). Supplemental analgesic requirements with diclofenac were significantly less in group BM2 (93 +/- 29 mg) compared with group B (145 +/- 12 mg) and group BM1 (148 +/- 16 mg, P < .001). Time to block regression was longer in group B (182 +/- 30 minutes) compared with group BM1 (152 +/- 32 minutes) and group B (126 +/- 20 minutes) (both P < .001). Arterial pressure, heart rate, oxygen saturation, sedation score, and time to first void were comparable between groups. Group B had a significantly higher incidence of nausea and vomiting than groups BM1 and BM2 (P = .02). No neurologic deficits were observed.</AbstractText>Intrathecal midazolam 2 mg provided a moderate prolongation of postoperative analgesia when used as an adjunct to bupivacaine in patients undergoing cesarean delivery. Intrathecal midazolam, 1 mg and 2 mg, decreased postoperative nausea and vomiting.</AbstractText>
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2,333,328 |
Direct observation of protein folding in nanoenvironments using a molecular ruler.
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We observe folding of horse heart cytochrome c in various environments including nano-compartments (micelles and reverse micelles). Using picosecond-resolved Förster resonance energy transfer (FRET) dynamics of an extrinsic covalently attached probe dansyl (donor) at the surface of the protein to a heme group (acceptor) embedded inside the protein, we measured angstrom-resolved donor-acceptor distances in the environments. The overall structural perturbations of the protein revealed from the FRET experiments are in close agreement with our circular dichroism (CD) and dynamic light scattering (DLS) studies on the protein in a variety of solution conditions. The change of segmental motion of the protein due to imposed restriction in the nano-compartments compared to that in bulk buffer is also revealed by temporal fluorescence anisotropy of the dansyl probe.
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2,333,329 |
Modification of cutaneous vasodilator response to heat stress by daytime exogenous melatonin administration.
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In humans, the nocturnal fall in internal temperature is associated with increased endogenous melatonin and with a shift in the thermoregulatory control of skin blood flow (SkBF), suggesting a role for melatonin in the control of SkBF. The purpose of this study was to test whether daytime exogenous melatonin would shift control of SkBF to lower internal temperatures during heat stress, as is seen at night. Healthy male subjects (n = 8) underwent body heating with melatonin administration (Mel) or without (control), in random order at least 1 wk apart. SkBF was monitored at sites pretreated with bretylium to block vasoconstrictor nerve function and at untreated sites. Cutaneous vascular conductance, calculated from SkBF and arterial pressure, sweating rate (SR), and heart rate (HR) were monitored. Skin temperature was elevated to 38 degrees C for 35-50 min. Baseline esophageal temperature (Tes) was lower in Mel than in control (P < 0.01). The Tes threshold for cutaneous vasodilation and the slope of cutaneous vascular conductance with respect to Tes were also lower in Mel at both untreated and bretylium-treated sites (P < 0.05). The Tes threshold for the onset of sweating and the Tes for a standard HR were reduced in Mel. The slope of the relationship of HR, but not SR, to Tes was lower in Mel (P < 0.05). These findings suggest that melatonin affects the thermoregulatory control of SkBF during hyperthermia via the cutaneous active vasodilator system. Because control of SR and HR are also modified, a central action of melatonin is suggested.
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2,333,330 |
Prenatal nicotine exposure alters the nicotinic receptor subtypes that modulate excitation of parasympathetic cardiac neurons in the nucleus ambiguus from primarily alpha3beta2 and/or alpha6betaX to alpha3beta4.
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Nicotinic receptors play an essential role in central cardiorespiratory function, however, the types of nicotinic receptors responsible for activating cardiac vagal neurons in the nucleus ambiguus that control heart rate are unknown. This study tests whether alpha-conotoxin MII and alpha-conotoxin AuIB sensitive nicotinic receptors are involved in augmentation of glutamatergic neurotransmission and changes in holding current in cardiac vagal neurons, and whether exposure to nicotine in the prenatal period alters these responses. The nicotinic agonist cytisine significantly increased the holding current and amplitude of glutamatergic mEPSCs. In unexposed animals alpha-conotoxin MII (100nM) significantly reduced the increase in mEPSC amplitude and change in holding current evoked by cytisine. However, in animals prenatally exposed to nicotine, alpha-conotoxin MII blunted but did not block the increase in mEPSC amplitude but blocked the increase in holding current evoked by cytisine. In unexposed animals, alpha-conotoxin AuIB (10microM) blocked the cytisine evoked increase in mEPSC amplitude and inhibited but did not abolish the increase in holding current. In contrast, in animals exposed to nicotine, alpha-conotoxin AuIB blunted the increase in mEPSC amplitude, and completely abolished the cytisine evoked increase in holding current. These data demonstrate that the prenatal nicotine exposure alters the nicotinic receptors involved in excitation of cardiac vagal neurons.
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2,333,331 |
Superoxide radical production by allopurinol and xanthine oxidase.
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Oxypurinol, an inhibitor of xanthine oxidase (XO), is being studied to block XO-catalyzed superoxide radical formation and thereby treat and protect failing heart tissue. Allopurinol, a prodrug that is converted to oxypurinol by xanthine oxidase, is also being studied for similar purposes. Because allopurinol, itself, may be generating superoxide radicals, we currently studied the reaction of allopurinol with xanthine oxidase and confirmed that allopurinol does produce superoxide radicals during its conversion to oxypurinol. At pH 6.8 and 25 degrees C in the presence of 0.02 U/ml of XO, 10 and 20 microM allopurinol both produced 10 microM oxypurinol and 2.8 microM superoxide radical (determined by cytochrome C reduction). The 10 microM allopurinol was completely converted to oxypurinol, while the 20 microM allopurinol required a second addition of xanthine oxidase to complete the conversion. Fourteen percent of the reducing equivalents donated from allopurinol or xanthine reacted with oxygen to form superoxide radicals. Superoxide dismutase prevented the reduction of cytochrome C by these substrates. At higher xanthine oxidase concentrations, or at lower temperatures, more of the 20 microM allopurinol was converted to oxypurinol during the initial reaction. At lower xanthine oxidase concentrations, or higher temperatures, less conversion occurred. At pH 7.8, the amount of superoxide radicals produced from allopurinol and xanthine was nearly doubled. These results indicate that allopurinol is a conventional substrate that generates superoxide radicals during its oxidation by xanthine oxidase. Oxypurinol did not produce superoxide radicals.
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2,333,332 |
Effect of meloxicam and butorphanol on minimum alveolar concentration of isoflurane in rabbits.
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To determine the effects of meloxicam and butorphanol on minimum alveolar concentration of isoflurane (MAC(ISO)) in rabbits.</AbstractText>10 healthy young adult female rabbits.</AbstractText>Rabbits were anesthetized with isoflurane on 3 occasions in a blinded, randomized complete block design to determine the MAC(ISO) associated with administration of meloxicam (0, 0.3, or 1.5 mg/kg, PO) and butorphanol (0.4 mg/kg, IV). The MAC(ISO) was determined by use of a paw clamp technique as the end-tidal concentration of isoflurane halfway between the values that allowed or inhibited purposeful movement. Rectal temperature, end-tidal CO2 concentration, heart rate, oxygen saturation, and arterial blood pressure were measured to evaluate cardiopulmonary function.</AbstractText>Mean +/- SE MAC(ISO) in saline (0.9% NaCl) solution-treated rabbits was 2.49 +/- 0.07% and was not significantly different from that associated with administration of meloxicam at 0.3 mg/kg (2.56 +/- 0.07%) or 1.5 mg/kg (2.66 +/- 0.07%). Butorphanol significantly reduced the MAC(ISO) to 2.30 +/- 0.07% when administered with saline solution alone, 2.27 +/- 0.07% when administered with 0.3 mg of meloxicam/kg, and 2.33 +/- 0.07% when administered with 1.5 mg of meloxicam/kg. The percentage reduction in MAC(ISO) was significantly greater for rabbits that received butorphanol and meloxicam at either dose, compared with butorphanol and saline solution.</AbstractText>Results indicated that meloxicam does not have a direct isoflurane-sparing effect and does not interfere with the anesthetic-sparing effect of butorphanol in rabbits.</AbstractText>
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2,333,333 |
L-type calcium channel alpha-subunit and protein kinase inhibitors modulate Rem-mediated regulation of current.
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Cardiac voltage-gated L-type Ca channels (Ca(V)) are multiprotein complexes, including accessory subunits such as Ca(V)beta2 that increase current expression. Recently, members of the Rad and Gem/Kir-related family of small GTPases have been shown to decrease current, although the mechanism remains poorly defined. In this study, we evaluated the contribution of the L-type Ca channel alpha-subunit (Ca(V)1.2) to Ca(V)beta2-Rem inhibition of Ca channel current. Specifically, we addressed whether protein kinase A (PKA) modulation of the Ca channel modifies Ca(V)beta2-Rem inhibition of Ca channel current. We first tested the effect of Rem on Ca(V)1.2 in human embryonic kidney 293 (HEK-293) cells using the whole cell patch-clamp configuration. Rem coexpression with Ca(V)1.2 reduces Ba current expression under basal conditions, and Ca(V)beta2a coexpression enhances Rem block of Ca(V)1.2 current. Surprisingly, PKA inhibition by 133 nM H-89 or 50 microM Rp-cAMP-S partially relieved the Rem-mediated inhibition of current activity both with and without Ca(V)beta2a. To test whether the H-89 action was a consequence of the phosphorylation status of Ca(V)1.2, we examined Rem regulation of the PKA-insensitive Ca(V)1.2 serine 1928 (S1928) to alanine mutation (Ca(V)1.2-S1928A). Ca(V)1.2-S1928A current was not inhibited by Rem and when coexpression with Ca(V)beta2a was not completely blocked by Rem coexpression, suggesting that the phosphorylation of S1928 contributes to Rem-mediated Ca channel modulation. As a model for native Ca channel complexes, we tested the ability of Rem overexpression in HIT-T15 cells and embryonic ventricular myocytes to interfere with native current. We find that native current is also sensitive to Rem block and that H-89 pretreatment relieves the ability of Rem to regulate Ca current. We conclude that Rem is capable of regulating L-type current, that release of Rem block is modulated by cellular kinase pathways, and that the Ca(V)1.2 COOH terminus contributes to Rem-dependent channel inhibition.
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2,333,334 |
Micropatterns of propagation.
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Alterations in microscopic conduction could contribute to microreentry and arrhythmogenesis in pathological settings. This chapter reviews microconduction in the ventricular myocardium. Gap junctions play a significant role in longitudinal and transverse propagation of the action potential wavefront in the ventricle. Studies of microscopic conduction in patterned cultures of neonatal rodent myocytes have provided novel insights into the role of gap junctions, the effects of uncoupling versus altered excitability, and the contribution of discontinuities and branching. Decreased gap junctional coupling can contribute to slowing of conduction and development of unidirectional block. However, in the setting of structural inhomogeneities and unbalanced current source and load, decreased coupling can, at times, improve conduction and be 'anti-arrhythmic,' attesting to the complexity of intercellular coupling as a therapeutic target. Genetically engineered mouse models of Cx43 depletion demonstrate slow conduction and arrhythmogenesis that appears to be reentrant in nature. Studies in these models provide novel insights into the contribution of gap junctions to impulse propagation and arrhythmogenesis in the intact heart. Overall, gap junction expression, distribution and heterogeneity are important contributors to microscopic conduction, and alterations in any of these can contribute to the development of an arrhythmogenic substrate in pathological states.
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2,333,335 |
Response to myocardial ischemia/reperfusion injury involves Bnip3 and autophagy.
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Ischemia and reperfusion (I/R) injury is associated with extensive loss of cardiac myocytes. Bnip3 is a mitochondrial pro-apoptotic Bcl-2 protein which is expressed in the adult myocardium. To investigate if Bnip3 plays a role in I/R injury, we generated a TAT-fusion protein encoding the carboxyl terminal transmembrane deletion mutant of Bnip3 (TAT-Bnip3DeltaTM) which has been shown to act as a dominant negative to block Bnip3-induced cell death. Perfusion with TAT-Bnip3DeltaTM conferred protection against I/R injury, improved cardiac function, and protected mitochondrial integrity. Moreover, Bnip3 induced extensive fragmentation of the mitochondrial network and increased autophagy in HL-1 myocytes. 3D rendering of confocal images revealed fragmented mitochondria inside autophagosomes. Enhancement of autophagy by ATG5 protected against Bnip3-mediated cell death, whereas inhibition of autophagy by ATG5K130R enhanced cell death. These results suggest that Bnip3 contributes to I/R injury which triggers a protective stress response with upregulation of autophagy and removal of damaged mitochondria.
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2,333,336 |
Safety of amiodarone in the prevention of postoperative atrial fibrillation: a meta-analysis.
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A meta-analysis was conducted to assess the safety of amiodarone in the prevention of postoperative atrial fibrillation.</AbstractText>A search of the medical literature was conducted to identify randomized controlled trials of prophylactic amiodarone use in cardiothoracic surgery. Studies were independently reviewed by three investigators and selected for inclusion if they met the following three criteria: (1) randomized controlled trial of amiodarone versus placebo or routine treatment, (2) patients underwent coronary artery bypass graft or valvular surgery, and (3) reported data on the frequency of at least one of the following safety endpoints: bradycardia, hypotension, heart block, nausea, cerebral vascular accident, myocardial infarction, and death. Both random- and fixed-effects models were used to determine any significant associations between amiodarone and safety endpoints.</AbstractText>Eighteen trials were analyzed. A total of 3408 patients were enrolled in these trials (1736 received amiodarone and 1672 received placebo). Amiodarone increased the odds of developing bradycardia (odds ratio [OR], 1.70; 95% confidence interval [CI], 1.05-2.74) and hypotension (OR, 1.62; 95% CI, 1.04-2.54). The administration of i.v. amiodarone, an average daily dose exceeding 1 g, and postoperative amiodarone administration were each associated with a greater likelihood of hemodynamic adverse effects. Amiodarone did not appear to affect other safety endpoints.</AbstractText>Meta-analysis showed amiodarone to be associated with an increased risk of developing bradycardia and hypotension when used for the prophylaxis of postoperative atrial fibrillation. The greatest risk in the occurrence of these adverse events arose when using regimens containing i.v. amiodarone, initiating prophylaxis during the postoperative period, and using regimens with average daily doses exceeding 1 g.</AbstractText>
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2,333,337 |
The voltage dependence of recovery from use-dependent block by QX-222 separates mechanisms for drug egress in the cardiac sodium channel.
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In neuronal sodium channels of squid giant axons, recovery from QX-222 block is slowed by hyperpolarization. However, in ventricular cells, hyperpolarization speeds recovery. Previously, we showed that isoform-specific residues in the external side of the cardiac sodium channel isoform (D1P-loop C373 and D4S6 T1752) influence use-dependent block (UDB) by lidocaine. To determine whether these isoformspecific residues contribute to the contrasting voltage-dependent recovery observed in ventricular myocytes, we measured recovery rates from UDB by QX-222 at holding potentials of 120, 140, 160 and 180 mV for wild-type cardiac channel (WT), the mutants C373Y (CY) and T1752V (TV), and C373Y/T1752V (CY/TV). Unlike neuronal channels, cardiac sodium channels recovered from QX block faster at hyperpolarized potentials. All mutations slowed QX-222 recovery, with the greatest rate reduction observed for the double mutant, indicating that the isoform-specific residues define external drug paths. The recovery rates varied linearly with voltage over the range tested, and we used the slopes of rate versus voltage plots to quantify voltage dependence. The TV mutation caused reduction in recovery rates without changing the slope, indicating that the mutation closed a voltage-independent egress path. The CY mutation, however, flattened the slope and reduced the voltage dependence of recovery. In addition, the reduction in rate caused by CY/TV is less than the sum of those for CY and TV, suggesting that the impacts of these two residues are interrelated. Therefore, we propose that the isoform-specific residues C373 and T1752 change recovery from UDB by distinct mechanisms but determine a common drug egress path.
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2,333,338 |
Increased AAI mode pacing threshold after termination of atrial fibrillation by acute administration of disopyramide phosphate.
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We studied changes in atrial pacing threshold after termination of atrial fibrillation (AF) by acute administration of disopyramide phosphate (DP) to elucidate the suitable setting for atrial pacing output before AF termination.</AbstractText>Four patients with sick sinus syndrome implanted with AAI mode pacemakers were examined. Disopyramide phosphate (2 mg/kg body weight) was injected intravenously for termination of a total of eight AF episodes. The maximal pacing threshold after AF termination (5.2+/-0.8 V at 0.45 ms) was significantly higher than that at baseline (1.3+/-0.2 V at 0.45 ms; P<0.01) and the average increment was 433+/-68%. During a period free from AF, an acute administration of DP did not increase the atrial pacing threshold and serum disopyramide levels were not toxic.</AbstractText>The increased atrial pacing threshold observed after AF termination cannot be explained by the action of DP alone. However, our results suggest that atrial pacing output should be set at the maximum value before DP is administered to induce AF termination in patients with AAI pacemaker-dependent bradyarrhythmias.</AbstractText>
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2,333,339 |
Pregnancy, lupus and antiphospholipid syndrome (Hughes syndrome).
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Autoimmune diseases (AD) occur frequently in women during their childbearing years and may influence pregnancy outcome and neonatal health. Patients with systemic lupus erythematosus (SLE) can experience a disease flare-up during pregnancy with potential negative effects on the product of conceptus, especially if the disease is active. Recurrent pregnancy loss is now considered as a treatable clinical condition associated with the presence of circulating antiphospholipid antibodies (aPL). The neonatal lupus syndromes (NLS), caused by the transplacental passage of maternal IgG anti-Ro/SS-A and anti-La/SS-B antibodies to the fetus, carry significant morbidity and mortality in case of cardiac manifestations. Immunosuppressive agents are often administered during pregnancy in order to control maternal disease and to ensure a better pregnancy outcome. Nowadays, owing to our increasing knowledge of the disease pathophysiological mechanisms and the development of combined medical-obstetric clinics, pregnancy outcome in patients with AD has notably improved.
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2,333,340 |
Recombinant P-selectin glycoprotein-ligand-1 delays thrombin-induced platelet aggregation: a new role for P-selectin in early aggregation.
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1. P-selectin is involved, with P-selectin glycoprotein (GP)-ligand-1 (PSGL-1), in platelet/leukocyte interactions during thrombo-inflammatory reactions; it also stabilizes platelet aggregates. Its antagonism accelerates thrombolysis and enhances the anti-aggregatory effects of GPIIb-IIIa inhibitors. This study was designed to investigate the mechanisms of P-selectin-mediated platelet aggregation. 2. In freshly isolated human platelets, P-selectin translocation after thrombin stimulation increased rapidly to 48, 72, and 86% positive platelets after 60, 120, and 300 s, respectively. Platelet aggregation at 60 s post-stimulation averaged 46.7 +/- 1.9% and its extent followed closely the kinetics of P-selectin translocation. 3. Pre-treatment of platelets with P-selectin antagonists, a recombinant PSGL-1 (rPSGL-Ig) or a blocking monoclonal antibody, significantly delayed platelet aggregation in a dose-dependent manner. At 100 microg ml(-1) of rPSGL-Ig, platelet aggregation was completely inhibited up to 60 s post-stimulation and increased thereafter to reach maximal aggregation at 5 min. The second phase of platelet aggregation, in the presence of rPSGL-Ig, was completely prevented by the addition of a GPIIb-IIIa antagonist (Reopro) at 60 s, whereas its addition in the absence of rPSGL-Ig was without any significant effect. 4. Combination of rPSGL-Ig with Reopro or with an inhibitor of Pi3K (LY294002), which reduces GPIIb-IIIa activation, showed to be more effective in inhibiting platelet aggregation, in comparison to the effects observed individually. 5. rPSGL-Ig blocks P-selectin, whereas Reopro and LY294002 block GPIIb-IIIa and its activation, respectively, without a major effect on the percentage of platelets expressing P-selectin. 6. In summary, platelet P-selectin participates with GPIIb-IIIa in the initiation of platelet aggregation. Its inhibition, with rPSGL-Ig, delays the aggregation process and increases the anti-aggregatory potency of Reopro. Thus, combination of P-selectin and GPIIb-IIIa antagonism may constitute a promising therapeutic option in the management of thrombotic disorders.
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2,333,341 |
Unrecognized drug-drug interactions: a cause of intraoperative cardiac arrest?
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Many physicians overlook, or are unaware of, most drug-drug interactions. In our patient, the local anesthetic used for an axillary block may have been the precipitating drug in a cascade of drug-drug interactions that resulted in a cardiac arrest. The combination of multiple preoperative drug-drug interactions prevented the return of a stable native cardiac rhythm for almost 24 h. The mechanisms of interactions of these frequently used drugs are described, and the reader is guided to sources that identify and simplify the understanding of potentially dangerous drug-drug interactions.
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2,333,342 |
Subarachnoid butorphanol augments lidocaine sensory anaesthesia in calves.
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To determine the efficacy and safety of subarachnoid butorphanol combined with lidocaine, six calves were studied. Each calf underwent two treatments, at least one week apart, via subarachnoid injection: (1) butorphanol (0.03 mg/kg) plus 2% lidocaine (4 mg/kg) and (2) 2% lidocaine (4 mg/kg) alone. Subarachnoid injections were performed at the lumbosacral space. Analgesia, motor block, sedation, heart rate, arterial blood pressure, respiratory rate, arterial oxygen saturation as measured by pulse oximetry, and rectal temperature were compared before and after subarachnoid administration of drugs. Subarachnoid administration of the butorphanol-lidocaine combination induced bilateral prolonged analgesia extending from the coccygeal to the T11-T13 dermatomes in the calves, with minimal sedation and severe ataxia. Cardiovascular effects were significant in both treatments: heart rate was increased, and there was a minimal decrease in arterial pressure. It was concluded that adding a small dose of butorphanol to subarachnoid lidocaine in calves is effective and safe.
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2,333,343 |
Metalloprotein-dependent decomposition of S-nitrosothiols: studies on the stabilization and measurement of S-nitrosothiols in tissues.
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The stabilization of S-nitrosothiols is critical for the development of assays to measure their concentration in tissues. Low-molecular-weight S-nitrosothiols are unstable in tissue homogenates, even in the presence of thiol blockers or metal-ion chelators. The aim of this study was to try and stabilize low-molecular-weight S-nitrosothiols in tissue and gain insight into the mechanisms leading to their decomposition. Rat tissues (liver, kidney, heart, and brain) were perfused and homogenized in the presence of a thiol-blocking agent (N-ethylmaleimide) and a metal-ion chelator (DTPA). Incubation of liver homogenate with low-molecular-weight S-nitrosothiols (L-CysNO, D-CysNO, and GSNO) resulted in their rapid decomposition in a temperature-dependent manner as measured by chemiluminescence. The decomposition of L-CysNO requires a cytoplasmic factor, with activity greatest in liver > kidney > heart > brain > plasma, and is inhibitable by enzymatic proteolysis or heating to 80 degrees C, suggesting that a protein catalyzes the decomposition of S-nitrosothiols. The ability of liver homogenate to catalyze the decomposition of L-CysNO is up-regulated during endotoxemia and is dependent on oxygen, with the major product being nitrate. Multiple agents were tested for their ability to block the decomposition of L-CysNO without success, with the exception of potassium ferricyanide, which completely blocked CysNO decomposition in liver homogenates. This suggests that a ferrous protein (or group of ferrous proteins) may be involved. We also show that homogenization of tissues in ferricyanide-containing buffers in the presence of N-ethylmaleimide and DTPA can stabilize both low- and high-molecular-weight S-nitrosothiols in tissues before the measurement of their concentration.
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2,333,344 |
Sitaxsentan: an endothelin-A receptor antagonist for the treatment of pulmonary arterial hypertension.
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Endothelin (ET-1) is a potent vasoconstrictor and smooth muscle mitogen that mediates its effects through activation of ET-A and ET-B receptors. Pulmonary arterial hypertension (PAH) encompasses a heterogeneous group of disorders characterised by inappropriate overactivation of the ET system. There is clear evidence that strategies that block both ET receptors are associated with clinical improvement in PAH. However, there are theoretical physiological advantages to treatments that specifically inhibit only the ET-A receptor. Sitaxsentan is an orally active selective ET-A receptor antagonist that in recent clinical trials has demonstrated improvements in exercise capacity, functional class and haemodynamics in PAH patients with modified New York Heart Association class II, III and IV symptoms.
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2,333,345 |
Transplanted neonatal cardiomyocytes as a potential biological pacemaker in pigs with complete atrioventricular block.
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Sinus node dysfunction and severe heart block are major indications for electronic pacemaker implantation. The aim of the present study was to investigate the feasibility of an alternative approach by using spontaneously excitable cell grafts to serve as a biological pacemaker.</AbstractText>Enzymatically isolated neonatal atrial cardiomyocytes (including sinus nodal cells) were grafted into the free wall of the left ventricle of 5 male pigs. In the control group (n = 4), the medium was used for injecting. Three weeks after the transplantation the pigs underwent catheter ablation of the atrioventricular (AV) node. Microelectrode technique was used to record the transmembrane action potential of myocytes from cell- and medium-injected preparations. Immunohistochemistry was used to verify the grafted cells and the establishment of the gap junctions between donor and host cardiomyocytes.</AbstractText>After the creation of complete AV-block, a higher average idioventricular rate was observed in cell-grafted pigs than that in control pigs (89 +/- 13 vs. 30 +/- 11 bpm, P < 0.05). Administering isoprenaline caused a significant increase in the idioventricular rate from 89 +/- 13 to 120 +/- 18 bpm in the cell-grafted animals (P < 0.05). Microelectrode recordings showed that the spontaneously beating rate was significantly higher in the cell-implanted than that in the control preparations (82 +/- 17 vs. 33 +/- 13 bpm, P < 0.05). Furthermore, the immunofluorescence microscopy identified the DAPI-labeled donor cells, and the connexin-43 and N-cadherin positive junctions between them and host cardiomyocytes.</AbstractText>Grafted neonatal atrial cardiomyocytes are able to survive and integrate into the host myocardium, and show a pacing function that can be modulated by autonomic agents.</AbstractText>
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2,333,346 |
Use of bovine somatotropin for increased skeletal and lean tissue growth of Holstein steers.
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One hundred-sixty Holstein growing-finishing steers (initial BW of 185 kg) were blocked by BW to determine the effectiveness of long-term bovine somatotropin (bST) administration on lean, skeletal, and carcass measurements. Steers were randomly allocated to 4 treatments (10 steers/treatment) within a block (n = 4 blocks). Treatments were control, no bST (C-C); bST from d 0 to 182 (bST-C); bST from d 183 to slaughter (C-bST); and bST from d 0 to slaughter (bST-bST). Steers received a s.c. injection of placebo or bST at 14-d intervals. Doses were 320 mg of bST/injection from d 0 to 112 and 640 mg of bST/injection from d 113 to slaughter. The last treatment was administered 31 d before slaughter. Steers received a 14% CP (DM basis) diet from d 0 to 182 and 11.5% CP from d 183 to slaughter that consisted of dry, whole-shelled corn and a pelleted protein-mineral supplement. Steers were slaughtered when BW per block averaged 615 kg (d 325, 353, 367, and 381 for the 4 blocks, respectively). Thirty steers were removed from the study because of poor performance with respect to their pen mates, illness, lameness, death, incomplete castration, and incorrect treatment. Serum IGF-I concentrations increased 151% (P < 0.01) from d 7 through 35 in bST-treated steers compared with control steers. During the first 182 d, bST-C and bST-bST steers were heavier (P < 0.01) and had greater (P < 0.01) ADG, G:F, hip height, and hip height gain compared with C-C and C-bST steers. From d 183 to slaughter, C-bST steers had reduced (P < 0.05) daily DMI and greater G:F than bST-C steers. At final slaughter, C-bST and bST-bST steers had greater (P < 0.05) hip height than C-C steers. Noncarcass weight was increased and dressing percent reduced (P < 0.05) in C-bST and bST-bST steers compared with C-C steers. Quality grade was least (P < 0.05) in bST-bST carcasses compared with C-C, whereas bST-C and C-bST carcasses were intermediate. At final slaughter, steers receiving bST had greater (P < 0.05) carcass protein and water composition and lower (P < 0.05) carcass lipid and lipid accretion than C-C steers. Bovine somatotropin was effective in reducing carcass fat and increasing edible lean. Administering bST to young, lightweight steers increased skeletal growth and noncarcass weight without an increase in total carcass weight, but decreased carcass quality.
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The safety of digoxin as a pharmacological treatment of atrial fibrillation.<Pagination><StartPage>453</StartPage><EndPage>467</EndPage><MedlinePgn>453-67</MedlinePgn></Pagination><Abstract><AbstractText>Digoxin has traditionally been the drug of choice for ventricular rate control in patients with chronic atrial fibrillation (AF), with or without heart failure (HF) with systolic dysfunction. In patients with permanent AF, digoxin monotherapy is ineffective to control ventricular rate during exercise, but the combination of digoxin with a beta-blocker or a non-dihydropyridine calcium channel antagonist can control heart rate both at rest and during exercise. Only a few randomised, controlled studies have evaluated the adverse effects of digoxin in patients with AF in a systematic way and side effects requiring drug withdrawal have rarely been reported. When reported, the most frequent adverse effects were cardiac arrhythmias (ventricular arrhythmias, AV block of varying degrees and sinus pauses). This evidence suggested that, in contrast to other antiarrhythmic drugs, digoxin is a safe drug in patients with AF. However, this safety profile can be erroneous due to the short follow-up of the studies and patient selection. Because patients with HF have been excluded in most studies, the safety profile of digoxin in this population has not been directly addressed. Early recognition that an arrhythmia is related to digoxin intoxication as well as recognition of concomitant medications or medical conditions that may directly alter the pharmacokinetic profile of digoxin, or indirectly alter its cardiac effects by pharmacodynamic interactions remain essential for safe and effective use of digoxin in patients with AF.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Tamargo</LastName><ForeName>Juan</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Department of Pharmacology, School of Medicine, Universidad Complutense, 28040 Madrid, Spain. [email protected]</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Delpón</LastName><ForeName>Eva</ForeName><Initials>E</Initials></Author><Author ValidYN="Y"><LastName>Caballero</LastName><ForeName>Ricardo</ForeName><Initials>R</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType><PublicationType UI="D016454">Review</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>Expert Opin Drug Saf</MedlineTA><NlmUniqueID>101163027</NlmUniqueID><ISSNLinking>1474-0338</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000889">Anti-Arrhythmia Agents</NameOfSubstance></Chemical><Chemical><RegistryNumber>73K4184T59</RegistryNumber><NameOfSubstance UI="D004077">Digoxin</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000889" MajorTopicYN="N">Anti-Arrhythmia Agents</DescriptorName><QualifierName UI="Q000009" MajorTopicYN="N">adverse effects</QualifierName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName><QualifierName UI="Q000627" MajorTopicYN="Y">therapeutic use</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D001281" MajorTopicYN="N">Atrial Fibrillation</DescriptorName><QualifierName UI="Q000188" MajorTopicYN="Y">drug therapy</QualifierName><QualifierName UI="Q000503" MajorTopicYN="N">physiopathology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D004077" MajorTopicYN="N">Digoxin</DescriptorName><QualifierName UI="Q000009" MajorTopicYN="N">adverse effects</QualifierName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName><QualifierName UI="Q000627" MajorTopicYN="Y">therapeutic use</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D004347" MajorTopicYN="N">Drug Interactions</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D016903" MajorTopicYN="N">Drug Monitoring</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004562" MajorTopicYN="N">Electrocardiography</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading></MeshHeadingList><NumberOfReferences>113</NumberOfReferences></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2006</Year><Month>4</Month><Day>14</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2007</Year><Month>10</Month><Day>5</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2006</Year><Month>4</Month><Day>14</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">16610972</ArticleId><ArticleId IdType="doi">10.1517/14740338.5.3.453</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">16610351</PMID><DateCompleted><Year>2006</Year><Month>04</Month><Day>27</Day></DateCompleted><DateRevised><Year>2019</Year><Month>11</Month><Day>09</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">0171-2004</ISSN><JournalIssue CitedMedium="Print"><Issue>171</Issue><PubDate><Year>2006</Year></PubDate></JournalIssue><Title>Handbook of experimental pharmacology</Title><ISOAbbreviation>Handb Exp Pharmacol</ISOAbbreviation></Journal>Molecular basis of isolated cardiac conduction disease.<Pagination><StartPage>331</StartPage><EndPage>347</EndPage><MedlinePgn>331-47</MedlinePgn></Pagination><Abstract><AbstractText>Cardiac conduction disorders are among the most common rhythm disturbances causing disability in millions of people worldwide and necessitating pacemaker implantation. Isolated cardiac conduction disease (ICCD) can affect various regions within the heart, and therefore the clinical features also vary from case to case. Typically, it is characterized by progressive alteration of cardiac conduction through the atrioventricular node, His-Purkinje system, with right or left bundle branch block and QRS widening. In some instances, the disorder may progress to complete atrioventricular block, with syncope and even death. While the role of genetic factors in conduction disease has been suggested as early as the 1970s, it was only recently that specific genetic loci have been reported. Multiple mutations in the gene encoding for the cardiac voltage-gated sodium channel (SCN5A), which plays a fundamental role in the initiation, propagation, and maintenance of normal cardiac rhythm, have been linked to conduction disease, allowing for genotype-phenotype correlation. The electrophysiological characterization of heterologously expressed mutant Na+ channels has revealed gating defects that consistently lead to a loss of channel function. However, studies have also revealed significant overlap between aberrant rhythm phenotypes, and single mutations have been identified that evoke multiple distinct rhythm disorders with common gating lesions. These new insights highlight the complexities involved in linking single mutations, ion-channel behavior, and cardiac rhythm but suggest that interplay between multiple factors could underlie the manifestation of the disease phenotype.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Viswanathan</LastName><ForeName>P C</ForeName><Initials>PC</Initials><AffiliationInfo><Affiliation>Vanderbilt University Medical Center, 560 Preston Research Building, 2220 Pierce Avenue, Nashville, TN 37232-6602, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Balser</LastName><ForeName>J R</ForeName><Initials>JR</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D016454">Review</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>Germany</Country><MedlineTA>Handb Exp Pharmacol</MedlineTA><NlmUniqueID>7902231</NlmUniqueID><ISSNLinking>0171-2004</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D015222">Sodium Channels</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D001145" MajorTopicYN="N">Arrhythmias, Cardiac</DescriptorName><QualifierName UI="Q000209" MajorTopicYN="Y">etiology</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000628" MajorTopicYN="N">therapy</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D017147" MajorTopicYN="N">Defibrillators, Implantable</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D015640" MajorTopicYN="N">Ion Channel Gating</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D009154" MajorTopicYN="Y">Mutation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D015222" MajorTopicYN="N">Sodium Channels</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName><QualifierName UI="Q000502" MajorTopicYN="N">physiology</QualifierName></MeshHeading></MeshHeadingList><NumberOfReferences>48</NumberOfReferences></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2006</Year><Month>4</Month><Day>14</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2006</Year><Month>4</Month><Day>28</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2006</Year><Month>4</Month><Day>14</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">16610351</ArticleId><ArticleId IdType="doi">10.1007/3-540-29715-4_13</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">16610350</PMID><DateCompleted><Year>2006</Year><Month>04</Month><Day>27</Day></DateCompleted><DateRevised><Year>2021</Year><Month>10</Month><Day>20</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">0171-2004</ISSN><JournalIssue CitedMedium="Print"><Issue>171</Issue><PubDate><Year>2006</Year></PubDate></JournalIssue><Title>Handbook of experimental pharmacology</Title><ISOAbbreviation>Handb Exp Pharmacol</ISOAbbreviation></Journal>Therapy for the Brugada syndrome.<Pagination><StartPage>305</StartPage><EndPage>330</EndPage><MedlinePgn>305-30</MedlinePgn></Pagination><Abstract><AbstractText>The Brugada syndrome is a congenital syndrome of sudden cardiac death first described as a new clinical entity in 1992. Electrocardiographically characterized by a distinct coved-type ST segment elevation in the right precordial leads, the syndrome is associated with a high risk for sudden cardiac death in young and otherwise healthy adults, and less frequently in infants and children. The ECG manifestations of the Brugada syndrome are often dynamic or concealed and may be revealed or modulated by sodium channel blockers. The syndrome may also be unmasked or precipitated by a febrile state, vagotonic agents, alpha-adrenergic agonists, beta-adrenergic blockers, tricyclic or tetracyclic antidepressants, a combination of glucose and insulin, and hypokalemia, as well as by alcohol and cocaine toxicity. An implantable cardioverter-defibrillator (ICD) is the most widely accepted approach to therapy. Pharmacological therapy aimed at rebalancing the currents active during phase 1 of the right ventricular action potential is used to abort electrical storms, as an adjunct to device therapy, and as an alternative to device therapy when use of an ICD is not possible. Isoproterenol and cilostazol boost calcium channel current, and drugs like quinidine inhibit the transient outward current, acting to diminish the action potential notch and thus suppress the substrate and trigger for ventricular tachycardia/fibrillation (VT/VF).</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Antzelevitch</LastName><ForeName>C</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Masonic Medical Research Laboratory, 2150 Bleecker Street, Utica, NY 13501, USA. [email protected]</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Fish</LastName><ForeName>J M</ForeName><Initials>JM</Initials></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>R01 HL047678</GrantID><Acronym>HL</Acronym><Agency>NHLBI NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>HL47678</GrantID><Acronym>HL</Acronym><Agency>NHLBI NIH HHS</Agency><Country>United States</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D052061">Research Support, N.I.H., Extramural</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType><PublicationType UI="D016454">Review</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>Germany</Country><MedlineTA>Handb Exp Pharmacol</MedlineTA><NlmUniqueID>7902231</NlmUniqueID><ISSNLinking>0171-2004</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000889">Anti-Arrhythmia Agents</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000889" MajorTopicYN="N">Anti-Arrhythmia Agents</DescriptorName><QualifierName UI="Q000627" MajorTopicYN="N">therapeutic use</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D002037" MajorTopicYN="N">Bundle-Branch Block</DescriptorName><QualifierName UI="Q000150" MajorTopicYN="N">complications</QualifierName><QualifierName UI="Q000175" MajorTopicYN="N">diagnosis</QualifierName><QualifierName UI="Q000503" MajorTopicYN="N">physiopathology</QualifierName><QualifierName UI="Q000628" MajorTopicYN="Y">therapy</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D003645" MajorTopicYN="N">Death, Sudden</DescriptorName><QualifierName UI="Q000209" MajorTopicYN="Y">etiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D017147" MajorTopicYN="N">Defibrillators, Implantable</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004562" MajorTopicYN="N">Electrocardiography</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D013577" MajorTopicYN="N">Syndrome</DescriptorName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2006</Year><Month>4</Month><Day>14</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2006</Year><Month>4</Month><Day>28</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2006</Year><Month>4</Month><Day>14</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">16610350</ArticleId><ArticleId IdType="mid">NIHMS10275</ArticleId><ArticleId IdType="pmc">PMC1474239</ArticleId><ArticleId IdType="doi">10.1007/3-540-29715-4_12</ArticleId></ArticleIdList><ReferenceList><Reference><Citation>Aligs M, Wilde A. “Brugada” syndrome: clinical data and suggested pathophysiological mechanism. 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Circulation. 1999;100:1660–1666.</Citation><ArticleIdList><ArticleId IdType="pubmed">10517739</ArticleId></ArticleIdList></Reference></ReferenceList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">16610344</PMID><DateCompleted><Year>2006</Year><Month>04</Month><Day>27</Day></DateCompleted><DateRevised><Year>2019</Year><Month>11</Month><Day>09</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">0171-2004</ISSN><JournalIssue CitedMedium="Print"><Issue>171</Issue><PubDate><Year>2006</Year></PubDate></JournalIssue><Title>Handbook of experimental pharmacology</Title><ISOAbbreviation>Handb Exp Pharmacol</ISOAbbreviation></Journal>Sodium calcium exchange as a target for antiarrhythmic therapy.<Pagination><StartPage>159</StartPage><EndPage>199</EndPage><MedlinePgn>159-99</MedlinePgn></Pagination><Abstract><AbstractText>In search of better antiarrhythmic therapy, targeting the Na/Ca exchanger is an option to be explored. The rationale is that increased activity of the Na/Ca exchanger has been implicated in arrhythmogenesis in a number of conditions. The evidence is strong for triggered arrhythmias related to Ca2+ overload, due to increased Na+ load or during adrenergic stimulation; the Na/Ca exchanger may be important in triggered arrhythmias in heart failure and in atrial fibrillation. There is also evidence for a less direct role of the Na/Ca exchanger in contributing to remodelling processes. In this chapter, we review this evidence and discuss the consequences of inhibition of Na/Ca exchange in the perspective of its physiological role in Ca2+ homeostasis. We summarize the current data on the use of available blockers of Na/Ca exchange and propose a framework for further study and development of such drugs. Very selective agents have great potential as tools for further study of the role the Na/Ca exchanger plays in arrhythmogenesis. For therapy, they may have their specific indications, but they carry the risk of increasing Ca2+ load of the cell. Agents with a broader action that includes Ca2+ channel block may have advantages in other conditions, e.g. with Ca2+ overload. Additional actions such as block of K+ channels, which may be unwanted in e.g. heart failure, may be used to advantage as well.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Sipido</LastName><ForeName>K R</ForeName><Initials>KR</Initials><AffiliationInfo><Affiliation>'Lab. of Experimental Cardiology, KUL, Campus Gasthuisberg O/N 7th floor, Herestraat 49, B-3000 Leuven, Belgium. [email protected]</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Varro</LastName><ForeName>A</ForeName><Initials>A</Initials></Author><Author ValidYN="Y"><LastName>Eisner</LastName><ForeName>D</ForeName><Initials>D</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D016454">Review</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>Germany</Country><MedlineTA>Handb Exp Pharmacol</MedlineTA><NlmUniqueID>7902231</NlmUniqueID><ISSNLinking>0171-2004</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C101670">2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000814">Aniline Compounds</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000889">Anti-Arrhythmia Agents</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D010647">Phenyl Ethers</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C430918">SEA 0400</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D019831">Sodium-Calcium Exchanger</NameOfSubstance></Chemical><Chemical><RegistryNumber>GYV9AM2QAG</RegistryNumber><NameOfSubstance UI="D013890">Thiourea</NameOfSubstance></Chemical><Chemical><RegistryNumber>SY7Q814VUP</RegistryNumber><NameOfSubstance UI="D002118">Calcium</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000200" MajorTopicYN="N">Action Potentials</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000814" MajorTopicYN="N">Aniline Compounds</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000889" MajorTopicYN="N">Anti-Arrhythmia Agents</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D001145" MajorTopicYN="N">Arrhythmias, Cardiac</DescriptorName><QualifierName UI="Q000209" MajorTopicYN="N">etiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D002118" MajorTopicYN="N">Calcium</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006332" MajorTopicYN="N">Cardiomegaly</DescriptorName><QualifierName UI="Q000150" MajorTopicYN="N">complications</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006321" MajorTopicYN="N">Heart</DescriptorName><QualifierName UI="Q000502" MajorTopicYN="N">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006333" MajorTopicYN="N">Heart Failure</DescriptorName><QualifierName UI="Q000150" MajorTopicYN="N">complications</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D009206" MajorTopicYN="N">Myocardium</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D010647" MajorTopicYN="N">Phenyl Ethers</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D019831" MajorTopicYN="N">Sodium-Calcium Exchanger</DescriptorName><QualifierName UI="Q000037" MajorTopicYN="Y">antagonists & inhibitors</QualifierName><QualifierName UI="Q000502" MajorTopicYN="N">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D013890" MajorTopicYN="N">Thiourea</DescriptorName><QualifierName UI="Q000031" MajorTopicYN="N">analogs & derivatives</QualifierName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading></MeshHeadingList><NumberOfReferences>174</NumberOfReferences></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2006</Year><Month>4</Month><Day>14</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2006</Year><Month>4</Month><Day>28</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2006</Year><Month>4</Month><Day>14</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">16610344</ArticleId><ArticleId IdType="doi">10.1007/3-540-29715-4_6</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">16610342</PMID><DateCompleted><Year>2006</Year><Month>04</Month><Day>27</Day></DateCompleted><DateRevised><Year>2019</Year><Month>11</Month><Day>09</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">0171-2004</ISSN><JournalIssue CitedMedium="Print"><Issue>171</Issue><PubDate><Year>2006</Year></PubDate></JournalIssue><Title>Handbook of experimental pharmacology</Title><ISOAbbreviation>Handb Exp Pharmacol</ISOAbbreviation></Journal>Cardiac Na+ channels as therapeutic targets for antiarrhythmic agents.
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Digoxin has traditionally been the drug of choice for ventricular rate control in patients with chronic atrial fibrillation (AF), with or without heart failure (HF) with systolic dysfunction. In patients with permanent AF, digoxin monotherapy is ineffective to control ventricular rate during exercise, but the combination of digoxin with a beta-blocker or a non-dihydropyridine calcium channel antagonist can control heart rate both at rest and during exercise. Only a few randomised, controlled studies have evaluated the adverse effects of digoxin in patients with AF in a systematic way and side effects requiring drug withdrawal have rarely been reported. When reported, the most frequent adverse effects were cardiac arrhythmias (ventricular arrhythmias, AV block of varying degrees and sinus pauses). This evidence suggested that, in contrast to other antiarrhythmic drugs, digoxin is a safe drug in patients with AF. However, this safety profile can be erroneous due to the short follow-up of the studies and patient selection. Because patients with HF have been excluded in most studies, the safety profile of digoxin in this population has not been directly addressed. Early recognition that an arrhythmia is related to digoxin intoxication as well as recognition of concomitant medications or medical conditions that may directly alter the pharmacokinetic profile of digoxin, or indirectly alter its cardiac effects by pharmacodynamic interactions remain essential for safe and effective use of digoxin in patients with AF.</Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Tamargo</LastName><ForeName>Juan</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Department of Pharmacology, School of Medicine, Universidad Complutense, 28040 Madrid, Spain. [email protected]</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Delpón</LastName><ForeName>Eva</ForeName><Initials>E</Initials></Author><Author ValidYN="Y"><LastName>Caballero</LastName><ForeName>Ricardo</ForeName><Initials>R</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType><PublicationType UI="D016454">Review</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>Expert Opin Drug Saf</MedlineTA><NlmUniqueID>101163027</NlmUniqueID><ISSNLinking>1474-0338</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000889">Anti-Arrhythmia Agents</NameOfSubstance></Chemical><Chemical><RegistryNumber>73K4184T59</RegistryNumber><NameOfSubstance UI="D004077">Digoxin</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000889" MajorTopicYN="N">Anti-Arrhythmia Agents</DescriptorName><QualifierName UI="Q000009" MajorTopicYN="N">adverse effects</QualifierName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName><QualifierName UI="Q000627" MajorTopicYN="Y">therapeutic use</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D001281" MajorTopicYN="N">Atrial Fibrillation</DescriptorName><QualifierName UI="Q000188" MajorTopicYN="Y">drug therapy</QualifierName><QualifierName UI="Q000503" MajorTopicYN="N">physiopathology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D004077" MajorTopicYN="N">Digoxin</DescriptorName><QualifierName UI="Q000009" MajorTopicYN="N">adverse effects</QualifierName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName><QualifierName UI="Q000627" MajorTopicYN="Y">therapeutic use</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D004347" MajorTopicYN="N">Drug Interactions</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D016903" MajorTopicYN="N">Drug Monitoring</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004562" MajorTopicYN="N">Electrocardiography</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading></MeshHeadingList><NumberOfReferences>113</NumberOfReferences></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2006</Year><Month>4</Month><Day>14</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2007</Year><Month>10</Month><Day>5</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2006</Year><Month>4</Month><Day>14</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">16610972</ArticleId><ArticleId IdType="doi">10.1517/14740338.5.3.453</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">16610351</PMID><DateCompleted><Year>2006</Year><Month>04</Month><Day>27</Day></DateCompleted><DateRevised><Year>2019</Year><Month>11</Month><Day>09</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">0171-2004</ISSN><JournalIssue CitedMedium="Print"><Issue>171</Issue><PubDate><Year>2006</Year></PubDate></JournalIssue><Title>Handbook of experimental pharmacology</Title><ISOAbbreviation>Handb Exp Pharmacol</ISOAbbreviation></Journal><ArticleTitle>Molecular basis of isolated cardiac conduction disease.</ArticleTitle><Pagination><StartPage>331</StartPage><EndPage>347</EndPage><MedlinePgn>331-47</MedlinePgn></Pagination><Abstract>Cardiac conduction disorders are among the most common rhythm disturbances causing disability in millions of people worldwide and necessitating pacemaker implantation. Isolated cardiac conduction disease (ICCD) can affect various regions within the heart, and therefore the clinical features also vary from case to case. Typically, it is characterized by progressive alteration of cardiac conduction through the atrioventricular node, His-Purkinje system, with right or left bundle branch block and QRS widening. In some instances, the disorder may progress to complete atrioventricular block, with syncope and even death. While the role of genetic factors in conduction disease has been suggested as early as the 1970s, it was only recently that specific genetic loci have been reported. Multiple mutations in the gene encoding for the cardiac voltage-gated sodium channel (SCN5A), which plays a fundamental role in the initiation, propagation, and maintenance of normal cardiac rhythm, have been linked to conduction disease, allowing for genotype-phenotype correlation. The electrophysiological characterization of heterologously expressed mutant Na+ channels has revealed gating defects that consistently lead to a loss of channel function. However, studies have also revealed significant overlap between aberrant rhythm phenotypes, and single mutations have been identified that evoke multiple distinct rhythm disorders with common gating lesions. These new insights highlight the complexities involved in linking single mutations, ion-channel behavior, and cardiac rhythm but suggest that interplay between multiple factors could underlie the manifestation of the disease phenotype.</Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Viswanathan</LastName><ForeName>P C</ForeName><Initials>PC</Initials><AffiliationInfo><Affiliation>Vanderbilt University Medical Center, 560 Preston Research Building, 2220 Pierce Avenue, Nashville, TN 37232-6602, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Balser</LastName><ForeName>J R</ForeName><Initials>JR</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D016454">Review</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>Germany</Country><MedlineTA>Handb Exp Pharmacol</MedlineTA><NlmUniqueID>7902231</NlmUniqueID><ISSNLinking>0171-2004</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D015222">Sodium Channels</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D001145" MajorTopicYN="N">Arrhythmias, Cardiac</DescriptorName><QualifierName UI="Q000209" MajorTopicYN="Y">etiology</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000628" MajorTopicYN="N">therapy</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D017147" MajorTopicYN="N">Defibrillators, Implantable</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D015640" MajorTopicYN="N">Ion Channel Gating</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D009154" MajorTopicYN="Y">Mutation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D015222" MajorTopicYN="N">Sodium Channels</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName><QualifierName UI="Q000502" MajorTopicYN="N">physiology</QualifierName></MeshHeading></MeshHeadingList><NumberOfReferences>48</NumberOfReferences></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2006</Year><Month>4</Month><Day>14</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2006</Year><Month>4</Month><Day>28</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2006</Year><Month>4</Month><Day>14</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">16610351</ArticleId><ArticleId IdType="doi">10.1007/3-540-29715-4_13</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">16610350</PMID><DateCompleted><Year>2006</Year><Month>04</Month><Day>27</Day></DateCompleted><DateRevised><Year>2021</Year><Month>10</Month><Day>20</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">0171-2004</ISSN><JournalIssue CitedMedium="Print"><Issue>171</Issue><PubDate><Year>2006</Year></PubDate></JournalIssue><Title>Handbook of experimental pharmacology</Title><ISOAbbreviation>Handb Exp Pharmacol</ISOAbbreviation></Journal><ArticleTitle>Therapy for the Brugada syndrome.</ArticleTitle><Pagination><StartPage>305</StartPage><EndPage>330</EndPage><MedlinePgn>305-30</MedlinePgn></Pagination><Abstract>The Brugada syndrome is a congenital syndrome of sudden cardiac death first described as a new clinical entity in 1992. Electrocardiographically characterized by a distinct coved-type ST segment elevation in the right precordial leads, the syndrome is associated with a high risk for sudden cardiac death in young and otherwise healthy adults, and less frequently in infants and children. The ECG manifestations of the Brugada syndrome are often dynamic or concealed and may be revealed or modulated by sodium channel blockers. The syndrome may also be unmasked or precipitated by a febrile state, vagotonic agents, alpha-adrenergic agonists, beta-adrenergic blockers, tricyclic or tetracyclic antidepressants, a combination of glucose and insulin, and hypokalemia, as well as by alcohol and cocaine toxicity. An implantable cardioverter-defibrillator (ICD) is the most widely accepted approach to therapy. Pharmacological therapy aimed at rebalancing the currents active during phase 1 of the right ventricular action potential is used to abort electrical storms, as an adjunct to device therapy, and as an alternative to device therapy when use of an ICD is not possible. Isoproterenol and cilostazol boost calcium channel current, and drugs like quinidine inhibit the transient outward current, acting to diminish the action potential notch and thus suppress the substrate and trigger for ventricular tachycardia/fibrillation (VT/VF).</Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Antzelevitch</LastName><ForeName>C</ForeName><Initials>C</Initials><AffiliationInfo><Affiliation>Masonic Medical Research Laboratory, 2150 Bleecker Street, Utica, NY 13501, USA. [email protected]</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Fish</LastName><ForeName>J M</ForeName><Initials>JM</Initials></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>R01 HL047678</GrantID><Acronym>HL</Acronym><Agency>NHLBI NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>HL47678</GrantID><Acronym>HL</Acronym><Agency>NHLBI NIH HHS</Agency><Country>United States</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D052061">Research Support, N.I.H., Extramural</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType><PublicationType UI="D016454">Review</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>Germany</Country><MedlineTA>Handb Exp Pharmacol</MedlineTA><NlmUniqueID>7902231</NlmUniqueID><ISSNLinking>0171-2004</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000889">Anti-Arrhythmia Agents</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000889" MajorTopicYN="N">Anti-Arrhythmia Agents</DescriptorName><QualifierName UI="Q000627" MajorTopicYN="N">therapeutic use</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D002037" MajorTopicYN="N">Bundle-Branch Block</DescriptorName><QualifierName UI="Q000150" MajorTopicYN="N">complications</QualifierName><QualifierName UI="Q000175" MajorTopicYN="N">diagnosis</QualifierName><QualifierName UI="Q000503" MajorTopicYN="N">physiopathology</QualifierName><QualifierName UI="Q000628" MajorTopicYN="Y">therapy</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D003645" MajorTopicYN="N">Death, Sudden</DescriptorName><QualifierName UI="Q000209" MajorTopicYN="Y">etiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D017147" MajorTopicYN="N">Defibrillators, Implantable</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004562" MajorTopicYN="N">Electrocardiography</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D013577" MajorTopicYN="N">Syndrome</DescriptorName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2006</Year><Month>4</Month><Day>14</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2006</Year><Month>4</Month><Day>28</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2006</Year><Month>4</Month><Day>14</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">16610350</ArticleId><ArticleId IdType="mid">NIHMS10275</ArticleId><ArticleId IdType="pmc">PMC1474239</ArticleId><ArticleId IdType="doi">10.1007/3-540-29715-4_12</ArticleId></ArticleIdList><ReferenceList><Reference><Citation>Aligs M, Wilde A. “Brugada” syndrome: clinical data and suggested pathophysiological mechanism. 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Genotype-phenotype relationship in Brugada syndrome: electrocardiographic features differentiate SCN5A-related patients from non-SCN5A-related patients. J Am Coll Cardiol. 2002;40:350–356.</Citation><ArticleIdList><ArticleId IdType="pubmed">12106943</ArticleId></ArticleIdList></Reference><Reference><Citation>Suzuki H, Torigoe K, Numata 0, Yazaki S. Infant case with a malignant form of Brugada syndrome. J Cardiovasc Electrophysiol. 2000;11:1277–1280.</Citation><ArticleIdList><ArticleId IdType="pubmed">11083249</ArticleId></ArticleIdList></Reference><Reference><Citation>Tada H, Nogami A, Shimizu W, Naito S, Nakatsugawa M, Oshima S, Taniguchi K. ST segment and T wave alternans in a patient with Brugada syndrome. Pacing Clin Electrophysiol. 2000;23:413–415.</Citation><ArticleIdList><ArticleId IdType="pubmed">10750148</ArticleId></ArticleIdList></Reference><Reference><Citation>Tada H, Sticherling C, Oral H, Morady F. Brugada syndrome mimicked by tricyclic antidepressant overdose. J Cardiovasc Electrophysiol. 2001;12:275.</Citation><ArticleIdList><ArticleId IdType="pubmed">11232630</ArticleId></ArticleIdList></Reference><Reference><Citation>Takehara N, Makita N, Kawabe J, Sato N, Kawamura Y, Kitabatake A, Kikuchi K. A cardiac sodium channel mutation identified in Brugada syndrome associated with atrial standstill. J Intern Med. 2004;255:137–142.</Citation><ArticleIdList><ArticleId IdType="pubmed">14687250</ArticleId></ArticleIdList></Reference><Reference><Citation>Takenaka S, Emori T, Koyama S, Morita H, Fukushima K, Ohe T. Asymptomatic form of Brugada syndrome. Pacing Clin Electrophysiol. 1999;22:1261–1263.</Citation><ArticleIdList><ArticleId IdType="pubmed">10461307</ArticleId></ArticleIdList></Reference><Reference><Citation>Tan HL, Bezzina CR, Smits JP, Verkerk AO, Wilde AA. Genetic control of sodium channel function. Cardiovasc Res. 2003;57:961–973.</Citation><ArticleIdList><ArticleId IdType="pubmed">12650874</ArticleId></ArticleIdList></Reference><Reference><Citation>Tanaka H, Kinoshita 0, Uchikawa S, Kasai H, Nakamura M, Izawa A, Yokoseki 0, Kitabayashi H, Takahashi W, Yazaki Y, Watanabe N, Imamura H, Kubo K. Successful prevention of recurrent ventricular fibrillation by intravenous isoproterenol in a patient with Brugada syndrome. Pacing Clin Electrophysiol. 2001;24:1293–1294.</Citation><ArticleIdList><ArticleId IdType="pubmed">11523620</ArticleId></ArticleIdList></Reference><Reference><Citation>Tsuchiya T, Ashikaga K, Honda T, Arita M. Prevention of ventricular fibrillation by cilostazol, an oral phosphodiesterase inhibitor, in a patient with Brugada syndrome. J Cardiovasc Electrophysiol. 2002;13:698–701.</Citation><ArticleIdList><ArticleId IdType="pubmed">12139296</ArticleId></ArticleIdList></Reference><Reference><Citation>van Den Berg MP, Wilde AA, Viersma TJW, Brouwer J, Haaksma J, van der Hout AH, Stolte-Dijkstra I, Bezzina TCR, Van Langen IM, Beaufort-Krol GC, Cornel JH, Crijns HJ. Possible bradycardic mode of death and successful pacemaker treatment in a large family with features of long QT syndrome type 3 and Brugada syndrome. J Cardiovasc Electrophysiol. 2001;12:630–636.</Citation><ArticleIdList><ArticleId IdType="pubmed">11405394</ArticleId></ArticleIdList></Reference><Reference><Citation>Vatta M, Dumaine R, Varghese G, Richard TA, Shimizu W, Aihara N, Nademanee K, Brugada R, Brugada J, Veerakul G, Li H, Bowles NE, Brugada P, Antzelevitch C, Towbin JA. Genetic and biophysical basis of sudden unexplained nocturnal death syndrome (SUNDS), a disease allelic to Brugada syndrome. Hum Mol Genet. 2002;11:337–345.</Citation><ArticleIdList><ArticleId IdType="pubmed">11823453</ArticleId></ArticleIdList></Reference><Reference><Citation>Weiss R, Barmada MM, Nguyen T, Seibel JS, Cavlovich D, Kornblit CA, Angelilli A, Villanueva F, McNamara DM, London B. Clinical and molecular heterogeneity in the Brugada syndrome. A novel gene locus on chromosome 3. Circulation. 2002;105:707–713.</Citation><ArticleIdList><ArticleId IdType="pubmed">11839626</ArticleId></ArticleIdList></Reference><Reference><Citation>Wichter T, Matheja P, Eckardt L, Kies P, Schafers K, Schulze-Bahr E, Haverkamp W, Borggrefe M, Schober 0, Breithardt G, Schafers M. Cardiac autonomic dysfunction in Brugada syndrome. Circulation. 2002;105:702–706.</Citation><ArticleIdList><ArticleId IdType="pubmed">11839625</ArticleId></ArticleIdList></Reference><Reference><Citation>Wilde AA, Antzelevitch C, Borggrefe M, Brugada J, Brugada R, Brugada P, Corrado D, Hauer RN, Kass RS, Nademanee K, Priori SG, Towbin JA. Proposed diagnostic criteria for the Brugada syndrome: consensus report. Circulation. 2002a;106:2514–2519.</Citation><ArticleIdList><ArticleId IdType="pubmed">12417552</ArticleId></ArticleIdList></Reference><Reference><Citation>Wilde AA, Antzelevitch C, Borggrefe M, Brugada J, Brugada R, Brugada P, Corrado D, Hauer RN, Kass RS, Nademanee K, Priori SG, Towbin JA. Proposed diagnostic criteria for the Brugada syndrome: consensus report. Eur Heart J. 2002b;23:1648–1654.</Citation><ArticleIdList><ArticleId IdType="pubmed">12448445</ArticleId></ArticleIdList></Reference><Reference><Citation>Yan GX, Antzelevitch C. Cellular basis for the electrocardiographic Jwave. Circulation. 1996;93:372–379.</Citation><ArticleIdList><ArticleId IdType="pubmed">8548912</ArticleId></ArticleIdList></Reference><Reference><Citation>Yan GX, Antzelevitch C. Cellular basis for the Brugada Syndrome and other mechanisms of arrhythmogenesis associated with ST segment elevation. Circulation. 1999;100:1660–1666.</Citation><ArticleIdList><ArticleId IdType="pubmed">10517739</ArticleId></ArticleIdList></Reference></ReferenceList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">16610344</PMID><DateCompleted><Year>2006</Year><Month>04</Month><Day>27</Day></DateCompleted><DateRevised><Year>2019</Year><Month>11</Month><Day>09</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">0171-2004</ISSN><JournalIssue CitedMedium="Print"><Issue>171</Issue><PubDate><Year>2006</Year></PubDate></JournalIssue><Title>Handbook of experimental pharmacology</Title><ISOAbbreviation>Handb Exp Pharmacol</ISOAbbreviation></Journal><ArticleTitle>Sodium calcium exchange as a target for antiarrhythmic therapy.</ArticleTitle><Pagination><StartPage>159</StartPage><EndPage>199</EndPage><MedlinePgn>159-99</MedlinePgn></Pagination><Abstract>In search of better antiarrhythmic therapy, targeting the Na/Ca exchanger is an option to be explored. The rationale is that increased activity of the Na/Ca exchanger has been implicated in arrhythmogenesis in a number of conditions. The evidence is strong for triggered arrhythmias related to Ca2+ overload, due to increased Na+ load or during adrenergic stimulation; the Na/Ca exchanger may be important in triggered arrhythmias in heart failure and in atrial fibrillation. There is also evidence for a less direct role of the Na/Ca exchanger in contributing to remodelling processes. In this chapter, we review this evidence and discuss the consequences of inhibition of Na/Ca exchange in the perspective of its physiological role in Ca2+ homeostasis. We summarize the current data on the use of available blockers of Na/Ca exchange and propose a framework for further study and development of such drugs. Very selective agents have great potential as tools for further study of the role the Na/Ca exchanger plays in arrhythmogenesis. For therapy, they may have their specific indications, but they carry the risk of increasing Ca2+ load of the cell. Agents with a broader action that includes Ca2+ channel block may have advantages in other conditions, e.g. with Ca2+ overload. Additional actions such as block of K+ channels, which may be unwanted in e.g. heart failure, may be used to advantage as well.</Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Sipido</LastName><ForeName>K R</ForeName><Initials>KR</Initials><AffiliationInfo><Affiliation>'Lab. of Experimental Cardiology, KUL, Campus Gasthuisberg O/N 7th floor, Herestraat 49, B-3000 Leuven, Belgium. [email protected]</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Varro</LastName><ForeName>A</ForeName><Initials>A</Initials></Author><Author ValidYN="Y"><LastName>Eisner</LastName><ForeName>D</ForeName><Initials>D</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D016454">Review</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>Germany</Country><MedlineTA>Handb Exp Pharmacol</MedlineTA><NlmUniqueID>7902231</NlmUniqueID><ISSNLinking>0171-2004</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C101670">2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000814">Aniline Compounds</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000889">Anti-Arrhythmia Agents</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D010647">Phenyl Ethers</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C430918">SEA 0400</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D019831">Sodium-Calcium Exchanger</NameOfSubstance></Chemical><Chemical><RegistryNumber>GYV9AM2QAG</RegistryNumber><NameOfSubstance UI="D013890">Thiourea</NameOfSubstance></Chemical><Chemical><RegistryNumber>SY7Q814VUP</RegistryNumber><NameOfSubstance UI="D002118">Calcium</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000200" MajorTopicYN="N">Action Potentials</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000814" MajorTopicYN="N">Aniline Compounds</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000889" MajorTopicYN="N">Anti-Arrhythmia Agents</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D001145" MajorTopicYN="N">Arrhythmias, Cardiac</DescriptorName><QualifierName UI="Q000209" MajorTopicYN="N">etiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D002118" MajorTopicYN="N">Calcium</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006332" MajorTopicYN="N">Cardiomegaly</DescriptorName><QualifierName UI="Q000150" MajorTopicYN="N">complications</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006321" MajorTopicYN="N">Heart</DescriptorName><QualifierName UI="Q000502" MajorTopicYN="N">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006333" MajorTopicYN="N">Heart Failure</DescriptorName><QualifierName UI="Q000150" MajorTopicYN="N">complications</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D009206" MajorTopicYN="N">Myocardium</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D010647" MajorTopicYN="N">Phenyl Ethers</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D019831" MajorTopicYN="N">Sodium-Calcium Exchanger</DescriptorName><QualifierName UI="Q000037" MajorTopicYN="Y">antagonists & inhibitors</QualifierName><QualifierName UI="Q000502" MajorTopicYN="N">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D013890" MajorTopicYN="N">Thiourea</DescriptorName><QualifierName UI="Q000031" MajorTopicYN="N">analogs & derivatives</QualifierName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading></MeshHeadingList><NumberOfReferences>174</NumberOfReferences></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2006</Year><Month>4</Month><Day>14</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2006</Year><Month>4</Month><Day>28</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2006</Year><Month>4</Month><Day>14</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">16610344</ArticleId><ArticleId IdType="doi">10.1007/3-540-29715-4_6</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">16610342</PMID><DateCompleted><Year>2006</Year><Month>04</Month><Day>27</Day></DateCompleted><DateRevised><Year>2019</Year><Month>11</Month><Day>09</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">0171-2004</ISSN><JournalIssue CitedMedium="Print"><Issue>171</Issue><PubDate><Year>2006</Year></PubDate></JournalIssue><Title>Handbook of experimental pharmacology</Title><ISOAbbreviation>Handb Exp Pharmacol</ISOAbbreviation></Journal><ArticleTitle>Cardiac Na+ channels as therapeutic targets for antiarrhythmic agents.</ArticleTitle><Pagination><StartPage>99</StartPage><EndPage>121</EndPage><MedlinePgn>99-121</MedlinePgn></Pagination><Abstract>There are many factors that influence drug block of voltage-gated Na+ channels (VGSC). Pharmacological agents vary in conformation, charge, and affinity. Different drugs have variable affinities to VGSC isoforms, and drug efficacy is affected by implicit tissue properties such as resting potential, action potential morphology, and action potential frequency. The presence of polymorphisms and mutations in the drug target can also influence drug outcomes. While VGSCs have been therapeutic targets in the management of cardiac arrhythmias, their potential has been largely overshadowed by toxic side effects. Nonetheless, many VGSC blockers exhibit inherent voltage- and use-dependent properties of channel block that have recently proven useful for the diagnosis and treatment of genetic arrhythmias that arise from defects in Na+ channels and can underlie idiopathic clinical syndromes. These defective channels suggest themselves as prime targets of disease and perhaps even mutation specific pharmacological interventions.
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2,333,348 |
[COX-2 mediates U50488H-induced delayed cardioprotection in isolated rat heart].
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To determine whether U50488H, a selective agonist of kappa-opioid receptor, could induce biphasic (early and late) cardioprotection against myocardial ischemia/reperfusion injury and to explore the underlying mechanisms.</AbstractText>Isolated perfused rat hearts were subjected to 30 min of ischemia followed by 120 min reperfusion and the cardiac function was evaluated.</AbstractText>Left ventricular end-diastolic pressure (LVEDP), left ventricular developed pressure (LVDP) and maximal velocity of contraction and relaxation (+/-dP/dtmax) were improved when U50488H was administered 1 or 24 h before ischemia (P<0.05). Myocardial infarct size, activities of creatine kinase (CK) and lactate dehydrogenase (LDH) in the coronary effluent were lower in the U50488H pretreatment group than those in the control group. Administration of a selective cyclooxygenase-2 (COX-2) inhibitor, celecoxib abolished the late phase of cardioprotection produced by administration of U50488H 24 h before ischemia. Activities of CK and LDH in the coronary effluent were higher in U50488H and celecoxib co-pretreatment group than those in U50488H group. However, administration of celecoxib did not block the early phase of cardioprotection by 1 h treatment of U50488H before ischemia.</AbstractText>The late (but not the early) phase of cardioprotection induced by kappa-opioid receptor agonist might be mediated by COX-2.</AbstractText>
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2,333,349 |
Prolongation of the cardiac QTc interval in Turner syndrome.
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Anatomic anomalies of the cardiovascular system occur in approximately 50% of individuals with Turner syndrome (TS), with the specific genetic cause(s) for the heart defects still unknown. Because congenital heart disease may be associated with conduction system abnormalities, we compared electrocardiograms (ECGs) in 100 women with TS and 100 age-matched female controls. Women with TS were significantly more likely to demonstrate left posterior fascicular block (p < 0.005), accelerated AV conduction (p < 0.006), and T wave abnormalities (p < 0.006). The PR interval was significantly shorter (137 +/- 17 vs. 158 +/- 18 ms, p < 0.0001) and the rate-corrected QT interval (QTc) significantly longer in women with TS than in controls (423 +/- 19 ms vs. 397 +/- 18 ms; p < 0.0001). Twenty-one women with TS but no controls had a QTc greater than 440 ms. We found no statistically significant relation between body habitus, cardiac dimensions, evidence of congenital heart disease, or metabolic parameters and the incidence of ECG abnormalities or QTc duration in TS. Cardiac conduction and repolarization abnormalities appear to be intrinsic features of TS, suggesting that deletion of the second sex chromosome has more profound effects on the cardiovascular system than previously recognized, and that ECG analysis should be included in evaluating and monitoring patients with Turner syndrome.
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2,333,350 |
The role of heterogeneities and intercellular coupling in wave propagation in cardiac tissue.
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Electrical heterogeneities play a role in the initiation of cardiac arrhythmias. In certain pathological conditions such as ischaemia, current sinks can develop in the diseased cardiac tissue. In this study, we investigate the effects of changing the amount of heterogeneity and intercellular coupling on wavefront stability in a cardiac cell culture system and a mathematical model of excitable media. In both systems, we observe three types of behaviour: plane wave propagation without breakup, plane wave breakup into spiral waves and plane wave block. In the theoretical model, we observe a linear decrease in propagation velocity as the number of heterogeneities is increased, followed by a rapid, nonlinear decrease to zero. The linear decrease results from the heterogeneities acting independently on the wavefront. A general scaling argument that considers the degree of system heterogeneity and the properties of the excitable medium is used to derive a dimensionless parameter that describes the interaction of the wavefront with the heterogeneities.
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2,333,351 |
NAC and DTT promote TGF-beta1 monomer formation: demonstration of competitive binding.
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TGF-Beta plays an important role in the genesis and progression of pulmonary fibrosis. We sought to determine the role of mononuclear phagocytes in the activation of TGF-beta and found that freshly isolated peripheral blood monocytes spontaneously released TGF-beta. Stimulating these monocytes with GM-CSF or LPS, but not MCSF, augmented the activation of TGF-beta. In human monocytes, the free thiol compounds DTT and NAC decreased the activity of TGF-beta, without affecting TGF-beta mRNA transcription. Both NAC and DTT lessened the biological activity of recombinant active TGF-beta in a cell-free system. We found that NAC and DTT reduced dimeric active TGF-beta from a 25 kDa protein to 12.5 kDa inactive monomer. This conversion was reversed using the oxidizing agent diamide. Diamide also restored biological activity to NAC or DTT-treated TGF-beta. Reduction of TGF-beta to monomers could competitively inhibit active dimeric TGF-beta and block intracellular signaling events. Our observations suggest that modulation of the oxidative state of TGF-beta may be a novel therapeutic approach for patients with pulmonary fibrosis.
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2,333,352 |
Conduction system disease in fetuses evaluated for irregular cardiac rhythm.
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To determine the prevalence of 1st and 2nd degree AV block in fetuses with an irregular cardiac rhythm, and to summarize outcome of these pregnancies.</AbstractText>The diagnosis of irregular cardiac rhythm or 'skipped beats' includes isolated ectopy that resolves spontaneously. Recently, Doppler measurements of the 'mechanical' PR interval have been shown to identify AV conduction disease prenatally. Prenatal therapy of these conduction abnormalities may limit the progression to more advanced disease either in utero or after birth.</AbstractText>A retrospective review was performed of fetuses evaluated between 1996 and 2004 with the findings of irregular cardiac rhythm. 1st or 2nd degree AV block was diagnosed on Doppler and M-mode recordings, and confirmed using either fetal magnetocardiography (fMCG) or postnatal 12-lead ECG. Dexamethasone was administered to 4 mothers with abnormal fetal AV conduction in the setting of anti-Ro/anti-La antibodies.</AbstractText>Of 702 fetuses initially referred for arrhythmia, 306 had an irregular rhythm. Eight (2.6%) had intermittent 1st or 2nd degree AV block confirmed by fMCG and/or postnatal 12-lead ECG. AV block was presumed idiopathic in 2, associated with congenital long QT syndrome in 2 or with clinically unsuspected maternal anti-Ro or anti-La antibodies in 4. During the intrauterine period there was no progression to complete AV block and all were born alive at 34-40 weeks of gestation.</AbstractText>A small but clinically significant population of fetuses with irregular rhythm will have 1st or 2nd degree AV block. Transplacental therapy may limit the intrauterine progression to more advanced disease.</AbstractText>Copyright 2006 S. Karger AG, Basel.</CopyrightInformation>
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"Sensing alternans" in a patient with a newly implanted pacemaker.
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This report describes the case of an 80-year-old man with a history of coronary artery disease who presented with acute pericarditis secondary to pacemaker lead perforation of the ventricular wall 2 days after undergoing dual lead pacemaker implantation. The electrocardiogram revealed sinus rhythm with an intra-atrial conduction delay and intermittent failure of atrial sensing as evidenced by alternating atrial spikes in every other P wave. The noted pericardial effusion and the likely shifting of the atrial lead with each alternate beat caused the "sensing alternans" that was seen on the admission electrocardiogram.
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2,333,354 |
Cardiac-specific elevations in thyroid hormone enhance contractility and prevent pressure overload-induced cardiac dysfunction.
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Thyroid hormone (TH) is critical for cardiac development and heart function. In heart disease, TH metabolism is abnormal, and many biochemical and functional alterations mirror hypothyroidism. Although TH therapy has been advocated for treating heart disease, a clear benefit of TH has yet to be established, possibly because of peripheral actions of TH. To assess the potential efficacy of TH in treating heart disease, type 2 deiodinase (D2), which converts the prohormone thyroxine to active triiodothyronine (T3), was expressed transiently in mouse hearts by using the tetracycline transactivator system. Increased cardiac D2 activity led to elevated cardiac T3 levels and to enhanced myocardial contractility, accompanied by increased Ca(2+) transients and sarcoplasmic reticulum (SR) Ca(2+) uptake. These phenotypic changes were associated with up-regulation of sarco(endo)plasmic reticulum calcium ATPase (SERCA) 2a expression as well as decreased Na(+)/Ca(2+) exchanger, beta-myosin heavy chain, and sarcolipin (SLN) expression. In pressure overload, targeted increases in D2 activity could not block hypertrophy but could completely prevent impaired contractility and SR Ca(2+) cycling as well as altered expression patterns of SERCA2a, SLN, and other markers of pathological hypertrophy. Our results establish that elevated D2 activity in the heart increases T3 levels and enhances cardiac contractile function while preventing deterioration of cardiac function and altered gene expression after pressure overload.
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2,333,355 |
Recurrent congenital heart block in neonatal lupus.
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Congenital heart block (CHB) is the main complication of neonatal lupus (NL) and is strongly associated with the presence of anti-SSA/Ro and anti-SSB/La antibodies. The recurrence of CHB in subsequent pregnancies in mothers with these antibodies is uncommon, occurring in approximately 15% of cases. We describe here a case of recurrent CHB in a previously asymptomatic mother with Sjögren syndrome and discuss the current strategies for the prevention and treatment of CHB in NL.
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2,333,356 |
[Dorsal medulla oblongata stroke after a wasp sting].
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Although wasp stings can cause local reactions such as pain, flare, edema, swelling and severe reactions, including anaphylaxis; neurological vascular complications are rare.</AbstractText>We report a case of a 36-year-old male who developed focal neurological symptoms after a wasp sting. The brain MRI showed an infarct in the left dorsal medulla. The blood test has showed an elevated level of venom-specific IgE antibodies and the skin test with wasp venom was highly positive. Improvement occurred rapidly after treatment with methylprednisone. The postulated mechanisms include vasoconstriction and platelet aggregation secondary to an injection of distinct allergens contained in wasp venom.</AbstractText>It would thus be important to ask patients about any recent wasp sting, in order to provide appropriate treatment.</AbstractText>
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2,333,357 |
Accelerated memory cell homeostasis during T cell depletion and approaches to overcome it.
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Partial T cell depletion is used in solid organ transplantation as a valuable strategy of peritransplant induction immunosuppression. Using a murine cardiac allograft model, we recently demonstrated that this led to lymphopenia-induced (homeostatic) proliferation among the residual nondepleted lymphocytes. Rather than promoting tolerance, peritransplant T cell-depleting Abs actually resulted in resistance to tolerance induction by costimulatory blockade. In this study we show that memory T cells predominate shortly after subtotal lymphodepletion due to two distinct mechanisms: relative resistance to depletion and enhanced homeostatic proliferation. In contrast, regulatory cells (CD4+ CD25+ Foxp3+) are depleted as efficiently as nonregulatory cells and exhibit reduced homeostatic expansion compared with memory cells. The resistance to tolerance induction seen with subtotal T cell depletion can be overcome in two different ways: first, by the adoptive transfer of additional unprimed regulatory cells at the time of transplant, and second, by the adjunctive use of nondepleting anti-CD4 and anti-CD8 mAbs, which effectively block homeostatic expansion. We conclude that the resistance to tolerance induction seen after subtotal lymphocyte depletion can be attributed to alterations in the balance of naive, memory, and regulatory T cells. These data have clinically relevant implications related to the development of novel strategies to overcome resistance to tolerance.
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2,333,358 |
[Obstetrical management of patients at risk of neonatal lupus syndrome: review of the literature].
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Fetuses and infants of women with anti-SSA/Ro and anti-SSB/La antibodies are at risk of neonatal lupus syndrome, featuring skin lesions, hematological and hepatic disorders, and congenital heart block (CHB) in the absence of severe cardiac malformation. The prevalence of CHB in newborns of anti-SSA/Ro positive women with known connective tissue disease is 1 to 2% and the risk of recurrence ranges from 10 to 17%. CHB is definitive and is associated with significant morbidity (pacemaker must be implanted in 2/3 of cases) and mortality (16 to 19%). Myocardial involvement may either be associated or appear subsequently. Other manifestations are discussed. For anti-SSA/Ro positive pregnant women, echocardiograms should be performed every 2 weeks from 16 to 24 weeks of gestation, and every week in case of past history of CHB. Electrocardiogram should be performed in the first days of life for all children to detect incomplete CHB. Therapy for CHB detected in utero is based on fluorinated steroids, especially betamethasone. Its efficiency is variable.
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2,333,359 |
Adenosine test in the diagnosis of unexplained syncope: marker of conducting tissue disease or neurally mediated syncope?
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Adenosine test (supine administration of a 20 mg intravenous bolus with electrocardiographic and blood pressure monitoring) has been endorsed by the European Society of Cardiology guidelines on syncope management as an 'experimental' test in the diagnosis of unexplained syncope. The test is quick and cheap, but there is no consensus as to what condition, if any, the adenosine test is exposing, with conducting tissue disease and neurally mediated syncope proposed by various authors. In this article, we review the possible mechanisms underlying a positive adenosine test, its safety, and a comprehensive examination of the literature supporting each of the putative causal diagnoses.
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Heart rate variability-guided prophylactic treatment of severe hypotension after subarachnoid block for elective cesarean delivery.
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Baseline low-to-high frequency ratio (LF/HF) of heart rate variability predicted hypotension after subarachnoid block (SAB). LF/HF-guided treatment of hypotension with vasopressors or colloids was investigated.</AbstractText>In 80 women scheduled to undergo cesarean delivery during SAB, LF/HF and systolic blood pressure (SBP) were analyzed. Patients were randomly assigned to a control group (n = 40) or a treatment group (n = 40). Control patients were assigned by their baseline LF/HF to one of two subgroups: LF/HF less than 2.5 or LF/HF greater than 2.5. Treatment patients with baseline LF/HF greater than 2.5 were treated with vasopressor infusion right after SAB (n = 20) or colloid prehydration until LF/HF decreased below 2.5 (n = 20). The incidences of hypotension (SBP < 80 mmHg) and hypertension (SBP > 140 mmHg) were investigated. LF/HF is presented as median and range, and SBP is presented as mean +/- SD.</AbstractText>Three of 17 control patients with low baseline LF/HF (1.7 [1.3/1.8]) demonstrated hypotension, and mean SBP remained stable (lowest SBP = 105 +/- 14 mmHg). In contrast, 20 of 23 control patients with high baseline LF/HF (3.8 [3.3/4.8]; P < 0.0001 vs. low baseline LF/HF) demonstrated hypotension after SAB: lowest SBP = 78 +/- 15 mmHg (P < 0.0001 vs. lowest SBP of control group with low baseline LF/HF). LF/HF-guided vasopressor therapy prevented hypotension in 19 of 20 patients: baseline SBP = 123 +/- 15 mmHg, lowest SBP = 116 +/- 17 mmHg. Mean prophylactic colloid infusion of 1,275 +/- 250 ml reduced elevated baseline LF/HF from 5.4 (4.1/7.5) to 1.3 (0.8/1.59) (P < 0.0001). Hypotension was prevented in 17 of 20 patients: baseline SBP = 115 +/- 13 mmHg, lowest SBP = 104 +/- 19 mmHg. No hypertensive episode was recognized.</AbstractText>LF/HF may be a tool to guide prophylactic therapy of patients at high risk for hypotension after SAB. Vasopressor therapy tended to be more effective compared with colloid prehydration.</AbstractText>
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2,333,361 |
Complex haplotypes derived from noncoding polymorphisms of the intronless alpha2A-adrenergic gene diversify receptor expression.
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Alpha(2A)-adrenergic receptors (alpha(2A)AR) regulate multiple central nervous system, cardiovascular, and metabolic processes including neurotransmitter release, platelet aggregation, blood pressure, insulin secretion, and lipolysis. Complex diseases associated with alpha(2A)AR dysfunction display familial clustering, phenotypic heterogeneity, and interindividual variability in response to therapy targeted to alpha(2A)ARs, suggesting common, functional polymorphisms. In a multiethnic discovery cohort we identified 16 single-nucleotide polymorphisms (SNPs) in the alpha(2A)AR gene organized into 17 haplotypes of two major phylogenetic clades. In contrast to other adrenergic genes, variability of the alpha(2A)AR was primarily due to SNPs in the promoter, 5' UTR and 3' UTR, as opposed to the coding block. Marked ethnic variability in the frequency of SNPs and haplotypes was observed: one haplotype represented 70% of Caucasians, whereas Africans and Asians had a wide distribution of less common haplotypes, with the highest haplotype frequencies being 16% and 35%, respectively. Despite the compact nature of this intronless gene, local linkage disequilibrium between a number of SNPs was low and ethnic-dependent. Whole-gene transfections into BE(2)-C human neuronal cells using vectors containing the entire approximately 5.3-kb gene without exogenous promoters were used to ascertain the effects of haplotypes on alpha(2A)AR expression. Substantial differences (P < 0.001) in transcript and cell-surface protein expression, by as much as approximately 5-fold, was observed between haplotypes, including those with common frequencies. Thus, signaling by this virtually ubiquitous receptor is under major genetic influence, which may be the basis for highly divergent phenotypes in complex diseases such as systemic and pulmonary hypertension, heart failure, diabetes, and obesity.
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2,333,362 |
Reversible vagal blockade in conscious rats using a targeted delivery device.
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Reversible methods of nerve blockade greatly aid neurophysiological and behavioral studies. We have developed an implantable device for the local delivery of anesthetics to the area surrounding the vagal nerve in rats. The device consists of a thick silicone tube for insulating the nerves from the surrounding tissue, and a thin silicone tube for the infusion of anesthetics into the insulating tube. The in vivo performance of the device was tested electrophysiologically, and cardiovascular responses to vagal stimulation were measured in conscious animals. Nerve conductivity was completely blocked by injection of a small amount (<20 microl) of 1% lidocaine, with conductivity subsequently recovering gradually after 10-40 min. Electrical stimulation of the right vagus nerve in conscious rats increased arterial pressure while decreasing heart rate. The local blockade of afferent fibers abolished the arterial pressure response but preserved the bradycardic response to vagal nerve stimulation. The targeted delivery device was useful for reversible vagal blockade in conscious rats.
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2,333,363 |
hERG potassium channels and cardiac arrhythmia.
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hERG potassium channels are essential for normal electrical activity in the heart. Inherited mutations in the HERG gene cause long QT syndrome, a disorder that predisposes individuals to life-threatening arrhythmias. Arrhythmia can also be induced by a blockage of hERG channels by a surprisingly diverse group of drugs. This side effect is a common reason for drug failure in preclinical safety trials. Insights gained from the crystal structures of other potassium channels have helped our understanding of the block of hERG channels and the mechanisms of gating.
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2,333,364 |
Clonidine addition prolongs the duration of caudal analgesia.
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In this study, using a dose-ranging design, we examined the effects of clonidine with 0.125% bupivacaine on the duration of post-operative analgesia in caudal anaesthesia in children.</AbstractText>We conducted a controlled, prospective study of clonidine in caudal anaesthesia in 60 children, aged 1-10 years, undergoing elective inguinal hernia repair. Induction and maintenance of anaesthesia were performed by inhalation of sevoflurane and nitrous oxide. The children were randomized in a double-blind fashion to four groups, and were given a caudal anaesthetic with either 0.125% plain isobaric bupivacaine (1 ml/kg) or bupivacaine plus 1, 1.5 or 2 microg/kg of clonidine. The blood pressure and heart rate were recorded peri-operatively. Analgesia was evaluated by the modified Children's Hospital of Eastern Ontario Pain Scale (mCHEOPS) or a visual analogue scale (VAS). Paracetamol was given when the mCHEOPS score was greater than five or when the VAS score was greater than 30 mm. The monitoring of scores for pain, haemodynamic changes and post-operative nausea and vomiting was performed by nurses blind to the study allocation.</AbstractText>The duration of analgesia was found to be significantly longer in the group given bupivacaine plus 2 microg/kg of clonidine (median, 650 min; range, 300-900 min). Peri-operative hypotension and bradycardia, post-operative respiratory depression and motor block were not recorded in any patient.</AbstractText>The addition of clonidine to 0.125% bupivacaine prolongs the duration of post-operative analgesia without any respiratory or haemodynamic side-effects.</AbstractText>
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2,333,365 |
Potential vascular alpha1-adrenoceptor blocking properties of an array of 5-HT receptor ligands in the rat.
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This study set out to analyse the potential ability of some 5-hydroxytryptamine (5-HT) receptor ligands widely used in cardiovascular experimental models to interact with vascular alpha1-adrenoceptors in the pithed rat. These ligands included: methiothepin, methysergide and metergoline (5-HT(1)/5-HT2); WAY-100635, buspirone, ipsapirone and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (5-HT(1A)); GR127935 (5-HT(1B/1D)); ketanserin, ritanserin, spiperone and pizotifen (5-HT2); granisetron and metoclopramide (5-HT3); tropisetron (5-HT3/5-HT4); ergotamine (5-HT(1B/1D), 5-ht(5A/5B)); clozapine (5-HT6/5-HT7); as well as LY215840 and mesulergine (5-HT2/5-HT7). For this purpose, the increases in diastolic blood pressure produced by the selective alpha1-adrenoceptor agonist, phenylephrine, were analysed before and after the above antagonists or saline. The adrenoceptor antagonist properties of prazosin (alpha1) and yohimbine (alpha2) were also analysed for comparison. Thus, the phenylephrine-induced vasopressor responses were dose-dependently antagonised with the following apparent rank order of potency by: prazosin > or = methiothepin > ketanserin > clozapine > or = lisuride >> buspirone; this potency correlates with the affinity of these compounds for alpha1-adrenoceptor binding sites. In contrast, the other compounds were either devoid of any blocking effect on--or even potentiated (i.e. lisuride, methysergide, 8-OH-DPAT, granisetron and GR127935)--the responses to phenylephrine. These results show that methiothepin, ketanserin, clozapine, lisuride and buspirone can block alpha1-adrenoceptors in the rat systemic vasculature.
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2,333,366 |
Reduced cardiac output is associated with decreased mitochondrial efficiency in the non-ischemic ventricular wall of the acute myocardial-infarcted dog.
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Cardiogenic shock is the leading cause of death among patients hospitalized with acute myocardial infarction (MI). Understanding the mechanisms for acute pump failure is therefore important. The aim of this study is to examine in an acute MI dog model whether mitochondrial bio-energetic function within non-ischemic wall regions are associated with pump failure. Anterior MI was produced in dogs via ligation of left anterior descending (LAD) coronary artery, that resulted in an infract size of about 30% of the left ventricular wall. Measurements of hemodynamic status, mitochondrial function, free radical production and mitochondrial uncoupling protein 3 (UCP3) expression were determined over 24 h period. Hemodynamic measurements revealed a > 50% reduction in cardiac output at 24 h post infarction when compared to baseline. Biopsy samples were obtained from the posterior non-ischemic wall during acute infarction. ADP/O ratios for isolated mitochondria from non-ischemic myocardium at 6 h and 24 h were decreased when compared to the ADP/O ratios within the same samples with and without palmitic acid (PA). GTP inhibition of (PA)-stimulated state 4 respiration in isolated mitochondria from the non-ischemic wall increased by 7% and 33% at 6 h and 24 h post-infarction respectively when compared to sham and pre-infarction samples. This would suggest that the mitochondria are uncoupled and this is supported by an associated increase in UCP3 expression observed on western blots from these same biopsy samples. Blood samples from the coronary sinus measured by electron paramagnetic resonance (EPR) methods showed an increase in reactive oxygen species (ROS) over baseline at 6 h and 24 h post-infarction. In conclusion, mitochondrial bio-energetic ADP/O ratios as a result of acute infarction are abnormal within the non-ischemic wall. Mitochondria appear to be energetically uncoupled and this is associated with declining pump function. Free radical production may be associated with the induction of uncoupling proteins in the mitochondria.
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2,333,367 |
Detection method to minimize variability in photoplethysmographic signals for timing-related measurement.
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Photoplethysmography (PPG) is a common optical technique used to monitor peripheral pulsation. Studies have shown that minimal variability in phase characteristics is critical to attain accurate estimation of timing-related measurements, such as heart rate and pulse transit time. Observed abrupt changes from baseline of these measurements have shown to identify abnormalities in clinical studies. This study investigates nominal fluctuations when different detection settings were used on the PPG signals. The results indicate that there can be differences in variations observed, and an appropriate detection setting can minimize phase-induced errors in clinical interpretation of timing-related physiologic measurements.
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2,333,368 |
Time course of cardiovascular neural regulation during programmed 20-sec apnea in rats.
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Long-term hypoxia results in hemodynamic breakdown in patients in the intensive care unit; however, intermittent hypoxia causes hypertension in individuals with sleep apnea. The objective of this study was to explore the sequential cardiovascular neural alterations in response to acute hypoxic apnea.</AbstractText>The authors conducted a prospective, randomized animal study.</AbstractText>The study was conducted in a university animal laboratory.</AbstractText>A programmable apnea model was developed in anesthetized rats, in which a 20-sec period of apnea was produced and subsequently divided into the early (2.0 to 7.9 secs), middle (8.0 to 13.9 secs), and late apneic phases (14.0 to 19.9 secs) and immediate reventilatory phase (20.0 to 25.9 secs).</AbstractText>Evident hypoxia developed during 20-sec apnea. Arterial pressure increased in the early apneic phase and returned to control level in the middle phase. Significant hypotension developed in the late apneic phase and deteriorated in the reventilatory phase. Interbeat interval increased mildly along the apneic event. The increase of pressure in the early and middle phases was inhibited by propranolol (1.0 mg/kg intravenously [iv]) but was provoked by phentolamine (2.5 mg/kg iv). The decrease of pressure in the late and reventilatory phases was reversed, at least in part, by phentolamine. Atropine (0.5 mg/kg iv) did not produce discernible effects in the arterial pressure. The increase of interbeat interval was suppressed by propranolol. Power spectral analysis of arterial pressure variability demonstrated significant increases of the low-frequency (sympathetic vasomotor activity) and normalized high-frequency (cardiac sympathetic modulation) power after reventilation.</AbstractText>Although the sympathetic activity is excited during and after a hypoxic apnea, the immediate pressor effect is related to an inotropic response of cardiac sympathetic regulation, whereas the negative chronotropic and subsequent depressor effect is associated with a failure in the cardiovascular response to sympathetic excitation.</AbstractText>
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2,333,369 |
Quaternary derivatives of granatanol diesters: potent, ultrashort acting non-depolarizing neuromuscular relaxants.
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The purpose of this study was to explore the feasibility of utilizing the granatanol: N-methyl [9-azabicyclo (3.3.1) nonane] 3-alpha-ol as the terminal group in a series of new bisquaternary azabicycyclic diester-type neuromuscular blocking agents. Fifty two bisquaternary ammonium derivatives of several dicarboxylic acid esters of granatanol and three similar derivatives of pseudo granatanol have been investigated for neuromuscular blocking (NMB) potency (ED(50) s), onset and recovery of action and for cardiovascular side effects. All agents were studied first in anesthetized rats, and selected agents were subjected to further pharmacodynamic testing in rabbits, juvenile pigs, cats, dogs and monkeys. One agent was tested in continuous i.v. infusion mode in comparison with its corresponding tropine diester and the aminosteroid muscle relaxant, rocuronium. Several new and highly potent NMB granatanol derivatives are described, which are largely similar in NMB potency to the previously described tropine: N-methyl [8-azabicyclo (3.2.1)] 3-alpha-ol diester derivatives. The majority of the presently described granatanol derivatives displayed ultrashort onset and duration of actions. In that respect some of these agents proved to be the fastest and shortest acting non-depolarizing muscle relaxants described so far. On the negative side, many, but not all, granatanol derivatives produced cardiovascular side effects: e.g. changes in heart rate and blood pressure. Like with the similar tropinyl diester derivatives, cardiac vagal block was present with the majority of these agents as assessed in the rat, pig and cat. Few glutaryl, fumaryl and cyclobutane (trans) 1,2-dicarboxylyl granatanol diesters quaternized with disubstituted benzyl halides, bearing p-acyloxy radicals, showed excellent NMB profile. In these derivatives, however, the rapid decomposition of the p-acyloxy groups leads to formation of toxic quinone methene metabolites which precludes their further pharmaceutical development. The pseudo granatanol derivatives were less potent in the rat than the corresponding granatanols and were not further investigated. We conclude that the 9-azabicyclo (3.3.1) nonane (granatane) ring system can successfully replace the similar 8-azabicyclo (3.2.1) octane (tropane) ring system in building potent, utrashort acting NMB agents.
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2,333,370 |
Relationship between adiponectin, glycemic control and blood lipids in diabetic type 2 postmenopausal women with and without complication of ischemic heart disease.
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Recently major adipocytokine, adiponectin, are thought to play important roles in the regulation of cardiovascular and metabolic homeostasis. We compared serum adiponectin concentrations and lipid profile in diabetic patients with and without complication of cardiovascular disease in postmenopausal women.</AbstractText>We included 120 female subjects between the age of 45 and 60 years. The subjects were divided into 3 groups and each group comprised of 40 subjects. First group comprised of normal healthy controls, second group diabetic type 2 patients with no history of ischemic heart disease (IHD) and the third group diabetic patients with IHD. Serum adiponectin concentrations, serum triglycerides, cholesterol, LDL cholesterol and HDL cholesterol concentrations were determined.</AbstractText>Values of fasting and random blood glucose, serum triglycerides, cholesterol, LDL cholesterol were significantly increased (P<0.001) in diabetic patients with IHD as compared with normal control subjects except for serum adiponectin and HDL cholesterol concentrations, which were significantly decreased (P<0.001) in diabetic patients and diabetic patients with IHD group. When values of cholesterol, triglycerides, LDL cholesterol, HDL cholesterol, fasting and random blood glucose and adiponectin were compared among diabetic and diabetic patients with IHD, it was observed that they were significantly increased (P<0.001) except for adiponectin, which was decreased significantly (P<0.001) and random blood glucose, LDL and HDL cholesterol in which no change was observed between the 2 groups.</AbstractText>Serum adiponectin concentrations may be a predictor for development of cardiovascular disease in postmenopausal diabetic patients.</AbstractText>
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2,333,371 |
Life-threatening bradyarrhythmia after massive azithromycin overdose.
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9-month-old infant was inadvertently administered azithromycin 50 mg/kg, taken from floor stock, instead of the prescribed ceftriaxone. Shortly thereafter, she became unresponsive and pulseless. The initial heart rhythm observed when cardiopulmonary resuscitation was started was a widecomplex bradycardia, with a prolonged rate-corrected QT interval and complete heart block. The baby was resuscitated with epinephrine and atropine, but she suffered severe anoxic encephalopathy. Torsade de pointes and QT-interval prolongation have been reported after administration of macrolide antibiotics, including azithromycin, both intravenously and orally. This has occurred especially in the context of coadministered drugs that inhibit the cytochrome P450 (CYP) 3A4 isoenzyme, such as ketoconazole and astemizole. However, bradycardia with complete heart block has not, to our knowledge, been reported specifically with intravenous administration of azithromycin alone, either with therapeutic doses or overdose. Clinicians should be alerted about the potential of azithromycin to cause life-threatening bradycardia, and pharmacy systems should be implemented to ensure special care in the safe administration of this drug, especially when dispensed from a point-of-care source.
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2,333,372 |
Association of protein tyrosine phosphatase-N1 polymorphisms with coronary calcified plaque in the Diabetes Heart Study.
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Individuals with type 2 diabetes are at increased risk of cardiovascular disease (CVD) mortality and display increased levels of subclinical CVD. Genetic variation in PTPN1, a diabetes susceptibility gene, was investigated for a role in diabetic atherosclerosis. The PTPN1 gene encodes protein tyrosine phosphatase-1B, which is ubiquitously expressed and plays a role in the regulation of several signaling pathways. Subclinical atherosclerosis was assessed in 590 Caucasian participants with type 2 diabetes in the Diabetes Heart Study using B-mode ultrasound measurement of carotid intima-media thickness (IMT) and computed tomography measurement of carotid calcified plaque (CarCP) and coronary calcified plaque (CorCP). Twenty-three single nucleotide polymorphisms (SNPs) in PTPN1 were genotyped and assessed for association with IMT, CarCP, and CorCP. A total of 12 SNPs within a block of linkage disequilibrium encompassing the coding sequence of PTPN1 were significantly associated with CorCP (P values from <0.0001 to 0.043) and 3 SNPs also within the block approached significance (P values from 0.058 to 0.066). In addition, a nine-SNP haplotype (GACTTCAGO) was also associated with increased CorCP under a dominant model (P = 0.01). No association was detected with IMT or CarCP. The associated SNPs and haplotype are the same as those observed to be associated with type 2 diabetes, insulin resistance, and fasting glucose in previous studies. With the inclusion of the most likely haplo-genotype for each individual, the heritability estimate of CorCP increased from 0.53 +/- 0.1 to 0.57 +/- 0.1 (P = 8.1 x 10(-10)), suggesting a modest but detectable effect of this gene on the phenotype of CorCP in type 2 diabetic patients.
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2,333,373 |
Normal neuropsychological development in children with congenital complete heart block who may or may not be exposed to high-dose dexamethasone in utero.
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Antenatal and postnatal treatment with dexamethasone (DEX) may negatively affect the neuropsychological development in children. Maternal anti-Ro/Sjögren's syndrome A (SSA) antibodies may also be associated with learning disabilities in offspring.</AbstractText>To assess neuropsychological development in babies exposed to very high dosages of DEX in utero, whose mothers were anti-Ro/SSA positive.</AbstractText>13 children with congenital complete heart block (CHB) (11 exposed and 2 not exposed to DEX) and 3 healthy siblings, all of anti-Ro/SSA-positive women, were evaluated. 11 preschool-aged children (5 boys) were assessed using Griffiths Mental Development Scales. 5 school-aged children (2 boys) were examined using Wechsler Intelligence Scale for Children-Revised to check IQ and reading tests to explore the existence of learning disabilities or dyslexia. None of the children had had major neonatal complications, although those with CHB had to be paced at different intervals from birth.</AbstractText>The children had been exposed in utero to a mean total dose of 186.6 mg DEX. IQ levels were always normal (mean IQ 105.1, standard deviation (SD) 9.5). Only one child had a learning disability, of borderline clinical significance, but this child had never been exposed to DEX.</AbstractText>No negative effects were found on the neuropsychological development in this cohort of children, even if they had been exposed to maternal anti-Ro/SSA antibodies and to very high dosages of DEX (much higher than those used to improve fetal lung maturity). These findings might be of interest in view of the large number of infants exposed in the past to repeated antenatal courses of steroids.</AbstractText>
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2,333,374 |
Flecainide sensitivity of a Na channel long QT mutation shows an open-channel blocking mechanism for use-dependent block.
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A long QT mutation in the cardiac sodium channel, D1790G (DG), shows enhanced flecainide use-dependent block (UDB). The relative importance of open and inactivated states of the channel in flecainide UDB has been controversial. We used a modifiable, inactivation-deficient mutant channel that contains the F1486C mutation in the IFM motif to investigate the UDB difference between the wild-type (WT-ICM) and DG (DG-ICM) channels. UDB at 5 Hz was greater in DG-ICM than WT-ICM, and IC50 values for steady-state UDB were 7.19 and 18.06 microM, respectively. When [2-(trimethyammonium) ethyl]methanethiosulfonate bromide (MTSET) was included in the pipette and fast inactivation was disabled, IC50 was 5.04 microM for DG-ICM and 12.63 microM for WT-ICM. We measured open-channel block by flecainide directly in MTSET-treated, noninactivating ICM channels. Steady-state block was higher for DG-ICM than WT-ICM (IC50 was 2.34 microM for DG-ICM and 5.87 microM for WT-ICM), suggesting that open-channel block is an important determinant of flecainide UDB. We obtained association (kon) and dissociation (koff) rates for open-channel block by the Langmuir-isotherm model. They were koff = 31.37 s(-1), kon = 5.83 s(-1).microM(-1), and calculated Kd = 5.38 microM for WT-ICM (where Kd = koff/kon); and koff = 24.88 s(-1), kon = 9.54 s(-1).microM(-1), and calculated Kd = 2.61 microM for DG-ICM. These Kd values were similar to IC50 measured from steady-state open-channel block. Furthermore, we modeled UDB mathematically by using these kinetic rates and found that the model predicted experimental UDB accurately. The recovery from UDB had a minor contribution to UDB. Flecainide UDB is predominantly determined by an open-channel blocking mechanism, and DG-ICM channels appeared to have an altered open-channel state with higher flecainide affinity than WT-ICM.
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2,333,375 |
Intrathecal fentanyl as adjunct to hyperbaric bupivacaine in spinal anesthesia for caesarean section.
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To compare the effect of adding fentanyl to intrathecal bupivacaine on the onset, duration and quality of spinal anesthesia and its effect of mother and neonate.</AbstractText>Single blind randomized controlled clinical trial.</AbstractText>Department of Anesthesiology, Surgical Intensive Care Unit and Pain Management, Dow University of Health Sciences and Civil Hospital, Karachi, from January 2003 to June 2004.</AbstractText>Sixty young adult females, ASA physical status I and II, with singleton pregnancy undergoing elective or emergency cesarean section under spinal anesthesia were randomly allocated to receive spinal anesthesia either by using 0.75% hyperbaric bupivacaine 1.5 ml with 0.25 ml normal saline or 0.75% hyperbaric bupivacaine 1.5 ml with 0.25 ml fentanyl (12.5 microg). Blood pressure, heart rate, respiratory rate, oxygen saturation, sensory level, motor block, pain score and side effects were observed every 2 minutes for first 20 minutes, then at-5 minute interval throughout the surgery, thereafter at 30 minutes interval until the patient complained of pain.</AbstractText>Comparing the bupivacaine group, time to achieve highest sensory level was significantly shorter in fentanyl group (*p < 0.05), while the duration of complete analgesia (time from injection to first report of pain) lasted significantly more longer in fentanyl group (184+/-20 minutes) than bupivacaine group (126+/-10 minutes). Duration of effective analgesia was also significantly more prolonged in fentanyl group (p < 0.05). There was no significant difference in the incidence of side effects between the two groups.</AbstractText>Addition of fentanyl to intrathecal bupivacaine results in faster onset with improved peri-operative anesthesia without increasing the side effects.</AbstractText>
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2,333,376 |
Trypanosoma cruzi infection and nuclear factor kappa B activation prevent apoptosis in cardiac cells.<Pagination><StartPage>1580</StartPage><EndPage>1587</EndPage><MedlinePgn>1580-7</MedlinePgn></Pagination><Abstract><AbstractText>Studies of cardiac pathology and heart failure have implicated cardiomyocyte apoptosis as a critical determinant of disease. Recent evidence indicates that the intracellular protozoan parasite Trypanosoma cruzi, which causes heart disease in chronically infected individuals, impinges on host apoptotic pathways in a cell type-dependent manner. T. cruzi infection of isolated neuronal cells and cardiomyocytes protects against apoptotic cell death, whereas apoptosis is triggered in T cells in T. cruzi-infected animals. In this study, we demonstrate that the ability of T. cruzi to protect cardiac cells in vitro from apoptosis triggered by a combination of tumor necrosis factor alpha and serum reduction correlates with the presence of intracellular parasites and involves activation of host cell NF-kappaB. We further demonstrate that the apoptotic block diminishes activation of caspase 3. The ability of T. cruzi to prevent apoptosis of infected cardiomyocytes is likely to play an important role in establishment of persistent infection in the heart while minimizing potential damage and remodeling that is associated with cardiomyocyte apoptosis in cardiovascular disease.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Petersen</LastName><ForeName>Christine A</ForeName><Initials>CA</Initials><AffiliationInfo><Affiliation>Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA. [email protected]</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Krumholz</LastName><ForeName>Katherine A</ForeName><Initials>KA</Initials></Author><Author ValidYN="Y"><LastName>Carmen</LastName><ForeName>John</ForeName><Initials>J</Initials></Author><Author ValidYN="Y"><LastName>Sinai</LastName><ForeName>Anthony P</ForeName><Initials>AP</Initials></Author><Author ValidYN="Y"><LastName>Burleigh</LastName><ForeName>Barbara A</ForeName><Initials>BA</Initials></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>K08 AI50803</GrantID><Acronym>AI</Acronym><Agency>NIAID NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R01 AI47960</GrantID><Acronym>AI</Acronym><Agency>NIAID NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R01 AI049367-05A1</GrantID><Acronym>AI</Acronym><Agency>NIAID NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>K08 AI050803</GrantID><Acronym>AI</Acronym><Agency>NIAID NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R01 AI049367</GrantID><Acronym>AI</Acronym><Agency>NIAID NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>R01 AI047960</GrantID><Acronym>AI</Acronym><Agency>NIAID NIH HHS</Agency><Country>United States</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D052061">Research Support, N.I.H., Extramural</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Infect Immun</MedlineTA><NlmUniqueID>0246127</NlmUniqueID><ISSNLinking>0019-9567</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D016328">NF-kappa B</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D017209" MajorTopicYN="Y">Apoptosis</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D002478" MajorTopicYN="N">Cells, Cultured</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D002598" MajorTopicYN="N">Chagas Cardiomyopathy</DescriptorName><QualifierName UI="Q000469" MajorTopicYN="N">parasitology</QualifierName><QualifierName UI="Q000473" MajorTopicYN="N">pathology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D018482" MajorTopicYN="N">Muscle, Skeletal</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000469" MajorTopicYN="Y">parasitology</QualifierName><QualifierName UI="Q000473" MajorTopicYN="N">pathology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D032383" MajorTopicYN="N">Myocytes, Cardiac</DescriptorName><QualifierName UI="Q000166" MajorTopicYN="N">cytology</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName><QualifierName UI="Q000469" MajorTopicYN="Y">parasitology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D016328" MajorTopicYN="N">NF-kappa B</DescriptorName><QualifierName UI="Q000037" MajorTopicYN="N">antagonists & inhibitors</QualifierName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D051381" MajorTopicYN="N">Rats</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D017207" MajorTopicYN="N">Rats, Sprague-Dawley</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D014349" MajorTopicYN="N">Trypanosoma cruzi</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName><QualifierName UI="Q000502" MajorTopicYN="Y">physiology</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2006</Year><Month>2</Month><Day>24</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2006</Year><Month>6</Month><Day>6</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2006</Year><Month>2</Month><Day>24</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">16495529</ArticleId><ArticleId IdType="pmc">PMC1418648</ArticleId><ArticleId IdType="doi">10.1128/IAI.74.3.1580-1587.2006</ArticleId><ArticleId IdType="pii">74/3/1580</ArticleId></ArticleIdList><ReferenceList><Reference><Citation>Aoki, H., P. 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Dis. 180:480-486.</Citation><ArticleIdList><ArticleId IdType="pubmed">10395865</ArticleId></ArticleIdList></Reference></ReferenceList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">16493932</PMID><DateCompleted><Year>2006</Year><Month>03</Month><Day>30</Day></DateCompleted><DateRevised><Year>2006</Year><Month>02</Month><Day>23</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">0038-0814</ISSN><JournalIssue CitedMedium="Print"><Issue>702 Suppl</Issue><PubDate><Year>2006</Year><Season>Jan-Feb</Season></PubDate></JournalIssue><Title>Soins; la revue de reference infirmiere</Title><ISOAbbreviation>Soins</ISOAbbreviation></Journal>[Nursing care for automatic implantable defibrillators].
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Studies of cardiac pathology and heart failure have implicated cardiomyocyte apoptosis as a critical determinant of disease. Recent evidence indicates that the intracellular protozoan parasite Trypanosoma cruzi, which causes heart disease in chronically infected individuals, impinges on host apoptotic pathways in a cell type-dependent manner. T. cruzi infection of isolated neuronal cells and cardiomyocytes protects against apoptotic cell death, whereas apoptosis is triggered in T cells in T. cruzi-infected animals. In this study, we demonstrate that the ability of T. cruzi to protect cardiac cells in vitro from apoptosis triggered by a combination of tumor necrosis factor alpha and serum reduction correlates with the presence of intracellular parasites and involves activation of host cell NF-kappaB. We further demonstrate that the apoptotic block diminishes activation of caspase 3. The ability of T. cruzi to prevent apoptosis of infected cardiomyocytes is likely to play an important role in establishment of persistent infection in the heart while minimizing potential damage and remodeling that is associated with cardiomyocyte apoptosis in cardiovascular disease.
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2,333,377 |
A randomised comparison of 0.5% bupivacaine with a lidocaine/epinephrine/fentanyl mixture for epidural top-up for emergency caesarean section after "low dose" epidural for labour.
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When extending a fentanyl-containing, low-dose labour epidural for emergency caesarean section it has been shown that there is no difference in time to surgical readiness between plain bupivacaine 0.5% and mixtures of lidocaine/epinephrine or lidocaine/bupivacaine/epinephrine. However, it is not known whether adding fentanyl to the lidocaine/epinephrine mixture would increase speed of onset or improve the efficacy of the mixture when topping up for an emergency caesarean section.</AbstractText>In a prospective, single blind study we compared plain 0.5% bupivacaine with a lidocaine/epinephrine/fentanyl mixture for extending previous low-dose epidural analgesia for emergency caesarean section in 68 patients.</AbstractText>There was a significantly longer median preparation time for the mixture than for the single drug (3.0 v 1.25 min: P < 0.0005). The median onset time for block of T7 to touch from the start of the top-up was 13.8 min for the mixture and 17.5 min for plain bupivacaine. This difference was not statistically significant and was offset by the longer preparation time. No general anaesthetics were required for poor blocks and the need for other intraoperative supplementation was not significantly different between the groups (bupivacaine 5/34, lidocaine mixture 2/26).</AbstractText>The use of a lidocaine/epinephrine/fentanyl mixture conferred no clear statistically significant benefit over the use of plain 0.5% bupivacaine when used to extend fentanyl containing low-dose labour epidural analgesia for emergency caesarean section, but the lidocaine solution is cheaper and less toxic than the alternatives.</AbstractText>
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2,333,378 |
A computer-aided ECG diagnostic tool.
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Jordan lacks companies that provide local medical facilities with products that are of help in daily performed medical procedures. Because of this, the country imports most of these expensive products. Consequently, a local interest in producing such products has emerged and resulted in serious research efforts in this area. The main goal of this paper is to provide local (the north of Jordan) clinics with a computer-aided electrocardiogram (ECG) diagnostic tool in an attempt to reduce time and work demands for busy physicians especially in areas where only one general medicine doctor is employed and a bulk of cases are to be diagnosed. The tool was designed to help in detecting heart defects such as arrhythmias and heart blocks using ECG signal analysis depending on the time-domain representation, the frequency-domain spectrum, and the relationship between them. The application studied here represents a state of the art ECG diagnostic tool that was designed, implemented, and tested in Jordan to serve wide spectrum of population who are from poor families. The results of applying the tool on randomly selected representative sample showed about 99% matching with those results obtained at specialized medical facilities. Costs, ease of interface, and accuracy indicated the usefulness of the tool and its use as an assisting diagnostic tool.
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2,333,379 |
Role of capsaicin-sensitive sensory nerves in mediation of the cardiovascular effects of the essential oil of croton zehntneri leaves in anaesthetized rats.
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The essential oil of Croton zehntneri Pax et Hoffm. (EOCZ) contains anethole (42%) and estragole (46%), two isomers that share some chemical structural similarities with capsaicin. The present study investigated the cardiovascular effects of EOCZ and the role of capsaicin-sensitive sensory nerve fibres in the mediation of these effects in anaesthetized rats. 2. Intravenous bolus injection of EOCZ (1-20 mg/kg) elicited dose-dependent hypotension and bradycardia that were immediate and transient. Similar responses were also observed with anethole and estragole (both at 10 mg/kg). After cervical bivagotomy or perineural treatment of both cervical vagus nerves with capsaicin (250 mg/mL) to selectively block the conduction of sensory C-fibres, both cardiovascular responses to EOCZ (10 mg/kg) were abolished. 3. Like capsaicin, an epigastric retrograde intra-arterial injection of EOCZ (10 mg/kg, i.a.) into the femoral artery elicited a monophasic hypotensive response. This reflex response was blocked by either neonatal pretreatment with capsaicin (50 mg/kg, s.c.) or intrathecal injection of the substance P receptor antagonist RP 67580 (7.8 nmol, at the spinal level L5-L6), suggesting that it is mediated exclusively by substance P-containing primary afferent fibres. 4. The cardiovascular responses to EOCZ (10 mg/kg, i.v.) were also significantly reduced by the selective vallinoid TPRV1 receptor antagonist capsazepine (1 mg/kg, i.v.). 5. It is concluded that i.v. administration of EOCZ in anaesthetized rats elicits a capsaicin-like bradycardic and depressor reflex, which appears to be mediated by the activation of vallinoid TPRV1 receptors located on vagal sensory nerves. Like capsaicin, i.a. injection of EOCZ induces a spinally mediated sensory reflex.
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2,333,380 |
No apparent requirement for neuronal sodium channels in excitation-contraction coupling in rat ventricular myocytes.
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The majority of Na channels in the heart are composed of the tetrodotoxin (TTX)-resistant (KD, 2 to 6 micromol/L) "cardiac" NaV1.5 isoform; however, TTX-sensitive (KD, 1 to 25 nmol/L) "neuronal" Na channel isoforms have recently been detected in several cardiac preparations. In the present study, we determined the functional subcellular localization of Na channel isoforms (according to their TTX sensitivity) in rat ventricular myocytes by recording INa in control and detubulated myocytes. We found that TTX-sensitive INa (KD, &8.8 nmol/L) makes up 14+/-3% of total INa in control and < or =4% in detubulated myocytes and calculated that &80% of TTX-sensitive INa is located in the t-tubules, where it generates &1/3 of t-tubular INa. In contrast, TTX-resistant INa is located predominantly (&78%) at the surface membrane. We also investigated the possible contribution of TTX-sensitive INa to excitation-contraction coupling, using 200 nmol/L TTX to selectively block TTX-sensitive INa. TTX decreased the rate of depolarization of the action potential by 10% but did not delay the rise of systolic Ca2+ in the center of the cell (transverse confocal line scan), suggesting that TTX-sensitive INa does not play a role in synchronizing Ca2+ release at the t-tubules; the amplitude of the Ca2+ transient and contraction were also unchanged by 200 nmol/L TTX. The quantity of charge entering via ICa elicited by control or TTX action potential waveforms was similar, suggesting that the trigger for Ca2+ release is not altered by blocking TTX-sensitive INa. We conclude that neuronal INa is concentrated at the t-tubules, but there is no evidence of a requirement for these channels in normal excitation-contraction coupling in ventricular myocytes.
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2,333,381 |
Vardenafil: a novel type 5 phosphodiesterase inhibitor reduces myocardial infarct size following ischemia/reperfusion injury via opening of mitochondrial K(ATP) channels in rabbits.
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cGMP and opening of mitochondrial K(ATP) channel play an important role in preconditioning of the heart following ischemia/reperfusion (I/R) injury. We investigated the cardioprotective effect of vardenafil (VAR) (Levitra), a highly selective and biochemically potent inhibitor of phosphodiesterase-5 (PDE-5) that enhances erectile function in men through up-regulation of cGMP. Rabbits were treated with VAR (0.014 mg/kg, iv) or volume-matched saline, 30 min prior to 30 min of sustained regional ischemia followed by 3 h of reperfusion. 5-hydroxydecanoate (5-HD, 5 mg/kg, iv) or HMR 1098 (HMR, 3 mg/kg, iv), the respective blockers of mitochondrial or sarcolemmal K(ATP) channels were administered 10 min before I/R. Infarct size was measured by computer morphometry of tetrazolium stained sections. Vardenafil treatment caused decrease in mean arterial blood pressure from 93.5+/-2.6 to 82.2+/-1.5 mmHg and increase in heart rate from baseline value of 151+/-20 to 196+/-4.6 bpm (mean+/-standard error of mean (S.E.M.), P<0.05) within 5 min. The infarct size (% of risk area) was reduced from 33.8+/-1.3 in control rabbits to 14.3+/-2.2 (58% reduction, P<0.05). 5-HD abolished VAR-induced protection as demonstrated by increase in infarct size to 34.5+/-2.3 (P<0.05, N=6 per group). In contrast, HMR failed to block the protective effect of VAR (infarct size, 14.3+/-2.2 versus 16.3+/-1.0 in VAR + HMR, P>0.05). Neither inhibitors of the K(ATP) channel influenced the infarct size in the control rabbits, as shown by infarct size of 34.9+/-1.1 and 33.3+/-1.4 in animals treated with 5-HD and HMR, respectively. For the first time, we demonstrate that VAR induces protective effect against I/R injury via opening of mitochondrial K(ATP) channel. These results further support our hypothesis that the novel class of PDE-5 inhibitors induce protective effect in the ischemic heart, in addition to their well known clinical effects in the treatment of erectile dysfunction in men.
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2,333,382 |
Association of socioeconomic status with functional capacity, heart rate recovery, and all-cause mortality.
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Lower socioeconomic status (SES) confers heightened cardiovascular risk and mortality, although the mediating pathways are unclear.</AbstractText>To evaluate the extent to which exercise physiologic characteristics account for the association between lower SES and mortality.</AbstractText><AbstractText Label="DESIGN, SETTING, AND PARTICIPANTS" NlmCategory="METHODS">Prospective cohort study of 30 043 consecutive patients living in 7 counties in northeast Ohio referred between 1990 and 2002 for symptom-limited stress testing for evaluation of known or suspected coronary artery disease. Follow-up for mortality continued through February 2004.</AbstractText>Estimated functional capacity in metabolic equivalents and heart rate recovery, physiologic characteristics that are determined directly from exercise; testing and all-cause mortality during a median follow-up of 6.5 years.</AbstractText>Multivariable models adjusting for demographics, insurance status, smoking status, and clinical confounders demonstrated a strong association between a composite SES score based on census block data and functional capacity (adjusted odds ratio comparing 25th with 75th percentile values, 1.72; 95% confidence interval [CI], 1.56-1.89; P<.001) as well as heart rate recovery (adjusted odds ratio comparing 25th with 75th percentile values, 1.18; 95% CI, 1.07-1.30; P<.001). There were 2174 deaths, with mortality risk increasing from 5% to 10% as SES decreased by quartile (P<.001). Cox proportional hazards models that included all confounding variables except exercise physiologic characteristics demonstrated increased mortality as SES decreased (adjusted hazard ratio comparing 25th with 75th percentile values, 1.32; 95% CI, 1.22-1.42; P<.001). After further adding functional capacity and heart rate recovery, the magnitude of this relationship was reduced (comparing 25th with 75th percentile values; adjusted hazard ratio, 1.17; 95% CI, 1.08-1.26; P<.001), with these variables explaining 47% of the association.</AbstractText>Impaired functional capacity and abnormal heart rate recovery were strongly associated with lower SES and accounted for a major proportion of the correlation between SES and mortality. Efforts to modify these clinical features among patients with low SES may narrow disparities in mortality.</AbstractText>
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2,333,383 |
Sugammadex, a new reversal agent for neuromuscular block induced by rocuronium in the anaesthetized Rhesus monkey.
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Binding of the steroidal molecule of rocuronium by a cyclodextrin is a new concept for reversal of neuromuscular block. The present study evaluated the ability of Sugammadex Org 25969, a synthetic gamma-cyclodextrin derivative, to reverse constant neuromuscular block of about 90% induced by rocuronium or the non-steroidal neuromuscular blocking drugs, mivacurium or atracurium, in the anaesthetized Rhesus monkey.</AbstractText>After a bolus injection of rocuronium, mivacurium or atracurium, a continuous infusion of these drugs was started to maintain the first twitch contraction of the train-of-four at approximately 10% of its baseline value. After a steady state block of at least 10 min the infusion was stopped and the preparation was allowed to recover spontaneously. This process was repeated, but at the time the infusion was stopped, either sugammadex 0.5 or 1.0 mg kg(-1) was given in the rocuronium-induced blockade and sugammadex 1.0 mg kg(-1) was given in the mivacurium- and atracurium-induced blockade.</AbstractText>Sugammadex caused a rapid and complete reversal of rocuronium-induced neuromuscular block. The recovery time to train of four ratio=0.9 after spontaneous recovery was 14.4 min (sd=3.4 min; n=14). This was reduced significantly (P<0.001) to 3.7 min (sd=3.3 min; n=4) with sugammadex 0.5 mg kg(-1) and to 1.9 min (sd=1.0 min; n=4) with sugammadex 1.0 mg kg(-1). Signs of residual blockade or re-curarization were not observed. Reversal of mivacurium- or atracurium-induced neuromuscular block (n=2 in each experiment) by sugammadex (1.0 mg kg(-1)) was not effective. In all experiments, injection of sugammadex had no effects on blood pressure or heart rate.</AbstractText>Sugammadex is effective in reversing rocuronium, but not mivacurium- or atracurium-induced neuromuscular block.</AbstractText>
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2,333,384 |
Atractyloside and 5-hydroxydecanoate block the protective effect of puerarin in isolated rat heart.
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The aim of the present study was to determine whether the clinically effective cardioprotection conferred by puerarin (Pue) against ischemia and reperfusion is mediated by mitochondrial transmembrane pores and/or channels. Hearts isolated from male Sprague-Dawley rats were perfused on a Langendorff apparatus and subjected to 30 min of global ischemia followed by 120 min of reperfusion. The production of formazan, which provides an index of myocardial viability, was measured by absorbance at 550 nm, and the level of lactate dehydrogenase (LDH) in the coronary effluent was determined. In this model, Pue (0.0024-2.4 mmol/l) had a dose-dependent, negatively inotropic effect. Pretreatment with Pue at 0.24 mmol/l for 5 min before ischemia increased myocardial formazan content, reduced LDH release, improved recovery of left ventricular end-diastolic pressure and rate-pressure product (left ventricular developed pressure multiplied by heart rate) during reperfusion. Administration of atractyloside (20 micromol/l), an opener of the mitochondrial permeability transition pore, for the first 20 min of reperfusion, and 5-hydroxydecanoate (100 micromol/l), the mitochondrial-specific ATP-sensitive potassium channel blocker, for 20 min before ischemia, attenuated the protective effects of Pue. In mitochondria isolated from hearts pretreated with 0.24 mmol/l Pue for 5 min, a significant inhibition of Ca(2+)-induced swelling was observed, and this inhibition was attenuated by 5-hydroxydecanoate. In isolated ventricular myocytes, pretreatment with Pue prevented ischemia-induced cell death and depolarization of the mitochondrial membrane, and atractyloside and 5-hydroxydecanoate attenuated the effects of Pue. These findings indicate that puerarin protects the myocardium against ischemia and reperfusion injury via inhibiting mitochondrial permeability transition pore opening and activating the mitochondrial ATP-sensitive potassium channel.
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2,333,385 |
Extracellular ATP-stimulated current in wild-type and P2X4 receptor transgenic mouse ventricular myocytes: implications for a cardiac physiologic role of P2X4 receptors.
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P2X receptors, activated by extracellular ATP, may be important in regulating cardiac function. The objective of the present study was to characterize the electrophysiologic actions of P2X4 receptors in cardiac myocytes and to determine whether they are involved in mediating the effect of extracellular ATP. Membrane currents under voltage clamp were determined in myocytes from both wild-type (WT) and P2X4 receptor-overexpressing transgenic (TG) mice. The P2X agonist 2-meSATP induced an inward current at -100 mV that was greater in magnitude (2-fold) in TG than in WT ventricular cells. In the presence of the P2X4 receptor-selective allosteric enhancer ivermectin (3 microM), the 2-meSATP-stimulated current increased significantly in both WT and TG ventricular cells, consistent with an important role of P2X4 receptors in mediating the ATP current not only in TG but also WT myocytes. That the current in both WT and TG cells showed similar voltage-dependence and reverse potential (approximately 0 mV) further suggests a role for this receptor in the normal electrophysiological action of ATP in WT murine cardiac myocytes. The P2X antagonist suramin was only able to block partially the 2-meSATP-stimulated current in WT cells, implying that both P2X4 receptor and another yet-to-be-identified P2X receptor mediate this current.
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2,333,386 |
Prospective, randomised, controlled trial to study the effect of intracoronary injection of verapamil and adenosine on coronary blood flow during percutaneous coronary intervention in patients with acute coronary syndromes.
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To study the impact of injection of verapamil and adenosine in the coronary arteries on TIMI (Thrombolysis in Myocardial Infarction) frame count (TFC) after percutaneous coronary intervention (PCI) in patients with an acute coronary syndrome (ACS).</AbstractText>Prospective, randomised, controlled study of the intracoronary administration of normal saline versus verapamil versus adenosine in patients undergoing PCI in the setting of an ACS, even when flow is visually established to be normal or near normal. Patients were randomised to receive verapamil (n = 49), adenosine (n = 51) or normal saline (n = 50) after PCI. Quantitative angiography, TIMI flow grade (TFG), TFC and myocardial blush grade were assessed before PCI, after PCI and after drugs were given. Wall motion index (WMI) was measured at days 1 and 30.</AbstractText>9 patients in the verapamil group developed transient heart block, not seen with adenosine (p <or= 0.001). Compared with saline, coronary flow measured by TFC improved significantly and WMI improved slightly but insignificantly in both the verapamil (TFC: p = 0.02; mean difference in improvement in WMI: 0.09, 95% confidence interval (CI) 0.015 to 0.17, p = 0.02) and the adenosine groups (TFC: p = 0.002; mean difference in improvement in WMI: 0.08, 95% CI 0.004 to 0.16, p = 0.04). The improvements in TFC and WMI did not differ significantly between the verapamil and the adenosine groups (TFC: p = 0.2; mean difference in improvement in WMI: 0.01, 95% CI -0.055 to 0.08, p = 0.7, respectively).</AbstractText>Administration of verapamil or adenosine significantly improves coronary flow and WMI after PCI in the setting of an ACS. Flow and WMI did not differ significantly between verapamil and adenosine but verapamil was associated with the development of transient heart block.</AbstractText>
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2,333,387 |
[Adenosine reduces intracellular free calcium concentration in guinea pig ventricular myocytes].
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To observe the effects of adenosine on intracellular calcium concentration ([Ca2+]i) level in guinea pig ventricular myocytes and to define the possible mechanisms involved.</AbstractText>The effects of adenosine on [Ca2+]i were investigated in guinea pig ventricular myocytes. [Ca2+]i was detected by laser confocal microscopy and represented by relative fluorescent intensity ((FI-FI0)/FI0, %, FIo: control, FI: administration of drugs).</AbstractText>(1) Adenosine (10, 50, 100 micromol/L) reduced [Ca2+]i of ventricular myocytes in both normal Tyrode's solution and Ca(2+) -free Tyrode's solution in a concentration-dependent manner. (2) Tyrode's solution containing 30 mmol/L KCl (high K+ Tyrode's solution) induced [Ca2+]i elevation in ventricular myocytes, while adenosine (10, 50, 100 micromol/L) markedly inhibited the increase in [Ca2+]i induced by KCl. (3) Pretreatment with DPCPX (1 micromol/L) significantly reduced the effects of adenosine (100 micromol/L) in high K+ Tyrode's solution. The effects of adenosine (100 micromol/L) on [Ca2+]i in high K+ Tyrode's solution were also partially attenuated by pretreatment with L-NAME (1 mmol/L). (4) Adenosine (100 micromol/L) markedly inhibited the low concentration of ryanodine-induced [Ca2+]i increase in Ca(2+) -free Tyrode's solution. (5) When the propagating waves of elevated [Ca2+]i (Ca2+ waves) were produced by increasing extracellular Ca2+ concentration from 1 mmol/L to 10 mmol/L, adenosine (100 micromol/L) could block the propagating waves of elevated [Ca2+]i, reduce the frequency and duration of propagating waves, and reduce [Ca2+]i as well.</AbstractText>Adenosine may reduce the [Ca2+]i in isolated guinea pig ventricular myocytes via inhibiting Ca2+ influx and alleviating Ca2+ release from sarcoplasmic reticulum(SR). The reduction of Ca2+ influx might be due to the inhibition of voltage-dependent Ca2+ channel via adenosine A1 receptor, and NO might be involved in this process.</AbstractText>
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2,333,388 |
[Intravenous dexmedetomidine for sedation does not interfere with sensory and motor block duration during spinal anesthesia.].
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The association among local and regional anesthesia is a very useful and common practice. However, some patients may become anxious and require sedation. Benzodiazepines, opioids and propofol are widely used for this aim. Alpha2-adrenergic agonists have hypnotic and sedative properties and represent an alternative to promote hemodynamic stability and minor respiratory depression. This study aimed at evaluating the safety and the interference of intravenous dexmedetomidine or midazolam on sensory and motor block duration spinal anesthesia.</AbstractText>Thirty five adult female patients, physical status ASA I and II, were submitted to spinal anesthesia with hyperbaric 0.5% bupivacaine (15 mg) for elective gynecologic surgery. The patients were randomized and distributed in two groups: Group M (n = 17) - sedation with 0.25 microg.kg-1.min-1 midazolam continuous infusion and Group D (n = 18) sedation with 0.5 microg.kg-1.min-1 dexmedetomidine continuous infusion. Infusion rate was adjusted to maintain BIS between 60 and 80. The following parameters were evaluated: SBP, DBP, HR, SpO2, BIS sensory and motor block extension and duration (Bromage scale).</AbstractText>There were no statistically significant differences between groups in age, weight, sensory block level, blood pressure and heart rate variation and sensory and motor block duration.</AbstractText>Intravenous dexmedetomidine for sedation has not interfered with hemodynamic parameters, spinal anesthesia sensory and motor block duration or extension and it is a good option for sedation during local/regional anesthesia.</AbstractText>
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2,333,389 |
Spontaneous pulmonary interstitial emphysema in a term unventilated infant.
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Pulmonary interstitial emphysema (PIE) is a form of air block most frequently seen in ventilated preterm infants with severe lung disease; it is rarely reported in spontaneously breathing term infants. We report on an infant previously diagnosed with laryngomalacia and congestive heart failure and with evidence of antenatal stroke before the onset of pulmonary disease. He presented at 6 weeks of age with spontaneous pneumothorax. Focal cystic changes were seen on imaging studies of the lungs. There was no prior history of mechanical ventilation. Prior chest X-rays did not show cystic changes. He subsequently underwent resection of the affected lung areas. Pathologic examination revealed persistent PIE with cystic expansion, pleural blebs, and reactive pleuritis, as well as subpleural air-space enlargement. The patient did well postoperatively and was discharged home without further problems. This case demonstrates that PIE can occur in an infant without any history of mechanical ventilation, suggesting the need for a high index of suspicion for PIE, even in nonventilated and spontaneously breathing term neonates. PIE should be included in the differential diagnosis of cystic lung lesions in all young infants.
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2,333,390 |
Effects of sulfonylureas on mitochondrial ATP-sensitive K+ channels in cardiac myocytes: implications for sulfonylurea controversy.
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Mitochondrial ATP-sensitive K(+) (mitoK(ATP)) channel plays a key role in cardioprotection. Hence, a sulfonylurea that does not block mitoK(ATP) channels would be desirable to avoid damage to the heart. Accordingly, we examined the effects of sulfonylureas on the mitoK(ATP) channel and mitochondrial Ca(2+) overload.</AbstractText>Flavoprotein fluorescence in rabbit ventricular myocytes was measured to assay mitoK(ATP) channel activity. The mitochondrial Ca(2+) concentration was measured by loading cells with rhod-2.</AbstractText>The mitoK(ATP) channel opener diazoxide (100 microM) reversibly increased flavoprotein oxidation to 31.8 +/- 4.3% (n = 5) of the maximum value induced by 2,4-dinitrophenol. Glimepiride (10 microM) alone did not oxidize the flavoprotein, and the oxidative effect of diazoxide was unaffected by glimepiride (35.4 +/- 3.2%, n = 5). Similarly, the diazoxide-induced flavoprotein oxidation was unaffected both by gliclazide (10 microM) and by tolbutamide (100 microM). Exposure to ouabain (1 mM) for 30 min produced mitochondrial Ca(2+) overload, and the intensity of rhod-2 fluorescence increased to 197.4 +/- 7.2% of baseline (n = 11). Treatment with diazoxide significantly reduced the ouabain-induced mitochondrial Ca(2+) overload (149.6 +/- 5.1%, n = 11, p < 0.05 versus ouabain alone), and the effect was antagonized by the mitoK(ATP) channel blocker 5-hydroxydecanoate (189.8 +/- 27.8%, n = 5) and glibenclamide (193.1 +/- 7.7%, n = 8). On the contrary, cardioprotective effect of diazoxide was not abolished by glimepiride (141.8 +/- 7.8%, n = 6), gliclazide (139.0 +/- 9.4%, n = 5), and tolbutamide (141.1 +/- 4.5%, n = 7).</AbstractText>Our results indicate that glimepiride, gliclazide, and tolbutamide have no effect on mitoK(ATP) channel, and do not abolish the cardioprotective effects of diazoxide. Therefore, these sulfonylureas, unlike glibenclamide, do not interfere with the cellular pathways that confer cardioprotection.</AbstractText>
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2,333,391 |
Protection from the toxicity of diisopropylfluorophosphate by adeno-associated virus expressing acetylcholinesterase.
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Organophosphorus esters (OP) are highly toxic chemicals used as pesticides and nerve agents. Their acute toxicity is attributed to inhibition of acetylcholinesterase (AChE, EC 3.1.1.7) in nerve synapses. Our goal was to find a new therapeutic for protection against OP toxicity. We used a gene therapy vector, adeno-associated virus serotype 2 (AAV-2), to deliver murine AChE to AChE-/- mice that have no endogenous AChE activity. The vector encoded the most abundant form of AChE: exons 2, 3, 4, and 6. Two-day old animals, with an immature immune system, were injected. AChE delivered intravenously was expressed up to 5 months in plasma, liver, heart, and lung, at 5-15% of the level in untreated wild-type mice. A few mice formed antibodies, but antibodies did not block AChE activity. The plasma AChE was a mixture of dimers and tetramers. AChE delivered intramuscularly had 40-fold higher activity levels than in wild-type muscle. None of the AChE was collagen-tailed. No retrograde transport through the motor neurons to the central nervous system was detected. AChE delivered intrastriatally assembled into tetramers. In brain, the AAV-2 vector transduced neurons, but not astrocytes and microglia. Vector-treated AChE-/- mice lived longer than saline-treated controls. AChE-/- mice were protected from diisopropylfluorophosphate-induced respiratory failure when the vector was delivered intravenously, but not intrastriatally. Since vector-treated animals had no AChE activity in diaphragm muscle, protection from respiratory failure came from AChE in other tissues. We conclude that AChE scavenged OP and in this way protected the activity of butyrylcholinesterase (BChE, EC 3.1.1.8) in motor endplates.
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2,333,392 |
Is a dual-sensor pacemaker appropriate in patients with sino-atrial disease? Results from the DUSISLOG study.
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Rate-responsive pacemakers (PMs) are often supplied with accelerometer (XL) and minute ventilation (MV) sensors to provide a physiologic rate response according to patient needs. No information is available about the real benefit of dual-sensor rate-responsive pacing on the daily life of patients.</AbstractText>DUSISLOG (Dual Sensor vs Single Sensor comparison using patient activity LOGbook) is a two-arm prospective, randomized, multicenter study that enrolled 105 patients who received a rate-responsive PM (Insignia), Guidant Corp.). After 1 month of DDD pacing at 60 ppm lower rate, a single sensor (XL or MV, randomized) was activated for 3 months at the manufacturer's suggested nominal settings, followed by a 3-month period with dual sensors optimized with automatic response. During the last month of each period, the following data concerning patient physical activity were retrieved from PM diagnostics (Activity Log): mean percentage of physical activity, mean intensity of activity. Quality of life (QoL) scores and 6-minute walk test (WT) were also recorded.</AbstractText>Single-sensor rate-responsive pacing resulted in symptomatic benefit equally with XL and MV sensors while no additional benefit was found using dual sensor. In a subgroup analysis, patients (17%) with marked chronotropic incompetence and with 0% atrial sensing received benefits from single sensor with an additional advantage from sensor (QoL: +21 +/- 14% P < 0.05; WT: +17 +/- 7% P < 0.02).</AbstractText>In most patients with rate-responsive devices, a single sensor is sufficient to achieve a satisfactory rate response. A dual sensor combination and optimization provides an additional benefit only in a selected population with an advanced atrial chronotropic disease.</AbstractText>
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2,333,393 |
Associations of childhood and adulthood height and the components of height with insulin-like growth factor levels in adulthood: a 65-year follow-up of the Boyd Orr cohort.
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Taller individuals with longer legs have a higher risk of cancer but a lower risk of coronary heart disease.</AbstractText>We investigated whether childhood height and its components are associated with the IGF system in adulthood.</AbstractText>We analyzed data from 429 participants of the Boyd Orr cohort, for whom height measured in childhood (mean age, 7.4 yr) in 1937-1939 could be related to levels of IGF-I, IGF-II, IGF binding protein (IGFBP)-2, and IGFBP-3 in adulthood (mean age, 71.1 yr). In 385 participants, measured height in adulthood could be related to IGF levels.</AbstractText>In fully adjusted models (controlling for age, sex, socioeconomic factors, lifestyle, and body mass index), childhood height and its components were not associated with adult circulating IGF-I, IGF-II, or IGFBP-2 levels. IGFBP-3 was 85.5 ng/ml higher (95% confidence interval, -11.6 to 182.5; P = 0.08) per sd increase in childhood trunk length and 83.6 ng/ml lower (95% confidence interval, -10.3 to 177.5; P = 0.08) per sd increase in childhood leg/trunk ratio. Height in adulthood was not associated with IGF-I, IGF-II, or IGFBP-3 and was inversely associated with IGFBP-2 (P = 0.05) after additionally controlling for childhood height.</AbstractText>There was no evidence that associations of childhood height with cancer and coronary heart disease risk are mediated by IGF-I in adulthood. The anthropometric associations with IGFBP-2 and IGFBP-3 could be chance findings but warrant additional investigation. IGF levels in childhood may be more important determinants of long-term disease risk than adult levels.</AbstractText>
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2,333,394 |
Effect of low-dose dexmedetomidine or clonidine on the characteristics of bupivacaine spinal block.
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The purpose of this study was to compare the onset and duration of sensory and motor block, as well as the hemodynamic changes and level of sedation, following intrathecal bupivacaine supplemented with either dexmedetomidine or clonidine.</AbstractText>In a prospective, double-blind study, 60 patients undergoing transurethral resection of prostate or bladder tumor under spinal anesthesia were randomly allocated to one of three groups. Group B received 12 mg of hyperbaric bupivacaine, group D received 12 mg of bupivacaine supplemented with 3 microg of dexmedetomidine and group C received 12 mg of bupivacaine supplemented with 30 microg of clonidine. The onset times to reach peak sensory and motor levels, and the sensory and motor regression times, were recorded. Hemodynamic changes and the level of sedation were also recorded.</AbstractText>Patients in groups D and C had a significantly shorter onset time of motor block and significantly longer sensory and motor regression times than patients in group B. The mean time of sensory regression to the S1 segment was 303 +/- 75 min in group D, 272 +/- 38 min in group C and 190 +/- 48 min in group B (B vs. D and B vs. C, P < 0.001). The regression of motor block to Bromage 0 was 250 +/- 76 min in group D, 216 +/- 35 min in group C and 163 +/- 47 min in group B (B vs. D and B vs. C, P < 0.001). The onset and regression times were not significantly different between groups D and C. The mean arterial pressure, heart rate and level of sedation were similar in the three groups intra-operatively and post-operatively.</AbstractText>Dexmedetomidine (3 microg) or clonidine (30 microg), when added to intrathecal bupivacaine, produces a similar prolongation in the duration of the motor and sensory block with preserved hemodynamic stability and lack of sedation.</AbstractText>
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2,333,395 |
Analysis of effects of connexin-mimetic peptides in rat mesenteric small arteries.
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Synthetic peptides homologous to the extracellular loops of the major vascular connexins represent a novel class of gap junction blockers that have been used to assess the role of direct cellular communication in arteries and veins. However, the specificity of action of such peptides on the coupling between smooth muscle cells (SMCs) has not yet been fully characterized. Isolated third-order rat mesenteric arteries were therefore studied with respect to isometric tension (myography), intracellular Ca2+ concentration ([Ca2+]i) (Ca2+ -sensitive dyes), membrane potential, and input resistance (sharp intracellular glass electrodes). Confocal imaging was used for visualization of [Ca2+]i events in individual SMCs in the arterial wall and membrane currents (patch clamp) measured in individual SMCs isolated from the same arteries. A triple peptide combination (37,43Gap 27 + 40Gap 27 + 43Gap 26) increased intercellular resistance (measured as input resistance) in intact arterial segments without affecting the membrane conductance of individual cells and also interrupted electrical coupling between pairs of rat aortic A7r5 myocytes. In intact arterial segments, the peptides desynchronized [Ca2+]i transients in individual SMCs and abolished vasomotion without suppressing Ca2+ transients in individual cells. They also depolarized SMCs, increased [Ca2+]i, and attenuated acetylcholine-induced, endothelium-dependent smooth muscle hyperpolarization. Experiments with endothelium-denuded arteries suggested that the depolarization produced by the peptides under basal conditions was in part secondary to electrical uncoupling of the endothelium from SMCs with loss of a tonic hyperpolarizing effect of the endothelium. Taken together, the results indicate that connexin-mimetic peptides block electrical signaling in rat mesenteric small arteries without exerting major nonjunctional effects.
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2,333,396 |
TRAIL-expressing T cells induce apoptosis of vascular smooth muscle cells in the atherosclerotic plaque.
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Acute coronary syndromes (ACS) are precipitated by a rupture of the atherosclerotic plaque, often at the site of T cell and macrophage infiltration. Here, we show that plaque-infiltrating CD4 T cells effectively kill vascular smooth muscle cells (VSMC). VSMCs sensitive to T cell-mediated killing express the death receptor DR5 (TNF-related apoptosis-inducing ligand [TRAIL] receptor 2), and anti-TRAIL and anti-DR5 antibodies block T cell-mediated apoptosis. CD4 T cells that express TRAIL upon stimulation are expanded in patients with ACS and more effectively induce VSMC apoptosis. Adoptive transfer of plaque-derived CD4 T cells into immunodeficient mice that are engrafted with human atherosclerotic plaque results in apoptosis of VSMCs, which was prevented by coadministration of anti-TRAIL antibody. These data identify that the death pathway is triggered by TRAIL-producing CD4 T cells as a direct mechanism of VSMC apoptosis, a process which may lead to plaque destabilization.
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2,333,397 |
KChIP2b modulates the affinity and use-dependent block of Kv4.3 by nifedipine.
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Rapidly activating Kv4 voltage-gated ion channels are found in heart, brain, and diverse other tissues including colon and uterus. Kv4.3 can co-assemble with KChIP ancillary subunits, which modify kinetic behavior. We examined the affinity and use dependence of nifedipine block on Kv4.3 and its modulation by KChIP2b. Nifedipine (150 microM) reduced peak Kv4.3 current approximately 50%, but Kv4.3/KChIP2b current only approximately 27%. Nifedipine produced a very rapid component of open channel block in both Kv4.3 and Kv4.3/KChIP2b. However, recovery from the blocked/inactivated state was strongly sensitive to KChIP2b. Kv4.3 Thalf,recovery was slowed significantly by nifedipine (120.0+/-12.4 ms vs. 213.1+/-18.2 ms), whereas KChIP2b eliminated nifedipine's effect on recovery: Kv4.3/KChIP2b Thalf,recovery was 45.3+/-7.2 ms (control) and 47.8+/-8.2 ms (nifedipine). Consequently, Kv4.3 exhibited use-dependent nifedipine block in response to a series of depolarizing pulses which was abolished by KChIP2b. KChIPs alter drug affinity and use dependence of Kv4.3.
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2,333,398 |
Subarachnoid anesthesia for loco-regional antiblastic perfusion with circulatory block (stop-flow perfusion).
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Loco-regional antiblastic perfusion with circulatory block (stop-flow perfusion, SFP) is a procedure designed to treat solid tumors of the limb and pelvis in an advanced stage, like melanoma, sarcoma of the soft tissues and colon-rectal cancer. The aim of this study was to evaluate if subarachnoid anesthesia could represent a safe and suitable anesthetic technique for this procedure.</AbstractText>Thirty SFP procedures were performed in the angiographic room, 15 for the treatment of lower-limb neoplasias and 15 for pelvic neoplasias. The patients (ASA I-III) had a mean age of 59.1 years (range: 19-81 years). The patients were given different dosages of bupivacaine (range: 10-20 mg) in hyperbaric solution at the concentration of 0.5% and 1% by lumbar subarachnoid injection at different levels (from T12-L1 to L3-L4). Standard monitoring was set up (ECG, pulse-oximetry, and non-invasive artery pressure). The use of any anesthetic and analgesic drug, eventually used in the intra- or postoperative period, was recorded.</AbstractText>The lumbar puncture was approached at L1-L2 and L2-L3 levels in 80% of the cases. Doses of bupivacaine between 12 mg and 14 mg were administered in 2/3 of the cases. Bupivacaine was formulated in hyperbaric solution and administered at a concentration of 0.5% (8 patients) or 1% (22 patients). Complica-tions related to the anesthetic technique were absent. Intraoperative pain control was almost complete with one exception, when the procedure lasted unusually long. Pain control was satisfying immediately after the procedure as well: only in 3 cases were non-opiod analgesics administered within the first 6 h.</AbstractText>Spinal subarachnoid anesthesia has proven to be an effective, safe, and easy-to-manage technique for carrying out SFP procedure in a non-conventional environment such as an angiographic room. It was free of serious side effects and well tolerated even in patients in poor general conditions.</AbstractText>
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2,333,399 |
RF9, a potent and selective neuropeptide FF receptor antagonist, prevents opioid-induced tolerance associated with hyperalgesia.
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Neuropeptide FF (NPFF) has been proposed to play a role in pain modulation, opioid tolerance, and several other physiological processes. However, pharmacological agents that would help define physiological roles for this peptide are still missing. Here we report the discovery of a potent and selective NPFF receptor antagonist, RF9, that can be administered systemically. This compound does not show any effects by itself but can block efficiently the increase in blood pressure and heart rate evoked by NPFF. When chronically coinjected with heroin, RF9 completely blocks the delayed and long-lasting paradoxical opioid-induced hyperalgesia and prevents the development of associated tolerance. Our data indicate that NPFF receptors are part of a bona fide antiopioid system and that selective antagonists of these receptors could represent useful therapeutic agents for improving the efficacy of opioids in chronic pain treatment.
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