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2,334,200 |
Development of heart block in children of SSA/SSB-autoantibody-positive women is associated with maternal age and displays a season-of-birth pattern.
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Congenital heart block may develop in the fetuses of Ro/SSA-positive and La/SSB-positive mothers. Recurrence rates of only 10-20% despite persisting maternal antibodies indicate that additional factors are critical for the establishment of heart block. The authors investigated the influence of other maternal and fetal factors on heart block development in a Swedish population-based cohort.</AbstractText>The influence of fetal gender, maternal age, parity and time of birth on heart block development was analysed in 145 families, including Ro/La-positive (n=190) and Ro/La-negative (n=165) pregnancies.</AbstractText>There was a recurrence rate of 12.1% in Ro/La-positive women, and no recurrence in Ro/La-negative women. Fetal gender and parity did not influence the development of heart block in either group. Maternal age in Ro/La-positive pregnancies with a child affected by heart block was, however, significantly higher than in pregnancies resulting in babies without heart block (p<0.05).Seasonal timing of pregnancy influenced the outcome. Gestational susceptibility weeks 18-24 occurring during January-March correlated with a higher proportion of children with heart block and lower vitamin D levels during the same period in a representative sample of Swedish women and a corresponding higher proportion of children with heart block born in the summer (p<0.02). Maternal age or seasonal timing of pregnancy did not affect the outcome in Ro/La-negative pregnancies.</AbstractText>This study identifies maternal age and seasonal timing of pregnancy as novel risk factors for heart block development in children of Ro/La-positive women. These observations may be useful for counselling when pregnancy is considered.</AbstractText>
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2,334,201 |
Characterization of splice variants of the genes encoding human mitochondrial HMG-CoA lyase and HMG-CoA synthase, the main enzymes of the ketogenesis pathway.
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The genes HMGCS2 and HMGCL encode the two main enzymes for ketone-body synthesis, mitochondrial HMG-CoA synthase and HMG-CoA lyase. Here, we identify and describe possible splice variants of these genes in human tissues. We detected an alternative transcript of HMGCS2 carrying a deletion of exon 4, and two alternative transcripts of HMGCL with deletions of exons 5 and 6, and exons 5, 6 and 7, respectively. All splice variants maintained the reading frame. However, Western blot studies and overexpression measurements in eukaryotic or prokaryotic cell models did not reveal HL or mHS protein variants. Both genes showed a similar distribution of the inactive variants in different tissues. Surprisingly, the highest percentages were found in tissues where almost no ketone bodies are synthesized: heart, skeletal muscle and brain. Our results suggest that alternative splicing might coordinately block the two main enzymes of ketogenesis in specific human tissues.
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2,334,202 |
Arrhythmia formation in subclinical ("silent") long QT syndrome requires multiple insults: quantitative mechanistic study using the KCNQ1 mutation Q357R as example.
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In subclinical or silent long QT syndrome, the QT interval is normal under basal conditions. The hypothesis that insults to the repolarization reserve may cause arrhythmias in silent mutation carriers but not in noncarriers has been proposed as a general principle, yet crucial aspects remain descriptive, lacking quantification.</AbstractText>To utilize accurate mathematical models of the human action potential and β-adrenergic stimulation to quantitatively investigate arrhythmia-formation mechanisms peculiar to silent long QT syndrome, using mutation Q357R in KCNQ1 (α subunit of slow-delayed rectifier I(Ks)) as a paradigm.</AbstractText>Markov models were formulated to account for altered I(Ks) kinetics in Q357R compared with wild type and introduced into a detailed model of the human ventricular myocyte action potential.</AbstractText>Dominant negative loss of I(Ks) available reserve accurately represents Q357R. Action potential prolongation with mutant I(Ks) was minimal, reproducing the silent phenotype. Partial block of rapid delayed rectifier current (I(Kr)) was needed in addition to fast pacing and isoproterenol application to cause early afterdepolarizations (EADs) in epicardial cells with mutant I(Ks), but this did not produce EADs in wild type. Reduced channel expression at the membrane, not I(Ks) kinetic differences, caused EADs in the silent mutant. With mutant I(Ks), isoproterenol plus partial I(Kr) block resulted in dramatic QT prolongation in the pseudo-electrocardiogram and EADs formed without I(Kr) block in mid-myocardial cells during simulated exercise onset.</AbstractText>Multiple severe insults are needed to evince an arrhythmic phenotype in silent mutation Q357R. Reduced membrane I(Ks) expression, not kinetic changes, underlies the arrhythmic phenotype.</AbstractText>Copyright © 2012 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.</CopyrightInformation>
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2,334,203 |
Usefulness of the 12-lead electrocardiogram in the follow-up of patients with cardiac resynchronization devices. Part I.
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Cardiac resynchronization therapy (CRT) has added a new dimension to the electrocardiographic evaluation of pacemaker function. During left ventricular (LV) pacing from the posterior or posterolateral coronary vein, a correctly positioned lead V1 registers a tall R wave and there is right axis deviation in the frontal plane with few exceptions. During simultaneous biventricular stimulation from the right ventricular (RV) apex and LV site in the coronary venous system, the QRS complex is often positive (dominant) in lead V1 and the frontal plane QRS axis usually points to the right superior quadrant and occasionally the left superior quadrant. The reported incidence of a dominant R wave in lead V1 during simultaneous biventricular pacing (RV apex) varies from 50% to almost 100% for reasons that are not clear. During simultaneous biventricular pacing from the posterior or posterolateral coronary vein with the RV lead in the outflow tract, the paced QRS in lead V1 is often negative and the frontal plane paced QRS axis is often directed to the right inferior quadrant (right axis deviation). A negative paced QRS complex in lead V1 during simultaneous biventricular pacing with the RV lead at the apex can be caused by incorrect placement of the lead V1 electrode (too high on the chest), lack of LV capture, LV lead displacement, pronounced latency (true exit block), conduction delay around the LV stimulation site, ventricular fusion with the intrinsic QRS complex, coronary venous LV pacing via the middle or anterior cardiac vein, unintended placement of two leads in the RV and severe conduction abnormalities within the LV myocardium. Most of these situations can cause a QS complex in lead V1 which should be interpreted (excluding fusion) as reflecting RV preponderance in the depolarization process. Barring the above causes, a negative complex in lead V1 is unusual and it probably reflects a different activation of a heterogeneous biventricular substrate (ischemia, scar, His-Purkinje participation). The latter is basically a diagnosis of exclusion. With a non-dominant R wave in lead V1, programming the V-V interval with LV preceding RV may bring out a diagnostic dominant R wave in lead V1 representing the contribution of LV stimulation to the overall depolarization process. In this situation the emergence of a dominant R wave confirms the diagnosis of prolonged LV latency (exit delay) or an LV intramyocardial conduction abnormality near the LV pacing site but it rules out the various causes of LV lead malfunction or misplacement.
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2,334,204 |
Is clonidine an adequate alternative to epinephrine as a vasoconstrictor in patients with hypertension?
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To evaluate the safety and efficacy of an admixture of lidocaine with clonidine with regard to the anesthetic abilities, hemodynamic parameters, and postoperative pain control and to compare the results with those obtained with a lidocaine-epinephrine solution.</AbstractText>A total of 50 patients with poorly controlled, moderate hypertension (American Society of Anesthesiologists class II) who presented for uncomplicated upper third molar extraction were included in a double-blind study. The time of onset of action, duration, and intensity of anesthesia and the vasoconstrictor properties were evaluated. The hemodynamic changes (ie, systolic blood pressure, diastolic blood pressure, mean arterial pressure, heart rate, ST-segment depression of 1 mm or greater, and cardiac arrhythmias) were recorded. The presence of postoperative pain and analgesic requirements were also compared. The results were analyzed using an unpaired, type sample equal-variance t test with the Bonferroni correction.</AbstractText>Of the 50 patients with hypertension (American Society of Anesthesiologists class II), 25 received 2 mL of 2% lidocaine with clonidine (15 μg/mL) and 25 received lidocaine with epinephrine (12.5 μg/mL). There were no significant differences between the 2 agents with regard to the time of onset of action, duration or intensity of anesthesia, or the vasoconstrictor properties. The clonidine group showed better hemodynamic parameters compared with the epinephrine group. The clonidine group showed significantly lesser postoperative pain and, therefore, had lesser analgesic consumption.</AbstractText>Clonidine could be a useful and safe alternative to epinephrine for intraoral block anesthesia with lidocaine in patients with hypertension and American Society of Anesthesiologists class II.</AbstractText>Copyright © 2012 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.</CopyrightInformation>
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2,334,205 |
[Application of ganglion impar block in patient with coccyx dislocation].
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Sacrococcygeal dislocation is a rare injury. The ganglion impar (also called the ganglion of Walther) is a single, small solitary, sympathetic ganglion located in the retrorectal space, anterior to the sacrococcygeal joint or coccyx. It provides the nociceptive and sympathetic supply to the perineal structure. Ganglion impar blockade is not a routinely used anesthetic and analgesic procedure in clinical practice. An elective intrarectal manuel treatment was planned for a woman patient with coccyx dislocation due to falling down from a chair 5 days ago. Ganglion impar block was performed with saccrococcygeal approach using 22 gauge spinal needle along with fluoroscopy following routine monitorization. Blood pressure, heart rate, peripheral oxygen saturation and visual analog scale (VAS) were recorded before and, after block with three minute intervals. VAS value of the patient, 8 before the procedure, decreased 50% 6 minutes after block. Intrarectal manuel treatment was applied to the patient with VAS of 0 at 9th minute. Hemodynamic values were within normal limits during and after the procedure and no motor block was observed. The patient with VAS of 0 at 2nd and 6th hour after block was discharged. VAS of 0 was determined at 24th and 48th hour by phone call. In conclusion, ganglion impar block provided adequate analgesia without causing any complications during and after the intrarectal manuel treatment for the patient with coccyx dislocation. However, we believe that further clinical studies are required to establish the safety and efficiency of this technique for other procedures at perianal region.
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2,334,206 |
Neuraxial blockade for external cephalic version: a systematic review.
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The desire to decrease the number of cesarean deliveries has renewed interest in external cephalic version. The rationale for using neuraxial blockade to facilitate external cephalic version is to provide abdominal muscular relaxation and reduce patient discomfort during the procedure, so permitting successful repositioning of the fetus to a cephalic presentation. This review systematically examined the current evidence to determine the safety and efficacy of neuraxial anesthesia or analgesia when used for external cephalic version.</AbstractText>A systematic literature review of studies that examined success rates of external cephalic version with neuraxial anesthesia was performed. Published articles written in English between 1945 and 2010 were identified using the Medline, Cochrane, EMBASE and Web of Sciences databases.</AbstractText>Six, randomized controlled studies were identified. Neuraxial blockade significantly improved the success rate in four of these six studies. A further six non-randomized studies were identified, of which four studies with control groups found that neuraxial blockade increased the success rate of external cephalic version. Despite over 850 patients being included in the 12 studies reviewed, placental abruption was reported in only one patient with a neuraxial block, compared with two in the control groups. The incidence of non-reassuring fetal heart rate requiring cesarean delivery in the anesthesia groups was 0.44% (95% CI 0.15-1.32).</AbstractText>Neuraxial blockade improved the likelihood of success during external cephalic version, although the dosing regimen that provides optimal conditions for successful version is unclear. Anesthetic rather than analgesic doses of local anesthetics may improve success. The findings suggest that neuraxial blockade does not compromise maternal or fetal safety during external cephalic version.</AbstractText>Crown Copyright © 2011. Published by Elsevier Ltd. All rights reserved.</CopyrightInformation>
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2,334,207 |
VANG-1 and PRKL-1 cooperate to negatively regulate neurite formation in Caenorhabditis elegans.
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Neuritogenesis is a critical early step in the development and maturation of neurons and neuronal circuits. While extracellular directional cues are known to specify the site and orientation of nascent neurite formation in vivo, little is known about the genetic pathways that block inappropriate neurite emergence in order to maintain proper neuronal polarity. Here we report that the Caenorhabditis elegans orthologues of Van Gogh (vang-1), Prickle (prkl-1), and Dishevelled (dsh-1), core components of planar cell polarity (PCP) signaling, are required in a subset of peripheral motor neurons to restrict neurite emergence to a specific organ axis. In loss-of-function mutants, neurons display supernumerary neurites that extend inappropriately along the orthogonal anteroposterior (A/P) body axis. We show that autonomous and non-autonomous gene activities are required early and persistently to inhibit the formation or consolidation of growth cone protrusions directed away from organ precursor cells. Furthermore, prkl-1 overexpression is sufficient to suppress neurite formation and reorient neuronal polarity in a vang-1- and dsh-1-dependent manner. Our findings suggest a novel role for a PCP-like pathway in maintaining polarized neuronal morphology by inhibiting neuronal responses to extrinsic or intrinsic cues that would otherwise promote extraneous neurite formation.
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2,334,208 |
Inhibition of endoplasmic reticulum stress by intermedin(1-53) protects against myocardial injury through a PI3 kinase-Akt signaling pathway.
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Intermedin (IMD) is a novel member of the calcitonin/calcitonin gene-related peptide family. We aimed to explore whether the cardioprotective effect of IMD is mediated by inhibiting myocardial endoplasmic reticulum (sarcoplasmic reticulum) stress (ERS). In vitro, IMD(1-53) (10(-9), 10(-8), and 10(-7) mol/l) directly inhibited the upregulation of ERS markers such as glucose-regulated protein 78, CCAAT/enhancer binding protein homologous protein, and caspase-12 induced by the ERS inducers tunicamycin (Tm, 10 mg/ml) or dithiothreitol (DTT, 2 mmol/l) in cardiac tissue. IMD(1-53) also inhibited Tm- or DTT-induced upregulation of cleaved activating transcription factor 6 and 4. These inhibitory effects of IMD(1-53) were abolished by the IMD receptor antagonist IMD(17-47) (10(-6) mol/l) and phosphoinositide 3-kinase inhibitor LY294002 (10 μmol/l). However, preincubation with PD98059 (20 μmol/l), an extracellular signal-regulated protein kinase inhibitor, and H89 (10 μmol/l), a protein kinase A inhibitor, could not block the ERS-inhibiting effects of IMD(1-53). Furthermore, in an in vivo model of myocardium ischemia/reperfusion (I/R) in rats, administration of IMD(1-53) (20 nmol/kg, intravenously) greatly attenuated ERS and ameliorated myocardium impairment induced by I/R. IMD(1-53) could exert its cardioprotective effect by inhibiting myocardial ERS, which might be mediated by the phosphoinositide 3-kinase/Akt signaling pathway.
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2,334,209 |
Subarachnoid bupivacaine and pethidine for caesarean section: assessment of quality of perioperative analgesia and side effects.
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This study determined the quality of perioperative analgesia and side effect profile of spinal bupivacaine plus pethidine for caesarean section.</AbstractText>Patients were randomised to receive 2.0mL of bupivacaine + pethidine 7.5mg or 2.0mL bupivacaine + saline of equal volume. Spinal anaesthesia was instituted at L2/3, L3/4 or L4/5 using a 25G pencil point spinal needle. Heart rate, blood pressure and oxygen saturation were monitored. Timelines such as time of injection of study medication, skin incision, delivery time, termination of surgery and time to first request for analgesia as well as complications were noted. Demographic characteristics were also recorded.</AbstractText>50 patients were studied in 2 groups and the demographic characteristics were similar. Addition of pethidine resulted in block height greater than T6 and longer duration of analgesia (256.9 ± 112.2 min.) compared with the saline group (160.5 ± 65.0 min; p = 0.0005). Maternal hypotension occurred more in the pethidine group (10/25 vs 2/25; p = 0.01). Peritoneal irritation and inadequate anaesthesia were more frequent in the saline group. Nausea and vomiting and drowsiness were mild and occurred only in the pethidine group. In the Post Anaesthetic Care Unit (PACU), more patients reported pain in the saline group (p = 0.002).</AbstractText>Bupivacaine with pethidine 7.5mg resulted in better quality of anaesthesia, longer postoperative analgesia with acceptable side effect profile. This will be of value in the management of post-caesarean section pain particularly in the resource poor setting.</AbstractText>
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2,334,210 |
Pharmacology of renal endothelin receptors.
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Endothelin (ET)-1 is the major isoform in the human kidney where it interacts with two G protein-coupled receptors, ET(A) and ET(B). It contains high densities of ET receptors, but in contrast to most other peripheral organs, the majority (70%) are of the ET(B) subtype and largely have a differential distribution to ET(A) receptors within renal cells, thus mediating contrasting physiological and pathophysiological actions. ET-1 remains the most potent constrictor of human-isolated vessels, including those of the kidney which are particularly sensitive to the actions of this peptide. The pharmacological response is unusual in being sustained for a considerable period of time and slow to wash out. Smooth muscle cells of the renal vasculature mainly express ET(A) receptors, and ET(A)-selective antagonists fully block these constrictor responses. The vascular endothelium only expresses ET(B) receptors. ET-1 also acts in an autocrine or paracrine manner, and binds to ET(B) receptors to stimulate the release of vasodilators. ET-1 is unusual amongst the mammalian bioactive peptides in possessing two disulphide bridges, conferring resistance to enzymatic degradation. However, the plasma half-life of ET-1 is surprisingly short as a result of the second major function of endothelial ET(B) receptors in removing ET-1 from the circulation, mainly in the kidneys and lungs. Thus, ET(B) receptors have a critical role in protecting target organs such as the heart and may limit the detrimental vasoconstrictor effect caused by upregulation of ET-1 associated with disease. Inhibition of the renal medullary ET(B) system causes sodium retention because of its role in systemic fluid and electrolyte homeostasis. ET(A)/ET(B) antagonists would be expected to block the beneficial vasodilatory, clearing, and natriuretic actions of ET(B) receptors. Since many of the deleterious actions of ET-1, vasoconstriction, mesangial cell proliferation, and inflammation occur mainly via ET(A) receptors, selective ET(A) blockade may be more beneficial in renal disease.
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2,334,211 |
Effects of limited and excess protein intakes of pregnant gilts on carcass quality and cellular properties of skeletal muscle and subcutaneous adipose tissue in fattening pigs.
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The aim of this study was to investigate whether dietary protein intake of gilts during gestation below (50%) or above (250%) recommendations affects body composition, carcass and meat quality, and properties of skeletal muscle and subcutaneous adipose tissue (SCAT) in offspring at d 83 and 188 of age. German Landrace gilts were fed isoenergetic gestation diets (~13.7 MJ of ME/kg) containing a low (LP, 6.5%; n = 18), an adequate (AP, 12.1%; n = 20), or a high (HP, 30%; n = 16) protein content from mating until farrowing. Within 48 h of birth, offspring were cross-fostered to sows fed a standard diet. On d 83 of age, no effects of the LP diet on BW and body composition were detected, whereas HP pigs showed a slight growth delay (P = 0.06) associated with increased relative weights of small intestine (P < 0.01) and brain (P = 0.08), and reduced relative thymus weight (P < 0.01). On d 188 of age, BW was not different among the dietary groups. However, the carcass of LP pigs contained less (P = 0.01) lean and more (P = 0.07) fat compared with AP and HP pigs, which was only pronounced in pigs originating from large litters (P < 0.05). Like skeletal muscles (P = 0.06), the heart muscle weighed less (P = 0.02) in LP than AP pigs. Compared with AP pigs, LP pigs exhibited a fewer (P = 0.09) total number of myofibers in semitendinosus muscle plus LM both at d 83 and 188 of age, whereas total muscular DNA was less (P = 0.02) at d 188 only. The mRNA abundance of IGF2 measured on d 188 was reduced in SCAT (P = 0.03) and LM (P = 0.07) of LP compared with AP pigs. No changes in muscular fiber type frequency, capillary density, or creatine kinase activity, as well as SCAT adipocyte size and number, were observed at either stages of age. Meat quality characteristics remained unchanged at d 83, whereas Warner-Bratzler shear force value in LM was decreased (P = 0.03) in LP compared with AP pigs on d 188 of age. The results suggest that the maternal LP diet impairs prenatal myofiber formation, reduces the potential of postnatal lean growth related to reduced IGF2 mRNA expression and myonuclear accumulation, and consequently changes carcass quality toward reduced lean proportion and improved tenderness at market weight. In contrast, except for a slight transient growth delay, excess dietary protein during gestation seems to have little effect on the fetal programming of postnatal muscle and adipose tissue phenotype of the progeny.
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2,334,212 |
Temperature dependence of cardiac sarcoplasmic reticulum Ca²⁺-ATPase from rainbow trout Oncorhynchus mykiss.
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In this work, the temperature dependence of the sarco-endoplasmic reticulum Ca(2+) -ATPase (SERCA2) activity from rainbow trout Oncorhynchus mykiss cardiac ventricles was measured and compared with the mammalian SERCA2 isoform. The rate of ATP-dependent Ca(2+) transport catalysed by O. mykiss vesicles was totally abolished by thapsigargin and the Ca(2+) ionophore A(23187) . At warm temperatures (25 and 30° C), the SERCA2 from O. mykiss ventricles displayed the same rate of Ca(2+) uptake. At 35° C, the activity of the O. mykiss enzyme decreased after 20 min of reaction time. The rate of Ca(2+) uptake catalysed by the mammalian SERCA2 was temperature dependent exhibiting its maximal activity at 35° C. In contrast to the rate of Ca(2+) uptake, the rate of ATP hydrolysis catalysed by O. mykiss SERCA2 was not significantly different at 25 and 35° C, but the rate of ATP hydrolysis catalysed by the rat Rattus norvegicus SERCA2 isoform at 35° C was two-fold higher than at 25° C. At low temperatures (5 to 20° C), the rate of Ca(2+) uptake from O. mykiss SR was less temperature dependent than the R. norvegicus isoform, being able to sustain a high activity even at 5° C. The mean ±s.e. Q(10) values calculated from 25 to 35° C for ATP hydrolysis were 1·112 ± 0·026 (n = 3) and 2·759 ± 0·240 (n = 5) for O. mykiss and R. norvegicus, respectively. Taken together, the results show that the O. mykiss SERCA2 was not temperature dependent over the 10 to 25° C temperature interval commonly experienced by the animal in vivo. The Q(10) value of SERCA2 was significantly lower in O. mykiss than R. norvegicus which may be key for cardiac function over the wide environmental temperatures experienced in this eurythermal fish.
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2,334,213 |
Dexmedetomidine for the prevention of shivering during spinal anesthesia.
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The aim of this study was to evaluate the effect of dexmedetomidine on shivering during spinal anesthesia.</AbstractText>Sixty patients (American Society of Anesthesiologists physical status I or II, aged 18-50 years), scheduled for elective minor surgical operations under spinal anesthesia with hyperbaric bupivacaine, were enrolled. They were administered saline (group C, n = 30) or dexmedetomidine (group D, n = 30). Motor block was assessed using a Modified Bromage Scale. The presence of shivering was assessed by a blinded observer after the completion of subarachnoid drug injection.</AbstractText>Hypothermia was observed in 21 patients (70%) in group D and in 20 patients (66.7%) in group C (p = 0.781). Three patients (10%) in group D and 17 patients (56.7%) in group C experienced shivering (p = 0.001). The intensity of shivering was lower in group D than in group C (p = 0.001). Time from baseline to onset of shivering was 10 (5-15) min in group D and 15 (5-45) min in group C (p = 0.207).</AbstractText>Dexmedetomidine infusion in the perioperative period significantly reduced shivering associated with spinal anesthesia during minor surgical procedures without any major adverse effect during the perioperative period. Therefore, we conclude that dexmedetomidine infusion is an effective drug for preventing shivering and providing sedation in patients during spinal anesthesia.</AbstractText>
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2,334,214 |
The relationship between ventricular electrical delay and left ventricular remodelling with cardiac resynchronization therapy.<Pagination><StartPage>2516</StartPage><EndPage>2524</EndPage><MedlinePgn>2516-24</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1093/eurheartj/ehr329</ELocationID><Abstract><AbstractText Label="AIMS" NlmCategory="OBJECTIVE">The aim of the present study was to evaluate the relationship between left ventricular (LV) electrical delay, as measured by the QLV interval, and outcomes in a prospectively designed substudy of the SMART-AV Trial.</AbstractText><AbstractText Label="METHODS AND RESULTS" NlmCategory="RESULTS">This was a multicentre study of patients with advanced heart failure undergoing cardiac resynchronization therapy (CRT) defibrillator implantation. In 426 subjects, QLV was measured as the interval from the onset of the QRS from the surface ECG to the first large peak of the LV electrogram. Left ventricular volumes were measured by echocardiography at baseline and after 6 months of CRT by a blinded core laboratory. Quality of life (QOL) was assessed by a standardized questionnaire. When separated by quartiles based on QLV duration, reverse remodelling response rates (>15% reduction in LV end systolic volume) increased progressively from 38.7 to 68.4% and QOL response rate (>10 points reduction) increased from 50 to 72%. Patients in the highest quartile of QLV had a 3.21-fold increase (1.58-6.50, P = 0.001) in their odds of a reverse remodelling response after correcting for QRS duration, bundle branch block type, and clinical characteristics by multivariate logistic regression analysis.</AbstractText><AbstractText Label="CONCLUSION" NlmCategory="CONCLUSIONS">Electrical dyssynchrony, as measured by QLV, was strongly and independently associated with reverse remodelling and QOL with CRT. Acute measurements of QLV may be useful to guide LV lead placement.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Gold</LastName><ForeName>Michael R</ForeName><Initials>MR</Initials><AffiliationInfo><Affiliation>Medical University of South Carolina, 25 Courtenay Drive, ART 7031, Charleston, SC 29425-5920, USA. [email protected]</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Birgersdotter-Green</LastName><ForeName>Ulrika</ForeName><Initials>U</Initials></Author><Author ValidYN="Y"><LastName>Singh</LastName><ForeName>Jagmeet P</ForeName><Initials>JP</Initials></Author><Author ValidYN="Y"><LastName>Ellenbogen</LastName><ForeName>Kenneth A</ForeName><Initials>KA</Initials></Author><Author ValidYN="Y"><LastName>Yu</LastName><ForeName>Yinghong</ForeName><Initials>Y</Initials></Author><Author ValidYN="Y"><LastName>Meyer</LastName><ForeName>Timothy E</ForeName><Initials>TE</Initials></Author><Author ValidYN="Y"><LastName>Seth</LastName><ForeName>Milan</ForeName><Initials>M</Initials></Author><Author ValidYN="Y"><LastName>Tchou</LastName><ForeName>Patrick J</ForeName><Initials>PJ</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D016448">Multicenter Study</PublicationType><PublicationType UI="D016449">Randomized Controlled Trial</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2011</Year><Month>08</Month><Day>29</Day></ArticleDate></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>Eur Heart J</MedlineTA><NlmUniqueID>8006263</NlmUniqueID><ISSNLinking>0195-668X</ISSNLinking></MedlineJournalInfo><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000368" MajorTopicYN="N">Aged</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D001145" MajorTopicYN="N">Arrhythmias, Cardiac</DescriptorName><QualifierName UI="Q000628" MajorTopicYN="N">therapy</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D058406" MajorTopicYN="N">Cardiac Resynchronization Therapy</DescriptorName><QualifierName UI="Q000379" MajorTopicYN="Y">methods</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D017147" MajorTopicYN="Y">Defibrillators, Implantable</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004562" MajorTopicYN="N">Electrocardiography</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006329" MajorTopicYN="N">Heart Conduction System</DescriptorName><QualifierName UI="Q000502" MajorTopicYN="N">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006333" MajorTopicYN="N">Heart Failure</DescriptorName><QualifierName UI="Q000628" MajorTopicYN="Y">therapy</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008875" MajorTopicYN="N">Middle Aged</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D011446" MajorTopicYN="N">Prospective Studies</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D011788" MajorTopicYN="N">Quality of Life</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D016896" MajorTopicYN="N">Treatment Outcome</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D018487" MajorTopicYN="N">Ventricular Dysfunction, Left</DescriptorName><QualifierName UI="Q000628" MajorTopicYN="N">therapy</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D020257" MajorTopicYN="N">Ventricular Remodeling</DescriptorName><QualifierName UI="Q000502" MajorTopicYN="Y">physiology</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="entrez"><Year>2011</Year><Month>8</Month><Day>31</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2011</Year><Month>8</Month><Day>31</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2012</Year><Month>2</Month><Day>7</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">21875862</ArticleId><ArticleId IdType="pmc">PMC3195261</ArticleId><ArticleId IdType="doi">10.1093/eurheartj/ehr329</ArticleId><ArticleId IdType="pii">ehr329</ArticleId></ArticleIdList><ReferenceList><Reference><Citation>Cazeau S, Leclercq C, Lavergne T, Walker S, Varma C, Linde C, Garrigue S, Kappenberger L, Haywood GA, Santini M, Bailleul C, Daubert JC. 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Heart failure decompensation and all-cause mortality in relation to percent biventricular pacing in patients with heart failure: is a goal of 100% biventricular pacing necessary? J Am Coll Cardiol. 2009;53:355–360. doi:10.1016/j.jacc.2008.09.043.</Citation><ArticleIdList><ArticleId IdType="doi">10.1016/j.jacc.2008.09.043</ArticleId><ArticleId IdType="pubmed">19161886</ArticleId></ArticleIdList></Reference><Reference><Citation>Ypenburg C, Westernberg JJ, Bleeker GB, Van de Veire N, Marsan NA, Henneman MM, van der Wall EE, Schalij MJ, Abraham TP, Barold SS, Bax JJ. Noninvasive imaging in cardiac resynchronization therapy - Part 1: selection of patients. 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Circulation. 2010;122:985–992. doi:10.1161/CIRCULATIONAHA.110.955039.</Citation><ArticleIdList><ArticleId IdType="doi">10.1161/CIRCULATIONAHA.110.955039</ArticleId><ArticleId IdType="pubmed">20733097</ArticleId></ArticleIdList></Reference></ReferenceList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">21873750</PMID><DateCompleted><Year>2012</Year><Month>01</Month><Day>16</Day></DateCompleted><DateRevised><Year>2013</Year><Month>11</Month><Day>21</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">1512-0112</ISSN><JournalIssue CitedMedium="Internet"><Issue>196-197</Issue><PubDate><Year>2011</Year><Season>Jul-Aug</Season></PubDate></JournalIssue><Title>Georgian medical news</Title><ISOAbbreviation>Georgian Med News</ISOAbbreviation></Journal>Variable profile of individual heart rate responses to cold water immersion apnea in healthy late adolescent men.
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Holding breath combined with immersion of face in cool water induces diving reflex consisting in bradycardia, peripheral vasoconstriction, and preferential redistribution of blood to the vital organs. The individual responses are variable, highly expressed in young children to weaken with age. Detailed assessment of the cardiac response to diving in late adolescents who are mostly prone to unexpected diving experiments and related complications are of practical importance. The study was performed to the investigate the heart rate (HR) response to controlled breath-hold diving in cold water in young healthy late adolescents aged 17.5 - 20.4. Twenty volunteers performed a procedure consisting in immersion of face in cold water during possibly long breath-holding. Beat-to-beat HR was assessed from the continuous ECG recording. Average diving time (tD) was 77.5±10.5 s, ranging from 61.7 to 95.4 s. Apnea and face immersion induced a biphasic response: an increase in HR was followed by its gradual decrease to reach a final limit of the response 47.7±9.0 beats/min at 55.2±16.1 s of dive. Within a variable time course of the evoked responses, two patterns of the HR decrease were distinguished: monoexponential decay functions fitted best for 8 (40%) subjects with a constant rate τ 31.3±11.4 s-1, whereas the 60% majority displayed a two phase negative chronotropic effect with constant rates: τ1 10.3±4.2 s-1 and τ1 25.5±10.1 s-1. The initial, anticipatory excitation influenced the HR response: the higher was the initial HR increase, the more pronounced was bradycardia. Disturbances of heart rhythm were observed in majority of subjects: supraventricular ectopic beats (40%), ventricular beats (20%), I-degree AV block (30%), II-degree Mobitz I block (15%), junctional rhythm (60%). In one case pair of ventricular ectopic beats looked severe and the trial was rapidly terminated. In conclusion, the unquestionable potency of late adolescents towards diving challenges, accompanied with a vigorous emotionally driven initial cardioexcitation meets a relevant vulnerability for arrhythmias.
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2,334,215 |
Ischemia induces closure of gap junctional channels and opening of hemichannels in heart-derived cells and tissue.
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Gap junction intercellular communication (GJIC) and hemichannel permeability may have important roles during an ischemic insult. Our aim was to evaluate the effect of ischemia on gap junction channels and hemichannels.</AbstractText>We used neonatal rat heart myofibroblasts and simulated ischemia with a HEPES buffer with high potassium, low pH, absence of glucose, and oxygen tension was reduced by dithionite. Microinjection, western blot, immunofluorescence, cell viability and dye uptake were used to evaluate the effects induced by dithionite. Isolated perfused rat hearts were used to analyse infarct size.</AbstractText>Short period with simulated ischemia reduced the ability to transfer a dye between neighbouring cells, which indicated reduced GJIC. Prolonged exposure to simulated ischemia caused opening of hemichannels, and cell death was apparent while gap junction channels remained closed. Connexin 43 became partially dephosphorylated and the total amount decreased during simulated ischemia. We were not able to detect the alternative hemichannel-forming protein, Pannexin 1, in these cells. The potential importance of Connexin 43 or Pannexin 1 hemichannels in ischemia-induced infarct in the intact heart was studied by perfusion of the heart in the presence of peptides that block one or the other type of hemichannels. The connexin-derived peptide, Gap26, significantly reduced the infract/risk zone ratio (control 48.7±4.2% and Gap26 19.4±4.1%, p<0.001), while the pannexin-derived peptide, (10)Panx1, did not change infarct/risk ratio.</AbstractText>Connexin 43 is most likely responsible for both closure of gap junction channels and opening of hemichannels during simulated ischemia in neonatal rat heart myofibroblasts. Opening of connexin 43 hemichannels during ischemia-reperfusion seems to be an important mechanism for ischemia-reperfusion injury in the heart. By preventing the opening of these channels during early ischemia-reperfusion the infarct size becomes significantly reduced.</AbstractText>Copyright © 2011 S. Karger AG, Basel.</CopyrightInformation>
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2,334,216 |
Is carotid endarterectomy under the cervical plexus block safe for all patients with various degree of cardiovascular risk?
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The result of the GALA study did not answer the question whether it is safe to perform carotid endarterectomy (CEA) under the cervical plexus block (CPB) in patients at high cardiovascular (CV) risk. The aim of the study was to compare CV stability and the frequency of cardiovascular and neurological complications in 3 groups of patients with various degree of CV risk who underwent CEA under CPB.</AbstractText>60 patients operated on in CPB were divided into the 3 groups according to the degree of their CV risk (I: very high, II: medium, III: low).</AbstractText>Chi-square, Kruskal Wallis test.</AbstractText>No statistically significant difference was confirmed in the changes of blood pressure (MAP, BP syst, BP diast), heart rate, cardiovascular complications, the rate of the shunt insertion and neurological complications and the level of haemodynamic instability, except for hypotension (p = 0.041) in the three groups. Life threatening CV complications did not occur in any of the groups. The frequency of haemodynamic changes and postoperative complications: hypertension (I--40%, II--60%, III--60%), hypotension (I--35%, II--25%, III--5%), arrhythmias (I--30%, II--15%, III--10%), neurological complications: 2x (TIA), the frequency of shunt insertion: 15 %.</AbstractText>CPB can be performed in all three groups of patients, even in high-risk cardiac patients. The results will have to be confirmed in a larger group of patients in future (Tab. 3, Fig. 4, Ref. 16).</AbstractText>
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2,334,217 |
Overexpression of NF-κB inhibitor alpha in Cynoglossus semilaevis impairs pathogen-induced immune response.
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IκBα is a member of the NF-κB inhibitor family that inhibits NF-κB activity by sequestering NF-κB in an inactive form in the cytosol. Unlike mammalian IκBα, which has been extensively studied, very little is known about the function of fish IκBα. In this study, we identified and analyzed an IκBα homologue, CsIκBα from half-smooth tongue sole (Cynoglossus semilaevis), a marine flatfish with important economic value. The deduced amino acid sequence of CsIκBα contains 308 residues and shares 58-82% overall sequence identities with the IκBα of a number of teleosts. In silico analysis identified in CsIκBα conserved domains that in mammals are known to be involved in phosphorylation, ubiquitination, and degradation of IκBα. Quantitative real time RT-PCR detected constitutive expression of CsIκBα in gut, spleen, liver, gill, heart, brain, muscle, and kidney. Experimental challenge with a bacterial pathogen-induced significant inductions of CsIκBα expression in head and trunk kidney, which, however, were transient and much lower in magnitude than that of interleukin-1β. To examine the effect of unregulated overexpression of CsIκBα in a live fish model, tongue sole were administered via intramuscular injection with plasmid pCNCsIkBa, which constitutively expresses CsIκBα. PCR, RT-PCR, and immunohistochemistry analysis showed that pCNCsIkBa was able to translocate to internal tissues, where transcription and translation of the recombinant CsIκBα took place. Compared to control fish, fish administered with pCNCsIkBa were impaired in the ability to block bacterial dissemination and survival in kidney and exhibited significantly reduced expression of multiple immune genes. These results suggest the possible existence in tongue sole of a NF-κB-IκBα signaling pathway that is negatively regulated by CsIκBα and required for effective defense against bacterial infection.
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2,334,218 |
Current experience and prospect of internet consultation in fetal cardiac ultrasound.
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Internet consultation with volume ultrasound is one of the strategies studied to attempt to improve prenatal detection of congenital heart defects (CHD).</AbstractText>This methodology is a form of telemedicine in which a volume block of the fetal heart (either static 3D or STIC volume dataset) is acquired by an operator (non-expert) and transmitted via internet for remote consultation. Naturally, this methodology is suitable for remote locations or those with less access to specialists able to confirm or rule out a prenatal diagnosis of CHD.</AbstractText>The use of internet consultation demonstrates that some intracardiac anomalies can be ruled out and others confirmed, thus enabling the parents to prepare for the likely outcome of the pregnancy and to modify the perinatal management.</AbstractText>Internet consultation offers a good alternative for fetuses from more isolated locations with a high risk of CHD. Moreover, this methodology could become an interesting tool for distance learning and training.</AbstractText>2011 S. Karger AG, Basel.</CopyrightInformation>
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Angiotensin II type-1 receptor-JAK/STAT pathway mediates the induction of visfatin in angiotensin II-induced cardiomyocyte hypertrophy.
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The new adipocytokine visfatin is closely associated with the cardiovascular diseases, and expression of visfatin is elevated in the heart failure patients. However, at the cellular level, little work has been done on visfatin expression in the cardiomyocyte hypertrophy. Here, the authors investigated the expression and mechanisms of visfatin in angiotensin II (Ang II)-induced cardiomyocyte hypertrophy in vitro by means of the cultured neonatal rat cardiomyocytes.</AbstractText>After primary culture of 2- to 3-day-old Sprague-Dawley rat cardiomyocytes and cardiac fibroblasts, cardiomyocytes were pretreated with Ang II. Ang II type-1 receptor (AT1-R) antagonist telmisartan and Ang II type-2 receptor antagonist PD123319 were used to block effects of Ang II. These inhibitors used for the AT1-R pathway determination included SP600125, AG490 and U0126. Cell viability was examined using the 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay. The expression of visfatin was examined by means of reverse transcription-polymerase chain reaction and Western blot. The expression of brain natriuretic peptide was examined through western-blot analysis.</AbstractText>Visfatin was found expressed in cardiomyocytes as well as cardiac fibroblasts, and there was no significant difference at the mRNA and protein levels of visfatin. Ang II treatment induced the increased expression of visfatin and brain natriuretic peptide in a dose- and time-dependent manner in cardiomyocytes, and pretreatment with AT1-R antagonist telmisartan completely blocked Ang II-induced visfatin expression increasement. The increased visfatin expression was also blocked by the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway inhibitor AG490.</AbstractText>Visfatin expression was increased mainly through the AT1-R-JAK/STAT pathway in the process of Ang II-induced cardiomyocyte hypertrophy.</AbstractText>
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2,334,220 |
Secreted frizzled-related protein-1 improves postinfarction scar formation through a modulation of inflammatory response.
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The inflammatory response after myocardial infarction plays a crucial role in the healing process. Lately, there is accumulating evidence that the Wnt/Frizzled pathway may play a distinct role in inflammation. We have shown that secreted frizzled-related protein-1 (sFRP-1) overexpression reduced postinfarction scar size, and we noticed a decrease in neutrophil infiltration in the ischemic tissue. We aimed to further elucidate the role of sFRP-1 in the postischemic inflammatory process.</AbstractText>We found that in vitro, sFRP-1 was able to block leukocyte activation and cytokine production. We transplanted bone marrow cells (BMCs) from transgenic mice overexpressing sFRP-1 into wild-type recipient mice and compared myocardial healing with that of mice transplanted with wild-type BMCs. These results were compared with those obtained in transgenic mice overexpressing sFRP-1 specifically in endothelial cells or in cardiomyocytes to better understand the spatiotemporal mechanism of the sFRP-1 effect. Our findings indicate that when overexpressed in the BMCs, but not in endothelial cells or cardiomyocytes, sFRP-1 was able to reduce neutrophil infiltration after ischemia, by switching the balance of pro- and antiinflammatory cytokine expression, leading to a reduction in scar formation and better cardiac hemodynamic parameters.</AbstractText>sFRP-1 impaired the loop of cytokine amplification and decreased neutrophil activation and recruitment into the scar, without altering the neutrophil properties. These data support the notion that sFRP-1 may be a novel antiinflammatory factor protecting the heart from damage after myocardial infarction.</AbstractText>
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2,334,221 |
Cardiomyocyte specific ablation of p53 is not sufficient to block doxorubicin induced cardiac fibrosis and associated cytoskeletal changes.
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Doxorubicin (Dox) is an anthracycline used to effectively treat several forms of cancer. Unfortunately, the use of Dox is limited due to its association with cardiovascular complications which are manifested as acute and chronic cardiotoxicity. The pathophysiological mechanism of Dox induced cardiotoxicity appears to involve increased expression of the tumor suppressor protein p53 in cardiomyocytes, followed by cellular apoptosis. It is not known whether downregulation of p53 expression in cardiomyocytes would result in decreased rates of myocardial fibrosis which occurs in response to cardiomyocyte loss. Further, it is not known whether Dox can induce perivascular necrosis and associated fibrosis in the heart. In this study we measured the effects of acute Dox treatment on myocardial and perivascular apoptosis and fibrosis in a conditional knockout (CKO) mouse model system which harbours inactive p53 alleles specifically in cardiomyocytes. CKO mice treated with a single dose of Dox (20 mg/kg), did not display lower levels of myocardial apoptosis or reactive oxygen and nitrogen species (ROS/RNS) compared to control mice with intact p53 alleles. Interestingly, CKO mice also displayed higher levels of interstitial and perivascular fibrosis compared to controls 3 or 7 days after Dox treatment. Additionally, the decrease in levels of the microtubule protein α-tubulin, which occurs in response to Dox treatment, was not prevented in CKO mice. Overall, these results indicate that selective loss of p53 in cardiomyocytes is not sufficient to prevent Dox induced myocardial ROS/RNS generation, apoptosis, interstitial fibrosis and perivascular fibrosis. Further, these results support a role for p53 independent apoptotic pathways leading to Dox induced myocardial damage and highlight the importance of vascular lesions in Dox induced cardiotoxicity.
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2,334,222 |
Hepatic peroxisome proliferator-activated receptor-γ-fat-specific protein 27 pathway contributes to obesity-related hypertension via afferent vagal signals.
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Obesity is commonly associated with hypertension. Increased sympathetic tonus in obese subjects contributes to the underlying mechanism. However, the precise mechanisms whereby obesity induces this sympathetic activation remain unclear. Hepatic peroxisome proliferator-activated receptor (PPAR)-γ2 expression, which is reportedly upregulated during obesity development, affects sympathetic activation via hepatic vagal afferents. Herein, we report involvement of this neuronal relay in obesity-related hypertension.</AbstractText>Peroxisome proliferator-activated receptor-γ and a direct PPARγ target, fat-specific protein 27 (Fsp27), were adenovirally overexpressed or knocked down in the liver, in combination with surgical dissection or pharmacological deafferentation of the hepatic vagus. Adenoviral PPARγ2 expression in the liver raised blood pressure (BP) in wild-type but not in β1/β2/β3 adrenergic receptor-deficient mice. In addition, knockdown of endogenous PPARγ in the liver lowered BP in murine obesity models. Either surgical dissection or pharmacological deafferentation of the hepatic vagus markedly blunted BP elevation in mice with diet-induced and genetically-induced obesity. In contrast, BP was not elevated in other models of hepatic steatosis, DGAT1 and DGAT2 overexpressions, in which PPARγ is not upregulated in the liver. Thus, hepatic PPARγ upregulation associated with obesity is involved in BP elevation during obesity development. Furthermore, hepatic expression of Fsp27 raised BP and the effect was blocked by hepatic vagotomy. Hepatic Fsp27 is actually upregulated in murine obesity models and its knockdown reversed BP elevation.</AbstractText>The hepatic PPARγ-Fsp27 pathway plays important roles in the development of obesity-related hypertension via afferent vagal signals from the liver.</AbstractText>
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2,334,223 |
Regulation of hypothalamic renin-angiotensin system and oxidative stress by aldosterone.
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In rats with salt-induced hypertension or postmyocardial infarction, angiotensin II type 1 receptor (AT(1)R) densities and oxidative stress increase and neuronal NO synthase (nNOS) levels decrease in the paraventricular nucleus (PVN). The present study was designed to determine whether these changes may depend on activation of the aldosterone -'ouabain' neuromodulatory pathway. After intracerebroventricular (i.c.v.) infusion of aldosterone (20 ng h(-1)) for 14 days, blood pressure (BP) and heart rate (HR) were recorded in conscious Wistar rats, and mRNA and protein for nNOS, endothelial NO synthase (eNOS), AT(1)R and NADPH oxidase subunits were assessed in brain tissue. Blood pressure and HR were significantly increased by aldosterone. Aldosterone significantly increased mRNA and protein of AT(1)R, P22phox, P47phox, P67phox and Nox2, and decreased nNOS but not eNOS mRNA and protein in the PVN, as well as increased the angiotensin-converting enzyme and AT(1)R binding densities in the PVN and supraoptic nucleus. The increases in BP and HR, as well as the changes in mRNA, proteins and angiotensin-converting enzyme and AT(1)R binding densities were all largely prevented by concomitant i.c.v. infusion of Digibind (to bind 'ouabain') or benzamil (to block presumed epithelial sodium channels). These data indicate that aldosterone, via 'ouabain', increases in the PVN angiotensin-converting enzyme, AT(1)R and oxidative stress, but decreases nNOS, and suggest that endogenous aldosterone may cause the similar pattern of changes observed in salt-sensitive hypertension and heart failure postmyocardial infarction.
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2,334,224 |
Electrophysiological effects of ivabradine in dog and human cardiac preparations: potential antiarrhythmic actions.
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Ivabradine is a novel antianginal agent which inhibits the pacemaker current. The effects of ivabradine on maximum rate of depolarization (V(max)), repolarization and spontaneous depolarization have not yet been reported in human isolated cardiac preparations. The same applies to large animals close to human in heart size and spontaneous frequency. Using microelectrode technique action potential characteristics and by applying patch-clamp technique ionic currents were studied. Ivabradine exerted concentration-dependent (0.1-10 μM) decrease in the amplitude of spontaneous diastolic depolarization and reduction in spontaneous rate of firing of action potentials and produced a concentration- and frequency-dependent V(max) block in dog Purkinje fibers while action potential duration measured at 50% of repolarization was shortened. In the presence of ivabradine, at 400 ms cycle length, V(max) block developed with an onset kinetic rate constant of 13.9 ± 3.2 beat(-1) in dog ventricular muscle. In addition to a fast recovery of V(max) from inactivation (τ=41-46 ms) observed in control, a second slow component for recovery of V(max) was expressed (offset kinetics of V(max) block) having a time constant of 8.76 ± 1.34 s. In dog after attenuation of the repolarization reserve ivabradine moderately but significantly lengthened the repolarization. In human, significant prolongation of repolarization was only observed at 10 μM ivabradine. Ivabradine in addition to the Class V antiarrhythmic effect also has Class I/C and Class III antiarrhythmic properties, which can be advantageous in the treatment of patients with ischemic heart disease liable to disturbances of cardiac rhythm.
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2,334,225 |
Stimulus appraisal modulates cardiac reactivity to briefly presented mutilation pictures.
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Emotional reactions to threatening situations can be either advantageous for human adaptation or unfavorable for physical and mental health if sustained over prolonged periods of time. These contrasting effects mostly depend on the individual's capacity for emotion regulation. It has been shown, for example, that changing appraisal can alter the course of emotional processing. In the present study, the influence of stimulus appraisal over cardiac reactivity to briefly presented (200ms) mutilation pictures was tested in the context of an affective classification task. Heart rate and reaction time of twenty-four undergraduate students were monitored during the presentation of pictures (neutral or mutilated bodies) in successive blocks. In one condition (real), participants were told that the pictures depicted real events. In the other condition (fictitious), they were told that the pictures were taken from movie scenes. As expected, the results showed a more pronounced bradycardia to mutilation pictures, in comparison to neural pictures, in the real context. In the fictitious context, a significant attenuation of the emotional modulation (defensive bradycardia) was observed. However, this attenuation seemed to be transient because it was only observed in the first presentation block of the fictitious context. Reaction time to classify mutilation pictures, compared to neutral pictures, was slower in both contexts, reflecting the privileged processing of emotionally laden material. The present findings show that even briefly presented mutilation pictures elicit a differential cardiac reactivity and modulate behavioral performance. Importantly, changing stimulus appraisal attenuates the emotional modulation of cardiac reactivity (defensive bradycardia).
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2,334,226 |
Use of transesophageal atrial pacing to provide temporary chronotropic support in a dog undergoing permanent pacemaker implantation.
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A 14.5-kg, 13-year-old female spayed Cocker spaniel was evaluated because of episodic hind limb weakness. Results of examination were consistent with sick sinus syndrome with intermittent second-degree atrioventricular block. Transesophageal atrial pacing was successful in providing chronotropic support during permanent pacemaker implantation. Transesophageal atrial pacing appears to be a viable option for temporary atrial pacing in dogs with hemodynamically marked bradycardia without significant atrioventricular blockade.
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Letter by Williams et al regarding article, "Bundle-branch block morphology and other predictors of outcome after cardiac resynchronization therapy in medicare patients".<Pagination><StartPage>e170</StartPage><EndPage>e172</EndPage><MedlinePgn>e170; author reply e172</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1161/CIRCULATIONAHA.110.008318</ELocationID><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Williams</LastName><ForeName>Lynne</ForeName><Initials>L</Initials></Author><Author ValidYN="Y"><LastName>Beadle</LastName><ForeName>Roger</ForeName><Initials>R</Initials></Author><Author ValidYN="Y"><LastName>Frenneaux</LastName><ForeName>Michael</ForeName><Initials>M</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016422">Letter</PublicationType><PublicationType UI="D016420">Comment</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Circulation</MedlineTA><NlmUniqueID>0147763</NlmUniqueID><ISSNLinking>0009-7322</ISSNLinking></MedlineJournalInfo><CitationSubset>IM</CitationSubset><CommentsCorrectionsList><CommentsCorrections RefType="CommentOn"><RefSource>Circulation. 2010 Nov 16;122(20):2022-30</RefSource><PMID Version="1">21041691</PMID></CommentsCorrections></CommentsCorrectionsList><MeshHeadingList><MeshHeading><DescriptorName UI="D002037" MajorTopicYN="N">Bundle-Branch Block</DescriptorName><QualifierName UI="Q000401" MajorTopicYN="Y">mortality</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D017147" MajorTopicYN="Y">Defibrillators, Implantable</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D012042" MajorTopicYN="Y">Registries</DescriptorName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="entrez"><Year>2011</Year><Month>8</Month><Day>4</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2011</Year><Month>8</Month><Day>4</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2012</Year><Month>1</Month><Day>12</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">21810670</ArticleId><ArticleId IdType="doi">10.1161/CIRCULATIONAHA.110.008318</ArticleId><ArticleId IdType="pii">124/5/e170</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">21790765</PMID><DateCompleted><Year>2012</Year><Month>03</Month><Day>08</Day></DateCompleted><DateRevised><Year>2013</Year><Month>11</Month><Day>21</Day></DateRevised><Article PubModel="Print"><Journal><JournalIssue CitedMedium="Print"><Issue>39</Issue><PubDate><Year>2011</Year><Month>Aug</Month></PubDate></JournalIssue><Title>Equine veterinary journal. Supplement</Title><ISOAbbreviation>Equine Vet J Suppl</ISOAbbreviation></Journal>Cardiovascular effects of N-butylscopolammonium bromide and xylazine in horses.
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N-butylscopolammonium bromide (NBB) and xylazine are commonly used medications for the treatment of spasmodic colic and other forms of abdominal pain in horses. Both NBB and xylazine exert significant effects on the cardiovascular system and other vital systems of horses.</AbstractText>To evaluate the effects of i.v. administration of NBB, xylazine, and the combination of NBB and xylazine on heart rate, other commonly measured physiological parameters, cardiac rhythm and blood pressure.</AbstractText>Six mature horses of mixed breed were used. In a random cross-over design, each horse was given 0.3 mg/kg bwt of NBB i.v., 0.25 mg/kg bwt xylazine i.v., and a combination of 0.3 mg/kg bwt NBB and 0.25 mg/kg bwt xylazine. Heart rate, physiological parameters, cardiac rhythm and indirect blood pressure were recorded at timed intervals before and 60 min following administration.</AbstractText>Heart rate and blood pressure were significantly elevated immediately following administration of NBB or NBB with xylazine. Administration of NBB with xylazine resulted in significantly greater initial and peak blood pressure values than with NBB alone. Administration of xylazine resulted in a decrease in heart rate, with an initial increase in blood pressure followed by a decrease in blood pressure. Sinus tachycardia was seen with NBB, and NBB and xylazine administration. First and second degree atrioventricular block was identified with xylazine administration. Ventricular tachycardia was identified in one horse following NBB and xylazine administration.</AbstractText>Results of this study suggest that the effects of administration of NBB alone or in combination with xylazine to horses with colic, especially to those with systemic cardiovascular compromise, should be considered carefully to assess condition and predict prognosis accurately, and to avoid potential adverse effects.</AbstractText>© 2011 EVJ Ltd.</CopyrightInformation>
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2,334,228 |
Table Tilt Versus Pelvic Tilt Position for Intrauterine Resuscitation during Spinal Anaesthesia for Caesarian Section.
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This study was undertaken to compare the effects on intrauterine resuscitation by table tilt versus pelvic tilt position after spinal anaesthesia for Caesarian Section. PATIENTS #ENTITYSTARTX00026;</AbstractText>FIFTY ASA I AND II PATIENTS WHO FULFILLED THE ELIGIBILITY CRITERIA WERE ENROLLED IN THE STUDY AND WERE DIVIDED INTO TWO GROUPS: group W (Pelvic tilt with wedge under right hip and group L- (15(0)left lateral table tilt) and received spinal anaesthesia. The following parameters were recorded. Heart rate (HR), mean arterial pressure (MAP) at baseline, 2mins, 5 min and then 5 min thereafter. Mean height of block, Total no. of segments blocked, Onset Time of sensory block (in Minutes), ephedrine doses, incidence of hypotension & bradycardia, APGAR score at 1& 5 Minutes.</AbstractText>The decrease in MAP was much more in wedged position as compared to table tilt position also the incidence of hypotension was 40% in wedged position as compared to 12% in table tilt position. Mean height of block, Total no. of segments blocked, and boluses of inj. ephedrine used were more in the wedged position than in table tilt position.</AbstractText>Wedge placement caused increased incidence of hypotension and higher blockade after spinal anaesthesia as compared to left lateral table tilt position, there was no adverse effects on foetus and patients tolerated wedge better than left lateral table tilt position. Also surgery was easier to perform after wedge placement.</AbstractText>
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2,334,229 |
An efficient compression scheme for 4-D medical images using hierarchical vector quantization and motion compensation.
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This paper proposes an efficient compression scheme for compressing time-varying medical volumetric data. The scheme uses 3-D motion estimation to create a homogenous preprocessed data to be compressed by a 3-D image compression algorithm using hierarchical vector quantization. A new block distortion measure, called variance of residual (VOR), and three 3-D fast block matching algorithms are used to improve the motion estimation process in term of speed and data fidelity. The 3-D image compression process involves the application of two different encoding techniques based on the homogeneity of input data. Our method can achieve a higher fidelity and faster decompression time compared to other lossy compression methods producing similar compression ratios. The combination of 3-D motion estimation using VOR and hierarchical vector quantization contributes to the good performance.
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2,334,230 |
Revisiting the reticulum: feedforward and feedback contributions to motor program parameters in the crab cardiac ganglion microcircuit.
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The neurogenic heartbeat of crustaceans is controlled by the cardiac ganglion (CG), a central pattern generator (CPG) microcircuit composed of nine neurons. In most decapods, five "large" motor neurons (MNs) project from the CG to the myocardium, where their excitatory synaptic signals generate the rhythmic heartbeat. The processes of four "small" premotor neurons (PMNs) are confined to the CG, where they provide excitatory drive to the MNs via impulse-mediated chemical signals and electrotonic coupling. This study explored feedforward and feedback interactions between the PMNs and the MNs in the CG of the blue crab (Callinectes sapidus). Three methods were used to compare the activity of the MNs and the PMNs in the integrated CG to their autonomous firing patterns: 1) ligatures were tightened on the ganglion trunk that connects the PMNs and MNs; 2) TTX was applied focally to suppress selectively PMN or MN activity; and 3) sucrose pools were devised to block reversibly PMN or MN impulse conduction. With all treatments, the PMNs and MNs continued to produce autonomous rhythmic bursting following disengagement. Removal of PMN influence resulted in a significantly reduced MN duty cycle that was mainly attributable to a lower autonomous burst frequency. Conversely, after removal of MN feedback, the PMN duty cycle was increased, primarily due to a prolonged burst duration. Application of sucrose to block impulse conduction without eliminating PMN oscillations disclosed significant contributions of spike-mediated PMN-to-MN signals to the initiation and prolongation of the MN burst. Together, these observations support a view of the Callinectes CG composed of two classes of spontaneously bursting neurons with distinct endogenous rhythms. Compartmentalized feedforward and feedback signaling endow this microcircuit with syncytial properties such that the intrinsic attributes of the PMNs and MNs both contribute to shaping all parameters of the motor patterns transmitted to the myocardium.
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2,334,231 |
Powerful technique to test selectivity of agents acting on cardiac ion channels: the action potential voltage-clamp.
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Action potential voltage-clamp (APVC) is a technique to visualize the profile of various currents during the cardiac action potential. This review summarizes potential applications and limitations of APVC, the properties of the most important ion currents in nodal, atrial, and ventricular cardiomyocytes. Accordingly, the profiles ("fingerprints") of the major ion currents in canine ventricular myocytes, i.e. in cells of a species having action potential morphology and set of underlying ion currents very similar to those found in the human heart, are discussed in details. The degree of selectivity of various compounds, which is known to be a critical property of drugs used in APVC experiments, is overviewed. Thus the specificity of agents known to block sodium (tetrodotoxin, saxitoxin), potassium (chromanol 293B, HMR 1556, E-4031, dofetilide, sotalol, 4-aminopyridine, BaCl(2)), calcium (nifedipine, nisolpidine, nicardipine, diltiazem, verapamil, gallopamil), and chloride (anthracene-9-carboxylic acid, DIDS) channels, the inhibitor of the sodium-calcium exchanger (SEA0400), and the activator of sodium current (veratridine) are accordingly discussed. Based on a theory explaining how calcium current inhibitors block calcium channels, the structural comparison of the studied substances usually confirmed the results of the literature. Using these predictions, a hypothetical super-selective calcium channel inhibitor structure was designed. APVC is a valuable tool not only for studying the selectivity of the known ion channel blockers, but is also suitable for safety studies to exclude cardiac ion channel actions of any agent under development.
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2,334,232 |
What is the risk of hyperkalaemia in heart failure?
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Chronic heart failure (CHF) is the only major cardiovascular disease whose prevalence and incidence are thought to be increasing. Potassium balance may be lost both through the neurohormonal mechanisms involved in cardiovascular diseases and through the drugs used in their treatment. Avoiding both hypo- and hyperkalemia is difficult but beneficial in CHF.</AbstractText>Aldosterone production is decreased in the elderly, diabetic patients, and those receiving drugs that block the production or action of renin and angiotensin II. As a result, these groups, as well as those with already impaired potassium excretion due to progressive age or disease-related decline in glomerular filtration rate, are particularly vulnerable to the development of hyperkalemia.</AbstractText>Evidence from several studies suggests that, in patients with CHF, serum potassium should be maintained between 4.0 and 5.5 mEq/L. To gain the maximum benefit from aldosterone antagonists it is necessary to individualize their use; it is also necessary to carefully monitor electrolytes.</AbstractText>
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2,334,233 |
The feasibility of using thermal strain imaging to regulate energy delivery during intracardiac radio-frequency ablation.
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A method is introduced to monitor cardiac ablative therapy by examining slope changes in the thermal strain curve caused by speed of sound variations with temperature. The sound speed of water-bearing tissue such as cardiac muscle increases with temperature. However, at temperatures above about 50°C, there is no further increase in the sound speed and the temperature coefficient may become slightly negative. For ablation therapy, an irreversible injury to tissue and a complete heart block occurs in the range of 48 to 50°C for a short period in accordance with the well-known Arrhenius equation. Using these two properties, we propose a potential tool to detect the moment when tissue damage occurs by using the reduced slope in the thermal strain curve as a function of heating time. We have illustrated the feasibility of this method initially using porcine myocardium in vitro. The method was further demonstrated in vivo, using a specially equipped ablation tip and an 11-MHz microlinear intracardiac echocardiography (ICE) array mounted on the tip of a catheter. The thermal strain curves showed a plateau, strongly suggesting that the temperature reached at least 50°C.
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2,334,234 |
The effects of atracurium on bispectral index (BIS) values in dogs anaesthetized with isoflurane.
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Balanced anaesthesia techniques employ specific drugs in addition to general anaesthetics. The potential effect of some of these drugs on the bispectral index (BIS) remains unclear. BIS seems to be unaffected by the administration of neuromuscular blockers while opioids may block nociceptive-induced BIS increases in anaesthetized humans. In this study, the effect of a single dose of atracurium on BIS values was assessed in dogs premedicated with morphine and anaesthetized with isoflurane (1 MAC). Fifteen female dogs undergoing elective ovariohysterectomy were employed. BIS values were recorded before and after the administration of atracurium. These values were then recorded again once the animals were surgically stimulated. The end tidal isoflurane concentration, cardiovascular and respiratory parameters were recorded through the study. Results show that the mean (±SD) BIS values decreased slightly, but significantly (P=0.033) from 67±8.42 to 65±5.84 after the administration of atracurium. Despite significant increase in heart rate and arterial pressure during the surgical phase, the mean BIS values were not modified by ovariohysterectomy. Atracurium appeared to have minimal clinical effect on the BIS in anaesthetized dogs.
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2,334,235 |
Awake caudal anesthesia for inguinal hernia operations: successful use in low birth weight neonates.
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Neonates with inguinal hernia face a relatively high risk of incarcerated hernia and bowel obstruction and this therefore requires surgical treatment. Complications following general anesthesia even for minor surgery are more common in low birth weight neonates than in term neonates. Caudal epidural anesthesia without adjunct general anesthesia has been recommended for neonates to reduce the risk of postoperative complications. The successful application of awake caudal anesthesia with levobupivacaine for inguinal hernia repair in 15 low birth weight neonates is reported. Single dose caudal epidural anesthesia was administered for inguinal hernia surgery to avoid complications associated with general anesthesia. Caudal block was performed with 2.5 mg/kg body weight (BW) levobupivacaine. Caudal anesthesia can be recommended as an effective technique for avoiding postoperative anesthetic complications in low birth weight neonates.
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2,334,236 |
Dual stem cell therapy after myocardial infarction acts specifically by enhanced homing via the SDF-1/CXCR4 axis.
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G-CSF based stem cell mobilization and stabilization of cardiac SDF-1 by DPP-IV-inhibition (dual stem cell therapy) improve heart function and survival after myocardial infarction. However, it is barely understood whether this new approach acts specifically through the SDF-1/CXCR4 axis, stimulation of resident cardiac stem cells and improved myocardial perfusion. Therefore, we aimed to clarify the role of the SDF1/CXCR4 axis with respect to the benefits of a dual stem cell based therapy.</AbstractText><AbstractText Label="METHODOLOGY/PRINCIPAL FINDINGS" NlmCategory="RESULTS">After surgically induced ligation of the LAD, SDF-1/CXCR4 interactions were specifically blocked by the CXCR4 receptor antagonist AMD3100 in G-CSF and Diprotin A treated C57BL/6 mice. G-CSF+DipA treated and non-treated animals served as controls. Because AMD3100 is known to mobilize bone marrow derived stem cells (BMCs) in high concentrations, the optimal dosage (1.25mg per kg body weight) sufficient to block CXCR4 without stimulating mobilization was established. AMD3100 treatment of G-CSF and Diprotin A stimulated mice significantly decreased myocardial homing of circulating stem cells (FACS analysis) and inverted the beneficial effects of (i) cardiac remodeling (histological analyses), (ii) heart function (Millar tip catheterization) and (iii) survival (Kaplan-Meier curves). G-CSF treatment in combination with DPP-IV inhibition enhanced neovascularization at the infarct border zone which was related to an improved myocardial blood flow as measured by SPECT. Moreover, dual stem cell treatment effectively stimulated the pool of resident cardiac stem cells (FACS) which was reversed by AMD3100 treatment.</AbstractText><AbstractText Label="CONCLUSIONS/SIGNIFICANCE" NlmCategory="CONCLUSIONS">Our data give final proof that homing through the SDF-1/CXCR-4 axis is essential for the success of dual stem cell therapy.</AbstractText>Copyright © 2011 Elsevier B.V. All rights reserved.</CopyrightInformation>
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Acute and residual interactive effects of repeated administrations of oral methamphetamine and alcohol in humans.
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Although methamphetamine and alcohol are commonly used together in a binge-like pattern, there is a dearth of empirical data investigating the repeated effects of this drug combination. The current study examined acute and residual mood, performance, and physiological effects of methamphetamine alone, alcohol alone, and the combination. Nine adult male volunteers completed this 20-day within-participant, residential laboratory study. During four 5-day blocks of sessions, participants were administered oral methamphetamine (0, 10 mg) combined with alcohol (0, 0.375, 0.75 g/kg) three times (day 2: AM, day 2: PM, and day 3: PM). Breath alcohol concentrations, cardiovascular, subjective, and cognitive/psychomotor performance effects were assessed before drug administration and repeatedly thereafter. Subjective and objective sleep measures were also assessed; residual effects were assessed on days 3-5 of each block. Following the first drug administration, the methamphetamine-alcohol combination produced greater elevations of heart rate and ratings of "good drug effect" compared to either drug alone. Methamphetamine attenuated alcohol-related performance decrements and feelings of intoxication, whereas alcohol attenuated methamphetamine-related sleep disruptions. By the third administration, many of these effects were significantly diminished, suggesting that participants developed tolerance. Few residual effects were observed. These data show that methamphetamine combined with alcohol produced a profile of effects that was different from the effects of either drug alone. The largely positive effects of the drug combination (i.e., greater euphoria, and fewer performance and sleep disruptions) might explain why these drugs are often used in combination.
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2,334,238 |
A variant of fibroblast growth factor receptor 2 (Fgfr2) regulates left-right asymmetry in zebrafish.
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Many organs in vertebrates are left-right asymmetrical located. For example, liver is at the right side and stomach is at the left side in human. Fibroblast growth factor (Fgf) signaling is important for left-right asymmetry. To investigate the roles of Fgfr2 signaling in zebrafish left-right asymmetry, we used splicing blocking morpholinos to specifically block the splicing of fgfr2b and fgfr2c variants, respectively. We found that the relative position of the liver and the pancreas were disrupted in fgfr2c morphants. Furthermore, the left-right asymmetry of the heart became random. Expression pattern of the laterality controlling genes, spaw and pitx2c, also became random in the morphants. Furthermore, lefty1 was not expressed in the posterior notochord, indicating that the molecular midline barrier had been disrupted. It was also not expressed in the brain diencephalon. Kupffer's vesicle (KV) size became smaller in fgfr2c morphants. Furthermore, KV cilia were shorter in fgfr2c morphants. We conclude that the fgfr2c isoform plays an important role in the left-right asymmetry during zebrafish development.
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2,334,239 |
Replicability and 40-year predictive power of childhood ARC types.
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We examined 3 questions surrounding the undercontrolled, overcontrolled, and resilient-or Asendorpf-Robins-Caspi (ARC)-personality types originally identified by Block (1971). In analyses of the teacher personality assessments of over 2,000 children in 1st through 6th grade in 1959-1967 and follow-up data on general and cardiovascular health outcomes in over 1,100 adults recontacted 40 years later, we found bootstrapped internal replication clustering suggesting that Big Five scores were best characterized by a tripartite cluster structure corresponding to the ARC types. This cluster structure was fuzzy rather than discrete, indicating that ARC constructs are best represented as gradients of similarity to 3 prototype Big Five profiles; ARC types and degrees of ARC prototypicality showed associations with multiple health outcomes 40 years later. ARC constructs were more parsimonious but, depending on the outcome, comparable or slightly worse classifiers than the dimensional Big Five traits. Forty-year incident cases of heart disease could be correctly identified with 67% accuracy by childhood personality information alone and stroke incidence with over 70% accuracy. Findings support the theoretical validity of ARC constructs, their treatment as continua of prototypicality rather than discrete categories, and the need for further understanding the robust predictive power of childhood personality for midlife health.
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2,334,240 |
Significant differences in global genomic DNA methylation by gender and race/ethnicity in peripheral blood.
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Reduced levels of global DNA methylation are associated with genomic instability and are independent predictors of cancer risk. Little is known about the environmental determinants of global DNA methylation in peripheral blood. We examined the association between demographic and lifestyle factors and levels of global leukocyte DNA methylation in 161 cancer-free subjects enrolled in the North Texas Healthy Heart Study aged 45-75 years in 2008. We used in-person interviews for demographics and lifestyle factors, a self-administrated Block food frequency questionnaire for diet, and bioelectrical impedance analysis and CT-scan for body composition. We measured genomic DNA methylation using bisulfite conversion of DNA and pyrosequencing for LINE-1. Body composition measures including body mass index, waist circumference, areas of subcutaneous fat and visceral fat, percent of fat mass and fat-free mass were not associated with global genomic DNA methylation after controlling the effect of age, gender and race/ethnicity. Instead, female gender was significantly associated with a reduced level of global methylation (β = -2.77, 95% CI: -4.33, -1.22). Compared to non-Hispanic whites, non-Hispanic blacks (β = -2.02, 95% CI: -3.55, -0.50) had significantly lower levels of global methylation. No association was found with age, cigarette smoking, alcohol drinking and dietary intake of nutrients in one-carbon metabolism. Global leukocyte DNA methylation differs by gender and race/ethnicity, suggesting these variables need to be taken into consideration in studies of global DNA methylation as an epigenetic marker for cancer.
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2,334,241 |
[Study on the relative specificity of the heart and lung meridians in brain with fMRI].
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To study the central modulation mechanism on the relative specificity of the Heart and Lung Meridians and to provide the experimental evidence for deeply study on correlation between meridian-viscera and brain.</AbstractText>Ten healthy students in Anhui College of TCM were chosen and a modified block design was adopted. After 32 time points of resting and 32 of rotation needling, then 48 of resting and 32 stimulating, and 16 resting time points, functional imagings were collected at last. All the process would last for 10 min 44 sec. Acupuncture work was finished by one acupuncturist with extensive experience by acupuncture at the left Shenmen (HT 7) or Taiyuan (LU 8) with the disposable sterile stainless steel needle, and uniform reinforcing-reducing method was used with frequency of 1 Hz and depth of 1.0 cm. After the experiment, the sensation of acupuncture and the other feeling or psychic process were inquired and recorded detailedly. These data were analyzed by AFNI software.</AbstractText>Acupuncture at Taiyuan (LU 8) could excite the contralateral frontal lobe, apical lobe, cerebral ganglion, VI, VIII areas and inferior semilunar lobule of cerebellum, and restrain bilateral callosal gyrus and homolateral gyrus rectus. Acupuncture at Shenmen (HT 7) could excite the contralateral IV-VIII areas of cerebellum, and homolateral VI, VII areas of cerebellum, and restrain parts of homolateral apical lobe.</AbstractText>Acupuncture at Shenmen (HT 7) of the Heart Meridian and Taiyuan (LU 8) of the Lung Meridian can excite or restrain different brain areas, indicating that there are relatively specific corresponding brain areas for the Heart Meridian and Lung Meridian.</AbstractText>
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2,334,242 |
Anti-Ro/SSA-associated corrected QT interval prolongation in adults: the role of antibody level and specificity.
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Recent evidence suggests that anti-Ro/SSA antibodies, strongly associated with the development of congenital heart block, may also be arrhythmogenic for the adult heart. In fact, anti-Ro/SSA-positive patients with connective tissue disease (CTD) frequently display corrected QT (QTc) prolongation associated with an increase in ventricular arrhythmias. However, QTc prolongation prevalence markedly differs throughout the studies (10-60%), but the reason why is not yet clear. The aim of this study was to evaluate whether anti-Ro/SSA-associated QTc prolongation in adult patients with CTD is related to antibody level and specificity.</AbstractText>Forty-nine adult patients with CTD underwent a resting 12-lead electrocardiogram recording to measure QTc interval, and a venous withdrawal to determine anti-Ro/SSA antibody level and specificity (anti-Ro/SSA 52 kd and anti-Ro/SSA 60 kd) by immunoenzymatic methods and Western blotting.</AbstractText>In our population, a direct correlation was demonstrated between anti-Ro/SSA 52-kd level and QTc duration (r = 0.38, P = 0.007), patients with a prolonged QTc had higher levels of anti-Ro/SSA 52 kd with respect to those with a normal QTc (P = 0.003), and patients with a moderate to high level (≥50 units/ml) of anti-Ro/SSA 52 kd showed a longer QTc interval (P = 0.008) and a higher QTc prolongation prevalence (P = 0.008) than those with a low positive/negative level (<50 units/ml). On the contrary, no association was found between QTc and anti-Ro/SSA 60-kd level.</AbstractText>In anti-Ro/SSA-positive adult patients with CTD, the occurrence of QTc prolongation seems strictly dependent on the anti-Ro/SSA 52-kd level. This finding, possibly explaining the different QTc prolongation prevalence reported, strengthens the hypothesis that an extremely specific autoimmune cross-reaction is responsible for the anti-Ro/SSA-dependent interference on ventricular repolarization.</AbstractText>Copyright © 2011 by the American College of Rheumatology.</CopyrightInformation>
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2,334,243 |
Role of sphenopalatine ganglion block for postoperative analgesia after functional endoscopic sinus surgery.
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The aim of this study was to evaluate the analgesic efficacy of sphenopalatine ganglion block performed under general anesthesia in patients undergoing functional endoscopic sinus surgery (FESS) with operative blood loss and postoperative complications (headache, visual disturbances, nausea, vomiting, sore throat, swallow difficulty). Forty-five consenting patients were randomized to receive bilateral sphenopalatine ganglion block with saline (Group S, n = 15), bupivacaine 0.5% (Group B, n = 15), or levobupivacaine 0.5% (Group L, n = 15) immediately following induction of general anesthesia. Esmolol was given during the intraoperative period for a 20% increase in arterial mean pressure or heart rate. Postoperative pain scores were checked on arrival at the postanesthesia care unit, 2, 6, and 24 h after surgery and diclofenac was administered intramuscularly for pain score ≥ 4. A statistically significant reduction was present in postoperative Visual Analog Scale scores between Group S and the block Groups B and L (p < 0.05). In Group L and B, fewer patients required additional analgesics in the postoperative 24 h (p < 0.0001). The comparison of postoperative complications was not statistically significant among the groups (p > 0.05). Sphenopalatine ganglion block with bupivacaine or levobupivacaine improved postoperative analgesia associated with better surgeon and patient satisfaction after FESS.
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2,334,244 |
A novel role of endothelin-1 in linking Toll-like receptor 7-mediated inflammation to fibrosis in congenital heart block.
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Autoimmune associated congenital heart block (CHB) may result from pathogenic cross-talk between inflammatory and profibrosing pathways. Incubation of macrophages with immune complexes (IC) composed of Ro60, a target of the pathologic maternal autoantibodies necessary for CHB, hY3 ssRNA, and affinity-purified anti-Ro60 antibody induces the Toll-like receptor 7 (TLR7)-dependent generation of supernatants that provoke a fibrosing phenotype in human fetal cardiac fibroblasts. We show herein that these cells are a major source of TGFβ and that endothelin-1 (ET-1) is one of the key components responsible for the profibrosing effects generated by stimulated macrophages. Supernatants from macrophages incubated with IC induced the fibroblast secretion of TGFβ, which was inhibited by treating the macrophages with an antagonist of TLR7. Under the same conditions, the induced fibroblast secretion of TGFβ was decreased by inhibitors of the ET-1 receptors ETa or ETb or by an anti-ET-1 antibody but not by an isotype control. Exogenous ET-1 induced a profibrosing phenotype, whereas fibroblasts transfected with either ETa or ETb siRNA were unresponsive to the profibrosing effects of the IC-generated macrophage supernatants. Immunohistochemistry of the hearts from two fetuses dying with CHB revealed the presence of ET-1-producing mononuclear cells in the septal region in areas of calcification and fibrosis. In conclusion, these data support a novel role of ET-1 in linking TLR7 inflammatory signaling to subsequent fibrosis and provide new insight in considering therapeutics for CHB.
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2,334,245 |
Evidence for Trypanosoma cruzi in adipose tissue in human chronic Chagas disease.
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Trypanosoma cruzi the cause of Chagas disease persists in tissues of infected experimental animals and humans. Here we demonstrate the persistence of the parasite in adipose tissue from of three of 10 elderly seropositive patients with chronic chagasic heart disease. Nine control patients had no parasites in the fat. We also demonstrate that T. cruzi parasitizes primary adipocytes in vitro. Thus, in humans as in mice the parasite may persist in adipose tissue for decades and become a reservoir of infection.
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2,334,246 |
Cardiac valve calcification is a marker of vascular disease in prevalent hemodialysis patients.
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Vascular and valvular calcifications are a common finding in chronic kidney disease (CKD) patients and are associated with increased morbidity and mortality. We investigated the hypothesis that calcification of the cardiac valves is a marker of coronary artery calcification (CAC) and thoracic aorta calcification (AoC) in hemodialysis (CKD-5) patients.</AbstractText>This was a cross-sectional study of 145 maintenance CKD stage 5 (CKD-5) patients. All patients underwent electron beam tomography for quantification of CAC and AoC score via the Agatston score. The presence of calcification of the cardiac valves was assessed by standard bi-dimensional echocardiography.</AbstractText>Eighty-four of the study patients (58%) had echocardiographic evidence of valvular calcification. A significant and graded association between valvular calcification and CAC as well as AoC was detected. Patients with 1 or 2 calcified valves had a significantly greater likelihood of having a CAC score >1,000 (odds ratio [OR] = 5.94; 95% confidence interval [95% CI], 1.91-18.44; p=0.002; and OR=3.27; 95%CI, 1.36-7.88; p=0.007, respectively). Similarly, the presence of 1 or 2 calcified valves was associated with an eightfold and threefold increased probability of an AoC score greater than the third quartile, respectively.</AbstractText>This cross-sectional analysis shows that calcification of the cardiac valves is closely associated with vascular calcification, an established marker of risk in prevalent hemodialysis patients.</AbstractText>
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2,334,247 |
Cardiovascular alterations heralded by intrathecal baclofen bolus.
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We describe two patients in whom serious bradycardia and arterial hypotension occurred after a small intrathecal baclofen (ITB) test bolus. Both patients suffered from severe spasticity (one due to brain injury, one due to spinal cord injury). Medical history and diagnostic examinations revealed no previous cardiological problems. Ten minutes following a 50 μg ITB bolus, patient 1 developed bradycardia (58 bpm) and incomplete right branch block, lasting for 3 hours. In patient 2, a 20 μg ITB bolus was followed after 5 minutes by severe bradycardia (30 bpm) and hypotension (60/30 mmHg), without loss of consciousness, lasting for 10 minutes. Exaggerated muscle tone was alleviated in both patients after 2 hours by the applied doses. Neither patient underwent implantation of a permanent pump system, both were continued on oral baclofen. Despite numerous unremarkable repeat cardiological exams, both patients suffered fatal cardiac arrest one and two months later, respectively. Our observations suggest that ITB may herald cardiovascular dysfunction in predisposed patients. Careful cardiological examination before ITB treatment, and close monitoring during ITB testing in particular, is advised.
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2,334,248 |
Relative contribution of changes in sodium current versus intercellular coupling on reentry initiation in 2-dimensional preparations of plakophilin-2-deficient cardiac cells.
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Loss of expression of the desmosomal protein plakophilin-2 (PKP2) leads to decreased gap junction-mediated (GJ) coupling, and alters the amplitude and kinetics of sodium current in cardiac myocytes. Whether these modifications, alone or in combination, are sufficient to act as arrhythmogenic substrates remains undefined.</AbstractText>This study sought to characterize arrhythmia susceptibility and reentry dynamics consequent to loss of PKP2 expression, and to assess the relative contribution of cell uncoupling versus alterations in sodium current in generation of reentry.</AbstractText>Monolayers of neonatal rat ventricular myocytes were treated with oligonucleotides that either prevented or failed to prevent PKP2 expression. Numerical simulations modeled experimentally observed modifications in I(Na), GJ coupling, or both (models PKP2-Na, PKP2-GJ, and PKP2-KD, respectively). Relative roles of sodium current density versus kinetics were further explored.</AbstractText>Loss of PKP2 expression increased incidence of rotors and decreased frequency of rotation. Mathematical simulations revealed that single premature stimuli initiated rotors in models PKP2-Na and PKP2-KD, but not PKP2-GJ. Changes in sodium current kinetics, rather than current density, were key to reentry initiation. Anatomical barriers led to vortex shedding, wavebreaks, and rotors when I(Na) kinetics, but not GJ coupling or I(Na) density, were altered.</AbstractText>PKP2-dependent changes in sodium current kinetics lead to slow conduction, increased propensity to functional block, and vortex shedding. Changes in GJ or I(Na) density played only a minor role on reentry susceptibility. Changes in electrical properties of the myocyte caused by loss of expression of PKP2 can set the stage for rotors even if anatomical homogeneity is maintained.</AbstractText>Copyright © 2011 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.</CopyrightInformation>
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2,334,249 |
Reentrant excitation in an analog-digital hybrid circuit model of cardiac tissue.
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We propose an analog-digital hybrid circuit model of one-dimensional cardiac tissue with hardware implementation that allows us to perform real-time simulations of spatially conducting cardiac action potentials. Each active nodal compartment of the tissue model is designed using analog circuits and a dsPIC microcontroller, by which the time-dependent and time-independent nonlinear current-voltage relationships of six types of ion channel currents employed in the Luo-Rudy phase I (LR-I) model for a single mammalian cardiac ventricular cell can be reproduced quantitatively. Here, we perform real-time simulations of reentrant excitation conduction in a ring-shaped tissue model that includes eighty nodal compartments. In particular, we show that the hybrid tissue model can exhibit real-time dynamics for initiation of reentries induced by uni-directional block, as well as those for phase resetting that leads to annihilation of the reentry in response to impulsive current stimulations at appropriate nodes and timings. The dynamics of the hybrid model are comparable to those of a spatially distributed tissue model with LR-I compartments. Thus, it is conceivable that the hybrid model might be a useful tool for large scale simulations of cardiac tissue dynamics, as an alternative to numerical simulations, leading toward further understanding of the reentrant mechanisms.
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2,334,250 |
Spinal anaesthesia in paediatric patients undergoing surgery of sub umbilical region of the body.
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The use of spinal anaesthesia in infants and children requiring surgeries of sub umbilical region is gaining considerable popularity worldwide. But in our setups in South Asia. this technique has not gained popularity yet. The objective of this prospective study was to evaluate the haemodynamic and respiratory safety of spinal anaesthesia in infants and children.</AbstractText>In our study, 66 paediatric patients of age ranging from 6 months to 10 years of either sex, ASA I and II, undergoing surgeries of sub umbilical regions were included. Spinal anaesthesia was administered with Quincke 25 gauge needles at L3-L4 and L4-L5 space in the lateral decubitus position after premedication. Mean Arterial Blood Pressure (MAP), Heart rate, Sp(O2), duration of surgery and attempts of spinal block were the data recorded.</AbstractText>Out of the 66 patients, intra-operative Mean Arterial Blood Pressure (MAP) was normal in 65 (98.5%) of the patients. Heart rate was increased in 57 (86.4%) patients, intra operatively. Pulse oximetery was normal during surgery in all the children. Duration of surgery was less than one hour in 48 (72.7%) patients and it was between 1-2 hours in 18 (27.3%) of the patients. Feasibility in the form of attempts was first in 37 patients and second in 29 patients.</AbstractText>The ease of performance and the safety regarding cardio- respiratory functions makes spinal anaesthesia as an alternative to general anaesthesia in infants and children undergoing surgeries of sub umbilical regions.</AbstractText>
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2,334,251 |
Life threatening hyperkalemia chronic kidney diseases patients treated with trimethoprim-sulfamethoxazole: a case series.
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We report a case series of patients that develop severe life threatening hyperkalemia after use of a commonly prescribe oral antibiotic, Trimethoprim-Sulfamethoxazole. The three patients required acute hemodialysis to normalize serum potassium levels after development of hypotension and heart block due to hyperkalemia. All had preexisting chronic kidney disease. Some of them were on medications that interfere with the effects of aldosterone. Patients with chronic kidney disease, particularly those receiving other medications that may also contribute to the development of hyperkalemia, should be closely monitored for this complication when Trimethoprim-containing antibiotic is needed. In these cases, other antibiotic therapy alternatives should be considered.
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2,334,252 |
Intravenous fentanyl during shoulder arthroscopic surgery in the sitting position after interscalene block increases the incidence of episodes of bradycardia hypotension.
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Episodes of bradycardia hypotension (BH) or vasovagal syncope have a reported incidence of 13-29% during arthroscopic shoulder surgery in the sitting position after an interscalene block (ISB). This study was designed to investigate whether intravenous fentanyl during shoulder arthroscopy in the sitting position after ISB would increase or worsen the incidence of BH episodes.</AbstractText>In this prospective study, 20 minutes after being in a sitting position, 160 patients who underwent ISB were randomized to receive saline (S, n = 40), 50 µg of fentanyl (F-50, n = 40), 100 µg of fentanyl (F-100, n = 40) or 30 mg of ketorolac (K-30, n = 40) randomly. We assessed the incidence of BH episodes during the operation and the degree of maximal reduction (Rmax) of blood pressure (BP) and heart rate (HR).</AbstractText>The incidence of BH episodes was 10%, 15%, 27.5% and 5% in the S, F-50, F-100 and K-30 groups, respectively. Mean Rmax of systolic BP in the F-100 group was significantly decreased as compared to the S group (-20.0 ± 4.5 versus -6.3 ± 1.6%, P = 0.004). Similarly, mean Rmax of diastolic BP in the F-100 group was also significantly decreased (P = 0.008) as compared to the S group.</AbstractText>These results suggest that fentanyl can increase the incidence of BH episodes during shoulder arthroscopic surgery in the sitting position after ISB.</AbstractText>
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2,334,253 |
Partial-thickness rotator cuff tears.
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Although the incidence of partial-thickness rotator cuff tears (PTRCTs) was reported to be from 13% to 32% in cadaveric studies, the actual incidence is not yet known. The causes of PTRCTs can be explained by either extrinsic or intrinsic theories. Studies suggest that intrinsic degeneration within the rotator cuff is the principal factor in the pathogenesis of rotator cuff tears. Extrinsic causes include subacromial impingement, acute traumatic events, and repetitive microtrauma. However, acromially initiated rotator cuff pathology does not occur and extrinsic impingement does not cause pathology on the articular side of the tendon. An arthroscopic classification system has been developed based on the location and depth of the tear. These include the articular, bursal, and intratendinous areas. Both ultrasound and magnetic resonance image are reported with a high accuracy of 87%. Conservative treatment, such as subacromial or intra-articular injections and suprascapular nerve block with or without block of the articular branches of the circumflex nerve, should be considered prior to operative treatment for PTRCTs.
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2,334,254 |
Preliminary finding on a new calcium channel entry blocker chemotype: 5,6-diamino-4-hydroxy-2-mercaptopyrimidine derivatives.
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We report the preliminary in vitro characterization of a series of pyrimidines as a new chemotype that modulates cardiovascular parameters and relaxes ileum smooth muscle according to classical calcium entry blockers. Tested compounds showed an interesting negative inotropic selectivity. In patch-clamp experiments they block L- over T-type calcium currents. Two requisites seem essential for the activity: lipophilic substituents in positions 2 and 5 of the pyrimidine ring and the acetamidic function in position 6.
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2,334,255 |
Eomesodermin, HAND1, and CSH1 proteins are induced by cellular stress in a stress-activated protein kinase-dependent manner.
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Eomesodermin (Eomes) is a transcription factor essential for trophoblast development. Stress stimuli activate stress-activated protein kinase (MAPK8/9) and modulate transcription factors in trophoblast stem cells (TSC). In this study, we test the hypothesis that stress-induced Eomes upregulation and downstream trophoblast development are MAPK8/9-dependent. Immunocytochemical and immunoblot assays suggest that Eomes is induced by hyperosmolar stress in a dose- and time-dependent manner. Two MAPK8/9 inhibitors that work by different mechanisms, LJNKl1 and SP600125, block induction of Eomes protein by stress. During normal TSC differentiation, the transcription factor heart and neural crest derivatives expressed 1 (HAND1) is dependent on Eomes, and chorionic somatomammotropin hormone 1 (CSH1) expression is dependent on HAND1. Similar to Eomes, HAND1 and CSH1 induction by stress are MAPK8/9-dependent, and CSH1 is induced in nearly all stressed TSC. CSH1 induction normally requires downregulation of the transcription factor inhibitor of differentiation 2 (ID2) as well as HAND1 upregulation. It was shown previously that hyperosmolar stress induces AMP-activated protein kinase (PRKAA1/2)-dependent ID2 loss in a MAPK8/9-independent manner. Inhibition of PRKAA1/2 with compound C and LJNKl1, more than MAPK8/9 inhibitors alone, inhibits the induction of CSH1 by stress. Taken together these data suggest that stress-induced MAPK8/9 and PRKAA1/2 regulate transcription factors Eomes/HAND1 and ID2, respectively. Together this network mediates induction of CSH1 by stress. Therefore, stress triggers a proportional increase in a normal early TSC differentiation event that could be adaptive in inducing CSH1. But the flexibility of TSC to undergo stress-induced differentiation could lead to pathophysiological consequences if stress endured and TSC differentiation became unbalanced.
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2,334,256 |
Quantification of repolarization reserve to understand interpatient variability in the response to proarrhythmic drugs: a computational analysis.
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"Repolarization reserve" is frequently invoked to explain why potentially proarrhythmic drugs cause, across a population, a range of changes to cardiac action potentials (APs). However, the mechanisms underlying this interindividual variability are not understood quantitatively.</AbstractText>The purpose of this study was to perform a novel analysis of mathematical models of ventricular myocytes to quantify repolarization reserve and gain insight into the factors responsible for variability in the response to proarrhythmic drugs.</AbstractText><AbstractText Label="METHODS/RESULTS" NlmCategory="RESULTS">In several models of human or canine ventricular myocytes, variability was simulated by randomizing model parameters and running repeated simulations. With each randomly generated set of parameters, APs before and after simulated 75% block of the rapid delayed rectifier current (I(Kr)) were calculated. Multivariable regression was performed to determine how much each model parameter attenuated or exacerbated the AP prolongation caused by the I(Kr)-blocking drug. Simulations with a human ventricular myocyte model suggest that drug response is influenced most strongly by (1) the density of I(Kr), (2) the density of slow delayed rectifier current I(Ks), (3) the voltage dependence of I(Kr) inactivation, (4) the density of L-type Ca2+ current, and (5) the kinetics of I(Ks) activation. The analysis also identified mechanisms underlying nonintuitive behavior, such as ionic currents that prolong baseline APs but decrease drug-induced AP prolongation. Finally, the simulations provided quantitative insight into conditions that aggravate the drug response, such as silent ion channel mutations and heart failure.</AbstractText>These modeling results provide the first thorough quantification of repolarization reserve and improve our understanding of interindividual variability in adverse drug reactions.</AbstractText>Copyright © 2011 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.</CopyrightInformation>
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2,334,257 |
Mid-scale free-flow electrophoresis with gravity-induced uniform flow of background buffer in chamber for the separation of cells and proteins.
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A large-scale free-flow electrophoresis (LS-FFE) is often too large for cell separation of lab scale, whereas micro-FFE (μFFE) has great difficulty in cell isolation due to easy blockage by cell accumulation in μFFE. In this study, a mid-scale FFE (MS-FFE) is developed for cell and protein separations. The volume of the separation chamber (70×40×0.1-0.8 mm) is from 280 μL to 2.24 mL, much lower than that in an LS-FFE but higher than that in a μFFE. Gravity is used for uniform flow of the background buffer only via a single pump with 16 channels and the sample is injected via an adjuster originally used for clinical intravenous injection. The experiments reveal that the hydrodynamic and electrohydrodynamic flows are much stable, and the Joule heat can be effectively dispersed without obvious positive or negative deviation as shown by the omega plots. By the device, Escherichia coli and Staphylococcus aureus, which easily accumulate to block μFFE and are separated with difficulty due to their same negative charges carried, can be well isolated under the conditions of 4.5 mM pH 8.5 Tris-boric buffer (4.5 mM Tris, 4.5 mM boric acid) with 0.10 mM ethylene diamine tetraacetic acid and 5% m/v sucrose, 200 μL/min, 800 V, and sample injection via inlet 4. The mid-scale FFE device could also be used for the separation of three model proteins of horse heart cytochrome c, myoglobin and bovine serum albumin. The device has clear significance for mid-scale separation of cells and proteins.
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2,334,258 |
Sugammadex, a promising reversal drug. A review of clinical trials.
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According to published data, sugammadex, rapidly reverses (2-5 min) shallow and profound NM block induced by rocuronium and vecuronium, without being connected with serious adverse events. It is accepted that in order to reverse shallow block, the suggested dose of sugammadex comes up to 2 mg/kg. Profound level of NM block demands 4 mg/kg in order to defy few responses at the post titanic count. Doses of sugammadex lower than 1 mg/kg may lead to rebound of rocuronium's effect. Higher doses of sugammadex (12 16 mg/g) are used in rescue reversal. In children and adolescents the 2 mg/kg dose is both effective and well tolerated, while, to date, data regarding infants are scarce. In patients with renal failure, 2 mg/kg of sugammadex resulted in a mean time to recovery of TOF ratio to 0.9 in 2 min, which was quicker than the time of reversal by acetylcholinesterase inhibitors. Investigations in cardiac patients undergoing noncardiac surgery suggest that 2 and 4 mg/kg of sugammadex are both safe and effective. Compared with neostigmine, sugammadex has no need to use muscarinic antagonists and therefore is not associated with variations in heart rate. Trials indicate that sugammadex acts faster than edrophonium and neostigmine. Sugammadex is a promising, well tolerated agent that enables fast reversal in different depths of NM block -shallow and profound- and in different patients populations. After completion of trial probation and settlement of issues concerning estimated cost and cost impact, it is believed to play a leading part in future anesthesiology.
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2,334,259 |
Toll-like receptor 4/nuclear factor-kappa B pathway is involved in myocardial injury in a rat chronic stress model.
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Chronic stress is considered to predispose to various cardiovascular events such as coronary artery disease, hypertension, and even heart failure. In this study, rats were exposed to stress for 1 day, 1, 2, 3, and 4 weeks to establish a chronic stress model. A specific toll-like receptor 4 (TLR4) antagonist eritoran was used to block the activity of TLR4. On the second day after the last stress exposure, the animals were killed. The expression of TLR4 mRNA and nuclear factor-kappa B (NF-κB) DNA-binding activity in the myocardium were measured using reverse transcriptase polymerase chain reaction and electrophoretic mobility shift assay. The proinflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL-6) in myocardium were assayed by enzyme-linked immunosorbent assay. Myocardial injury was evident after chronic stress for 2 weeks. The TLR4 mRNA expression reached a peak after stress for 1 week. It was sustained at a stable level after stress exposure for 3 weeks and was restored to a nearly normal level in the fourth week. NF-κB DNA-binding activity was significantly enhanced after the stress for 1 day and markedly enhanced again after a 2-week stress exposure. It was weakened and reached a normal level after stress exposure for 4 weeks. The levels of TNF-α and IL-6 gradually increased and reached peaks after stress for 4 weeks. Meanwhile, eritoran significantly decreased the TLR4 mRNA expression and NF-κB activity in rats from the 2-week stress group. However, it did not downregulate the levels of TNF-α and IL-6. Importantly, it significantly improved the myocardial injury induced by the chronic stress. In conclusion, TLR4/NF-κB participates in myocardial injury during chronic stress.
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2,334,260 |
The effect of the sitting upright or 'beachchair' position on cerebral blood flow during anaesthesia for shoulder surgery.
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The sitting upright or 'beachchair' position is commonly used for shoulder arthroscopic surgery. There is a theoretical concern that anaesthetised patients placed in this posture are at risk of reduced cerebral blood flow (CBF), especially if there is associated hypotension. This study investigated the effect of anaesthetic-induced hypotension on estimated cerebral blood flow in patients placed in the beachchair position for shoulder surgery. Forty patients were randomised to either sedation (propofol infusion 10 to 20 mg x hour 1, n = 20) or general anaesthesia using sub minimum alveolar concentration of sevoflurane (n = 20). All patients received an interscalene brachial plexus regional block. Internal carotid artery blood flow was measured using the time averaged velocity of the spectral Doppler waveform, and was then used as an estimate of global CBF. Following a pre-anaesthesia study, measurement of internal carotid artery blood flow was made before and after beachchair positioning, and at five-minute intervals during surgery. Beachchair positioning during general anaesthesia significantly decreased the mean arterial pressure (34 +/- 10 mmHg) compared to sedation (4 +/- 2 mmHg, P < 0.01), and vasopressor therapy was required more often. However, CBF remained constant in both anaesthetised (P = 0.83) and sedated patients (P = 0.68) despite beachchair positioning, and the fall in mean arterial pressure in the anaesthetised patients. There was no significant difference in CBF between groups (P = 0.91). These findings indicate that in patients in the beachchair position receiving sevoflurane anaesthesia, CBF is maintained when mean arterial pressure is above 70 mmHg, consistent with intact autoregulation.
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Multiple phenotypes in adult mice following inactivation of the Coxsackievirus and Adenovirus Receptor (Car) gene.<Pagination><StartPage>e20203</StartPage><MedlinePgn>e20203</MedlinePgn></Pagination><ELocationID EIdType="pii" ValidYN="Y">e20203</ELocationID><ELocationID EIdType="doi" ValidYN="Y">10.1371/journal.pone.0020203</ELocationID><Abstract><AbstractText>To determine the normal function of the Coxsackievirus and Adenovirus Receptor (CAR), a protein found in tight junctions and other intercellular complexes, we constructed a mouse line in which the CAR gene could be disrupted at any chosen time point in a broad spectrum of cell types and tissues. All knockouts examined displayed a dilated intestinal tract and atrophy of the exocrine pancreas with appearance of tubular complexes characteristic of acinar-to-ductal metaplasia. The mice also exhibited a complete atrio-ventricular block and abnormal thymopoiesis. These results demonstrate that CAR exerts important functions in the physiology of several organs in vivo.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Pazirandeh</LastName><ForeName>Ahmad</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Ludwig Institutet for Cancer Research, Stockholm Branch, Stockholm, Sweden.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Sultana</LastName><ForeName>Taranum</ForeName><Initials>T</Initials></Author><Author ValidYN="Y"><LastName>Mirza</LastName><ForeName>Momina</ForeName><Initials>M</Initials></Author><Author ValidYN="Y"><LastName>Rozell</LastName><ForeName>Björn</ForeName><Initials>B</Initials></Author><Author ValidYN="Y"><LastName>Hultenby</LastName><ForeName>Kjell</ForeName><Initials>K</Initials></Author><Author ValidYN="Y"><LastName>Wallis</LastName><ForeName>Karin</ForeName><Initials>K</Initials></Author><Author ValidYN="Y"><LastName>Vennström</LastName><ForeName>Björn</ForeName><Initials>B</Initials></Author><Author ValidYN="Y"><LastName>Davis</LastName><ForeName>Ben</ForeName><Initials>B</Initials></Author><Author ValidYN="Y"><LastName>Arner</LastName><ForeName>Anders</ForeName><Initials>A</Initials></Author><Author ValidYN="Y"><LastName>Heuchel</LastName><ForeName>Rainer</ForeName><Initials>R</Initials></Author><Author ValidYN="Y"><LastName>Löhr</LastName><ForeName>Matthias</ForeName><Initials>M</Initials></Author><Author ValidYN="Y"><LastName>Philipson</LastName><ForeName>Lennart</ForeName><Initials>L</Initials></Author><Author ValidYN="Y"><LastName>Sollerbrant</LastName><ForeName>Kerstin</ForeName><Initials>K</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2011</Year><Month>06</Month><Day>03</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>PLoS One</MedlineTA><NlmUniqueID>101285081</NlmUniqueID><ISSNLinking>1932-6203</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C568772">CLMP protein, mouse</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D062727">Coxsackie and Adenovirus Receptor-Like Membrane Protein</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D011991">Receptors, Virus</NameOfSubstance></Chemical><Chemical><RegistryNumber>094ZI81Y45</RegistryNumber><NameOfSubstance UI="D013629">Tamoxifen</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D054537" MajorTopicYN="N">Atrioventricular Block</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D001284" MajorTopicYN="N">Atrophy</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D001522" MajorTopicYN="N">Behavior, Animal</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D062727" MajorTopicYN="N">Coxsackie and Adenovirus Receptor-Like Membrane Protein</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005298" MajorTopicYN="N">Fertility</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D055786" MajorTopicYN="N">Gene Knockout Techniques</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D020868" MajorTopicYN="Y">Gene Silencing</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D007413" MajorTopicYN="N">Intestinal Mucosa</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D007422" MajorTopicYN="N">Intestines</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName><QualifierName UI="Q000473" MajorTopicYN="N">pathology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D051379" MajorTopicYN="N">Mice</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D009043" MajorTopicYN="N">Motor Activity</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D046790" MajorTopicYN="N">Pancreas, Exocrine</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName><QualifierName UI="Q000473" MajorTopicYN="N">pathology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D010641" MajorTopicYN="Y">Phenotype</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D011991" MajorTopicYN="N">Receptors, Virus</DescriptorName><QualifierName UI="Q000172" MajorTopicYN="Y">deficiency</QualifierName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D013629" MajorTopicYN="N">Tamoxifen</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D013950" MajorTopicYN="N">Thymus Gland</DescriptorName><QualifierName UI="Q000166" MajorTopicYN="N">cytology</QualifierName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading></MeshHeadingList><CoiStatement><b>Competing Interests: </b>The authors have declared that no competing interests exist.</CoiStatement></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2011</Year><Month>1</Month><Day>4</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2011</Year><Month>4</Month><Day>27</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2011</Year><Month>6</Month><Day>16</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2011</Year><Month>6</Month><Day>16</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2011</Year><Month>10</Month><Day>1</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">21674029</ArticleId><ArticleId IdType="pmc">PMC3108585</ArticleId><ArticleId IdType="doi">10.1371/journal.pone.0020203</ArticleId><ArticleId IdType="pii">PONE-D-11-00711</ArticleId></ArticleIdList><ReferenceList><Reference><Citation>Coyne CB, Bergelson JM. 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To determine the normal function of the Coxsackievirus and Adenovirus Receptor (CAR), a protein found in tight junctions and other intercellular complexes, we constructed a mouse line in which the CAR gene could be disrupted at any chosen time point in a broad spectrum of cell types and tissues. All knockouts examined displayed a dilated intestinal tract and atrophy of the exocrine pancreas with appearance of tubular complexes characteristic of acinar-to-ductal metaplasia. The mice also exhibited a complete atrio-ventricular block and abnormal thymopoiesis. These results demonstrate that CAR exerts important functions in the physiology of several organs in vivo.</Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Pazirandeh</LastName><ForeName>Ahmad</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Ludwig Institutet for Cancer Research, Stockholm Branch, Stockholm, Sweden.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Sultana</LastName><ForeName>Taranum</ForeName><Initials>T</Initials></Author><Author ValidYN="Y"><LastName>Mirza</LastName><ForeName>Momina</ForeName><Initials>M</Initials></Author><Author ValidYN="Y"><LastName>Rozell</LastName><ForeName>Björn</ForeName><Initials>B</Initials></Author><Author ValidYN="Y"><LastName>Hultenby</LastName><ForeName>Kjell</ForeName><Initials>K</Initials></Author><Author ValidYN="Y"><LastName>Wallis</LastName><ForeName>Karin</ForeName><Initials>K</Initials></Author><Author ValidYN="Y"><LastName>Vennström</LastName><ForeName>Björn</ForeName><Initials>B</Initials></Author><Author ValidYN="Y"><LastName>Davis</LastName><ForeName>Ben</ForeName><Initials>B</Initials></Author><Author ValidYN="Y"><LastName>Arner</LastName><ForeName>Anders</ForeName><Initials>A</Initials></Author><Author ValidYN="Y"><LastName>Heuchel</LastName><ForeName>Rainer</ForeName><Initials>R</Initials></Author><Author ValidYN="Y"><LastName>Löhr</LastName><ForeName>Matthias</ForeName><Initials>M</Initials></Author><Author ValidYN="Y"><LastName>Philipson</LastName><ForeName>Lennart</ForeName><Initials>L</Initials></Author><Author ValidYN="Y"><LastName>Sollerbrant</LastName><ForeName>Kerstin</ForeName><Initials>K</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2011</Year><Month>06</Month><Day>03</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>PLoS One</MedlineTA><NlmUniqueID>101285081</NlmUniqueID><ISSNLinking>1932-6203</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C568772">CLMP protein, mouse</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D062727">Coxsackie and Adenovirus Receptor-Like Membrane Protein</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D011991">Receptors, Virus</NameOfSubstance></Chemical><Chemical><RegistryNumber>094ZI81Y45</RegistryNumber><NameOfSubstance UI="D013629">Tamoxifen</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D054537" MajorTopicYN="N">Atrioventricular Block</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D001284" MajorTopicYN="N">Atrophy</DescriptorName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D001522" MajorTopicYN="N">Behavior, Animal</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D062727" MajorTopicYN="N">Coxsackie and Adenovirus Receptor-Like Membrane Protein</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005298" MajorTopicYN="N">Fertility</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D055786" MajorTopicYN="N">Gene Knockout Techniques</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D020868" MajorTopicYN="Y">Gene Silencing</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D007413" MajorTopicYN="N">Intestinal Mucosa</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D007422" MajorTopicYN="N">Intestines</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName><QualifierName UI="Q000473" MajorTopicYN="N">pathology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D051379" MajorTopicYN="N">Mice</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D009043" MajorTopicYN="N">Motor Activity</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D046790" MajorTopicYN="N">Pancreas, Exocrine</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName><QualifierName UI="Q000473" MajorTopicYN="N">pathology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D010641" MajorTopicYN="Y">Phenotype</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D011991" MajorTopicYN="N">Receptors, Virus</DescriptorName><QualifierName UI="Q000172" MajorTopicYN="Y">deficiency</QualifierName><QualifierName UI="Q000235" MajorTopicYN="Y">genetics</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D013629" MajorTopicYN="N">Tamoxifen</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D013950" MajorTopicYN="N">Thymus Gland</DescriptorName><QualifierName UI="Q000166" MajorTopicYN="N">cytology</QualifierName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading></MeshHeadingList><CoiStatement><b>Competing Interests: </b>The authors have declared that no competing interests exist.</CoiStatement></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2011</Year><Month>1</Month><Day>4</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2011</Year><Month>4</Month><Day>27</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2011</Year><Month>6</Month><Day>16</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2011</Year><Month>6</Month><Day>16</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2011</Year><Month>10</Month><Day>1</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">21674029</ArticleId><ArticleId IdType="pmc">PMC3108585</ArticleId><ArticleId IdType="doi">10.1371/journal.pone.0020203</ArticleId><ArticleId IdType="pii">PONE-D-11-00711</ArticleId></ArticleIdList><ReferenceList><Reference><Citation>Coyne CB, Bergelson JM. 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Mol Ther. 2008;16:1937–1943.</Citation><ArticleIdList><ArticleId IdType="pubmed">18813278</ArticleId></ArticleIdList></Reference></ReferenceList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">21673649</PMID><DateCompleted><Year>2011</Year><Month>08</Month><Day>30</Day></DateCompleted><DateRevised><Year>2021</Year><Month>10</Month><Day>20</Day></DateRevised><Article PubModel="Electronic"><Journal><ISSN IssnType="Electronic">1940-087X</ISSN><JournalIssue CitedMedium="Internet"><Issue>52</Issue><PubDate><Year>2011</Year><Month>Jun</Month><Day>07</Day></PubDate></JournalIssue><Title>Journal of visualized experiments : JoVE</Title><ISOAbbreviation>J Vis Exp</ISOAbbreviation></Journal><ArticleTitle>Coronary artery ligation and intramyocardial injection in a murine model of infarction.</ArticleTitle><ELocationID EIdType="pii" ValidYN="Y">2581</ELocationID><ELocationID EIdType="doi" ValidYN="Y">10.3791/2581</ELocationID><Abstract>Mouse models are a valuable tool for studying acute injury and chronic remodeling of the myocardium in vivo. With the advent of genetic modifications to the whole organism or the myocardium and an array of biological and/or synthetic materials, there is great potential for any combination of these to assuage the extent of acute ischemic injury and impede the onset of heart failure pursuant to myocardial remodeling. Here we present the methods and materials used to reliably perform this microsurgery and the modifications involved for temporary (with reperfusion) or permanent coronary artery occlusion studies as well as intramyocardial injections. The effects on the heart that can be seen during the procedure and at the termination of the experiment in addition to histological evaluation will verify efficacy. Briefly, surgical preparation involves anesthetizing the mice, removing the fur on the chest, and then disinfecting the surgical area. Intratracheal intubation is achieved by transesophageal illumination using a fiber optic light. The tubing is then connected to a ventilator. An incision made on the chest exposes the pectoral muscles which will be cut to view the ribs. For ischemia/reperfusion studies, a 1 cm piece of PE tubing placed over the heart is used to tie the ligature to so that occlusion/reperfusion can be customized. For intramyocardial injections, a Hamilton syringe with sterile 30 gauge beveled needle is used. When the myocardial manipulations are complete, the rib cage, the pectoral muscles, and the skin are closed sequentially. Line block analgesia is effected by 0.25% marcaine in sterile saline which is applied to muscle layer prior to closure of the skin. The mice are given a subcutaneous injection of saline and placed in a warming chamber until they are sternally recumbent. They are then returned to the vivarium and housed under standard conditions until the time of tissue collection. At the time of sacrifice, the mice are anesthetized, the heart is arrested in diastole with KCl or BDM, rinsed with saline, and immersed in fixative. Subsequently, routine procedures for processing, embedding, sectioning, and histological staining are performed. Nonsurgical intubation of a mouse and the microsurgical manipulations described make this a technically challenging model to learn and achieve reproducibility. These procedures, combined with the difficulty in performing consistent manipulations of the ligature for timed occlusion(s) and reperfusion or intramyocardial injections, can also affect the survival rate so optimization and consistency are critical.
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Effect of carotid sinus nerve blockade on hemodynamic stability during carotid endarterectomy under local anesthesia.
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To find out whether routine carotid sinus nerve blockade with lidocaine during carotid endarterectomy under local anesthesia results in perioperative changes in blood pressure and heart rate.</AbstractText>This was a prospective, randomized, single-center study, conducted in a university hospital. A total of 120 patients undergoing carotid endarterectomy under local anesthesia were randomly assigned to three equal groups. Patients with previous carotid endarterectomy were excluded from the study. During the operation the carotid sinus area was infiltrated as follows: group 1 received 2 mL of 1% lidocaine; group 2 received 2 mL of 0.9% NaCl; and group 3 received no infiltration. The carotid sinus nerve was spared in all patients. Blood pressure and heart rate were invasively monitored during the operation and 12 hours postoperatively over the radial artery cannula. Preoperative values were calculated as a mean of three noninvasive measurements on the day before surgery. Data comprised of arterial blood pressures and heart rates from 32 time point measurements for each patient were analyzed.</AbstractText>There was no significant difference among the groups regarding the mean arterial blood pressures and mean heart rates during the follow-up period. There was no significant difference among groups regarding the number of patients that required vasoactive therapy at any time of measurement.</AbstractText>Routine infiltration of carotid sinus area with 1% lidocaine during carotid endarterectomy performed under local anesthesia has no significant impact on mean arterial blood pressure and heart rate during the operative procedure and the following 12 postoperative hours.</AbstractText>Copyright © 2011 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.</CopyrightInformation>
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2,334,263 |
The role of blood flow in determining the sites of atherosclerotic plaques.
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Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipids and inflammatory cells along the inner walls of arteries, and is an underlying cause of cardiovascular disease. Atherosclerotic lesions develop predominantly at branches, bends, and bifurcations in the arterial tree because these sites are exposed to low or disturbed blood flow, which exerts low/oscillatory shear stress on the vessel wall. This mechanical environment alters endothelial cell physiology by enhancing inflammatory activation. In contrast, regions of the arterial tree that are exposed to uniform, unidirectional blood flow and experience high shear stress are protected from inflammation and lesion development. Shear stress is sensed by the endothelium via mechanoreceptors and is subsequently transduced into biochemical signals resulting in modulation of proinflammatory signaling pathways. In this article, we address the molecular mechanisms behind the spatial localization of vascular inflammation and atherosclerosis, with particular focus on studies by our own group of two key proinflammatory signaling pathways, the mitogen-activated protein kinase pathway and the nuclear factor-kappa-B pathway.
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2,334,264 |
Localisation of SCN10A gene product Na(v)1.8 and novel pain-related ion channels in human heart.
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We have shown that the gene SCN10A encoding the sodium channel Na(v)1.8 is a susceptibility factor for heart block and serious ventricular arrhythmia. Since Na(v)1.8 is known to be present in nerve fibres that mediate pain, it may be related to both cardiac pain and dysrhythmia. The localisation of Na(v)1.8 and other key nociceptive ion channels, including Na(v)1.7, Na(v)1.9, capsaicin receptor TRPV1, and purinergic receptor P2X(3), have not been reported in human heart. The aim of this study was to determine the distribution of Na(v)1.8, related sodium and other sensory channels in human cardiac tissue, and correlate their density with sympathetic nerves, regenerating nerves (GAP-43), and vascularity. Human heart atrial appendage tissues (n = 13) were collected during surgery for valve disease. Tissues were investigated by immunohistology using specific antibodies to Na(v)1.8 and other markers. Na(v)1.8 immunoreactivity was detected in nerve fibres and fascicles in the myocardium, often closely associated with small capillaries. Na(v)1.8 nerve fibres per mm(2) correlated significantly with vascular markers. Na(v)1.8-immunoreactivity was present also in cardiomyocytes with a similar distribution pattern to that seen with connexins, the specialised gap junction proteins of myocardial intercalated discs. Na(v)1.5-immunoreactivity was detected in cardiomyocytes but not in nerve fibres. Na(v)1.7, Na(v)1.9, TRPV1, P2X(3)/P2X(2), and GAP43 positive nerve fibres were relatively sparse, whereas sympathetic innervation and connexin43 were abundant. We conclude that sodium channel Na(v)1.8 is present in sensory nerves and cardiomyocytes of human heart. Na(v)1.8 and other pain channels provide new targets for the understanding and treatment of cardiac pain and dysrhythmia.
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2,334,265 |
Dynamic modulation of Ca2+ sparks by mitochondrial oscillations in isolated guinea pig cardiomyocytes under oxidative stress.
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Local control of Ca(2+)-induced Ca(2+) release (CICR) depends on the spatial organization of L-type Ca(2+) channels and ryanodine receptors (RyR) in the dyad. Analogously, Ca(2+) uptake by mitochondria is facilitated by their close proximity to the Ca(2+) release sites, a process required for stimulating oxidative phosphorylation during changes in work. Mitochondrial feedback on CICR is less well understood. Since mitochondria are a primary source of reactive oxygen species (ROS), they could potentially influence the cytosolic redox state, in turn altering RyR open probability. We have shown that self-sustained oscillations in mitochondrial inner membrane potential (ΔΨ(m)), NADH, ROS, and reduced glutathione (GSH) can be triggered by a laser flash in cardiomyocytes. Here, we employ this method to directly examine how acute changes in energy state dynamically influence resting Ca(2+) spark occurrence and properties. Two-photon laser scanning microscopy was used to monitor cytosolic Ca(2+) (or ROS), ΔΨ(m), and NADH (or GSH) simultaneously in isolated guinea pig cardiomyocytes. Resting Ca(2+) spark frequency increased with each ΔΨ(m) depolarization and decreased with ΔΨ(m) repolarization without affecting Ca(2+) spark amplitude or time-to-peak. Stabilization of mitochondrial energetics by pretreatment with the superoxide scavenger TMPyP, or by acute addition of 4'-chlorodiazepam, a mitochondrial benzodiazepine receptor antagonist that blocks the inner membrane anion channel, prevented or reversed, respectively, the increased spark frequency. Cyclosporine A did not block the ΔΨ(m) oscillations or prevent Ca(2+) spark modulation by ΔΨ(m). The results support the hypothesis that mitochondria exert an influential role on the redox environment of the Ca(2+) handling subsystem, with mechanistic implications for the pathophysiology of cardiac disease.
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2,334,266 |
Comparison of ex-vivo high-resolution episcopic microscopy with in-vivo four-dimensional high-resolution transvaginal sonography of the first-trimester fetal heart.
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To compare the capability of three-dimensional (3D) reconstructed images produced by high-resolution episcopic microscopy (HREM) with that of in-vivo four-dimensional high-resolution transvaginal sonography (4D-HRTVS) to discern morphological features of the first-trimester human fetal heart.</AbstractText>This was a prospective study of fetal hearts between 9 and 14 weeks' gestation. For ex-vivo 3D analysis, 30 human fetal hearts (at 9 + 0 to 14 + 6 weeks) were retrieved from surgical terminations of pregnancy. The specimens were embedded in resin and episcopic ('block-face') imaging was used to obtain a digital volume dataset (HREM) using 3-micron slicing. 4D-HRTVS was performed in 28 separate pregnancies at 10 + 2 to 14 + 0 weeks using a Voluson E8 ultrasound machine with volumetric transvaginal RIC 6-12-MHz transducers. Heart volumes obtained by both methods were compared to assess their ability to demonstrate first-trimester cardiac morphology. Comparisons were made in the transverse and sagittal planes, and using volume rendering.</AbstractText>All hearts were structurally normal, although abdominal situs was not examined in the isolated hearts that underwent HREM. 4D-HRTVS demonstrated each of the complete five transverse cardiac views in 32-86% of cases. HREM showed four features unique to the first-trimester human heart: prominent atrial appendages, spiral ventricular arrangement, prominent coronary arteries and thickened arterial walls. 4D-HRTVS could demonstrate the first two, but ultrasound resolution was too poor to quantify wall thickness and demonstrate coronary arteries in the 3-5-mm diameter heart.</AbstractText>4D-HRTVS showed limited morphological features of the first-trimester fetal heart compared with HREM. HREM provides a gold standard of ex-vivo imaging against which developments in ultrasound resolution could be compared.</AbstractText>Copyright © 2012 ISUOG. Published by John Wiley & Sons, Ltd.</CopyrightInformation>
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2,334,267 |
Prenatal pharmacotherapy for fetal anomalies: a 2011 update.
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Fetal therapy can be defined as any prenatal treatment administered to the mother with the primary indication to improve perinatal or long-term outcomes for the fetus or newborn. This review provides an update of the pharmacological therapies that are solely directed at the fetus with anomalies and outlines a future transcriptomic approach. Fetal anomalies targeted with prenatal pharmacotherapy are a heterogeneous group of structural, endocrine, and metabolic conditions, including congenital cystic adenomatoid malformation (CCAM), congenital adrenal hyperplasia, congenital heart block, fetal tachyarrhythmias, inborn errors of metabolism, fetal thyroid disorders, and polyhydramnios. To date, the majority of pharmacotherapies for fetal anomalies have been evaluated only in retrospective, uncontrolled studies. The way forward will be with an evidence-based approach to prenatal pharmacological interventions.
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2,334,268 |
Simulation of the undiseased human cardiac ventricular action potential: model formulation and experimental validation.
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Cellular electrophysiology experiments, important for understanding cardiac arrhythmia mechanisms, are usually performed with channels expressed in non myocytes, or with non-human myocytes. Differences between cell types and species affect results. Thus, an accurate model for the undiseased human ventricular action potential (AP) which reproduces a broad range of physiological behaviors is needed. Such a model requires extensive experimental data, but essential elements have been unavailable. Here, we develop a human ventricular AP model using new undiseased human ventricular data: Ca(2+) versus voltage dependent inactivation of L-type Ca(2+) current (I(CaL)); kinetics for the transient outward, rapid delayed rectifier (I(Kr)), Na(+)/Ca(2+) exchange (I(NaCa)), and inward rectifier currents; AP recordings at all physiological cycle lengths; and rate dependence and restitution of AP duration (APD) with and without a variety of specific channel blockers. Simulated APs reproduced the experimental AP morphology, APD rate dependence, and restitution. Using undiseased human mRNA and protein data, models for different transmural cell types were developed. Experiments for rate dependence of Ca(2+) (including peak and decay) and intracellular sodium ([Na(+)](i)) in undiseased human myocytes were quantitatively reproduced by the model. Early afterdepolarizations were induced by I(Kr) block during slow pacing, and AP and Ca(2+) alternans appeared at rates >200 bpm, as observed in the nonfailing human ventricle. Ca(2+)/calmodulin-dependent protein kinase II (CaMK) modulated rate dependence of Ca(2+) cycling. I(NaCa) linked Ca(2+) alternation to AP alternans. CaMK suppression or SERCA upregulation eliminated alternans. Steady state APD rate dependence was caused primarily by changes in [Na(+)](i), via its modulation of the electrogenic Na(+)/K(+) ATPase current. At fast pacing rates, late Na(+) current and I(CaL) were also contributors. APD shortening during restitution was primarily dependent on reduced late Na(+) and I(CaL) currents due to inactivation at short diastolic intervals, with additional contribution from elevated I(Kr) due to incomplete deactivation.
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2,334,269 |
Proteasome inhibitor treatment in alcoholic liver disease.
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Oxidative stress, generated by chronic ethanol consumption, is a major cause of hepatotoxicity and liver injury. Increased production of oxygen-derived free radicals due to ethanol metabolism by CYP2E1 is principally located in the cytoplasm and in the mitochondria, which does not only injure liver cells, but also other vital organs, such as the heart and the brain. Therefore, there is a need for better treatment to enhance the antioxidant response elements. To date, there is no established treatment to attenuate high levels of oxidative stress in the liver of alcoholic patients. To block this oxidative stress, proteasome inhibitor treatment has been found to significantly enhance the antioxidant response elements of hepatocytes exposed to ethanol. Recent studies have shown in an experimental model of alcoholic liver disease that proteasome inhibitor treatment at low dose has cytoprotective effects against ethanol-induced oxidative stress and liver steatosis. The beneficial effects of proteasome inhibitor treatment against oxidative stress occurred because antioxidant response elements (glutathione peroxidase 2, superoxide dismutase 2, glutathione synthetase, glutathione reductase, and GCLC) were up-regulated when rats fed alcohol were treated with a low dose of PS-341 (Bortezomib, Velcade(®)). This is an important finding because proteasome inhibitor treatment up-regulated reactive oxygen species removal and glutathione recycling enzymes, while ethanol feeding alone down-regulated these antioxidant elements. For the first time, it was shown that proteasome inhibition by a highly specific and reversible inhibitor is different from the chronic ethanol feeding-induced proteasome inhibition. As previously shown by our group, chronic ethanol feeding causes a complex dysfunction in the ubiquitin proteasome pathway, which affects the proteasome system, as well as the ubiquitination system. The beneficial effects of proteasome inhibitor treatment in alcoholic liver disease are related to proteasome inhibitor reversibility and the rebound of proteasome activity 72 h post PS-341 administration.
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2,334,270 |
Effect of block-periodized exercise training on bone and coronary heart disease risk factors in early post-menopausal women: a randomized controlled study.
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The purpose of this 12 month randomized exercise intervention was to determine the effect of a block-periodized multipurpose exercise program on bone mineral density (BMD) and parameters of the metabolic syndrome (MetS) in early post-menopausal women. Eighty-five subjects (52.3 ± 2.4 years) living in the area of Erlangen (Germany) were randomly assigned into an exercise (EG, n=43) or a wellness-control group (CG: n=42). The EG performed a periodized multipurpose exercise program with 4-6-week blocks of high-intensity bone-specific exercise intermitted by 10-12 weeks of exercise dedicated to increase endurance and reduce cardiac and metabolic risk factors. The CG performed a low-volume/low-intensity "wellness" program to increase well-being. After 12 months, significant exercise effects were observed for the lumbar spine (LS) BMD as assessed by quantitative computed tomography [total BMD (EG: -0.3 ± 2.1% vs CG: -2.1 ± 2.2%, P=0.015); trabecular BMD (EG: -0.7 ± 3.4% vs CG: -4.7 ± 4.9%, P=0.001) and dual-energy x-ray absorptiometry (DXA) (EG: -0.1 ± 2.2% vs CG: -2.0 ± 2.0%, P=0.002)]. However, no significant effects were observed for total hip BMD as assessed by DXA (P=0.152). Although all MetS parameters were favorably affected among the EG, only the effect for waist circumference was significant. In summary, short periods of bone-specific intervention embedded in longer periods of exercises dedicated to improve cardiovascular and metabolic risk factors positively affected BMD at the LS.
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2,334,271 |
The effect of ketamine on the MACBAR of sevoflurane in dogs.
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To determine the effect of intravenous ketamine on the minimum alveolar concentration of sevoflurane needed to block autonomic response (MAC(BAR)) to a noxious stimulus in dogs.</AbstractText>Randomized, crossover, prospective design.</AbstractText>Eight, healthy, adult male, mixed-breed dogs, weighing 11.2-16.1 kg.</AbstractText>Dogs were anesthetized with sevoflurane on two occasions, 1 week apart, and baseline MAC(BAR) (B-MAC(BAR)) was determined on each occasion. MAC(BAR) was defined as the mean of the end-tidal sevoflurane concentrations that prevented and allowed an increase (≥15%) in heart rate or invasive mean arterial pressure in response to a noxious electrical stimulus (50 V, 50 Hz, 10 ms). Dogs then randomly received either a low-dose (LDS) or high-dose series (HDS) of ketamine, and treatment MAC(BAR) (T-MAC(BAR)) was determined. The LDS had an initial loading dose (LD) of 0.5 mg kg(-1) and constant rate infusion (CRI) at 6.25 μg kg(-1) minute(-1), followed, after T-MAC(BAR) determination, by a second LD (1 mg kg(-1)) and CRI (12.5 μg kg(-1) minute(-1)). The HDS had an initial LD (2 mg kg(-1)) and CRI (25 μg kg(-1) minute(-1)) followed by a second LD (3 mg kg(-1)) and CRI (50 μg kg(-1) minute(-1)). Data were analyzed with a mixed-model anova and are presented as LSM ± SEM.</AbstractText>The B-MAC(BAR) was not significantly different between treatments. Ketamine at 12.5, 25, and 50 μg kg(-1) minute(-1) decreased sevoflurane MAC(BAR), and the maximal decrease (22%) occurred at 12.5 μg kg(-1) minute(-1). The percentage change in MAC(BAR) was not correlated with either the log plasma ketamine or norketamine concentration.</AbstractText>Ketamine at clinically relevant doses of 12.5, 25, and 50 μg kg(-1) minute(-1) decreased sevoflurane MAC(BAR), although the reduction was neither dose-dependent nor linear.</AbstractText>© 2011 The Authors. Veterinary Anaesthesia and Analgesia. © 2011 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesiologists.</CopyrightInformation>
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2,334,272 |
[Health valuations for patients with chronic ischemic heart disease].
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The study deals with the question of how patients with chronic ischemic heart disease assess different health situations that can be achieved by rehabilitation. Furthermore it examines which factors influence these health valuations and whether the predictors vary depending on the level of education.</AbstractText>The health valuations of n = 331 patients with chronic ischemic heart disease are compiled using visual analogue scales (VAS). In addition to sociodemographic questions, generic and illness-specific scales (SF-12, MacNew) for the health-related quality of life (HRQOL) are used as potential predictors of the health valuations. Additional basic medical data were provided by the physician. Hierarchical regression analyses are conducted; the sociodemographic, medical and HRQOL variables are included stepwise. Since many variables are observed for the regression models, an imputation of missing values is made.</AbstractText>The health dimensions "Self-care and domestic life" and "Mobility" are assigned the highest values on the VAS. The lowest preference is assigned to the dimensions "Reduction of symptoms" and "Information about the disease". The differences between the health dimensions are statistically significant. Sociodemographic variables explain up to 3.6% of the variance of health valuations, with level of education and living with a partner being the most important predictors. The medical variables included in the second step explain between 2.1 and 6.8% incremental variance; the most important predictor is the operation performed prior to rehabilitation (bypass, heart valve). The HRQOL variables in the third block provide 7.1-24.9% incremental explanation of variance, by far the highest percentage. This is mainly achieved using the 3 MacNew scales (emotional, social and physical functioning). The overall explanation of variance for the health valuations is 17.1-28.8%. For patients with a higher level of education, the total explanation of variance is about 9.2% higher on average than for the total sample and lies between 21.2 and 44.1%.</AbstractText>The health dimensions examined are assessed quite differently by the patients. The most significant factor of influence is the HRQOL. In the subgroup of patients with a higher level of education, the predictive strength of the variables examined is considerably higher in comparison with the total sample. Since the health valuations can be predicted to a limited extent only using other data arising during routine care, it is necessary to implement special methods for compiling health valuations.</AbstractText>© Georg Thieme Verlag KG Stuttgart · New York.</CopyrightInformation>
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2,334,273 |
Regadenoson is a safe and well-tolerated pharmacological stress agent for myocardial perfusion imaging in post-heart transplant patients.
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The safety and tolerability of regadenoson (REG), a newer adenosine A(2a) receptor agonist, has not been tested in orthotopic heart transplant (OHT) patients.</AbstractText>Retrospective review of a tertiary care center experience of OHT patients who underwent a REG single-photon emission computed tomography (SPECT) study as part of the work-up for cardiac allograft vasculopathy. The control group included those same patients who had prior adenosine-based SPECT.</AbstractText>A total of 40 patients met the above criteria. Mean time from OHT to adenosine-SPECT and REG-SPECT was 8.2 ± 4.8 years vs 9.8 ± 4.5 years, respectively (P < .001). Both vasodilators had similar side effect profiles (P = .10), produced significant heart rate acceleration and asymptomatic hypotension (P < .001). There were no episodes of bradycardia and/or AV block with REG. Despite adjustment for medication status, adenosine was still associated with more conduction abnormalities (8 vs 1 event with REG, P = .02) including five episodes of 2nd degree AV block (Mobitz type II) and three episodes of sinus pause.</AbstractText>This is the first reported use of REG in OHT patients. REG appears to be safe and well tolerated without significant cardiovascular adverse events.</AbstractText>
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2,334,274 |
Block of the hERG channel by bupivacaine: Electrophysiological and modeling insights towards stereochemical optimization.
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The hERG voltage-gated potassium channel mediates the cardiac I(Kr) current, which is crucial for the duration of the cardiac action potential. Undesired block of the channel by certain drugs may prolong the QT interval and increase the risk of malignant ventricular arrhythmias. Although the molecular determinants of hERG block have been intensively studied, not much is known about its stereoselectivity. Levo-(S)-bupivacaine was the first drug reported to have a higher affinity to block hERG than its enantiomer. This study strives to understand the principles underlying the stereoselectivity of bupivacaine block with the help of mutagenesis analyses and molecular modeling simulations. Electrophysiological measurements of mutated hERG channels allowed for the identification of residues involved in bupivacaine binding and stereoselectivity. Docking and molecular mechanics simulations for both enantiomers of bupivacaine and terfenadine (a non-stereoselective blocker) were performed inside an open-state model of the hERG channel. The predicted binding modes enabled a clear depiction of ligand-protein interactions. Estimated binding affinities for both enantiomers were consistent with electrophysiological measurements. A similar computational procedure was applied to bupivacaine enantiomers towards two mutated hERG channels (Tyr652Ala and Phe656Ala). This study confirmed, at the molecular level, that bupivacaine stereoselectively binds the hERG channel. These results help to lay the foundation for structural guidelines to optimize the cardiotoxic profile of drug candidates in silico.
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2,334,275 |
Three independent mechanisms contribute to tetracaine inhibition of cardiac calcium release channels.
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Tetracaine is a tertiary amine local anaesthetic which inhibits ryanodine receptors (RyRs), the calcium release channels of the sarcoplasmic reticulum (SR). Tetracaine has been extensively used to study the role of the SR Ca(2+) fluxes in muscle cells, yet a detailed understanding of tetracaine action on RyR channels is lacking. Here we investigate tetracaine effects in single channel recording of sheep cardiac RyRs in lipid bilayers. Tetracaine decreased channel conductance (block) and open probability (inhibition). The IC(50) for inhibition had complex dependencies on membrane voltage and cytoplasmic [ATP], [Ca(2+)] and pH. We identify three mechanisms underlying these actions. First, a voltage-dependent, slow inhibition in which luminal and cytoplasmic tetracaine compete for a common neutral/cation binding site within the trans-membrane RyR domain to induce long closed events (~100 ms). The apparent binding rate is proportional to the RyR closed probability, indicating that it only operates on closed channels. Second, a voltage-independent, pH sensitive fast inhibition in which cytoplasmic and luminal tetracaine compete for a site located on the cytoplasmic domain of the RyR to induce fast closed events (~2 ms). Its IC(50) is not dependent on the open/closed conformation of RyR. Finally, a voltage-dependent block of the channel by cytoplasmic tetracaine reduced channel conductance. We develop a model for tetracaine inhibition which predicts that under diastolic conditions, i.e. when RyRs are mainly closed, the slow mechanism has the highest potency (IC(50)~200 μM) of the three mechanisms and is therefore the dominant form of inhibition. However, during periods of Ca(2+) release, i.e. when RyRs are open, the slow mechanism becomes ineffective, leaving the fast inhibition (IC(50)~2 mM) as the dominant effect. Because of this closed state inhibition property, tetracaine loses its efficacy when RyRs open. This has the effect of increasing the feedback on SR Ca(2+) release generated by cytoplasmic and luminal Ca(2+).
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2,334,276 |
Increasing dihydrobiopterin causes dysfunction of endothelial nitric oxide synthase in rats in vivo.
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An elevation of oxidized forms of tetrahydrobiopterin (BH(4)), especially dihydrobiopterin (BH(2)), has been reported in the setting of oxidative stress, such as arteriosclerotic/atherosclerotic disorders, where endothelial nitric oxide synthase (eNOS) is dysfunctional, but the role of BH(2) in the regulation of eNOS activity in vivo remains to be evaluated. This study was designed to clarify whether increasing BH(2) concentration causes endothelial dysfunction in rats. To increase vascular BH(2) levels, the BH(2) precursor sepiapterin (SEP) was intravenously given after the administration of the specific dihydrofolate reductase inhibitor methotrexate (MTX) to block intracellular conversion of BH(2) to BH(4). MTX/SEP treatment did not significantly affect aortic BH(4) levels compared with control treatment. However, MTX/SEP treatment markedly augmented aortic BH(2) levels (291.1 ± 29.2 vs. 33.4 ± 6.4 pmol/g, P < 0.01) in association with moderate hypertension. Treatment with MTX alone did not significantly alter blood pressure or BH(4) levels but decreased the BH(4)-to-BH(2) ratio. Treatment with MTX/SEP, but not with MTX alone, impaired ACh-induced vasodilator and depressor responses compared with the control treatment (both P < 0.05) and also aggravated ACh-induced endothelium-dependent relaxations (P < 0.05) of isolated aortas without affecting sodium nitroprusside-induced endothelium-independent relaxations. Importantly, MTX/SEP treatment significantly enhanced aortic superoxide production, which was diminished by NOS inhibitor treatment, and the impaired ACh-induced relaxations were reversed with SOD (P < 0.05), suggesting the involvement of eNOS uncoupling. These results indicate, for the first time, that increasing BH(2) causes eNOS dysfunction in vivo even in the absence of BH(4) deficiency, demonstrating a novel insight into the regulation of endothelial function.
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2,334,277 |
Non-human leukocyte antigen antibodies reactive with endothelial cells could be involved in early loss of renal allografts.
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Preformed donor-specific human leukocyte antigen (HLA) antibodies have been associated with allograft dysfunction and failure. However, recipients of HLA-identical kidneys can develop acute humoral rejection, implicating putative pathogenic antibodies that are directed against non-HLA antigens. We investigated the presence of endothelial cell-reactive antibodies in 11 patients who experienced early loss of their transplanted kidneys owing to humoral rejection and 1 loss from renal venal thrombosis. We examined the potential efficacy of intravenous immunoglobulin to block the binding of these antibodies, as previously suggested for anti-HLA antibodies.
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2,334,278 |
Association of the idiotype:antiidiotype antibody ratio with the efficacy of intravenous immunoglobulin treatment for the prevention of recurrent autoimmune-associated congenital heart block.
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Congenital heart block (CHB), a manifestation of neonatal lupus, is associated with maternal anti-Ro/SSA and anti-La/SSB autoantibodies and recurs in ∼18% of subsequent pregnancies. This study was undertaken to investigate the effect of the idiotype:antiidiotype (Id:anti-Id) antibody ratio in the ability of intravenous immunoglobulin (IVIG) administered during subsequent pregnancies to prevent CHB.</AbstractText>We studied 16 anti-Ro/SSA and anti-La/SSB-positive pregnant women from the Preventive IVIG Therapy for Congenital Heart Block study who had previously given birth to a child with neonatal lupus. In 3 of the mothers, the study pregnancy resulted in the birth of a child with neonatal lupus (2 with CHB and 1 with rash). Sequential serum samples were obtained from all mothers immediately before the administration of IVIG during pregnancy and were evaluated for antibodies against the major B cell epitope 349-364aa of La/SSB (idiotype) and its antiidiotypic antibodies.</AbstractText>Following IVIG treatment, serum titers of anti-La(349-364) (Id antibodies) decreased in 80% of the mothers, and in 60% an increase in anti-Id antibodies against anti-La(349-364) was observed. The Id:anti-Id ratio was significantly higher in mothers whose offspring developed neonatal lupus compared to mothers who gave birth to a healthy child (P<0.0001). Removal of anti-Id antibodies substantially increased the reactivity against La(349-364) in sera from 5 of 7 mothers tested. All IVIG preparations were examined for Id and anti-Id antibody activity. IVIG from batches administered to mothers who gave birth to a healthy child had an Id:anti-Id activity ratio of <1, in contrast to that given to mothers who gave birth to a child with neonatal lupus. Addition of the IVIG preparations to the maternal sera further enhanced antiidiotypic activity (by up to 4.7-fold) in 11 of 13 patients studied.</AbstractText>This is the first study in humans to demonstrate that IVIG influences the Id-anti-Id network of a specific pathogenic autoantibody. Specifically, we showed that IVIG enhanced the anti-Id antibody response in pregnant women with anti-La/SSB antibodies. A high Id:anti-Id ratio in both the IVIG preparation and the maternal serum may explain the absence of an effect of IVIG in preventing recurrent neonatal lupus in some cases.</AbstractText>Copyright © 2011 by the American College of Rheumatology.</CopyrightInformation>
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2,334,279 |
Interactions between ankyrin-G, Plakophilin-2, and Connexin43 at the cardiac intercalated disc.
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The early description of the intercalated disc defined 3 structures, all of them involved in cell-cell communication: desmosomes, gap junctions, and adherens junctions. Current evidence demonstrates that molecules not involved in providing a physical continuum between cells also populate the intercalated disc. Key among them is the voltage-gated sodium channel complex. An important component of this complex is the cytoskeletal adaptor protein Ankyrin-G (AnkG).</AbstractText>To test the hypothesis that AnkG partners with desmosome and gap junction molecules and exerts a functional effect on intercellular communication in the heart.</AbstractText>We used a combination of microscopy, immunochemistry, patch-clamp, and optical mapping to assess the interactions between AnkG, Plakophilin-2, and Connexin43. Coimmunoprecipitation studies from rat heart lysate demonstrated associations between the 3 molecules. With the use of siRNA technology, we demonstrated that loss of AnkG expression caused significant changes in subcellular distribution and/or abundance of PKP2 and Connexin43 as well as a decrease in intercellular adhesion strength and electric coupling. Regulation of AnkG and of Na(v)1.5 by Plakophilin-2 was also demonstrated. Finally, optical mapping experiments in AnkG-silenced cells demonstrated a shift in the minimal frequency at which rate-dependence activation block was observed.</AbstractText>These experiments support the hypothesis that AnkG is a key functional component of the intercalated disc at the intersection of 3 complexes often considered independent: the voltage-gated sodium channel, gap junctions, and the cardiac desmosome. Possible implications to the pathophysiology of inherited arrhythmias (such as arrhythmogenic right ventricular cardiomyopathy) are discussed.</AbstractText>
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2,334,280 |
Comparison of relative potency of intrathecal bupivacaine for motor block in pregnant versus non-pregnant women.
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Pregnancy is associated with facilitated spread of spinal and epidural anesthesia. There are limited data available for relative potency of motor block of neuraxial local anesthetics in non-pregnant versus pregnant women. The purpose of this study was to investigate the median effective dose (ED(50)) of intrathecal isobaric bupivacaine for motor block in non-pregnant and pregnant women and to estimate the respective potency ratio.</AbstractText>American Society of Anesthesiologists physical status I and II pregnant (n=35) and non-pregnant (n=35) patients undergoing elective cesarean delivery or elective gynecological surgery under combined spinal-epidural anesthesia were enrolled. According to the up-down sequential allocation technique, the dose of intrathecal isobaric bupivacaine for each patient was determined by the response of the previous patient in both groups. The initial dose of bupivacaine was 4 mg and the testing interval was set at 0.5 mg. Efficacy was determined by the occurrence of motor block in either lower limb as assessed by the modified Bromage scale within 5 min of spinal injection.</AbstractText>The ED(50) of intrathecal bupivacaine for motor block was 4.51 (95% confidence interval (CI) 4.27-4.76) mg for non-pregnant women and 3.96 (95% CI 3.83-4.08) mg for pregnant women. The relative potency ratio for motor block for pregnant versus non-pregnant women was 1.14 (95% CI 1.05-1.24), (P=0.0037).</AbstractText>Intrathecal bupivacaine was 1.14 times more potent for motor block in pregnant versus non-pregnant women. Our current data confirm the difference in local anesthetic requirement between non-pregnant and pregnant patients.</AbstractText>Copyright © 2011 Elsevier Ltd. All rights reserved.</CopyrightInformation>
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2,334,281 |
The potential role of Th17 in mediating the transition from acute to chronic autoimmune inflammation: rheumatoid arthritis as a model.
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T helper 17 cells (Th17) have arisen in the last 15 years as major effector cells in several chronic inflammatory states. In synovitis associated with rheumatoid arthritis (RA), Th17 emerged as being involved in driving the active acute phases and correlated with local and systemic parameters of inflammation; in particular, TCRζ(dim) Th17 appear to be the greatest producers of IL-17 at the single-cell level. IL-1beta and IL-6, along with IL-23, arose as the major drivers of differentiation and local development of Th17, while IL-15 and cell-cell contact can trigger the local production of IL-17. TNF-alpha inhibition can reversibly block the migration of pathogenic effector memory TCRzeta(dim) T cells and CCR6+ Th17 from peripheral blood to inflamed tissues. IL-17 is a potent chemoattractant for pre-committed CD4+ T cells and neutrophils, and may promote the migration of B cells to lymphoid follicles in the chronic phase of synovial inflammation. Importantly, IL-17 drives osteoclastogenesis and neoangiogenesis in the RA joint. These data strongly suggest that Th17 are key effector cells in driving the transition from the acute to the chronic phase of RA inflammation.
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2,334,282 |
Characteristics of unilateral spinal anesthesia at different speeds of intrathecal injection.
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Unilateral spinal anesthesia is performed to provide restriction of sympathetic and motor block. The purpose of this study is to compare the effect of different speeds of intrathecal injection on unilateral spinal anesthesia.</AbstractText>The patient cohort comprised 66 patients who were placed in the lateral position with the side to be operated on dependent. After dural puncture, the needle aperture was turned towards the dependent side, and hyperbaric 0.5% bupivacaine was injected at a rate of 1 ml/min in Group Slow patients (Group S, n = 33) or 0.5 ml/min in Group Extra Slow patients (Group ES, n = 33). The lateral position was maintained for 15 min. Skin temperature, loss of pinprick sensation, and degree of motor block were recorded.</AbstractText>There were significant differences in the characteristics of the non-operative side between the groups when on the block. Sensorial block was unilateral in 25 (75.8%) patients in Group S and in 29 patients in Group ES (87.9%) 15 min post-injection. At the end of the operation (approximately 50 min after spinal anesthesia), strictly unilateral anesthesia was present in 31 patients in Group ES (93.9%) and in 22 patients in Group S (66.6%) (p < 0.05). Unilateral sensory and motor block were observed in both groups, and the incidence of strict unilateral block was significantly higher in group ES patients.</AbstractText>The result of the study show that the extra-slow injection of hyperbaric bupivacaine provided strictly unilateral sensorial and sympathetic block in 93.9 and 87.9% of the patients, respectively, and that a slow injection of low doses of hyperbaric 0.5% bupivacaine 1 ml was sufficient to provide unilateral spinal anesthesia.</AbstractText>
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2,334,283 |
Impact of therapeutic hypothermia onset and duration on survival, neurologic function, and neurodegeneration after cardiac arrest.
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Post-cardiac-arrest therapeutic hypothermia improves outcomes in comatose cardiac arrest survivors. This study tests the hypothesis that the efficacy of post-cardiac-arrest therapeutic hypothermia is dependent on the onset and duration of therapy.</AbstractText>Prospective randomized laboratory investigation.</AbstractText>University research laboratory.</AbstractText>A total of 268 male Long Evans rats.</AbstractText>Post-cardiac-arrest therapeutic hypothermia.</AbstractText>Adult male Long Evans rats that achieved return of spontaneous circulation after a 10-min asphyxial cardiac arrest were block randomized to normothermia (37°C ± 1°C) or therapeutic hypothermia (33°C ± 1°C) initiated 0, 1, 4, or 8 hrs after return of spontaneous circulation and maintained for 24 or 48 hrs. Therapeutic hypothermia initiated 0, 1, 4, and 8 hrs after return of spontaneous circulation resulted in 7-day survival rates of 45%*, 36%*, 36%*, and 14%, respectively, compared to 17% for normothermic controls and survival with good neurologic function rates of 24%*, 24%*, 19%*, and 0%, respectively, compared to 2% for normothermic controls (*p < .05 vs. normothermia). These outcomes were not different when therapeutic hypothermia was maintained for 24 vs. 48 hrs. In contrast, hippocampal CA1 pyramidal neuron counts were 53% ± 27%*, 53% ± 19%*, 51% ± 24%*, and 65% ± 16%* of normal, respectively, when therapeutic hypothermia was initiated 0, 1, 4, or 8 hrs after return of spontaneous circulation compared to 9% in normothermic controls (*p < .01 vs. normothermia). Furthermore, surviving neuron counts were greater when therapeutic hypothermia was maintained for 48 hrs compared to 24 hrs (68% ± 15%* vs. 42% ± 22%, *p < .0001).</AbstractText>In this study, post-cardiac-arrest therapeutic hypothermia resulted in comparable improvement of survival and survival with good neurologic function when initiated within 4 hrs after return of spontaneous circulation. However, histologic assessment of neuronal survival revealed a potentially broader therapeutic window and greater neuroprotection when therapeutic hypothermia was maintained for 48 vs. 24 hrs.</AbstractText>
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2,334,284 |
Neonatal lupus erythematosus: a report of four cases.
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Neonatal lupus erythematosus is a very rare disease, clinically characterized by skin lesions that resemble those of subacute or discoid lupus erythematosus and/or congenital heart block. Generally, when patients have skin manifestations, they have no cardiac defects and vice-versa; however, in 10% of cases these manifestations may coexist. Other findings may include hematologic, hepatic and neurological abnormalities. This condition is caused by the transplacental passage of maternal autoantibodies against Ro (95%), La and, less frequently, U1-ribonucleoprotein (U1-RNP). The present case report describes four patients with clinical, histopathological and immunological findings compatible with neonatal lupus erythematosus, their treatment and progress.
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2,334,285 |
Toxoplasmosis in a post-transplant bronchoalveolar lavage: a case report.
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Toxoplasma gondii usually causes an asymptomatic and then latent infection in human adults; however, a potentially fatal disseminated form can occur in immunocompromised patients. Given that the diagnosis of acute Toxoplasma infection, as opposed to latent disease, relies on finding direct evidence of T. gondii infection in tissue, pathologic examination is critical. There have only been a few reports describing the cytomorphology of Toxoplasma in exfoliative cytology, and no reports of the findings in Thin Prep. In this report, we describe a fatal case of toxoplasmosis in a cardiac transplant patient that was diagnosed by respiratory cytopathology. Although the extracellular organisms were well visualized on the Wright-Giemsa stained cytospin, they were only faintly seen on the Pap-stained cytospin trapped within mucin and were not easily appreciated on the ThinPrep slides nor the H&E stained cell block sections. An immunohistochemical stain for Toxoplasma performed on the cell block was strongly positive, and an autopsy performed on the patient confirmed disseminated infection. Our case illustrates that the diagnosis of Toxoplasma in exfoliative cytology specimens can be challenging since organisms are not well visualized on ThinPrep or Pap-stained material; therefore, Wright-Giemsa stained material can be particularly helpful.
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2,334,286 |
Tropomyosin is in a reduced state in rabbit psoas muscle.
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Tropomyosin (Tm) purified from skeletal and cardiac muscle often contains disulfide bonds due to oxidation of cysteine groups that are in close proximity in the coiled-coil structure. Are these disulfide crosslinks present in the muscle or produced by oxidation during preparation? To answer this question we reacted one part of freshly dissected rabbit psoas muscle fibers, which was permeabilized with Triton X-100, with N-ethyl maleimide (NEM) to block cysteine groups and another part with 5,5'-dithiobis(2-nitro benzoate) (DTNB) to facilitate disulfide bond formation by interchain sulfhydryl-disulfide exchange. We found, by high resolution gradient SDS polyacrylamide gels, that the NEM-treated muscle was only composed of uncrosslinked Tm and the DTNB treated muscle was composed of disulfide-crosslinked Tm. This work indicates that Tm exists in a reduced state in rabbit psoas muscle.
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2,334,287 |
Site-directed mutagenesis of the CC chemokine binding protein 35K-Fc reveals residues essential for activity and mutations that increase the potency of CC chemokine blockade.
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Chemokines of the CC class are key mediators of monocyte recruitment and macrophage differentiation and have a well documented role in many inflammatory diseases. Blockade of chemokine activity is therefore an attractive target for anti-inflammatory therapy. 35K (vCCI) is a high-affinity chemokine binding protein expressed by poxviruses, which binds all human and murine CC chemokines, preventing their interaction with chemokine receptors. We developed an Fc-fusion protein of 35K with a modified human IgG1 Fc domain and expressed this construct in human embryonic kidney 293T cells. Purified 35K-Fc is capable of inhibiting CC chemokine-induced calcium flux, chemotaxis, and β-arrestin recruitment in primary macrophages and transfected cells. To elucidate the residues involved in chemokine neutralization, we performed site-directed mutagenesis of six key amino acids in 35K and expressed the mutant Fc-fusion proteins in vitro. We screened the mutants for their ability to block chemokine-induced β-arrestin recruitment in transfected cells and to inhibit primary macrophage signaling in an electric cell substrate impedance sensing assay. Using a sterile model of acute inflammation, zymosan-induced peritonitis, we confirmed that wild-type 35K-Fc can reduce monocyte recruitment, whereas one mutant (R89A) showed a more pronounced blockade of monocyte influx and another mutant (E143K) showed total loss of function. We believe that 35K-Fc will be a useful tool for exploring the role of CC chemokines in chronic inflammatory pathologies, and we have identified a higher potency form of the molecule that may have potential therapeutic applications in chronic inflammatory disease.
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2,334,288 |
Membrane sealant Poloxamer P188 protects against isoproterenol induced cardiomyopathy in dystrophin deficient mice.
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Cardiomyopathy in Duchenne muscular dystrophy (DMD) is an increasing cause of death in patients. The absence of dystrophin leads to loss of membrane integrity, cell death and fibrosis in cardiac muscle. Treatment of cardiomyocyte membrane instability could help prevent cardiomyopathy.</AbstractText>Three month old female mdx mice were exposed to the β(1) receptor agonist isoproterenol subcutaneously and treated with the non-ionic tri-block copolymer Poloxamer P188 (P188) (460 mg/kg/dose i.p. daily). Cardiac function was assessed using high frequency echocardiography. Tissue was evaluated with Evans Blue Dye (EBD) and picrosirius red staining.</AbstractText>BL10 control mice tolerated 30 mg/kg/day of isoproterenol for 4 weeks while death occurred in mdx mice at 30, 15, 10, 5 and 1 mg/kg/day within 24 hours. Mdx mice tolerated a low dose of 0.5 mg/kg/day. Isoproterenol exposed mdx mice showed significantly increased heart rates (p < 0.02) and cardiac fibrosis (p < 0.01) over 4 weeks compared to unexposed controls. P188 treatment of mdx mice significantly increased heart rate (median 593 vs. 667 bpm; p < 0.001) after 2 weeks and prevented a decrease in cardiac function in isoproterenol exposed mice (Shortening Fraction = 46 ± 6% vs. 35 ± 6%; p = 0.007) after 4 weeks. P188 treated mdx mice did not show significant differences in cardiac fibrosis, but demonstrated significantly increased EBD positive fibers.</AbstractText>This model suggests that chronic intermittent intraperitoneal P188 treatment can prevent isoproterenol induced cardiomyopathy in dystrophin deficient mdx mice.</AbstractText>
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2,334,289 |
Antihyperhomocysteinemic and antihyperlipidemic effect of Trichilia connaroides in methionine-induced hyperhomocysteinemic animals.
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The current study investigates the antihyperhomocysteinemic and antihyperlipidemic effect of chloroform and methanol extracts of the leaves of Trichilia connaroides in methionine-induced hyperhomocysteinemic rats. Hyperhomocysteinemia was induced in albino Wistar rats by oral administration of L-Methionine (1 gm / kg) and they were treated simultaneously with chloroform and methanol extracts (100 mg / kg) from the leaves of Trichilia connaroides. Serum homocysteine, lipid profile, and products of lipid peroxidation (MDA) in the heart homogenate were recorded and treated for statistical significance. Hyperhomocysteinemic animals recorded significantly elevated serum homocysteine changes in lipid profile (P < 0.01) and Thibarbituric acid reactive substances (P < 0.01), compared to the vehicle control animals. Animals treated with chloroform and methanol extracts recorded significantly (P < 0.01) lower serum homocysteine, entire lipid profile, LPO (P < 0.01), except a significant increase in HDL-cholesterol (P < 0.01) compared to hyperhomocysteinemic animals. Thus, we conclude that chloroform and methanol extracts of Trichilia connaroides have significant antihyperhomocysteinemic and antihyperlipidemic effects on methionine-induced hyperhomocysteinemic animals. Trichilia connaroides, therefore, holds promise as a cardioprotective herb.
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2,334,290 |
Cystic fibrosis: a new target for 4-Imidazo[2,1-b]thiazole-1,4-dihydropyridines.
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The pharmacology of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel has attracted significant interest in recent years with the aim to search for rational new therapies for diseases caused by CFTR malfunction. Mutations that abolish the function of CFTR cause the life-threatening genetic disease cystic fibrosis (CF). The most common cause of CF is the deletion of phenylalanine 508 (ΔF508) in the CFTR chloride channel. Felodipine, nifedipine, and other antihypertensive 1,4-dihydropyridines (1,4-DHPs) that block L-type Ca(2+) channels are also effective potentiators of CFTR gating, able to correct the defective activity of ΔF508 and other CFTR mutants ( Mol. Pharmacol. 2005 , 68 , 1736 ). For this purpose, we evaluated the ability of the previously and newly synthesized 4-imidazo[2,1-b]thiazoles-1,4-dihydropyridines without vascular activity and inotropic and/or chronotropic cardiac effects ( J. Med. Chem. 2008 , 51 , 1592 ) to enhance the activity of ΔF508-CFTR. Our studies indicate compounds 17, 18, 20, 21, 38, and 39 as 1,4-DHPs with an interesting profile of activity.
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2,334,291 |
Serum verapamil concentrations before and after Intralipid® therapy during treatment of an overdose.
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CONTEXT. Intralipid® infusion is useful in reversing cardiac and central nervous system toxicity of local anesthetic drugs, and recent reports suggest utility in other drug overdoses. CASE DETAILS. A 47-year-old man presented to the emergency department with hypotension and complete heart block 3 h after a sustained-release verapamil overdose. He was given supportive care including calcium and hyperinsulinemia/euglycemia therapy. Nineteen and 29 h post-ingestion, Intralipid® was administered as a bolus, followed by an infusion. OBJECTIVE. The objective of this study was to determine the serum verapamil concentrations before and after Intralipid® administration and to ascertain its clinical effects. DISCUSSION. It was found that administration of Intralipid® was followed by a decrease in verapamil concentration once the lipid had been removed from the sample, demonstrating that Intralipid® was effective in sequestering verapamil, effectively removing it from the serum, and supporting its use in the treatment of verapamil overdose. Intralipid® administration was associated with an increase in the patient's blood pressure, but because other vasoactive drugs were given at the same time, it was difficult to determine its relative contribution to clinical improvement.
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2,334,292 |
Complete heart block and death following lamotrigine overdose.
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CONTEXT. Lamotrigine is used for both seizure and psychiatric disorders. Overdoses typically follow a benign course. CASE DETAILS. A 19-year-old male with bipolar disorder ingested 4  g of lamotrigine. The patient suffered from multiple seizures, charcoal aspiration, respiratory arrest, prolongation of the QRS interval on electrocardiogram, complete heart block, multiorgan failure and ultimately death. DISCUSSION. We describe the emergency department (ED) and ICU course for this patient and briefly review the toxic effects of lamotrigine and the pharmacokinetics with and without hemodialysis.
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2,334,293 |
Pregnancy related complications in patients with systemic lupus erythematosus, an egyptian experience.
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Systemic Lupus Erythematosus (SLE) has a tendency to occur in women in their reproductive years, causing complications during pregnancy and labour. Conversely, pregnancy can cause flares of disease activity, often necessitating immediate intervention.</AbstractText>to study pregnancy related complications in patients with SLE.</AbstractText>The study included 48 SLE pregnant females. 27 patients with 38 pregnancies, their data viewed retrospectively from medical records, and 21 patients with 21 pregnancies followed up prospectively. The laboratory data included ANA, DNA, APL antibodies and anti Ro/SSA. The disease activity was calculated according to the Systemic Lupus Activity Measure. Ultrasound was performed to confirm gestational age and assess for the presence of any congenital fetal malformations, and then repeated monthly to detect any abnormality including intrauterine growth restriction. At 30 weeks gestation and onwards, assessment of fetal wellbeing including daily fetal kick chart and once weekly non stress test was performed. Doppler blood flow velocimetry was done for those with abnormal fetal heart rate pattern. After labour, the neonate was examined for complications including complete heart block and neonatal lupus.</AbstractText>Anti dsDNA was found in 95% of the patients, anti Ro/SSA in 6% and anti APL in 30%. 57% of the patients followed up prospectively had active disease in the 1st trimester, 24% in the 2nd and 62% in the 3rd trimester. The most common maternal complication was preeclampsia 33%, followed by spontaneous abortion 20%. Prematurity was the most common fetal complication 37%, followed by intrauterine growth restriction 29%. 2 neonates were born with congenital heart block and 1 with neonatal lupus.</AbstractText>Pregnancy in SLE patients is associated with a higher risk of obstetric complications affecting both the mother and the fetus. Preeclampsia was the most common complication followed by prematurity. Preeclampsia was significantly associated with third trimester disease activity.</AbstractText>
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2,334,294 |
Mitochondria determine the differentiation potential of cardiac mesoangioblasts.
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An understanding of cardiac progenitor cell biology would facilitate their therapeutic potential for cardiomyocyte restoration and functional heart repair. Our previous studies identified cardiac mesoangioblasts as precommitted progenitor cells from the postnatal heart, which can be expanded in vitro and efficiently differentiated in vitro and in vivo to contribute new myocardium after injury.Based on their proliferation potential in culture, we show here that two populations of mesoangioblasts can be isolated from explant cultures of mouse and human heart.Although both populations express similar surface markers, together with a panel of instructive cardiac transcription factors, they differ significantly in their cellular content of mitochondria. Slow dividing (SD) cells, containing many mitochondria, can be efficiently differentiated with 5-azacytidine (5-aza) to generate cardiomyocytes expressing mature structural markers. In contrast, fast dividing (FD) mesoangioblasts, which contain decreased quantities of mitochondria, do not respond to 5-aza treatment.Notably, increasing mitochondrial numbers using pharmacological nitric oxide (NO) donors reverses the differentiation block in FD mesoangioblasts and leads to a progressive maturation to cardiomyocytes; conversely decreasing mitochondrial content, using respiratory chain inhibitors and chloramphenicol, perturbs cardiomyocyte differentiation in SD populations. Furthermore, isolated cardiac mesoangioblasts from aged mouse and human hearts are found to be almost exclusively mitochondria low FD populations, which are permissive for cardiomyocyte differentiation only after NO treatment. Taken together,this study illustrates a key role for mitochondria in cardiac mesoangioblast differentiation and raises the interesting possibility that treatments, which increase cellular mitochondrial content, may have utility for cardiac stem cell therapy.
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2,334,295 |
How do aminoadamantanes block the influenza M2 channel, and how does resistance develop?
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The interactions between channels and their cognate blockers are at the heart of numerous biomedical phenomena. Herein, we unravel one particularly important example bearing direct pharmaceutical relevance: the blockage mechanism of the influenza M2 channel by the anti-flu amino-adamantyls (amantadine and rimantadine) and how the channel and, consequently, the virus develop resistance against them. Using both computational analyses and experimental verification, we find that amino-adamantyls inhibit M2's H(+) channel activity by electrostatic hindrance due to their positively charged amino group. In contrast, the hydrophobic adamantyl moiety on its own does not impact conductivity. Additionally, we were able to uncover how mutations in M2 are capable of retaining drug binding on the one hand yet rendering the protein and the mutated virus resistant to amino-adamantyls on the other hand. We show that the mutated, drug-resistant protein has a larger binding pocket for the drug. Hence, despite binding the channel, the drug remains sufficiently mobile so as not to exert a H(+)-blocking positive electrostatic hindrance. Such insight into the blocking mechanism of amino-adamantyls, and resistance thereof, may aid in the design of next-generation anti-flu agents.
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2,334,296 |
Effects of stochastic channel gating and distribution on the cardiac action potential.
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Ion channels exhibit stochastic conformational changes determining their gating behavior. In addition, the process of protein turnover leads to a natural variability of the number of membrane and gap junctional channels. Nevertheless, in computational models, these two aspects are scarcely considered and their impacts are largely unknown. We investigated the effects of stochastic current fluctuations and channel distributions on action potential duration (APD), intercellular conduction delays (ICDs) and conduction blocks using a modified ventricular cell model (Rudy et al.) with Markovian formulations of the principal ion currents (to simulate their stochastic open-close gating behavior) and with channel counts drawn from Poisson distributions (to simulate their natural variability). In single cells, APD variability (coefficient of variation: 1.6% at BCL=1000ms) was essentially caused by stochastic channel gating of I(Ks), persistent I(Na) and I(Ca,L). In cell strands, ICD variability induced by stochastic channel gating and Poissonian channel distributions was low under normal conditions. Nonetheless, at low intercellular coupling levels, Poissonian gap junctional channel distribution resulted in a large ICD variability (coefficient of variation >20%), highly heterogeneous conduction patterns and conduction blocks. Therefore, the stochastic behavior of current fluctuations and channel distributions can contribute to the heterogeneity of conduction patterns and to conduction block, as observed previously in experiments in cardiac tissue with altered intercellular coupling.
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2,334,297 |
Dietary patterns are associated with levels of global genomic DNA methylation in a cancer-free population.
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Animal studies have provided direct evidence that dietary factors induce changes in DNA methylation patterns. In humans, studies on diet and DNA methylation have yielded inconsistent findings. Because humans tend to consume foods and nutrients that are highly interrelated, study of dietary patterns may have improved the power of detecting the effect of diet on DNA methylation. Using data collected from 149 participants aged 45-75 y in the North Texas Healthy Heart Study, we examined the relationship between dietary patterns and levels of genomic DNA methylation in peripheral blood leukocytes. Dietary data were collected from study participants using the Block FFQ. Genomic DNA methylation was measured using bisulfite conversion of DNA and real-time PCR (MethyLight) for LINE-1. Two dietary patterns were identified using factor analysis: a "prudent" dietary pattern characterized by a high intake of vegetables and fruits, and a "Western" dietary pattern characterized by a high intake of meats, grains, dairy, oils, and potatoes. The prudent dietary pattern was associated with a lower prevalence of DNA hypomethylation (Q(4) vs. Q(1); OR = 0.33, 95% CI: 0.12-0.92) and the association was dose dependent (P-trend = 0.04). There was no apparent association between the Western dietary pattern and global leukocyte DNA methylation (Q(4) vs. Q(1); OR = 1.28, 95% CI: 0.47-3.47; P-trend = 0.55). Thus, a dietary pattern characterized by a high intake of vegetables and fruits may protect against global DNA hypomethylation. Future studies with a larger sample size need to confirm that this association holds longitudinally.
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2,334,298 |
Trigeminocardiac reflex, bilateral sagittal split ramus osteotomy, Gow-Gates block: a randomized controlled clinical trial.
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The behavior of trigeminocardiac reflex (TCR) during maxillofacial surgeries has not yet been sufficiently studied and knowledge of its behavior is limited to some case reports. The present study aimed to assess the occurrence of TCR in bilateral sagittal split ramus osteotomy and to determine the possible effect of Gow-Gates block on its incidence.</AbstractText>Twenty candidates for bilateral sagittal split ramus osteotomy (included were American Society of Anesthesiologists I Class III patients with a prognathism of 3 to 5 mm) were given routine general anesthesia after at least 12 hours of fasting. All patients received Gow-Gates mandibular nerve block on 1 random side (case ramus; the other side was used as the control) after induction of general anesthesia before surgery. Pulse rate was recorded at baseline, soft tissue cutting, bone cutting, sagittal splitting, setback manipulation, and recovery. Mean pulse rate values were compared statistically using t test for the 2 sides in patients.</AbstractText>No statistically significant differences were found between the blocked and control sides except during ramus sagittal splitting and setback manipulation (P < .0001), when a significantly decreased pulse rate was recorded for the control ramus compared with the blocked ramus.</AbstractText>The present study provides further evidence for the complex neurophysiologic mechanism and probable prevention of peripheral TCR. The results of the present study should be further validated through future studies but already provide strong evidence that peripheral and central TCR may act differently based on slightly different pathways.</AbstractText>Copyright © 2011 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.</CopyrightInformation>
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2,334,299 |
Contribution of lifetime smoking habit in France and Northern Ireland to country and socioeconomic differentials in mortality and cardiovascular incidence: the PRIME Study.
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This study examines the contribution of lifetime smoking habit to the socioeconomic gradient in all-cause and smoking-related mortality and in cardiovascular incidence in two countries.</AbstractText>10,600 men aged 50-59 years were examined in 1991-4 in centres in Northern Ireland and France and followed annually for 10 years. Deaths and cardiovascular events were documented. Current smoking habit, lifetime smoking (pack-years) and other health behaviours were evaluated at baseline. As socio-occupational coding schemes differ between the countries seven proxy socioeconomic indicators were used.</AbstractText>Lifetime smoking habit showed marked associations with most socioeconomic indicators in both countries, but lifetime smoking was more than 10 pack-years greater overall in Northern Ireland and smoking patterns differed. Total mortality was 49% higher in Northern Ireland than in France, and smoking-related mortality and cardiovascular incidence were 93% and 92% higher, respectively. Both lifetime smoking and fibrinogen contributed independently to these differentials, but together explained only 42% of the difference in total mortality between countries, adjusted for both biological and lifestyle confounders. Socioeconomic gradients were steeper for total and smoking-related mortality than for cardiovascular incidence. Residual contributions of lifetime smoking habit ranged from 6% to 34% for the seven proxy indicators of socioeconomic position for total and smoking-related mortality. Socioeconomic gradients in cardiovascular incidence were minimal following adjustment for confounders.</AbstractText>In Northern Ireland and France lifetime smoking appeared to explain a significant part of the gradients in total and smoking-related mortality between socioeconomic groups, but the contribution of smoking was generally small for cardiovascular incidence.</AbstractText>
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