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2,332,200 | L-cysteine prevents oxidation-induced block of the cardiac Na+ channel via interaction with heart-specific cysteinyl residues in the P-loop region. | The present study investigated the protective effects of L-cysteine on the oxidation-induced blockade of Na+ channel a-subunits, hH1 (cardiac) and hSkM1 (skeletal), expressed in COS7 cells. Na+ currents were recorded by the whole-cell patch clamp technique (n = 3-7). L-cysteine alone blocked hH1 and hSkM1 in a dose-dependent manner, with saturating L-cysteine block at 3,000 micromol/L. Hg2+, a potent sulfhydryl oxidizing agent, blocked hH1 with a time to 50% inhibition (Time50%) of 20s. Preperfusion of COS7 cells with 100 micromol/L L-cysteine significantly slowed the Hg2+ block of hH1 (Time50% = 179 s). L-cysteine did not prevent Hg2+ block of hSkM1 (Time50% = 37s) or the C373Y hH1 mutant (Time50% = 43s). As for other sulfo-amino acids, homocysteine prevented the Hg2+ block of hH1, with the Time50% (70s) being significantly smaller than that of L-cysteine, whereas methionine did not prevent the Hg2+ block of hH1. L-cysteine did not prevent the Cd2+ block of hH1. These results indicate that L-cysteine selectively acts on heart-specific Cys373 in the P-loop region of hH1 to prevent Cys373 from the oxidation-induced sulfur-Hg-sulfur bridge formation. |
2,332,201 | A new method of continuous maxillary nerve block with an indwelling catheter. | We describe continuous maxillary nerve block at the pterygopalatine fossa and investigate the efficacy of this technique for perioperative pain control in oral surgery.</AbstractText>Sixteen patients undergoing radical maxillary sinusotomy were enrolled; group I (n = 8) received general anesthesia without maxillary nerve block, and group II (n = 8) received maxillary nerve block before general anesthesia. The intraoperative concentration of sevoflurane, the extent of blockade, and total analgesics (diclofenac sodium) needed after surgery were recorded.</AbstractText>The mean sevoflurane concentration was significantly lower in group II. Diclofenac sodium consumption was significantly reduced in group II.</AbstractText>Indwelling maxillary nerve catheter methods decrease anesthetic consumption and provide good postoperative analgesia.</AbstractText> |
2,332,202 | Use of piritramide for analgesia and sedation during peribulbar nerve block for cataract surgery. | To investigate the effects of pre-block analgesia and sedation using piritramide on haemodynamic stability, endocrine stress response and patients' pain perception.</AbstractText>In a randomized, single-blinded, placebo-controlled study, 60 patients having cataract surgery with peribulbar block were randomly assigned into two groups: group A (n = 30) received 0.05 mg/kg piritramide (Dipidolor) intravenously; group B received normal saline intravenously prior to peribulbar block. Mean arterial pressure, heart rate, respiratory rate and pulse oximetry were recorded perioperatively. Pain from peribulbar block was assessed using a verbal analogue scale. Urinary excretion of vanillylmandelic acid was measured to assess the endocrine stress response. Using a questionnaire, patients assessed their anxiety and back pain before and during surgery.</AbstractText>Mean arterial pressure remained near baseline in group A. In group B, a significant increase in mean arterial pressure after peribulbar block was found (p < 0.001). In addition, a significant increase in urinary excretion of vanillylmandelic acid was found in group B (p = 0.013). Pain scores (p < 0.001), anxiety before nerve block (p = 0.02) and during surgery (p < 0.001) and back pain (p = 0.003) were significantly lower in group A.</AbstractText>The presented study suggests that using piritramide for analgesia and sedation prior to peribulbar block produces haemodynamic stability and reduces pain perception and endocrine stress response.</AbstractText>Copyright 2002 S. Karger AG, Basel</CopyrightInformation> |
2,332,203 | Synthetic matrix metalloproteinase inhibitor decreases early cardiac neural crest migration in chicken embryos. | During early embryonic development, cardiac neural crest (NC) cells emerge from the forming neural tube, migrate beneath the ectoderm, enter the pharyngeal arches, and subsequently participate in the septation of the heart. Like tumor cells, NC cells penetrate through basement membranes and invade extracellular matrix during their emigration and migration and, therefore, are liable to use similar invasive mechanisms. Matrix metalloproteinases (MMPs) are a family of zinc proteolytic enzymes known to be important in cell migration and invasion of normal and metastatic cells. In an earlier study, we found that the spatial and temporal distribution pattern of MMP-2 positively correlates with cardiac NC migration, suggesting MMP enzymatic activity may be important in mediating cardiac cell NC migration. To test this hypothesis, a synthetic MMP inhibitor, KB8301, was used to block MMP enzymatic activity during in vitro and in vivo cardiac NC cell migration in chick embryos. Injection of KB8301 into the cell-free space adjacent to the neural tube at the level of the second somite before the NC cells emigrated caused major morphologic anomalies in embryos and disrupted cardiac NC morphogenesis. Unilateral injection of KB8301 at lower concentrations, significantly decreased cardiac NC migration on the injected side compared with the noninjected side and compared with that of the injected controls. This decrease correlated with a decrease in MMP activity in the embryos and was not attributable to differences in embryo size or rate of embryonic development after injection. KB8301 also significantly decreased the rate of NC cell motility and distance NC cells migrated from explanted neural tubes and increased cell area and perimeter. These data suggest that MMP enzymatic activity is an important mediator of early cardiac NC migration and that perturbation of endogenous MMP activity may lead to NC-related congenital defects. |
2,332,204 | Anaesthetic and postoperative analgesic effects of spinal clonidine as an additive to prilocaine in the transurethral resection of urinary bladder tumours. | The alpha 2-adrenoceptor agonist clonidine has potent central antinociceptive properties. The study was designed to investigate the effects of the combined subarachnoid administration of clonidine and prilocaine on spinal block and postoperative analgesia for the transurethral resection of tumours in the urinary bladder.</AbstractText>The controlled, prospective, double-blind study enrolled 40 patients scheduled for elective transurethral resection of bladder tumours under spinal anaesthesia with prilocaine. Patients were randomly assigned to receive an intrathecal injection of prilocaine 75 mg alone (control group) or in combination with clonidine 75 micrograms. We assessed haemodynamic changes (non-invasive arterial pressure, heart rate), pulse oximetry, the upper level of block, the onset and duration of sensory and motor block, postoperative analgesia and any adverse effects.</AbstractText>There were no statistically significant differences in demographic data, heart rate, onset time or the levels of sensory or motor block. Analgesia lasted significantly longer in the clonidine group (498.4 +/- 226.9 versus 187.2 +/- 103.1 min; P < 0.05). The duration of motor block was longer in the clonidine group (165.5 +/- 30.6 min) than in the control group (139.7 +/- 40.4 min; P < 0.05) and the duration of sensory block was also longer in the clonidine group (157.3 +/- 24.5 min) than in the control group (137.2 +/- 31.2 min; P < 0.05). Fewer patients in the recovery room needed metamizol (dipyrone) in the clonidine group (5%) than in the control group (50%). Arterial pressure decreased significantly in the clonidine group 75-135 min after the block.</AbstractText>The addition of clonidine 75 micrograms to prilocaine 75 mg for subarachnoid anaesthesia increased the duration of sensory and motor block and reduced the need for additional postoperative analgesics by providing excellent analgesia for about 8 h during recovery from transurethral resection of bladder tumours.</AbstractText> |
2,332,205 | Prophylactic IM small-dose phenylephrine blunts spinal anesthesia-induced hypotensive response during surgical repair of hip fracture in the elderly. | In a double-blinded, placebo-controlled, randomized study, we evaluated the effect of prophylactic IM phenylephrine at doses of 1.5 and 3 mg on hyperbaric tetracaine spinal anesthesia-induced hypotension in 90 normotensive and hypertensive patients aged >65 yr undergoing surgery for hip fracture. Thirty normotensive patients received 1.5 or 3 mg of phenylephrine IM (N/P-1.5 and N/P-3.0 groups; n = 15 in each), whereas controls received saline (N/C group; n = 15), and 45 hypertensive patients were treated in a similar manner (H/P-1.5, H/P-3.0, and H/C groups; n = 15 in each). All groups had a peak sensory block height of T9, with a range of T8 to T10. The incidence of hypotension (>25% decrease in mean arterial blood pressure [MAP] from baseline) was significantly lower in the patients who received phenylephrine 1.5 or 3 mg than in the controls, both in the normotensive and hypertensive groups (P < 0.01). The N/P-3.0 and N/P-1.5 groups and the H/P-3.0 group had significantly lower percentage reductions in MAP (P < 0.05) and required significantly smaller doses of rescue IV ephedrine (P < 0.05) than did the N/C group or the H/C group. The H/P-1.5 group also required significantly less rescue IV ephedrine (P < 0.05), although it was not sufficient to significantly attenuate the percentage decrease in MAP compared with that in the H/C group. Bradycardia (heart rate <50 bpm) as an adverse effect after IM administration of phenylephrine was not observed in any of the groups. Hypertension (MAP >20% increase from baseline) after medication occurred in the N/P-3.0 and H/P-3.0 groups, but not in the N/P-1.5 and H/P-1.5 groups. We conclude that prophylactic IM injection of 1.5 mg of phenylephrine is a safe (defined as the inhibition of bradycardia and hypertension) and effective means of reducing the incidence of hypotension associated with spinal anesthesia in normotensive and hypertensive elderly patients.</AbstractText>We evaluated the efficacy and safety of small-dose IM phenylephrine for prophylaxis against spinal anesthesia-induced hypotension in normotensive and hypertensive elderly patients. Phenylephrine 1.5 mg IM was effective for reducing the incidence of hypotension and avoided adverse effects.</AbstractText> |
2,332,206 | The dose-sparing effect of clonidine added to ropivacaine for labor epidural analgesia. | To determine the effects of clonidine with ropivacaine during epidural labor analgesia, we studied 66 nulliparous women in early active labor. Women were randomized to receive ropivacaine 0.1% 8 mL plus 75 microg of clonidine (Group 1), ropivacaine 0.2% 8 mL plus 0.5 mL of NaCl 0.9% (Group 2), or ropivacaine 0.2% 8 mL plus 75 microg of clonidine (Group 3) 5 min after a bupivacaine 7.5 mg with epinephrine 15 microg test dose. Upon request, additional analgesia with ropivacaine 0.1% 8 mL followed by ropivacaine 0.2% 8 mL/h was administered. With clonidine, duration of analgesia was increased (132 +/- 48 min [Group 1] and 154 +/- 42 min [Group 3] versus 91 +/- 44 min [Group 2]; P < 0.05), and total ropivacaine dose over the first 4 h was significantly reduced (40.5 +/- 15 mg [Group 1] and 47.0 +/- 16 mg [Group 3] versus 72.5 +/- 18 mg [Group 2]; P < 0.01). The incidence of more profound motor block was more frequent in Group 2 (P < 0.05). Although there was a trend for more women receiving clonidine to require ephedrine for treatment of hypotension, this did not seem to have an impact on fetal outcome or incidence of cesarean deliveries for nonreassuring fetal heart rate tracings. This study demonstrates the dose-sparing effect of clonidine when added to ropivacaine.</AbstractText>The effect of adding 75 microg of clonidine to ropivacaine for epidural labor analgesia was studied. Clonidine increased analgesia duration and produced dose sparing compared with ropivacaine alone. Despite a tendency for hypotension in women receiving clonidine, there was no apparent effect on delivery mode or neonatal outcome.</AbstractText> |
2,332,207 | Propofol-sufentanil anesthesia for thyroid surgery: optimal concentrations for hemodynamic and electroencephalogram stability, and recovery features. | Hypnotics and opioids interact synergistically to block responses to surgery and different dose combinations may be used to provide adequate anesthesia. In this study, we sought to determine the optimal concentrations of propofol and sufentanil, given by target-controlled infusions, to ensure hemodynamic stability, adequate hypnosis (assessed by electroencephalogram bispectral index), and fast recovery for a moderately painful operation. Forty-five patients, ASA physical status I or II, undergoing thyroidectomy, were randomly assigned to a sufentanil target concentration (STC) that was maintained throughout surgery (0.1, 0.2, or 0.3 ng/mL). The propofol target concentration was adjusted to keep mean arterial blood pressure within 30% of a reference value, and bispectral index between 40 and 60. Adequate anesthesia was obtained in all groups. Hypertension and clinically dangerous movements were more frequent with the small STC, and hypotension requiring treatment was more frequent with the large STC. Propofol target concentration during surgery decreased significantly with increasing STC (median at thyroid removal 5.0, 4.0, and 2.5 microg/mL, respectively) as well as the propofol consumption (740, 668, 474 mg/h). The 0.3 ng/mL STC significantly delayed the return of spontaneous breathing.</AbstractText>Given as a target-controlled infusion for thyroid surgery, sufentanil 0.3 ng/mL for intubation and 0.2 ng/mL during surgery, combined with propofol 4 microg/mL (corresponding to a maintenance infusion rate of approximately 7-10 mg. kg(-1). h(-1)), is recommended to ensure both optimal intraoperative stability and fast recovery.</AbstractText> |
2,332,208 | SOGC clinical practice guidelines. Hirsutism: evaluation and treatment. | To review the etiology, evaluation, and treatment of hirsutism.</AbstractText>A thorough history and physical examination plus selected laboratory evaluations will confirm the diagnosis and direct treatment.</AbstractText>Pharmacologic interventions can suppress ovarian or adrenal androgen production and block androgen receptors in the hair follicle. Hair removal methods and lifestyle modifications may improve or hasten the therapeutic response.</AbstractText>At least six to nine months of therapy are required to produce improvement in hirsutism.</AbstractText>The quality of evidence reported in this guideline has been determined using the criteria described by the Canadian Task Force on the Periodic Health Examination.</AbstractText>Hirsutism can be slowly but dramatically improved with a three-pronged approach to treatment: mechanical hair removal, suppression of androgen production, and androgen receptor blockade. Lifestyle changes including weight loss and exercise will lower serum androgen levels and improve self-esteem. The patient should be educated regarding associated health problems or long-term medical consequences of hyperandrogenism, including obesity, irregular menses, anovulation, infertility, pregnancy-induced hypertension, diabetes, hyperlipidemia, hypertension, and heart disease.</AbstractText> |
2,332,209 | Effect of addition of clonidine to local anaesthetic mixture for peribulbar block. | Clonidine added to local anaesthetics prolongs the duration of anaesthesia and analgesia of peripheral, neuraxial and retrobulbar blocks. The present randomized blinded controlled study was conducted to evaluate the effect of the addition of clonidine to local anaesthetic mixture on the quality, onset time, duration of peribulbar block, perioperative analgesia and patients' comfort. The study comprised two groups of 12 patients each. Group A (control) patients received 7 ml of a mixture of 2% lignocaine and hyaluronidase with 1 ml normal saline, while group B (clonidine group) patients had clonidine 1 microg/kg added to the above mixture. Onset and duration of lid akinesia, globe anaesthesia and akinesia, time to first analgesic medication and total analgesic requirement were assessed. Patients were monitored for heart rate, blood pressure, sedation and respiratory depression. Addition of clonidine to local anaesthetic mixture resulted in a significant increase in duration of lid akinesia (85.4+/-25.6 vs 173.3+/-35.3 min, P<0.001), globe anaesthesia (63.2+/-6.9 vs 78.8+/-17.5 min, P=0.012) and globe akinesia (161.3+/-24.3 vs 201.2+/-45.7 min, P=0.016). The onset time and quality of block were similar in both the groups. No significant haemodynamic, respiratory or sedative effects were recorded. The perioperative pain scores and the analgesic requirements were significantly (P<0.01) lower in group B patients. We found that addition of clonidine 1 microg/kg to local anaesthetic mixture significantly increases the duration of anaesthesia and analgesia after peribulbar block. |
2,332,210 | Transdifferentiation of cardiac fibroblasts, a fetal factor in anti-SSA/Ro-SSB/La antibody-mediated congenital heart block. | The signature lesion of autoantibody-associated congenital heart block (CHB) is fibrosis of the conducting tissue. To date, participation of myofibroblasts in the cascade to injury has been unexplored. The importance of myofibroblast/macrophage cross-talk is demonstrated by the novel finding of these cell types in the heart of a neonate dying of CHB. This clue to pathogenesis prompted consideration of the mechanism by which maternal anti-SSA/Ro-SSB/La Abs initiate an inflammatory response and promote fibrosis. Isolated cardiocytes from 16-24 wk abortuses were rendered apoptotic by exposure to poly (2-) hydroxyethylmethacrylate; flow cytometry confirmed surface expression of Ro/La. Apoptotic cardiocytes were incubated with affinity-purified Abs to 52 and 60 kDa Ro from CHB mothers (opsonized) or IgG fractions from healthy donors (nonopsonized). Macrophages cultured with opsonized apoptotic cardiocytes expressed proinflammatory markers, supported by a three-fold increase in active alpha(V)beta(3) integrin. Fetal cardiac fibroblasts exposed to supernatants obtained from macrophages incubated with opsonized apoptotic cardiocytes (but not nonopsonized) dramatically increased expression of the myofibroblast marker alpha-smooth muscle actin (SMAc). The "opsonized" supernatant reversed an inhibitory effect of the "nonopsonized" supernatant on proliferation of fibroblasts (120 vs 69%, p < 0.05). Parallel experiments examined the effects of two cytokines and their neutralizing Abs on fibroblasts. TGFbeta1 increased SMAc staining but decreased proliferation. TNF-alpha did not affect either readout. Addition of anti-TGFbeta1 Abs to the "opsonized" supernatant blocked SMAc expression but increased proliferation, while anti-TNF-alpha blocking Abs had no effects. These data suggest that transdifferentiation of cardiac fibroblasts to a scarring phenotype is a pathologic process initiated by maternal Abs. |
2,332,211 | Remote preconditioning by infrarenal occlusion of the aorta protects the heart from infarction: a newly identified non-neuronal but PKC-dependent pathway. | Ischemic preconditioning is a powerful mechanism in reducing infarct size of the heart. Protection can be performed either by an ischemic stimulus of the heart itself or by ischemia of an organ distant to the heart. To address the question whether this remote preconditioning is transduced by neuronal or humoral factors an in situ model of infrarenal occlusion of the aorta (IOA) in the rat was developed. Furthermore, the signal transduction pathways of classical and remote preconditioning regarding protein kinase C, which is one of the key enzymes in classical preconditioning, were compared.</AbstractText>Controls (30 min regional ischemia followed by 2 h of reperfusion) had an infarct size of 62+/-5% whereas classical preconditioning reduced it to 10+/-3% of the risk zone (P< or =0.001). Fifteen minutes IOA without reperfusion of the aorta had no influence on infarct size (52+/-4%). When, however, IOA was performed for 15, 10, or 5 min, respectively, followed by a 10-min reperfusion period the size of myocardial infarction decreased significantly. This decrease was dependent on the duration of IOA (18+/-3%, 37+/-8%, 42+/-2%, respectively; P< or =0.001 for the time-dependent linear trend in decrease of infarct size). Fifteen minutes IOA showed the strongest protection which was comparable to classical preconditioning (18+/-3%, P< or =0.001 vs. control). Blockade of the nervous pathway by 20 mg/kg hexamethonium could not inhibit the protection afforded by IOA (14+/-4%). Using chelerythrine, a selective protein kinase C-inhibitor, at a dose of 5 mg/kg body weight, protection from remote (68+/-4%, P< or =0.001 vs. 15 min IOA followed by 10 min of reperfusion without chelerythrine) as well as from classical preconditioning (56+/-5%, P< or =0.001) was completely blocked.</AbstractText>Protection of the heart by remote preconditioning using IOA is as powerful as classical preconditioning. Both protection methods share protein kinase C as a common element in their signal transduction pathways. Since hexamethonium could not block the protection from IOA and a reperfusion period has to be necessarily interspaced between the IOA and the infarct inducing ischemia of the heart, a neuronal signal transmission from the remote area to the heart can be excluded with certainty. A humoral factor must be responsible for the remote protection. Interestingly the production of the protecting factor is dependent on the duration of the ischemia of the lower limb. The protecting substance, which must be upstream of protein kinase C, remains to be identified.</AbstractText> |
2,332,212 | Rapid effects of aldosterone and spironolactone in the isolated working rat heart. | Chronic administration of aldosterone promotes myocardial fibrosis in rats. The Randomized Aldactone Evaluation Study reported that the aldosterone antagonist spironolactone improved outcome in patients with congestive heart failure, suggesting a deleterious effect of aldosterone in the heart. Aldosterone has been shown to have rapid nongenomic effects in different tissues including the heart. However, the hemodynamic actions of aldosterone and spironolactone are not well characterized. In this study, we examined the hemodynamic effects of aldosterone and its receptor antagonist, spironolactone, in the isolated rat heart by use of the Langendorff-Neely technique. Perfusion with 10 nmol/L aldosterone increased contractility by 45% within 2 to 4 minutes (P<0.01). Similar to the aldosterone effect, 10 nmol/L spironolactone increased contractility by 41% (P<0.01). Furthermore, 100-fold molar excess of spironolactone did not block the aldosterone effect. Perfusion of aldosterone plus spironolactone resulted in the highest increase in contractility 106% (P<0.01). The threshold response for aldosterone occurred within physiological concentrations (0.5 to 1 nmol/L), and maximal contractility was achieved with 10 nmol/L aldosterone. For spironolactone, the threshold and maximal contractile responses occurred at concentrations readily achieved with clinical dosing, 0.1 to 0.5 nmol/L and 1.0 nmol/L, respectively. These data demonstrate that aldosterone and spironolactone have rapid, positive inotropic actions on the myocardium. Moreover, addition of spironolactone to aldosterone increased contractility beyond the maximal responses elicited by each agent when perfused alone, thus suggesting different pathways of action. Furthermore, the intrinsic inotropic effects of spironolactone might be relevant to the apparent beneficial effect this compound has in patients with congestive heart failure. |
2,332,213 | Temperature control and recovery of bowel function after laparoscopic or laparotomic colorectal surgery in patients receiving combined epidural/general anesthesia and postoperative epidural analgesia. | We compared the effects of a laparoscopic (n = 23) versus laparotomic (n = 21) technique for major abdominal surgery on temperature control in 44 patients undergoing colorectal surgery during a combined epidural/general anesthesia. A thoracic epidural block up to T4 was induced with 6-10 mL of 0.75% ropivacaine; general anesthesia was induced with thiopental, fentanyl, and atracurium IV and maintained with isoflurane. Core temperature was measured with a bladder probe and recorded every 15 min after the induction. In both groups, core temperature decreased to 35.2 degrees C (range, 34 degrees C-36 degrees C) at the end of surgery. After surgery, normothermia returned after 75 min (60-120 min) in the Laparoscopy group and 60 min (45-180 min) in the Laparotomy group (P = 0.56). No differences in postanesthesia care unit discharge time were reported between the two groups. The degree of pain during coughing was smaller after laparoscopy than laparotomy from the 24th to the 72nd observation times (P < 0.01). Morphine consumption was 22 mg (2-65 mg) in the Laparotomy group and 5 mg (0-45 mg) in the Laparoscopy group (P = 0.02). The time to first flatus was shorter after laparoscopy (24 h [16-72 h]) than laparotomy (72 h [26-96 h]) (P = 0.0005), and the first intake of clear liquid occurred after 48 h (24-72 h) in the Laparoscopy group and after 96 h (90-96 h) in the Laparotomy group (P = 0.0005). Although laparoscopic surgery provides positive effects on the degree of postoperative pain and recovery of bowel function, the reduction in heat loss produced by minimizing bowel exposure with laparoscopic surgery does not compensate for the anesthesia-related effects on temperature control, and active patient warming must also be used with laparoscopic techniques.</AbstractText>This prospective, randomized, controlled study demonstrates that laparoscopic colorectal surgery results in less postoperative pain and earlier recovery of bowel function than conventional laparotomy but does not reduce the risk for perioperative hypothermia. Accordingly, active warming must be provided to patients also during laparoscopic procedures.</AbstractText> |
2,332,214 | Neural control of the heart: developmental changes in ionic conductances in mammalian intrinsic cardiac neurons. | The expression and properties of ionic channels were investigated in dissociated neurons from neonatal and adult rat intracardiac ganglia. Changes in the hyperpolarization-activated and ATP-sensitive K+ conductances during postnatal development and their role in neuronal excitability were examined. The hyperpolarization-activated nonselective cation current, Ih, was observed in all neurons studied and displayed slow time-dependent rectification. An inwardly rectifying K+ current, IK(IR), was present in a population of neurons from adult but not neonatal rats and was sensitive to block by extracellular Ba2+ Using the perforated-patch recording configuration, an ATP-sensitive K+ (KATP) conductance was identified in > or = 50% of intracardiac neurons from adult rats. Levcromakalim evoked membrane hyperpolarization, which was inhibited by the sulphonylurea drugs, glibenclamide and tolbutamide. Exposure to hypoxic conditions also activated a membrane current similar to that induced by levcromakalim and was inhibited by glibenclamide. Changes in the complement of ion channels during postnatal development may underlie observed differences in the function of intracardiac ganglion neurons during maturation. Furthermore, activation of hyperpolarization-activated and KATP channels in mammalian intracardiac neurons may play a role in neural regulation of the mature heart and cardiac function during ischaemia-reperfusion. |
2,332,215 | Effect of axillary brachial plexus blockade on baroreflex-induced skin vasomotor responses: assessing the effectiveness of sympathetic blockade. | The combination of laser Doppler flowmetry and non-invasive blood pressure monitoring allows the continuous observation of cutaneous vascular resistance (CVR). Continuous recording of unmodulated skin blood flow (SBF) is very sensitive to artefacts, rendering the method unreliable. In contrast, intermittent short lasting challenges of the CVR by cardiovascular autonomic reflexes may provide information about the responsiveness of the sympathetic nervous system in the skin.</AbstractText>Eleven patients with below-wrist hand surgery (six males and five females; aged 35.2+/-7.1 years) performed Valsalva maneuver following axillary blockade. Skin blood flow was continuously monitored on the forearm of the side axillary blockade, as well as on the contra-lateral forearm, which was used as the control. The responses were expressed as changes compared with the baseline level derived from a resting period of 30 s. The maximal change in CVR was determined during the late strain phase of the Valsalva maneuver on both sides. For numerical comparison the change in CVR on the axillary blockade and control sides were simultaneously calculated.</AbstractText>During the Valsalva maneuver a significant increase in CVR was observed on the control side with a maximum value during the late strain phase (baseline 0.18+/-0.1 and late strain phase 0.42+/-0.2 relative units; P<0.01). In contrast, only minimal changes were detected on the side of axillary blockade in CVR (baseline 0.17+/-0.8 and late strain 0.16+/-0.2 relative units; P=NS).</AbstractText>Our findings support the disputed hypothesis that the human skin microvasculature is involved in baroreflex regulation under thermoneutral conditions. The determination of baroreflex stimulus-induced microvascular responses may serve as a feasible method for monitoring the effectiveness of sympathetic blockade.</AbstractText> |
2,332,216 | Effects of right stellate ganglion block on the autonomic nervous function of the heart: a study using the head-up tilt test. | The effect of peripheral sympathetic block on the autonomic nerve function of the heart was studied using the head-up tilt test (HUTT) and right stellate ganglion block (RSGB). Blood pressure (BP), heart rate (HR) and the parameters of power spectral analysis of HR variability recorded during the HUTT were measured in 8 patients with chronic pain syndrome before and after RSGB. In the control state, the mean HR and the LF/HF component recorded during HUTT significantly increased whereas the HF component markedly decreased. Conversely, the mean HR and LF/HF and HF components during HUTT did not significantly alter after the RSGB procedure. There were no significant differences between the BP values before and after RSGB. These results suggest that RSGB suppresses cardiac sympathetic function without significantly affecting BP and thus may be a safe and effective therapy for the chronic pain syndrome. |
2,332,217 | Epinephrine is not a useful addition to intrathecal fentanyl or fentanyl-bupivacaine for labor analgesia. | Intrathecal fentanyl provides effective labor analgesia for a limited time with frequent side effects. We evaluated the effects of adding epinephrine to intrathecal fentanyl with and without bupivacaine.</AbstractText>Eighty healthy, term, nulliparous parturients with cervical dilation of 5 cm or less received combined spinal-epidural (CSE) analgesia. Subjects were randomized in a double-blind fashion to 1 of 4 intrathecal solutions containing fentanyl 35 microg with either saline (F); bupivacaine 2.5 mg + saline (FB); bupivacaine 2.5 mg + epinephrine 100 microg (FBE); or epinephrine 100 microg + saline (FE). Patients were evaluated for visual analog pain score, duration of spinal analgesia (time until patient request for additional analgesia), nausea/vomiting, pruritus, sensory and motor block, maternal blood pressure, and fetal heart rate (FHR).</AbstractText>Intrathecal bupivacaine significantly prolonged fentanyl analgesia with or without epinephrine (P =.018), but epinephrine did not significantly prolong the duration of fentanyl alone or with bupivacaine (F, 92 +/- 39 minutes; FB, 125 +/- 31 minutes; FBE, 134 +/- 42 minutes; and FE, 117 +/- 48 minutes). Intrathecal epinephrine was associated with a higher incidence of severe nausea (P =.001), and the FBE group had more lower extremity weakness (P =.047). There was no difference in the incidence of severe pruritus, FHR deceleration, or delivery outcome between the groups.</AbstractText>These results suggest that intrathecal epinephrine does not prolong the duration of fentanyl or fentanyl with bupivacaine for labor analgesia in nulliparous parturients. Additionally, intrathecal epinephrine did not decrease the incidence of side effects and therefore cannot be recommended.</AbstractText> |
2,332,218 | Effect of intrathecal non-NMDA EAA receptor antagonist LY293558 in rats: a new class of drugs for spinal anesthesia. | Excitatory amino acid receptors are important for both sensory and motor function in the spinal cord. We studied the effects of intrathecal LY293558, a competitive non-N-methyl-D-aspartate excitatory amino acid receptor antagonist, on motor and sensory function in rats to determine whether drugs blocking these receptors could potentially be used as alternative agents to local anesthetics for spinal anesthesia.</AbstractText>Rats were tested before and 15-240 min after intrathecal injection of 5 nmol (in 10 microl) LY293558. Sensory function was tested at the hind paw using withdrawal response to pin prick and withdrawal to pinch with sharp forceps. Motor performance (ambulation, placing reflex, and Rotorod time), blood pressure, and heart rate were also evaluated. Some tests were repeated the next day. Responses after LY293558 were compared to injection of 40 microl bupivacaine, 0.75%. Pin-prick responses at the forepaw, chest, abdomen, hind leg, and hind paw were also examined after intrathecal LY293558.</AbstractText>Intrathecal LY293558 blocked both sensory and motor responses through 180 min; complete recovery was present the following day. No change in blood pressure or heart rate occurred. The effects of LY293558 were more pronounced and sustained than those of bupivacaine. Segmental blockade of the response to pin prick was present after LY293558.</AbstractText>Drugs like LY293558 that block alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA)/kainate receptors may be an alternative to local anesthetics for spinal anesthesia in humans.</AbstractText> |
2,332,219 | Contribution of N-methyl-d-aspartate receptors in the anteroventral third ventricular region to vasopressin secretion, but not to cardiovascular responses provoked by hyperosmolality and prostaglandin E2 in conscious rats. | The aim of this study is to pursue roles of N-methyl-d-aspartate (NMDA) receptors in the anteroventral third ventricular region (AV3V; a pivotal area for autonomic functions) in controlling vasopressin (AVP) release and cardiovascular system. In conscious rats, we examined effects of AV3V infusion of MK-801 (a selective antagonist for NMDA receptor) on plasma AVP, osmolality, electrolytes, arterial pressure and heart rate, in the absence or presence of NMDA, hyperosmotic or prostaglandin (PG) E2 stimulus. The AV3V infusion of NMDA caused significant increases in plasma AVP, osmolality and sodium, hematocrit, arterial pressure and heart rate after 5 or 15min. When NMDA was administered into the cerebral ventricle, relatively smaller elevations were observed only in plasma AVP and arterial pressure. The effects of AV3V infusion of NMDA were nearly completely prevented by MK-801 applied to the same region before 15min. The application of MK-801 was also potent to block rises of plasma AVP elicited by AV3V injection of PGE2 or i.v. infusion of hypertonic saline. However, it inhibited neither increases of arterial pressure and heart rate due to the PGE2 treatment nor those of arterial pressure, plasma osmolality and sodium in response to the osmotic load. Histological analysis on the AV3V infusion sites of NMDA, MK-801 and PGE2 indicated that they had been located in the structures such as the median and medial preoptic nuclei, periventricular nucleus and medial preoptic area. These results suggest that stimulation of AV3V NMDA receptors in the basal state may facilitate AVP secretion and cause pressor and tachycardiac actions, and that these receptors may be involved in both the hyperosmolality- and PGE2-induced hormone release, but not in the cardiovascular responses to these stimuli. |
2,332,220 | Involvement of sigma receptors in the behavioral effects of cocaine: evidence from novel ligands and antisense oligodeoxynucleotides. | Pharmacological and molecular biological tools were used to validate the involvement of sigma receptors in the actions of cocaine. Radioligand binding studies demonstrated significant levels of sigma receptors in the brain and heart, where cocaine interacts preferentially with the sigma(1) subtype. In behavioral pharmacological studies using mice, nine novel sigma receptor antagonists significantly attenuated cocaine-induced convulsions, while structural analogs with weak interactions with sigma receptors were ineffective. In contrast to the protection provided by the antagonists, a classical sigma receptor agonist exacerbated the convulsive effects of cocaine. The antagonists also attenuated cocaine-induced lethality, with the best compound protecting against death even when administered as a post-treatment. At doses where the antagonists had no effect on baseline locomotor activity, they significantly attenuated the locomotor stimulatory effects of cocaine, suggesting their ability to block the psychomotor as well as the toxic effects of cocaine. To further validate that the anti-cocaine effects were achieved by interfering with cocaine's access to sigma receptors, antisense oligodeoxynucleotides against sigma(1) receptors were shown to attenuate the convulsive and locomotor stimulatory effects of cocaine. Together, the studies support the involvement of sigma receptors, particularly the sigma(1) subtype, in the behavioral effects of cocaine. |
2,332,221 | NF-kappaB as a therapeutic target in cancer. | The transcription factor nuclear factor (NF)-kappaB is activated in certain cancers and in response to chemotherapy and radiation. The transcriptional activation of genes associated with cell proliferation, angiogenesis, metastasis and suppression of apoptosis appears to lie at the heart of the ability of NF-kappaB to promote oncogenesis and cancer therapy resistance. Supporting these findings are recent experiments, performed in vitro and using xenograft models of cancer, which implicate NF-kappaB inhibition as an important new approach for the treatment of certain hematological malignancies and as an adjuvant approach in combination with chemotherapy or radiation for a variety of cancers. Clinical trials with drugs that block NF-kappaB are currently in progress with promising results. However, as there is currently no drug that blocks specific NF-kappaB activation, conclusions drawn with small-molecule inhibitors must be interpreted carefully. |
2,332,222 | Microcomplex--a new incomplete heart block pattern. | This article reports a new, transient, but identical electrocardiogram presentation in 2 patients at 2 different institutions. While its mechanism is uncertain, analysis by exclusion suggests that a diffusely prolonged but nonhomogenous myocardial refractoriness may have altered both QRS morphology and amplitude and also may have resulted in periods of 2:1 AV block. |
2,332,223 | Spatial characteristics of sarcoplasmic reticulum Ca2+ release events triggered by L-type Ca2+ current and Na+ current in guinea-pig cardiac myocytes. | Ca2+ signals in cardiac muscle cells are composed of spatially limited elementary events termed Ca2+ sparks. Several studies have also indicated that Ca2+ signals smaller than Ca2+ sparks can be elicited. These signals have been termed Ca2+ quarks and were proposed to result from the opening of a single Ca2+ release channel of the sarcoplasmic reticulum. We used laser-scanning confocal microscopy to examine the subcellular properties of Na+ current (I(Na))- and L-type Ca2+ current (I(Ca,L))-induced Ca2+ transients in voltage-clamped ventricular myocytes isolated from guinea-pigs. Both currents, I(Na) and I(Ca,L), evoked substantial, global Ca2+ transients. To examine the spatiotemporal properties of such Ca2+ signals, we performed power spectral analysis of these Ca2+ transients and found that both lacked spatial frequency components characteristic for Ca2+ sparks. The application of 10 microM verapamil to partially block L-type Ca2+ current reduced the corresponding Ca2+ transients down to individual Ca2+ sparks. In contrast, I(Na)-induced Ca2+ responses were still spatially homogeneous and lacked Ca2+ sparks even for small current amplitudes. By using high resistance patch pipettes (> 4 MOmega) to exaggerate the loss of voltage control during I(Na), Ca2+ sparks appeared superimposed on a homogeneous Ca2+ release component and were exclusively triggered during the flow of I(Na). In the presence of 10 microM ryanodine both I(Ca,L) and I(Na) elicited small, residual Ca2+ transients that were spatially homogeneous but displayed distinctively different temporal profiles. We conclude that I(Na) is indeed able to cause Ca2+ release in guinea-pig ventricular myocytes. In contrast to I(Ca,L)-induced Ca2+ transients, which are built up from the recruitment of individual Ca2+ sparks, the I(Na)-evoked cellular responses were always homogeneous, indicating that their underlying elementary Ca2+ release event is distinct from the Ca2+ spark. Thus, I(Na)-induced Ca2+ transients are composed of smaller Ca2+ signals, most likely Ca2+ quarks. |
2,332,224 | A serologic marker for fetal risk of congenital heart block. | To analyze the humoral immune response to Ro/SSA and La/SSB antigens in detail, in order to identify markers in mothers at high risk of having children with congenital heart block (CHB).</AbstractText>Serum samples were obtained from 9 Ro/La-positive mothers who gave birth to affected children, from their 8 newborns with CHB, and from 26 Ro/La-positive mothers whose children were healthy. Antibodies against Ro 52-kd, Ro 60-kd, and La were analyzed by enzyme-linked immunosorbent assay and immunoblotting, using recombinant proteins and synthetic peptides.</AbstractText>IgG anti-Ro 52-kd antibodies were detected in all mothers who gave birth to children with CHB, as well as in their affected children, but were less frequent and at lower levels in control mothers. Fine mapping revealed a striking difference in which the response in mothers with affected children was dominated by antibodies to amino acids 200-239 of the Ro 52-kd protein (P = 0.0002), whereas the primary activity in control mothers was against amino acids 176-196 (P = 0.001). Furthermore, 8 of 9 mothers of children with CHB had antibody reactivity against amino acids 1-135 of the Ro 52-kd protein, containing 2 putative zinc fingers reconstituted under reducing conditions.</AbstractText>The results suggest that development of CHB is strongly dependent on a specific antibody profile to Ro 52-kd, which may be a useful tool to identify pregnant Ro/La-positive women at risk of delivering a baby with CHB. Close monitoring of mothers at high risk would enable early detection of a block that is still developing and allow early treatment to combat more serious complications.</AbstractText> |
2,332,225 | The highly selective CRF(2) receptor antagonist K41498 binds to presynaptic CRF(2) receptors in rat brain. | 1. Novel analogues of antisauvagine-30 (aSvg-30), a selective antagonist for CRF(2) receptors, have been synthesized and characterized in vitro and in vivo. 2. The analogues were tested for their ability to compete for [(125)I-Tyr(0)]Svg binding and to inhibit Svg-stimulated adenylate cyclase activity in human embryonic kidney (HEK) 293 cells, permanently transfected with cDNA coding for the human CRF(1) (hCRF(1)), hCRF(2alpha) and hCRF(2beta) receptor. One analogue [D-Phe(11), His(12), Nle(17)]Svg(11-40), named K41498, showed high affinity binding to hCRF(2alpha) (K(i)=0.66+/-0.03 nM) and hCRF(2beta) (K(i)=0.62+/-0.01 nM) but not the hCRF(1) receptor (k(i)=425+50 nM) and decreased Svg-stimulated cAMP accumulation in hCRF(2) expressing cells. In conscious Wistar-Kyoto rats, K41498 (1.84 microg, i.v.) antagonized the hypotensive response to systemic urocortin (1.4 microg, i.v.), but did not block the pressor response to centrally administered urocortin (2.35 microg, i.c.v.). 3. K41498 was subsequently radio-iodinated, and in autoradiographic studies, specific (sensitive to rat urocortin, astressin and aSvg30, but insensitive to antalarmin) binding of (125)I-K41498 (100 pM) was detected in the heart and in selected brain regions including the nucleus tractus solitarius (NTS), spinal trigeminal nucleus, lateral septum and around the anterior and middle cerebral arteries. 4. Following unilateral nodose ganglionectomy, binding of (125)I-K41498 was reduced by 65% in the ipsilateral NTS, indicative of presynaptic CRF(2) receptors on vagal afferent terminals. 5. These data demonstrate that K41498 is a useful tool to study native CRF(2) receptors in the brain and periphery. |
2,332,226 | A case of Kearns-Sayre syndrome with autoimmune thyroiditis and possible Hashimoto encephalopathy. | The Kearns-Sayre syndrome (characterized by onset before 20, chronic ophthalmoplegia, pigmentary retinal degeneration and at least 1 of the following symptoms: ataxia, heart block and high protein content in the cerebrospinal fluid) is a severe variant of chronic progressive external ophthalmoplegia (CPEO) with frequent re-arrangements of the mitochondrial DNA (mtDNA). The aim of this paper is to report a sporadic paediatric case of Kearns-Sayre syndrome with mtDNA heteroplasmic deletion, absence of cytochrome c oxidase in many muscle fibers, autoimmune thyroiditis followed by depressive phobic disturbances, slowing EEG, hyperreflexia, tremor and visual hallucinations, in which the diagnosis of possible encephalopathy associated with autoimmune thyroid disease (Hashimoto encephalopathy) was made. We speculated that in this patient, predisposed by mitochondrial deletion, anti-thyroid antibodies may have interfered with mitochondrial cerebral function, causing Hashimoto encephalopathy and facilitating ophthalmoplegia. It seems important to study anti-thyroid antibodies in every case of Kearns-Sayre syndrome, specially if ophthalmoplegia is recent, even in order to the therapy. |
2,332,227 | Comparison of effects of anti-IL-3, IL-5 and GM-CSF treatments on eosinophilopoiesis and airway eosinophilia induced by allergen. | Allergic inflammation is dominated by eosinophils. IL-3, IL-5, and GM-CSF are involved in production and activation of eosinophils. IL-5 has been reported to be crucial for the induction of airway eosinophilia. However, the contribution of IL-3 and GM-CSF to allergic airway inflammation remains to be determined. To address this issue, ovalbumin-sensitized Balb/c mice were repeatedly exposed to allergen via airway route. Animals were pretreated intraperitoneally with neutralising anti-IL-3, anti-IL-5 and/or anti-GM-CSF antibodies. Newly produced inflammatory cells were pulse-labelled with the thymidine analogue 5-bromo-2'-deoxyuridine (BrdU), which is incorporated into DNA during the cell mitosis. BAL and bone marrow cells were collected 24 h after the last allergen exposure, and differential cell counts and immunocytochemical detection of BrdU-labelled cells were performed. Anti-IL-5 strongly reduced both BAL and bone marrow eosinophilia, as well as the number of BrdU-positive BAL-granulocytes. In contrast, anti-IL-3 and anti-GM-CSF alone had little and no inhibitory effect on these responses, respectively. Even the combined treatment with anti-IL-3 and anti-GM-CSF showed only a non-significant tendency to attenuate these responses. These data suggest that the efficacy of treatments with anti-IL-3 and anti-GM-CSF is much weaker than that with anti-IL-5. IL-5 may be the preferred target to block eosinophilia in allergic diseases. |
2,332,228 | [Heart blocks in gallstone]. | In this study, I analysed the AV blocks and BB blocks which I found in gallstone.</AbstractText>The objectives were to find if the heart blocks are in relationship with gallstone or not.</AbstractText>From 1122 patients with gallstone--13 had the AV blocks and 95 had BB blocks. All of these were examined: physical examinations, abdominal echography and Ecg.</AbstractText>This study, 1.15% from the patients had AV blocks and 6.68% had BB blocks, especially RBB blocks, LBB blocks and AV1 block.</AbstractText>I approximate that these diseases of the heart can coexist with gallstone.</AbstractText> |
2,332,229 | A new brachial plexus block technique in dogs. | To evaluate the feasibility and efficacy of a new technique of brachial plexus anesthesia in dogs.</AbstractText>Prospective, experimental study.</AbstractText>Twelve adult mongrel dogs, six males and six females weighing 14.8 ± 1.75 kg.</AbstractText>The animals were sedated with acepromazine 0.05 mg kg-1</sup> and anesthetized with propofol (6 mg kg-1</sup>, IV bolus) followed by an infusion of 212 μg kg-1</sup> minute-1</sup>. The brachial plexus block technique was performed utilizing the brachial artery as an anatomic landmark, the needle was inserted from the axilla and a nerve stimulator was used to ensure the accuracy of needle placement. Bupivacaine (0.375% with 5 μg mL-1</sup> epinephrine) was used at a dose rate of 4 mg kg-1</sup>. Dogs underwent mid-diaphyseal osteotomies of the humerus followed by intramedullary pin fixation.</AbstractText>Onset time to motor and sensory block were 9.70 ± 5.52 and 26.20 ± 8.86 minutes, respectively. Analgesia lasted for 11.11 ± 0.47 hours. The block was effective in 91.6% of the animals, being verified by anesthesia of the whole front limb distal to the shoulder. One animal became hypotensive after the block and did not undergo the surgery at that time. In the remaining 10 animals the heart and respiratory rates, blood pressure, blood gas parameters and plasma bicarbonate concentration did not show any statistically significant alterations during the surgical procedure.</AbstractText>This brachial plexus block technique is effective in most cases to provide surgical analgesia for the front limb distal to the shoulder.</AbstractText>Various surgical procedures in the front limb can be performed with a regional anesthetic technique without the use and concomitant risks of general anesthesia in dogs. Long-lasting analgesia associated with this technique may also provide a valuable tool for the management of pain in the forelimb.</AbstractText>Copyright © 2002 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.</CopyrightInformation> |
2,332,230 | [Neonatal lupus: clinical features and risk of congenital cardiac heart block in newborns from mothers with anti Ro/SSA antibodies]. | OBJECTIVE: To assess the prevalence of Congenital Heart Block (CHB) in newborns from anti Ro/SS-A antibodies positive mothers affected by connective tissue diseases (CTD) and to evaluate the prevalence of other manifestations of Neonatal Lupus (NL) and the electrocardiographic abnormalities. METHODS: A prospective study was conducted on 100 anti Ro/SS-A positive mothers that were followed before and during their 118 pregnancies (4 twin pregnancies and 18 second pregnancies). Counterimmunoelectroforesis (CIE) and immunoblot (IB) were used to test antibodies to extractable nuclear antigens (ENA). RESULTS: Only 2 cases of CHB (1.8%) were found among the 112 living newborns. In one case the mother with primary Sjögren's Syndrome (pSS) was anti Ro 60 and 52kD positive while in the other case the mother affected by undifferentiated connective tissue disease (UCTD) was anti Ro 60kD and anti La positive. No fetal death was due to CHB. There were no cutaneous rashes at birth while mild hepatic enzyme alterations were observed in 21 (68%) of the 31 tested newborns. In 22 healthy newborns an ECG have been registered and in 4 cases (18.2%) sinus bradycardia was found. During the follow up 7 suckling showed Cutaneous Neonatal Lupus. Moreover a six month girl developed Kawasaki Syndrome. CONCLUSIONS: The risk of delivering a child with CHB is 1.8% in anti Ro/SS-A positive mothers with CTD. This finding is extremely important in the preconceptional counseling of anti-Ro/SS-A positive women. Furthermore mild electrocardiographic abnormalities may be found in their healthy newborns. |
2,332,231 | The relative motor blocking potencies of epidural bupivacaine and ropivacaine in labor. | Minimal local analgesic concentrations (MLAC) have been used to determine the epidural analgesic potencies of bupivacaine and ropivacaine. There are no reports of the motor blocking potencies of these drugs. We sought to determine the motor block MLAC of both drugs and their relative potency ratio. Sixty ASA physical status I and II parturients were randomized to one of two groups, during the first stage of labor. Each received a 20-mL bolus of epidural bupivacaine or ropivacaine. The first woman in each group received 0.35%. Up-down sequential allocation was used to determine subsequent concentrations at a testing interval of 0.025%. Effective motor block was defined as a Bromage score <4 within 30 min. The up-down sequences were analyzed by using the Dixon and Massey method and probit regression to quantify the motor block minimal local analgesic concentration. Two-sided P < 0.05 defined significance. The motor block minimal local analgesic concentration for bupivacaine was 0.326% (95% confidence interval [CI], 0.285-0.367) and for ropivacaine was 0.497% (95% CI, 0.431-0.563) (P = 0.0008). The ropivacaine/bupivacaine potency ratio was 0.66 (95% CI, 0.52-0.82). This is the first MLAC study to estimate the motor blocking potencies of bupivacaine and ropivacaine. Ropivacaine was significantly less potent for motor block, at 66% that of bupivacaine.</AbstractText>The results of this study demonstrate that epidural ropivacaine is less potent than epidural bupivacaine in producing motor blockade during labor. The motor block potency relation is similar to the sensory potency ratio for these two drugs.</AbstractText> |
2,332,232 | Solution structure of peptide toxins that block mechanosensitive ion channels. | Mechanosensitive channels (MSCs) play key roles in sensory processing and have been implicated as primary transducers for a variety of cellular responses ranging from osmosensing to gene expression. This paper presents the first structures of any kind known to interact specifically with MSCs. GsMTx-4 and GsMtx-2 are inhibitor cysteine knot peptides isolated from venom of the tarantula, Grammostola spatulata (Suchyna, T. M., Johnson, J. H., Hamer, K., Leykam, J. F., Gage, D. A., Clemo, H. F., Baumgarten, C. M., and Sachs, F. (2000) J. Gen. Physiol. 115, 583-598). Inhibition of cationic MSCs by the higher affinity GsMtx-4 (K(D) approximately 500 nm) reduced cell size in swollen and hypertrophic heart cells, swelling-activated currents in astrocytes, and stretch-induced arrhythmias in the heart. Despite the relatively low affinity, no cross-reactivity has been found with other channels. Using two-dimensional NMR spectroscopy, we determined the solution structure of GsMTx-4 and a lower affinity (GsMTx-2; K(D) approximately 6 microm) peptide from the same venom. The dominant feature of the two structures is a hydrophobic patch, utilizing most of the aromatic residues and surrounded with charged residues. The spatial arrangement of charged residues that are unique to GsMTx-4 and GsMTx-2 may underlie the selectivity of these peptides. |
2,332,233 | Effects of streptomycin sulphate on I(CaL), I(Kr) and I(Ks) in guinea-pig ventricular myocytes. | In single guinea pig ventricular myocytes, streptomycin sulphate (streptomycin) reduced intracellular Ca(2+) transients (IC(50) 1.9 mM) and contractility (IC(50) 1.0 mM), 2 mM streptomycin prolonged the action potential. Under switch voltage clamp, 2 mM streptomycin reduced the L-type Ca(2+) current (I(CaL)) amplitude and (Ca(2+)-dependent) relative inactivation at positive membrane potentials and reduced the rapid and slow components of the delayed rectifier current (I(K)). This latter effect seemed Ca(2+)-dependent, not being seen when nifedipine and BAPTA were used to reduce intracellular Ca(2+). Fifty micromolars of streptomycin had no significant effects on any parameter studied. We conclude that the negative inotropic effect of streptomycin results from blockade of I(CaL), and thus, a reduction of intracellular Ca(2+) transients, while prolongation of the action potential is more consistent with effects on I(K). These observations link mechanical and electrical effects of streptomycin that may be important, for example, when streptomycin is used to block stretch-activated events in cardiac muscle. |
2,332,234 | Pathogenic mechanisms of sand tampan toxicoses induced by the tick, Ornithodoros savignyi.<Pagination><StartPage>1007</StartPage><EndPage>1016</EndPage><MedlinePgn>1007-16</MedlinePgn></Pagination><Abstract><AbstractText>The tick, Ornithodoros savignyi has been implicated in inducing paralysis and tampan toxicosis. In this study, a basic toxin (TSGP4) was identified and the presence of an acidic toxin (TSGP2) was confirmed. Both basic and acidic toxins were more lethal than previously described, with TSGP4 (34microg) and TSGP2 (24microg) causing mortality of adult mice within 30min. Pathological effects on the cardiac system, notably of salivary gland extract on an isolated rat heart perfusion system and of purified toxins on mouse electrocardiogram patterns could be observed. TSGP4 caused Mobitz type ventricular block, while TSGP2 induced ventricular tachycardia. Conversely, fractions from reversed phase high performance liquid chromatography preparations caused paralysis-like symptoms of the limbs after only 48h. The toxins also differ from previously described tick paralysis toxins in terms of molecular behavior and properties. These results indicate that tampan toxicoses and tick paralysis are unrelated pathogenic phenomena.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Mans</LastName><ForeName>Ben J</ForeName><Initials>BJ</Initials><AffiliationInfo><Affiliation>Department of Biochemistry, University of Pretoria, South Africa.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Steinmann</LastName><ForeName>Christiaan M L</ForeName><Initials>CM</Initials></Author><Author ValidYN="Y"><LastName>Venter</LastName><ForeName>Jacobus D</ForeName><Initials>JD</Initials></Author><Author ValidYN="Y"><LastName>Louw</LastName><ForeName>Abraham I</ForeName><Initials>AI</Initials></Author><Author ValidYN="Y"><LastName>Neitz</LastName><ForeName>Albert W H</ForeName><Initials>AW</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></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>Toxicon</MedlineTA><NlmUniqueID>1307333</NlmUniqueID><ISSNLinking>0041-0101</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D019476">Insect Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D014020">Tissue Extracts</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D014118">Toxins, Biological</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D002851" MajorTopicYN="N">Chromatography, High Pressure Liquid</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D066298" MajorTopicYN="N">In Vitro Techniques</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D019476" MajorTopicYN="N">Insect Proteins</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName><QualifierName UI="Q000633" MajorTopicYN="N">toxicity</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D051379" MajorTopicYN="N">Mice</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D009200" MajorTopicYN="N">Myocardial Contraction</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D026861" MajorTopicYN="N">Ornithodoros</DescriptorName><QualifierName UI="Q000472" MajorTopicYN="N">pathogenicity</QualifierName><QualifierName UI="Q000502" MajorTopicYN="Y">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D051381" MajorTopicYN="N">Rats</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D017207" MajorTopicYN="N">Rats, Sprague-Dawley</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D012469" MajorTopicYN="N">Salivary Glands</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D013984" MajorTopicYN="Y">Tick Infestations</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D013985" MajorTopicYN="N">Tick Paralysis</DescriptorName><QualifierName UI="Q000209" MajorTopicYN="Y">etiology</QualifierName><QualifierName UI="Q000503" MajorTopicYN="N">physiopathology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D014020" MajorTopicYN="N">Tissue Extracts</DescriptorName><QualifierName UI="Q000008" MajorTopicYN="N">administration & dosage</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D014118" MajorTopicYN="N">Toxins, Biological</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName><QualifierName UI="Q000633" MajorTopicYN="N">toxicity</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D018754" MajorTopicYN="N">Ventricular Dysfunction</DescriptorName><QualifierName UI="Q000139" MajorTopicYN="N">chemically induced</QualifierName><QualifierName UI="Q000503" MajorTopicYN="N">physiopathology</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2002</Year><Month>6</Month><Day>22</Day><Hour>10</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2003</Year><Month>2</Month><Day>8</Day><Hour>4</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2002</Year><Month>6</Month><Day>22</Day><Hour>10</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">12076655</ArticleId><ArticleId IdType="doi">10.1016/s0041-0101(02)00098-3</ArticleId><ArticleId IdType="pii">S0041010102000983</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">12076486</PMID><DateCompleted><Year>2002</Year><Month>08</Month><Day>09</Day></DateCompleted><DateRevised><Year>2018</Year><Month>12</Month><Day>21</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Electronic">1469-493X</ISSN><JournalIssue CitedMedium="Internet"><Issue>2</Issue><PubDate><Year>2002</Year></PubDate></JournalIssue><Title>The Cochrane database of systematic reviews</Title><ISOAbbreviation>Cochrane Database Syst Rev</ISOAbbreviation></Journal>Cardioselective beta-blockers for chronic obstructive pulmonary disease. | The tick, Ornithodoros savignyi has been implicated in inducing paralysis and tampan toxicosis. In this study, a basic toxin (TSGP4) was identified and the presence of an acidic toxin (TSGP2) was confirmed. Both basic and acidic toxins were more lethal than previously described, with TSGP4 (34microg) and TSGP2 (24microg) causing mortality of adult mice within 30min. Pathological effects on the cardiac system, notably of salivary gland extract on an isolated rat heart perfusion system and of purified toxins on mouse electrocardiogram patterns could be observed. TSGP4 caused Mobitz type ventricular block, while TSGP2 induced ventricular tachycardia. Conversely, fractions from reversed phase high performance liquid chromatography preparations caused paralysis-like symptoms of the limbs after only 48h. The toxins also differ from previously described tick paralysis toxins in terms of molecular behavior and properties. These results indicate that tampan toxicoses and tick paralysis are unrelated pathogenic phenomena.</Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Mans</LastName><ForeName>Ben J</ForeName><Initials>BJ</Initials><AffiliationInfo><Affiliation>Department of Biochemistry, University of Pretoria, South Africa.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Steinmann</LastName><ForeName>Christiaan M L</ForeName><Initials>CM</Initials></Author><Author ValidYN="Y"><LastName>Venter</LastName><ForeName>Jacobus D</ForeName><Initials>JD</Initials></Author><Author ValidYN="Y"><LastName>Louw</LastName><ForeName>Abraham I</ForeName><Initials>AI</Initials></Author><Author ValidYN="Y"><LastName>Neitz</LastName><ForeName>Albert W H</ForeName><Initials>AW</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></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>Toxicon</MedlineTA><NlmUniqueID>1307333</NlmUniqueID><ISSNLinking>0041-0101</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D019476">Insect Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D014020">Tissue Extracts</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D014118">Toxins, Biological</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D002851" MajorTopicYN="N">Chromatography, High Pressure Liquid</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D066298" MajorTopicYN="N">In Vitro Techniques</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D019476" MajorTopicYN="N">Insect Proteins</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName><QualifierName UI="Q000633" MajorTopicYN="N">toxicity</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D051379" MajorTopicYN="N">Mice</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D009200" MajorTopicYN="N">Myocardial Contraction</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D026861" MajorTopicYN="N">Ornithodoros</DescriptorName><QualifierName UI="Q000472" MajorTopicYN="N">pathogenicity</QualifierName><QualifierName UI="Q000502" MajorTopicYN="Y">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D051381" MajorTopicYN="N">Rats</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D017207" MajorTopicYN="N">Rats, Sprague-Dawley</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D012469" MajorTopicYN="N">Salivary Glands</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D013984" MajorTopicYN="Y">Tick Infestations</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D013985" MajorTopicYN="N">Tick Paralysis</DescriptorName><QualifierName UI="Q000209" MajorTopicYN="Y">etiology</QualifierName><QualifierName UI="Q000503" MajorTopicYN="N">physiopathology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D014020" MajorTopicYN="N">Tissue Extracts</DescriptorName><QualifierName UI="Q000008" MajorTopicYN="N">administration & dosage</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D014118" MajorTopicYN="N">Toxins, Biological</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName><QualifierName UI="Q000633" MajorTopicYN="N">toxicity</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D018754" MajorTopicYN="N">Ventricular Dysfunction</DescriptorName><QualifierName UI="Q000139" MajorTopicYN="N">chemically induced</QualifierName><QualifierName UI="Q000503" MajorTopicYN="N">physiopathology</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2002</Year><Month>6</Month><Day>22</Day><Hour>10</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2003</Year><Month>2</Month><Day>8</Day><Hour>4</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2002</Year><Month>6</Month><Day>22</Day><Hour>10</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">12076655</ArticleId><ArticleId IdType="doi">10.1016/s0041-0101(02)00098-3</ArticleId><ArticleId IdType="pii">S0041010102000983</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">12076486</PMID><DateCompleted><Year>2002</Year><Month>08</Month><Day>09</Day></DateCompleted><DateRevised><Year>2018</Year><Month>12</Month><Day>21</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Electronic">1469-493X</ISSN><JournalIssue CitedMedium="Internet"><Issue>2</Issue><PubDate><Year>2002</Year></PubDate></JournalIssue><Title>The Cochrane database of systematic reviews</Title><ISOAbbreviation>Cochrane Database Syst Rev</ISOAbbreviation></Journal><ArticleTitle>Cardioselective beta-blockers for chronic obstructive pulmonary disease.</ArticleTitle><Pagination><StartPage>CD003566</StartPage><MedlinePgn>CD003566</MedlinePgn></Pagination><Abstract><AbstractText Label="BACKGROUND" NlmCategory="BACKGROUND">Beta-blocker therapy has a proven mortality benefit in patients with hypertension, heart failure and coronary artery disease, as well as during the perioperative period. These drugs have traditionally been considered contraindicated in patients with chronic obstructive pulmonary disease (COPD).<AbstractText Label="OBJECTIVES" NlmCategory="OBJECTIVE">To assess the effect of cardioselective beta-blockers on respiratory function of patients with COPD.<AbstractText Label="SEARCH STRATEGY" NlmCategory="METHODS">A comprehensive search of EMBASE, MEDLINE and CINAHL was performed using the Cochrane Airways Group registry to identify randomised blinded controlled trials from 1966 to May 2001. The search was completed using the terms: asthma*, bronchial hyperreactivity*, respiratory sounds*, wheez*, obstructive lung disease* or obstructive airway disease*, and adrenergic antagonist*, sympatholytic* or adrenergic receptor block*. We did not exclude trials on the basis of language.<AbstractText Label="SELECTION CRITERIA" NlmCategory="METHODS">Randomised, blinded, controlled trials of single dose or longer duration that studied the effects of cardioselective beta-blockers on the forced expiratory volume in 1 second (FEV1) or symptoms in patients with COPD.<AbstractText Label="DATA COLLECTION AND ANALYSIS" NlmCategory="METHODS">Two independent reviewers extracted data from the selected articles, reconciling differences by consensus. Two interventions studied were the administration of beta-blocker, given either as a single dose or for longer duration, and the use of beta2-agonist given after the study drug.<AbstractText Label="MAIN RESULTS" NlmCategory="RESULTS">Eleven studies of single-dose treatment and 8 of treatment for longer duration, ranging from 2 days to 12 weeks, met selection criteria. Cardioselective beta-blockers produced no statistically significant change in FEV1 or respiratory symptoms compared to placebo, given as a single dose (Weighted Mean Difference -2.05% [95% Confidence interval, -6.05 to 1.96%]) or for longer duration (WMD -2.55% [95% CI, -5.94 to 0.84]), and did not significantly affect the FEV1 treatment response to beta2-agonists. Exacerbations and hospitalizations were recorded in all trials, but none occurred during the periods of study, in either group. A subgroup analysis revealed no significant change in results for those participants with severe chronic airways obstruction or for those with a reversible obstructive component.<AbstractText Label="REVIEWER'S CONCLUSIONS" NlmCategory="CONCLUSIONS">The available evidence suggests that cardioselective beta-blockers, given to patients with COPD do not produce a significant short-term reduction in airway function or in the incidence of COPD exacerbations. However, the trials were small and of short duration. Given their demonstrated benefit in conditions such as heart failure, coronary artery disease and hypertension, cardioselective beta-blockers should be considered for patients with COPD, but administered with careful monitoring since data concerning long term administration and their effects during exacerbations are not available. |
2,332,235 | The protective and anti-protective effects of ethanol in a myocardial infarct model. | Recent data indicate that acute alcohol exposure can have a preconditioning-like protective effect on the heart. We investigated the effect of ethanol exposure shortly before regional ischemia in an infarct model. Both in the open-chest rabbit and in the isolated rabbit heart, exposure of the heart to ethanol significantly reduced infarct size, but only if the alcohol were washed out or sufficiently metabolized before the onset of ischemia. If ethanol were still present during ischemia, it could not only prevent its own protective effect, but also abolish protection induced by ischemic preconditioning or the mitochondrial K(ATP) channel activator diazoxide. In the in vitro model, we tested for possible mediators of ethanol-induced protection and made comparisons to the signaling cascade of ischemic preconditioning. Neither adenosine receptor blockade with 8-(p-sulfophenyl) theophylline, scavenging of free radicals with N-2-mercaptopropionyl glycine, nor closure of K(ATP) channels with glibenclamide affected ethanol's protective effect. However, either a PKC inhibitor or a protein tyrosine kinase inhibitor could completely block ethanol-induced infarct size reduction. Both the protective and anti-protective effects of ethanol had a threshold of about 5 mM. Thus, ethanol-induced protection is mediated by protein kinase C and at least one protein tyrosine kinase, but, in contrast to ischemic preconditioning, is not triggered by either adenosine receptors, free radicals, or K(ATP) channels. Ethanol can only exert its protective effect if it is removed before the onset of ischemia. If still present during ischemia, ethanol has the opposite effect, and inhibits preconditioning by an as yet unidentified mechanism. |
2,332,236 | Influence of anesthetic flow rate delivered by the Wand Local Anesthetic System on pain response to palatal injections. | To compare pain response between two different flow rates (slow versus fast) of local anesthetic solution injected into palatal tissue using the recently available Wand Local Anesthetic System (WLAS), which provides the technologic advance to permit reliable replication of constant injection flow rates, regardless of tissue resistance.</AbstractText>Twenty adult subjects received bilateral palatal injections of local anesthetic in random sequence during the same appointment following topical anesthesia application. Pain response was measured by subjective self-report using a visual analogue scale, a quantified verbal descriptor scale, and a comparison to prior injection experience, as well as an operator's global assessment of the subject's pain response. Heart rate, as a physiologic indicator of pain response, was also recorded.</AbstractText>All measurements of pain response were statistically less for the slow compared to the fast injection rate. No significant difference in mean heart rate, however, was demonstrated between the two flow rates. A slow, constant flow rate (161 sec/mL) of a 0.3 mL volume of local anesthetic solution was statistically less painful than a fast flow rate (29 sec/mL) during palatal injection. Contrary to the manufacturer's claim, the WLAS reduced but did not eliminate pain elicited by palatal injections in some patients.</AbstractText> |
2,332,237 | Cocaine binds to a common site on open and inactivated human heart (Na(v)1.5) sodium channels. | The inhibition by cocaine of the human heart Na+ channel (Na(v)1.5) heterologously expressed in Xenopus oocytes was investigated. Cocaine produced little tonic block of the resting channels but induced a characteristic, use-dependent inhibition during rapid, repetitive stimulation, suggesting that the drug preferentially binds to the open or inactivated states of the channel. To investigate further the state dependence, depolarizing pulses were used to inactivate the channels and promote cocaine binding. Cocaine produced a slow, concentration-dependent inhibition of inactivated channels, which had an apparent K(D) of 3.4 microM. Mutations of the interdomain III-IV linker that remove fast inactivation selectively abolished this high-affinity component of cocaine inhibition, which appeared to be linked to the fast inactivation of the channels. A rapid component of cocaine inhibition persisted in the inactivation-deficient mutant that was enhanced by depolarization and was sensitive to changes in the concentration of external Na+, properties that are consistent with a pore-blocking mechanism. Cocaine induced a use-dependent inhibition of the non-inactivating mutant and delayed the repriming at hyperpolarized voltages, indicating that the drug slowly dissociated when the channels were closed. Mutation of a conserved aromatic residue (Y1767) of the D4S6 segment weakened both the inactivation-dependent and the pore-blocking components of the cocaine inhibition. The data indicate that cocaine binds to a common site located within the internal vestibule and inhibits cardiac Na+ channels by blocking the pore and by stabilizing the channels in an inactivated state. |
2,332,238 | Open channel block by KCB-328 [1-(2-amino-4-methanesulfonamidophenoxy)-2-[N-(3,4-dimethoxyphenethyl)-N-methylamino]ethane hydrochloride] of the heterologously expressed human ether-a-go-go-related gene K+ channels. | KCB-328 [1-(2-amino-4-methanesulfonamidophenoxy)-2-[N-(3,4-dimethoxyphenethyl)-N-methylamino]ethane hydrochloride] is a newly synthesized class III antiarrhythmic drug and is known to be highly effective against various types of arrhythmias induced by coronary artery ligation, reperfusion, and programmed electrical stimulation. To understand the potential ionic mechanisms, we examined the effects of KCB-328, which encodes the rapidly activating delayed rectifier K(+) current in cardiac tissues, on human ether-a-go-go-related gene (HERG) channels expressed in Xenopus oocytes. The amplitudes of steady-state currents and tail currents of HERG were decreased by KCB-328 dose dependently. The decrease became more pronounced at more positive potential, suggesting that the block of HERG by KCB-328 is voltage-dependent. IC(50) values at -30, -20, -10, 0, +10, +20, +30, and +40 mV were 7.6 +/- 0.5, 4.8 +/- 0.4, 3.2 +/- 0.3, 2.1 +/- 0.3, 1.7 +/- 0.2, 1.4 +/- 0.2, 1.3 +/- 0.1, and 1.2 +/- 0.1 microM, respectively. Induction of block depended on depolarization beyond the threshold for channel opening. In addition, time-dependent block developed slowly, with tau = 1.7 +/- 0.3 s (100 microM) at 0 mV, and was delayed by a stronger depolarization to +80 mV, at which HERG channel is inactivated. We can conclude that KCB-328 preferentially blocks open (or activated) HERG channels. The block of HERG current might in part explain the underlying ionic mechanism for the antiarrhythmic and proarrhythmic effect of KCB-328. |
2,332,239 | Evidence that NOS2 acts as a trigger and mediator of late preconditioning induced by acute systemic hypoxia. | Chronic systemic hypoxia (SH) enhances myocardial ischemic tolerance in mammals. We studied the delayed cardioprotection caused by acute SH and associated signaling mechanism. Conscious adult male mice were exposed to one or two cycles of hypoxia (H; 10% O(2)) or normoxia (21% O(2)) for various durations (30 min, 2 h, 4 h) followed by 24 h of reoxygenation. Hearts were isolated 24 h later and subjected to ischemia-reperfusion in a Langendorff model. Infarct size was reduced in mice pretreated with one (H4h) or two cycles (H4hx2) of 4 h SH compared with normoxia mice (P < 0.05), which was abolished by an inducible nitric oxide synthase (NOS2) inhibitor (S-methylisothiourea, 3 mg/kg) given before SH or ischemia. H4hx2 also failed to reduce infarct size in NOS2 knockout mice. Cyclooxygenase-2 (COX-2) inhibitor (NS-398, 10 mg/kg) did not block the protection given either before H4hx2 or ischemia. A two- to three fold increase in myocardial NOS2 expression was observed in H4h, H2hx2, and H4hx2 (P < 0.05), whereas endothelial NOS (NOS3) or COX-2 remained unchanged. We conclude that acute SH induces delayed cardioprotection, which is triggered and mediated by NOS2, but not by NOS3 or COX-2. |
2,332,240 | Hypoxia influences generation and propagation of electrical activity in embryonic cardiomyocyte clusters. | The influence of tissue hypoxia on the generation and propagation of excitation was studied in spontaneously beating embryonic cardiomyocyte clusters grown in eight 9-12 days old embryoid bodies. Within the embryoid bodies one to three separately active clusters of cardiomyocytes were found, each having its own pacemaker cell. Lowering of tissue PO(2) caused bradycardia as well as arrhythmia in all embryoid bodies investigated. The mean frequency of the extracellularly recorded action potentials decreased under conditions of pronounced hypoxia from a mean of 1.4-1.8 Hz to below 0.8 Hz. In three embryoid bodies hypoxia-sensitive as well as hypoxia-tolerant cardiomyocyte clusters were found. The hypoxia-insensitive cardiomyocytes showed a low frequency of spontaneous activity. In addition to the observed changes in the generation of excitation, tissue hypoxia caused an approximately 60% reduction in the velocity of conduction within the cardiomyocyte clusters. Moreover, in at least one of the eight experiments propagation failure with an incomplete block in spread of excitation was observed. All hypoxia-induced effects on generation and propagation of embryonic cardiomyocyte excitation were completely reversible after reoxygenation. |
2,332,241 | Outcome of pregnancy in Asian women with systemic lupus erythematosus: experience of a single perinatal centre in Singapore. | To study maternal and fetal outcomes in women with systemic lupus erythematosus (SLE).</AbstractText>Retrospective study of 27 pregnancies in 18 women with SLE in a single centre.</AbstractText>The mean age was 30 years and most patients were nulliparous. Twenty-six of 27 pregnancies were in disease remission at the time of booking. Renal impairment was present in 7 pregnancies (6 women), of whom 2 were in end-stage renal disease on dialysis. Gestational diabetes developed in 4 pregnancies. There were 6 cases of pre-existing hypertension and 5 with superimposed pre-eclampsia. One woman developed intrapartum eclampsia. Two women had secondary antiphospholipid syndrome (APS) and suffered late fetal losses; in addition, they also developed SLE flares in the form of autoimmune haemolytic anaemia in the postpartum period. There was no maternal mortality. There was one termination of pregnancy for severe renal disease. The median gestational age at delivery was 38 weeks (range, 24 to 40 weeks) and the mean birth weight was 3047 g; the median Apgar scores were 8 and 9 at 1 and 5 minutes of life, respectively. There were 5 cases of intrauterine growth restriction (IUGR), 4 of which occurred in women with renal impairment. There were no cases of congenital heart block or neonatal lupus. There was a late fetal loss at 24 weeks in a woman with secondary APS. There were 2 preterm deliveries (7.4%) due to intervention for IUGR.</AbstractText>Good pregnancy outcomes can be expected in women with SLE in remission. Pre-pregnancy counselling is crucial to achieve this. All pregnancies should still be considered high risk and be managed jointly between the obstetricians, the perinatologists and the physicians. In particular, those with renal impairment are at increased risk of IUGR, superimposed pre-eclampsia and preterm births. Co-existing APS augurs a poorer prognosis for pregnancy outcome, and may present atypically as autoimmune haemolytic anaemia in the postpartum period.</AbstractText> |
2,332,242 | [Annual report of perioperative mortality and morbidity for the year 2000 at certified training hospitals of Japanese Society of Anesthesiologists: with a special reference to anesthetic methods--report of the Japanese Society of Anesthesiologists Committee on Operating Room Safety]. | The Committee on Operating Room Safety of Japan Society of Anesthesiologists (JSA) sends annually confidential questionnaires of perioperative mortality and morbidity (cardiac arrest, severe hypotension, severe hypoxia) to Certified Training Hospitals of JSA. This report is a special reference to anesthetic methods in perioperative mortality and morbidity in 2000. Five hundreds and twenty hospitals reported perioperative mortality and morbidity referred to anesthetic methods and total numbers of reported cases were 910,007. The percentage of cases reported by each anesthetic method was as follows; inhalation anesthesia 45.47%, total intravenous anesthesia (TIVA) 6.15%, inhalation anesthesia + epidural or spinal or conduction block 24.48%, TIVA + epidural or spinal or conduction block 6.33%, spinal with continuous epidural block (CSEA) 3.67%, epidural anesthesia 1.92%, spinal anesthesia 10%, conduction block 0.47% and others 1.49%. The incidence of cardiac arrest per 10,000 cases due to all etiology (anesthetic management, preoperative complications, intraoperative complications, surgery, others) is estimated to be 6.55 cases in average; 5.36 cases in inhalation anesthesia, 30.72 cases in total intravenous anesthesia (TIVA), 4.62 cases in inhalation anesthesia + epidural or spinal or conduction block, 2.6 cases in TIVA + epidural or spinal or conduction block, 1.2 cases in spinal with continuous epidural block (CSEA), 0.57 cases in epidural anesthesia, 1.65 cases in spinal anesthesia, 2.36 cases in conduction block and 46.38 cases in other methods. However, the incidence of cardiac arrest per 10,000 cases totally attributable to anesthetic management is estimated to be 0.54 cases in average; 0.34 cases in inhalation anesthesia, 1.07 cases in TIVA, 0.58 cases in inhalation anesthesia + epidural or spinal or conduction block, 0.17 cases in TIVA + epidural or spinal or conduction block, 0.9 cases in CSEA, 0.57 cases in epidural anesthesia, 0.99 cases in spinal anesthesia, zero case in conduction block and 1.47 cases in other methods. The incidence of severe hypotension per 10,000 cases due to all etiology is estimated to be 11.14 cases in average; 11.31 cases in inhalation anesthesia, 36.61 cases in TIVA, 9.29 cases in inhalation anesthesia + epidural or spinal or conduction block, 6.59 cases in TIVA + epidural or spinal or conduction block, 3.59 cases in CSEA, 6.3 cases in epidural anesthesia, 4.39 cases in spinal anesthesia, 2.36 cases in conduction block and 23.56 cases in other methods. On the other hand, the incidence of severe hypotension per 10,000 cases totally attributable to anesthetic management is estimated to be 1.25 cases in average; 0.97 cases in inhalation anesthesia, 0.89 cases in TIVA, 1.39 cases in inhalation anesthesia + epidural or spinal or conduction block, 1.39 cases in TIVA + epidural or spinal or conduction block, 2.09 cases in CSEA, 3.44 cases in epidural anesthesia, 1.87 cases in spinal anesthesia, zero case in conduction block and zero case in other methods. The incidence of severe hypoxia per 10,000 cases due to all etiology is estimated to be 4.8 cases in average; 6.35 cases in inhalation anesthesia, 9.64 cases in TIVA, 3.82 cases in inhalation anesthesia + epidural or spinal or conduction block, 2.26 cases in TIVA + epidural or spinal or conduction block, 0.3 cases in CSEA, 1.15 case in epidural anesthesia, 1.21 cases in spinal anesthesia, zero case in conduction block and 5.89 cases in other methods. On the other hands, the incidence of severe hypoxia per 10,000 cases totally attributable to anesthetic management is estimated to be 1.98 cases in average; 3.09 cases in inhalation anesthesia, 2.32 cases in TIVA, 1.3 cases in inhalation anesthesia + epidural or spinal or conduction block, 0.87 cases in TIVA + epidural or spinal or conduction block, zero case in CSEA, zero case in epidural anesthesia, 0.55 cases in spinal anesthesia, zero case in conduction block and zero case in other methods. The mortality rate of cardiac arrest within 7 postoperative days per 10,000 cases due to all etiology is estimated to be 3.55 (54.2%) cases in average; 3.12 (58.1%) cases in inhalation anesthesia, 19.29 (62.8%) cases in TIVA, 1.17 (25.2%) cases in inhalation anesthesia + epidural or spinal or conduction block, 0.52 (20%) cases in TIVA + epidural or spinal or conduction block, zero cases in CSEA, zero case in epidural anesthesia, 0.33 (20%) cases in spinal anesthesia, zero case in conduction block and 39.76 (85.7%) cases in other methods. On the other hands, the mortality rate of cardiac arrest per 10,000 cases totally attributable to anesthesia is estimated to be 0.07 (12.2%) case in average, 0.07 (21.4%) case in inhalation anesthesia, 0.18 (16.8%) case in TIVA, zero case in inhalation anesthesia + epidural or spinal or conduction block, zero case in TIVA + epidural or spinal or conduction block, zero case in CSEA, zero case in epidural anesthesia, 0.11 (11.1%) case in spinal anesthesia, zero case in conduction block and 0.74 (50%) case in other methods. Five major combinations of listed critical incidents, causes and anesthetic methods were as follows: 18.93 cases in TIVA, preoperative complications and severe hypotension; 18.75 cases in TIVA, preoperative complications and cardiac arrest; 11.07 cases in TIVA, surgery and severe hypotension; 6.79 cases in TIVA, surgery and cardiac arrest; 5.24 cases in inhalation anesthesia, preoperative complications and severe hypotension. In summary: 1. There was no significant difference with regard to perioperative mortality and morbidity due to anesthetic management among anesthetic methods. 2. The percentage of each anesthetic method in 2000 was not different significantly from that in 1999 in spite of increased cases reported. 3. Incidence of severe hypotension due to all etiology of TIVA in 2000 decreased significantly compared with that in 1999 (P < 0.05). This may be attributed to the decreased incidence in preoperative complication (shock) and massive bleeding due to surgery. |
2,332,243 | [Neonatal lupus erythematosus and neurologic involvement: an incidental association?]. | Neonatal lupus erythematosus is a rare disorder characterized by cutaneous lesions of the face and/or congenital heart block. The transplacental transfer of maternal anti-Ro/SSA, anti-La/SSB, or anti-U1RNP antibodies is responsible for the development of the disease. Few cases of neonatal lupus erythematosus with neurological involvement were reported in the medical literature.</AbstractText>A 36-week GA female infant presented with neonatal lupus erythematosus comprising cutaneous, hematologic and hepatic disorders with a favorable outcome. However, cutaneous atrophy and hyperpigmentation persisted. Spastic paraparesis was diagnosed at the age of six months.</AbstractText>The neurological lesions in neonatal lupus erythematosus could either be related to the presence of anti-Ro/SSA antibodies of maternal origin, or of anticardiolipin antibodies.</AbstractText> |
2,332,244 | Cardiotoxicity of new antihistamines and cisapride. | Although the new second-generation nonsedative antihistamines terfenadine and astemizole were launched as highly selective and specific H(1)-receptor antagonists, they were later found to cause prolongation of the QT-interval and severe cardiac arrhythmias. The prolongation of the QT-interval is caused by the blockade of one or more of the cardiac potassium channels, among which the delayed rectifier I(Kr), encoded by the HERG-gene, appears to be the most significant. The potency of the prokinetic drug cisapride to block I(Kr) appears to be similar to that of terfenadine (IC(50) about 50 nmol/l). These drugs cause problems when overdosed, used in combination with inhibitors of their CYP3A4-mediated metabolism, or when given to individuals with altered drug kinetics (the aged) or patients with existing cardiac disease (congenitally long QT). Moreover, interactions with other QT-interval prolonging drugs require special attention. Active hydrophilic metabolites of the second-generation antihistaminic compounds (ebastine-carebastine, loratadine-desloratadine, terfenadine-fexofenadine, astemizole-norastemizole) are new compounds with probably reduced risk for drug interactions and cardiac toxicity. |
2,332,245 | Teratogen-induced activation of caspase-9 and the mitochondrial apoptotic pathway in early postimplantation mouse embryos. | Previously we showed that teratogen-induced cell death in mouse embryos is apoptotic in nature, i.e., involves the release of cytochrome c from mitochondria and the subsequent activation of caspase-3, cleavage of poly (ADP-ribose) polymerase (PARP), and internucleosomal DNA fragmentation. Herein we show that hyperthermia, 4-hydroperoxycyclophosphamide, and staurosporine also activate caspase-9, the apical caspase in the mitochondrial apoptotic pathway. Activation of procaspase-9 is associated with the cleavage of this proenzyme and the generation of two forms of the large subunit, primarily a 39-kDa subunit (p39) but also a lesser amount of a 37-kDa subunit (p37). We also present data that support the idea that the teratogen-induced formation of the p37 subunit in vivo occurs by the cytochrome c-mediated processing of procaspase-9, whereas the p39 subunit is formed by an amplification loop involving caspase-3. We also previously showed that the release of cytochrome c, activation of caspase-3, cleavage of PARP, and DNA fragmentation are blocked in cells of the developing heart, which are resistant to teratogen-induced cell death. We now show that this block in the mitochondrial apoptotic pathway in heart cells extends to the activation of procaspase-9. Thus, our cumulative data indicate that hyperthermia, 4-hydroperoxycyclophosphamide, and staurosporine induce cell death in Day 9 mouse embryos by activating the mitochondrial apoptotic pathway. In addition, our data suggest that cells of the Day 9 mouse embryo that are resistant to teratogen-induced cell death possess multiple mechanisms for inhibiting the mitochondrial apoptotic pathway after a teratogenic exposure. |
2,332,246 | [Continuous postoperative epidural analgesia in abdominal surgery using ropivacain]. | We studied the selective block on patients receiving epidural Ropivacain (R) infusion for postoperative analgesia after major abdominal surgery. Twenty patients received R and twenty patients received Bupivacain (B) via peridural catheter during and after surgery. The patients' age ranged between 40 and 80 and they belonged to ASA I, II and III risk group. The epidural catheter was inserted one day before surgery and the proper position was tested by 80 mg Lidocaine. The epidural needle was inserted via T10-L1 interspaces in upper abdominal surgery and through L1-L3 interspaces in lower abdominal surgery. After the operation continuous epidural infusion of 2 mg/ml solution of R or 2.5 mg/ml solution of B was started. The infusion rate was changed according to the grade of sensory and motor block. The following parameters were observed during the postoperative 72 hours: blood pressure, heart rate, arterial blood O2 saturation, modified Bromage (BMG) score, verbal analogue scale (VAS), the spread of sensory block. Satisfactory sensory blockade was achieved with both local anaesthetics. The required daily dose of R and B increased during 72 hours. VAS scores reached their maximum level within 24 hours and were lower in the R group than in the B group but the difference was not significant. We experienced that 0.25% B causes more intense motor block than 0.2% R in equianalgetic dose but the difference did not reach a significant level. The infusion rate was often decreased because of the unwanted motor block caused by 0.25% B leading to insufficient postoperative analgesia. Because of this fact patients receiving B required opioid addition more often. Our conclusion is that R/B relative dose ratio is 1.2 suggesting that these local anaesthetics have different analgesic potency. |
2,332,247 | Assessment of the effect of dextromethorphan and ketamine on the acute nociceptive threshold and wind-up of the second pain response in healthy male volunteers. | The aim of this study was to assess the efficacy of dextromethorphan and ketamine relative to placebo on the acute nociceptive threshold and wind-up of second pain response in healthy male volunteers.</AbstractText>The trial was a randomized, double-blind, placebo-controlled, three period crossover, double dummy design in 12 healthy male volunteers. During each of the three periods (which were separated by a 1 week washout period) each volunteer received either a single oral dose of 0.7 mg kg(-1) dextromethorphan and placebo to ketamine, or placebo to dextromethorphan followed by a single intravenous injection of 0.375 mg kg(-1) ketamine, or placebo to both dextromethorphan and ketamine. The trial did not schedule administration of both ketamine and dextromethorphan together. Acute nociceptive thresholds and wind-up of second pain were measured in the skin of the thenar eminence of the ventral surfaces of the right and left hands, using a SOMEDIC thermotest apparatus, before and at the estimated tmax for dextromethorphan (i.e. 2.15 h). Blood pressure and heart rate were also monitored before dosing and after the dosing regimen.</AbstractText>Neither dextromethorphan nor ketamine had any significant effect on acute nociceptive thresholds on either hand (P>0.05). Moreover, dextromethorphan was without any significant effect (P>0.05) on the wind-up of the second pain response on either hand. The lsmean number of stimuli tolerated vs placebo (95% confidence intervals of the difference in number of stimuli in parentheses) were 15.84 vs 16.48 (-5.52, 4.24) and 11.75 vs 15.25 (-11.89, 4.90) for left- and right-hand, respectively, following dextromethorphan administration. In contrast ketamine produced significant reductions in wind-up to second pain in both the left and right hands (P=0.0002 and 0.0386, respectively). The lsmean numbers of stimuli tolerated vs placebo (95% confidence intervals of the difference in number of stimuli in parentheses) were 28.41 vs 16.48 (6.60, 17.25) and 25.00 vs 15.25 (0.58, 18.93) for left- and right-hand, respectively.</AbstractText>Wind-up of second pain induced by noxious heat is sensitive to intervention by ketamine, which is known to block the NMDA receptor. These data infer that the wind-up phenomenon evoked by noxious heat involves the activation of NMDA receptors. This volunteer model of pain may have utility in the evaluation of agents that modulate their antinociceptive actions via NMDA mechanisms.</AbstractText> |
2,332,248 | Disrupting effects of polychlorinated biphenyls on gonadal development and reproductive functions in chickens. | Polychlorinated biphenyls (PCBs) are worldwide persistent pollutants that have produced detrimental effects on endocrine function and reproduction in a variety of species. The present study revealed effects of PCBs on gonadal development and functions in chickens of different ages. Aroclor 1254 (0-100 microg/egg) was injected into Hyline chicken eggs before incubation. The adult chickens received Aroclor 1254 by gavage (50 mg/kg BW). It was observed that in day 5 embryos, PCBs resulted in a dose-dependent decrease of primordial germ cell (PGC) numbers, and caused PGCs pyknosis and vacuolation. Clomiphen failed to block the effects of PCBs. In the newly hatched chicken, PCBs induced a marked decrease in area of the transverse sections, diameter and relative area of the testicular tubules. The differentiation of germ cells was retarded after PCB treatment. In contrast, the area of the left ovarian transverse sections, the thickness of ovarian cortex and the number of oocytes increased dramatically in the female chickens after PCB exposure. In the adult chickens, PCBs caused no significant changes in body weight, respiration, heart rate, body temperature, red and white blood cell number, but induced a marked decrease in the testicular weight, and severe damage of the seminiferous tubules. The number of the spermatogenic cells and serum testosterone level were decreased significantly by PCBs. On the contrary, in the laying hens there was no significant effect of PCB on egg quality except a slight decrease in egg weight. These results indicated that PCBs exerted its disrupting effects on chicken reproduction with a sex and stage-related pattern, and in vivo disruption of gonadal development represents a possible model for risk assessment of environmental endocrine disrupters by in ovo treatment. |
2,332,249 | Regulation of corticotropin-releasing factor receptor type 2beta messenger ribonucleic acid by interleukin-1beta in rat vascular smooth muscle cells. | Corticotropin-releasing factor receptor type 2 (CRF R2) messenger RNA (mRNA) expression in the rodent heart or vessels is modulated by exposure to urocortin and glucocorticoids. In addition, we previously found that incubation with a variety of cytokines, such as interleukin (IL)-1 and IL-6, and tumor necrosis factor-alpha also reduced CRF R2beta mRNA expression, with IL-1beta being the most effective. In this study, we further explored the regulation of CRF R2beta mRNA levels by IL-1beta in the rat vascular smooth muscle A7r5 cells.</AbstractText>A7r5 cells were incubated with IL-1beta, urocortin, or both for 6 h, after pre-incubating with or without anti-IL-1beta antibody (Ab) for 30 min, and then CRF R2beta mRNA levels were measured by RNase protection assay. Cells were incubated with lipopolysaccharides, IL-1beta, IL-6, dexamethasone, forskolin, or urocortin for 20 min, and then intracellular cAMP was measured by cAMP RIA.</AbstractText>IL-1beta produced a significant time-dependent decrease in CRF R2beta mRNA levels. Combined urocortin and IL-1beta administration did not have synergistic effects on the decrease in CRF R2beta mRNA levels. IL-1beta Ab failed to block the ability of urocortin to regulate CRF R2beta mRNA levels, suggesting that urocortin regulated CRF R2beta mRNA levels via another pathway than IL-1beta production. Urocortin induced the intracellular cAMP production in A7r5 cells, while IL-1beta failed to induce it.</AbstractText>The multifactorial regulation of CRF R2beta mRNA expression in the A7r5 cells serves to limit the inotropic and chronotropic effects of CRF R2 agonists such as urocortin during prolonged physical or immune challenge.</AbstractText>Copyright 2002 S. Karger AG, Basel</CopyrightInformation> |
2,332,250 | Differential activation by Ca2+, ATP and caffeine of cardiac and skeletal muscle ryanodine receptors after block by Mg2+. | The block of rabbit skeletal ryanodine receptors (RyR1) and dog heart RyR2 by cytosolic [Mg2+], and its reversal by agonists Ca2+, ATP and caffeine was studied in planar bilayers. Mg2+ effects were tested at submaximal activating [Ca2+] (5 microM). Approximately one third of the RyR1s had low open probability ("LA channels") in the absence of Mg2+. All other RyR1s displayed higher activity ("HA channels"). Cytosolic Mg2+ (1 mM) blocked individual RyR1 channels to varying degrees (32 to 100%). LA channels had residual P(o) <0.005 in 1 mM Mg2+ and reactivated poorly with [Ca2+] (100 microM), caffeine (5 mM), or ATP (4 mM; all at constant 1 mM Mg2+). HA channels had variable activity in Mg2+ and variable degree of recovery from Mg2+ block with Ca2+, caffeine or ATP application. Nearly all cardiac RyR2s displayed high activity in 5 microM [Ca2+]. They also had variable sensitivity to Mg2+. However, the RyR2s consistently recovered from Mg2+ block with 100 microM [Ca2+] or caffeine application, but not when ATP was added. Thus, at physiological [Mg2+], RyR2s behaved as relatively homogeneous Ca2+/caffeine-gated HA channels. In contrast, RyR1s displayed functional heterogeneity that arises from differential modulatory actions of Ca2+ and ATP. These differences between RyR1 and RyR2 function may reflect their respective roles in muscle physiology and excitation-contraction coupling. |
2,332,251 | Mandibular nerve block treatment for trismus associated with hypoxic-ischemic encephalopathy. | We describe the use of mandibular nerve block for the management of bilateral trismus associated with hypoxic-ischemic encephalopathy.</AbstractText>The patient was a 65-year-old man with bilateral trismus due to hypoxic-ischemic encephalopathy. Despite his impaired consciousness, we performed fluoroscopically guided bilateral mandibular nerve block. The bilateral symptoms were sufficiently improved, without obvious side effects, by injecting a local anesthetic near the right mandibular nerve and a neurolytic near the left mandibular nerve.</AbstractText>Mandibular nerve block may be an effective treatment for patients with bilateral trismus due to ischemic-encephalopathy, even when consciousness is impaired.</AbstractText> |
2,332,252 | Paracervical block for labor analgesia: a brief historic review. | This historic review was written to clarify the known efficacy and side effects of paracervical blockade for labor analgesia. Although the popularity of the technique has diminished considerably, it continues to be used by some clinicians with ostensibly good results. The Cochrane Controlled Trials Register (CCTR;SR-PREG) and the electronic database MEDLINE were searched for studies reported in English to determine efficacy and side effects of paracervical block. Four randomized controlled studies specifically addressed paracervical block efficacy as assessed by parturients during labor with results of excellent or good analgesia among approximately 75%. Postparacervical block fetal bradycardia is the most significant side effect with a reported incidence ranging from 0% to approximately 40%. Overall, it appears that the incidence of postparacervical block fetal bradycardia is approximately 15%. However, the etiology of the observed fetal bradycardia remains unclear, and the incidence of adverse impact on fetal or neonatal outcome remains uncertain because there are too few trials with too few patients. |
2,332,253 | Effects of smoking marijuana on brain perfusion and cognition. | The effects of smoking marijuana on regional cerebral blood flow (rCBF) and cognitive performance were assessed in 12 recreational users in a double-blinded, placebo-controlled study. PET with [(15)Oxygen]-labeled water ([(15)O]H(2)O) was used to measure rCBF before and after smoking of marijuana and placebo cigarettes, as subjects repeatedly performed an auditory attention task. Smoking marijuana resulted in intoxication, as assessed by a behavioral rating scale, but did not significantly alter mean behavioral performance on the attention task. Heart rate and blood pressure increased dramatically following smoking of marijuana but not placebo cigarettes. However, mean global CBF did not change significantly. Increased rCBF was observed in orbital and mesial frontal lobes, insula, temporal poles, anterior cingulate, as well as in the cerebellum. The increases in rCBF in anterior brain regions were predominantly in "paralimbic" regions and may be related to marijuana's mood-related effects. Reduced rCBF was observed in temporal lobe auditory regions, in visual cortex, and in brain regions that may be part of an attentional network (parietal lobe, frontal lobe and thalamus). These rCBF decreases may be the neural basis of perceptual and cognitive alterations that occur with acute marijuana intoxication. There was no significant rCBF change in the nucleus accumbens or other reward-related brain regions, nor in basal ganglia or hippocampus, which have a high density of cannabinoid receptors. |
2,332,254 | An analytical study of the physiology and pathology of the propagation of cardiac action potentials. | Many cardiac diseases are caused by the abnormal propagation of electrical waves. Previous experimental and modelling work is reviewed, then a detailed study of the mathematics of cardiac propagation is presented. Pathologies are examined in the context of the models by varying parameters in the models to mimic different pathological states. Ionic models of cells are simplified to form analytically tractable models of the propagation of electrical cardiac waves. The roles that sodium channel activation and inactivation play in determining the conduction velocity are studied in detail, and the roles of resting potential currents in conduction block are calculated. The effect of curvature on the conduction velocity is examined, and the conditions in which curvature leads to conduction block and fibrillation are discussed. Hyperkalaemia (important during ischaemia) is modelled, and the model correctly describes the bi-phasic relation between propagation velocity and extracellular potassium. |
2,332,255 | P2X purinergic receptor channel expression and function in bovine aortic endothelium. | We examined bovine aortic endothelial cells (BAECs) for the functional expression of P2X receptors, the ATP-gated cation channels. We identified the P2X subtypes present in BAECs using RT-PCR. mRNA was present for only three of seven family members: P2X4, P2X5, and P2X7. We then characterized agonist-activated currents in whole cell and outside-out patch recordings using 2-methyl-thio-ATP (MeSATP) as a P2X4 and P2X5 receptor agonist and 2',3'-O-(4-benzoylbenzoyl)ATP (BzATP) as a P2X7 receptor agonist. MeSATP (10-20 microM) produced current with characteristics of P2X4 receptors. The current was an inwardly rectifying current, reversed near 0 mV, slowly desensitized, was not blocked by suramin (300 microM) or reactive blue (60 microM), and had a single channel conductance of 36 pS. BzATP (10-100 microM), on the other hand, activated a 9-pS channel with sustained activity in the continued presence of the agonist. BzATP-activated current was blocked by reactive blue (60 microM) and by suramin (approximately 50% block at 300 microM). We confirmed, by immunocytochemistry, the presence of P2X4 and P2X7 protein. The agonists failed, however, to induce significant uptake of the large molecule YO-PRO, indicating the lack of pore development that has been demonstrated for P2X7 and P2X4 in response to agonist in some cell types. |
2,332,256 | Phosphorylation of eNOS initiates excessive NO production in early phases of portal hypertension. | Akt, also known as protein kinase B, is a serine/threonine kinase. Akt becomes active when phosphorylated by the activation of receptor tyrosine kinases, G protein-coupled receptors, and mechanical forces such as shear stress. Studies in vitro have shown that Akt can directly phosphorylate endothelial nitric oxide (NO) synthase (eNOS) and activate the enzyme, leading to NO production. The aim of this study was to test the hypothesis that the phosphorylation of eNOS plays a role in the enhanced NO production observed in early portal hypertension. Male Sprague-Dawley rats were subjected to either sham or portal vein ligation (PVL), and mesenteric arterial beds were used for ex vivo perfusion studies. Mesenteric arterial beds from PVL rats had an approximately 60-70% decrease in response to methoxamine (an alpha(1)-agonist and vasoconstrictor) compared with the sham group (P < 0.01). When N(G)-monomethyl-L-arginine (a NOS inhibitor) was added to the perfusion, the difference in perfusion pressure between the two groups was abolished, suggesting that enhanced NO production in the PVL group blunted the response to the vasoconstrictor. The reduced responsiveness in PVL was not due to changes in eNOS expression but was due to an increase in enzyme-specific activity, suggesting posttranslational modification of eNOS. The phosphorylation of eNOS at Ser(1176) was significantly increased by twofold (P < 0.05) in the PVL group. Furthermore, PVL significantly increased Akt phosphorylation (an active form of Akt) by threefold (P < 0.05). When vessels were treated with wortmannin (10 nM) to block the phosphatidylinositol-3-OH-kinase/Akt pathway, NO-induced vasodilatation was significantly reduced. These results suggest that the phosphorylation of eNOS by Akt activates the enzyme and may be the first step leading to an initial increase in NO production in portal hypertension. |
2,332,257 | Anandamide-induced vasorelaxation in rabbit aortic rings has two components: G protein dependent and independent. | The endogenous cannabinoid anandamide (arachidonylethanolamide) produces vasorelaxation in different vascular beds. In the present study, we found that anandamide and a metabolically stable analog, methanandamide, produced dose-dependent (10 nM-10 microM) vasorelaxation of approximately 80% in a rabbit aortic ring preparation in an endothelium-dependent manner. Non-endothelium-dependent vasorelaxation was observed to be a maximum of 20-22% at >10 microM methanandamide. The efficacious CB(1) receptor analogs desacetyllevonantradol (10 microM) and WIN55212-2 (10 microM) failed to produce vasorelaxation; however, the endothelium-dependent vasorelaxation evoked by methanandamide was partially (75%) blocked by the CB(1) receptor antagonist SR141716A. The VR(1) vanilloid receptor antagonist capsazepine or the calcitonin gene-related peptide (CGRP) antagonist CGRP-(8-37) partially attenuated (25%) the vasorelaxation in endothelium-intact preparations and greatly reduced the response in endothelium-denuded preparations. Pretreatment of aortic rings with N(G)-nitro-L-arginine methyl ester completely blocked the methanandamide-, capsaicin-, and CGRP-induced vasorelaxation. Pretreatment of aortic rings with pertussis toxin attenuated the methanandamide-induced vasorelaxation in endothelium-intact aortic rings, indicating the involvement of G(i/o) proteins in the vasorelaxation; however, pertussis toxin treatment failed to block the endothelium-independent response. Thus, in the rabbit aorta, methanandamide-induced vasorelaxation exhibits two components: 1) in endothelium-intact rings, an SR141716A-sensitive, non-CB(1) receptor component that requires pertussis toxin-sensitive G proteins and nitric oxide (NO) production; and 2) in endothelium-denuded rings, a component that is mediated by VR(1) vanilloid receptors and possibly by the subsequent release of CGRP that requires NO production but is independent of pertussis toxin-sensitive G proteins. |
2,332,258 | Block of the background K(+) channel TASK-1 contributes to arrhythmogenic effects of platelet-activating factor. | Platelet-activating factor (PAF), an inflammatory phospholipid, induces ventricular arrhythmia via an unknown ionic mechanism. We can now link PAF-mediated cardiac electrophysiological effects to inhibition of a two-pore domain K(+) channel [TWIK-related acid-sensitive K(+) background channel (TASK-1)]. Superfusion of carbamyl-PAF (C-PAF), a stable analog of PAF, over murine ventricular myocytes causes abnormal automaticity, plateau phase arrest of the action potential, and early afterdepolarizations in paced and quiescent cells from wild-type but not PAF receptor knockout mice. C-PAF-dependent currents are insensitive to Cs(+) and are outwardly rectifying with biophysical properties consistent with a K(+)-selective channel. The current is blocked by TASK-1 inhibitors, including protons, Ba(2+), Zn(2+), and methanandamide, a stable analog of the endogenous lipid ligand of cannabinoid receptors. In addition, when TASK-1 is expressed in CHO cells that express an endogenous PAF receptor, superfusion of C-PAF decreases the expressed current. Like C-PAF, methanandamide evoked spontaneous activity in quiescent myocytes. C-PAF- and methanandamide-sensitive currents are blocked by a specific protein kinase C (PKC) inhibitor, implying overlapping signaling pathways. In conclusion, C-PAF blocks TASK-1 or a closely related channel, the effect is PKC dependent, and the inhibition alters the electrical activity of myocytes in ways that would be arrhythmogenic in the intact heart. |
2,332,259 | Mitochondrial ROS initiate phosphorylation of p38 MAP kinase during hypoxia in cardiomyocytes. | The p38 mitogen-activated protein kinase (MAPK) is phosphorylated in response to oxidative stress. Mitochondria in cardiomyocytes increase their generation of reactive oxygen species (ROS) during hypoxia (1-5% O(2)). These ROS participate in signal transduction pathways involved in adaptive responses, including ischemic preconditioning and gene transcription. The present study therefore tested the hypothesis that hypoxia induces p38 MAPK phosphorylation by augmenting mitochondrial ROS generation. In cardiomyocytes, phosphorylation of p38 was observed in a PO(2)-dependent manner during hypoxia. This response was inhibited by rotenone, thenoyltrifluoroacetone, and myxothiazol, inhibitors of mitochondrial complexes I, II, and III, respectively. A similar inhibition was observed in the cells pretreated with anion channel inhibitor DIDS, which may block ROS release from mitochondria. During normoxia, increases in mitochondrial ROS elicited by azide (1-2 mM) or by the mitochondrial inhibitor antimycin A caused increased phosphorylation of p38. Brief treatment with exogenous H(2)O(2) during normoxia also induced phosphorylation of p38 as hypoxia, but this effect was not abolished by myxothiazol or DIDS. The antioxidant N-acetyl-cysteine abolished the p38 response to hypoxia, presumably by scavenging H(2)O(2), but the mitogen extracellular receptor kinase inhibitor PD-98059 did not inhibit p38 phosphorylation during hypoxia. Thus physiological hypoxia leads to p38 phosphorylation through a mechanism that requires electron flux in the proximal region of the mitochondrial electron transport chain, which suggests that either H(2)O(2) or superoxide participates in activating that process. |
2,332,260 | [Nursing process in advanced cardiopulmonary resuscitation]. | The process male nurse is a systematic and organized method to offer effective and efficient cares guided to the achievement of solving real problems of health, reducing the incidence and the duration. It is organized and systematic for that consists of five sequential and interrelated steps: Valuation, diagnostic, planning, execution and evaluation, in which are carried out interrelated actions, thought to maximize the long term results. The nurse process is based on the notion that the success of the cares is measured by the degree of effectiveness and the degree of satisfaction and the patient's progress. Applying this method in the Advanced Cardiac Live Support (ACLS) the identification of a cardiovascular or cardiopulmonary urgency was achieved that implies advanced treatment of the air road, defibrillation and appropriate medications to the circumstances. The ACLS challenges the nurses in charge from the patient's attention to make decisions quick low pressure and in dramatic scenes. Reason why it develops the flowing process male nurse in the advanced cardiopulmonary reanimation due to the incidence of these events in the National Institute of Cardiology Ignacio Chávez, which should guarantee the benefit of services in basic and advanced cardiopulmonary reanimation for personal with a high formation level in all the units of intensive cares and services of hospitalization in integrated form and stratified this way to avoid that it progresses to situations that cause the death or leave irreversible sequels since in the central nervous system the time it is a factor critical for the treatment of this events. |
2,332,261 | PKC-delta inhibition does not block preconditioning-induced preservation in mitochondrial ATP synthesis and infarct size reduction in rats. | We have previously demonstrated that cardioprotection induced by the infusion of a selective delta1-opioid agonist is mediated by the specific translocation of PKC-delta to the mitochondria in in vivo rat hearts and via opening of the mitochondrial KATP channel. Ischemic preconditioning (IPC) is also thought to involve the translocation of specific isoforms of PKC and KATP channel activation. Therefore, we utilized the PKC-delta selective antagonist, rottlerin, to assess the effect of inhibition of this isozyme on cardioprotection induced by one-cycle of IPC prior to 30 minutes of ischemia and 2 hours of reperfusion. Infarct size (IS) was determined by tetrazolium chloride staining and expressed as a percent of the area at risk (AAR). Non-preconditioned control animals had an IS/AAR of 59.7 +/- 1.6. IPC significantly reduced the extent of myocardial infarction (6.3 +/- 1.4). Rottlerin, 0.3 mg/kg, did not alter IS/AAR in control animals (55.0 +/- 5.6), and had no significant effect on IS/AAR in preconditioned animals (14.4 +/- 3.8). Additionally, we demonstrated, using a luciferase-based assay to determine the rate of ATP synthesis and state of mitochondrial bioenergetics, that IPC preserves ATP synthesis in the ischemic myocardium and that this preservation is attenuated by the isoform non-selective PKC inhibitor, chelerythrine, but not by the delta-selective antagonist, rottlerin. These data suggest that PKC-delta does not play an important role in IPC and that differences in isoform importance are evident during pharmacological versus ischemia-induced preconditioning. |
2,332,262 | [A case of AV block (Mobitz II type) during recovery from general anesthesia combined with epidural anesthesia]. | A 59-year-old female underwent total hysterectomy for cancer of the corpus uteri. Epidural catheterization was performed at T 12/L 1 interspace. Anesthesia was induced with propofol (80 mg) and vecuronium (6 mg) and maintained with nitrous oxide (66%) and sevoflurane (0.8-1.5%) in oxygen. Six ml of 1.5% lidocaine containing 1: 200,000 epinephrine was injected intermittently through the epidural catheter for epidural anesthesia. Surgery was performed uneventfully. During her recovery from anesthesia, Mobitz II heart blocks and bradycardia were observed when the discharge in the oral cavity was aspirated. The AV blocks disappeared within 2 min, but similar arrhythmia was observed when the discharge in the oral cavity was aspirated again. Stimulation of the trachea by a suction drainage reversed the arrhythmia to the normal sinus rhythm. The trachea was extubated, and arrhyththmia was no longer observed in the operating room, but when the patient vomited, the next morning, bradycardia occurred and she lost consciousness. Two weeks later, there were no abnormal findings in echocardiography, Holter ECG, master-double ECG, and scintigraphy of the heart. It is likely that in this patient stimulation of the oral cavity by suction drainage and vomiting triggered vagovagal reflex, causing the AV block. |
2,332,263 | [Cardiac sarcoidosis diagnosed by thoracoscopically resected lung nodule: report of a case]. | A 71-year-old woman was admitted to our hospital with general fatigue and dyspnea. Emergency pacemaker implantation was performed after diagnosis of complete AV block. After 1 month, a small lung nodule, which had been 10 mm in diameter 1 year ago, was revealed to have grown to 15 mm in diameter by CT scan. Thoracoscopical resection of the lung nodule resulted in sarcoidosis. Abnormality in the posteroinferior heart was detected by 99mTC-PYP myocardial perfusion scintigraphy and it was diagnosed as cardiac sarcoidosis. |
2,332,264 | Pacemaker pocket infection due to acremonium species. | Fungal infections involving the pacemaker pocket after pacemaker implantation procedure are extremely rare. This report describes the case of a 53-year-old woman with pacemaker pocket infection due to acremonium species. The authors emphasize that this patient did not have any predisposing factors to fungal infections. |
2,332,265 | Constrictive pericarditis complicating endovascular pacemaker implantation. | A patient is described who has 6 months of progressive dyspnea and peripheral edema for 4 years following implantation of an endovascular pacemaker, which was complicated by a large hemorrhagic pericardial effusion. Evaluation was consistent with constrictive pericarditis, which is an extremely unusual complication of pacemaker implantation. |
2,332,266 | Cerebrovascular carbon dioxide reactivity in children anaesthetized with sevoflurane. | To determine the effects of sevoflurane on cerebrovascular carbon dioxide reactivity (CCO2R), middle cerebral artery blood flow velocity (CBFV) was measured at different levels of PE'CO2 by transcranial Doppler sonography in 16 ASA I or II children, aged 18 months to 7 yr undergoing elective urological surgery.</AbstractText>Anaesthesia comprised 1.0 MAC sevoflurane and air in 30% oxygen delivered through an Ayre's T piece by intermittent positive-pressure ventilation, and a caudal epidural block with 0.25% bupivacaine 1.0 ml kg(-1) without epinephrine. PE'CO2 was randomly adjusted to 25, 35, 45 and 55 mm Hg (3.3, 4.6, 5.9 and 7.2 kPa) with an exogenous source of CO2, while maintaining ventilation variables constant.</AbstractText>CBFV increased as PE'CO2 increased from 25 to 35, and to 45 mm Hg (P<0.001), but did not increase significantly with an increase in PE'CO2 from 45 to 55 mm Hg. Mean heart rate and arterial pressure remained constant.</AbstractText>CCO2R is preserved in healthy children anaesthetized with 1.0 MAC sevoflurane.</AbstractText> |
2,332,267 | Modulation of endotoxin-induced cardiopulmonary dysfunction by S-nitroso-albumin. | Nitric oxide (NO) is an endogenous vasodilator and modulator of inflammation. During endotoxemia, the beneficial effects of NO are overwhelmed by the inflammatory cascade, resulting in a functional depletion of NO. S-nitroso-albumin (S-NO-alb) exists as a novel and highly stable NO thiol complex that slowly releases NO into the vascular micro-environment. Using a porcine model, we examined the ability of intravenous S-NO-alb to modulate cardiopulmonary dysfunction characteristic of endotoxemia. Pigs were anesthetized, instrumented for standard cardiopulmonary function measurements, and randomly assigned to receive: (i) albumin + saline; (ii) albumin + LPS; or (iii) S-NO-alb + LPS. Cardiopulmonary parameters were evaluated every 30 min and ex vivo phorbol myristate acetate (PMA)-stimulated superoxide release was serially determined as a marker of in vivo neutrophil priming. Lung myeloperoxidase (MPO) activity was measured as a marker of neutrophil migration into the lung. LPS-induced cardiopulmonary dysfunction was characterized by a sustained elevation in mean pulmonary arterial pressure, pulmonary vascular resistance, and peak intratracheal pressure, as well as a reduction in cardiac index, stroke volume index and PaO(2) over 6 h. Pretreatment with S-NO-alb attenuated LPS-induced cardiopulmonary dysfunction without adversely affecting systemic hemodynamics. Moreover, S-NO-alb blunted the LPS-induced hypoxemic response and reduced neutrophil activation. S-NO-alb did not, however, attenuate LPS-induced increases in lung MPO. Our results suggest that S-NO-alb can selectively modulate endotoxin-induced pulmonary dysfunction, attenuate neutrophil priming and block the early mortality (40%) in this model. |
2,332,268 | Current practices: immunosuppression induction, maintenance, and rejection regimens in contemporary post-heart transplant patient treatment. | Cardiac transplantation is the definitive treatment for eligible patients with end-stage cardiomyopathy. Survival rates have improved dramatically during the last 10 years, especially since the advent of cyclosporine-A. Cardiac allograft rejection, previously considered a major cause of early mortality after transplantation, is no longer the limiting factor for early survival, with the use of newer and more specific immunosuppression regimens. Very few randomized, prospective trials, including comparisons between immunosuppression regimens, have been conducted in this area. Therefore, practices vary with physician and institutional experience. Most centers use a multipronged approach to immunosuppression, targeting multiple sites in the immune cascade that lead to allograft rejection. Multiple new agents in development are reviewed. Drugs such as sirolimus and its derivative, everolimus, act on specific intracellular receptors within lymphocytes, whereas other medications such as Daclizumab (Roche Laboratories, Nutley, NJ) block the interleukin-2 receptor on the surface of activated T cells. The immune response to foreign antigens is complex, with multiple redundant levels. Immunosuppression regimens continue to seek a fine balance between overimmunosuppression and insufficient protection, which may lead to allograft rejection or loss. |
2,332,269 | A comparison of intrathecal fentanyl and sufentanil for labor analgesia. | The use of intrathecal opioids for labor analgesia continues to gain popularity, but there are limited data to guide this use. Previously, the authors established the ED50 for 60 min of labor analgesia from intrathecal sufentanil using an up-down sequential allocation study design. The current study first establishes an ED50 for intrathecal fentanyl using this same study design to establish an intrathecal potency ratio for fentanyl and sufentanil and then uses this ratio to compare the efficacy, duration of analgesia, and side effects from comparable doses of intrathecal fentanyl and sufentanil.</AbstractText>Seventy-five healthy nulliparous women requesting labor analgesia were enrolled in this two-part study. In phase I, 20 women received varying doses of fentanyl to establish an ED50 for 60 min of labor analgesia. In phase II, 55 women were randomized to receive either 36 microg intrathecal fentanyl or 8 microg sufentanil (2 times the ED50s) via a combined spinal-epidural technique and by double-blinded design. Pain relief, side effects, block height, maternal hemodynamics, and fetal heart rate were assessed throughout the study. The duration of spinal analgesia was considered to be the time from injection of study drug to the time of the patient's first request for additional analgesia.</AbstractText>The ED50 of intrathecal fentanyl for 60 min of labor analgesia was found to be 18.2 microg, and therefore, the potency ratio of intrathecal sufentanil to intrathecal fentanyl at the ED50 level is 4.4:1. The duration of spinal analgesia was significantly longer from 8 microg intrathecal sufentanil than from 36 microg intrathecal fentanyl (104 +/- 34 vs. 79 +/- 34 min, P = 0.009). Otherwise, patient demographics, maternal hemodynamics, duration of labor, mode of delivery, motor block, subjective leg weakness, pruritus, nausea, pinprick sensory levels, visual analog scale pain scores, fetal bradycardia, and Apgar scores were similar between groups.</AbstractText>The relative potency of intrathecal sufentanil to fentanyl for labor analgesia is 4.4:1. When using intrathecal opioids alone for early labor analgesia, 8 microg sufentanil produces labor analgesia lasting approximately 25 min longer than from 36 microg fentanyl, without a statistically significant increase in side effects. However, when making a choice between fentanyl and sufentanil, one must consider other important factors, such as the higher cost of sufentanil and the greater risk of dosing error due to the higher potency of sufentanil compared with fentanyl.</AbstractText> |
2,332,270 | Prevention of mitochondrial oxidative damage using targeted antioxidants. | Mitochondrial-targeted antioxidants that selectively block mitochondrial oxidative damage and prevent some types of cell death have been developed. These antioxidants are ubiquinone and tocopherol derivatives and are targeted to mitochondria by covalent attachment to a lipophilic triphenylphosphonium cation. Because of the large mitochondrial membrane potential, these cations accumulated within mitochondria inside cells, where the antioxidant moiety prevents lipid peroxidation and protects mitochondria from oxidative damage. The mitochondrially localized ubiquinone also protected mammalian cells from hydrogen peroxide-induced apoptosis while an untargeted ubiquinone analogue was ineffective against apoptosis. When fed to mice these compounds accumulated within the brain, heart, and liver; therefore, using these mitochondrial-targeted antioxidants may help investigations of the role of mitochondrial oxidative damage in animal models of aging. |
2,332,271 | Evidence-based goals versus achievement in clinical practice in secondary prevention of coronary heart disease: findings in EUROASPIRE II. | Recommendations for reducing risk of recurrence in patients with established coronary heart disease (CHD) or other atherosclerotic disease were published by the Joint European Societies in 1994 and 1998. The first EUROASPIRE survey of clinical practice of secondary CHD prevention, performed in 1995 and 1996, found that 19% of CHD patients smoked cigarettes, 25% had body mass index (BMI) > or =30 kg/m(2), 53% had blood pressure > or =140/90 mmHg, and 44% had plasma total cholesterol > or =5.5 mmol/l. EUROASPIRE II, conducted in 1999 and 2000, found that 21% of patients smoked cigarettes, 31% had BMI > or =30 kg/m(2), 50% had blood pressure > or =140/90 mmHg, and 58% had serum total cholesterol > or =5.0 mmol/l. It is clear that there are still considerable opportunities in Europe to reduce risk of recurrent CHD through lifestyle changes, rigorous control of other risk factors, and more effective use of proven drug therapies. |
2,332,272 | Comparison of two benzodiazepines used for sedation of children undergoing suturing of a laceration in an emergency department. | (1) To determine if oral diazepam (POD) is as effective in sedating children less than 6 years of age for laceration repair as oral midazolam (POM) or intranasal midazolam (INM); and (2) To determine if patients stayed longer in the department after sedation when given POD for sedation.</AbstractText><AbstractText Label="DESIGN/METHODS" NlmCategory="METHODS">Block-randomized, single-blind trial.</AbstractText>Tertiary pediatric emergency department.</AbstractText>Patients 1 to 5 years old with a laceration requiring sutures were enrolled.</AbstractText>All patients had topical anesthetic applied to the wound and were randomly assigned to POD 0.5 mg/kg, POM 1.0 mg/kg, or INM 0.4 mg/kg for sedation.</AbstractText>One hundred twenty-nine patients were enrolled, 42 POD, 45 POM, and 42 INM. Each group was similar at baseline for age, heart rate, respiratory rate, blood pressure, oxygen saturation, previous laceration or sedation, anxiety score, and site of laceration. POM and POD were better tolerated than INM (P = 0.05 and 0.034), respectively. Time to sedation was significantly longer in POD (31.0 +/- 9 min) than INM (26.1 +/- 9 min) (P = 0.011) but there was no significant difference when comparing the other groups. However, this difference was not clinically significant. POD was significantly worse at sedating children compared with POM and INM on all four scores (ie, doctor, nurse, parent, and investigator), but INM and POM were equivalent. Total time in the department was no different between POM and INM or POM and POD, but was significantly different for POD (53.9 +/- 16 min) and INM (48 +/- 12 min); however, this difference was minimal. More patients were said to be drowsy at home in the POM group (51%) than the POD group (32%).</AbstractText>The oral route of delivery of POM and POD was better tolerated than INM. POM and INM were more effective at sedation than POD, but there was no clinical difference between any groups for time to sedation or time to discharge. More patients in the POM group had side effects after leaving the department. POD may be an alternative to POM, but a higher dose may be required, possibly with longer recovery times.</AbstractText> |
2,332,273 | On the role of phosphatase in regulation of cardiac L-type calcium current by cyclic GMP. | Does cGMP, via protein kinase G, inhibit cAMP-stimulated Ca(2+) current (I(Ca(L))) in mammalian ventricular myocytes by phosphorylating the calcium channel at a site different from that acted on by cAMP or by dephosphorylating the calcium channel through phosphatase(s)? We tested these possibilities in guinea pig ventricular myocytes superfused with Tyrode's solution (35 degrees C) and dialyzed with adenosine 5'-O-(3-thiotriphosphate) ([ATPgammaS](pip)). ATPgammaS is a kinase substrate but thiophosphorylated proteins are not phosphatase substrates. With 5 mM [ATPgammaS](pip), I(Ca(L)) increased gradually over 20 to 25 min and then rapidly in the presence of 3-isobutyl-1-methylxanthine. 8-Bromo-cGMP (8-Br-cGMP; 1 mM) did not inhibit I(Ca(L)) significantly (-3 +/- 11.8%, n = 21) in contrast to results with ATP dialysis (). Similar results were obtained with 0.1 mM carbachol (CCh). I(Ca(L)) increased after longer dialysis (>/=40 min) with ATPgammaS; again, 8-Br-cGMP had no effect. Also, isoproterenol (ISO) did not stimulate and CCh, alone or in the presence of ISO, did not inhibit I(Ca(L)). Block of CCh effect by ATPgammaS, although consistent with cGMP action in muscarinic inhibition, could be explained by guanosine 5'-O-(3-thiotriphosphate) (GTPgammaS) formation from ATPgammaS via nucleoside diphosphate kinase. GTPgammaS uncouples muscarinic and beta-adrenoceptors from intracellular effectors. Failure of 8-Br-cGMP to reduce I(Ca(L)) irreversibly excludes calcium channel phosphorylation as an inhibitory mechanism. We propose that cGMP inhibits I(Ca(L)) by activating phosphatase(s) in guinea pig ventricular myocytes. |
2,332,274 | Double-blind comparison of the variability in spontaneous recovery of cisatracurium- and vecuronium-induced neuromuscular block in adult and elderly patients. | This study was designed to compare variability in the offset of two neuromuscular blocking agents with different elimination pathways.</AbstractText>The spontaneous recovery profiles of cisatracurium and vecuronium were compared in adult (18-64 years) and elderly (> or =65 years) patients receiving N2O/O2/fentanyl/propofol anaesthesia. Patients were randomised to receive an initial bolus dose and maintenance doses of 3xED95, respectively, 0.6xED95 for cisatracurium (0.15 and 0.03 mg.kg-1) or 2xED95, respectively, and 0.4xED95 for vecuronium (0.1 and 0.02 mg.kg(-1)), as recommended in their prescribing information. Administration of the study drugs was double-blinded, and neuromuscular transmission was monitored using mechanomyography of the evoked response of the adductor pollicis, following ulnar nerve stimulation.</AbstractText>The clinically effective duration (minutes) of the initial bolus dose, defined as the mean time to 25% T1 recovery (+/-SD), for the adult and elderly patients was 53.5+/-9.8 and 57.3+/-11.5 for cisatracurium, respectively, and 34.1+/-9.0 and 47.5+/-14.4 for vecuronium, respectively. The duration of spontaneous sufficient recovery (SSR), defined as the mean (+/-SD) time interval in minutes from 25% T1 recovery to a T4:T1 ratio > or =0.8 after the last bolus dose, for the adult, respectively, elderly patients was 28.3+/-8.0 and 31.7+/-10.0 for cisatracurium and 38.5+/-13.2 and 60.3+/-26.1 for vecuronium.</AbstractText>Whereas both the clinically effective duration and the duration of SSR are comparable between the adult and the elderly patients receiving cisatracurium, they differ substantially between these two age groups for vecuronium. Furthermore, the variability in offset is significantly lower in patients receiving cisatracurium, especially in the elderly, which may be of particular clinical interest.</AbstractText> |
2,332,275 | Endothelin receptor antagonists--an overview. | In thirteen years since the appearance of Endothelin (ET) on the international scene, possibility of its involvement in a variety of diseases has attracted the attention of medicinal chemists in search of novel therapeutics for various cardiovascular diseases (CVDs). Discovery of pharmaceutical agents which either block the generation of ET from its precursor or antagonize its binding to cellular receptor, should not only provide means to assess the physiological role of ET, but lead to useful therapy for conditions associated with altered production or responsiveness to ET. In this review article, we have attempted to present in a classified format, the kaleidoscope of ET receptor antagonists that have emerged through structure activity relationship studies using the parent peptide as well as from screening of various compound libraries. By all indications, the variety and range of small molecules that are currently under investigation continues to open up newer opportunities and lures fresh groups of scientists into this research arena. Presently a number of these compounds are in the clinics, being evaluated for their beneficial effects in a range of human pathologies such as essential hypertension and chronic heart failure. |
2,332,276 | Reciprocal regulatory interactions between the Notch and Ras signaling pathways in the Drosophila embryonic mesoderm.<Pagination><StartPage>226</StartPage><EndPage>242</EndPage><MedlinePgn>226-42</MedlinePgn></Pagination><Abstract><AbstractText>Convergent intercellular signals must be precisely integrated in order to elicit specific biological responses. During specification of muscle and cardiac progenitors from clusters of equivalent cells in the Drosophila embryonic mesoderm, the Ras/MAPK pathway--activated by both epidermal and fibroblast growth factor receptors--functions as an inductive cellular determination signal, while lateral inhibition mediated by Notch antagonizes this activity. A critical balance between these signals must be achieved to enable one cell of an equivalence group to segregate as a progenitor while its neighbors assume a nonprogenitor identity. We have investigated whether these opposing signals directly interact with each other, and we have examined how they are integrated by the responding cells to specify their unique fates. Our findings reveal that Ras and Notch do not function independently; rather, we have uncovered several modes of cross-talk between these pathways. Ras induces Notch, its ligand Delta, and the epidermal growth factor receptor antagonist, Argos. We show that Delta and Argos then synergize to nonautonomously block a positive autoregulatory feedback loop that amplifies a fate-inducing Ras signal. This feedback loop is characterized by Ras-mediated upregulation of proximal components of both the epidermal and fibroblast growth factor receptor pathways. In turn, Notch activation in nonprogenitors induces its own expression and simultaneously suppresses both Delta and Argos levels, thereby reinforcing a unidirectional inhibitory response. These reciprocal interactions combine to generate the signal thresholds that are essential for proper specification of progenitors and nonprogenitors from groups of initially equivalent cells.</AbstractText><CopyrightInformation>Copyright 2002 Elsevier Science (USA).</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Carmena</LastName><ForeName>Ana</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Program in Molecular Biology, Memorial Sloan-Kettering Cancer Institute, New York, New York 10021, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Buff</LastName><ForeName>Eugene</ForeName><Initials>E</Initials></Author><Author ValidYN="Y"><LastName>Halfon</LastName><ForeName>Marc S</ForeName><Initials>MS</Initials></Author><Author ValidYN="Y"><LastName>Gisselbrecht</LastName><ForeName>Stephen</ForeName><Initials>S</Initials></Author><Author ValidYN="Y"><LastName>Jiménez</LastName><ForeName>Fernando</ForeName><Initials>F</Initials></Author><Author ValidYN="Y"><LastName>Baylies</LastName><ForeName>Mary K</ForeName><Initials>MK</Initials></Author><Author ValidYN="Y"><LastName>Michelson</LastName><ForeName>Alan M</ForeName><Initials>AM</Initials></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>R01 GM056989</GrantID><Acronym>GM</Acronym><Agency>NIGMS NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>GM 56989</GrantID><Acronym>GM</Acronym><Agency>NIGMS NIH HHS</Agency><Country>United States</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType><PublicationType UI="D013487">Research Support, U.S. Gov't, P.H.S.</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Dev Biol</MedlineTA><NlmUniqueID>0372762</NlmUniqueID><ISSNLinking>0012-1606</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D029721">Drosophila Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D008565">Membrane Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C497759">N protein, Drosophila</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D051880">Receptors, Notch</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D015534">Trans-Activators</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 3.6.5.2</RegistryNumber><NameOfSubstance UI="D018631">ras Proteins</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004330" MajorTopicYN="N">Drosophila</DescriptorName><QualifierName UI="Q000196" MajorTopicYN="Y">embryology</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D029721" MajorTopicYN="N">Drosophila Proteins</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004625" MajorTopicYN="N">Embryo, Nonmammalian</DescriptorName><QualifierName UI="Q000502" MajorTopicYN="N">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006321" MajorTopicYN="N">Heart</DescriptorName><QualifierName UI="Q000196" MajorTopicYN="N">embryology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D020935" MajorTopicYN="N">MAP Kinase Signaling System</DescriptorName><QualifierName UI="Q000502" MajorTopicYN="N">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008565" MajorTopicYN="N">Membrane Proteins</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008648" MajorTopicYN="N">Mesoderm</DescriptorName><QualifierName UI="Q000502" MajorTopicYN="Y">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D018482" MajorTopicYN="N">Muscle, Skeletal</DescriptorName><QualifierName UI="Q000196" MajorTopicYN="N">embryology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D010641" MajorTopicYN="N">Phenotype</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D051880" MajorTopicYN="N">Receptors, Notch</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D015398" MajorTopicYN="N">Signal Transduction</DescriptorName><QualifierName UI="Q000502" MajorTopicYN="Y">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D013234" MajorTopicYN="N">Stem Cells</DescriptorName><QualifierName UI="Q000502" MajorTopicYN="N">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D015534" MajorTopicYN="N">Trans-Activators</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D018631" MajorTopicYN="N">ras Proteins</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2002</Year><Month>4</Month><Day>12</Day><Hour>10</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2002</Year><Month>6</Month><Day>1</Day><Hour>10</Hour><Minute>1</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2002</Year><Month>4</Month><Day>12</Day><Hour>10</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">11944933</ArticleId><ArticleId IdType="doi">10.1006/dbio.2002.0606</ArticleId><ArticleId IdType="pii">S0012160602906068</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">11944238</PMID><DateCompleted><Year>2002</Year><Month>07</Month><Day>25</Day></DateCompleted><DateRevised><Year>2016</Year><Month>10</Month><Day>18</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">0023-2130</ISSN><JournalIssue CitedMedium="Print"><Issue>11</Issue><PubDate><Year>2001</Year><Month>Nov</Month></PubDate></JournalIssue><Title>Klinichna khirurhiia</Title><ISOAbbreviation>Klin Khir</ISOAbbreviation></Journal>[Prophylaxis of atrioventricular block in surgery of reentry tachycardia]. | Convergent intercellular signals must be precisely integrated in order to elicit specific biological responses. During specification of muscle and cardiac progenitors from clusters of equivalent cells in the Drosophila embryonic mesoderm, the Ras/MAPK pathway--activated by both epidermal and fibroblast growth factor receptors--functions as an inductive cellular determination signal, while lateral inhibition mediated by Notch antagonizes this activity. A critical balance between these signals must be achieved to enable one cell of an equivalence group to segregate as a progenitor while its neighbors assume a nonprogenitor identity. We have investigated whether these opposing signals directly interact with each other, and we have examined how they are integrated by the responding cells to specify their unique fates. Our findings reveal that Ras and Notch do not function independently; rather, we have uncovered several modes of cross-talk between these pathways. Ras induces Notch, its ligand Delta, and the epidermal growth factor receptor antagonist, Argos. We show that Delta and Argos then synergize to nonautonomously block a positive autoregulatory feedback loop that amplifies a fate-inducing Ras signal. This feedback loop is characterized by Ras-mediated upregulation of proximal components of both the epidermal and fibroblast growth factor receptor pathways. In turn, Notch activation in nonprogenitors induces its own expression and simultaneously suppresses both Delta and Argos levels, thereby reinforcing a unidirectional inhibitory response. These reciprocal interactions combine to generate the signal thresholds that are essential for proper specification of progenitors and nonprogenitors from groups of initially equivalent cells.<CopyrightInformation>Copyright 2002 Elsevier Science (USA).</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Carmena</LastName><ForeName>Ana</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Program in Molecular Biology, Memorial Sloan-Kettering Cancer Institute, New York, New York 10021, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Buff</LastName><ForeName>Eugene</ForeName><Initials>E</Initials></Author><Author ValidYN="Y"><LastName>Halfon</LastName><ForeName>Marc S</ForeName><Initials>MS</Initials></Author><Author ValidYN="Y"><LastName>Gisselbrecht</LastName><ForeName>Stephen</ForeName><Initials>S</Initials></Author><Author ValidYN="Y"><LastName>Jiménez</LastName><ForeName>Fernando</ForeName><Initials>F</Initials></Author><Author ValidYN="Y"><LastName>Baylies</LastName><ForeName>Mary K</ForeName><Initials>MK</Initials></Author><Author ValidYN="Y"><LastName>Michelson</LastName><ForeName>Alan M</ForeName><Initials>AM</Initials></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>R01 GM056989</GrantID><Acronym>GM</Acronym><Agency>NIGMS NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>GM 56989</GrantID><Acronym>GM</Acronym><Agency>NIGMS NIH HHS</Agency><Country>United States</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType><PublicationType UI="D013487">Research Support, U.S. Gov't, P.H.S.</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Dev Biol</MedlineTA><NlmUniqueID>0372762</NlmUniqueID><ISSNLinking>0012-1606</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D029721">Drosophila Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D008565">Membrane Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C497759">N protein, Drosophila</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D051880">Receptors, Notch</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D015534">Trans-Activators</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 3.6.5.2</RegistryNumber><NameOfSubstance UI="D018631">ras Proteins</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004330" MajorTopicYN="N">Drosophila</DescriptorName><QualifierName UI="Q000196" MajorTopicYN="Y">embryology</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D029721" MajorTopicYN="N">Drosophila Proteins</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004625" MajorTopicYN="N">Embryo, Nonmammalian</DescriptorName><QualifierName UI="Q000502" MajorTopicYN="N">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006321" MajorTopicYN="N">Heart</DescriptorName><QualifierName UI="Q000196" MajorTopicYN="N">embryology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D020935" MajorTopicYN="N">MAP Kinase Signaling System</DescriptorName><QualifierName UI="Q000502" MajorTopicYN="N">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008565" MajorTopicYN="N">Membrane Proteins</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008648" MajorTopicYN="N">Mesoderm</DescriptorName><QualifierName UI="Q000502" MajorTopicYN="Y">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D018482" MajorTopicYN="N">Muscle, Skeletal</DescriptorName><QualifierName UI="Q000196" MajorTopicYN="N">embryology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D010641" MajorTopicYN="N">Phenotype</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D051880" MajorTopicYN="N">Receptors, Notch</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D015398" MajorTopicYN="N">Signal Transduction</DescriptorName><QualifierName UI="Q000502" MajorTopicYN="Y">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D013234" MajorTopicYN="N">Stem Cells</DescriptorName><QualifierName UI="Q000502" MajorTopicYN="N">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D015534" MajorTopicYN="N">Trans-Activators</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D018631" MajorTopicYN="N">ras Proteins</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2002</Year><Month>4</Month><Day>12</Day><Hour>10</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2002</Year><Month>6</Month><Day>1</Day><Hour>10</Hour><Minute>1</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2002</Year><Month>4</Month><Day>12</Day><Hour>10</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">11944933</ArticleId><ArticleId IdType="doi">10.1006/dbio.2002.0606</ArticleId><ArticleId IdType="pii">S0012160602906068</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">11944238</PMID><DateCompleted><Year>2002</Year><Month>07</Month><Day>25</Day></DateCompleted><DateRevised><Year>2016</Year><Month>10</Month><Day>18</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">0023-2130</ISSN><JournalIssue CitedMedium="Print"><Issue>11</Issue><PubDate><Year>2001</Year><Month>Nov</Month></PubDate></JournalIssue><Title>Klinichna khirurhiia</Title><ISOAbbreviation>Klin Khir</ISOAbbreviation></Journal><ArticleTitle>[Prophylaxis of atrioventricular block in surgery of reentry tachycardia].</ArticleTitle><Pagination><StartPage>23</StartPage><EndPage>25</EndPage><MedlinePgn>23-5</MedlinePgn></Pagination><Abstract>Experience of treatment of 85 patients with reentry tachycardia of atrioventricular node was analyzed. In 10 patients (first group) dottal applications directed from coronary sinus ostium toward atrioventricular bundle (AVB) were applied; in 75 (second group)--from the tricuspid valve ring deep inside atrium on the coronary sinus ostium. Temporary disorder of atrioventricular conductivity of different degree was observed in 3 patients of first group and in 1--of the second group, in whom applications were plotted in the middle of distance between coronary sinus ostium and AVB. In one observation several commissures were situated between electrocardiograms of atrium and ventriculus, not permitting to reveal trustworthy the presence of AVB potential. |
2,332,277 | Intravenous regional anesthesia with clonidine in the management of complex regional pain syndrome of the knee. | To evaluate the safety and efficacy of administering intravenous regional anesthesia (IVRA) with clonidine in the management of complex regional pain syndrome (CRPS) of the knee.</AbstractText>Prospective, non-blinded study.</AbstractText>University-affiliated pain management center.</AbstractText>7 patients with the diagnosis of CRPS of the knee. The diagnosis of CRPS was made if a) patients had at least four of these symptoms: allodynia, hyperesthesia, edema, vasomotor changes, pain with a burning quality, sudomotor changes, joint stiffness, or temperature differences between extremities; b) patients had significant pain relief (>75%) after a lumbar sympathetic block.</AbstractText>Each patient received IVRA with a solution containing clonidine 1 microg/kg in a total volume of 50 mL 0.5% lidocaine. IVRA clonidine (IVRA-C) was performed on each patient up to six times (maximum of once a week for six weeks). MEASUREMETNS: Pain was assessed using a verbal pain scale (VPS) between 0 and 10 before each IVRA-C treatment. Duration of pain relief was defined as the time during which the patients experienced no pain (VPS = 0). Continuous electrocardiogram (ECG) and pulse oximetry (SpO2) were monitored and blood pressure was recorded every 5 minutes for the first 60 minutes after tourniquet deflation.</AbstractText>Five patients received complete pain relief with 4 to 6 IVRA-C blocks. The two remaining patients reached a therapeutic plateau from IVRA-C, but had persistent anatomic lesions contributing to the recurrence of their CRPS. No patient experienced hypotension (mean arterial pressure < or = 20% baseline), hypoxemia (SpO2 < or = 90%), bradycardia (heart rate < or =H 60 beats/min), or excessive sedation.</AbstractText>IVRA-C is a useful treatment modality in the management of CRPS of the knee. Clonidine doses of 1 microg/kg appear to be well tolerated without significant side effects.</AbstractText> |
2,332,278 | Antibodies against the C-terminal peptide of rabbit oviductin inhibit mouse early embryo development to pass 2-cell stage. | A full-length rabbit oviductin cDNA(1909bp) was cloned. It consists of a 5'-UTR of 52bp, an open reading frame (ORF) of 1374bp and a 3'-UTR of 483bp and has more than 80% homology with that of other mammal oviductins. N-terminal peptide (NTP) (384 residues) and C-terminal peptide (CTP) (73 residues) of deduced protein precursor has about 80% and 50% identity with that of other mammals respectively. Fusion proteins GST-NTP 368(1R-368N)and GST-CTP73 (369F-441A) were expressed and purified. NH2-terminal of CTP sequencing reveals that the purified protein is consistent with the deduced one. In order to study the function of NTP and CTP the mouse anti-NTP and rabbit anti-CTP antisera were prepared. Tissue-specific (skeleton muscle, oviduct, uterus, ovary, liver, heart and brain) analysis indicated that rabbit oviductin was only found in oviduct. The conditioned medium derived from the rabbit oviduct mucosa epithelial cells has a function of overcoming the early embryonic development block of Kunming mouse cultured in vitro. Anti-CTP antiserum could totally inhibit the early embryo development at 2-cell stage cultured in the conditioned culture medium, but anti-NTP antiserum couldn't. There was a positive relationship between the ratio of early embryos at development block and the dosage of anti-CTP antiserum added in the conditioned culture medium. These results suggest that oviductin has a function not only on fertilization, but also on the release of early embryonic development block, and the later function domain of rabbit oviductin may be situate in its C-terminal. |
2,332,279 | Antidysrhythmic agents at the turn of the twenty-first century: a current review. | The use of class IA agents is gradually on the decline, primarily as a result of its unfavorable risk-to-benefit ratio. Lidocaine, a class IB agent, has been widely used in the acute treatment of VT. However, alternate drugs are being considered increasingly as first-line agents in the acute treatment of VT. Class IC drugs are contraindicated in patients with structural cardiac abnormalities and have a limited usefulness in the management of dysrhythmias. Beta-blockers continue to increase their role in cardiology, and subsequently their use in managing dysrhythmias. Class III agents, including amiodarone, sotalol, ibutilide, and dofetilide, are among the most widely used antidysrhythmics. Class IV calcium channel blockers have a limited usefulness in tachydysrhythmias. Digoxin and adenosine have unique antidysrhythmic properties and will likely retain their roles as antidysrhythmic agents. In the wake of the effectiveness of amiodarone, the drug that crosses all classes, some now question the benefit of pure agents that block a single, specific ion channel in the heart. After CAST8 demonstrated that antidysrhythmics can increase mortality while seemingly suppressing dysrhythmias, new drugs will continue to undergo intense scrutiny with regard to their efficacy, safety, and usefulness in treating dysrhythmias. |
2,332,280 | Intensity modulated versus non-intensity modulated radiotherapy in the treatment of the left breast and upper internal mammary lymph node chain: a comparative planning study. | To compare and evaluate intensity modulated (IMRT) and non-intensity modulated radiotherapy techniques in the treatment of the left breast and upper internal mammary lymph node chain.</AbstractText>The breast, upper internal mammary chain (IMC), heart and lungs were delineated on a computed tomography (CT)-scan for 12 patients. Three different treatment plans were created: (1) tangential photon fields with oblique IMC electron-photon fields with manually optimized beam weights and wedges, (2) wide split tangential photon fields with a heart block and computer optimized wedge angles, and (3) IMRT tangential photon fields. For the IMRT technique, an inverse planning program (KonRad) generated the intensity profiles and a clinical three-dimensional treatment planning system (U-MPlan) optimized the segment weights. U-MPlan calculated the dose distribution for all three techniques. The normal tissue complication probabilities (NTCPs) for the organs at risk (ORs) were calculated for comparison.</AbstractText>The average root mean square deviation of the differential dose-volume histogram of the breast planning target volume was 4.6, 3.9 and 3.5% and the average mean dose to the IMC was 97.2, 108.0 and 99.6% for the oblique electron, wide split tangent and IMRT techniques, respectively. The average NTCP for the ORs (i.e. heart and lungs) were comparable between the oblique electron and IMRT techniques (<or=0.7%). The wide split tangent technique resulted in higher NTCP values (>or=2%) for the ORs.</AbstractText>The lowest NTCP values were found with the oblique electron and the IMRT techniques. The IMRT technique had the best breast and IMC target coverage.</AbstractText> |
2,332,281 | Preserved semantic access in global amnesia and hippocampal damage. | C.B., a right-handed 33-year-old man, presented with anterograde amnesia after acute heart block. Cognitive abilities were normal except for serious impairment of long-term episodic memory. The access to semantic information was fully preserved. Magnetic resonance showed high signal intensity and marked volume loss in the hippocampus bilaterally; the left and right parahippocampal gyrus, lateral occipito-temporal gyrus, inferior temporal gyrus, and lateral temporal cortex were normal. This case underlines that global amnesia associated with hippocampal damage does not affect semantic memory. Although the hippocampus is important in retrieving context-linked information, its role is not so crucial in retrieving semantic contents. Cortical areas surrounding the hippocampus and lateral temporal areas might guide the recall of semantic information. |
2,332,282 | Rationale for the use of aldosterone antagonists in congestive heart failure. | Traditionally, the role of aldosterone in heart failure was thought to be a result of its effects on epithelial cells where it induces sodium reabsorption and potassium excretion with subsequent haemodynamic effects from intravascular volume expansion. On this basis, spironolactone, a non-selective aldosterone antagonist, has been used for the treatment of congestive heart failure to block aldosterone-mediated effects in epithelial cells. The Randomized Aldactone Evaluation Study (RALES), in which spironolactone was added to existing therapy in patients with heart failure, showed a significant reduction in morbidity and mortality. These results suggest that the role of aldosterone in the pathophysiology of cardiovascular disease may be more complex than previously recognised. There now is extensive experimental and growing clinical evidence for an important physiological role for aldosterone in the pathology of cardiac and renal disease. Classical effects of aldosterone are mediated via its nuclear receptor. Novel non-epithelial effects of aldosterone are mediated via a second messenger system, which involves activation of the sodium/hydrogen antiporter. These effects of aldosterone have been demonstrated in the kidney, vascular smooth muscle cell and leukocytes, and in the regulation of rapid corticotropin suppression. It has been hypothesised that cardiac damage induced by aldosterone is independent of the presence of hypertension. In support of this, experimental evidence demonstrates that cardiovascular damage induced by aldosterone can be prevented by administration of a selective mineralocorticoid receptor antagonist. These findings suggest the dissociation between cardiovascular lesions and high blood pressure, and highlight the importance of aldosterone in the pathological changes. |
2,332,283 | Self-care in adults with sickle cell disease. | This article summarizes the psychometric evaluation of the Chronic Illness Assessment Interview for Sickle Cell Disease (CIAI-SCD), an instrument based on a model of self-care for adult patients with chronic medical conditions. The CIAI-SCD was administered to 104 adults with sickle cell disease. A factor analysis identified three factors that reflected the psychological constructs of Personal Satisfaction and Perceived Control (Factor 1), Feeling Concerned and Worried (Factor 2), and Feeling Supported (Factor 3). Preliminary evidence for the internal consistency, test-retest reliability content validity, and construct validity of the CIAI-SCD was obtained. After further refinement and validation, the CIAI-SCD may be a useful tool for assessing factors related to self-care skills among adults with sickle cell disease. |
2,332,284 | [Disorders of mitochondrial energy metabolism in patients with the Kearns-Sayre syndrome]. | Kearns-Sayre syndrome is a multisystem disorder caused by rearrangements of mitochondrial genome including various deletions and/or duplications. The aim of the study is to analyse the impact of mitochondrial DNA (mtDNA) deletions on the mitochondrial energetic metabolism in five patients with Kearns-Sayre syndrome.</AbstractText>The course of the disease is progressive in all patients. All of them have bilateral ptosis and external opthalmoplegia, four have retinitis pigmentosa, three have progressive muscle weakness and three have pacemaker because of complete A-V heart block. One patient underwent renal transplantation at the age of 12 because of a chronic renal failure. Southern blot analysis in muscle tissue revealed large scale heteroplasmic mtDNA deletions (3-7.4 kb) in all patients, the number of mutated copies of mtDNA ranged from 50 to 70%. Spectrophotometric measurements of respiratory chain complexes activities in muscle tissue revealed various combinations of defects of complex III, IV and I + III activities in all patients. Nevertheless, the lactic acidosis was permanently present only in one patient. Ragged-red fibers were found in two patients.</AbstractText>Although the diagnostic of Kearns-Sayre syndrome is based on clinical features, molecular analysis of mtDNA is necessary to confirm the diagnosis. The prognosis of the disease is unfavourable and co-operation between the patient and various specialists is necessary for the treatment, which is currently only symptomatic.</AbstractText> |
2,332,285 | Vasopressin inhibits sarcolemmal ATP-sensitive K+ channels via V1 receptors activation in the guinea pig heart. | To examine the effect of vasopressin on the sarcolemmal ATP-sensitive K (K(ATP)) channel, cell-attached, insideout and open-cell-attached methods of patch clamp techniques were used in isolated guinea pig ventricular myocytes. Suppressing both glycolytic and oxidative ATP production attained K(ATP) channel activation. In the cell-attached mode, vasopressin inhibited KATP channels in a concentration-dependent manner with an IC50 of 15.1+/-1.8 nmol/L. In the inside-out configuration, vasopressin failed to block K(ATP) channels. In the cell-attached mode, manning compound (1 micromol/L), a V1 receptor-selective antagonist, blocked the inhibitory action of vasopressin, although OPC-31260 (1 micromol/L), a V2 receptor-selective antagonist could not affect the action of vasopressin. In addition, vasopressin lost its inhibitory action on K(ATP) channels when the channel was activated by pinacidil, a K channel opener and in the open-cell-attached mode effected by streptolysin-O. Thus, the inhibitory action of vasopressin K(ATP) channels may occur via V1 receptor related mechanism. |
2,332,286 | Onset time and duration of rocuronium, atracurium and mivacurium in pediatric patients. | Neuromuscular blockers (NMB) are widely used in pediatric anesthesia, but there is no ideal NMB. This study aimed at evaluating onset and recovery time, hemodynamic changes and tracheal intubation conditions of rocuronium, atracurium and mivacurium in pediatric patients.</AbstractText>Participated in this study 67 children aged 30 months to 12 years, physical status ASA I and II, who were allocated into three groups: G1 = 0.9 mg kg(-1) rocuronium (n = 22); G2 = 0.5 mg kg(-1) atracurium (n = 22); G3 = 0.15 mg kg(-1) mivacurium (n = 23). Anesthesia was induced with 50 microg kg(-1) alfentanil, 3 mg kg(-1) propofol, sevoflurane and N2O/O2. Neuromuscular block was monitored by acceleromyography on the ulnar nerve pathway. The following parameters were evaluated: onset time (OT), clinical duration (T25) relaxation time (T75) and recovery time (T(25-75)). Heart rate (HR) and mean blood pressure (MBP) were recorded in 6 moments, as well as tracheal intubation conditions.</AbstractText>Median OT was: G1 = 0.6 min, G2 = 1.3 min, G3 = 1.9 min. Median T25 was: G1 = 38 min, G2 = 41.5, G3 = 8.8 min. Median T75 was: G1 = 57.7 min; G2 = 54.6 min, G3 = 13.6 min. Median T(25-75) was: G1 = 19.7 min, G2 = 13.1 min and G3 = 4.8 min. Tracheal intubation conditions were excellent for most children in all groups. There were no significant MBP and HR clinical changes.</AbstractText>Rocuronium (0.9 mg kg(-1)) had the fastest onset time and mivacurium (0.15 mg kg(-1)) the shortest recovery time in pediatric patients anesthetized with sevoflurane. Rocuronium, mivacurium and atracurium had also not determined significant hemodynamic changes and allowed for excellent tracheal intubation conditions.</AbstractText> |
2,332,287 | Ryanodine-induced structural alterations in the RyR channel suggested by neomycin block. | In Mead and Williams, (Biophys. J. 82:1953-1963, 2002) we have reported that neomycin is a potent partial blocker of single purified sheep cardiac SR calcium release channels. Neomycin is unusual in that it is capable of blocking when applied to either the cytosolic or the luminal face of the channel. Block at either aspect of the channel is both concentration- and voltage-dependent, but exhibits different blocking parameters. In this study we have investigated the actions of neomycin on ion handling in the ryanodine-modified channel. Neomycin is more effective at the cytosolic face, having a Kb(0) value of 534.9 +/- 35.17 nM compared with a Kb(0) value of 971.5 +/- 66.62 nM for the luminal face. The voltage dependence also differs at the two sites. Values of zdelta for cytosolic and luminal neomycin are 1.09 +/- 0.04 and -0.57 +/- 0.03, respectively. The interaction of neomycin with the ryanodine-modified channel differs notably from that in the unmodified channel. Voltage-dependent relief of block is not observed after ryanodine modification, and the luminal blocking characteristics are altered. This suggests that ryanodine induces changes at the luminal mouth of the channel and may confer increased rigidity to the channel protein. |
2,332,288 | Block of the ryanodine receptor channel by neomycin is relieved at high holding potentials. | In this study we have investigated the actions of the aminoglycoside antibiotic neomycin on K+ conductance in the purified sheep cardiac sarcoplasmic reticulum (SR) calcium-release channel (RyR). Neomycin induces a concentration- and voltage-dependent partial block from both the cytosolic and luminal faces of the channel. Blocking parameters for cytosolic and luminal block are markedly different. Neomycin has a greater affinity for the luminal site of interaction than the cytosolic site: zero-voltage dissociation constants (Kb(0)) are respectively 210.20 +/- 22.80 and 589.70 +/- 184.00 nM for luminal and cytosolic block. However, neomycin also exhibits voltage-dependent relief of block at holding potentials >+60 mV when applied to the cytosolic face and a similar phenomenon may occur with luminal neomycin at high negative holding potentials. These observations indicate that, under appropriate conditions, neomycin is capable of passing through the RyR channel. |
2,332,289 | Prophylactic intravenous bolus ephedrine for elective Caesarean section under spinal anaesthesia. | To evaluate the efficacy and optimal dose of prophylactic intravenous ephedrine for the prevention of maternal hypotension associated with spinal anaesthesia for Caesarean section.</AbstractText>After patients had received an intravenous preload of 0.5 L of lactated Ringer's solution, spinal anaesthesia was administered in the sitting position with hyperbaric bupivacaine 2.5 mL 0.5% combined with 25 microg fentanyl. A total of 68 patients were randomized to receive a simultaneous 2 mL bolus intravenously of either 0.9% saline (Group C, n = 20), ephedrine 6 mg (Group E-6, n = 24), or ephedrine 12 mg (Group E-12, n = 22). Further rescue boluses of ephedrine 6 mg were given if systolic arterial pressure fell to below 90 mmHg, greater than 30% below baseline, or if symptoms suggestive of hypotension were reported.</AbstractText>There was a significantly higher incidence of hypotension in Group C (60% patients) compared to Group E-12 (27%), but not in Group E-6 (50%). The 95% Confidence Interval for the difference in proportions between Groups C and E-12 was 6-60%, P < 0.05. Fewer rescue boluses of ephedrine were required in Group E-12 compared with Group C (1.8 +/- 1.2 vs. 3.3 +/- 2.1, P < 0.05). There were no significant differences in the incidence of maternal nausea or vomiting, or of neonatal acidaemia between groups.</AbstractText>A prophylactic bolus of ephedrine 12 mg intravenously given at the time of intrathecal block, plus rescue boluses, leads to a lower incidence of hypotension following spinal anaesthesia for elective Caesarean section compared to intravenous rescue boluses alone.</AbstractText> |
2,332,290 | Dofetilide block involves interactions with open and inactivated states of HERG channels. | Rapidly activating delayed rectifier current ( IKr) is the key target of class III antiarrhythmic drugs including dofetilide. Due to its complex gating properties, the precise channel state or states that interact with these agents remain poorly defined. We have undertaken a careful analysis of the state dependence of HERG channel block by dofetilide in Xenopus oocytes and Chinese Hamster Ovary (CHO) cells by devising a protocol in which brief sampling pulses were superimposed over a wide range of test potentials. The rate of block onset, maximal steady-state block and IC50 were similar for all test potentials over the activation range, demonstrating that the drug probably interacts with open and/or inactivated but not resting HERG channels with high affinity. Reducing the fraction of inactivated channels at 0 mV by augmenting the external potassium concentration did not alter the sensitivity to dofetilide. In contrast, the S631A and S620T HERG mutations both eliminated inward rectification and reduced dofetilide affinity by approximately 10- and approximately 100-fold respectively. We have also found a novel ultra-slow activation process which occurs in wild type HERG channels at threshold potentials. Overall, our data imply that dofetilide block occurs equally at all voltages positive to the activation threshold, and that the drug interacts with HERG channels in both the open and inactivated states. |
2,332,291 | Reexpression of the nifedipine-resistant calcium channel during dedifferentiation of adult rat ventricular cardiomyocytes. | Using an adult rat ventricular culture model and whole-cell patch-clamp technique, we investigated whether the nifedipine-resistant calcium current observed at the neonatal stage but not at the adult stage could be reobserved under dedifferentiating conditions.</AbstractText>Application of 2 microM nifedipine totally inhibited the inward calcium current (carried by 5 mM Ba2+) in freshly isolated cells from adult rat heart, but it failed to block it completely when cells are cultured for 8 to 12 days. Dose-response curves of nifedipine in the range from 2 to 50 microM showed a residual current that represented, in the presence of 2 microM nifedipine, 16.4%+/-1.8% (n = 10) and 20.4%+/-1.5% (n = 10) of the total current in 8- and 12-day-old cultured cells, respectively. In these conditions, its density at 0 mV increased slightly during culture (-2.1+/-0.2 pA/pF, n = 7, and -3.2+/-0.4 pA/pF, n = 8, after 8 and 12 days in culture, respectively), without modification in the current-to-voltage curve, as well as in kinetics properties.</AbstractText>These results show that nifedipine-resistant calcium current, which has been shown to be developmentally regulated in rat ventricular cardiomyocytes, can be reexpressed in cultured-dedifferentiated cells. Its possible expression and implication in physiopathologic function are suggested.</AbstractText> |
2,332,292 | Characterisation of the human voltage-gated potassium channel gene, KCNA7, a candidate gene for inherited cardiac disorders, and its exclusion as cause of progressive familial heart block I (PFHBI). | Mutations in genes encoding cardiac ion channels and their subunits are responsible for several genetic cardiac disorders. We characterised the human gene KCNA7, encoding the voltage-gated potassium channel Kv1.7 and compared its coding sequence with that of the mouse orthologue, kcna7. Both genes are encoded by two exons separated by a conserved intron, unlike all the other Kv1-family genes that contain intronless coding regions. KCNA7 and kcna7 encode proteins of 456 amino acid residues that share >95% sequence identity, and the mouse channel has biophysical and pharmacological properties closely resembling the ultra-rapidly activating delayed rectifier (I(Kur)) in cardiac tissue. Using reverse transcriptase-PCR, KCNA7 mRNA was detected in adult human heart. We determined that KCNA7 resides on chromosome 19q13.3 in a region that also contains the progressive familial heart block I (PFHBI) locus. Direct sequencing of KCNA7's coding sequence in PFHB1-affected individuals revealed no pathogenic sequence changes, but two single nucleotide polymorphisms detected in exon 2 result in amino acid substitutions. These results provide evidence for the exclusion of this candidate as the PFHB1-causative gene, although mutations in regulatory and non-coding regions cannot be excluded. As ion channel-encoding genes have been implicated in a growing number of genetic conditions, the data presented may facilitate further analysis of the role of KCNA7 and its product in the heart. |
2,332,293 | The cardiotoxicity of local anesthetics: the place of ropivacaine. | Central and regional block procedures have a well-defined role as safe and effective methods in modern anesthesia and analgesia with long-acting local anesthetics. Recent studies have shown that the incidence of intoxication by these drugs is a rare but catastrophic event. As classic neuronal sodium channel inhibitors, local anesthetics block peripheral fast voltage-gated sodium channels on neuronal axons, and these drugs have a particularly high level of activity in the CNS and the cardiovascular system. CNS-toxicity follows a two-stage process, whereby at lower concentrations inhibitory neurons are blocked first resulting in generalized convulsions, and at higher concentrations a global CNS depression can be seen. Although seizures are an impressive clinical syndrome, they can often be treated safely without permanent damage. More important is the cardiotoxicity of these drugs, which can be divided into indirect cerebrally mediated and a direct myocardial component. Like CNS-toxicity in general, indirect cardiotoxicity demonstrates an initial stimulating effect, followed by a depressive component at higher concentrations. Direct myocardial actions are comprised of negative chronotropic, dromotropic and inotropic effects. For dromotropy, stereoselectivity was found. The S-(-)-isomers of the longacting local anesthetics were less delayed compared to racemic mixtures and the R-(+)-enantiomers. For inotropy, no stereospecific depression of this parameter was noted between isomers of ropivacaine or bupivacaine, but bupivacaine produced a significantly greater depression of LV pressure than ropivacaine, mepivacaine, or lidocaine. Pharmacokinetic differences in lipophilicity of local anesthetics correlate well with the depression mitochondrial ATP-synthesis in fast metabolizing cells. Intracellular ATP-level may be involved in contractility and resuscitation of cardiomyocytes, as be proven by in-vitro and in-vivo data. Therefore the use of pure optical S-(-)-isomers of local anesthetics may help to reduce these rare but catastrophic events. Presently, ropivacaine appears to be the safest long-acting local anesthetic. |
2,332,294 | Preconditioning blocks cardiocyte apoptosis: role of K(ATP) channels and PKC-epsilon. | The aims of this study were to determine whether preconditioning blocks cardiocyte apoptosis and to determine the role of mitochondrial ATP-sensitive K(+) (K(ATP)) channels and the protein kinase C epsilon-isoform (PKC-epsilon) in this effect. Ventricular myocytes from 10-day-old chick embryos were used. In the control series, 10 h of simulated ischemia followed by 12 h of reoxygenation resulted in 42 +/- 3% apoptosis (n = 8). These results were consistent with DNA laddering and TdT-mediated dUTP nick-end labeling (TUNEL) assay. Preconditioning, elicited with three cycles of 1 min of ischemia separated by 5 min of reoxygenation before subjection to prolonged simulated ischemia, markedly attenuated the apoptotic process (28 +/- 4%, n = 8). The selective mitochondrial K(ATP) channel opener diazoxide (400 micromol/l), given before ischemia, mimicked preconditioning effects to prevent apoptosis (22 +/- 4%, n = 6). Pretreatment with 5-hydroxydecanoate (100 micromol/l), a selective mitochondrial K(ATP) channel blocker, abolished preconditioning (42 +/- 2%, n = 6). In addition, the effects of preconditioning and diazoxide were blocked with the specific PKC inhibitors Gö-6976 (0.1 micromol/l) or chelerythrine (4 micromol/l), given at simulated ischemia and reoxygenation. Furthermore, preconditioning and diazoxide selectively activated PKC-epsilon in the particulate fraction before simulated ischemia without effect on the total fraction, cytosolic fraction, and PKC delta-isoform. The specific PKC activator phorbol 12-myristate 13-acetate (0.2 micromol/l), added during simulated ischemia and reoxygenation, mimicked preconditioning to block apoptosis. Opening mitochondrial K(ATP) channels blocks cardiocyte apoptosis via activating PKC-epsilon in cultured ventricular myocytes. Through this signal transduction, preconditioning blocks apoptosis and preserves cardiac function in ischemia-reperfusion. |
2,332,295 | Effect of dietary levels of vitamin E (all-rac-tocopheryl acetate) with or without added fat on weanling pig performance and tissue alpha-tocopherol concentration. | Two experiments involving 496 cross-bred pigs evaluated the efficacy of various dietary levels of vitamin E, with or without supplemental fat, on postweaning pig performance and weekly serum and terminal tissue alpha-tocopherol concentrations. The first trial involved 248 pigs weaned at an average of 15 d of age and 4.8 kg BW. The experiment was a randomized complete block design conducted in seven replicates. Vitamin E was added as dl-alpha-tocopheryl acetate at 0, 20, 40, 60, 80, 100, 150, or 200 IU/kg diet. Pigs were bled initially and at 7-d intervals for a 42-d period. Liver and s.c. adipose tissue samples were collected from six pigs per treatment group at 42 d. In Exp. 2, a 2 x 4 factorial arrangement of treatments in a randomized complete block design was conducted in seven replicates. The experiment used a total of 248 pigs weaned at 19 d of age and averaged 6.4 kg BW. Four vitamin E levels (0, 20, 40, and 60 IU/kg diet) and two added fat levels of 0 or 5% were fed for 35 d. Four pigs per treatment pen were bled weekly, and at 35 d a total of four pigs per treatment group were killed and liver, heart, and s.c. adipose tissues were collected and analyzed for alpha-tocopherol. The basal diet in both experiments contained an average 7.9 IU for period 1, and later diets averaged 11.0 IU vitamin E/kg. In both experiments serum alpha-tocopherol concentrations declined from weaning to 7 d after weaning and continued to decline each week after weaning when the basal diets were fed. Serum alpha-tocopherol concentrations increased (P < 0.01) each week as the dietary vitamin E level increased in both experiments. In Exp. 2, when fat was added to the diet serum alpha-tocopherol concentrations were higher (P < 0.01) than in diets without added fat. Liver, heart muscle, and adipose tissue alpha-tocopherol concentrations increased (P < 0.01) as vitamin E level increased, but at the higher dietary vitamin E level the liver surpassed the adipose tissue in its alpha-tocopherol concentration. Liver and adipose alpha-tocopherol concentrations were higher (P < 0.01) when fat was added to the diet. These results indicate that supplementation of 40 to 60 IU/kg diet with added fat resulted in a relatively constant balance of serum and tissue concentration of alpha-tocopherol during the nursery period, but when fat was not supplemented a dietary vitamin E level of 80 to 100 IU/kg diet may be needed. The current NRC recommendations for vitamin E for the pig from 5 to 20 kg BW may need to be reevaluated. |
2,332,296 | Postischemic inotropic support of the dysfunctional heart. | To determine relative adenine nucleotide regeneration and improvement in left ventricular (LV) function using three commonly used adrenergic agents--epinephrine, dobutamine, and phenylephrine---during reperfusion after a period of global ischemia. After initial resuscitation from cardiac arrest, adrenergic agents are frequently required to support postischemic LV dysfunction. However, the relative effectiveness and associated bioenergetic changes associated with these agents in the postischemic heart are unclear.</AbstractText>Prospective, controlled laboratory study.</AbstractText>University research laboratory.</AbstractText>Isolated, perfused Sprague-Dawley rat hearts.</AbstractText>After 20 mins of global ischemia, isolated rat hearts were reperfused for 30 mins with Krebs-Henseleit solution alone (control, n = 8), or with the addition of equipotent doses of epinephrine 1 microM (n = 8), dobutamine 0.3 microM (n = 8), or phenylephrine 50 microM (n = 8). In a second experiment, an alpha-1 antagonist, prazosin was given with phenylephrine to block the presumed alpha-1 agonist effect of phenylephrine.</AbstractText>A constant volume balloon was placed in the left ventricle to measure LV pressure and derived parameters of LV function. Adenine nucleotide concentrations were derived at various time points using high-performance liquid chromatography. During reperfusion, the phenylephrine group had significant improvement in LV function and cardiac efficiency in contrast to epinephrine and dobutamine. Total adenine nucleotides tended to be highest in the phenylephrine group with significant increases in adenosine diphosphate and adenosine monophosphate and no significant loss of adenosine triphosphate. The phenylephrine-induced increase in heart rate and developed pressure could be blocked with an alpha-1 antagonist, prazosin.</AbstractText>In the isolated reperfused heart, phenylephrine, mediated by alpha-1 agonism, significantly improves postischemic LV dysfunction without worsening the overall myocardial metabolic state.</AbstractText> |
2,332,297 | L-type Ca(2+) currents overlapping threshold Na(+) currents: could they be responsible for the "slip-mode" phenomenon in cardiac myocytes? | Phosphorylation of Na channels has been suggested to increase their Ca permeability. Termed "slip-mode conductance" (SMC), this hypothesis predicts that Ca influx via protein kinase A (PKA)-modified Na channels can induce sarcoplasmic reticulum (SR) Ca release. We tested this hypothesis by determining if SR Ca release is graded with I(Na) in the presence of activated PKA (with Isoproterenol, ISO). V(m), I(m), and [Ca](i) were measured in feline (n=26) and failing human (n=19) ventricular myocytes. Voltage steps from -70 through -40 mV were used to grade I(Na). Na channel antagonists (tetrodotoxin), L-type Ca channel (I(Ca,L)) antagonists (nifedipine, cadmium, verapamil), and agonists (Bay K 8644, FPL 64176) were used to separate SMC from I(Ca,L). In the absence of ISO, I(Na) was associated with SR Ca release in human but not feline myocytes. After ISO, graded I(Na) was associated with small amounts of SR Ca release in feline myocytes and the magnitude of release increased in human myocytes. I(Na)-related SR Ca release was insensitive to tetrodotoxin (n=10) but was blocked by nifedipine (n=10) and cadmium (n=3). SR Ca release was induced over the same voltage range in the absence of ISO with Bay K 8644 and FPL 64176 (n=9). Positive voltage steps (to 0 mV) to fully activate Na channels (SMC) in the presence of ISO and Verapamil only caused SR Ca release when block of I(Ca,L) was incomplete. We conclude that PKA-mediated increases in I(Ca,L) and SR Ca loading can reproduce many of the experimental features of SMC. |
2,332,298 | Prorenin-induced myocyte proliferation: no role for intracellular angiotensin II. | Cardiomyocytes bind, internalize, and activate prorenin, the inactive precursor of renin, via a mannose 6-phosphate receptor (M6PR)--dependent mechanism. M6PRs couple directly to G-proteins. To investigate whether prorenin binding to cardiomyocytes elicits a response, and if so, whether this response depends on angiotensin (Ang) II, we incubated neonatal rat cardiomyocytes with 2 nmol/L prorenin and/or 150 nmol/L angiotensinogen, with or without 10 mmol/L M6P, 1 micromol/L eprosartan, or 1 micromol/L PD123319 to block M6P and AT(1) and AT(2) receptors, respectively. Protein and DNA synthesis were studied by quantifying [(3)H]-leucine and [(3)H]-thymidine incorporation. For comparison, studies with 100 nmol/L Ang II were also performed. Neither prorenin alone, nor angiotensinogen alone, affected protein or DNA synthesis. Prorenin plus angiotensinogen increased [(3)H]-leucine incorporation (+21 +/- 5%, mean +/- SEM, P<0.01), [(3)H]-thymidine incorporation (+29 +/- 6%, P<0.01), and total cellular protein (+14 +/- 3%, P<0.01), whereas Ang II increased DNA synthesis only (+34 +/- 7%, P<0.01). Eprosartan, but not PD123319 or M6P, blocked the effects of prorenin plus angiotensinogen as well as the effects of Ang II. Medium Ang II levels during prorenin and angiotensinogen incubation were <1 nmol/L. In conclusion, prorenin binding to M6PRs on cardiomyocytes per se does not result in enhanced protein or DNA synthesis. However, through Ang II generation, prorenin is capable of inducing myocyte hypertrophy and proliferation. Because this generation occurs independently of M6PRs, it most likely depends on the catalytic activity of intact prorenin in the medium (because of temporal prosegment unfolding) rather than its intracellular activation. Taken together, our results do not support the concept of Ang II generation in cardiomyocytes following intracellular prorenin activation. |
2,332,299 | Visualization of conductive spinal cord activity using a biomagnetometer. | The authors measured conductive cervical spinal cord evoked magnetic fields (SCEFs) after thoracic spinal cord stimulation in cats and visualized spinal cord activities.</AbstractText>To evaluate the usefulness of magnetic field measurement.</AbstractText>Magnetic field measurement has several theoretical advantages compared with electric potential measurement. Although biomagnetometers for the brain and heart are already on the market and are widely used, methods for magnetic field measurement of the spinal cord have not been established.</AbstractText>Cervical laminectomy was performed on adult cats under anesthesia and the dural tube was exposed. Electrical stimuli were applied to the lower thoracic spinal cord by a catheter epidural electrode. SCEFs were recorded using a biomagnetometer specially designed for recording spinal cord action potentials. SCEFs were measured at 35 different points over the cervical spine and isomagnetic field maps of SCEFs were constructed. Thereafter, the spinal cord was transected completely at C5 and SCEFs were measured again.</AbstractText>The detected SCEFs showed a clear biphasic configuration. The first deflection of the magnetic fields from the left side was directed outward, but the right-side deflection was directed inward. The second deflection showed reversed polarity. The isomagnetic field maps of SCEFs clearly demonstrated the quadrupolar pattern and propagated at a conduction velocity of 80-120 m/s. After spinal cord transection, the propagation of SCEFs stopped at the transection site, and the SCEFs could not be obtained above the site.</AbstractText>The authors concluded that magnetic field measurement is useful for evaluation of spinal cord function. Moreover, it was apparent that SCEFs could indicate conduction block in the spinal cord.</AbstractText> |
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