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2,332,000 | Identification of genes expressed during myocardial development. | To identify genes expressed in the fetal heart that are potentially important for myocardial development and cardiomyocyte proliferation.</AbstractText>mRNAs from fetal (29 weeks) and adult cardiomyocytes were use for suppression subtractive hybridization (SSH). Both forward (fetal as tester) and reverse (adult as driver) subtractions were performed. Clones confirmed by dot-blot analysis to be differentially expressed were sequenced and analyzed.</AbstractText>Differential expressions were detected for 39 out of 96 (41%) clones on forward subtraction and 24 out of 80 (30%) clones on reverse. For fetal dominating genes, 28 clones matched to 10 known genes (COL1A2, COL3A1, endomucin, HBG1, HBG2, PCBP2, LOC51144, TGFBI, vinculin and PND), 9 clones to 5 cDNAs of unknown functions (accession AK021715, AF085867, AB040948, AB051460 and AB051512) and 2 clones had homology to hEST sequences. For the reverse subtraction, all clones showed homology to mitochondrial transcripts.</AbstractText>We successfully applied SSH to detect those genes differentially expressed in fetal cardiac myocytes, some of which have not been shown relative to myocardial development.</AbstractText> |
2,332,001 | Lower prevalence of intraventricular block in African-American patients compared with Caucasian patients: an electrocardiographic study II. | Electrocardiographic (ECG) differences occur between African-American and white persons.</AbstractText>Intraventricular conduction abnormalities of ECGs of 2,123 African-American and white hospital patients ages 20-99 years were studied in a consecutive manner.</AbstractText>Intraventricular conduction abnormalities develop later in life and are less common in African-American patients, compared with white patients. The prevalence of conduction abnormalities increases with advancing age in both races. Left- and right ventricular conduction abnormalities begin to rise at age 50 for white patients but begin to rise at age 70 for African-American patients. The prevalence of left ventricular conduction abnormalities peaks in the ninth decade of life in both races but declines in both races in the tenth decade of life. The prevalence of right ventricular conduction abnormalities gradually increases and peaks in the tenth decade of life in both races.</AbstractText>The prevalence of intraventricular block is significantly less in African-American patients, compared with white patients--occurring in 8.6% of African-American patients and in 15.2% of white patients. The prevalence of intraventricular block is lowest in African-American women at 6.5% and highest in white men at 16.8%.</AbstractText> |
2,332,002 | Severe acute respiratory syndrome: relationship between radiologic and clinical parameters. | To quantify severity of severe acute respiratory syndrome (SARS) on chest radiographs and to determine its relationship with clinical parameters.</AbstractText>Forty patients (mean age, 42.90 years +/- 14.01 [SD]; median age, 41.5 years; age range, 25-82 years) with clinically diagnosed SARS were evaluated. Heart rate, oxygen saturation, temperature, and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were recorded daily. Severity of lung changes on chest radiographs was scored according to percentage of involved lung. Radiographic scores at days of admission, treatment, and maximal radiographic score were extracted for statistical analysis with clinical parameters. Time to maximal radiographic score from admission and days between onset and beginning of treatment were determined. Correlations between radiographic and clinical parameters were evaluated with Spearman rank correlation. Sex differences with respect to clinical and radiographic parameters were evaluated with Mann-Whitney test.</AbstractText>Median chest radiographic scores peaked 5 days after beginning of treatment before they declined. Maximal and treatment radiographic scores were inversely related to oxygen saturation (r = -0.67, P <.001; r = -0.35, P =.03). Admission radiographic score was correlated with admission AST level (r = 0.53, P =.003); treatment radiographic score, with treatment ALT and AST levels (r = 0.43, P =.007; r = 0.42, P =.019); and time to maximal radiographic score, with AST level at maximal radiographic score (r = -0.45, P =.006), admission radiographic score (r = -0.55, P <.001), treatment radiographic score (r = -0.58, P <.001), and admission ALT and AST levels (r = -0.44, P =.007; r = -0.58, P =.001). Treatment delay was associated with AST level at maximal radiographic score (r = 0.53, P =.001), treatment radiographic score (r = 0.60, P <.001), and time to maximal radiographic score (r = -0.36, P =.02). No sex differences occurred with respect to radiographic and clinical parameters (P >.05).</AbstractText>Severity of lung abnormalities quantified on chest radiographs correlates with clinical and laboratory parameters.</AbstractText>Copyright RSNA, 2003</CopyrightInformation> |
2,332,003 | Anti-monocyte chemoattractant protein-1 gene therapy attenuates left ventricular remodeling and failure after experimental myocardial infarction. | Increased expression of monocyte chemoattractant protein-1 (MCP-1) has recently been described in clinical and experimental failing heart. However, its pathophysiological significance in heart failure remains obscure. We thus determined whether MCP-1 is increased in post-myocardial infarction (MI) hearts and its blockade can attenuate the development of left ventricular (LV) remodeling and failure.</AbstractText>Anterior MI was produced in mice by ligating the left coronary artery. After 4 weeks, MI mice exerted LV dilatation and contractile dysfunction in association with myocyte hypertrophy and interstitial fibrosis of noninfarcted LV. MCP-1 mRNA levels were increased by 40-fold in noninfarcted LV 1 day after ligation, which persisted until 28 days. To block the MCP-1 signals, an N-terminal deletion mutant of the human MCP-1 gene was transfected into the limb skeletal muscle 3 days before and 14 days after ligation. This method improved the survival rate of mice with MI at 4 weeks (61% versus 87%, P<0.05) as well as attenuated LV cavity dilatation and contractile dysfunction, interstitial fibrosis, recruitment of macrophages, and myocardial gene expression of tumor necrosis factor-alpha and transforming growth factor-beta compared with the nontreated MI mice despite the comparable infarct size calculated as percent LV circumference.</AbstractText>The activation of MCP-1 expression contributes to the LV remodeling and failure after MI. An anti-MCP-1 gene therapy can be a useful novel strategy for preventing post-MI heart failure.</AbstractText> |
2,332,004 | The gigantocellular depressor area revisited. | 1. In studies conducted with Dr Donald Reis we described a functionally distinct region of the rat medullary reticular formation that we called the Gigantocellular Depressor Area (GiDA). The GiDA was defined as a region from which vasodepressor and sympathoinhibitory responses were evoked by nanoinjections of glutamate. We later showed that cells in the GiDA project to autonomic nuclei in the medulla, brainstem, and spinal cord, including the intermediolateral cell column. We also showed that kainic acid lesions of the GiDA induce hypertension and block the baroreceptor reflex evoked by electrical stimulation of the aortic depressor nerve. The present studies describe the effects of muscimol nanoinjections into the GiDA. 2. Nanoinjections of muscimol were made in the GiDA of anesthetized rats and changes in arterial pressure, heart rate, and responses to aortic depressor nerve stimulation were measured. 3. Bilateral nanoinjections of muscimol into the GiDA evoke an increase in arterial pressure and lead to fulminating hypertension. Unilateral injections of muscimol into the GiDA block the baroreflex response evoked by electrical stimulation of the ipsilateral aortic depressor nerve. However, these unilateral injections of muscimol into the GiDA evoked profound falls in arterial pressure to nearly spinal levels. In spite of this fall in blood pressure, heart rate also decreased significantly and there was not a compensatory tachycardia. Both the arterial pressure and baroreceptor responses required several hours to recover following the muscimol injections. 4. Although these data are consistent with the proposal that the GiDA is critical for the baroreflex. the opposing effects on blood pressure of unilateral and bilateral injections of muscimol are difficult to reconcile with ourcurrent models of central sympathetic regulation. |
2,332,005 | Simultaneous administration of a low-dose mixture of donor bone marrow cells and splenocytes plus adenovirus containing the CTLA4Ig gene result in stable mixed chimerism and long-term survival of cardiac allograft in rats. | T-cell costimulatory blockade combined with donor bone marrow transfusion may induce mixed chimerism, rendering robust tolerance in transplanted organs and cells. However, most protocols entail high doses of donor bone marrow cells (BMCs) or repeated administration of costly agents that block costimulatory pathways, thus delaying clinical development. To circumvent these shortcomings, we developed a strategy in which the dosage of donor BMCs was reduced but compensated by donor splenocytes (SPLCs). Furthermore, repeated administration of costly agents was replaced with a single injection of adenovirus expressing a gene of interest. In rat cardiac transplantation models, cardiac allografts from DA (RT-1a) rats were transplanted heterotopically into the abdomen of LEW (RT-11) recipient rats. Immediately after cardiac transplantation, an adenovirus vector (AdCTLA4Ig; 5 x 10(9) plaque-forming units) containing the gene for CTLA4Ig was administered to recipients (n = 6) simultaneously with a low dose of donor BMCs (1 x 10(8)/rat) and SPLCs (5 x 10(7)/rat) via the portal vein. The treated LEW recipient rats developed long-lasting mixed chimerism (>10% at >100 days) and exhibited long-term cardiac allografts (mean survival time of > 200 days) compared with control recipients. Moreover, recipients displaying long-lasting mixed chimerism accepted subsequent donor skin allografts while promptly rejecting third-party skin allografts. These results suggest that blockade of the CD28-B7 pathway, using adenovirus-mediated CTLA4Ig gene transfer, in concert with a low dosage of donor BMCs and SPLCs, may represent a feasible strategy to induce stable mixed chimerism and permit long-term survival of cardiac allografts. |
2,332,006 | [Hormonal life in systemic lupus and other connective tissue diseases]. | Among connective tissue diseases, systemic lupus erythematosus is the illness that is most concerned by hormonal life events. The sex ratio is 9/1, and symptoms begin mostly during the third decade, sometimes during birth pill contraception or during pregnancy. As soon as systemic lupus is under control of an efficient treatment, pregnancy is no longer contra-indicated. A medical multidisciplinary surveillance is required. Complicated pregnancy concerns mother and baby. Lupus flares are more frequent during the second and third trimesters as well as during the post-partum period. Usually the intensity is moderate. Severe flares concern patients with renal involvement, hypertension and renal insufficiency and are mostly seen in patients with unplanified pregnancy and yet with still active lupus. Foetal death occurs in 10-30% of the cases, depending on the lupus activity and severity (renal lupus). Prematurity remains an important cause of morbidity (30% of live births). Foetal deaths and prematurity are even more frequent if the patient has an antiphospholipid syndrome. Neonatal cutaneous lupus and auriculo-ventricular congenital heart block is infrequent (1% of SLE patients with anti-Ro/SSA antibodies). Among other connective tissue diseases, polymyositis has a very severe obstetrical prognosis for both mother and foetus. Among primary vasculitis, polyarteritis nodosa, as found during pregnancy, can herald a very bad prognosis. |
2,332,007 | Contributions of social context to inequalities in years of life lost to heart disease in Texas, USA. | Several recent articles have pointed to the effect of social context on heart disease mortality after adjusting for individual level indicators. This study investigates the contributions of individual socioeconomic factors (sex, race, and education) and social context at the neighborhood level (wealth, education, social capital, and racial/ethnic composition), and the county level (social inequality, human and social capital, economic and demographic characteristics) on premature cardiovascular mortality. Death certificate information was obtained for all those who died of heart disease in Texas, USA, in 1991. Deaths were geocoded to obtain block-group, census tract, and county social context from the census. Multilevel hierarchical models quantified the contributions of individual characteristics and block-group, tract, and county social context on years of potential life lost to heart disease. Cross-level analyses investigated the interaction between individual and contextual factors. Being female, having more education, and residing in areas with higher median house value were associated with less premature mortality. Although blacks and Hispanics lost more years of life to heart disease than whites, blacks and Hispanics living in tracts with higher own racial/ethnic group density lost fewer years of life than their peers living in less homogenous tracts. At the county level, premature mortality was negatively associated with social capital. The tract and county level variances were statistically significant indicating the importance of social context to premature heart disease mortality. Plausible mechanisms through which these effects operate are explored. Social context at the block-group, tract, and county level played an important role, though a smaller role than individual factors, in explaining years of life lost to heart disease. |
2,332,008 | [Papulo-erythematous eruption of neonatal lupus]. | Neonatal lupus is rare and cutaneous lesions are usually suggestive of the diagnosis. We describe the case an infant with atypical clinical and histological aspects.</AbstractText>A female newborn, 6 weeks of life, presented since 3 weeks a papulo-erythematous eruption involving the trunk and the 4 limbs. Cutaneous biopsy showed a dermal infiltrate of mononuclear cells, which corresponded morphologically to lymphocytes. But myelo-monocytic origin was proved by immunostaining. This result could be seen in hematodermia and macrophagic activation syndrome, but we had no clinical sign for these diagnosis. Later, she presented an erythema of the eyelids and erythematous papules of the face leading to suspicion of neonatal lupus. Questioning the mother revealed that she had Raynaud's syndrome since 1995. Antinuclear factors were positive in the patient and her mother, corresponding to antiSSA and antiSSB antibodies. She exhibited cytolytic hepatitis but no congenital heart block. Direct immunofluorescence was negative. The clinical evolution was good with complete clearing of the eruption at the age of 3 months. At 10 months, clinical and biological examinations were normal, with no arguments for haematological disease.</AbstractText>This observation is original because of the initial papulo-erythematous eruption which is rare in neonatal lupus. Diagnosis was confirmed when specific secondary cutaneous lesions appeared. The biopsy of the first eruption showed a myelo-monocytic infiltrate which has never been described in neonatal lupus. However cutaneous biopsies are rarely performed in neonatal lupus and immunostaining is lacking in the literature.</AbstractText> |
2,332,009 | [The time-course of action of rapacuronium and mivacurium after early reversal following equally lasting relaxation]. | This study was designed to compare the time course of action and the safety profile of Rapacuronium and Mivacurium in day case dental surgery. After Ethics Committee approval 61 healthy adult patients, scheduled for dental day case surgery, were randomised in an assessor-blinded manner to receive either 1.5 mg/kg Rapacuronium with and without 0.05 neostigmine 5 min later (19 patients each) or a total of 0.25 mg/kg Mivacurium (n = 16). Anaesthesia was induced using Propofol 2 - 5.1 mg/kg and Remifentanil 24 - 73 mcg/kg/h and maintained with Desflurane in N2O/O2 (2/1). Endotracheal intubation was performed when maximum blockade was achieved and scored by a blinded intubator. Neuromuscular block was monitored using the train-of-four response to supramaximal stimuli at the ulnar nerve every 15 seconds using acceleromyography (TOF Watch SX). Onset time, clinical duration (reappearance of the third twitch of a TOF-stimulation) and recovery to T4/T1 > 0.9 were recorded. Speed of recovery was evaluated by the time difference between reappearance of the third twitch and T4/T1 > 0.9. The intubating conditions at the time of maximum block revealed no statistically significant differences between the three groups. Changes in blood pressure, heart rate and airway pressure were not significant. Onset time in subjects who received Rapacuronium (99 +/- 29 s) was faster compared to the onset time in those who received Mivacurium (157 +/- 36 s). Also clinical duration was significantly shorter following Rapacuronium without reversal (12 +/- 4 min) as well as with reversal (9 +/- 1 min) compared with Mivacurium (21 +/- 5 min)). Patients treated with Rapacuronium and reversal recovered faster (14 +/- 8 min)) compared to the other two groups (Mivacurium: 20 +/- 6 min, Rapacuronium without reversal: 31 +/- 9 min). The fraction of clinical duration of the total duration was highest following Mivacurium (51 %) when compared with Rapacuronium/Neostigmine (43 %) and Rapacuronium (28 %). |
2,332,010 | Questions about dexamethasone use for the prevention of anti-SSA related congenital heart block. | Mothers with anti-SSA/Ro antibodies who have had a previous fetus with congenital heart block (CHB) have a risk of recurrence estimated to be up to 16%.</AbstractText>To improve the management of these "high risk patients" by determining (a) whether or not prophylactic treatment is efficient; (b) whether or not fluorinated steroids (betametasone and dexamethasone) that do cross the placenta in an active form are safe for the fetus; and (c) which prophylactic treatment should be used.</AbstractText>Retrospective study performed on seven mothers sent to a university hospital owing to a past history of one (six mothers) or two children (one mother) with CHB.</AbstractText>13 subsequent pregnancies occurred. No CHB was observed. All four pregnancies in women treated with 10 mg/day prednisone were uneventful. Three pregnancies in women receiving no steroids resulted in two early spontaneous abortions and one live birth. The six pregnancies in women treated with dexamethasone (4-5 mg/day) ended in one early and one late spontaneous abortion, two stillbirths, and two live births with intrauterine growth restriction and mild adrenal insufficiency. A histological study of one stillbirth disclosed intrauterine growth restriction and marked adrenal hypoplasia.</AbstractText>Adverse obstetric outcomes were often seen here and major concerns have been raised by paediatricians about the safety of fluorinated steroids, owing to the results of animals studies, retrospective data, and randomised trials. Because fluorinated steroids have not been shown to improve prophylactic treatment of CHB in pregnant women at high risk, their use is questionable.</AbstractText> |
2,332,011 | Electrophysiological effects of ginseng and ginsenoside Re in guinea pig ventricular myocytes. | Panax ginseng is a folk medicine with various cardiovascular actions; however, its underlying mechanisms of action are not well known. In the present study, we examined the effects of ginseng and its main component, ginsenoside Re, on action potentials and membrane currents recorded from isolated guinea pig ventricular myocytes with the whole-cell patch clamp technique. Ginseng (1 mg/ml) shortened the action potential duration in a rate-dependent manner. Ginseng depressed the L-type Ca2+ current (I(Ca-L)) in a mode of both tonic block and use-dependent block, and enhanced the slowly activating component of the delayed rectifier K+ current (I(Ks)). Ginsenoside Re 3 microM exhibited similar electrophysiological effects to those of 1 mg/ml ginseng, but of slightly smaller magnitude. Inhibition of I(Ca,L) and enhancement of I(Ks) by ginsenoside Re appear to be one of the main electrophysiological actions of ginseng in the heart, although contributions from other ingredients should be considered. |
2,332,012 | Single-shot intrathecal sufentanil with bupivacaine in late labour--analgesic quality and obstetric outcome. | To investigate the analgesic effect and obstetric outcome after single-shot intrathecal sufentanil with bupivacaine in late labour.</AbstractText>Forty multiparous women in advanced labour were given a spinal injection of sufentanil 7.5 microg and bupivacaine 2 mg. Pain intensity was recorded by the parturient on a visual analogue scale. The quality of pain relief was also rated with a verbal score directly after delivery. Side effects, such as hypotension, pruritus, sedation, nausea and motor block were noted. Obstetric parameters were followed and recorded. Apgar score and umbilical artery pH were noted.</AbstractText>Median visual analogue scores after 5, 15, 30, 60, 90, 120 and 150 min were 1.5, 0.5, 0, 1, 1.5, 2 and 3, respectively. Seventy-seven percent of the parturients scored the analgesic quality as excellent. Six parturients had hypotension. Motor block, sedation and nausea were rare. Pruritus was seen in 85% of the cases. No ceasarean section was performed. Vacuum extraction was done in six (15%) cases. Oxytocin augmentation was needed in 26 (65%) of the parturients. Fetal heart rate disturbances following the spinal block were seen in four cases. Apgar scores were high. No neonate had Apgar < 7.</AbstractText>Intrathecal block with sufentanil 7.5 microg in combination with bupivacaine 2 mg is a very effective pain relief in late labour. Due to its limited duration it is important to select women in rapid progress of labour, and active obstetric management is necessary. It is also very important that the obstetrician is aware of the risk of non-reassuring fetal heart rate changes after intrathecal block.</AbstractText> |
2,332,013 | Intrathecal midazolam added to bupivacaine improves the duration and quality of spinal anaesthesia. | The antinociceptive action of intrathecal midazolam is well documented. In this prospective study, we investigated the addition of midazolam to intrathecal bupivacaine on the duration and quality of spinal blockade.</AbstractText>Forty ASA I or II adult patients undergoing lower abdominal surgery were selected for the study. The patients were randomly allocated to receive 3 ml of 0.5% hyperbaric bupivacaine intrathecally either alone or with 1 mg of midazolam using a combined spinal epidural technique. The duration and quality of sensory and motor block, perioperative analgesia, haemodynamic changes, and sedation levels were assessed.</AbstractText>The duration of sensory block (i.e. time to regression to the S2 segment) was significantly longer in the midazolam group than the control group (218 min vs. 165 min; P < 0.001). The duration of motor block was also prolonged in the midazolam group as compared with the control group (P < 0.01). In 90% of the patients in the midazolam group, the quality of block was adequate during the intra-operative period as compared with only 65% of the patients in the control group (P < 0.05). The duration of effective analgesia was longer in the midazolam group than in the control group (199 vs. 103 min; P < 0.001). Blood pressure, heart rate, oxygen saturation and sedation scores were comparable in both groups. No neurological deficit or other significant adverse effects were recorded.</AbstractText>The addition of intrathecal midazolam to bupivacaine significantly improves the duration and quality of spinal anaesthesia and provides prolonged perioperative analgesia without significant side-effects.</AbstractText> |
2,332,014 | A subset of highly effective propafenone-type multidrug resistance modulators lacks effects on cardiac action potential and mechanical twitch parameters of rat papillary muscles. | In this study, we tested a series of 12 previously identified, highly effective propafenone-type multidrug resistance (MDR) modulators for their possible undesirable effects on cardiac tissue. We used rat papillary muscle preparations and quantitatively determined the potency of these substances to block action potential (AP) upstroke velocity (Vmax) and to prolong APD50. Simultaneously, the effects on isometric twitch parameters were evaluated. Concentration-response curves were obtained for all parameters. Within a subset of the compounds, we found a significant rank correlation (r' = 0.87; p < 0.05) between potencies to block Vmax (kiVmax) and to inhibit daunomycin efflux in MDR cells (IC50). Surprisingly, the most lipophilic compounds with additional aromatic side chains completely lacked effects on AP and mechanical twitch parameters, although they are the most effective MDR modulators. Additional structural modifications such as fluoride substitution of the aromatic ring, introduction of arylpiperazine or piperidine side chains, as well as modifying the hydrogen bond acceptor strength of the carbonyl group did not reestablish cardiac side effects. In contrast, when these substances were truncated at the phenylpropiophenone moiety of the propafenone core structure, cardiac effects reoccurred. We conclude that aromatic substituents in the vicinity of the nitrogen atom prevent interaction with ion channels, likely due to steric hindrance, and are thus a prerequisite for eliminating unwanted cardiac effects. |
2,332,015 | Autoantibodies in mothers of children with neonatal liver disease. | Neonatal lupus erythematosus (NLE) is associated with maternal anti-Ro/La autoantibodies. It is characterized by heart block and/or cutaneous skin lesions, and occasionally liver disease. This study was performed to determine whether idiopathic neonatal cholestasis (INC) represents NLE without its cardiac or cutaneous findings.</AbstractText>Sera were obtained for autoantibody analysis from mothers of children with INC (N = 11), biliary atresia (N = 25), other liver disease excluding viral hepatitis (liver disease control subjects, N = 14), and healthy children (normal control subjects [NC], N = 22).</AbstractText>The characteristic serologic findings of NLE, high titer antibodies to Ro and/or La, were absent in mothers from all groups. An unexpected finding was the prevalence of autoantibodies in mothers of infants with liver disease of any type. The frequency of maternal antinuclear antibodies at > or = 1:120 dilution was greater than the estimated frequency in the general population (22% vs. 9%, P = 0.044). The frequency of maternal low titer autoantibodies to 52 kD Ro detected by ELISA was significantly greater than in the NC group (31% vs. 5%, P = 0.014).</AbstractText>The majority of cases of INC do not represent NLE. The frequent presence of autoantibodies in mothers of infants in all neonatal liver disease groups raises the possibility that maternal serologic autoimmunity is associated with neonatal liver disease.</AbstractText> |
2,332,016 | Reversal of neuromuscular blockade and simultaneous increase in plasma rocuronium concentration after the intravenous infusion of the novel reversal agent Org 25969. | The purpose of this study was to determine the changes in the plasma concentration of rocuronium and the reversal of its neuromuscular blockade after the intravenous infusion of Org 25969, the novel neuromuscular block-reversal agent, in anesthetized guinea pigs.</AbstractText>Rocuronium was infused for 1 h at a rate of 12-19 nmol.kg-1.min-1 to produce a steady-state 90% neuromuscular block. After 30 min, a concomitant infusion of either the reversal agent Org 25969 at a rate of 50 nmol.kg-1.min-1 or an infusion of an equivalent volume of saline was started. The time course of plasma concentrations of rocuronium was determined by use of liquid chromatography-mass spectrometry/mass spectrometry.</AbstractText>In both treatment groups, a steady-state plasma concentration of rocuronium was obtained after 30 min. In the saline-treated group, the plasma concentration of rocuronium and depth of block remained constant. In the Org 25969 group, neuromuscular block was reversed while the rocuronium infusion was ongoing. Simultaneously, an increase in the total plasma concentration of rocuronium (free and complexed) was observed, even though the infusion rate of rocuronium was not changed. Compared with the saline-treated group, a small increase in the postmortem bladder concentration of rocuronium was detected.</AbstractText>The authors propose that the capture of rocuronium by Org 25969 causes the rapid reversal of neuromuscular block. The reversal can be explained by the rapid transfer of free rocuronium from the effect compartment (neuromuscular junction) to the central compartment, in which it is bound to Org 25969. This explains the increase in total plasma concentration of rocuronium (free and bound to Org 25969).</AbstractText> |
2,332,017 | Cytokine polymorphisms and histologic expression in autopsy studies: contribution of TNF-alpha and TGF-beta 1 to the pathogenesis of autoimmune-associated congenital heart block. | Although Abs to SSA/Ro-SSB/La are necessary for the development of congenital heart block (CHB), the low frequency suggests that fetal factors are contributory. Because CHB involves a cascade from inflammation to scarring, polymorphisms of the TNF-alpha promoter region and codons 10 and 25 of the TGF-beta gene were evaluated in 88 children (40 CHB, 17 rash, 31 unaffected siblings) and 74 mothers from the Research Registry for Neonatal Lupus (NL). Cytokine expression was assessed in autopsy material from two fetuses with CHB. Significantly increased frequency of the -308A (high-producer) allele of TNF-alpha was observed in all NL groups compared with controls. In contrast, the TGF-beta polymorphism Leu(10) (associated with increased fibrosis) was significantly higher in CHB children (genotypic frequency 60%, allelic frequency 78%) than unaffected offspring (genotypic frequency 29%, p = 0.016; allelic frequency 56%, p = 0.011) and controls, while there were no significant differences between controls and other NL groups. For the TGF-beta polymorphism, Arg(25), there were no significant differences between NL groups and controls. In fetal CHB hearts, protein expression of TGF-beta, but not TNF-alpha, was demonstrated in septal regions, extracellularly in the fibrous matrix, and intracellularly in macrophage infiltrates. Age-matched fetal hearts from voluntary terminations expressed neither cytokine. TNF-alpha may be one of several factors that amplify susceptibility; however, the genetic studies, backed by the histological data, more convincingly link TGF-beta to the pathogenesis of CHB. This profibrosing cytokine and its secretion/activation circuitry may provide a novel direction for evaluating fetal factors in the development of a robust animal model of CHB as well as therapeutic strategies in humans. |
2,332,018 | Clearance of apoptotic cells: TGF-beta in the balance between inflammation and fibrosis. | Transforming growth factor-beta (TGF-beta) has been considered an anti-inflammatory cytokine responsible for the bland removal of apoptotic cells. What is less established is the extent of secretion of this cytokine during the clearance of opsonized apoptotic cells via Fcgamma-mediated uptake. To date both decreased (favoring predominance of inflammation) and increased (favoring resolution of inflammation but potentially pro-fibrotic) responses have been demonstrated. IN an in vitro model of autoantibody-induced cardiac injury, we herein demonstrate that macrophages cocultured with apoptotic human fetal cardiocytes bound by anti-SSA/Ro antibodies secrete increased levels of TGF-beta. Prolonged secretion of this cytokine may contribute to the exuberant scarring seen in congenital heart block associated with maternal autoantibodies reactive with SSA/Rho and SSB/La antigens. |
2,332,019 | Deconvolving sequence variation in mixed DNA populations. | We present an original approach to identifying sequence variants in a mixed DNA population from sequence trace data. The heart of the method is based on parsimony: given a wildtype DNA sequence, a set of observed variations at each position collected from sequencing data, and a complete catalog of all possible mutations, determine the smallest set of mutations from the catalog that could fully explain the observed variations. The algorithmic complexity of the problem is analyzed for several classes of mutations, including block substitutions, single-range deletions, and single-range insertions. The reconstruction problem is shown to be NP-complete for single-range insertions and deletions, while for block substitutions, single character insertion, and single character deletion mutations, polynomial time algorithms are provided. Once a minimum set of mutations compatible with the observed sequence is found, the relative frequency of those mutations is recovered by solving a system of linear equations. Simulation results show the algorithm successfully deconvolving mutations in p53 known to cause cancer. An extension of the algorithm is proposed as a new method of high throughput screening for single nucleotide polymorphisms by multiplexing DNA. |
2,332,020 | Cardiovascular responses to microinjections of nociceptin into a midline area in the commissural subnucleus of the nucleus tractus solitarius of the rat. | Immunoreactivity for nociceptin, an endogenous ligand for the ORL1 opioid receptors, has been reported in the nucleus tractus solitarius (nTS). A midline area in the commissural subnucleus (nCom) of nTS is the site of peripheral chemoreceptor projections. This investigation was carried out in urethane-anesthetized, artificially ventilated, adult male Wistar rats, to study the cardiovascular effects of the activation of ORL1 receptors in a midline area of the nCom. Microinjections (30 nl) of nociceptin (0.15-0.62 mM) into the nCom elicited depressor and bradycardic responses. Prior microinjections of [N-Phe(1)]-nociceptin-(1-13)-NH(2) (4.5 mM), a specific antagonist for ORL1 opioid receptors, into the nCom blocked the effects of nociceptin (0.31 mM, the maximally effective concentration), but not endomorphin-2 (0.6 mM; an endogenous ligand for micro -opioid receptors). On of other hand, naloxone (0.125 mM; an antagonist for classical opioid receptors) did not block the effects of nociceptin, while it did block the effects of endomorphin-2. The blockade of nociceptin effects by [N-Phe(1)]-nociceptin-(1-13)-NH(2) and endomorphin-2 by naloxone, was not due to some nonspecific effects because the responses to L-Glu (5 mM) remained unaltered after the microinjection of these antagonists. These results indicate that activation of ORL1 receptors in the nCom may play a role in the regulation of cardiovascular function. |
2,332,021 | Randomized comparison between sevoflurane anaesthesia and unilateral spinal anaesthesia in elderly patients undergoing orthopaedic surgery. | This prospective, randomized study was conducted to compare unilateral spinal block using small doses of hyperbaric bupivacaine and single-agent anaesthesia with sevoflurane in elderly patients undergoing hip surgery.</AbstractText>Thirty patients (> 65 yr) undergoing hip fracture repair were randomly allocated to receive unilateral spinal anaesthesia with hyperbaric bupivacaine 7.5 mg 0.5% (Group Spinal, n = 15) or volatile induction and maintenance anaesthesia with sevoflurane (Group SEVO, n = 15). General anaesthesia was induced by increasing the inspired concentration to 5%. A laryngeal mask airway was placed without muscle relaxants, and the end-tidal concentrations of sevoflurane were adjusted to maintain cardiovascular stability. Hypotension (decrease in systolic arterial pressure > 20% from baseline), hypertension or bradycardia (heart rate < 50 beats min(-1)) requiring treatment, and the length of stay in the postanaesthesia care unit was recorded. Cognitive functions were evaluated the previous day, and 1 and 7 days after surgery with the Mini Mental State Examination test.</AbstractText>Hypotension occurred in seven patients of Group Spinal (46%) and in 12 patients of Group SEVO (80%) (P = 0.05). Phenylephrine was required to control hypotension in three spinal patients (21%) and four SEVO patients (26%) (n.s.). SEVO patients had lower heart rates than spinal patients from 15 to 60 min after anaesthesia induction (P = 0.01). Bradycardia was observed in three SEVO patients (22%). Discharge from the postanaesthesia care unit required 15 (range 5-30) min in Group Spinal and 55 (15-80) min in Group SEVO (P = 0.0005). Eight patients in Group Spinal (53%) and nine patients in Group SEVO (60%) showed cognitive decline (Mini Mental State Examination test decreased > or = 2 points from baseline) 24 h after surgery (n.s.). Seven days after surgery, confusion was still present in one patient of Group Spinal (6%) and in three patients of Group SEVO (20%) (n.s.).</AbstractText>In elderly patients undergoing hemiarthroplasty of the hip, induction and maintenance with sevoflurane provide a rapid emergence from anaesthesia without more depression of postoperative cognitive function compared with unilateral spinal anaesthesia. This technique represents an attractive option when patient refusal, lack of adequate co-operation or concomitant anticoagulant therapy contraindicate the use of spinal anaesthesia.</AbstractText> |
2,332,022 | Heterogeneous proliferative potential in regenerative adult newt cardiomyocytes. | Adult newt cardiomyocytes, in contrast to their mammalian counterparts, can proliferate after injury and contribute to the functional regeneration of the heart. In order to understand the mechanisms underlying this plasticity we performed longitudinal studies on single cardiomyocytes in culture. We find that the majority of cardiomyocytes can enter S phase, a process that occurs in response to serum-activated pathways and is dependent on the phosphorylation of the retinoblastoma protein. However, more than half of these cells stably arrest at either entry to mitosis or during cytokinesis, thus resembling the behaviour observed in mammalian cardiomyocytes. Approximately a third of the cells progress through mitosis and may enter successive cell divisions. When cardiomyocytes divided more than once, the proliferative behaviour of sister cells was significantly correlated, in terms of whether they underwent a subsequent cell cycle, and if so, the duration of that cycle. These observations suggest a mechanism whereby newt heart regeneration depends on the retention of proliferative potential in a subset of cardiomyocytes. The regulation of the remaining newt cardiomyocytes is similar to that described for their mammalian counterparts, as they arrest during mitosis or cytokinesis. Understanding the nature of this block and why it arises in some but not other newt cardiomyocytes may lead to an augmentation of the regenerative potential in the mammalian heart. |
2,332,023 | Characterization and regulation of T-type Ca2+ channels in embryonic stem cell-derived cardiomyocytes. | T-type Ca2+ channels may play a role in cardiac development. We studied the developmental regulation of the T-type currents (ICa,T) in cardiomyocytes (CMs) derived from mouse embryonic stem cells (ESCs). ICa,T was studied in isolated CMs by whole cell patch clamp. Subsequently, CMs were identified by the myosin light chain 2v-driven green fluorescent protein expression, and laser capture microdissection was used to isolate total RNA from groups of cells at various developmental time points. ICa,T showed characteristics of Cav3.1, such as resistance to Ni2+ block, and a transient increase during development, correlating with measures of spontaneous electrical activity. Real-time RT-PCR showed that Cav3.1 mRNA abundance correlated (r2 = 0.81) with ICa,T. The mRNA copy number was low at 7+4 days (2 copies/cell), increased significantly by 7+10 days (27/cell; P < 0.01), peaked at 7+16 days (174/cell), and declined significantly at 7+27 days (25/cell). These data suggest that ICa,T is developmentally regulated at the level of mRNA abundance and that this regulation parallels measures of pacemaker activity, suggesting that ICa,T might play a role in the spontaneous contractions during CM development. |
2,332,024 | Proportion and prognosis of healthy people with coved or saddle-back type ST segment elevation in the right precordial leads during 10 years follow-up.<Pagination><StartPage>1488</StartPage><EndPage>1493</EndPage><MedlinePgn>1488-93</MedlinePgn></Pagination><Abstract><AbstractText Label="AIMS" NlmCategory="OBJECTIVE">The aim of this study was to investigate long-term proportion and prognosis of healthy subjects with right precordial ST segment elevation without family history of sudden death.</AbstractText><AbstractText Label="METHODS AND RESULTS" NlmCategory="RESULTS">We followed up electrocardiograms (ECGs) of 3339 healthy subjects (male/female 2646/693) who underwent periodical medical examination form 1992 to 2001 to determine the relationship between year-to-year changes of ST segment morphology and the risk of fatal arrhythmias. Inclusion criterion was defined as presenting either coved or saddle back type ST segment elevation (>0.2 mV) in the right precordial leads. The cumulative total subjects who showed Brugada-like ECG changes at least once throughout the follow-up period were 69 (male/female 67/2; age 47.9+/-8.9 years, 2.1% of total subjects). During a follow-up period, annual mean proportion of coved or saddle back type ST elevation in the right precordial leads was 1.22+/-0.23% (0.88-1.88%). The morphological pattern of ST segment elevation was saddle-back in 77.3+/-7.9% and coved in 22.7+/-7.9% of subjects. Throughout the follow-up period, 39 subjects (56.5%) showed changes in ST segment elevation pattern. Twenty-nine subjects (42.0%) showed normalization of ST segment elevation at least once. Sixty-nine subjects were followed for a period of one to 10 years (median 4 years, interquartile range 4-8 years). Only one subject with persistent saddle-back type ST elevation had episodes of ventricular fibrillation (VF).</AbstractText><AbstractText Label="CONCLUSIONS" NlmCategory="CONCLUSIONS">The average proportion of healthy subject who had coved or saddle-back type of ST elevation in the right precordial leads without family history of sudden death was 1.22% and the risk of fatal arrhythmias was low (1/393.5 subject-years).</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Sakabe</LastName><ForeName>Masao</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>The Second Department of Internal Medicine, Toyama Medical and Pharmaceutical University, Toyama, Japan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Fujiki</LastName><ForeName>Akira</ForeName><Initials>A</Initials></Author><Author ValidYN="Y"><LastName>Tani</LastName><ForeName>Masanao</ForeName><Initials>M</Initials></Author><Author ValidYN="Y"><LastName>Nishida</LastName><ForeName>Kunihiro</ForeName><Initials>K</Initials></Author><Author ValidYN="Y"><LastName>Mizumaki</LastName><ForeName>Koichi</ForeName><Initials>K</Initials></Author><Author ValidYN="Y"><LastName>Inoue</LastName><ForeName>Hiroshi</ForeName><Initials>H</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>Eur Heart J</MedlineTA><NlmUniqueID>8006263</NlmUniqueID><ISSNLinking>0195-668X</ISSNLinking></MedlineJournalInfo><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D001145" MajorTopicYN="N">Arrhythmias, Cardiac</DescriptorName><QualifierName UI="Q000503" MajorTopicYN="Y">physiopathology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D004562" MajorTopicYN="N">Electrocardiography</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005500" MajorTopicYN="N">Follow-Up Studies</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006327" MajorTopicYN="N">Heart Block</DescriptorName><QualifierName UI="Q000503" MajorTopicYN="N">physiopathology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006339" MajorTopicYN="N">Heart Rate</DescriptorName><QualifierName UI="Q000502" MajorTopicYN="Y">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008875" MajorTopicYN="N">Middle Aged</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D011379" MajorTopicYN="N">Prognosis</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D011446" MajorTopicYN="N">Prospective Studies</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D013577" MajorTopicYN="N">Syndrome</DescriptorName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2003</Year><Month>8</Month><Day>16</Day><Hour>5</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2003</Year><Month>10</Month><Day>8</Day><Hour>5</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2003</Year><Month>8</Month><Day>16</Day><Hour>5</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">12919772</ArticleId><ArticleId IdType="doi">10.1016/s0195-668x(03)00323-3</ArticleId><ArticleId IdType="pii">S0195668X03003233</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">12917906</PMID><DateCompleted><Year>2003</Year><Month>09</Month><Day>25</Day></DateCompleted><DateRevised><Year>2020</Year><Month>05</Month><Day>11</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Electronic">1469-493X</ISSN><JournalIssue CitedMedium="Internet"><Issue>3</Issue><PubDate><Year>2003</Year></PubDate></JournalIssue><Title>The Cochrane database of systematic reviews</Title><ISOAbbreviation>Cochrane Database Syst Rev</ISOAbbreviation></Journal>Dietary advice given by a dietitian versus other health professional or self-help resources to reduce blood cholesterol. | The aim of this study was to investigate long-term proportion and prognosis of healthy subjects with right precordial ST segment elevation without family history of sudden death.</AbstractText>We followed up electrocardiograms (ECGs) of 3339 healthy subjects (male/female 2646/693) who underwent periodical medical examination form 1992 to 2001 to determine the relationship between year-to-year changes of ST segment morphology and the risk of fatal arrhythmias. Inclusion criterion was defined as presenting either coved or saddle back type ST segment elevation (>0.2 mV) in the right precordial leads. The cumulative total subjects who showed Brugada-like ECG changes at least once throughout the follow-up period were 69 (male/female 67/2; age 47.9+/-8.9 years, 2.1% of total subjects). During a follow-up period, annual mean proportion of coved or saddle back type ST elevation in the right precordial leads was 1.22+/-0.23% (0.88-1.88%). The morphological pattern of ST segment elevation was saddle-back in 77.3+/-7.9% and coved in 22.7+/-7.9% of subjects. Throughout the follow-up period, 39 subjects (56.5%) showed changes in ST segment elevation pattern. Twenty-nine subjects (42.0%) showed normalization of ST segment elevation at least once. Sixty-nine subjects were followed for a period of one to 10 years (median 4 years, interquartile range 4-8 years). Only one subject with persistent saddle-back type ST elevation had episodes of ventricular fibrillation (VF).</AbstractText>The average proportion of healthy subject who had coved or saddle-back type of ST elevation in the right precordial leads without family history of sudden death was 1.22% and the risk of fatal arrhythmias was low (1/393.5 subject-years).</AbstractText> |
2,332,025 | Molecular basis of vitamin E action: tocotrienol modulates 12-lipoxygenase, a key mediator of glutamate-induced neurodegeneration. | Vitamin E is a generic term for tocopherols and tocotrienols. This work is based on our striking evidence that, in neuronal cells, nanomolar concentrations of alpha-tocotrienol, but not alpha-tocopherol, block glutamate-induced death by suppressing early activation of c-Src kinase (Sen, C. K., Khanna, S., Roy, S., and Packer, L. (2000) J. Biol. Chem. 275, 13049-13055). This study on HT4 and immature primary cortical neurons suggests a central role of 12-lipoxygenase (12-LOX) in executing glutamate-induced neurodegeneration. BL15, an inhibitor of 12-LOX, prevented glutamate-induced neurotoxicity. Moreover, neurons isolated from 12-LOX-deficient mice were observed to be resistant to glutamate-induced death. In the presence of nanomolar alpha-tocotrienol, neurons were resistant to glutamate-, homocysteine-, and l-buthionine sulfoximine-induced toxicity. Long-term time-lapse imaging studies revealed that neurons and their axo-dendritic network are fairly motile under standard culture conditions. Such motility was arrested in response to glutamate challenge. Tocotrienol-treated primary neurons maintained healthy growth and motility even in the presence of excess glutamate. The study of 12-LOX activity and metabolism revealed that this key mediator of glutamate-induced neurodegeneration is subject to control by the nutrient alpha-tocotrienol. In silico docking studies indicated that alpha-tocotrienol may hinder the access of arachidonic acid to the catalytic site of 12-LOX by binding to the opening of a solvent cavity close to the active site. These findings lend further support to alpha-tocotrienol as a potent neuroprotective form of vitamin E. |
2,332,026 | Barium block of Kir2 and human cardiac inward rectifier currents: evidence for subunit-heteromeric contribution to native currents. | Kir2 subunits are believed to underlie the cardiac inwardly rectifying current I(K1). The subunit composition of native I(K1) currents is uncertain, and it has been suggested that heteromultimer formation may play a role.</AbstractText>We studied Ba(2+) block of homo- and heteromeric Kir2 channels in Xenopus oocytes and compared the properties observed to those of human cardiac I(K1) in cells isolated from myocardial biopsies of normal human hearts.</AbstractText>Homomeric expression of Kir2.1 and Kir2.3 produced currents with similar Ba(2+) sensitivities (e.g. IC(50) at -120 mV: 16.2+/-3.4, n=11 and 18.5+/-2.1, n=10, respectively), but these were less sensitive to Ba(2+) than native I(K1) (4.7+/-0.5 microM, n=10, P=0.001, P<0.001, respectively) and had different Ba(2+) blocking kinetics from cardiac I(K1). Kir2.2 sensitivity was similar to cardiac I(K1) (e.g., 2.8+/-0.4 microM, Kir2.2, n=9, vs. 4.7+/-0.5 microM for I(K1)), but the blocking kinetics of Kir2.2 were faster than those of I(K1). Currents resulting from co-expression of Kir2 subunits had similar Ba(2+) sensitivities and blocking kinetics among groups and were similar to I(K1) in both Ba(2+) sensitivity (e.g., IC(50) at -120 mV: 4.5+/-1.0, 2.5+/-0.5, and 2.3+/-0.4 microM for co-injected Kir2.1/2.2, n=6, Kir2.1/2.3, n=5, and Kir2.2/2.3, n=4, respectively) and blocking kinetics.</AbstractText>Co-injection of Kir2 subunits results in currents with Ba(2+) blocking properties different from homomeric Kir2 expression but similar to cardiac I(K1). These observations suggest that a substantial proportion of native I(K1) may result from heteromultimer formation among diverse Kir2 family subunits.</AbstractText> |
2,332,027 | Risk of mesh erosion with sacral colpopexy and concurrent hysterectomy. | To examine short- and long-term mesh-related complications in women undergoing abdominal sacral colpopexy with concurrent hysterectomy, compared with women with a prior hysterectomy undergoing sacral colpopexy alone.</AbstractText>Patient characteristics, hospital complications, postoperative clinical course, and long-term graft-related complications were reviewed for all women with genital prolapse who underwent abdominal sacral colopexy between 1996 and 1998. Women with concurrent hysterectomy were compared with women with vaginal prolapse after a prior hysterectomy.</AbstractText>One hundred twenty-four patients, 60 with concurrent hysterectomy and 64 with prior hysterectomy, were observed postoperatively for a median of 35.5 (0-74) months. Demographics of the two groups were similar, with a mean age of 65.1 +/- 9.4 years and a mean body mass index of 25.8 +/- 4.2 kg/m(2). Eighty percent of colpopexies used prolene synthetic mesh and 20% allograft material. Initial operative and hospital complications were rare in both groups and included a blood transfusion of 2 U, a ureteral transection, a wound infection, heart block, and an arrhythmia. Delayed graft complications included one mesh erosion in a patient with a prior hysterectomy that was managed by office resection (0.8%).</AbstractText>Concurrent hysterectomy with abdominal sacral colopopexy has a low incidence of mesh complications and can be used as a first-line treatment for genital prolapse.</AbstractText> |
2,332,028 | [Postoperative routine use of physostigmine on vigilance, cardiovascular parameters and need of analgesics]. | A central anticholinergic syndrome (CAS) can be related to the majority of anesthetic agents, but is often not recognized as such. Thus, most anesthesiologists seem to miss the occurrence of an anticholinergic syndrome especially when agitation and/or restlessness are the major symptoms. Therefore, the following study was undertaken to test the hypothesis that routine administration of the anticholinergic agent physostigmin is of benefit for patients in regard to vigilance, the cardiovascular system and the need of analgesics easing the time in the post anesthesia care unit (PACU).</AbstractText>After approval by the local ethics committee and written informed consent, 100 patients undergoing a cholecystectomy or a struma resection, were given either physostigmin (n = 51) or saline 0.9 % (n = 49) in a randomized fashion. The study was conceived to block a possible isoflurane-N2O/O2 (opioid-based plus relaxant) induced central anticholinergic syndrome and to evaluate the effects on the cardiovascular system on vigilance and on postoperative analgesic demand. Following parameters were measured: systolic and diastolic blood pressure, heart rate, respiratory rate, and arterial blood gases. In addition, vigilance was determined and typical anticholinergic symptoms (disorientation, slurred speech, agitation, nausea, emesis, cardiac arrhythmia and muscle shivering) were determined 10, 20, 40 and 60 minutes following the intravenous injection of physostigmin. Also, the need for the postoperative analgesic pethidine was evaluated among the two groups.</AbstractText>Except for a significant reduction in the need of analgesics, a reduced diastolic pressure and heart rate and a lower incidence of muscle shivering there was no difference among the two groups. One major side effect following the use of physostigmin was the higher incidence of nausea in the im mediate minutes following injection. This effect may be due to the rapid injection of the anticholinergic compound. Otherwise there were no detrimental effects of physostigmin in patients.</AbstractText>From the results it can be concluded that routine administration of an anticholinergic agent results in a short term beneficial effect in regard to vigilance, a lesser incidence of muscle shivering and a lesser demand for analgesics. However, because of the low incidence of a classical central anticholinergic syndrome, routine physostigmine is only indicated when agitation is diagnosed.</AbstractText> |
2,332,029 | Intravenous clonidine prolongs bupivacaine spinal anesthesia. | Prolongation of spinal anesthesia by oral clonidine premedication has been known. We hypothesized that intravenous clonidine administered after the spinal block may prolong spinal anesthesia.</AbstractText>To assess the prolongation of spinal anesthesia by intravenous clonidine, we designed a double-blind, placebo-controlled, prospective study. Patients scheduled for orthopedic surgery received 12 mg of 0.5% hyperbaric bupivacaine and were randomly divided into three groups (n = 26 in each group). In the clonidine 10-min group, 3 microg x kg-1 of clonidine was administered for 10 min immediately after the spinal block. In the clonidine 60-min group, 3 microg x kg-1 of clonidine was administered for 10 min, 50 min after the spinal block. The control group received normal saline. Sensory block was evaluated by pinprick and the duration was defined as the time for sensory block to regress to L1 dermatome. Duration of motor block was defined as the time required for the patient to flex his or her knee.</AbstractText>The duration of sensory block was longer in both the clonidine 10-min and clonidine 60-min groups compared with the control group (196 +/- 42 min, 179 +/- 41 min vs. 125 +/- 25 min, P < 0.05). The duration of motor block was longer in the clonidine 10-min group than in the control group (153 +/- 26 min vs. 131 +/- 29 min, P < 0.05). The lowest heart rate and mean blood pressure were not different among groups.</AbstractText>Intravenous clonidine administration within 1 h after the spinal block prolonged bupivacaine spinal anesthesia for approximately 1 h without adverse effects.</AbstractText> |
2,332,030 | [Neostigmine added to bupivacaine in axillary plexus block: which benefit?]. | Recent study showed that neostigmine (500 microg) by intra-articular produces postoperative analgesia without adverse effect. The author's goal was to determine whether 500 microg of neostigmine added to bupivacaine in axillary plexus block could prolonged postoperative analgesia without increasing the incidence of side effects.</AbstractText>Ninety patients scheduled for orthopedic or plastic surgery with axillary plexus block were randomly assigned to one of 3 groups : group 1 (TGr n = 30) received saline solution (1 ml) in the axillary plexus, group 2 (NAGr n = 30) received 500 microg (1 ml) neostigmine in the axillary plexus and group 3.500 microg neostigmine subcutaneously (NSGr n = 30). We evaluated visual analog pain scores (VAS), the consumption of the ketoprofene, nausea and vomiting incidence during the first 24 h. ANOVA, Kruskall Wallis and Fisher tests were used for statistical analysis. A p value of <0.05 was considered significant.</AbstractText>The VAS score was lower in NAGr (21 +/- 18) vs NSGr (31 +/- 14) and control group TGr (45 +/- 2) (p < 0.05). The consumption of the ketoprofene is 127 +/- 65 mg in NAGr vs 150 +/- 53 mg in NSGr and 200 +/- 50 mg in group TGr (p = 0.02). Incidence of nausea and vomiting was 3.5% in NAGr vs 6.8% in NSGr and 0% for TGr.</AbstractText>Neostigmine combined to a mixture of lidocaine and bupivacaine prolongs postoperative analgesia after axillary plexus block.</AbstractText> |
2,332,031 | [Autonomic hyperreflexia in tetraplegic pregnant patient: case report]. | Complications of pregnant patients with medullary injury include urinary infection, renal stones, anemia, decubitus ulcers, muscle spasms, sepsis, uterine hyperactivity and autonomic hyperreflexia. Autonomic hyperreflexia is the most severe anesthetic complication and should, before all, be prevented. It is often developed in patients with medullary transection at the level of the 5th to 7th thoracic vertebra or above. This report aims at presenting a case of tetraplegic pregnant patient with injury at the level of the 6th cervical vertebra, submitted to Cesarean section under continuous epidural anesthesia with 0.25% bupivacaine without vasoconstrictor associated to fentanyl.</AbstractText>Caucasian, tetraplegic primiparous term patient, 39 weeks of gestational age, 22 years old, 63 kg, 168 cm, physical status ASA II, admitted for elective Cesarean section. Patient reported spinomedullary trauma at C6, three years ago. After previous hydration with 1500 ml saline, epidural anesthesia was induced with medial puncture at L3-L4 interspace with the patient in the lateral position, disposable 17G Tuohy needle and without previous local infiltration anesthesia. Immediately after needle insertion, there was adjacent paravertebral muscles contraction, blood pressure increase (BP = 158 x 72 mmHg) and heart rate increase (HR = 90 bpm). Patient, however, did not refer pain. Needle was removed and local anesthesia was induced. Epidural block proceeded with 20 ml of 0.25% bupivacaine without vasoconstrictor associated to 100 microg spinal fentanyl and epidural catheter insertion in the cephalad direction (3 to 4 cm). Surgery went on without intercurrences with no need for blockade complementation. There were two arterial hypotension episodes in the first 24 postoperative hours, which were treated with lactated Ringers solution. Epidural catheter was maintained for 48 hours. Patient was discharged three days after.</AbstractText>For paraplegic or tetraplegic pregnant patients, continuous epidural anesthesia with low local anesthetic concentration without vasoconstrictor and associated to fentanyl is a good indication for instrumented or not vaginal delivery, and Cesarean sections to prevent autonomic hyperreflexia. It is also important that the epidural catheter remains for at least 24 hours after delivery to block sympathetic afference in case a crisis is triggered.</AbstractText> |
2,332,032 | Comparison of the effects of two intrathecal anaesthetic techniques for transurethral prostatectomy on haemodynamic and pulmonary function. | Transurethral prostatectomy is routinely performed under spinal anaesthesia. This technique can cause hypotension, which is particularly undesirable in the elderly. The objective was to compare spinal anaesthesia for transurethral prostatectomy using hyperbaric bupivacaine 15 mg (control group) and hyperbaric bupivacaine 10 mg (limiting spread by maintaining the upright position for 15 min) and fentanyl 25 microg (fentanyl group) in terms of haemodynamic and pulmonary function.</AbstractText>Thirty ASA I-III patients were randomly selected and underwent spinal anaesthesia with either hyperbaric bupivacaine 15 mg (immediately positioned supine) or hyperbaric bupivacaine 10 mg (upright for 15 min) and fentanyl 25 microg.</AbstractText>The greatest changes in mean arterial pressure (P = 0.9), ephedrine requirements (P = 0.8) and mean maximum change in forced vital capacity (P = 0.5) were similar in both groups.</AbstractText>The addition of fentanyl 25 microg to bupivacaine 10 mg and limiting the spread of the block does not improve either haemodynamic or pulmonary function compared with bupivacaine 15 mg in patients undergoing transurethral prostatectomy.</AbstractText> |
2,332,033 | Responsiveness vs. basal activity of plasma ANG II as a determinant of arterial pressure salt sensitivity. | Infusion of angiotensin II (ANG II) causes salt-sensitive hypertension. It is unclear whether this is due to the body's inability to suppress ANG II during increased salt intake or, rather, an elevated basal level of plasma ANG II itself. To distinguish between these mechanisms, Sprague-Dawley rats were instrumented with arterial and venous catheters for measurement of arterial pressure and infusion of drugs, respectively. The sensitivity of arterial pressure to salt was measured in four groups with the following treatments: 1) saline control (Con, n = 12); 2) administration of the angiotensin-converting enzyme inhibitor enalapril to block endogenous ANG II (ANG-Lo, n = 10); 3) administration of enalapril and 5 ng.kg(-1).min(-1) ANG II to clamp plasma ANG II at normal levels (ANG-Norm, n = 10); and 4) administration of enalapril and 20 ng.kg(-1).min(-1) ANG II to clamp ANG II at high levels (ANG-Hi, n = 10). Rats ingested a 0.4% NaCl diet for 3 days and then a 4.0% NaCl diet for 11 days. Arterial pressure of rats fed the 0.4% NaCl diet was lower in ANG-Lo (84 +/- 2 mmHg) compared with Con (101 +/- 3 mmHg) and ANG-Norm (98 +/- 4 mmHg) groups, whereas ANG-Hi rats were hypertensive (145 +/- 4 mmHg). Salt sensitivity was expressed as the change in arterial pressure divided by the change in sodium intake on the last day of the 4.0% NaCl diet. Salt sensitivity (in mmHg/meq Na) was lowest in Con rats (0.0 +/- 0.1) and progressed from ANG-Lo (0.8 +/- 0.2) to ANG-Norm (1.5 +/- 0.5) to ANG-Hi (3.5 +/- 0.5) rats. We conclude that the major determinant of salt sensitivity of arterial pressure is the basal level of plasma ANG II rather than the responsiveness of the renin-angiotensin system. |
2,332,034 | Degradation of phosphatidylethanol counteracts the apparent phospholipase D-mediated formation in heart and other organs. | Phosphatidylalcohols, such as phosphatidylethanol (PEth), are formed from phosphatidylcholine in the presence of a primary alcohol (e.g., ethanol). This 'transphosphatidylation' reaction is used as specific phospholipase D (PLD) assay. Accumulation of PEth in tissues is recognized as a reliable measure of PLD activity, as PEth is allegedly metabolically stable. The general validity of this assumption was reinvestigated in isolated rat heart, small intestine and brain slices. The half-times of 3H-PEth degradation (labelled with 3H-myristic acid and preformed by ethanol exposure for 30 min) were about 1 h in heart and small intestine, but 17 h in brain. As the formation of PEth is superimposed by simultaneous degradation, a mathematical model was established to calculate the differences between 'true' and 'apparent' PEth formation. As expected, this difference was relevant in heart and intestine, but not in brain tissue. For example, ischemia in the perfused heart for 30 min reversibly blocked PEth degradation and seemingly enhanced PEth formation; the block was reversed by ischemic preconditioning (IPC) and by pretreatment with diazoxide, an opener of mitochondrial K(ATP) channels. In conclusion, PEth degradation in heart was energy-dependent and rapid, which, when ignored, may lead to misinterpretation of PEth values with respect to PLD activity. |
2,332,035 | Block of HERG-carried K+ currents by the new repolarization delaying agent H 345/52. | The aim of this study was to analyze the block of HERG-carried membrane currents caused by H 345/52, a new antiarrhythmic compound with low proarrhythmic activity, in transfected mouse fibroblasts.</AbstractText>Using the whole-cell configuration of the voltage patch clamp technique, it was demonstrated that H 345/52 concentration-dependently blocked HERG-carried currents with an IC50 of 230 nM. H 345/52 preferentially bound to the open channel with unusually rapid kinetics and was trapped by channel closure. Voltage-independent behavior of H 345/52 was observed during both square-pulse and action potential clamp protocols. In contrast, the Class III agents dofetilide (10 nM) and almokalant (250 nM) demonstrated significant membrane potential-dependent effects during square-pulse clamp protocols. When using action potential clamp protocols, voltage dependence was seen with dofetilide but not with almokalant. Mathematical simulations of human ventricular action potentials predicted that the different voltage-dependent behaviors would not produce marked variations in action potential duration prolongation patterns.</AbstractText>We propose that block of IKr is the principal mechanism by which H 345/52 delays repolarization in human myocardium. The voltage independence of HERG/IKr block is unlikely to underlie the low proarrhythmic potential, and ancillary effects on other membrane currents must be considered.</AbstractText> |
2,332,036 | The effect of exogenous epinephrine on the incidence of hypotensive/bradycardic events during shoulder surgery in the sitting position during interscalene block. | Sudden hypotensive and/or bradycardic events (HBE) have been reported in 13%-28% of patients undergoing shoulder surgery in the sitting position during interscalene block. The Bezold-Jarisch reflex is the most likely mechanism for these events. It has been hypothesized that exogenous epinephrine might be a key component to the occurrence of HBE. We conducted this prospective, randomized study to verify this hypothesis. Patients received a local anesthetic solution with (Group E; n = 55) or without (Group P; n = 55) epinephrine for interscalene block; no further exogenous epinephrine was administered. Blood pressure control was achieved with IV urapidil, a peripheral vasodilator, as needed. The incidence of HBE was 11% in Group P versus 29% in Group E (P = 0.015). Increased intraoperative heart rate and arterial blood pressure were recorded in Group E (P = 0.000). Urapidil was administered to 13% of Group P and to 31% of Group E patients (P = 0.018). Urapidil administration induced a HBE in 4% of Group P and in 5% of Group E patients. We conclude that exogenous epinephrine is involved in the development of HBE in this setting.</AbstractText>Sudden hypotensive and/or bradycardic events occur during shoulder surgery in the sitting position during interscalene block. In this study, we demonstrated that the presence of epinephrine in the local anesthetic mixture significantly increases the incidence of these events.</AbstractText> |
2,332,037 | Novel hypotensive agents from Verbesina caracasana: structure, synthesis and pharmacology. | The number and the pharmacological activities of drugs featuring a guanidine group is actually amazing. Many synthetic guanidine derivatives have attracted pharmacologists in search of new antihypertensive drugs for their ability to block adrenergic nerve activity through central and/or peripheral mechanisms. As a result, compounds such as guanethidine, guanabenz, guanfacine, and pinacidil have been introduced in antihypertensive drug therapy. A crude methanol extract of the Venezuelan plant Verbesina caracasana Fries (Compositae), intravenously administered to mice, was found to induce biological effects such as erection of hair, initial stimulation and subsequent blockade of breathing. Biologically controlled purification yielded a series of active guanidine derivatives, namely G1-G7, which were extensively studied with the focus on the following items: (1) The structure determination of the active compounds by spectral data and a set of reactions; (2) The confirmation of the structures by a biogenetically oriented synthesis; (3) The study of the pharmacological profiles of the isolated drugs; (4) The synthesis of analogous and homologous products in the effort to shed some light on the structure-activity relationship. The metabolites of V. caracasana were characterized, in anesthetized rats, as hypotensive drugs of high (G2), mild (G1, G7) and low (G3,G5,G6) potency, devoid of consistent actions in heart rate, and provided with moderate stimulatory effects on cardiac inotropism and breathing (at selected non-toxic intravenous doses). Autonomic neurogenic components and/or peripheral adrenergic and cholinergic receptor-related pathways were involved in the cardiovascular effects. Synthetic analogs and homologs of G1 and G5 were all shown to be hypotensive drugs of low-mild potency, not affecting appreciably cardiac inotropism and/or breathing. The pharmacodynamic differences among the studied compounds were likely to depend on their ability to cross the blood-brain barrier, lipophilicity and pharmacokinetics. Since most of the compounds did not induce reflex tachycardia and depression of myocardial contractility as the majority of the antihypertensive drugs, they might be useful in the treatment of arterial hypertension of various genesis. |
2,332,038 | Nascent EDHF-mediated cerebral vasodilation in ovariectomized rats is not induced by eNOS dysfunction. | In estrogen-depleted [i.e., ovariectomized (Ovx)] animals, an endothelium-derived hyperpolarizing factor (EDHF)-like mechanism may arise to, at least partially, replace endothelial nitric oxide (NO) synthase (eNOS)-derived NO in modulating cerebral arteriolar tone. Additional findings show that eNOS expression and function is restored in estrogen-treated Ovx female rats, while the nascent EDHF-like activity disappears. Because NO has been linked to repression of EDHF activity in the periphery, the current study was undertaken to examine whether the nascent EDHF role in cerebral vessels of Ovx females relates to a chronically repressed eNOS-derived NO-generating function. We compared the effects of chronic NOS inhibition with Nomega-nitro-L-arginine-methyl ester (L-NAME; 100 mg. kg-1. day-1 for 3 wk) on EDHF-mediated pial arteriolar vasodilation in anesthetized intact, Ovx, and 17beta-estradiol-treated (0.1 mg. kg-1. day-1 ip, 1 wk) Ovx (OVE) female rats as well as in male rats that were prepared with closed cranial windows. In the chronic NOS inhibition groups, pial arteriolar responses were monitored in the absence (all groups) and presence (females only) of indomethacin (Indo; 10 mg/kg iv). Finally, the gap junction inhibitory peptide Gap 27 (300 muM) was applied to block EDHF-related vasodilation. NO donor (S-nitroso-N-acetyl-penicillamine) responses were similar in all rats studied. Acetylcholine (ACh) reactivity was virtually absent in control Ovx rats and chronically NOS-inhibited intact female, OVE, and male rats. However, a partial recovery of ACh reactivity was seen in L-NAME-treated Ovx females. In addition, in the presence of L-NAME, a normal CO2 reactivity was observed in all females, whereas a 50% reduction in CO2 reactivity was seen in males. In intact and OVE rats, both chronic and acute (NG-nitro-L-arginine suffusion) NOS inhibition, combined with Indo, depressed ADP-induced dilation by > or =50%, and subsequent application of Gap 27 had no further effect on ADP-induced vasodilation. ADP reactivity was retained in Ovx rats after combined chronic NOS inhibition and acute Indo, but was attenuated significantly by Gap 27. In males, Gap 27 had no effect on arteriolar reactivity. Taken together, our data demonstrate that in the cerebral microcirculation, NO does not have an inhibitory effect on EDHF production or action. The increased EDHF-like function in chronic estrogen-depleted animals is not due to eNOS deficiency, suggesting a more direct effect of estrogen in modulating EDHF-mediated cerebral vasodilation. |
2,332,039 | Validation of the MEDFICTS dietary questionnaire: a clinical tool to assess adherence to American Heart Association dietary fat intake guidelines. | Dietary assessment tools are often too long, difficult to quantify, expensive to process, and largely used for research purposes. A rapid and accurate assessment of dietary fat intake is critically important in clinical decision-making regarding dietary advice for coronary risk reduction. We assessed the validity of the MEDFICTS (MF) questionnaire, a brief instrument developed to assess fat intake according to the American Heart Association (AHA) dietary "steps".</AbstractText>We surveyed 164 active-duty US Army personnel without known coronary artery disease at their intake interview for a primary prevention cardiac intervention trial using the Block food frequency (FFQ) and MF questionnaires. Both surveys were completed on the same intake visit and independently scored. Correlations between each tools' assessment of fat intake, the agreement in AHA step categorization of dietary quality with each tool, and the test characteristics of the MF using the FFQ as the gold standard were assessed.</AbstractText>Subjects consumed a mean of 36.0 +/- 13.0% of their total calories as fat, which included saturated fat consumption of 13.0 +/- 0.4%. The majority of subjects (125/164; 76.2%) had a high fat (worse than AHA Step 1) diet. There were significant correlations between the MF and the FFQ for the intake of total fat (r = 0.52, P < 0.0001) and saturated fat (r = 0.52, P < 0.0001). Despite these modest correlations, the currently recommended MF cutpoints correctly identified only 29 of 125 (23.3%) high fat (worse than AHA Step 1) diets. Overall agreement for the AHA diet step between the FFQ and MF (using the previously proposed MF score cutoffs of 0-39 [AHA Step 2], 40-70 [Step 1], and > 70 [high fat diet]) was negligible (kappa statistic = 0.036). The MF was accurate at the extremes of fat intake, but could not reliably identify the 3 AHA dietary classifications. Alternative MF cutpoints of < 30 (Step 2), 30-50 (Step 1), and > 50 (high fat diet) were highly sensitive (96%), but had low specificity (46%) for a high fat diet. ROC curve analysis identified that a MF score cutoff of 38 provided optimal sensitivity 75% and specificity 72%, and had modest agreement (kappa = 0.39, P < 0.001) with the FFQ for the identification of subjects with a high fat diet.</AbstractText>The MEDFICTS questionnaire is most suitable as a tool to identify high fat diets, rather than discriminate AHA Step 1 and Step 2 diets. Currently recommended MEDFICTS cutpoints are too high, leading to overestimation of dietary quality. A cutpoint of 38 appears to be providing optimal identification of patients who do not meet AHA dietary guidelines for fat intake.</AbstractText> |
2,332,040 | Pathogenesis of Sjögren's syndrome. | The pathogenesis of Sjögren's syndrome is poorly understood. Genetic and environmental factors appear to contribute to the development of this syndrome. Viral infection is one of the most likely environmental factors. The primary lesion of Sjögren's syndrome is in the exocrine glands. A majority of the infiltrating cells in the lesion are CD(4+) CD45RO(+) memory T cells. Although antigen-presentation to T cells seems to occur in the exocrine tissues, these T cells are not fully activated. On the other hand, B cells comprise approximately 20% of the infiltrating cells, and several features of this syndrome are attributed to stimulated B cells. The presence of autoantibodies, such as anti-SS-A/Ro and SS-B/La antibodies, is one of the characteristic features and is associated with severe disorders. Some antibodies appear to play a direct pathogenic role, for example, in cases of congenital heart block and sicca symptoms. Chronic inflammation with possible T cell-dependent antigen stimulation appears to induce neoplastic transformation of lymphocytes. |
2,332,041 | Dose response study of caudal neostigmine for postoperative analgesia in paediatric patients undergoing genitourinary surgery. | Neostigmine given through the neuraxial route has been found to have analgesic properties. In this clinical trial, we evaluated for the first time the efficacy of a varying dose of caudal neostigmine for postoperative analgesia in children undergoing genitourinary surgery.</AbstractText>In this double blind prospective study, we studied 120 children ASA physical status I in age group of 2-8 years scheduled for surgical repair of hypospadias under general anaesthesia. Children were randomly allocated to one of the six groups (n = 20 each) and received either no caudal block (group C) or neostigmine (groups I-V) in doses of 10, 20, 30, 40 and 50 microgram.kg-1 respectively at the end of the surgery. Postoperatively pain was assessed using an objective pain score for 24 h. Blood pressure, heart rate, SpO2, total amount of analgesic consumed and adverse effects, if any, were also recorded.</AbstractText>The duration of postoperative analgesia did not differ significantly between group C and I (P > 0.05). There was significant prolongation in the duration of analgesia in rest of the groups (group II-3.52 +/- 1.37 h; group III-6.50 +/- 1.93 h; group IV-10.45 +/- 3.41 h; group V-13.70 +/- 5.52 h) (P < 0.05). A dose dependent increase in the incidence of nausea and vomiting was also observed with highest incidence in group IV and V (group C-15%; group I-20%; group II and III-30%; group IV-45% and group V-60%) (P < 0.05). No significant alteration in vital signs and other adverse effects were noticed.</AbstractText>Caudal neostigmine in the dose range of 20-50 microgram.kg-1 provides dose dependent analgesia. However, dose exceeding 30 microgram.kg-1 is associated with a higher incidence of nausea and vomiting.</AbstractText> |
2,332,042 | Effects of fentanyl on pain and hemodynamic response after retrobulbar block in patients having phacoemulsification. | To determine the effects of systemic fentanyl analgesia in preventing the pain related to the administration of retrobulbar anesthesia and cataract surgery.</AbstractText>Departments of Ophthalmology and Anesthesiology, School of Medicine, Kocatepe University, Afyon, Turkey.</AbstractText>One hundred twenty patients with American Society of Anesthesiologists physical status I to III scheduled for cataract surgery were evaluated in a single-blind randomized study. Patients with a history of hypertension, hyperthyroidism, or neurologic or psychiatric disorders were excluded. In the study (fentanyl) group, an intravenous bolus of fentanyl 2 microg/kg was slowly given 5 minutes before retrobulbar anesthesia was administered. In the control group, fentanyl was not given. There were 60 patients in each group. Demographic data were not statistically different between the 2 groups. The intensity of pain during injection and intraoperatively was measured by verbal pain scores. Hemodynamic stability was assessed by the heart rate (HR) and mean arterial pressure (MAP). End-tidal carbon dioxide concentrations and oxygen saturations were also recorded.</AbstractText>The changes in HR and MAP at 0, 10, 20, and 30 minutes were statistically significant between the fentanyl and control groups (P<.05). Fentanyl reduced pain scores significantly at all evaluations (P<.05).</AbstractText>The results suggest that fentanyl preemptively decreases injection and intraoperative hyperalgesia and provides hemodynamic stability without affecting patient cooperation, resulting in cataract surgery with retrobulbar anesthesia that is comfortable for both surgeon and patient.</AbstractText> |
2,332,043 | Incidence and spectrum of neonatal lupus erythematosus: a prospective study of infants born to mothers with anti-Ro autoantibodies. | Neonatal lupus erythematosus (NLE) is characterized by complete congenital heart block (CCHB), cutaneous rash, and laboratory abnormalities in infants born to mothers with autoantibodies directed against SSA/Ro, SSB/La, or both. We carried out a prospective study to determine the incidence of individual NLE features.</AbstractText>The study was performed in two centers: Toronto, Canada, and Milano, Italy. Mothers had been referred for the presence of anti-SSA/Ro autoantibodies, regardless of their diagnosis. All the children were seen at least once within the first 6 months of life for clinical evaluation and laboratory testing. The study group consisted of 128 infants born from 124 pregnancies in 112 women with anti-Ro antibodies with or without anti-La antibodies.</AbstractText>There were two cases of CCHB for an overall percentage of 1.6%. Twenty-one children (16%) developed cutaneous NLE. Laboratory testing showed hematologic abnormalities in 27% of the babies and elevation of liver enzymes in 26%.</AbstractText>Mothers with autoimmune diseases and anti-Ro antibodies are at risk of delivering a child with NLE but at a low risk of delivering a child with CCHB. Infants born to mothers with anti-Ro or anti-La antibodies should be monitored for other features of NLE in addition to CCHB.</AbstractText> |
2,332,044 | [Ephedrine shortens the onset of action of rocuronium but not atracurium]. | Ephedrine increases blood flow to muscles and may shorten the onset of action of rocuronium and atracurium.</AbstractText>A prospective study of 80 ASA I-III patients undergoing surgery under general anesthesia and randomized to 4 groups: ephedrine-rocuronium, placebo-rocuronium, ephedrine-atracurium and placebo-atracurium. Atracurium or rocuronium was administered at a dose of 0.04 mg.Kg-1. We monitored neuromuscular function by acceleromyography, ECG and pulse oxymetry, arterial blood pressure (ABP) using an intra-arterial catheter (AT), heart rate (HR) and carbon dioxide pressure. Patient characteristics, time to onset, duration and recovery from the neuromuscular block were recorded. HR and ABP were measured at baseline, 3 minutes after ephedrine dosing, 1 minute after induction, immediately after intubation and 5, 10 and 20 minutes after intubation.</AbstractText>Patient characteristics were similar in all groups. The time to onset of neuromuscular block was significantly shorter in the rocuronium and rocuronium-ephedrine groups than in the atracurium groups. Duration and recovery were similar in all groups. Patients premedicated with ephedrine experienced a significant increase in HR for 20 minutes. The only complications were 2 cases of self-limiting sinus tachycardia of less than 130 beats.min-1 in the ephedrine group.</AbstractText>Premeditation with 10 mg of ephedrine decreases the time until onset of action of rocuronium but does not affect the timing of atracurium.</AbstractText> |
2,332,045 | Marijuana alters the human cerebellar clock. | The effects of marijuana on brain perfusion and internal timing were assessed using [15O] water PET in occasional and chronic users. Twelve volunteers who smoked marijuana recreationally about once weekly, and 12 volunteers who smoked daily for a number of years performed a self-paced counting task during PET imaging, before and after smoking marijuana and placebo cigarettes. Smoking marijuana increased rCBF in the ventral forebrain and cerebellar cortex in both groups, but resulted in significantly less frontal lobe activation in chronic users. Counting rate increased after smoking marijuana in both groups, as did a behavioral measure of self-paced tapping, and both increases correlated with rCBF in the cerebellum. Smoking marijuana appears to accelerate a cerebellar clock altering self-paced behaviors. |
2,332,046 | The effect of FTY 720 on engraftment in a model of spontaneous allograft acceptance. | Further development in organ transplantation requires the utilization of new immunosuppressive drugs that-in addition to being effective against rejection-do not block tolerance. We previously reported that FTY 720, a drug that alters lymphocyte trafficking, has marked anti-rejection properties. We now investigate how FTY 720 influences tolerance in a model of graft acceptance by donor-specific blood transfusion (DSBT). Two different transplant models--heart transplantation (Htx) and intestinal transplantation (Itx)--were studied. We performed orthotopic Itx and heterotopic Htx using fully mismatched inbred male RA (RT1(p)) and PVG (RT1(c)) rats as donors and recipients. Tolerance was induced by DSBT on pre-transplant day -12. To test the effect of FTY 720 on DSBT-induced tolerance, we administered FTY 720 orally prior to DSBT. Itx: control rats succumbed to rejection at 18+/-4 days. DSBT alone prolonged survival to 101.9+/-18 days (P<0.05 vs untreated). Long-term survivors were tolerant (acceptance of secondary donor-specific Htx). Adjunction of FTY 720 prior to DSBT reduced survival to 55.9+/-44.7 days (P<0.05). However, long-term survivors still accepted secondary donor-specific Htx. Htx: control rats survived 9+/-0.6 days. DSBT alone prolonged survival indefinitely (>120 days) and induced tolerance (acceptance of secondary donor-specific Htx). Unlike in Itx, adjunction of FTY 720 prior to DSBT did not reduce Htx survival. Acceptance of secondary donor-specific Htx was not influenced by FTY 720. In Itx, FTY 720 counteracts the beneficial effect of pre-transplant DSBT and triggers acute rejection of primary, but not secondary grafts. In Htx, however, FTY 720 allows full development of tolerance. The mechanisms by which FTY 720 causes rejection in primary intestinal but not in heart grafts need to be elucidated. |
2,332,047 | Sino-atrial block during anesthesia in a patient with breast cancer being treated with the anticancer drug epirubicin. | Epirubicin, an anticancer drug, causes cardiotoxicity. We reported a case of sino-atrial block during general anesthesia in a woman with breast cancer who had received epirubicin. Anesthesiologists should be aware of the possible occurrence of sino-atrial block with epirubicin, and planting a pacemaker might be considered even in asymptomatic patients. |
2,332,048 | Neural and cardiac activities are altered by injection of picomoles of glutamate into the nucleus ambiguus of the rat. | A quantitative evaluation of the thresholds of changes in the firing rate/pattern and depolarizing block of the neuron and the bradycardiac response by pressure microinjection of 10 mM glutamate (Glu) into the region of the nucleus ambiguus (NA) of the ventral medulla was performed in anesthetized rats. A change in neuronal activity was shown with injection of about 2 pmol of Glu. A depolarizing block of single-unit activity could be observed at 2.9 +/- 0.3 nl (approximately 30 pmol, n = 22). Maximal bradycardiac response (-50 +/- 5%) was elicited with 4.4 +/- 0.7 nl (approximately 50 pmol, n = 10), which is significantly smaller than the ranges used in previous studies. Based on these results, a safe and effective use of 10 mM Glu to induce neuronal or physiological response should be in the range of a few nanoliters and less than 100 pmol, especially for the NA. |
2,332,049 | Growth, nutrient utilization, and body composition of dairy calves fed milk replacers containing different amounts of protein. | Male Holstein calves < 1 wk of age were allowed a 2-wk adaptation period after purchase, and then were blocked by BW and assigned randomly within block to either a baseline slaughter group or one of four experimental groups (n = 8 to 9 per group). Treatments were isocaloric milk replacers (12.5% solids) fed at 12% of BW that contained 16.1, 18.5, 22.9, or 25.8% CP (DM basis) from whey protein sources. After a 6-wk feeding period, all calves were slaughtered and the weights and chemical composition of the viscera-free carcasses (VFC; including head, hide, feet, and tail) were determined. Gain of BW (0.38, 0.45, 0.56, and 0.62 kg/d) and gain:feed ratio (0.51, 0.59, 0.71, and 0.78) increased linearly (P < 0.001) as dietary CP increased; rate of change in body length, wither height, and heart girth also increased linearly (P < or = 0.05). Balance measurements conducted during wk 3 and 4 of the experimental period showed that both absorbed N (16.9, 20.0, 25.8, and 30.6 g/d) and retained N (7.6, 9.0, 13.2, and 15.6 g/d) increased linearly (P < 0.001) as dietary CP increased. Retained N as a percentage of absorbed N increased linearly (P < 0.01) as dietary CP increased (44.3, 44.7, 50.7, and 50.9%), whereas biological value was unaffected (71.1, 68.7, 69.5, and 67.3%; P = 0.26). Digestible energy and ME represented 94.5 and 89.7% of intake energy, respectively, and were not affected by dietary CP content. Plasma urea N concentration increased linearly (2.9, 3.3, 4.6, and 6.0 mg/dL) as dietary CP increased. Contents of water (68.2, 69.1, 70.2, and 70.5%; P < 0.001) and protein (19.6, 20.0, 20.0, and 20.2%; P < 0.10) in VFC increased linearly, whereas contents of fat (7.2, 6.2, 5.5, and 5.2%; P < 0.001) and ash (5.1, 5.2, 4.8, and 4.7%; P < 0.02) decreased linearly as dietary CP increased. Trends in visceral tissue composition were similar to those for VFC. The content of water in VFC tissue gain increased, whereas contents of fat and energy decreased, as dietary CP increased. Final VFC energy and gain of energy in VFC were not affected by dietary CP. At similar initial ME intakes, increasing dietary CP (i.e., increasing protein: energy) linearly increased ADG, gain:feed, N retention, and deposition of lean tissue in VFC, demonstrating that diet composition can markedly affect components of body growth in preruminant dairy calves. |
2,332,050 | [Mivacurium--use for complications of facial-cranial surgery--personal experience]. | The aim of this study was to evaluate the effectiveness of mivacurium (Mivacron--GlaxoWellcome) during combined general anaesthesia in the operations on the facial cranium, after tracheal intubation performed using suxamethonium chloride (Chlorsuccillin--Polfa PL). We examined 20 patients, 17-65 years old, who were underwent operations due to facial and neck neoplasms or trauma. Patients were divided into two 10-person groups. In first group the dose of Mivacron for the induction of anaesthesia was 0.15 mg/kg of body weight, in second group the dose was 0.1 mg/kg of body weight. Next doses used during maintenance of anaesthesia were 0.1 mg/kg of body weight in both groups. Metohexital, fentanyl, nitrous oxide and oxygen were used for the maintenance of anaesthesia. The level of neuromuscular block was estimated using Ministim MS IIIA instrument. The mean time to maintain 95-99% neuromuscular block after inductive dose 0.15 mg/kg Mivacron was 15 minutes 26 seconds, and after the dose of 0.1 mg/kg--13 minutes 55 seconds. The time from the injection of the drug to maintain neuromuscular block was 1 minute 52 seconds and 1 minute 50 seconds, respectively. We did not observe neither negative influence of drug on the cardiovascular system nor the reactions of histamine release. Injection of suxamethonium chloride before the tracheal intubation did not prolong the time of Mivacron activity. Anticholinesterase agents was not use in any case. By 4 patient with heart failure prolongation of the activity time of Mivacurium was observed. The dose of 0.1 mg/kg, is efficient to maintain of the neuromuscular block on the stabile level. This allows the reduction of the total dose, and the decrease of the costs of the operation. |
2,332,051 | Mutations in cardiac sodium channels: clinical implications. | Voltage-gated sodium channels (VGSCs) are critical transmembrane proteins responsible for the rapid action potential upstroke in most excitable cells. Recently discovered mutations in VGSCs, which underlie idiopathic clinical disease, have emphasized the importance of these channels in tissues such as skeletal muscle, nervous system, and myocardium. Mutations in the gene encoding the cardiac sodium channel isoform (SCN5A) have been linked to at least three abnormal phenotypes: variant 3 of the Long QT syndrome (LQT-3); Brugada's syndrome (BrS); and isolated cardiac conduction disease (ICCD). Mutations in SCN5A manifest as one or more of these clinical phenotypes - the precise distinction between these diseases is increasingly subtle. Clinical management of LQT-3 and diagnosis of BrS with the local anesthetic flecainide has proven promising. Channels associated with LQT-3 (D1790G) and BrS (Y1795H) both show more sensitivity to flecainide than wild-type (WT) channels, while lidocaine sensitivity is unchanged. One plausible explanation for differential drug sensitivity is that mutant channels may allow more access to a receptor site compared with WT through altered protein allosteric changes during an action potential. The high affinity binding site for local anesthetic block has been identified in the pore region of the channel. This region is not water accessible during the closed state, thus requiring channel opening for charged drug (flecainide and mexiletine) access and block. Channel mutations which disrupt inactivation biophysics lead to increased drug binding by altering the time the binding site is accessible during an action potential. Neutral drugs (lidocaine) which are not dependent on channel opening for binding site access will not be sensitive to mutations that alter channel inactivation properties. Interestingly another LQT-3 mutant (Y1795C) shows no change in flecainide sensitivity, suggesting that although drug effects of SCN5A mutations cross disease boundaries, clinical management with flecainide will be beneficial to patients in a mutation-specific manner. |
2,332,052 | Peroxidation of docosahexaenoic acid is responsible for its effects on I TO and I SS in rat ventricular myocytes. | 1 Exposure to docosahexaenoïc acid (DHA), a long-chain polyunsaturated fatty acid, is known to block several ionic currents such as the transient outward current I(TO). It has also been reported to activate certain potassium channels. It has been suggested that these effects, observed in single-cell experiments, participate in the antiarrhythmic properties of these compounds in vivo. 2 DHA is highly prone to peroxidation. To investigate the influence peroxidation may have on the effects of DHA on ion channels, we studied I(TO) and the steady-state outward current I(SS) in isolated rat ventricular myocytes under ruptured whole-cell patch-clamp conditions. 3 A measure of 10 micro M DHA alone reduced I(TO), evoked by a pulse to +70 mV, by 74.8+/-10.8% (n=7) and activated a delayed outward current with kinetic properties different from I(SS). 4 When an antioxidant, alpha-tocopherol (1 micro M), was added together with DHA, the blockade of I(TO) was reduced to 38.5+/-7.7% (n=8) and the delayed outward current was not activated. alpha-Tocopherol alone had no effect on these currents. 5 When an oxidant, hydrogen peroxide (1 micro M), was applied together with DHA, the blockade of I(TO) was almost complete (98.4+/-1.0%, n=7) and a large delayed outward current was activated. A measure of 1 micro M hydrogen peroxide alone had no effect on these currents. 6 Measurements of nonperoxidized DHA in experimental solutions confirmed the negative relation between DHA concentration and the effects on the currents. 7 We conclude that rather than DHA itself, it is the peroxidation products of DHA that block I(TO) and activate a delayed outward current in in vitro single-cell experiments. These findings have important implications for the extrapolation of in vitro experimental findings to the antiarrhythmic effects of DHA in vivo because, in vivo, peroxidation of DHA is unlikely to occur. |
2,332,053 | Increments in the concentrations of sodium and calcium in cell compartments of stretched mouse ventricular myocytes. | Increments in total intracellular sodium [Na] and calcium concentration [Ca], expected from stretch activation of non-selective cation current I(SAC), were quantified by means of electron probe microanalysis (EPMA) with 16 nm spatial resolution.Voltage-clamped mouse ventricular myocytes were stretched by increasing the distance between patch pipette and a cell-attached stylus by 20%. After 2 min stretch, cells were shock-frozen for EPMA. Stretch incremented [Na] in peripheral cytosol from 23 to 48 mM, central cytosol from 17 to 29 mM, central mitochondria from 10 to 21 mM, nuclear envelope from 43 to 71 mM, nucleus from 12 to 24 mM. Stretch increased total [Ca] in peripheral cytosol from 570 to 840 microM, central cytosol from 404 to 840 microM. Mitochondrial [Ca] did not change. Stretch increased [Ca] in both nucleus (from 180 to 300 microM) and nuclear envelope (from 933 to 1530 microM) suggesting a calcium barrier function for the envelope. Block of I(SAC) by 50 microM streptomycin abolished stretch-induced increments in [Na] suggesting Na(+) influx with I(SAC) as underlying mechanism. Streptomycin abolished the stretch-induced increase in peripheral but not in central cytosolic [Ca], as if additional mechanisms to I(SAC) were involved in elevating central [Ca]. |
2,332,054 | Different patterns of parasympathetic activation in uni- and bilateral migraineurs. | Several lines of evidence support involvement of the parasympathetic system in migraine: (i) migraine-associated symptoms, such as exaggerated facial flushing, lacrimation and rhinorrhea; (ii) increased levels of cranial venous vasoactive intestinal peptide in migraineurs during attacks; and (iii) reports of migraine pain alleviation by intranasal instillation of lidocaine, which can block some of the parasympathetic outflow to the cranium. This study assessed cranial parasympathetic function in migraineurs in between attacks, assuming that abnormal function might imply involvement of the parasympathetics in migraine pathogenesis. We tested 39 female migraineurs outside attacks, of whom 11 had bilateral pain, 20 unilateral at a specific side and eight alternating unilateral head pain, and 16 controls. The trigemino-parasympathetic reflex was studied, using soapy and saline eye drops for stimulation of the afferent limb of the reflex arch, and cutaneous vascular response at the forehead for the efferent limb. The latter was recorded by photoplethysmography on both sides of the forehead. We found no difference in vasodilatation between migraineurs as a group and controls (83.7 +/- 6.5% and 80.8 +/- 7.6%, respectively, not significant). However, when analysing data by the site of pain, we found that those with bilateral pain had the largest vasodilatation response (141.6 +/- 16.2%, P < 0.05 versus controls, analysis of varance, post hoc Tukey-Kramer HSD), while those with unilateral pain had the least vasodilatation (45.5 +/- 3.3%, P < 0.05). The response of patients with alternating pain (97.2 +/- 12.6%) did not differ from controls. It is concluded that cranial parasympathetic function does differ among patients with various migraine types at rest. Based on the understanding of dysfunctional brainstem pain modulation in migraine, we suggest a model of within-brainstem interaction between the two locus coeruleus nuclei, which are involved in control of pain and cranial parasympathetic outflow. The model assumes various levels of inhibitory inter-relationships between these two nuclei; diminution or absence of the normal reciprocal inhibitory relationships between them may underlie the augmented cranial parasympathetic response in bilateral migraineurs, while an excess of reciprocal inhibitory relationship between them may underlie the diminished cranial parasympathetic response in unilateral migraineurs. These findings might help in clarifying inter-relationships between brainstem nuclei in the context of migraine pathogenesis. |
2,332,055 | Vaccinia virus complement control protein inhibits hyperacute xenorejection in a guinea pig-to-rat heterotopic cervical cardiac xenograft model by blocking both xenoantibody binding and complement pathway activation. | Vaccinia virus complement control protein (VCP) binds the activated third and fourth complement components and inhibits both alternative and classical pathways of activation. The ability of VCP to bind heparan sulfate allows the protein to attach itself to the cell surface, enabling it with many additional activities. Altogether, the many functions of VCP have been shown to suppress the inflammatory response of the host, helping the vaccinia virus to evade immune destruction. VCP has recently been shown to inhibit human anti-Gal alpha1-3 Gal antibody attachment to cultured porcine endothelial cells and reduce human neutrophil and NK killing of pig aortic endothelial cells through its ability to bind heparan sulfate. Here we demonstrate that in an in vivo guinea pig-to-rat heterotopic cervical cardiac xenograft model, recombinant VCP (rVCP) is able to block hyperacute xenograft rejection, significantly prolonging graft survival. Histopathological examination of transplanted hearts from rats receiving rVCP revealed a significant reduction in cardiac tissue damage as compared to control hearts. Finally, rVCP treated recipients demonstrated marked rVCP deposition on the endothelium and significantly less C3, IgG and IgM deposition in the tissue. rVCP is therefore able to inhibit hyperacute xenorejection by binding the endothelial surface, blocking complement fixation and activation, and preventing xenoantibody attachment. |
2,332,056 | Molecular dissection of the inward rectifier potassium current (IK1) in rabbit cardiomyocytes: evidence for heteromeric co-assembly of Kir2.1 and Kir2.2. | Cardiac inward rectifier K+ currents (IK1) play an important role in maintaining resting membrane potential and contribute to late phase repolarization. Members of the Kir2.x channel family appear to encode for IK1. The purpose of this study was to determine the molecular composition of cardiac IK1 in rabbit ventricle. Western blots revealed that Kir2.1 and Kir2.2, but not Kir2.3, are expressed in rabbit ventricle. Culturing rabbit myocytes resulted in an approximately 50% reduction of IK1 density after 48 or 72 h in culture which was associated with an 80% reduction in Kir2.1, but no change in Kir2.2, protein expression. Dominant-negative (DN) constructs of Kir2.1, Kir2.2 and Kir2.3 were generated and tested in tsA201 cells. Adenovirus-mediated over-expression of Kir2.1dn, Kir2.2dn or Kir2.1dn plus Kir2.2dn in cultured rabbit ventricular myocytes reduced IK1 density equally by 70% 72 h post-infection, while AdKir2.3dn had no effect, compared to green fluorescent protein (GFP)-infected myocytes. Previous studies indicate that the [Ba2+] required for half-maximum block (IC50) differs significantly between Kir2.1, Kir2.2 and Kir2.3 channels. The dependence of IK1 on [Ba2+] revealed a single binding isotherm which did not change with time in culture. The IC50 for block of IK1 was also unaffected by expression of the different DN genes after 72 h in culture. Taken together, these results demonstrate functional expression of Kir2.1 and Kir2.2 in rabbit ventricular myocytes and suggest that macroscopic IK1 is predominantly composed of Kir2.1 and Kir2.2 heterotetramers. |
2,332,057 | Protein kinase C-delta mediates adenosine A3 receptor-induced delayed cardioprotection in mouse. | We investigated the role of protein kinase C in adenosine A3 receptor (A3AR)-induced delayed cardioprotection in the mouse heart. Mice were treated with selective A3AR agonist N6-(3-iodobenzyl)adenosine-5'-N-methyluronamide (IB-MECA). Twenty-four hours later, hearts were perfused in the Langendorff mode and subjected to 30 min of global ischemia and 30 min of reperfusion. Infarct size was determined by computer morphometry of tetrazolium-stained sections, and ventricular function was monitored by inserting a fluid-filled balloon into the left ventricle (LV). Chelerythrine chloride (CHE, 5.0 mg/kg) and rottlerin (Rot, 0.3 mg/kg) were given 30 min before IB-MECA to block total and PKC-delta isoforms, respectively. IB-MECA caused postischemic reduction in necrosis and improvement in ventricular function, which was abolished by CHE. Western blot analysis demonstrated translocation of the PKC-delta isoform but not the alpha, epsilon, xi, eta isoform(s) from cytoplasm to the membrane fraction after 30 min of IB-MECA administration. A3AR antagonist MRS-1191 and CHE blocked the translocation of PKC-delta. Furthermore, IB-MECA-induced increase in nuclear factor-kappaB binding was diminished by CHE. These results provide direct evidence of an essential role of PKC, and more specifically, PKC-delta in A3AR-induced delayed cardioprotection. |
2,332,058 | A lupus-like syndrome develops in mice lacking the Ro 60-kDa protein, a major lupus autoantigen. | Antibodies against a conserved RNA-binding protein, the Ro 60-kDa autoantigen, occur in 24-60% of all patients with systemic lupus erythematosus. Anti-Ro antibodies are correlated with photosensitivity and cutaneous lesions in these patients and with neonatal lupus, a syndrome in which mothers with anti-Ro antibodies give birth to children with complete congenital heart block and photosensitive skin lesions. In higher eukaryotes, the Ro protein binds small RNAs of unknown function known as Y RNAs. Because the Ro protein also binds misfolded 5S rRNA precursors, it is proposed to function in a quality-control pathway for ribosome biogenesis. Consistent with a role in the recognition or repair of intracellular damage, an orthologue of Ro in the radiation-resistant eubacterium Deinococcus radiodurans contributes to survival of this bacterium after UV irradiation. Here, we show that mice lacking the Ro protein develop an autoimmune syndrome characterized by anti-ribosome antibodies, anti-chromatin antibodies, and glomerulonephritis. Moreover, in one strain background, Ro-/- mice display increased sensitivity to irradiation with UV light. Thus, one function of this major human autoantigen may be to protect against autoantibody development, possibly by sequestering defective ribonucleoproteins from immune surveillance. Furthermore, the finding that mice lacking the Ro protein are photosensitive suggests that loss of Ro function could contribute to the photosensitivity associated with anti-Ro antibodies in humans. |
2,332,059 | Interplay of ionic and structural heterogeneity on functional action potential duration gradients: Implications for arrhythmogenesis. | Action potential duration (APD) dispersion in the heart is governed by the underlying cellular architecture and the spatial distribution of the membrane properties. Understanding the contribution of each factor is important in designing more effective methods for the control of arrhythmias. Recent experimental studies have shown that the insertion of structural barriers in ionically heterogeneous tissue facilitates the formation of unidirectional block and discordant alternans. In this work, computational modeling is used to examine the effect of internal obstacles on the formation of functional APD gradients in ionically heterogeneous tissue. Intrinsic APD differences are introduced by assigning two discrete cell types to each half of a square domain. The combined effect of structural and ionic heterogeneities is shown to produce gradients in APD that are oblique to both the intrinsic gradients in APD and the physical boundary. Simulation results are presented that show that the magnitude and spatial extent of the subsequent APD gradients are modulated by the size and orientation of the obstacle, the degree of anisotropy, and the location of the pacing site. Long, thin internal obstacles are found to produce the greatest dispersion in APD. The combination of internal obstacles and ionic heterogeneities is shown to produce a substrate for re-entrant excitation following a pair of near threshold point stimuli. (c) 2002 American Institute of Physics. |
2,332,060 | Anti-CD25 monoclonal antibody therapy affects the death signals of graft-infiltrating cells after clinical heart transplantation. | To define whether immunosuppressive agents that block the interleukin (IL)-2 pathway could prevent activation-induced cell death of activated T cells in the graft, we measured expression of IL-2, IL-2 receptor alpha chain (CD25), IL-15, Fas, and Fas ligand by real time reverse transcription-polymerase chain reaction in cardiac allografts.</AbstractText>We characterized the phenotype of the infiltrating cells (CD3, CD68, CD25) by immunohistochemistry. The proportion of apoptotic graft-infiltrating cells was determined by TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling) staining. We analyzed endomyocardial biopsy specimens from cardiac allograft recipients who were treated with anti-CD25 monoclonal antibody (mAb) induction therapy (daclizumab) or with matching placebo in combination with cyclosporine, steroids, and mycophenolate mofetil.</AbstractText>Treatment with anti-CD25 mAb affected the number of infiltrating CD3 and CD68 cells and the IL-2-regulated apoptotic pathway. During anti-CD25 mAb treatment, significantly lower intragraft IL-2 and CD25 mRNA transcription levels and decreased numbers of CD25+ T cells were found compared with the levels measured in endomyocardial biopsy specimens from placebo-treated patients (5- to 10-fold, P=0.002 and P<0.0001, respectively). In these samples the intragraft mRNA expression levels of IL-15 were also lower (P=0.02). Inhibition of the IL-2 pathway by anti-CD25 mAb therapy was accompanied by reduced mRNA and protein of Fas ligand and not by reduced Fas expression (P=0.001 and P=0.03). TUNEL staining revealed that the proportion of graft-infiltrating cells was lower in the anti-CD25 mAb patient group than the proportion of apoptotic cells in patients receiving placebo (P=0.06).</AbstractText>Our data suggest that immunosuppressive agents that affect the IL-2 pathway hinder the mechanism of activation-induced cell death by which the immune system eliminates alloreactive cells.</AbstractText> |
2,332,061 | Neuromuscular blocking activity and therapeutic potential of mixed-tetrahydroisoquinolinium halofumarates and halosuccinates in rhesus monkeys. | Structure-activity relationships in rhesus monkeys for a novel mixed-onium class of ultra-short-acting nondepolarizing tetrahydroisoquinolinium neuromuscular blockers (NMBs) are described. Bis-onium chlorofumarate 20a with (1R,2S)-benzyltetrahydroisoquinolinium groups was a potent lead compound (ED(95) = 0.079 mg/kg) with an ultra-short duration of NMB effect (7.1 min) and a selectivity index (SI: defined as a ratio of the cardiovascular threshold dose to the ED(95)) similar to that of mivacurium (3). The mean threshold dose for cardiovascular effects with 20a was ca. 20 times its ED(95) value (SI = 20). A novel mixed-onium analogue of 20a was prepared by replacing the benzyltetrahydroisoquinolinium group distal to the fumarate chlorine atom with a (1S,2R)-phenyltetrahydroisoquinolinium moiety. The resulting mixed-onium chlorofumarate 24a displayed good NMB potency (ED(95) = 0.063 mg/kg), ultra-short duration of action (5.6 min) and an improved selectivity index (SI = 57). Several other mixed-onium derivatives containing octanedioate (25a; ED(95) = 0.103 mg/kg), difluorosuccinate (27c; ED(95) = 0.056 mg/kg), and fluorofumarate (28a; ED(95) = 0.137 mg/kg) linkers were also potent, ultra-short-acting NMBs with good to excellent selectivity index values (SI = 37-96). Octanedioate 25a was longer acting at higher doses compared to difluorosuccinate 27c and chlorofumarate 24a. Durations of NMB effect following a 0.4 mg/kg bolus dose (100% block) of 25a, 27c, and 24a were 16.9, 13.0, and 10.0 min, respectively. Recovery time for mixed-onium chlorofumarate 24a following a 1 h continuous infusion at 10-20 microg/kg/min (95-100% block) was ca. 5 min which is similar to that observed following a 0.2 mg/kg bolus dose of this compound and indicates a lack of cummulative effects. Preliminary studies with chlorofumarate 24a in whole human blood revealed that mixed-onium thiazolidine 29 was the major metabolite and that plasma cholinesterases do not play the primary role in duration of NMB effect. The NMB properties of 24a in rhesus monkeys led to its clinical evaluation as a possible alternative to succinylcholine. |
2,332,062 | Polymorphisms in the insulin-degrading enzyme gene are associated with type 2 diabetes in men from the NHLBI Framingham Heart Study. | Linkage studies have mapped a susceptibility gene for type 2 diabetes to the long arm of chromosome 10, where we have previously identified a quantitative trait locus that affects fasting blood glucose within the Framingham Heart Study cohort. One candidate gene in this region is the insulin-degrading enzyme (IDE), which, in the GK rat model, has been associated with nonobese type 2 diabetes. Single nucleotide polymorphisms (SNPs) were used to map a haplotype block in the 3' end of IDE, which revealed association with HbA(1c), fasting plasma glucose (FPG), and mean fasting plasma glucose (mFPG) measured over 20 years. The strongest associations were found in a sample of unrelated men. The lowest trait values were associated with a haplotype (TT, f approximately 0.32) containing the minor allele of rs2209772 and the major allele of the rs1887922 SNP (FPG P < 0.001, mFPG P < 0.003, HbA(1c) P < 0.025). Another haplotype (CC, f approximately 0.16) was associated with elevated HbA(1c) (P < 0.002) and type 2 diabetes (P < 0.001, odds ratio 1.96, 95% CI 1.28-3.00). The evidence presented supports the possibility that IDE is a susceptibility gene for diabetes in populations of European descent. |
2,332,063 | TRPC1 store-operated cationic channel subunit. | TRPC1 is a membrane protein that is highly conserved in mammals, amphibians and birds. It is widely expressed in cells throughout the body including in the heart and nervous system. Amino acid sequence analysis and over-expression studies indicate it is an ion channel that allows the transmembrane flux of small cations including sodium and calcium. In some cell types it is apparent that at least a fraction of TRPC1 exists in the plasma membrane. Inhibition of TRPC1 expression or block by TRPC1-specific antibody leads to attenuation of the plasma membrane calcium influx that occurs in response to depletion of calcium levels in sarcoplasmic or endoplasmic reticulum. TRPC1 would, therefore, seem to be a key subunit of store-operated channels (SOCs). TRPC1 is, nevertheless, unlikely to act alone. There is good evidence that it can heteromultimerise with the related proteins TRPC4, TRPC5 and polycystin-2; a tetrameric arrangement is envisaged, but not demonstrated. Like its relative in Drosophila, TRPC1 looks likely to function in a signalplex, a protein complex including inositol 1,4,5-triphosphate (IP(3)) receptor, plasma membrane calcium-ATPase, caveolin-1 and calmodulin. Its localisation in membranes is punctate and associated with functionally discrete calcium signals. TRPC1's function may not only be linked to SOCs but also to other cellular events including the nuclear translocation of the NFAT transcription factor. There is still much to be learned about this fundamental protein. |
2,332,064 | Neonatal lupus: review of proposed pathogenesis and clinical data from the US-based Research Registry for Neonatal Lupus. | Congenital heart block (CHB), a life-threatening manifestation of neonatal lupus, offers aunique opportunity to study the effect or arm of immunity and define the pathogenicity of an autoantibody in mediating tissue injury. This review focuses on our recent in vitro model which supports a cascade from antibody insult to unchecked fibrosis. In brief, it is proposed that the fetal cardiac myocyte undergoes apoptosis which facilitates transfer of intracellular Ro and La antigens to the surface where they are bound by circulating maternal autoantibodies (anti-SSA/Ro-SSB/La antibodies). Scavenging macrophages phagocytose these inadvertently "opsonized" cardiocytes, leading to the secretion of pro-inflammatory and pro-fibrotic cytokines, the latter of which transdifferentiate fibroblasts into myofibroblasts and thereby promote scarring. Immunohistologic study of a heart from a neonate dying of CHB supports this model in that macrophages and myofibroblasts were demonstrated. To facilitate both basic and clinical research, a Research Registry for Neonatal Lupus was established in 1994 by the U.S. National Institute of Arthritis, Musculoskeletal and Skin Diseases. Maternal and fetal outcomes are addressed as well as recurrence rates. Laboratory evaluation and management decisions during pregnancy are provided. |
2,332,065 | A comparison of propofol infusion and propofol/isoflurane anaesthesia in dexmedetomidine premedicated dogs. | The effects of propofol infusion were compared with propofol/isoflurane anaesthesia in six beagles premedicated with 10 microg/kg intramuscular (i.m.) dexmedetomidine. The suitability of a cold pressor test (CPT) as a stress stimulus in dogs was also studied. Each dog received isoflurane (end tidal 1.0%, induction with propofol) with and without CPT; propofol (200 microg/kg/min, induction with propofol) with and without CPT; premedication alone with and without CPT in a randomized block study in six separate sessions. Heart rate and arterial blood pressures and gases were monitored. Plasma catecholamine, beta-endorphin and cortisol concentrations were measured. Recovery profile was observed. Blood pressures stayed within normal reference range but the dogs were bradycardic (mean heart rate < 70 bpm). PaCO2 concentration during anaesthesia was higher in the propofol group (mean > 57 mmHg) when compared with isoflurane (mean < 52 mmHg). Recovery times were longer with propofol than when compared with the other treatments. The mean extubation times were 8 +/- 3.4 and 23 +/- 6.3 min after propofol/isoflurane and propofol anaesthesia, respectively. The endocrine stress response was similar in all treatments except for lower adrenaline level after propofol infusion at the end of the recovery period. Cold pressor test produced variable responses and was not a reliable stress stimulus in the present study. Propofol/isoflurane anaesthesia was considered more useful than propofol infusion because of milder degree of respiratory depression and faster recovery. |
2,332,066 | Growth factor-binding sequence in human alpha2-macroglobulin targets the receptor-binding site in transforming growth factor-beta. | alpha(2)-Macroglobulin (alpha(2)M) binds transforming growth factor-beta1 (TGF-beta1) and TGF-beta2, forcing these growth factors into a state of latency. The mechanism by which this occurs remains unclear. In this paper, we demonstrate that peptides, derived from the structure of human alpha(2)M (amino acids 714-729), bind directly to TGF-beta1 and block the binding of TGF-beta1 to the type I and II TGF-beta receptors. The alpha(2)M-derived peptides are notable for hydrophobic tripeptide sequences (WIW or VVV) and acidic residues (Glu(714) and Asp(719) in the mature alpha(2)M subunit), which may function analogously to the structural elements that mediate TGF-beta-binding in the type II receptor. Mutating Glu(714) and Asp(719) in the alpha(2)M-peptide-GST fusion protein, FP3, which contains the putative growth factor-binding site, significantly decreased the binding affinity of FP3 for TGF-beta1. The alpha(2)M-derived peptides, which bind TGF-beta1, inhibited the interaction of TGF-beta1 with its receptors in fetal bovine heart endothelial cells. The same peptides also inhibited the activity of TGF-beta1 in endothelial cell proliferation assays. These results demonstrate that alpha(2)M-derived peptides target the receptor-binding sequence in TGF-beta. |
2,332,067 | A randomized trial of caudal block with bupivacaine 4 mg x kg-1 (1.8 ml x kg-1) plus morphine (150 microg x kg-1) vs general anaesthesia with fentanyl for cardiac surgery. | Regional anaesthesia has been used effectively in paediatric patients undergoing cardiac surgery and is thought to be safe.</AbstractText>Thirty patients ASA physical status II-III undergoing scheduled palliative or corrective cardiac surgery, receiving premedication with midazolam and anaesthetic induction with sevoflurane, fentanyl and pancuronium were randomly allocated to two groups. In group 1, patients received bupivacaine 0.22% 4 mg.kg-1 (1.8 ml.kg-1) and morphine 150 microg x kg-1 by the caudal route. After a 20-min period for the block to take effect, sevoflurane 0.5-1.0% and fentanyl 5 microg x kg-1 were administered for maintenance of anaesthesia. In group 2, the anaesthetic technique was the same as in group 1, without a caudal block and fentanyl 25 microg x kg-1 was administered at the moment of surgical incision.</AbstractText>Cardiovascular and haemodynamic responses of patients receiving caudal block showed minor variations during the 20-min period between caudal and general anaesthesia. Fentanyl requirements during surgery were lower (P = 0.001) in patients with caudal block than patients with general anaesthesia. Extubation time was shorter (P = 0.034) in the caudal group. Two patients in the general anaesthesia group and one in the caudal group died because of postoperative complications.</AbstractText>Caudal block with bupivacaine 0.22% 4 mg.kg-1 (1.8 ml.kg-1) and morphine 150 microg x kg-1 was safe and effective for paediatric patients undergoing cardiac surgery. However, patients might have a better outcome with a reduction of morphine dosage and administration of a muscle relaxant of shorter duration of action than pancuronium.</AbstractText> |
2,332,068 | Prevention of chronic rejection with immunoregulatory cells induced by intrathymic immune modulation with class I allopeptides. | Intrathymic immune modulation with RT1.Aa allopeptides in the PVG.R8-to-PVG.1 U rat strain combination leads to long-term survival of cardiac allografts. This regimen, however, does not induce transplantation tolerance, since most long-surviving allografts undergo chronic rejection. We investigated recipients with chronic rejection for donor-specific immune nonresponsiveness and immunoregulatory cells as possible mechanisms responsible for long-term graft survival. There was a significant reduction in the proliferative response of T cells from long-term allograft recipients to donor alloantigens as compared with that of naïve T cells. Adoptive transfer of splenocytes from intrathymically manipulated primary long-term graft survivors into minimally irradiated secondary hosts resulted in indefinite survival of > 80% of allografts, providing evidence for immunoregulatory cells. Secondary recipients had total absence of donor-reactive cellular and humoral responses. Immunoregulation was also transferable from secondary to tertiary graft recipients. More importantly, there was a significant reduction in the incidence of chronic rejection in secondary hosts (> 85%) and complete prevention of acute and chronic rejection in tertiary hosts. This study demonstrates that intrathymic immunomodulation with class I allopeptides results in the generation of immunoregulatory cells that do not block chronic rejection in primary hosts where they develop, but prevent both acute and chronic allograft rejection when adoptively transferred into secondary and tertiary recipients. |
2,332,069 | ANA negative (Ro) lupus erythematosus with multiple major organ involvement: a case report. | Anti-nuclear antibody (ANA) negative systemic lupus erythematosus (SLE) occurs in about 4-13% of SLE cases. A small group of ANA negative SLE patients with positive anti-Ro antibodies usually present with typical vasculitic skin lesions which can be associated with photosensitivity, renal disease, congenital heart block or neonatal lupus. We present a case of a persistently ANA negative patient who presented with joint pain, rashes, mouth ulcer and alopecia. Clinical diagnosis of systemic lupus erythematosus was made even though ANA was negative. She was started on steroids and went into remission. Later, she developed several episodes of convulsions associated with fever and prominent vasculitic lesions. The patient was also found to have microscopic hematuria, proteinuria, anemia and thrombocytopenia. Renal biopsy showed lupus nephritis class 1B. Due to the prominent skin lesions, we performed anti-extractable nuclear antigens (ENA) antibodies test and anti-Ro turned out to be positive. The final diagnosis was ANA negative SLE (Ro lupus) with cutaneous, renal, musculoskeletal, hematological and cerebral Involvement. |
2,332,070 | Preclinical results of sirolimus treatment in transplant models. | Sirolimus (SRL; rapamycin) is a macrolide antibiotic, which modest anticandidal and tumoricidal activities were superseded by its immunosuppressive potential to block allograft rejection. The most intriguing biological characteristic of SRL emerged after demonstration of its potent synergism with cyclosporine (CsA). Naïve T cells, residing in the G(0) phase of the cell cycle, become activated by three signals. Signal 1 (T cell antigen receptor/alloantigen) and Signal 2 (CD28/B7) progress T cell to the early G(1) phase inducing production of interleukin-2 (IL-2) and other T cell growth factors (TGFs). Signal 3 (cytokine/cytokine receptor) initiate cell division and differentiation in the late G(1)/S phase. Whereas CsA binding to calcineurin blocks Signal 1/2, SRL binding to mammalian target of rapamycin (mTOR) blocks Signal 3. Our preclinical studies have established the in vivo principles of the effects exhibited by SRL alone on allograft survival, synergism between SRL and CsA as well as two drugs pharmacokinetic and pharmacodynamic interactions. In our experimental model, a 14-day i.v. continuous infusion of SRL by osmotic pump into rat recipients extended the survivals of heart allografts in a dose-dependent fashion. In comparison to untreated controls (MST of 6.3 +/- 0.5 days), 0.08 mg/kg SRL extended MST to 34.4 +/- 12.1 days, and 0.8 mg/kg to 74.1 +/- 20.2 days, with 6/18 allografts surviving for more than 100 days. Since almost identical results were produced by 10-fold higher SRL doses delivered by oral gavage, we estimated its bioavailability at 10%. Similarly, SRL prolonged the survivals of kidney, pancreas, and small bowel allografts in rats. At the same time large animal models cautioned about potential toxicities, namely intestinal vasculitis. The synergistic interactions of CsA and SRL may be explained by sequential effects in the early G(0)/G(1) versus late G1/S phases of cell cycle progression, respectively. The in vivo interaction of SRL with other immunosuppressive drugs was evaluated by the median effect analysis and the combination index (CI) values (CI = 1 shows additive, CI < 1, synergistic, and CI > 1, antagonistic, interactions). Oral SRL proved to be synergistic in both CsA-resistant mouse (CI = 0.4-1.5) and CsA-sensitive rat (CI = 0.3-0.6) models. The pharmacokinetic interactions of SRL and/or CsA were evaluated in rats for i.v. and oral formulations. Although low CsA and SRL i.v. doses did not affect each other levels, potent interaction was observed after oral gavage: CsA increased SRL levels by 2-11 folds; and, SRL increased CsA levels by 2-3-folds. Our results suggested that both pharmacodynamic and pharmacokinetic interactions contribute to the synergism between SRL and CsA. We also estimated the impact of CsA/SRL interaction on renal dysfunction, myelosuppression, and hyperlipidemia. Salt-depleted rats treated with SRL (0.4-6.4 mg/kg) and/or CsA (2.5-20 mg/kg) were examined for glomerular filtration rates (GFR), lipid levels, and bone marrow cellularity. CsA-induced kidney function deficiency was exacerbated by SRL. This exacerbation of renal dysfunction correlated with increased CsA levels in kidneys when combined with SRL. Furthermore, CsA potentiated SRL-mediated toxicities, namely myelosuppression and increased cholesterol. In conclusion, SRL therapy is synergistic with CsA but both drug levels should be carefully monitored to avoid toxic effects. |
2,332,071 | Effects of caffeine on potassium currents in isolated rat ventricular myocytes. | Rapid exposure of cardiac muscle to high concentrations of caffeine releases Ca(2+) from the sarcoplasmic reticulum (SR). This Ca(2+) is then extruded from the cell by the Na(+)/Ca(2+) exchanger. Measurement of the current carried by the exchanger (I(Na/Ca)) can therefore be used to estimate of the Ca(2+) content of the SR. Previous studies have shown that caffeine, however, can also inhibit K(+) currents. We therefore investigated whether the inhibitory effects of caffeine on these currents could contaminate measurements of I(Na/Ca). Caffeine caused partial inhibition of the inward rectifier K(+) current (I(K1)): the outward current at -40 mV was 1.15+/-0.24 pA/pF in control and decreased to 0.34+/-0.15 pA/pF in the presence of 10 mmol/l caffeine (P<0.05, n=15). This was similar to the effect of caffeine on the holding current observed at -40 mV in the absence of K(+) channel block and could therefore account for the contaminating effects of caffeine observed during measurements of I(Na/Ca). Moreover, caffeine also partially inhibited the transient outward ( I(to)) and the delayed rectifier (I(K)) K(+) currents. |
2,332,072 | Inhibition of HERG K+ current and prolongation of the guinea-pig ventricular action potential by 4-aminopyridine. | 4-Aminopyridine (4-AP) has been used extensively to study transient outward K+ current (ITO,1) in cardiac cells and tissues. We report here inhibition by 4-AP of HERG (the human ether-à-go-go-related gene) K+ channels expressed in a mammalian cell line, at concentrations relevant to those used to study ITO,1. Under voltage clamp, whole cell HERG current (IHERG) tails following commands to +30 mV were blocked with an IC50 of 4.4 +/- 0.5 mM. Development of block was contingent upon HERG channel gating, with a preference for activated over inactivated channels. Treatment with 5 mM 4-AP inhibited peak IHERG during an applied action potential clamp waveform by ~59 %. It also significantly prolonged action potentials and inhibited resurgent IK tails from guinea-pig isolated ventricular myocytes, which lack an ITO,1. We conclude that by blocking the alpha-subunit of the IKr channel, millimolar concentrations of 4-AP can modulate ventricular repolarisation independently of any action on ITO,1. |
2,332,073 | Maximum acceptable weights for asymmetric lifting of Chinese females. | This study used the psychophysical approach to evaluate the effects of asymmetric lifting on the maximum acceptable weight of lift (MAWL) and the resulting heart rate, oxygen uptake and rating of perceived exertion (RPE). A randomized complete block factorial design was employed. Twelve female college students lifted weights at three different lifting frequencies (one-time maximum, 1 and 4 lifts/min) in the sagittal plane and at three different asymmetric angles (30 degrees, 60 degrees, and 90 degrees ) from the floor to a 68-cm height pallet. This lifting experiment was conducted for a 1-h work period using a free-style lifting technique. The MAWLs for asymmetric lifting were significantly lower than those for symmetric lifting in the sagittal plane. The MAWL decreased with the increase in the angle of asymmetry. However, the heart rate, oxygen uptake and RPE remained unchanged. Though the MAWL decreased significantly with lifting frequency, both the physiological costs (heart rate and oxygen uptake) and rating of perceived exertion increased with the increase in lift frequency. The most stressed body part was the arm. Lifting frequency had no significant effect on the percentage decrease in MAWL from the sagittal plane values. On average, decreases of 5%, 9% and 14% for MAWL at 30 degrees, 60 degrees and 90 degrees asymmetric lifting, respectively, were revealed. This result was in agreement with the findings of Chinese males studied by Wu [Int. J. Ind. Ergonom. 25 (2000) 675]. The percentage decrease in MAWL with twisting angle for the Chinese participants was somewhat lower than those for Occidental participants. In addition, even though there was an increase in heart rate and RPE with the increase in the symmetrical lift angle for Occidental participants, it was different from the Chinese participants. Lastly, the 1991 NIOSH equation asymmetry multiplier is more conservative in comparison with the results of the present study. |
2,332,074 | [2003 update of the Guidelines of the Spanish Society of Cardiology on High Blood Pressure]. | Since publication of the Spanish Society of Cardiology Clinical Practice Guidelines on High Blood Pressure in January 2000, a new body of scientific evidence has been obtained that needs to be taken into account in clinical practice. A complete clinical evaluation by assessment of the global cardiovascular risk score should be done in patients with hypertension. In this connection, ECG findings and urine albumin excretion are of particular value. Up to now, the results of most important clinical trials indicate that the aim should be to normalize blood pressure, with stricter control in patients at higher risk (diabetes, target organ damage or left ventricular hypertrophy). Antihypertensive therapy should be selected on an individual basis, taking in account that patients with certain associated pathologies will benefit more from particular groups of drugs. Those with diabetes or left ventricular hypertrophy seem to benefit from pharmacological block of the renin-angiotensin system, and patients with heart failure from combined therapy with ACE inhibitors plus beta-blockers. |
2,332,075 | Mechano-electric feedback and arrhythmias. | The mechanical state of the heart feeds back to modify cardiac rate and rhythm. Mechanical stretch of myocardial tissue causes immediate and chronic responses that lead to the common end point of arrhythmia. This review provides a brief summary of the author's personal choice of contributions that she considers have fostered our understanding of the role of mechano-electric feedback in arrhythmogenesis. Acute mechanical stretch reversibly depolarises the cell membrane and shortens the action potential duration. These electrophysiological changes are related to the activation of mechano-sensitive ion channels. Several different ion channels are involved in the sensing of stretch, among them K(+)-selective, Cl(-)-selective, non-selective, and ATP-sensitive K(+) channels. Sodium and Ca(2+) entering the cells via non-selective ion channels are thought to contribute to the genesis of stretch-induced arrhythmia. Mechano-sensitive channels have been cloned from non-vertebrate and vertebrate species. Chronic stress on the heart activates gene expression in cardiomyocytes and non-myocytes. The signal transduction involves atrial natriuretic peptides and growth factors that initiate remodelling processes leading to hypertrophy which in turn may contribute to the electrical instability of the heart by increasing the responsiveness of mechano-sensitive channels. Selective block of these channels could provide some new form of treatment of mechanically induced arrhythmias, although at present there are no drugs available with sufficient selectivity. Detailed understanding of how mechanical strain on myocardial cells is translated into channel activation will allow to identify new targets for putative antiarrhythmic drugs. |
2,332,076 | New developments in the pharmacological treatment of chronic heart failure. | In recent years, rapid growth in the understanding of the pathophysiology of chronic heart failure has allowed for insights into many potential new therapeutic strategies. Yet until now, despite sound biological basis for efficacy and success in early-Phase studies, novel agents have not stood up to the scrutiny of late-Phase clinical trials. Indeed, remarkably negative results have been observed for vasopeptidase inhibitors, endothelin receptor antagonists and agents which block immune activation. However, efficacy data from other novel agents are still awaited, including the selective aldosterone receptor antagonist eplerenone, arginine vasopressin inhibitors, erythropoietin and hydroxy-methyl-glutaryl coenzyme A reductase inhibitors. Other classes of drugs which may enter clinical development include cardiac metabolic agents, matrix metalloproteinase inhibitors and advanced glycation end product antagonists. That the mortality and morbidity of patients with chronic heart failure remain unacceptably high makes the ongoing commitment to exploration of new drug therapies for the condition critical. |
2,332,077 | Glycolytic buffering affects cardiac bioenergetic signaling and contractile reserve similar to creatine kinase. | Creatine kinase (CK) and glycolysis represent important energy-buffering processes in the cardiac myocyte. Although the role of compartmentalized CK in energy transfer has been investigated intensely, similar duties for intracellular glycolysis have not been demonstrated. By measuring the response time of mitochondrial oxygen consumption to dynamic workload jumps (tmito) in isolated rabbit hearts, we studied the effect of inhibiting energetic systems (CK and/or glycolysis) on transcytosolic signal transduction that couples cytosolic ATP hydrolysis to activation of oxidative phosphorylation. Tyrode-perfused hearts were exposed to 15 min of the following: 1) 0.4 mM iodoacetamide (IA; n = 6) to block CK (CK activity <3% vs. control), 2) 0.3 mM iodoacetic acid (IAA; n = 5) to inhibit glycolysis (GAPDH activity <3% vs. control), or 3) vehicle (control, n = 7) at 37 degrees C. Pretreatment tmito was similar across groups at 4.3 +/- 0.3 s (means +/- SE). No change in tmito was observed in control hearts; however, in IAA- and IA-treated hearts, tmito decreased by 15 +/- 3% and 40 +/- 5%, respectively (P < 0.05 vs. control), indicating quicker energy supply-demand signaling in the absence of ADP/ATP buffering by CK or glycolysis. The faster response times in IAA and IA groups were independent of the size of the workload jump, and the increase in myocardial oxygen consumption during workload steps was unaffected by CK or glycolysis blockade. Contractile function was compromised by IAA and IA treatment versus control, with contractile reserve (defined as increase in rate-pressure product during a standard heart rate jump) reduced to 80 +/- 8% and 80 +/- 10% of baseline, respectively (P < 0.05 vs. control), and significant elevations in end-diastolic pressure, suggesting raised ADP concentration. These results demonstrate that buffering of phosphate metabolites by glycolysis in the cytosol contributes appreciably to slower mitochondrial activation and may enhance contractile efficiency during increased cardiac workloads. Glycolysis may therefore play a role similar to CK in heart muscle. |
2,332,078 | [Dynamics of the vagus effect on the cardiac rhythm during blockade of various subtypes of M-cholinoreceptors in cats]. | While single vagus bursts were used in cats with an incremental time delay following P-wave of the ECG, two zones were identified within the cardiac cycle differing from each other by their chronotropic responses. At the initial (approximately 120-130 ms) part of the cardiac cycle, an increase in the P-stimulus interval evoked a "moderate" (+8-16%) increment of the chronotropic response up to its maximal amplitude. Further increase of that interval provoked an "abrupt" (-80-90%) decrease of the vagus response. Block of M1-(pirenzepine), M2-(metoctramine and gallamine) or M3-(DAMP) cholinoreceptors diminished vagally-induced minimal and maximal prolongation of the ECG P-P interval and decreased the amplitude of its alterations associated with varying the position of vagus stimulus within the cardiac cycle. The coefficient delineating magnitude of the vagus effect over a zone with "moderate" changes of the chronotropic response was decreased after blocking the M1- and M2-cholinoreceptors, whereas duration of that zone was shortened following blockade of the M1- and M3-receptors. Velocity of the original vagus response and the rate of its subsequent decline decreased following blockade of the M1- and M2-subtypes of cholinoreceptors. |
2,332,079 | [Comparison of the hemodynamic response in subarachnoid anesthesia with bupivacaine versus bupivacaine with fentanyl in traumatology surgery in elderly patients]. | To compare the intraoperative hemodynamic effects and ephedrine requirements in elderly patients undergoing orthopedic surgery under subarachnoid anesthesia with hyperbaric bupivacaine with or without fentanyl.</AbstractText>Sixty patients over 75 years of age and scheduled for semi-urgent surgical repair of a fractured femur were randomized to two groups. Group F received subarachnoid surgery with 5 mg of bupivacaine and 15 micrograms of fentanyl. Group B received 7.5 mg bupivacaine. We recorded blood pressure, heart rate and oxygen saturation every 5 minutes and extension of anesthesia. Hemodynamic changes and ephedrine required by each patient were analyzed, along with side effects.</AbstractText>Group F patients were more hemodynamically stable 10 and 20 minutes after infusion of the anesthetic, and more hypotensive episodes occurred in group B. Group B consumed significantly more ephedrine (p < 0.05), administered to 22 patients in group B and 6 in group F. The total dose of ephedrine administered was greater in group B (190 mg) than in group F (40 mg). The extension of anesthetic block was sufficient for surgery in all cases. No side effects from fentanyl administration were observed.</AbstractText>Adding fentanyl to the local anesthetic used for subarachnoid anesthesia in elderly patients is effective for maintaining greater hemodynamic stability, allowing use of a lower dose of hyperbaric bupivacaine and reducing the need for intravenous ephedrine during surgery.</AbstractText> |
2,332,080 | Clinical efficacy of brachial plexus block with patient-controlled analgesia for postoperative analgesia and recovery in the antebrachium. | To evaluate the analgesic effect of brachial plexus block using patient-controlled analgesia device after micro-surgery in the antebrachium and its impact on postoperative recovery.</AbstractText>Twenty-four patients (ASA class I or II ) scheduled for micro-surgery in the antebrachium under brachial plexus block were randomly divided into PCBPA group (n=12) with patient-controlled analgesia and control group (n=12) without postoperative analgesia. In PCBPA group, postoperative patient-controlled analgesia was implemented using the mixture of 1% lidocaine and 0.25% bupivacaine and a computer- based system (Graseby 9300) with basal infusion of 2 ml/h, bolus dose of 3 ml and lockout time of 45 min. Visual analogue scale (VAS) was adopted for the evaluation of the pain intensity in both groups within 72 h after surgery, and changes in the mean arterial pressure (MAP) and heart rate (HR) observed during the peri-operation period.</AbstractText>VAS, MAP and HR in PCBPA group were significantly lower than those in the control group ( P<0.05) within 24 h after surgery, suggesting the effectiveness of the analgesic modality using patient-controlled analgesia, which also inhibits postoperative stress reaction and promotes recovery following micro-surgery of the antebrachium.</AbstractText> |
2,332,081 | Ketotifen reverses MDR1-mediated multidrug resistance in human breast cancer cells in vitro and alleviates cardiotoxicity induced by doxorubicin in vivo. | To investigate the effect of the antihistamine ketotifen on multidrug resistance in human breast cancer cells and doxorubicin toxicity in mice.</AbstractText>Clonogenicity assays were used to test the effect of ketotifen on human multidrug resistant breast cancer cell lines exposed to chemotherapeutic agents. Flow cytometry was used to measure accumulation of doxorubicin in cells. Fluorimetry was used to measure accumulation of doxorubicin in cardiac tissues. Histological analysis and toxicity studies in mice were used to test the effect of ketotifen on doxorubicin-induced toxicity.</AbstractText>Ketotifen was found to restore the sensitivity of P-glycoprotein-overexpressing multidrug-resistant MCF-7/adr cells to doxorubicin, mitoxantrone, VP-16 and vinblastine, but not to methotrexate or camptothecin. Ketotifen, however, was unable to restore sensitivity of BCRP-overexpressing MCF-7/mx cells or MRP-overexpressing MCF-7/vp cells to mitoxantrone or VP-16, respectively. In vivo, pretreatment of mice with ketotifen caused an increased accumulation of doxorubicin in cardiac tissue, consistent with a block in drug clearance. However, unlike verapamil, ketotifen pretreatment did not enhance doxorubicin toxicity but in fact provided protection, both at the level of cardiac tissue damage and in terms of survival.</AbstractText>Taken together, these observations show that ketotifen is unique in its ability both to reverse multidrug resistance due to P-glycoprotein overexpression and to provide cardioprotection to doxorubicin.</AbstractText> |
2,332,082 | The risk and effectiveness of transurethral resection of prostate. | To advise a patient to have transurethral resection of prostate (TURP) needs information on the benefit and complications of the procedure. Quality assurance also needs present results to be compared with future ones.</AbstractText>The authors wanted to know: 1. Whether TURP can decrease theInternational prostate symptom score (IPSS) and improve the Quality of Life (QOL) scores concerning urination at 1.5 months post-operatively for at least 25 per cent of the pre-operative scores?; 2. What are the common medical diseases in this type of patient?; and 3. What are the mortality and immediate complications of TURPF?</AbstractText>This was a prospective, before-after design trial. All patients who came to have TURP at a tertiary care hospital were studied. IPSS and QOL scores were recorded before surgery and again when the patients came back to follow up at 1.5 months after discharge. Patients were evaluated for cardiopulmonary reserve and congestive heart failure. Anesthetic technique of choice was spinal anesthesia with 0.5 per cent bupivacaine. Anesthetic and surgical complications were recorded if the definitions were met.</AbstractText>Pre-operative and 1.5 months post-operative scores were compared using paired t-test and 95 per cent confidence interval.</AbstractText>During the 13 months there were 269 consecutive males who received TURP. The mean +/- SD age was 70.4 +/- 8.8 years (range 35-97). The mean difference between pre- and post-operative IPSS was 6.7 +/- 9.1 (95% CI 5.2-7.8). Quality of Life also improved, the mean difference between pre- and post-operative QOL was 3.2 +/- 1.6 (95% CI 2.9-3.5). Most patients had ASA class 2. Common pre-operative existing diseases were hypertension (31.6%), ischemic heart disease (18.2%), diabetes (15.6%), and COPD (7.1%). Anesthetic techniques were spinal block (77.3%), epidural block (5.9%), continuous epidural (11.2%), and general anesthesia (5.6%). Intra-operative complications were reported and T URsyndrome occurred in 1 patient (0.37%). There was one surgical death 3 days post-operation, due to septic shock probably from bowel perforation.</AbstractText>The patients' symptoms and quality of life significantly improved, but there was 1 surgical death and 1 TUR syndrome among 269.</AbstractText> |
2,332,083 | Differential effects of phosphodiesterase-sensitive and -resistant analogs of cAMP on initiation of contraction in cardiac ventricular myocytes. | Amplitudes of cardiac contractions initiated by Ca2+-induced Ca2+ release (CICR) are proportional to the magnitude of Ca2+ current (ICa-L). However, large contractions accompanied by little inward current have been reported in some but not all studies in which cells were dialyzed with different analogs of cAMP. This study compares the effects of different phosphodiesterase (PDE)-resistant and PDE-sensitive analogs of cAMP on CICR, and investigates whether cAMP sensitizes CICR so that small currents induce large contractions. Experiments were conducted in voltage-clamped guinea pig ventricular myocytes at 37 degrees C, with different analogs of cAMP added to patch pipette solutions. With PDE sensitive Tris-cAMP, contraction-voltage relations were bell-shaped and proportional to ICa-L. In contrast, dialysis with PDE-resistant dibutyryl-cAMP resulted in sigmoidal contraction-voltage relations and large responses with little inward current. Similarly, in cells loaded with fura-2, large Ca2+ transients were elicited with little inward current in cells dialyzed with PDE-resistant but not PDE-sensitive cAMP. However, large transients were observed with PDE-sensitive cAMP when PDE was inhibited with 3-isobutyl-1-methylxanthine. When the amplitude of ICa-L was varied by partial block with Cd2+, or by partial inactivation, CICR remained proportional to the amplitude of ICa-L. Thus, cAMP altered the relationship between Ca2+ transients and membrane potential but did not sensitize conventional CICR coupled to ICa-L. Our results show that effects of different analogs of cAMP on contraction depend on the PDE resistance of the analog tested. Furthermore, PDE can play a major role in modulating cardiac contraction by altering the relationship between membrane potential and Ca2+ release. |
2,332,084 | Itraconazole or allopurinol in the treatment of chronic American trypanosomiasis: the regression and prevention of electrocardiographic abnormalities during 9 years of follow-up. | Several drugs are now known to have useful activity against Trypanosoma cruzi, the causative agent of human American trypanosomiasis (Chagas disease). However, the long-term effects of chemotherapy on the electrocardiographic (ECG) abnormalities associated with this disease have only been assessed for benznidiazole. In the present study, the ECG changes in 299 cases of chronic Chagas disease were followed for 9 years after treatment with itraconazole (N = 136) or allopurinol (N = 163). Among the 97 cases who were found to have ECG abnormalities immediately prior to their treatment, the two drugs appeared equally effective, such abnormalities being corrected in 23 (50%) of the 46 cardiopathy cases given itraconazole and 25 (49%) of the 51 given allopurinol (P > 0.05). Both of these 'cure rates' are much higher than the 8.1% frequency of abnormal-normal conversion observed among 198 'historical controls' (i.e. cases of chronic Chagas disease who had been left untreated; P < 0.05). Itraconazole appeared better than allopurinol at preventing the development of cardiopathy in the cases who appeared electrocardiographically normal at baseline. Among 202 such cases, only two (2.2%) of the 90 treated with itraconazole but 28 (25.0%) of the 112 given allopurinol were found to have developed ECG abnormalities during follow-up (P < 0.05). Therefore, although itraconazole and allopurinol are equally effective at reversing ECG alterations, itraconazole offers better protection against the development of new ECG abnormalities among those with chronic Chagas disease. |
2,332,085 | Two-decade-long trends (1975-1997) in the incidence, hospitalization, and long-term death rates associated with complete heart block complicating acute myocardial infarction: a community-wide perspective. | The purpose of this community-wide study was to describe a >2-decade-long experience (1975-97) in the incidence and death rates associated with complete heart block (CHB) in patients with acute myocardial infarction (AMI). Limited population-based data exist describing recent, and changes with time therein, incidence and case-fatality rates associated with CHB complicating AMI.</AbstractText>We conducted an observational study of 9082 metropolitan Worcester, Mass, residents (1990 census = 437,000) hospitalized with validated AMI in all greater Worcester hospitals during 11 1-year periods between 1975 and 1997.</AbstractText>Overall, CHB developed in 5.0% of patients with AMI. The incidence rates of CHB declined in the periods studied (6.0% in 1975/78 vs 3.1% in 1997). Declines in the occurrence of CHB were noted in patients with anterior or inferior/posterior MI. These trends remained after adjustment for other factors that might affect the risk of CHB. Patients in whom CHB developed experienced significantly higher hospital death rates than patients in whom CHB did not develop (46.8% vs 14.6%). However, improving trends in the hospital survival rate of patients with CHB were observed between 1975/78 (47.4% surviving) and 1997 (61.3% surviving). Patients in whom CHB developed during hospitalization were not at increased risk for dying after hospital discharge.</AbstractText>Our findings indicate that the incidence of CHB complicating AMI has declined with time. The hospital prognosis of patients in whom CHB developed has improved, but these patients remain at an increased risk of hospital mortality. The long-term prognosis of patients with inferior MI and CHB is similar to that of patients in whom CHB did not develop. Patients with anterior MI and CHB may be at an increased risk of long-term mortality.</AbstractText> |
2,332,086 | Interleukin-2 receptor blockade in cardiac transplantation: influence of HLA-DR locus incompatibility on treatment efficacy. | Because allograft rejection results from specific T-cell activation by donor human leukocyte antigens (HLA), new immunomodulatory therapies for organ-transplant recipients are used to selectively block T-cell activity without global immunosuppression. We investigated whether blockade of the high-affinity interleukin (IL)-2 receptor effectively prevented T-cell alloreactivity in cardiac transplantation.</AbstractText>A study of a humanized monoclonal antibody against the high-affinity IL-2 receptor (daclizumab) was performed in 70 adult, cardiac-transplant recipients. Patients were stratified based on the degree of donor-recipient HLA-DR matches. Primary and secondary endpoints were incidence and frequency of high-grade allograft rejections, IL-2-dependent, T-cell outgrowth from biopsy sites as measured by lymphocyte growth assay, and production of anti-HLA antibodies. Treatment with daclizumab significantly prevented development of high-grade acute rejection in recipients with at least one donor HLA-DR locus match during the first 3 months posttransplantation; in this group 0 of 13 (0%) treated with daclizumab experienced at least one high-grade rejection versus 3 of 13 (23%) controls (P=0.05). In addition, 1 of 12 (9%) daclizumab-treated patients experienced one or more episodes of IL-2-dependent, T-cell outgrowth versus 5 of 12 (42%) patients in the untreated group (P=0.05). In contrast, daclizumab used at the same dose and schedule was not as effective in fully HLA-DR-mismatched recipients. After cessation of daclizumab, allograft rejection increased to levels seen in controls.</AbstractText>IL-2-receptor blockade is effective for preventing alloreactivity and high-grade rejection in cardiac transplantation; however, its efficacy seemed to be influenced by the degree of donor-recipient, HLA-DR locus mismatching.</AbstractText> |
2,332,087 | Toxicity of botulinum neurotoxins in central nervous system of mice. | Botulinum neurotoxins (BoNTs) act specifically on cholinergic nerve terminals, where they cause a sustained block of acetylcholine release, and therefore they are powerful tools to study the role of cholinergic neurons in neuronal processes. Peripheral effects of BoNTs are widely documented while central effects have not been studied. Here, we report for the first time on the central toxicity of BoNT serotypes A and B following their direct intracerebroventricular (icv) injection in CD1 mice. The LD50 values were found to be in the range 0.5-1.0 x 10(-6)mg/kg. We recorded the following signs preceding animal death: piloerection and weight decrease appear first, followed by temperature decrease, eyelid closure, loss of sensorimotor reflexes, dehydration, dyspnea. Mice died of heart or respiratory failure. The surviving mice recovered completely within 4-6 days and regained the initial healthy conditions. At sub-lethal doses, the same clinical signs appear in a lighter form and with a longer time course. |
2,332,088 | Neonatal lupus erythematosus mimicking langerhans cell histiocytosis. | Neonatal lupus erythematosus (NLE) is an autoimmune disease characterized primarily by transient skin lesions and/or permanent congenital heart block. Other clinical findings include self-limited cytopenias and liver disease. The syndrome results from the passive transfer of maternal anti-SSA, anti-SSB, or anti-U1RNP autoantibodies to the fetus across the placenta. The cutaneous manifestations are generally analogous to those of subacute cutaneous lupus erythematosus (SCLE) and consist of small, erythematous macules that progress to annular plaques with delicate scaling. The skin lesions usually resolve within the first 6 months of life as maternal autoantibodies are cleared from the infant's circulation. We describe a patient with cutaneous NLE with hepatic and hematologic manifestations. The clinical presentation was atypical, with splenomegaly and petechiae at birth followed by a crusting, papulosquamous skin eruption of the scalp and face mimicking Langerhans cell histiocytosis (LCH). |
2,332,089 | Ropivacaine 0.15% plus sufentanil 0.5 microg/mL and ropivacaine 0.10% plus sufentanil 0.5 microg/mL are equivalent for patient-controlled epidural analgesia during labor. | We compared the administration of 0.15% ropivacaine plus 0.5 microg/mL of sufentanil with that of 0.10% ropivacaine plus 0.5 microg/mL of sufentanil for labor analgesia with patient-controlled epidural analgesia (PCEA) to determine whether a decreased concentration of ropivacaine could produce equally effective analgesia. One-hundred-thirty healthy pregnant women at term were randomized in a double-blinded fashion. The PCEA settings were as follows: 12-mL initial bolus, 5-mL bolus dose, 5-min lockout interval, and 10 mL/h basal infusion. Patient demographics and labor characteristics were comparable in both groups. No differences were observed for pain scores, maternal satisfaction, volume of anesthetic solution administered, number of boluses requested and delivered, need for supplemental boluses, mode of delivery, motor block, side effects, or Apgar scores. Patients in the 0.10% ropivacaine group used significantly less drug than those in the 0.15% group (mean, 57 mg; 95% confidence interval, 50.5-63.5 mg; versus mean, 88.0 mg; 95% confidence interval, 74.4-93.3 mg, respectively; P < 0.0001). Ropivacaine 0.10% plus 0.5 microg/mL of sufentanil administered via PCEA for labor analgesia is equally effective as ropivacaine 0.15% plus 0.5 microg/mL of sufentanil, with a 30% local anesthetic-sparing effect and a 40% reduction in cost. However, this reduction in local anesthetic is not associated with a decrease in the incidence of motor block, side effects, or instrumental deliveries.</AbstractText>Ropivacaine 0.10% plus 0.5 microg/mL of sufentanil given via patient-controlled epidural anesthesia for labor analgesia is equally as effective as ropivacaine 0.15% plus 0.5 microg/mL of sufentanil, with a 30% local anesthetic-sparing effect and a 40% reduction in cost. This reduction in ropivacaine concentration is not associated with a decrease in the incidence of motor block, side effects, or instrumental deliveries.</AbstractText> |
2,332,090 | The effect of epidural test dose on motor function after a combined spinal-epidural technique for labor analgesia. | Labor analgesia initiated with intrathecal bupivacaine and fentanyl, without a local anesthetic epidural test dose, provides effective analgesia and allows ambulation. In this study, we sought to determine the effect of a lidocaine-epinephrine test dose administered immediately after the initiation of combined spinal-epidural (CSE) analgesia with bupivacaine 2.5 mg and fentanyl 25 micro g on parturients' hemodynamic stability, posterior column function, motor strength, and subjective ability to walk. Parturients (n = 153) were randomized to receive either 3 mL of epidural saline or lidocaine 1.5% with epinephrine 1:200,000. Hemodynamic variables, proprioception, straight leg raise, and the modified Bromage score were analyzed in 110 parturients who completed the study protocol and were not different between groups. Vibratory sense, the ability to perform a partial deep knee bend and to step up on a stool, and the subjective ability to walk were impaired in a larger number of parturients in the lidocaine-epinephrine group at 30 min (P < 0.05). At 60 min, there were no differences between the groups except that fewer parturients in the lidocaine-epinephrine group could step up on a stool. The straight leg raise against resistance and the modified Bromage scale did not correlate well with other tests of motor strength (Spearman's rho, 0.273-0.405). These data suggest that the test dose should be avoided immediately after initiation of CSE analgesia when early ambulation is desired.</AbstractText>A lidocaine-epinephrine epidural test dose (3 mL of lidocaine 1.5% with epinephrine 1:200,000), injected immediately after the initiation of combined spinal-epidural labor analgesia with bupivacaine 2.5 mg and fentanyl 25 microg, may interfere with the ability to perform simple tests of motor function and ambulation.</AbstractText> |
2,332,091 | The effect of epidural neostigmine combined with ropivacaine and sufentanil on neuraxial analgesia during labor. | Spinal neostigmine produces analgesia without respiratory depression or hypotension but provokes major gastrointestinal side effects. Epidural injection of this drug, however, appears to induce analgesia devoid of such side effects. In this study, we evaluated the effect of a bolus of epidural neostigmine on the duration and magnitude of analgesia in early labor and assessed its eventual sparing effect on subsequent local anesthetic requirements. Epidural neostigmine methylsulfate (maximal dose 4 microg/kg) was added to 10 mL of ropivacaine 0.1%, with and without sufentanil 10 microg, to initiate analgesia. Twenty minutes after injection, pain score, sensory level, and motor block were assessed. Time until request for supplemental epidural medication was also recorded. Patient-controlled epidural analgesia with ropivacaine 0.1% was used for epidural supplementation. Maternal and fetal side effects were closely recorded. Neostigmine (4 microg/kg), when added to ropivacaine 10 mg, provided equivalent analgesia to ropivacaine 20 mg but was less effective than sufentanil 10 microg for the initiation of labor epidural analgesia. Further, neostigmine did not modify the subsequent patient-controlled epidural analgesia local anesthetic requirements during labor. No hemodynamic instability, additional motor block, or bothersome side effects were recorded.</AbstractText>The combination of epidural neostigmine (4 microg/kg) with the local anesthetic ropivacaine, with or without sufentanil, does not significantly enhance neuraxial analgesia during labor. Such a dose, however, has no bothersome side effects.</AbstractText> |
2,332,092 | PAF- and bradykinin-induced hyperpermeability of rat venules is independent of actin-myosin contraction. | We tested the hypothesis that acutely induced hyperpermeability is dependent on actin-myosin contractility by using individually perfused mesentery venules of pentobarbital-anesthetized rats. Venule hydraulic conductivity (Lp) was measured to monitor hyperpermeability response to the platelet-activating factor (PAF) 1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine or bradykinin. Perfusion with PAF (10 nM) induced a robust transient high Lp [24.3 +/- 1.7 x 10-7 cm/(s.cmH2O)] that peaked in 8.9 +/- 0.5 min and then returned toward control Lp [1.6 +/- 0.1 x 10-7 cm/(s.cmH2O)]. Reconstruction of venular segments with the use of transmission electron microscopy of serial sections confirmed that PAF induces paracellular inflammatory gaps. Specific inhibition of myosin light chain kinase (MLCK) with 1-10 microM 1-(5-iodonaphthalene-1-sulfonyl)-1H-hexahydro-1,4-diazepine hydrochloride (ML-7) failed to block the PAF Lp response or change the time-to-peak Lp. ML-7 reduced baseline Lp 50% at 40 min of pretreatment. ML-7 also increased the rate of recovery from PAF hyperpermeability measured as the decrease of half-time of recovery from 4.8 +/- 0.7 to 3.2 +/- 0.3 min. Inhibition of myosin ATPase with 5-20 mM 2,3-butanedione 2-monoxime also failed to alter the hyperpermeability response to PAF. Similar results were found using ML-7 to modulate responses. These experiments indicate that an actin-myosin contractile mechanism modulated by MLCK does not contribute significantly to the robust initial increase in permeability of rat venular microvessels exposed to two common inflammatory mediators. The results are consistent with paracellular gap formation by local release of endothelial-endothelial cell adhesion structures in the absence of contraction by the actin-myosin network. |
2,332,093 | Local cooling alters neural mechanisms producing changes in peripheral blood flow by spinal cord stimulation. | This study was performed to investigate the respective role of sensory afferent and sympathetic fibers in peripheral vasodilatation induced by spinal cord stimulation at different hindpaw skin temperatures. Cooling the skin was used as a strategy to enhance sympathetic activity [Am. J. Physiol.: Heart Circ. Physiol. 263 (1992) H1197]. Cutaneous blood flow in the footpad of anesthetized rats was recorded using laser Doppler flowmetry. Local cooling (<25 degrees C) or moderate local cooling (25-28 degrees C) of the hindpaw was produced with a cooling copper coil. Spinal cord stimulation delivered at clinically relevant parameters and with 30%, 60%, and 90% of motor threshold induced the early phase of vasodilatation in the cooled and the moderately cooled hindpaw. In addition, spinal cord stimulation at 90% of motor threshold produced the late phase of vasodilatation only in the cooled hindpaw, which was possible to block by the autonomic ganglion-blocking agent, hexamethonium. The early responses to spinal cord stimulation in the moderately cooled hindpaw were not affected by hexamethonium. In contrast, both the early and the late phase responses were eliminated by CGRP (8-37), an antagonist of the calcitonin gene-related peptide receptor. After dorsal rhizotomy, spinal cord stimulation at 90% of motor threshold elicited hexamethonium-sensitive vasodilatation in the cooled hindpaw (late phase). These results suggest that spinal cord stimulation-induced vasodilatation in the cooled hindpaw (<25 degrees C) is mediated via both the sensory afferent (early phase of vasodilatation) and via suppression of the sympathetic efferent activity (late phase) although the threshold for vasodilatation via the sympathetic efferent fibers is higher than that via sensory nerves. In contrast, vasodilatation via sensory afferent fibers may predominate with moderate temperatures (25-28 degrees C). Thus, two complementary mechanisms for spinal cord stimulation-induced vasodilatation may exist depending on the basal sympathetic tone. |
2,332,094 | A new short-acting non-depolarizing muscle relaxant (SZ1677) without cardiovascular side-effects. | In order to facilitate rapid tracheal intubation, the development of a rapid onset, short duration, non-depolarizing muscle relaxant without cardiovascular side-effects would be a significant accomplishment in the field of anesthesiology. The aim of the present study was to test the action of a new non-depolarizing muscle relaxant (SZ1677) on neuromuscular transmission, muscarinic (M2, M3) receptors and cardiovascular reactions and to compare it with clinically used muscle relaxants.</AbstractText>Neuromuscular transmission was studied by recording muscle contractions elicited by indirect electrical stimulation, using (i). in vitro isolated phrenic nerve-hemidiaphragm preparation of mice, rats and guinea pigs and (ii). in vivo sciatic nerve-anterior tibial muscle preparation of anesthetized rats, guinea pigs and cats. Cardiovascular effects of muscle relaxants were evaluated on the grounds of their effects on changes of blood pressure and heart rate induced by electrical stimulation of the right vagal nerve in anesthetized cats. To study postsynaptic antimuscarinic affinity of muscle relaxants on M3 receptors, oxotremorine-induced contractions of longitudinal muscle strip of guinea pig ileum were registered in their presence and absence.</AbstractText>One of more than 120 newly synthesized non-depolarizing muscle relaxants compounds, 1-3[alpha-hydroxy-17beta-acetyloxy-2beta-(1,4-dioxa-8-azaspiro[4,5]dec-8-yl)-5alpha-androstane-16beta-il] -1-(2-propenyl)pyrrolidinium bromide (SZ1677), excelled with its advantageous pharmacological properties: relatively short duration of action, no accumulation and lack of unwanted side-effects. Pharmacodynamic studies show that SZ1677 is a non-depolarizing neuromuscular blocking agent with a relatively short duration and rapid onset of action in a variety of laboratory animal species. It is without cumulative effect, does not reduce blood pressure, and fails to produce tachycardia. Significant cardiac vagal blocking effects were not observed even at concentrations or dosages of 8 times the ED90. This compound, unlike many other muscle relaxants, does not have atropine-like effects on human atrial tissue; it does not increase the release of NA from sympathetic innervation in the heart. In all practical ways, at least from the vantage point of the preclinical study, SZ1677 compares favorably with all presently available short-acting muscle relaxants, including rapacuronium.</AbstractText>In experiments, SZ1677 proved to be a short-acting neuromuscular blocking compound having a large safety margin between the doses required to produce neuromuscular block and those likely to lead to cardiovascular side-effects.</AbstractText> |
2,332,095 | SS-A/Ro52, an autoantigen involved in CD28-mediated IL-2 production. | An autoantibody against SS-A/Ro52 (Ro52) is most frequently found in the sera of patients with Sjögren's syndrome, systemic lupus erythematosus, and congenital heart block from anti-Ro52 Ab-positive mother. However, the physiological function of the autoantigen SS-A/Ro52 has not yet been elucidated. In this study, we describe the role of Ro52 protein in T cell activation. Overexpression of SS-A/Ro52 in Jurkat T cell resulted in enhanced IL-2 production following CD28 stimulation. Furthermore, transfection of anti-Ro52-specific small RNA duplexes partially blocked the expression of native and overexpressed Ro52 in Jurkat T cell, resulting in decreased IL-2 production via CD28 pathway in these cells. Finally, intracellular localization of Ro52 dramatically changed following CD28 stimulation. Our data reveal a novel function of Ro52 in CD28-mediated pathway, which eventually contributes to cytokine production and expression of the T cell biological programs. |
2,332,096 | Genistein and tyrphostin AG 556 block the action potential shortening in septic shock. | We have previously shown that an increase in NO activity activated ATP-sensitive potassium channel (K(ATP)) and shortened action potential duration (APD) in an endotoxic shock model. Because the increase in NO production and the decrease of APD appear to be downstream late events in endotoxic shock, we hypothesized that a common signaling pathway might mediate these effects.</AbstractText>Using a guinea pig model of endotoxic shock, we investigated the effect of genistein and tyrphostin AG 556 on the cardiac action potential. Adult Hartley guinea pigs (300 to 450 gm) were randomized into 2 treatment parts. In the chronic treatment part, guinea pigs were randomized to receive daily subcutaneous injection of one of the five agents: saline, genistein, tyrphostin AG 556, daidzein, and vehicle for 10 days. In the acute treatment part, these agents were administered by intraperitoneal injection 1 hour before endotoxic shock. The animals were then anesthetized and mechanically ventilated, and underwent 6-hour endotoxic shock or sham experiment.</AbstractText>In the chronic treatment part, the plasma nitrate concentration, myocardial guanosine 3',5'-cyclic monophosphate (cGMP) content, and APD at 90% repolarization (APD90) of papillary muscle showed no difference in the five groups before endotoxic shock. After 6-hour endotoxic shock, the elevation of plasma nitrate concentration and myocardial cGMP content was found significant in the control, the daidzein, and the vehicle groups, but was blunted in the genistein and the tyrphostin groups. The shortening of APD90 of papillary muscle was also significant in the control, the daidzein, and the vehicle groups, but blunted in the genistein and tyrphostin groups. There were similar findings in the acute treatment part, except the weaker effect of genistein and tyrphostin.</AbstractText>Genistein and tyrphostin AG 556, either administered chronically or acutely, significantly attenuate the cardiac APD shortening in endotoxic shock, presumably through the decrease in the plasma nitrate and the cardiac cGMP production. It is suggested that tyrosine kinase signaling plays an important role in the modulation of APD in endotoxic shock.</AbstractText> |
2,332,097 | Dental local anesthetics: alternative delivery methods. | The authors review four techniques for producing block and topical anesthesia that have been advocated as alternatives to conventional methods. The objective of this review is to examine the basis for each method's application in dentistry, including scientific studies where available.</AbstractText>The authors reviewed both historical (1912 and 1923) and more recent (1977 to present) reports relating to specific local anesthetic delivery systems. While this article is not a comprehensive literature review, the clinical reports and double-blind scientific reports from peer-reviewed publications are specific to the various attributes of the delivery systems being described. In addition, the authors identify any claims lacking scientific validity.</AbstractText>Several alternative local anesthetic delivery systems are clinically effective in producing local anesthesia. Potential adverse effects and complications do, however, differ from one technology to another, depending on the mechanical characteristics of the particular system. Finally, all of the alternative local anesthetic delivery systems represent additional costs when compared with those of conventional applications, and cost-effectiveness is an important factor to be considered when implementing these systems in a dental practice.</AbstractText>Alternative local anesthetic delivery systems may offer some advantages over conventional techniques in certain situations, although the costs may outweigh the advantages in certain cases.</AbstractText> |
2,332,098 | Cytomegalovirus antibody status of donor/recipient does not influence the incidence of bronchiolitis obliterans syndrome in lung transplantation. | We have previously reported that prophylaxis for cytomegalovirus (CMV) infection does not influence the incidence of bronchiolitis obliterans syndrome (BOS) at 2 years. The effect of CMV infection (without evidence of disease) on BOS is still not well understood. Moreover, the incidence and risk factors for development of BOS in CMV-antibody-negative donor/recipient matches in lung transplantation have not been described. The aim of this study is to determine the incidence of BOS in lung transplant patients with CMV-antibody-negative (-) donors (D) and recipients (R), and to evaluate the risk factors that predispose to BOS in this sub-group.</AbstractText>A retrospective study of data from the transplant database of our center was performed. All single-lung (SL), double-lung (DL) and heart-lung block (HL) transplant patients who survived >2 years post-transplant were included in the study group. They were grouped as follows: D(-)/R(-), n = 102; D(-)/R(+), n = 70; D(+)/R(-), n = 33, and D(+)/R(+), n = 92.</AbstractText>The 3-year BOS-free survival rates were 65%, 56%, 58% and 67%, respectively, and the incidence rates of BOS at 5 years post-transplant in the different groups were 57%, 62%, 78% and 55% (p > 0.05). In the D(-)/R(-) group, the significant risk factor for developing BOS was three or more episodes of acute rejection (p = 0.02). The mean numbers of acute rejection episodes per 100 patients-days within the first 6 months were 1.28, 1.06, 0.50 and 1.11 (p < 0.001 overall) for the four groups, respectively.</AbstractText>Although CMV is believed to be a risk factor for BOS, its absence did not affect the occurrence or incidence of BOS in lung transplant patients. The main risk factor for BOS in the CMV-antibody-negative population remains the number of acute rejection episodes within the first 6 months after transplantation.</AbstractText> |
2,332,099 | Ca2+ and voltage dependence of cardiac ryanodine receptor channel block by sphingosylphosphorylcholine. | The effect of sphingosylphosphorylcholine (SPC) on the cytoplasmic Ca(2+) and voltage dependence of channel gating by cardiac ryanodine receptors (RyR) was examined in lipid bilayer experiments. Micromolar concentrations of the lysosphingolipid SPC added to cis solutions rapidly and reversibly decreased the single-channel open probability (P(o)) of reconstituted RyR channels. The SPC-induced decrease in P(o) was marked by an increase in mean closed time and burst-like channel gating. Gating kinetics during intraburst periods were unchanged from those observed in the absence of the sphingolipid, although SPC induced a long-lived closed state that appeared to explain the observed decrease in channel P(o). SPC effects were observed over a broad range of cis [Ca(2+)] but were not competitive with Ca(2+). Interestingly, the sphingolipid-induced, long-lived closed state displayed voltage-dependent kinetics, even though other channel gating kinetics were not sensitive to voltage. Assuming SPC effects represent channel blockade, these results suggest that the blocking rate is independent of voltage whereas the unblocking rate is voltage dependent. Together, these results suggest that SPC binds directly to the cytoplasmic side of the RyR protein in a location in or near the membrane dielectric, but distinct from cytoplasmic Ca(2+) binding sites on the protein. |
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