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2,333,000 | [Are the NSAIDs able to compromising the cardio-preventive efficacy of aspirin?]. | Some studies have recently suggested a potential pharmacodynamic interaction between aspirin and some non-selective non-steroidal anti-inflammatory drugs (NSAIDs). We have evaluated the reality of this pharmacodynamic interaction and analyse its clinical pertinence.</AbstractText>Literature review (Medline search - December 2005).</AbstractText>Several ex vivo studies show that some non-selective NSAIDs can block the active site of Cox1 thus preventing aspirin from exerting its platelet anti-aggregating cardio-preventive action. Cox2 selective molecules do not act at this site. The few studies, mainly case reports, have analysed the potential loss of the cardiovascular preventive benefit of aspirin in patients receiving concomitantly non-selective anti-inflammatory drugs with controversial results.</AbstractText>It seems necessary to know the existence of this pharmacodynamic interaction between aspirin at a low dose and some non-selective anti-inflammatory drugs notably ibuprofen and naproxen. In the absence of a clear clinical demonstration, it is advisable to avoid the non-selective NSAIDs in patients treated with a low dose of aspirin. It might be advisable to switch to an anti-aggregating treatment other than aspirin (clopidrogel, etc.) in these cases. At the present time, however, there are no data on which to base such a recommendation.</AbstractText> |
2,333,001 | Type C coping, alexithymia, and heart rate reactivity are associated independently and differentially with specific immune mechanisms linked to HIV progression. | The maladaptive Type C coping style has been linked to disease progression in HIV and other immunologically mediated disorders. We hypothesized that strong Type C coping, higher levels of alexithymia, and greater cardiovascular (particularly heart rate) responses to, and prolonged recovery from stress would be associated with poorer functioning of immune parameters previously linked to HIV pathogenesis and progression: (1) antigen-stimulated production of the beta (beta)-chemokines MIP-1 alpha and MIP-1 beta, which bind to the HIV co-receptor CCR5 and block HIV entry into CD4(+) lymphocytes; and (2) antigen-stimulated production of the proinflammatory cytokine interleukin-6 (IL-6), which synergizes immune activation associated with HIV replication. We examined relations among psychological, cardiovascular, and immune variables in a baseline sample of 200 HIV-infected, predominantly African American outpatients attending an HIV primary care clinic in inner-city Baltimore. In regression analyses adjusted for CD4(+) count and age, strong Type C coping was associated with significantly higher IL-6 production, as predicted. The theoretically related construct of alexithymia was correlated with significantly lower stimulated production of HIV-inhibiting MIP-1 alpha. Independent of alexithymia, greater heart rate reactivity, and poorer heart rate recovery in response to experimental stressors were also significantly associated with lower production of MIP-1 alpha, adjusted for cardiovascular medications, methadone use, CD4(+) count, and age. These findings support our primary set of hypotheses that maladaptive Type C coping, alexithymia, and heart rate reactivity/recovery are associated with disturbances in two key immune parameters implicated in HIV pathogenesis. Our secondary hypothesis, that dysregulated heart rate reactivity may mediate the connections between Type C coping and/or alexithymia and IL-6/ MIP-1 alpha was not confirmed. The finding that Type C coping, alexithymia, and heart rate reactivity/recovery are associated independently and differentially with specific aspects of relevant immune functioning may reflect distinct biobehavioral pathways that contribute to HIV progression. |
2,333,002 | CDH1 gene polymorphisms, smoking, Helicobacter pylori infection and the risk of gastric cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC-EURGAST). | Despite declining incidence rates, gastric cancer (GC) is a major cause of death worldwide. E-Cadherin is an adhesion molecule that is thought to be involved in GC. Germline mutations in the E-Cadherin gene (CDH1) have been identified in hereditary diffuse GC. Also, a promoter polymorphism at position -160 C/A has been suggested to lead to transcriptional down regulation and has been shown to affect GC risk in some studies. However, very little information exists on the GC risk association of other CDH1 polymorphisms and it is unclear whether any associations may be different by GC anatomical sites or histological types. Thus, a case-control study (cases=245/controls=950) nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort was conducted to assess the GC risk association of eight CDH1 gene polymorphisms. None of the CDH1 polymorphisms or haplotypes analysed were associated with GC risk and no differences of effect were observed by Helicobacter pylori infection status. However, three CDH1 polymorphisms in the same haplotype block, including the CDH1-160C/A, interacted with smoking to increase GC risk in smokers but not in never smokers. These findings should be confirmed in larger independent studies. |
2,333,003 | Whole genome analyses suggest ischemic stroke and heart disease share an association with polymorphisms on chromosome 9p21. | Recently independent studies reported an association between coronary heart disease and single-nucleotide polymorphisms (SNPs) located at chromosome 9p21, near CDKN2A and CDKN2B genes. Given that stroke is a common complication after myocardial infarction, we investigated if the same SNPs were associated with ischemic stroke in our population.</AbstractText>We recently initiated a whole genome analysis of ischemic stroke and published the first stage of a case control study using >400,000 SNPs from Illumina Infinium Human-1 and HumanHap300 assays. We focused on SNPs recently associated with heart disease by Helgadottir and colleagues and SNPs from the same haplotype block.</AbstractText>In analyses both unadjusted and adjusted for stroke risk factors, significant associations with ischemic stroke were observed for SNPs from the same haplotype block previously associated with myocardial infarction. Significant association was also seen between disease and haplotypes involving these SNPs, both with and without adjustment for stroke risk factors (odd ratios: 1.01 to 2.65).</AbstractText>These data are important for 3 reasons: first, they suggest a genetic association for stroke; second, they suggest that this association shares pathogenic mechanisms with heart disease and diabetes; and third, they illustrate, that public release of data can facilitate rapid risk locus discovery.</AbstractText> |
2,333,004 | Cardiac glycosides as novel cancer therapeutic agents. | The class of steroid-like compounds designated cardiac glycosides includes well-known drugs such as digoxin, digitoxin, and ouabain. Their continued efficacy in treatment of congestive heart failure and as anti-arrhythmic agents is well appreciated. Less well known, however, is the emerging role of this category of compounds in the prevention and/or treatment of proliferative diseases such as cancer. New findings within the past five years have revealed these compounds to be involved in complex cell-signal transduction mechanisms, resulting in selective control of human tumor but not normal cellular proliferation. As such, they represent a promising form of targeted cancer chemotherapy. New clinical studies of their anticancer potential as single or adjuvant treatments may provide insight into these potentially valuable therapeutic options. This review focuses on recent findings on cellular pharmacology of cardiac glycosides as they relate to treatment of human cancer and attempts to explain why these agents have been overlooked in the past. |
2,333,005 | Isoproterenol enhancement of I(Ks) current in amiodarone-induced long QT syndrome. | The response over time of the QT interval and the Transmural Dispersion of Repolarization (TDR) to Isoproterenol infusion (ISO) in an 85 year-old-man with severe and syntomatic bradycardia, in the setting of an Amiodarone-induced Long QT Syndrome (LQTS) is the subject of this communication. ISO shortened the QT and decreased the TDR. We propose that ISO increased the generation of signals from the beta-Adrenergic Receptor (beta-AR) restoring the components of the hKCNQ1 macromolecular complex, thereby enhancing the I(Ks) function; shortening of the QT interval, reduction of the TDR and normalization of the T wave morphology was then possible. In Amiodarone-induced LQTS, the increase in I(Ks) activity promoted by beta-AR stimulation is prominent; at the same time, during I(Kr) block, I(Ks) activation limits excessive QT prolongation. Clinically, severe and syntomatic bradycardia was the main concern: ISO activation of the beta-AR proved useful both to increase heart rate and to reduce QT prolongation. A slow heart rate, associated to a prolonged QT interval and to a big TDR, are not sufficient to develop Torsades de Pointes in Amiodarone-induced LQTS. |
2,333,006 | Local prostaglandin blockade attenuates muscle mechanoreflex-mediated renal vasoconstriction during muscle stretch in humans. | During exercise, muscle mechanoreflex-mediated sympathoexcitation evokes renal vasoconstriction. Animal studies suggest that prostaglandins generated within the contracting muscle sensitize muscle mechanoreflexes. Thus we hypothesized that local prostaglandin blockade would attenuate renal vasoconstriction during ischemic muscle stretch. Eleven healthy subjects performed static handgrip before and after local prostaglandin blockade (6 mg ketorolac tromethamine infused into the exercising forearm) via Bier block. Renal blood flow velocity (RBV; Duplex Ultrasound), mean arterial pressure (MAP; Finapres), and heart rate (HR; ECG) were obtained during handgrip, post-handgrip muscle ischemia (PHGMI) followed by PHGMI with passive forearm muscle stretch (PHGMI + stretch). Renal vascular resistance (RVR, calculated as MAP/RBV) was increased from baseline during all paradigms except during PHGMI + stretch after the ketorolac Bier block trial where RVR did not change from baseline. Before Bier block, RVR rose more during PHGMI + stretch than during PHGMI alone (P < .01). Similar results were found after a saline Bier block trial (Delta53 +/- 13% vs. Delta35 +/- 10%; P < 0.01). However, after ketorolac Bier block, RVR was not greater during PHGMI + stretch than during PHGMI alone [Delta39 +/- 8% vs. Delta40 +/- 12%; P = not significant (NS)]. HR and MAP responses were similar during PHGMI and PHGMI + stretch (P = NS). Passive muscle stretch during ischemia augments renal vasoconstriction, suggesting that ischemia sensitizes mechanically sensitive afferents. Inhibition of prostaglandin synthesis eliminates this mechanoreceptor sensitization-mediated constrictor responses. Thus mechanoreceptor sensitization in humans is linked to the production of prostaglandins. |
2,333,007 | Topological mapping of the asymmetric drug binding to the human ether-à-go-go-related gene product (HERG) potassium channel by use of tandem dimers. | The human ether-à-go-go related gene product (HERG) channel is essential for electrical activity of heart cells, and block of this channel by many drugs leads to lethal arrhythmias. Tyr(652) and Phe(656) of the sixth transmembrane helix are candidates for the drug binding site. In the tetrameric HERG channel, a drug with asymmetric structure should interact unevenly with multiple residues from different subunits. To elucidate the topology of the drug-binding site, we constructed tandem dimers of HERG channels and the aromatic Tyr(652) and Phe(656) residues were replaced by alanine singly or doubly. Eight types of HERG channels, including homotetrameric mutants, having different numbers and arrangements of aromatic residues at the blocking site, were studied. Effects of cisapride on channels expressed in Xenopus laevis oocytes were examined electrophysiologically. The inhibition constants (K(i)) were increased significantly as the diagonal Tyr(652) were deleted, whereas those for the diagonal Phe(656)-deleted mutant were not changed. These results suggest that Tyr(652) residues from adjacent subunits contributed to the binding. Two types of double mutants of tandem dimers showed significantly distinct affinities, suggesting that the coexistence of Tyr(652) and Phe(656) on a subunit in diagonal position is crucial to having a high affinity. Thermodynamic double-mutant cycle analyses revealed interactions between Tyr(652) and Phe(656) upon binding. The kinetics and voltage-dependence of blocking suggested transitions of the binding site from low to high affinity. These approaches using a set of mutant HERG channels gave a dynamic picture of the spatial arrangements of residues that contribute to the drug-channel interaction. |
2,333,008 | Heart block and prolonged Q-Tc interval following muscle relaxant reversal: a case report. | Heart block and Q-Tc interval prolongation have been reported with several agents used in anesthesia, and the US Food and Drug Administration mandates evaluation of the Q-T interval with new drugs. Drug-induced Q-T interval prolongation may precipitate life-threatening arrhythmias, is considered a precursor for torsades de pointes, and may predict cardiovascular complications. In the patient described in this article, heart block occurred and the Q-Tc interval became prolonged after muscle relaxant reversal with neostigmine; both were considered to be related to the combination of agents used in the case, as well as to other predisposing factors such as morbid obesity. The agents used that affected cardiac conduction were neostigmine, desflurane, droperidol, dolasetron, and dexmedetomidine. Although the heart block was resolved after 2 doses of atropine, prolonged P-R and Q-Tc intervals persisted into the immediate postoperative period but returned to baseline within 4 hours. Clinical implications of this report include increasing awareness of the multitude of factors affecting Q-T interval prolongation during anesthesia. |
2,333,009 | Thought suppression enhances memory bias for threat material. | The current study examined the impact of thought suppression on indices of anxiety, including memory indices (implicit and explicit memory biases) and physiological indices (heart rate). The participants, 81 undergraduates scoring in the top quartile of a self-report measure of trait anxiety, were randomly assigned to one of three experimental groups: thought suppression (TS), thought concentration (TC), and thought wandering (TW). The TC and TW groups were included to control for the effects of effortful processing and exposure to stimuli, respectively. One block of threat words and one block of neutral words were presented under conditions of cognitive load, and participants' physiological responses and memory biases were measured. The thought suppression group exhibited an enhanced overall memory bias for threat words, driven by an elevated explicit memory bias, relative to the other two groups, a result that has implications for ironic processes theory and may inform information-processing models of anxiety. |
2,333,010 | Hypobaric intrathecal anaesthesia for partial hemipelvectomy in a dog. | To report the intrathecal use of a hypobaric anaesthetic solution for partial hemipelvectomy in a nine-year-old, neutered female, Golden Retriever dog, weighing 34 kg.</AbstractText>Under inhalational anaesthesia, with the dog lying in lateral recumbency and the surgical side uppermost, 1.9 ml of a hypobaric solution containing 3.42 mg of bupivacaine and 0.66 mg of morphine were administered in the subarachnoid space at L5-6 level 30 minutes before surgery. Following the intrathecal injection the dog was maintained for five minutes in a 10 degrees head-down position, then for three minutes in a 10 degrees head-up position.</AbstractText>Apart from a transient increase in heart and respiratory rates during resection of the sartorius muscle, which was treated with a plasma Target Controlled Infusion (TCI) of fentanyl, spinal anaesthesia provided cardiovascular stability and excellent relaxation of the surgical site. Neither motor blockade nor proprioceptive deficit were apparent in the contra-lateral hind limb at recovery, 200 minutes after injection. Postoperatively, rescue analgesia was not required in the 48 hours following surgery.</AbstractText>In dogs, the use of intrathecal hypobaric bupivacaine and morphine as a part of a balanced anaesthetic protocol should be considered during unilateral major orthopaedic surgeries of the pelvis and hind limb, as it allowed a reduction in the dose administered compared to isobaric solutions, providing selective spinal anaesthesia, excellent long-lasting analgesia, and rapid recovery of ambulation.</AbstractText> |
2,333,011 | Intrathecal meperidine for prevention of shivering during transurethral resection of prostate. | The aim of this study was to investigate low-dose intrathecal meperidine for prevention or alleviation of shivering after induction of spinal anesthesia for transurethral resection of the prostate (TURP).</AbstractText>In a randomized controlled trial, 80 patients scheduled for TURP under spinal anesthesia were assigned into two groups of case and control. Spinal anesthesia was performed using 75 mg of hyperbaric lidocaine 5% plus meperidine, 15 mg, in the patients of the case group and the same dose of lidocaine plus normal saline in the patients of the control group. Shivering episodes were recorded during the operation and in the recovery room. Data on systolic blood pressure, heart rate, arterial oxygen saturation, and body temperature were collected before the induction of anesthesia; 5, 15, and 30 minutes after the induction; and in the recovery room.</AbstractText>Maximum level of sensory block was similar in the patients of the case and control groups. Shivering was not seen in the patients who received meperidine, while in the control group, 11 (27.5%) experienced some degrees of shivering (P = .001). Blood pressure, body temperature, and arterial oxygen saturation did not have a clinically significant change and they were not different between the two groups. Side effects of opioids were unremarkable.</AbstractText>Low-dose intrathecal meperidine is effective and safe in reducing the incidence of shivering associated with spinal anesthesia for TURP.</AbstractText> |
2,333,012 | Bootstrapped two-electrode biosignal amplifier. | Portable biomedical instrumentation has become an important part of diagnostic and treatment instrumentation. Low-voltage and low-power tendencies prevail. A two-electrode biopotential amplifier, designed for low-supply voltage (2.7-5.5 V), is presented. This biomedical amplifier design has high differential and sufficiently low common mode input impedances achieved by means of positive feedback, implemented with an original interface stage. The presented circuit makes use of passive components of popular values and tolerances. The amplifier is intended for use in various two-electrode applications, such as Holter monitors, external defibrillators, ECG monitors and other heart beat sensing biomedical devices. |
2,333,013 | Systematic, genome-wide, sex-specific linkage of cardiovascular traits in French Canadians. | The sexual dimorphism of cardiovascular traits, as well as susceptibility to a variety of related diseases, has long been recognized, yet their sex-specific genomic determinants are largely unknown. We systematically assessed the sex-specific heritability and linkage of 539 hemodynamic, metabolic, anthropometric, and humoral traits in 120 French-Canadian families from the Saguenay-Lac-St-Jean region of Quebec, Canada. We performed multipoint linkage analysis using microsatellite markers followed by peak-wide linkage scan based on Affymetrix Human Mapping 50K Array Xba240 single nucleotide polymorphism genotypes in 3 settings, including the entire sample and then separately in men and women. Nearly one half of the traits were age and sex independent, one quarter were both age and sex dependent, and one eighth were exclusively age or sex dependent. Sex-specific phenotypes are most frequent in heart rate and blood pressure categories, whereas sex- and age-independent determinants are predominant among humoral and biochemical parameters. Twenty sex-specific loci passing multiple testing criteria were corroborated by 2-point single nucleotide polymorphism linkage. Several resting systolic blood pressure measurements showed significant genotype-by-sex interaction, eg, male-specific locus at chromosome 12 (male-female logarithm of odds difference: 4.16; interaction P=0.0002), which was undetectable in the entire population, even after adjustment for sex. Detailed interrogation of this locus revealed a 220-kb block overlapping parts of TAO-kinase 3 and SUDS3 genes. In summary, a large number of complex cardiovascular traits display significant sexual dimorphism, for which we have demonstrated genomic determinants at the haplotype level. Many of these would have been missed in a traditional, sex-adjusted setting. |
2,333,014 | Loss of cortical function in mice after decapitation, cervical dislocation, potassium chloride injection, and CO2 inhalation. | Electroencephalograms (EEG) and visual evoked potentials (VEP) in mice were recorded to evaluate loss of cortical function during the first 30 s after euthanasia by various methods. Tracheal cannulae (for positive-pressure ventilation, PPV) and cortical surface electrodes were placed in mice anesthetized with inhaled halothane. Succinylcholine was used to block spontaneous breathing in the mice, which then underwent continuous EEG recording. Photic stimuli (1 Hz) were presented to produce VEPs superimposed on the EEG. Anesthesia was discontinued immediately before euthanasia. Compared with that obtained before euthanasia, EEG activity during the 30-s study period immediately after euthanasia was significantly decreased after cervical dislocation (at 5 to 10 s), 100% PPV-CO2 (at 10 to 15 s), decapitation (at 15 to 20 s), and cardiac arrest due to KCl injection (at 20 to 25 s) but not after administration of 70% PPV-CO2. Similarly, these euthanasia methods also reduced VEP amplitude, although 100% PPV-CO2 treatment affected VEP amplitude more than it did EEG activity. Thus, 100% PPV-CO2 treatment significantly decreased VEP beginning 5 to 10 s after administration, with near abolition of VEP by 30 s. VEP amplitude was significantly reduced at 5 to 10 s after cervical dislocation and at 10 to 15 s after decapitation but not after either KCl or 70% PPV-CO2 administration. The data demonstrate that 100% PPV-CO2, decapitation, and cervical dislocation lead to rapid disruption of cortical function as measured by 2 different methods. In comparison, 70% PPV-CO2 and cardiac arrest due to intracardiac KCl injection had less rapid effects on cortical function. |
2,333,015 | Novel method for selecting immunosuppressive histone deacetylase (HDAC) inhibitors with minimal thrombocytopenia. | Histone deacetylase (HDAC) inhibitors repress interleukin-2 (IL-2) gene expression in T cells and possess immunosuppressive activity in vivo. In addition to its immunosuppressive activity, HDAC inhibitors block GATA binding protein-1 (GATA-1) gene expression in megakaryocytes and elicit thrombocytopenia. In this report we state that for a given immunosuppressive dose of HDAC inhibitor, the ratio of GATA-1 reporter gene activity relative to IL-2 reporter gene assay (G/I ratio of measured IC(50)) can be predictive of a HDAC inhibitor's thrombocytopenic effect. This study utilized nine HDAC inhibitors at a minimal effective dose in a rat heterotopic cardiac transplantation model and the resultant G/I ratios and platelet depletion rates were highly correlated (r=0.933). These results indicate that calculation of G/I ratio can be a novel method for selecting immunosuppressive HDAC inhibitor having minimal thrombocytopenic effect which will benefit the search for new immunosuppressants of greater safety and efficacy. |
2,333,016 | Cardio-renal recovery of hypoxic newborn pigs after 18%, 21% and 100% reoxygenation. | We examined the effects of 18%, 21% or 100% oxygen on the recovery of the heart and kidneys in a short-term survival model of neonatal hypoxia-reoxygenation (HR).</AbstractText>Controlled, block-randomized animal study.</AbstractText>University animal research laboratory.</AbstractText>Large White piglets (1-3 days, 1.7-2.5 kg).</AbstractText>Piglets received normocapnic hypoxia (15% oxygen) (2 h) and were reoxygenated with 18%, 21% or 100% oxygen (1 h) (n=7 per group) then 21% oxygen (2 h). Sham-operated pigs (n=7) had no HR.</AbstractText>Seventeen of 21 HR piglets recovered from moderate hypoxemia (mean PaO(2) 27-33 mmHg and pH 7.20-7.22, associated with tachycardia and hypotension). Systemic arterial pressure, heart rate, left renal arterial flow, oxygen transport, plasma troponin-I and creatinine levels were monitored and recovered with no differences among HR groups over 4 days after resuscitation. The 100% group had increased myocardial oxidative stress (oxidized glutathione levels) and the most cardiac HR-induced injury. There were no differences in renal oxidative stress and HR-induced injury among groups. Early oxygenation at 1 h after resuscitation correlated with the plasma troponin-I level at 6 h (r = -0.51 and 0.64 for SaO(2) and systemic oxygen extraction ratio, p<0.05, respectively) and renal HR-induced injury at 4 days (r =0.61 for renal oxygen delivery, p<0.05).</AbstractText>In hypoxic piglets, 18%, 21% and 100% reoxygenation caused similar systemic and renal hemodynamic and functional recovery. The indicators of oxidative stress and HR injury in myocardial and renal tissues suggest that the reoxygenation with 100% oxygen appears sub-optimal and the use of 18% oxygen offers no further benefit, when compared with 21% oxygen.</AbstractText> |
2,333,017 | Intravenous clonidine infusion in infants after cardiovascular surgery.<Pagination><StartPage>217</StartPage><EndPage>222</EndPage><MedlinePgn>217-22</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1111/j.1460-9592.2008.02413.x</ELocationID><Abstract><AbstractText Label="BACKGROUND" NlmCategory="BACKGROUND">The aim of this study was to investigate the hemodynamic profile and heart rhythm in infants who were given intravenous clonidine infusion after prolonged analgesia/sedation following cardiac surgery.</AbstractText><AbstractText Label="METHODS" NlmCategory="METHODS">This is a single center retrospective review. A total of 542 cardiovascular surgical procedures in infants aged 0-24 months with congenital heart disease were performed between 01/2003 and 12/2005 at the Deutsches Herzzentrum in Berlin. The majority received no long-term analgesia/sedation, but 50 (9%) of these infants received clonidine (dosed at 0.18-3.6 microg.kg(-1).h(-1)) for sedation and to reduce withdrawal symptoms such as CNS hyperactivation, hypertension, tachycardia, and fever. The hospital records of these infants were studied.</AbstractText><AbstractText Label="RESULTS" NlmCategory="RESULTS">Fifty infants (median age 5.0 months, median body weight 5.3 kg, 32 males/18 females) received prolonged analgesia/sedation to ensure hemodynamic stability. Clonidine infusion started on day 5 (median) after surgery. During clonidine treatment we found an age-related normalized profile of hemodynamic parameters with a reduction of heart rate and mean arterial pressure from the upper norm to the mean within 24 h (P < 0.001). In no case did clonidine cause low blood pressure resulting in additional therapy to reach the target blood pressure. There were no adverse effects on cardiac rhythm, especially no onset of atrioventricular block. Midazolam, fentanyl, and other opioids could be ended on day 4 of clonidine treatment.</AbstractText><AbstractText Label="CONCLUSIONS" NlmCategory="CONCLUSIONS">Although off-label, it is feasible to use clonidine infusions in infants in the PICU setting after cardiac surgery without hemodynamic problems arising.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Pohl-Schickinger</LastName><ForeName>Anja</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Department of Neonatology, University Hospital Charité, Berlin, Germany. anja.pohl@charite.de</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lemmer</LastName><ForeName>Julia</ForeName><Initials>J</Initials></Author><Author ValidYN="Y"><LastName>Hübler</LastName><ForeName>Michael</ForeName><Initials>M</Initials></Author><Author ValidYN="Y"><LastName>Alexi-Meskishvili</LastName><ForeName>Vladimir</ForeName><Initials>V</Initials></Author><Author ValidYN="Y"><LastName>Redlin</LastName><ForeName>Matthias</ForeName><Initials>M</Initials></Author><Author ValidYN="Y"><LastName>Berger</LastName><ForeName>Felix</ForeName><Initials>F</Initials></Author><Author ValidYN="Y"><LastName>Stiller</LastName><ForeName>Brigitte</ForeName><Initials>B</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>France</Country><MedlineTA>Paediatr Anaesth</MedlineTA><NlmUniqueID>9206575</NlmUniqueID><ISSNLinking>1155-5645</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000700">Analgesics</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000701">Analgesics, Opioid</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D006993">Hypnotics and Sedatives</NameOfSubstance></Chemical><Chemical><RegistryNumber>MN3L5RMN02</RegistryNumber><NameOfSubstance UI="D003000">Clonidine</NameOfSubstance></Chemical><Chemical><RegistryNumber>R60L0SM5BC</RegistryNumber><NameOfSubstance UI="D008874">Midazolam</NameOfSubstance></Chemical><Chemical><RegistryNumber>UF599785JZ</RegistryNumber><NameOfSubstance UI="D005283">Fentanyl</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000698" MajorTopicYN="N">Analgesia</DescriptorName><QualifierName UI="Q000379" MajorTopicYN="N">methods</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000700" MajorTopicYN="N">Analgesics</DescriptorName><QualifierName UI="Q000008" MajorTopicYN="Y">administration & dosage</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000701" MajorTopicYN="N">Analgesics, Opioid</DescriptorName><QualifierName UI="Q000009" MajorTopicYN="Y">adverse effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D001794" MajorTopicYN="N">Blood Pressure</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D001831" MajorTopicYN="N">Body Temperature</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D003000" MajorTopicYN="N">Clonidine</DescriptorName><QualifierName UI="Q000008" MajorTopicYN="Y">administration & dosage</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005283" MajorTopicYN="N">Fentanyl</DescriptorName><QualifierName UI="Q000009" MajorTopicYN="N">adverse effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006330" MajorTopicYN="N">Heart Defects, Congenital</DescriptorName><QualifierName UI="Q000601" MajorTopicYN="Y">surgery</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006339" MajorTopicYN="N">Heart Rate</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006993" MajorTopicYN="N">Hypnotics and Sedatives</DescriptorName><QualifierName UI="Q000009" MajorTopicYN="Y">adverse effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D007223" MajorTopicYN="N">Infant</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D007231" MajorTopicYN="N">Infant, Newborn</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D007262" MajorTopicYN="N">Infusions, Intravenous</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008874" MajorTopicYN="N">Midazolam</DescriptorName><QualifierName UI="Q000009" MajorTopicYN="N">adverse effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D012189" MajorTopicYN="N">Retrospective Studies</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D013375" MajorTopicYN="N">Substance Withdrawal Syndrome</DescriptorName><QualifierName UI="Q000517" MajorTopicYN="Y">prevention & control</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D013997" MajorTopicYN="N">Time Factors</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D016896" MajorTopicYN="N">Treatment Outcome</DescriptorName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="pubmed"><Year>2008</Year><Month>1</Month><Day>31</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2008</Year><Month>4</Month><Day>22</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2008</Year><Month>1</Month><Day>31</Day><Hour>9</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">18230064</ArticleId><ArticleId IdType="doi">10.1111/j.1460-9592.2008.02413.x</ArticleId><ArticleId IdType="pii">PAN2413</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedArticle><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">18229701</PMID><DateCompleted><Year>2008</Year><Month>03</Month><Day>12</Day></DateCompleted><DateRevised><Year>2013</Year><Month>11</Month><Day>21</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Print">2335-6928</ISSN><JournalIssue CitedMedium="Print"><PubDate><Year>2008</Year></PubDate></JournalIssue><Title>Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing</Title><ISOAbbreviation>Pac Symp Biocomput</ISOAbbreviation></Journal>Modeling ventricular interaction: a multiscale approach from sarcomere mechanics to cardiovascular system hemodynamics. | Direct ventricular interaction via the interventricular septum plays an important role in ventricular hemodynamics and mechanics. A large amount of experimental data demonstrates that left and right ventricular pump mechanics influence each other and that septal geometry and motion depend on transmural pressure. We present a lumped model of ventricular mechanics consisting of three wall segments that are coupled on the basis of balance laws stating mechanical equilibrium at the intersection of the three walls. The input consists of left and right ventricular volumes and an estimate of septal wall geometry. Wall segment geometry is expressed as area and curvature and is related to sarcomere extension. With constitutive equations of the sarcomere, myofiber stress is calculated. The force exerted by each wall segment on the intersection, as a result of wall tension, is derived from myofiber stress. Finally, septal geometry and ventricular pressures are solved by achieving balance of forces. We implemented this ventricular module in a lumped model of the closed-loop cardiovascular system (CircAdapt model) The resulting multiscale model enables dynamic simulation of myofiber mechanics, ventricular cavity mechanics, and cardiovascular system hemodynamics. The model was tested by performing simulations with synchronous and asynchronous mechanical activation of the wall segments. The simulated results of ventricular mechanics and hemodynamics were compared with experimental data obtained before and after acute induction of left bundle branch block (LBBB) in dogs. The changes in simulated ventricular mechanics and septal motion as a result of the introduction of mechanical asynchrony were very similar to those measured in the animal experiments. In conclusion, the module presented describes ventricular mechanics including direct ventricular interaction realistically and thereby extends the physiological application range of the CircAdapt model. |
2,333,018 | Adenosine modulates cardiovascular functions through activation of extracellular signal-regulated kinases 1 and 2 and endothelial nitric oxide synthase in the nucleus tractus solitarii of rats. | The nucleus tractus solitarius (NTS) is the primary integrative center for baroreflex. Adenosine has been shown to play an important modulatory role in blood pressure control in the NTS. Our previous results demonstrated that adenosine decreases blood pressure, heart rate, and renal sympathetic nerve activity and modulates baroreflex responses in the NTS. We also demonstrated that a nitric oxide synthase (NOS) inhibitor may block the cardiovascular effects of adenosine in the NTS, which suggests interaction between the adenosine receptor and NOS. However, the signaling mechanisms of adenosine that induce nitric oxide release in the NTS remain uncertain. The aim of the present study was to investigate the possible signal pathways involved in the cardiovascular regulation of adenosine in the NTS.</AbstractText>Adenosine was microinjected into the NTS of urethane-anesthetized male Sprague-Dawley rats. Blood pressure and heart rate decreased significantly after microinjection. The cardiovascular effects of adenosine were attenuated by prior administration of the mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor PD98059 (6 nmol/60 nL) or an endothelial NOS-selective inhibitor, L-NIO (6 nmol/60 nL); however, the neuronal NOS-specific inhibitor vinyl-L-NIO (600 pmol/60 nL) did not attenuate the cardiovascular effects of adenosine. Western blot and immunohistochemistry studies demonstrated that adenosine induced extracellular signal-regulated kinases 1 and 2 and endothelial NOS phosphorylation in the NTS. Pretreatment with PD98059 diminished the endothelial NOS phosphorylation evoked by adenosine.</AbstractText>These results represent a novel finding that extracellular signal-regulated kinases 1 and 2 is involved in cardiovascular regulation in the NTS. They also indicate that the cardiovascular modulatory effects of adenosine in the NTS are accomplished by activation of mitogen-activated protein kinase/extracellular signal-regulated kinases 1 and 2 and then endothelial NOS.</AbstractText> |
2,333,019 | HSP72 protects against obesity-induced insulin resistance. | Patients with type 2 diabetes have reduced gene expression of heat shock protein (HSP) 72, which correlates with reduced insulin sensitivity. Heat therapy, which activates HSP72, improves clinical parameters in these patients. Activation of several inflammatory signaling proteins such as c-jun amino terminal kinase (JNK), inhibitor of kappaB kinase, and tumor necrosis factor-alpha, can induce insulin resistance, but HSP 72 can block the induction of these molecules in vitro. Accordingly, we examined whether activation of HSP72 can protect against the development of insulin resistance. First, we show that obese, insulin resistant humans have reduced HSP72 protein expression and increased JNK phosphorylation in skeletal muscle. We next used heat shock therapy, transgenic overexpression, and pharmacologic means to overexpress HSP72 either specifically in skeletal muscle or globally in mice. Herein, we show that regardless of the means used to achieve an elevation in HSP72 protein, protection against diet- or obesity-induced hyperglycemia, hyperinsulinemia, glucose intolerance, and insulin resistance was observed. This protection was tightly associated with the prevention of JNK phosphorylation. These findings identify an essential role for HSP72 in blocking inflammation and preventing insulin resistance in the context of genetic obesity or high-fat feeding. |
2,333,020 | Cold virus fusion or stopping fusion cold--inhibitors of the human respiratory syncytial virus F protein. | Human respiratory syncytial virus (HRSV) is a major respiratory viral pathogen causing moderate to severe upper and lower respiratory tract infections in all ages and across a wide range of patient populations. There are no currently approved vaccines and although a number of candidates are in various stages of development, the challenges are quite substantial. Presently, only a single agent is approved for HRSV prophylaxis, and therapeutic treatment options are severely limited and ineffective, particularly in the infant population. Antibody prophylaxis is restricted to use in populations at high-risk for hospitalization (infants under 35 weeks gestational age, infants with chronic lung disease, and infants with congenital heart disease). Aerosol administration of the guanosine analog ribavirin has been approved for the treatment of severe HRSV LRTI in both children and mechanically ventilated patients; however, there is still debate over its overall benefit and the risks associated with its use. Current therapy for those hospitalized due to HRSV is supportive. As such, there is great medical need for the development of agents to prevent and treat HRSV infections in all populations. Interestingly, many of the discovered agents against HRSV, both neutralizing antibodies and small molecules inhibitors, target the viral fusion (F) glycoprotein. In particular, three distinct chemical classes as exemplified by JNJ-2408068, VP-14637, and BMS-433771, which appear to block conformational intermediates of the viral fusion protein are reviewed. |
2,333,021 | Carbon monoxide donors or heme oxygenase-1 (HO-1) overexpression blocks interleukin-18-mediated NF-kappaB-PTEN-dependent human cardiac endothelial cell death. | The objective of this study was to determine whether heme oxygenase-1 (HO-1) or heme metabolites exert cytoprotective effects on interleukin-18-mediated endothelial cell (EC) death. Treatment with interleukin (IL)-18 increased NF-kappaB activation and PTEN induction, suppressed Akt activation, and stimulated EC death. While ectopic expression of p65 enhanced PTEN transcription, adenoviral transduction of dnIkappaB-alpha, dnp65, or dnIKKbeta was inhibitory. Furthermore, IL-18 suppressed HO-1 mRNA expression via enhanced mRNA degradation. Overexpression of HO-1, treatment with HO-1 inducer hemin, or the CO donor cobalt (III) protoporphyrin IX all reversed IL-18-mediated NF-kappaB activation, PTEN induction, Akt suppression, and EC death. Furthermore, hemin induced HO-1 expression, and HO-1 knockdown, HO-1 inhibition, or CO scavengers all reversed the prosurvival effects of hemin. In addition, the CO donors CORM-1 and CORM-3 and the heme metabolites biliverdin and bilirubin attenuated IL-18-induced EC death via a similar signaling pathway. IL-18 induced p38alpha MAPK activation, and suppressed p38beta isoform expression. While p38alpha knockdown attenuated, p38beta knockdown potentiated IL-18-mediated EC death. Hemin and HO-1 reversed IL-18-mediated p38alpha induction and restored p38beta levels. These results demonstrate that IL-18 suppresses HO-1 expression and induces EC death. HO-1 overexpression, HO-1 induction, or treatment with heme metabolites all reverse IL-18-mediated p38alpha MAPK and NF-kappaB activation, PTEN induction, Akt suppression, and EC death. Thus, HO-1 inducers and CO donors may have the therapeutic potential to effectively block IL-18 signaling and reduce IL-18-dependent vascular injury and inflammation. |
2,333,022 | Copper dependence of the biotin switch assay: modified assay for measuring cellular and blood nitrosated proteins. | Studies have shown that modification of critical cysteine residues in proteins leads to the regulation of protein function. These modifications include disulfide bond formation, glutathionylation, sulfenic and sulfinic acid formation, and S-nitrosation. The biotin switch assay was developed to specifically detect protein S-nitrosation (S. R. Jaffrey et al., Nat. Cell Biol. 3:193-197; 2001). In this assay, proteins are denatured with SDS in the presence of methyl methane thiosulfonate (MMTS) to block free thiols. After acetone precipitation or Sephadex G25 separation to remove excess MMTS, HPDP-biotin and 1 mM ascorbate are added to reduce the S-nitrosothiol bonds and label the reduced thiols with biotin. The proteins are then separated by nonreducing SDS PAGE and detected using either streptavidin-HRP or anti-biotin-HRP conjugate. Our examination of this labeling scheme has revealed that the extent of labeling depends on the buffer composition and, importantly, on the choice of metal-ion chelator (DTPA vs EDTA). Unexpectedly, using purified S-nitrosated albumin, we have found that "contaminating" copper is required for the ascorbate-dependent degradation of S-nitrosothiol; this is consistent with the fact that ascorbate itself does not rapidly reduce S-nitrosothiols. Removal of copper from buffers by DTPA and other copper chelators preserves approximately 90% of the S-nitrosothiol, whereas the inclusion of copper and ascorbate completely eliminates the S-nitrosothiol in the preparation and increases the specific biotin labeling. These biotin switch experiments were confirmed using triiodide-based and copper-based reductive chemiluminescence. Additional modifications of the assay using N-ethylmaleimide for thiol blockade, ferricyanide pretreatment to stabilize S-nitrosated hemoglobin, and cyanine dye labeling instead of biotin are presented for the measurement of cellular and blood S-nitrosothiols. These results indicate that degradation of S-nitrosothiol in the standard biotin switch assay is metal-ion dependent and that experimental variability in S-nitrosothiol yields using this assay occurs secondary to the inclusion of metal-ion chelators in reagents and variable metal-ion contamination of buffers and labware. The addition of copper to ascorbate allows for a simple assay modification that dramatically increases sensitivity while maintaining specificity. |
2,333,023 | Dexmedetomidine continuous rate infusion during isoflurane anaesthesia in canine surgical patients. | To determine the effects of three rates of dexmedetomidine (DMED) constant rate infusion (CRI) on overall tissue perfusion, isoflurane (ISO) requirements, haemodynamics and quality of recovery in canine surgical patients.</AbstractText>Prospective, randomized, blinded clinical study.</AbstractText>Client-owned dogs presented for soft tissue or orthopaedic surgery.</AbstractText>Following intravenous (IV) pre-medication with DMED (5 microg kg(-1)) and buprenorphine (10 microg kg(-1)) and propofol induction, anaesthesia was maintained with ISO in oxygen/air supplemented with a DMED CRI (1, 2 or 3 microg kg(-1) hour(-1); groups 1, 2 and 3, respectively). Ventilation was controlled in all animals using intermittent positive pressure ventilation (IPPV). Monitoring included end-tidal (ET) gases, ECG, arterial blood pressure, body temperature and sequential arterial blood gas and lactate measurements. Quality of recovery was scored after intramuscular (IM) administration of atipamezole (ATI) (12.5 microg kg(-1)). Immediate post-operative analgesia was provided with carprofen and/or buprenorphine. An analysis of variance was conducted for repeated measurements obtained during 80 minutes after first incision. Categorical data were evaluated with Chi-square analyses.</AbstractText>Arterial blood pressure remained stable and within clinically acceptable limits. Mean heart rate in group 2 was significantly lower than in group 1. The incidence of 2nd degree AV block type II was significantly higher in group 3. Mean arterial lactate concentrations remained below 2 mmol/L in all groups during the study, with a significant increase occurring during recovery compared with surgery for group 3. Mean e'ISO% was similar and <1% in all groups. Complete recovery from anaesthesia was achieved after ATI administration and was of good quality in all but three animals.</AbstractText>Dexmedetomidine CRI is a reliable and valuable adjunct to ISO anaesthesia in maintaining surgical anaesthesia in ASA I-II dogs. Data reported indicate adequate overall tissue perfusion and a low ISO requirement while enabling a smooth and rapid recovery following ATI. The DMED CRI of 1 microg kg(-1) hour(-1) following a loading dose of 5 microg kg(-1) produced the most favourable results.</AbstractText> |
2,333,024 | [Measurement of the depth of anaesthesia]. | One of the most important mandates of the anaesthesiologist is to control the depth of anaesthesia. An unsolved problem is that a straight definition of the depth of anaesthesia does not exist. Concerning this it is rational to separate hypnosis from analgesia, from muscle relaxation and from block of cardiovascular reactions. Clinical surrogate parameters such as blood pressure and heart rate are not well-suited for a valid statement about the depth of hypnosis. To answer this question the brain has become the focus of interest as the target of anaesthesia. It is possible to visualize the brain's electrical activity from anelectroencephalogram (EEG). The validity of the spontaneous EEG as an anesthetic depth monitor is limited by the multiphasic activity, especially when anaesthesia is induced (excitation) and in deep anaesthesia (burst suppression). Recently, various commercial monitoring systems have been introduced to solve this problem. These monitoring systems use different interpretations of the EEG or auditory-evoked potentials (AEP). These derived and calculated variables have no pure physiological basis. For that reason a profound knowledge of the algorithms and a validation of the monitoring systems is an indispensable prerequisite prior to their routine clinical use. For the currently available monitoring systems various studies have been reported. At this time it is important to know that the actual available monitors can only value the sedation and not the other components of anaesthesia. For example, they cannot predict if a patient will react to a painful stimulus or not. In the future it would be desirable to develop parameters which allow an estimate of the other components of anaesthesia in addition to the presently available monitoring systems to estimate sedation and muscle relaxation. These could be sensoric-evoked potentials to estimate analgesia and AEPs for the detection of awareness. |
2,333,025 | Serotonergic and noradrenergic lesions suppress the enhancing effect of maternal exercise during pregnancy on learning and memory in rat pups. | The beneficial effects of exercise on learning and memory are well documented but the effects of prenatal exposure to maternal exercise on offspring are not clear yet. Using a two-trial-per-day Morris water maze for five consecutive days, succeeded by a probe trial 2 days later we showed that maternal voluntary exercise (wheel running) by pregnant rats increased the acquisition phase of the pups' learning. Maternal forced swimming by pregnant rats increased both acquisition and retention phases of the pups' learning. Also we found that the rat pups whose mother was submitted to forced-swimming during pregnancy had significantly higher brain, liver, heart and kidney weights compared with their sedentary counterparts. On the other hand we estimated the cell number of different regions of the hippocampus in the rat pups. We found that both exercise models during pregnancy increased the cell number in cornus ammonis subregion 1 (CA1) and dentate gyrus of the hippocampus in rat pups. To determine the role that noradrenergic and serotonergic neurotransmission and N-methyl-D-aspartate (NMDA) receptors hold in mediation of the maternal exercise in offspring, we used N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), p-chloroamphetamine (PCA) and MK-801 to eliminate or block the above systems, respectively. Blocking the NMDA receptors, significantly abolished learning and memory in rat pups from all three experimental groups. Elimination of noradrenergic or serotonergic input did not significantly attenuate the learning and memory in rat pups whose mothers were sedentary, while it significantly reversed the positive effects of maternal exercise during pregnancy on rat pups' learning and memory. The presented results suggest that noradrenergic and serotonergic systems in offspring brain seem to have a crucial specific role in mediating the effects of maternal physical activity during pregnancy on rat pups' cognitive function in both models of voluntary and forced exercise. |
2,333,026 | A biochemical approach to the problem of aging: "megaproject" on membrane-penetrating ions. The first results and prospects. | Antioxidants specifically addressed to mitochondria have been studied for their ability to decelerate aging of organisms. For this purpose, a project has been established with participation of several research groups from Belozersky Institute of Physico-Chemical Biology and some other Russian research institutes as well as two groups from the USA and Sweden, with support by the "Mitotechnology" company founded by "RAInKo" company (O. V. Deripaska and Moscow State University). This paper summarizes the first results of the project and estimates its prospects. Within the framework of the project, antioxidants of a new type (SkQ) were synthesized comprising plastoquinone (an antioxidant moiety), a penetrating cation, and decane or pentane linker. Using planar bilayer phospholipid membranes, we selected SkQ derivatives with the highest penetrating ability, namely plastoquinonyl-decyl-triphenylphosphonium (SkQ1), plastoquinonyl-decyl-rhodamine 19 (SkQR1), and methylplastoquinonyl-decyl-triphenylphosphonium (SkQ3). Anti- and prooxidant properties of these substances and also of ubiquinone and ubiquinonyl-decyl-triphenylphosphonium (MitoQ) were tested on isolated mitochondria. Micromolar concentrations of cationic quinones are found to be very strong prooxidants, but in lower (sub-micromolar) concentrations they display antioxidant activity. The antioxidant activity decreases in the series SkQ1=SkQR1>SkQ3>MitoQ, so the window between the anti- and prooxidant effects is smallest for MitoQ. SkQ1 is rapidly reduced by complexes I and II of the mitochondrial respiratory chain, i.e. it is a rechargeable antioxidant. Extremely low concentrations of SkQ1 and SkQR1 completely arrest the H2O2-induced apoptosis in human fibroblasts and HeLa cells (for SkQ1 C1/2=1.10(-9) M). Higher concentrations of SkQ are required to block necrosis initiated by reactive oxygen species (ROS). In mice, SkQ1 decelerates the development of three types of accelerated aging (progeria) and also of normal aging, and this effect is especially demonstrative at early stages of aging. The same pattern is shown in invertebrates (drosophila and daphnia). In mammals, the effect of SkQs on aging is accompanied by inhibition of development of such age-related diseases as osteoporosis, involution of thymus, cataract, retinopathy, etc. SkQ1 manifests a strong therapeutic action on some already developed retinopathies, in particular, congenital retinal dysplasia. With drops containing 250 nM SkQ1, vision is recovered in 50 of 66 animals who became blind because of retinopathy. SkQ1-containing drops instilled in the early stage of the disease prevent the loss of sight in rabbits with experimental uveitis and restore vision to animals that had already become blind. A favorable effect is also achieved in experimental glaucoma in rabbits. Moreover, the pretreatment of rats with 0.2 nmol SkQ1 per kg body weight significantly decreases the H2O2-induced arrhythmia of the isolated heart. SkQ1 strongly reduces the damaged area in myocardial infarction or stroke and prevents the death of animals from kidney infarction. In p53-/- mice, SkQ1 decreases the ROS level in the spleen cells and inhibits appearance of lymphomas which are the main cause of death of such animals. Thus, it seems reasonable to perform clinical testing of SkQ preparations as promising drugs for treatment of age-related and some other severe diseases of human and animals. |
2,333,027 | Effects of aging on beef chuck and loin muscles enhanced with ammonium hydroxide and salt. | The objective of this study was to determine whether aging would alter the beneficial effects (tenderness, juiciness, and flavor) of enhancing beef chuck and round steaks with a 20% solution of water, ammonium hydroxide, salt, and carbon monoxide. A randomized, complete block design was used, with 2 treatments [0% (control) and 20% (pump)], 3 aging periods (1, 2, and 3 wk), 3 muscles (M. triceps brachii from the clod heart, M. biceps femoris from the sirloin cap, and M. rectus femoris from the knuckle), and 3 replications. There were a total of 12 subprimals per treatment per aging period (n = 72 each). Individual steaks were cut to a thickness of 2.54 cm and packaged in a high-oxygen modified-atmosphere package (80% oxygen, 20% carbon dioxide). At the end of the aging period, steaks were vacuum packaged and frozen. Steaks were used to determine Warner-Bratzler shear force (WBS) and consumer sensory ratings. For all muscles, WBS values were lower for pump steaks than control at every aging period (P < 0.050). In addition, as aging period increased, WBS values for all steaks increased. Consumer taste panels revealed more desirability for tenderness, juiciness, flavor, and overall acceptability for pump steaks than control steaks. In addition, steaks aged for 1 d were more desirable than steaks aged for 7 and 14 d (P < 0.050). These data indicate that aging does not decrease the benefits (tenderness, juiciness, and flavor) of enhancement. |
2,333,028 | Individual heterogeneity in platelet response to lysophosphatidic acid: evidence for a novel inhibitory pathway. | The bioactive lipid lysophosphatidic acid (LPA) stimulates platelet actin reorganization, adhesion, shape change, and aggregation. LPA is present in blood and exposure or release of LPA after atherosclerotic plaque rupture has been proposed to trigger platelet thrombus formation.</AbstractText>In this report, we characterize heterogeneity in LPA responses among individuals. Platelets isolated from approximately 20% of healthy donors consistently failed to aggregate in response to LPA. Our studies indicate that, rather than lacking stimulatory pathways, platelets from "nonresponsive" donors respond to LPA by triggering inhibitory pathway(s) to block platelet aggregation. Consistent with this observation, LPA-induced aggregation could be partially restored to "nonresponsive" platelets by pharmacological inhibition of cAMP generation. LPA "nonresponsiveness" may be related to heightened platelet expression of LPA receptor 4 and PPARgamma. Among 70 patients with stable coronary artery disease (CAD), only 1 (1.4%) was identified as an LPA nonresponder. Moreover, in 33 patients presenting for diagnostic catheterization, CAD was identified as having a bivariate association with platelet LPA responder/nonresponder status.</AbstractText>Platelet LPA signaling may involve stimulatory and inhibitory pathways, with the inhibitory pathway predominating in approximately 20% of individuals. Diseases such as CAD that affect platelet reactivity may attenuate this inhibitory pathway in platelets.</AbstractText> |
2,333,029 | Hydrogen sulphide in the hypothalamus causes an ATP-sensitive K+ channel-dependent decrease in blood pressure in freely moving rats. | Hydrogen sulfide (H2S) is a naturally occurring gas that may act as an endogenous signaling molecule. In the brain, H2S is mainly produced by cystathionine beta-synthase (CBS) and its cellular effects have been attributed to interactions with N-methyl-D-aspartate (NMDA) receptors and cyclic adenosine 3',5'-monophosphate (cAMP). In contrast, direct vasodilator actions of H2S are most probably mediated by opening smooth muscle ATP-sensitive K+ (K(ATP)) channels. In the hypothalamus, K(ATP) channel-dependent mechanisms are involved in CNS-mediated regulation of blood pressure. In this report, we investigated the hypothesis that H2S may act via K(ATP) channels in the hypothalamus to regulate blood pressure. Mean arterial blood pressure (MAP) and heart rate were monitored in freely moving rats via a pressure transducer placed in the femoral artery. Drugs were infused via a cannula placed in the posterior hypothalamus. Infusion of 200 microM sodium hydrogen sulfide (NaHS), an H2S donor, into the hypothalamus of freely moving rats reduced MAP and heart rate. Infusion of 300 nM to 3 microM gliclazide dose-dependently blocked the effect of 200 microM NaHS. Infusion of the CBS activator, s-adenosyl-L-methionine (0.1 mM and 1 mM), likewise decreased MAP. Infusion of the CBS inhibitors aminooxyacetic acid (10 mM) and hydroxylamine (20 mM) increased MAP but did not block the effects of infusion of 200 microM NaHS. These data indicate that actions of H2S in the hypothalamus decrease blood pressure and heart rate in freely moving rats. This effect appears to be mediated by a K(ATP) channel-dependent mechanism and mimicked by endogenous H2S. |
2,333,030 | Quality assurance for interventional pain management procedures in private practice. | A recent study has indicated that quality assurance for interventional pain management procedures (IPMPs) can be achieved in university pain clinics. However, the issue of quality assurance for IPMPs in private practice has not yet been addressed.</AbstractText>This study was designed to monitor the quality of IPMPs in a private pain practice in north Florida.</AbstractText>From November 2005 to July 2006, we monitored the quality of IPMPs in a private pain practice in north Florida. Questionnaires regarding degree of pain relief, patient satisfaction, and complications were handed to patients immediately after the completion of each IPMP. Follow-up phone calls were also made to patients 1 day after the IPMPs.</AbstractText>A total of 771 (male: 249, female: 522) patients with a mean age of 58.1 years participated in the study. Office-based IPMPs included lumbar and cervical epidural steroid injections, lumbar and cervical facet joint blocks, selective nerve root blocks, lumbar and cervical sympathetic nerve blocks, sacroiliac joint injection, and large joint injections. Seven-hundred patients (90.8%) reported various degrees of pain relief immediately following IPMPs. Average pain score decreased by 4.3 on a 0 to 10 scale (p=<0.001). Number needed to be treated (NNT) to reach 50% or more pain relief immediately after IPMPs was 1.4. Six-hundred ninety-two (89.7%) patients were satisfied or very satisfied with the results of IPMPs. Sixty-two patients (8%) developed headaches after IPMPs, which lasted from 30 minutes to 4 days. None of these patients required a blood patch. Five patients developed moderate vasovagal responses during IPMPs, in which their heart rates decreased to <45/min, BP <90/60mmHg. The IPMPs were aborted immediately. All of these patients recovered uneventfully within a few minutes. No other serious adverse events were reported.</AbstractText>The results of the current study suggest that high quality private interventional pain programs with high efficacy, high patient satisfaction, and low complication rates can be achieved through appropriate staff training, proper monitoring of patients during IPMPs, and adequate handling of patients after the IPMPs.</AbstractText> |
2,333,031 | Male erectile dysfunction and cardiovascular disease: is there an intimate nexus? | Various studies report increased risk of erectile dysfunction (ED) in men with cardiovascular (CV) disease and postulate an intimate nexus between the two conditions.</AbstractText>To examine the association of ED with CV risk factors and disease in a population-based cross-sectional observational study conducted in Western Australia (WA). Method. Postal questionnaires were sent to randomly selected age-stratified male population samples obtained from the WA Electoral Roll.</AbstractText>In addition to items covering sociodemographic and self-reported clinical information, the 5-item International Index of Erectile Function (IIEF-5) was used.</AbstractText>Of the 1,580 participants, the ages of 1,514 were known and ranged from 20 to 99 years (mean 57.9, median 59.1, standard deviation 18.5). CV risk factors and disease were more prevalent with increasing age and among participants with ED and severe ED. The age-adjusted odds of ED were significantly higher among participants with hypertension (odds ratio [OR] 1.47; 95% confidence intervals [CI] 1.05, 2.07), ischemic heart disease (OR 1.80; 95% CI 1.10, 2.94), and stroke (OR 3.30; 95% CI 1.22, 8.88), and with these conditions and peripheral arterial disease grouped together as CV disease (OR 1.85; 95% CI 1.34, 2.56). Many participants with hyperlipidemia were receiving treatment, and the age-adjusted odds for ED were not significantly higher. The age-adjusted odds of ED among participants with diabetes mellitus were 2.76 (95% CI 1.52, 5.00), and were 3.21 (95% CI 1.03, 10.05) when hypertension and hyperlipidemia were also present.</AbstractText>The findings support the postulated intimate nexus between ED and CV disease. The adverse effects of age and CV risk factors and disease on erectile function compound each other. The socioeconomic, epidemiologic, and clinical implications are immense.</AbstractText> |
2,333,032 | A unilateral sympathetic blockade does not affect stress-related pain and muscle activity in patients with chronic musculoskeletal pain. | Chronic musculoskeletal pain is often exacerbated by mental and social stress. The association between stress and musculoskeletal pain is potentially mediated by peripheral sympathetic nerves, either directly or indirectly through muscle activity. In the present study we wanted to determine whether sympathetic blockade could affect either the pain or the muscular activity experienced during mental stress in patients with chronic musculoskeletal pain.</AbstractText>We performed a unilateral anaesthetic blockade of the lower cervical sympathetic ganglion (ganglion stellatum) in 18 patients with chronic musculoskeletal pain (10 with fibromyalgia and eight with chronic shoulder/neck pain). After the blockade the patients performed a 60-minute stressful task with low-grade mental stress that has induced pain and muscle activity in earlier experiments. Surface electromyography (SEMG) of the forehead, temples, neck, and shoulders, and heart rate and blood pressure were recorded together with ratings of pain.</AbstractText>We did not find any side or sidextime effect for pain or muscular activity in any of the four muscle groups (p>0.12).</AbstractText>We investigated the potential involvement of peripheral sympathetic nerves in stress-related musculoskeletal pain. A peripheral sympathetic block did not affect pain and muscle responses to a stressful task. Other explanatory models should be implemented and tested experimentally to further investigate the clinical impression that mental stress exacerbates pain in patients with chronic musculoskeletal pain.</AbstractText> |
2,333,033 | fMRI study of pain reaction in the brain under state of "Qigong". | In this study, 4 male Qigong masters (aged 60 +/- 12) who had Qigong practicing experience for more than 30 years were tested. By using the technique of fMRI, the change of brain function under the state of Qigong was observed through the peripheral pain stimulation generated by potassium penetrating method. The fMRI examination was running on a GE signa VH/3.0 T MRI machine and block design was used. The test was repeated several times, which was carried out before and 15 min after Qigong practicing. The heart and respiration rate of these 4 Qigong masters were monitored during the whole test. SPM2 was used for the data analysis, and the result showed that before Qigong practicing, besides SI and SII-insula regions, many other Brodmann areas, the cigulate cortex, the thalamus, and the cerebellum were all activated, while 15 min after that, the activated areas were decreased obviously, which were mainly at the SII-insula region and some other Brodmann areas. Since the SII-insula region was activated in both of these two states, further analysis of the response curve was focused on it. Its response amplitude under the state of Qigong (3.5%) was greater than that before Qigong (1.2%). Our result indicated that the main manifestation of brain functional change under Qigong was functional suppressing, but in some particular regions such as SII-insula region in our study, the response amplitude was increased. Further study of the exact physiological mechanism of Qigong is needed. |
2,333,034 | Remifentanil versus remifentanil with paracervical block on plasma remifentanil concentrations and pulmonary function tests for transvaginal ultrasound-guided oocyte retrieval. | The aim of this study is to compare plasma remifentanil concentrations and pulmonary function tests in subjects receiving remifentanil infusion (RI) versus RI with paracervical block (PCB) during transvaginal ultrasound-guided oocyte retrieval (TUGOR).</AbstractText>Prospective, randomized.</AbstractText>Assisted Conception Unit.</AbstractText>Forty American Society ofAnesthesiologists I subjects requiring TUGOR.</AbstractText>After ovarian hyperstimulation, subjects were randomly allocated into two groups to receive either RI (Group RI, n = 20) or RI with PCB (Group RI + PCB, n = 20).</AbstractText>Heart rate (HR), mean arterial pressure (MAP), peripheral oxygen saturation (SpO2), end tidal carbon dioxide (ETCO2) tension, forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC), and amount of remifentanil used were collected. Plasma remifentanil concentrations were calculated with STANPUMP software.</AbstractText>HR, MAP, ETCO2, SpO2, FEV1, and FVC did not differ between the groups. Total amount of remifentanil used were 486 +/- 1.81 microg and 321 +/- 0.87 microg in groups RI and RI + PCB, respectively, (p < 0.05). In Group RI, plasma remifentanil concentrations were 4.7 ng mL(-1) and 4.2 ng mL(-1) during the second transvaginal puncture, and at the end of TUGOR, respectively, whereas corresponding plasma remifentanil concentrations were 3.1 ng mL(-1) and 2.6 ng mL(-1) in Group RI + PCB (p < 0.05).</AbstractText>Both anesthesia regimens provided satisfactory analgesia without affecting FEV1 and FVC, but significantly higher plasma remifentanil concentrations were calculated when only RI was used as an anesthetic technique.</AbstractText> |
2,333,035 | Evaluation of caudal anesthesia performed in conscious infants for lower abdominal surgeries. | To assess the tolerance and efficiency of caudal anesthesia in infants undergoing lower abdominal surgery.</AbstractText>Thirty-five infants aged 2-13 weeks with a median gestational age of 35 weeks, were given single dose caudal epidural anesthesia (with bupivacaine) without sedation. This group of babies was treated at the Tabriz Children General Hospital between December 2006 and March 2007. We evaluated patients` analgesia (Beclere pain scale), blood pressure, heart rate changes, and apnea during the 24-hour postoperative period. Each patient was self-compared by Run test.</AbstractText>Three patients had pain requiring induction of general anesthesia. Out of 35 cases, 23 patients had non-significant changes in heart rate, 20 patients had non-significant changes in systolic blood pressure, and 17 patients had non-significant changes in diastolic blood pressure. None of the patients experienced apnea. Four patients required postoperative analgesic support for 2 hours, 2 patients for 3.5 hours, and 9 patients for 4 hours.</AbstractText>The present study shows that single dose caudal block can be used successfully in conscious babies for minor lower abdominal surgery, and may also facilitate postoperative pain management.</AbstractText> |
2,333,036 | Preoperative gabapentin: the effect on ropivacaine subarachnoid block and hemodynamics. | Gabapentin is an adjuvant analgesic and may enhance the spread of subarachnoid block. We investigated the effects of pretreatment with gabapentin on subarachnoid block characteristics and hemodynamics.</AbstractText>Seventy patients undergoing transurethral procedures under subarachnoid anesthesia with 2.2 mL of 0.75% ropivacaine were randomly assigned to receive preoperatively 400 mg of gabapentin 6 hourly, up to a total dose of 1200 mg, or placebo. Sensory and motor blocks were assessed every 30 min until regression of sensory block to L4. At the same time intervals, systolic and diastolic arterial blood pressures and heart rate were recorded.</AbstractText>There were no differences between groups in the sensory block levels or degree of motor block. Sensory block 150 min after the subarachnoid injection had regressed to L4 in 26 of 32 patients in the gabapentin group and in 25 of the 33 patients in the control group. Systolic arterial blood pressure was decreased in the gabapentin group (P = 0.002 for the main effect of group, and P = 0.03 at 60 min between the groups). The diastolic arterial blood pressure did not differ between the groups, but overall, the heart rate was more rapid in the gabapentin group (P = 0.002, but only for baseline values between the groups, P = 0.036).</AbstractText>Pretreatment with gabapentin had no effect on the spread of sensory block or the regression of motor block but was associated with lower systolic arterial blood pressure values in patients undergoing subarachnoid anesthesia with ropivacaine.</AbstractText> |
2,333,037 | An evaluation of natural (RRR-alpha-tocopheryl acetate) and synthetic (all-rac-alpha-tocopheryl acetate) vitamin E fortification in the diet or drinking water of weanling pigs. | Three experiments conducted with weanling pigs evaluated the effects of vitamin E added to the drinking water or diet on plasma and tissue alpha-tocopherol concentrations. When natural or synthetic vitamin E was used, it was added at an IU-equivalent basis, but natural vitamin E was 73.5% (mg basis) of the synthetic vitamin E. Experiment 1 used 18-d-old weanling pigs (n = 120) in a 3 x 2 factorial arrangement of treatments in a randomized complete block design with 4 replicates. The first factor evaluated the dietary levels of natural vitamin E (RRR-alpha-tocopheryl acetate) added at 0, 50, or 300 IU/kg, whereas the second factor was the natural vitamin E added to the drinking water at 0 or 100 IU/L. Pigs were bled at periodic intervals, and 1 pig per pen was killed at the end of the 21-d trial and tissues (liver, heart, lung, and loin) were collected for alpha-tocopherol analysis. When vitamin E was not added to the diet or water, plasma alpha-tocopherol declined over the 21-d period. Although there were some interactions (P < 0.01), tissue and plasma alpha-tocopherol concentrations increased linearly when vitamin E was added to the diet or water. Experiment 2 was a 3 x 2 factorial in a randomized complete block design with 4 replicates. A total of 96 pigs weaned at 18 d of age, with an initial BW of 6.2 kg, were fed a nonvitamin E fortified diet, but natural or synthetic (all-rac-alpha-tocopheryl acetate) vitamin E was added to their drinking water at 50, 100, or 150 IU/L. Pigs were bled at 0, 3, 7, 10, 14, and 21 d postweaning, with tissues (liver, lung, heart, and loin) collected for alpha-tocopherol analysis at d 21. The results indicated that plasma alpha-tocopherol concentrations increased (P < 0.01) as vitamin E increased, with greater tissue alpha-tocopherol concentrations (P < 0.01) when natural vitamin E was provided. Experiment 3 was conducted in 2 replicates, but pigs (n = 60) were not provided vitamin E in the diet or water for 7 d postweaning, and then natural or synthetic vitamin E was added to the drinking water as in Exp. 2 (50, 100, or 150 IU/L). Pigs were bled at 0, 2, 4, 6, 8, 10, and 24 h after being provided vitamin E to evaluate the absorption from each vitamin E source and level. Plasma alpha-tocopherol increased quadratically (P < 0.01) and plateaued at 8 to 10 h for each treatment group. These results indicate that adding vitamin E to the pig's water supply at weaning was more effective in increasing plasma alpha-tocopherol than when it was added to the diet during the initial 14 d postweaning, and that natural vitamin E was a superior source compared with synthetic vitamin E. |
2,333,038 | Comparison of the hemodynamic effects of a single 5 mg/kg dose of lidocaine with or without epinephrine for thoracic paravertebral block. | Epinephrine is often added to local anesthetic solutions to minimize and slow the systemic absorption of local anesthetics, and thus reduce the possibility of adverse effects of these drugs. In an earlier study we found that the injection of 5 mg/kg of lidocaine via the paravertebral route depressed myocardial contractility by up to 30%, with practically no changes in heart rate or blood pressure. In the present study we investigated whether these alterations are due to systemic absorption of the local anesthetic, and whether such absorption can be minimized by adding epinephrine to the local anesthetic solution.</AbstractText>A prospective, blind, and randomized study was made of 50 patients subjected to lung resection surgery. The subjects were divided into two groups: Lid group (5 mg/kg bolus dose of lidocaine in the thoracic paravertebral space) and Lid+E group (addition of 5 mcg/mL of epinephrine to the local anesthetic). The anesthetic solution was administered through a paravertebral catheter ipsilateral to the operative side. In addition to routine hemodynamic monitoring (heart rate and radial artery blood pressure), an aortic transpulmonary thermodilution catheter was inserted into the femoral artery for recording of the following variables: cardiac index, cardiac function index, maximum pressure derivative, global end diastolic volume, and intrathoracic total blood volume index. Data collection was carried out immediately before administration of the anesthetic solution and 15, 30, and 45 minutes after administration. Measurements were made of the plasma lidocaine levels at those same postparavertebral injection time points.</AbstractText>Prior to paravertebral dosing there were no differences in terms of the hemodynamic variables studied. However, 15 minutes after dosing in the Lid+E group, lesser reductions in contractility, cardiac function index, and cardiac index were recorded, compared with the Lid group, with a significant reduction in cardiac filling volumes. Blood lidocaine levels were 53% and 34% lower in Lid+E group, as recorded 15 and 30 minutes after injection. The patients who, 15 minutes after paravertebral injection, had blood lidocaine levels greater than 3 mcg/mL (independently of the type of anesthetic solution used) had a significant reduction in mean blood pressure, cardiac function index, cardiac index, and maximum pressure derivative, compared with the patients with lower blood lidocaine concentrations.</AbstractText>Addition of epinephrine to lidocaine when performing thoracic paravertebral block, attenuates the cardiodepressive effects associated with the systemic absorption of lidocaine and also, as a result of the beta-adrenergic consequences of epinephrine, systemic absorption from the paravertebral space.</AbstractText> |
2,333,039 | The efficacy and neurotoxicity of dexmedetomidine administered via the epidural route. | alpha(2)-Adrenoceptor agonists administered into the intrathecal and epidural space have been found to be effective in the treatment of chronic pain. Moreover, it was shown that they increase the analgesic effects of local anaesthetics and provide sedation, anxiolysis and haemodynamic stability. Dexmedetomidine, a potent and highly selective alpha(2)-adrenoceptor agonist, is in current clinical use, particularly in the intensive care unit. Our aim was to investigate whether dexmedetomidine produced motor and sensory blockade and neurotoxic effects when administrated via the epidural catheter in rabbits.</AbstractText>Twenty-one New Zealand white rabbits were included in the study. Animals were randomized into three groups. In Group L: lidocaine (2%), in Group LD: lidocaine (2%) + dexmedetomidine (5 microg) and in Group D: dexmedetomidine (10 microg) were administered by epidural catheter. Motor and sensory blockade were evaluated. After the evaluation of block, the animals were euthanized and their spinal cords removed for neuropathological evaluations.</AbstractText>Motor and sensory blockade were lower in Group D than in Group L and Group LD (P < 0.01). Although there were no differences between the groups for ischaemia of the medulla spinalis, evidence of demyelinization of the oligodendrocytes in the white matter in Group D was significantly higher than in Group L (P = 0.035).</AbstractText>We observed that dexmedetomidine does not have motor and sensory effects, but it may have a harmful effect on the myelin sheath when administered via the epidural route.</AbstractText> |
2,333,040 | State- and use-dependent block of muscle Nav1.4 and neuronal Nav1.7 voltage-gated Na+ channel isoforms by ranolazine. | Ranolazine is an antianginal agent that targets a number of ion channels in the heart, including cardiac voltage-gated Na(+) channels. However, ranolazine block of muscle and neuronal Na(+) channel isoforms has not been examined. We compared the state- and use-dependent ranolazine block of Na(+) currents carried by muscle Nav1.4, cardiac Nav1.5, and neuronal Nav1.7 isoforms expressed in human embryonic kidney 293T cells. Resting and inactivated block of Na(+) channels by ranolazine were generally weak, with a 50% inhibitory concentration (IC(50)) >/= 60 microM. Use-dependent block of Na(+) channel isoforms by ranolazine during repetitive pulses (+50 mV/10 ms at 5 Hz) was strong at 100 microM, up to 77% peak current reduction for Nav1.4, 67% for Nav1.5, and 83% for Nav1.7. In addition, we found conspicuous time-dependent block of inactivation-deficient Nav1.4, Nav1.5, and Nav1.7 Na(+) currents by ranolazine with estimated IC(50) values of 2.4, 6.2, and 1.7 microM, respectively. On- and off-rates of ranolazine were 8.2 microM(-1) s(-1) and 22 s(-1), respectively, for Nav1.4 open channels and 7.1 microM(-1) s(-1) and 14 s(-1), respectively, for Nav1.7 counterparts. A F1579K mutation at the local anesthetic receptor of inactivation-deficient Nav1.4 Na(+) channels reduced the potency of ranolazine approximately 17-fold. We conclude that: 1) both muscle and neuronal Na(+) channels are as sensitive to ranolazine block as their cardiac counterparts; 2) at its therapeutic plasma concentrations, ranolazine interacts predominantly with the open but not resting or inactivated Na(+) channels; and 3) ranolazine block of open Na(+) channels is via the conserved local anesthetic receptor albeit with a relatively slow on-rate. |
2,333,041 | Aprotinin reverses ECG abnormalities induced by Mesobuthus tamulus concanesis, Pocock venom in adult rats. | The kinins are implicated in the pathogenesis of scorpion envenomation. Therefore, this study was carried out to examine the involvement of kinins for the ECG abnormalities induced by M. tamulus concanesis, (BT) venom in anaesthetized rats. ECG was recorded using needle electrodes with limb lead II configuration. The PR interval, QRS wave pattern, QRS duration, ST segment and heart rate were examined in saline only, venom alone, and venom after aprotinin groups. BT venom (5 mg/kg) produced heart block of varying degree and ischemia-like changes in ECG wave pattern and the animals died within 30 min after exposure to venom. In aprotinin pretreated animals, the initial ECG changes produced by venom persisted, but after 15 min the ECG pattern improved and the animals survived for the entire period of observation (120 min). The results indicate that aprotinin protected the rats against the cardiotoxicity induced by BT venom. |
2,333,042 | AAV-mediated knockdown of phospholamban leads to improved contractility and calcium handling in cardiomyocytes. | Reduced contractility due to dysregulation of intracellular calcium (Ca(2+)) is a common pathologic feature of chronic heart failure. Calcium stores in the sarcoplasmic reticulum play a major role in regulating cardiac contractility. Several animal models of heart failure have been treated by altering the regulation of the sarcoplamic reticulum ATPase through ablation or down-regulation of its inhibitor peptide, phospholamban (PLN).</AbstractText>We have designed two small hairpin RNAs (shRNAs) to block the synthesis of PLN via RNA interference. These were tested in cell culture using a co-transfection assay and using adeno-associated virus (AAV)-mediated delivery to cardiomyocytes. Reverse-transcription polymerase chain reaction (RT-PCR) and Western blots were used to measure reduction in PLN mRNA and protein levels. Reduction of PLN was also documented by indirect immunofluorescence. Free cytosolic calcium and contractile properties of transduced cardiomyocytes was examined on fura-2-loaded cells. Direct cardiac injection was used to deliver AAV1-shRNAs to mice, and reduction of PLN was measured by indirect immunofluorescence.</AbstractText>Both siRNAs led to significant reduction of PLN RNA and protein levels in cultured cells. Down-regulation of PLN led to enhanced cell shortening and relaxation and to a decrease in the time constant of calcium decay, signs of improved contractility and calcium handling. In the hearts of AAV-infected mice, shRNA-transduced cells showed significant reduction in the level of PLN.</AbstractText>Our results suggest that AAV-delivered shRNAs mediated physiologically significant suppression of phospholamban that may be useful in combating the effects of chronic heart failure.</AbstractText> |
2,333,043 | Characterization of a novel S13F desmin mutation associated with desmin myopathy and heart block in a Chinese family. | Desmin myopathy was identified in a Chinese man with complete heart block and mild proximal and distal limb weakness. A novel heterozygous missense S13F mutation of the desmin gene was found to be associated with the myopathy. Family members carrying the mutation showed a similar or milder phenotype. The mutation is located at a protein kinase-C phosphorylation site within a highly conserved nonapeptide sequence in the head domain of the desmin protein. Expression of the mutant desmin cDNA in cell lines induced large desmin accumulations associated with preservation of a filamentous network. |
2,333,044 | Drugs and trafficking of ion channels: a new pro-arrhythmic threat on the horizon? | Tuning of functional expression levels of the ion channels that make up the cardiac action potential (AP) is crucial for preserving correct AP duration (APD) and QTc times. Many compounds inhibit human ether-à-go-go related gene (hERG)-mediated delayed rectifier currents and thus prolong cardiac repolarization that may cause life-threatening arrhythmias like Torsades de Pointes. An increasing number of drugs are found to inhibit hERG function by a dual mechanism of short-term channel block and long-term trafficking defects that operate over different time and concentration scales. In safety screens at present used by pharmaceutical companies, the short-term effect of channel block is covered. In contrast, specific screening for long-term trafficking defects is not common, with the consequent risk of drugs that disturb trafficking entering the market. Whether that poses another pro-arrhythmic threat for the patients treated has to be determined, but is not unlikely. |
2,333,045 | Iromycins from Streptomyces sp. and from synthesis: new inhibitors of the mitochondrial electron transport chain. | Two new alpha-pyridone metabolites, iromycins E and F, were isolated from cultures of strain Streptomyces sp. Dra 17, thus expanding the recently discovered iromycin family. The inhibitory potential on the mitochondrial respiratory chain was examined and revealed that iromycin metabolites block NADH oxidation in beef heart submitochondrial particles with different efficacy, yet remarkably show only very low cytotoxicity. Difference spectroscopic studies indicated that iromycins inhibit the electron transport at the site of complex I (NADH-ubiquinone oxidoreductase). Derivatives of the natural products were semisynthetically prepared and provided detailed insights into structure-activity relationships. Drawn from these results, there are strong similarities with the piericidins, which are among the most potent complex I inhibitors of the mitochondrial electron transport chain. Furthermore, total synthesis afforded new analogues, and the non-natural iromycin S (IC50 = 58 ng/mL) emerged as the most active compound, thus opening avenues of future studies with the iromycins as new valuable biochemical tools. |
2,333,046 | Intrapartum oximetry of the fetus. | Fetal monitoring during labor aims to identify fetal problems which, if uncorrected, may result in morbidity or death. A nonreassuring or abnormal fetal heart rate trace by cardiotocography (CTG) does not necessarily equate with fetal hypoxia and/or acidosis. However, in the absence of more objective data, the use of CTG often results in variable, but inappropriately high, operative delivery rates (forceps, vacuum, or cesarean delivery) for nonreassuring fetal status in many hospitals. The addition of fetal pulse oximetry (FPO) has the potential to improve the assessment of fetal well-being during labor. In this review we consider several aspects of FPO. Several factors, such as sensor to skin contact, uterine contractions, fetal hair, and caput succedaneum, influence the performance and use of FPO. Issues such as clinicians' perspectives of FPO sensor placement, maternal perspectives of FPO during labor, and an economic analysis have all favored FPO. Several randomized controlled trials (RCTs) of FPO reported a reduction in cesarean delivery for nonreassuring fetal status when FPO was added to conventional CTG monitoring, with no difference in overall cesarean delivery rates. One large RCT reported no difference in mode of birth for any indication. Several issues relevant to the future of FPO have been addressed by these RCTs, the major issue being that it makes no difference to cesarean rates. It may be argued that FPO has a valid clinical use in monitoring the fetus with congenital heart block. Additionally, in situations of nonreassuring fetal status and dystocia, FPO may provide the necessary reassurance until adequate resources for cesarean delivery are available. |
2,333,047 | Selective feticide in monoamniotic twin pregnancies by umbilical cord occlusion and transection. | In monoamniotic twin pregnancies discordant for fetal anomaly, parents may opt for selective feticide. However, the normal co-twin remains at risk of sudden demise from cord entanglement. We report on three cases of successful selective feticide by cord occlusion combined with cord transection.</AbstractText>We describe technical details and outcome of three monoamniotic twin pregnancies discordant for fetal anomaly (two cases of anencephaly and one case of congenital heart block) in which cord occlusion was followed by transection of the cord using contact laser.</AbstractText>The fetoscopic cord occlusion and transection using laser was successfully performed at 15, 16 and 19 weeks gestation, respectively. In one case, amniotic fluid leakage occurred after fetoscopy. The surviving co-twins were born at 36, 38 and 36 weeks gestation, respectively; two of the three were born vaginally and they were all healthy.</AbstractText>In monoamniotic twins, selective feticide using laser occlusion and transection of the umbilical cord is technically feasible and can lead to near-term vaginal birth of healthy co-twins.</AbstractText>Copyright 2007 S. Karger AG, Basel.</CopyrightInformation> |
2,333,048 | Analgesia for retrobulbar block--comparison of remifentanil, alfentanil and fentanyl. | The injection of retrobulbar block is associated with significant pain and discomfort. Therefore a short-acting IV analgesic before retrobulbar injection has been advocated.</AbstractText>To compare remifentanil, alfentanil and fentanyl in providing analgesia for retrobulbar block injection.</AbstractText>69 patients were enrolled randomly into three groups of 23 each to receive either Remifentanil 1 microg/kg, Alfentanil 20 microg/kg or Fentanyl 2 microg/kg as an IV bolus dose prior to retrobulbar injection. Mean arterial pressure (MAP) and heart rate (HR) were recorded and Numerical Pain Score (NPS) were assessed by a blinded observer.</AbstractText>Remifentanil prevented increase in MAP and HR while alfentanil and fentanyl were ineffective in this purpose (p < 0.05). NPS was significantly lower in remifentanil group (p < 0.05).</AbstractText>Remifentanil 1 microg/kg prior to retrobulbar injection provide excellent hemodynamic stability and ensure analgesia.</AbstractText> |
2,333,049 | A randomized controlled trial of femoral nerve blockade administered preclinically for pain relief in femoral trauma. | Analgesia at the location of the accident and on transport for femoral trauma is often delayed or insufficient. In this prospective, randomized, controlled study, we evaluated the preclinical use of femoral nerve blockade for reducing pain and anxiety compared with IV analgesia using metamizol.</AbstractText>Patients with painful femoral trauma, such as fracture or severe contusion, were randomized to receive at the site of the accident a femoral nerve blockade (n = 31) or IV analgesia with metamizol (n = 31). A visual analog scale (VAS) was used to assess pain and anxiety. Variables were assessed at baseline, during transport and upon arrival at the hospital.</AbstractText>In patients receiving the femoral nerve blockade, pain values decreased by half from VAS 86 +/- 6 mm at the site of the accident to VAS 41 +/- 15 mm during transport. Anxiety decreased by half from VAS 84 +/- 11 mm to VAS 39 +/- 14 mm. Heart rate decreased by 20 +/- 5 bpm. In the metamizol group, pain, anxiety, and heart rate did not decrease (P < 0.001). Time of treatment was 7.4 +/- 3.5 min longer in the femoral nerve blockade group.</AbstractText>Preclinically administered femoral nerve blockade effectively decreases pain, anxiety, and heart rate after femoral trauma. Regional blockade is an option for out-of-hospital analgesia administered by a trained physician.</AbstractText> |
2,333,050 | Clinical manifestations of cutaneous lupus erythematosus. | Cutaneous lupus erythematosus (CLE) is a chronic inflammatory autoimmune disease with a broad spectrum of clinical manifestations and a variable course. In numerous investigations, it has been shown that exogenous factors, such as UV-light and drugs, can induce this disease. However, not all clinical aspects can be explained and therefore, the pathogenesis of CLE is currently under extensive research. The various cutaneous manifestations of LE are divided into LE-nonspecific and LE-specific skin disease based on histologic criteria. LE-nonspecific manifestations are mostly associated with systemic LE but can also occur in other diseases and include particularly vascular skin lesions such as pe-riungual telangiectases. LE-specific skin disease includes the subtypes of CLE such as acute cutaneous LE (ACLE), subacute cutaneous LE (SCLE), chronic cutaneous LE (CCLE), and intermittent CLE (ICLE). The subdivision of these subtypes with different prognosis and course is supported by genetic, clinical, histologic, and immunoserologic findings. The subtypes of CLE require a specific morphological and clinical analysis, which is described in the first part of this review. In the second part of this review, further diagnostic procedures and therapeutic strategies in patients with CLE are discussed. |
2,333,051 | Smart and cationic poly(NIPA)/PEI block copolymers as non-viral vectors: in vitro and in vivo transfection studies. | In this study, in vitro and in vivo transfection of temperature-sensitive, polycationic poly(N-isopropylacrylamide) and polyethyleneimine copolymers (poly(NIPA)/PEI25L) were performed. Copolymer and copolymer-plasmid DNA (pDNA) complexes were positively charged as + 7.6 and + 12.8, respectively. Gel retardation assay confirmed good complex formation and release of plasmid DNA in response to temperature and pH. Cytotoxicity tests showed at least 80% smooth muscle cell (SMC) viability. The uptake of the complexes by SMCs was quite high; however, the best gene expression efficiency achieved with the copolymeric vectors was about 30% with the complex prepared with a polymer:plasmid ratio of 6. Gene expression efficiency was enhanced up to 50% by changing the temperature from 37 degrees C to 28 degrees C. Preliminary in vivo studies were performed above and below lower critical solution temperature (LCST) in lung, heart, liver, kidney, muscle and also subcutaneously in 5 week-old mice. The gene expression ratio was higher in lung, tibial muscle and subcutaneously than in other tissues (heart, liver and kidney) above LCST. Then, temperature decrease caused an increase in the amount of gene expression in tibial muscle and subcutaneously, revealing the contribution of temperature-sensitivity on DNA release and gene expression. |
2,333,052 | The effect of local anaesthesia on anaesthetic requirements for feline ovariectomy. | A dose of supplementary ketamine was used to evaluate the anaesthetic sparing effect of adding local anaesthesia to general anaesthesia in cats undergoing ovariectomy. Fifty-six healthy cats were randomly assigned to receive lidocaine 2% (group L) as skin infiltration (1 mg kg(-1)), topical application (splash block) on both the ovaries (2 mg kg(-1), each) and on abdominal muscular layers (1 mg kg(-1)), or an equal volume of NaCl 0.9% at the same sites (group S). Anaesthesia was induced with a mixture of 20 microg kg(-1) medetomidine and 5 mg kg(-1) ketamine administered intramuscularly. Rectal temperature, ECG, heart rate and respiratory rate were measured continuously. Ketamine supplemental boli (1 mg kg(-1), intravenously) were administered in response to movements during surgery. Local lidocaine significantly reduced the need for supplementary ketamine. All animals were returned to their owners without complications. With this protocol, local anaesthetics reduced the need for injectable anaesthetic during feline ovariectomy. |
2,333,053 | The ventrolateral periaqueductal gray is involved in the cardiovascular response evoked by l-glutamate microinjection into the lateral hypothalamus of anesthetized rats. | Microinjection of l-glutamate (l-glu: 1, 3, 10 and 30nmol/100nL) into the lateral hypothalamus (LH) caused dose-related depressor and bradycardiac responses. The cardiovascular response to l-glu stimulation of the LH was blocked by pretreatment of the ventrolateral portion of the periaqueductal gray matter (vlPAG) with CoCl2 (1mM/100nL), indicating the existence of a synaptic relay of the hypotensive pathway in that area. Furthermore, the response to l-glu was blocked by pretreatment of the vlPAG with 2nmol/100nL of the selective NMDA-receptor antagonist LY235959 and was not affected by pretreatment with 2nmol/100nL of the selective non-NMDA-receptor antagonist NBQX, suggesting a mediation of the hypotensive response by NMDA receptors in the vlPAG. In conclusion, our results indicate that the hypotensive pathway activated by microinjection of l-glu into the LH involves a NMDA synaptic relay in the vlPAG. |
2,333,054 | Effect of lumbar flexion on the extent of epidural blockade. | This study examined the effect of lumbar flexion on the extent of the epidural block during lumbar epidural anesthesia.</AbstractText>The epidural catheter was introduced at the L3-4 interspace with the patient in the lateral decubitus position with the surgical side down. After administering a test drug (3 mL of 2% lidocaine and 15 mug of epinephrine), the patients were randomly allocated to 1 of 2 groups: Group F (n = 16, lumbar spine flexed) and Group N (n = 17, lumbar spine in the neutral position). In both groups, 2% lidocaine (16 mL) mixed with sodium bicarbonate (2 mL) was administered through the epidural catheter while the patient maintained the lateral decubitus position with the lumbar spine either flexed or in the neutral position. All the patients maintained their respective positions for 5 minutes and were subsequently turned to the supine position. The pinprick block level and the degree of motor blockade were assessed every 10 minutes for 60 minutes after administering the local anesthetics. A 2-dermatomal difference in uppermost block between groups was determined to be clinically significant.</AbstractText>The median difference between groups in the uppermost pinprick block level was only 1.5 dermatomes and it did not satisfy our criteria for clinical significance. There were no significant differences between the 2 groups in the lowermost pinprick block level and the degree of motor block.</AbstractText>Lumbar flexion has no clinically relevant effect on sensory spread during epidural anesthesia.</AbstractText> |
2,333,055 | Measuring deterioration in international classification of functioning domains of people with multiple sclerosis who are ambulatory. | Measures to detect important effects related to physical therapy interventions must be able to detect an important change. The purpose of this study was to select the most responsive physical functioning measures for multiple sclerosis (MS) using the International Classification of Functioning, Disability and Health (ICF) as a framework.</AbstractText>The participants were 120 people with MS who were ambulatory from a population-based sample.</AbstractText>Physical functioning was assessed by quantitative clinical measures of activities (n=5) and body functions (n=7) and by self-reported performance in self-care, mobility, and domestic life domains in the activities and participation component of the ICF at baseline and 2 years later. A participant's perception of change and a change in Expanded Disability Status Scale (EDSS) scores were used as external criteria in the analysis of the receiver operating characteristic curve and the minimally important change score. The minimal detectable change was calculated as distribution-based responsiveness.</AbstractText>According to the external criteria, 51% of the participants showed deterioration as measured by their own perceptions compared with the 26% of the participants who showed deterioration as rated by the clinician. Regardless of the external criterion applied, the measures most responsive to deterioration were self-reported scores in self-care, mobility, and domestic life; distance walked and change in heart rate during a 6-minute walk test; 10-m walk test speeds, stride length, and cadence; repetitive squatting; and Box and Block Test scores.</AbstractText>The results show the relative responsiveness of different measures in the subsample who deteriorated and provide data that can facilitate the interpretation of score changes in people with MS who are ambulatory for future studies and in clinical practice.</AbstractText> |
2,333,056 | Enforced epithelial expression of IGF-1 causes hyperplastic prostate growth while negative selection is requisite for spontaneous metastogenesis. | The insulin-like growth factor-1 (IGF-1) signaling axis is important for cell growth, differentiation and survival and increased serum IGF is a risk factor for prostate and other cancers. To study IGF-1 action on the prostate, we created transgenic (PB-Des) mice that specifically express human IGF-1(des) in prostate epithelial cells. This encodes a mature isoform of IGF-1 with decreased affinity for IGF binding proteins (IGFBP) due to a 3-amino acid deletion in the N terminus. Expression of IGF-1(des) was sufficient to cause hyperplastic lesions in all mice, however the well-differentiated lesions did not progress to adenocarcinoma within a year. Remarkably, crossing the PB-Des mice to an established model of prostate cancer delayed progression of organ-confined tumors and emergence of metastatic lesions in young mice. While dissemination of metastatic lesions was widespread in old bigenic mice we did not detect IGF-1(des) in poorly differentiated primary tumors or metastatic lesions. Expression of endogenous IGF-1 and levels of P-Akt and P-Erk were reduced independent of age. These data suggest that increased physiologic levels of IGF-1 facilitate the emergence of hyperplastic lesions while imposing a strong IGF-1-dependent differentiation block. Selection against IGF-1 action appears requisite for progression of localized disease and metastogenesis. |
2,333,057 | Pharmacokinetic interaction between voriconazole and efavirenz at steady state in healthy male subjects. | A randomized, placebo-controlled (with respect to voriconazole), 2-period, multiple-dose intragroup fixed-dose sequence study was conducted in 34 healthy male subjects to evaluate the interactions between voriconazole (triazole antifungal agent) and efavirenz (reverse transcriptase inhibitor). In period 1, subjects received 200 mg twice-daily (bid) voriconazole (n = 17) or placebo (n = 17) for 3 days (400-mg bid loading doses on day 1). In period 2, following a 7-day washout, subjects received 400 mg once-daily (qd) efavirenz alone for 10 days (days 11-20). Then efavirenz was coadministered with 200 mg bid voriconazole or placebo for the next 9 days (days 21-29). Serial plasma voriconazole and efavirenz concentrations were measured on days 3, 19, and 29, and the safety data were collected throughout the study. The 400-mg qd efavirenz dose substantially reduced the steady-state mean voriconazole area under the curve over the dosing interval (AUC0-12) by 80% (90% confidence interval [CI], 75%-84%) and peak concentration (Cmax) by 66% (90% CI, 57%-73%). The decrease in voriconazole exposure during coadministration is probably mainly due to the induction of CYP2C19 and CYP2C9 by efavirenz. The 200 mg bid voriconazole increased the steady-state mean AUC0-24 and Cmax of efavirenz by 43% (90% CI, 36%-51%) and 37% (90% CI, 29%-46%), respectively. The increase in efavirenz exposure during coadministration is probably due to the inhibition of CYP3A4 by voriconazole. Coadministration of 200 mg bid voriconazole with 400 mg (or higher) qd efavirenz is contraindicated due to the clinically significant effect of efavirenz on voriconazole pharmacokinetics. |
2,333,058 | Coronary flow regulation in mouse heart during hypercapnic acidosis: role of NO and its compensation during eNOS impairment. | This study addressed the hypotheses that the hypercapnic flow response in wild-type (WT) mouse heart is mainly mediated by nitric oxide (NO) and, thus, severely blunted in endothelial nitric oxide synthase knockout (eNOS-KO) mice and in WT mice after continuous pharmacological block (2 weeks) of NOS enzymes (WT-LN).</AbstractText>Step changes of arterial pCO(2) were performed in isolated perfused hearts (n = 105). Contributions of NOS (L-NAME, TRIM), cyclooxygenase (indomethacin), epoxyeicosanotrienes (miconazole), adenosine A2A-receptors (SCH 58261), KV-channels (4-AP), KCa-channels (TEA), and K ATP-channels (glibenclamide) were studied in WT and eNOS-KO mouse hearts. Change of arterial pCO(2) increased coronary flow by 31.3 +/- 4% in WT, a response that was significantly decreased to 9.2 +/- 6% after L-NAME. Additional glibenclamide infusion (n = 5) completely abolished the steady-state flow increase during hypercapnic acidosis (-4.2 +/- 2.3%, P = 0.004 vs. control). Hearts from eNOS-KO mice as well as WT-LN showed a fully preserved flow response insensitive towards NOS-blockade. Whereas indomethacin, miconazole, TEA, and SCH 58261 were ineffective to reduce the flow response, glibenclamide blunted it in eNOS-KO hearts.</AbstractText>NO-production and K ATP-channel activation together may fully account for the steady-state hypercapnic flow response in mouse heart. However, chronic deletion of eNOS does not result in a reduced hypercapnic flow response. Enhanced activation of K ATP-channels and potentially Kv-channels contributes to the compensatory mechanisms involved in the hypercapnic flow response when eNOS activity is absent.</AbstractText> |
2,333,059 | The effects of suplatast tosilate (IPD-1151T) on innate immunity and antigen-presenting cells. | We previously demonstrated that the anti-allergic drug, suplatast tosilate (IPD-1151T), prolonged rat survival after heterotopic heart transplantation (HHT) and suppressed mixed lymphocyte reaction (MLR). In the present study, we investigated the effects of suplatast on T cells, lipopolysaccharides (LPS), or peptidoglycan (PGN)-stimulated cells and dendritic cells (DCs). The addition of suplatast to concanavalin A (ConA) blasts inhibited the proliferation of cells in which the gene expression of T-helper-1 (Th1) and T-helper-2 (Th2) cytokines including interferon (IFN)-gamma, interleukin (IL)-2, IL-4, and IL-10 were down-regulated with decreased concentration of the IFN-gamma and IL-10 in the supernatants of ConA blast cells. Suplatast also showed down-regulation of the toll-like receptor (TLR)2, TLR4, and CD14 gene expressions on splenocytes stimulated by LPS and PGN, TLR2 or TLR4 agonist, respectively. DCs treated with suplatast expressed lower levels of CD40, CD80, and CD86 and reduced IL-12 production. These results suggest that suplatast may modulate the TLRs on antigen-presenting cells (APCs) and thus block the pathway of Th1/Th2 cytokine production. |
2,333,060 | The effects of venlafaxine on autonomic functions in healthy volunteers. | Antidepressants that block norepinephrine uptake may cause unwanted effects on autonomic functions such as reduction of heart rate variability. This randomized, double-blind, placebo-controlled study examined the effects of venlafaxine on heart rate variability, vasoconstrictory responses (VRs) of cutaneous blood vessels, and pupillary light reflex in humans. Twelve healthy male subjects aged 23 to 32 years (mean +/- SD, 26 +/- 3 years) orally received 37.5 mg of venlafaxine BID for 7 days and subsequently 75 mg BID for another 7 days. After a 14-day washout phase, placebo was administered to the subjects for 14 days under randomized double-blind crossover conditions. Heart rate variability was diminished, and the dilation phase of VR was prolonged during multiple dosing with venlafaxine (P < 0.05). A significant increase in resting pupil diameter, a decrease in amplitude, an increase in latency, and a shortening of the 33% recovery time of the pupillary light reflex were noted with the drug, whereas no changes were observed under placebo condition. Sustained VR and shortening of the recovery time of the pupillary light reflex are consistent with sympathetic potentiation resulting from noradrenaline reuptake blockade in cutaneous blood vessels and iris. The decrease in amplitude and increase in latency of the pupillary light reflex could be indicative of centrally mediated parasympathetic inhibition. |
2,333,061 | Changes in Heart Rate Variability in patients under local anesthesia. | Spectral analysis of Heart Rate Variability (HRV) is widely used for the assessment of cardiovascular autonomic control. Several studies have shown the effect of anesthetic agents on HRV parameters. In this study a systematic approach of HRV analysis has been employed. The effect caused by the ectopic beats on the spectral measurements has been investigated and results are presented. A detrending method using Wavelet Packets has been developed which was able to remove slow varying trend from HRV signals without causing significant changes in the low frequency (LF) and high frequency (HF) component of the HRV signal. Using this methodology electrocardiogram (ECG) signals from 14 patients undergoing local anesthesia (brachial plexus block) were analyzed with parametric Autoregressive (AR) method. The results showed that the LF/HF ratio values calculated from the HRV signal decreases within an hour of the application of the brachial plexus block compared to the values at the start of the procedure. This change was noticed in approximately 80% of the patients. |
2,333,062 | Loss of type III transforming growth factor beta receptor expression increases motility and invasiveness associated with epithelial to mesenchymal transition during pancreatic cancer progression. | Epithelial to mesenchymal transitions (EMTs) contribute to increases in cellular motility and invasiveness during embryonic development and tumorigenesis. The transforming growth factor beta (TGF-beta) signaling pathway is a key regulator of EMT. The TGF-beta superfamily coreceptor, the type III TGF-beta receptor (TbetaRIII or betaglycan), is required for EMT during embryonic heart development and palate fusion. Here, we establish that in a pancreatic cancer model of EMT, TbetaRIII expression is specifically lost during EMT at the mRNA and protein levels, whereas levels of the TGF-beta type I and type II receptors are maintained at the mRNA level. Loss of TbetaRIII expression at the protein level precedes the loss of E-cadherin and cytoskeletal reorganization during early stages of EMT. However, maintaining TbetaRIII expression does not block these aspects of EMT, but instead suppresses the increased motility and invasiveness associated with EMT. Reciprocally, shRNA-mediated knockdown of endogenous TbetaRIII increases cellular motility without affecting Snail or E-cadherin levels. The ability of TbetaRIII to suppress motility and invasiveness does not depend on its cytoplasmic domain or its coreceptor function. Instead, this suppression of invasion is partially mediated by ectodomain shedding of TbetaRIII, generating soluble TbetaRIII (sTbetaRIII). In human pancreatic cancer specimens, TbetaRIII expression decreases at both the mRNA and protein levels, with the degree of loss correlating with worsening tumor grade. Taken together, these studies support a role for loss of TbetaRIII expression during the EMT of pancreatic cancer progression, with a specific role for sTbetaRIII in suppressing EMT-associated increases in motility and invasion. |
2,333,063 | Redox signaling at reperfusion is required for protection from ischemic preconditioning but not from a direct PKC activator. | Redox signaling prior to a lethal ischemic insult is an important step in triggering the protected state in ischemic preconditioning. When the preconditioned heart is reperfused a second sequence of signal transduction events, the mediator pathway, occurs which is believed to inhibit mitochondrial permeability transition pore formation that normally destroys mitochondria in much of the reperfused tissue. Prominent among the mediator pathway's events is activation of phosphatidylinositol 3-kinase and extracellular signal-regulated kinase. Recently it was found that both activation of PKC and generation of reactive oxygen species (ROS) at the time of reperfusion are required for protection in preconditioned hearts. To establish their relative order we tested whether ROS formation at reperfusion is required in hearts protected by direct activation of PKC at reperfusion. Isolated rabbit hearts were exposed to 30 min of regional ischemia and 2 h of reperfusion. Preconditioned hearts received 5 min of global ischemia and 10 min of reperfusion prior to the index ischemia. Another group of preconditioned hearts was exposed to 300 microM of the ROS scavenger N-(2-mercaptopropionyl) glycine (MPG) for 20 min starting 5 min prior to reperfusion. Infarct size was measured by triphenyltetrazolium staining. Preconditioning reduced infarct size from 36% +/- 2% of the ischemic zone in control hearts to only 18 +/- 2%. MPG during early reperfusion completely blocked preconditioning's protection (33 +/- 3% infarction). MPG given in the same dose and schedule to non-preconditioned hearts had no effect on infarct size. In the last group phorbol 12-myristate 13-acetate (PMA) (0.05 nM) was given to non-preconditioned hearts from 1 min before to 5 min after reperfusion in addition to MPG administered as in the other groups. MPG did not block protection from an infusion of PMA as infarct size was only 9 +/- 2% of the risk zone. We conclude that while redox signaling during the first few minutes of reperfusion is an essential component of preconditioning's protective mechanism, this step occurs upstream of PKC activation. |
2,333,064 | [The influence of nCPAP therapy on the autonomic nervous system dysfunction in OSA patients]. | Obstructive sleep (OSA) can induce severe arrhythmias, including prolonged periods of asystole and heart block. Heart rate variability (HRV) has gained importance as a technique employed to explore the autonomic nervous system (ANS) which plays an important role in arrythmogenesis.</AbstractText>Our aim was to investigate nocturnal HRV by spectral analysis of RR intervals before and after continuous positive airway pressure (nCPAP) therapy.</AbstractText>To confirm the relation between OSA and ANS dysfunction, we prospectively investigated ANS function in 24 patients (18 males, mean age 53 years) with moderate or severe OSA. Overnight polysomnography was performed before and after nCPAP therapy. We analyzed apnea/hypopnea index (AHI), desaturation index, mean arterial oxygen saturation, mean and standard deviation (SD) for nocturnal HRV triangular index and pNN50 before and after initiating CPAP treatment.</AbstractText>AHI decreased markedly from 51 to 3 events/h, desaturation index decreased from 45.9 to 3.62 events/h, and mean arterial oxygen saturation improved from 92.15% to 94.8%. Nocturnal HRV triangular index decreased from 18.3 to 12.85 as well as nocturnal pNN50 in all patients after initiating nCPAP therapy, suggesting that efficient nCPAP therapy may restore nocturnal autonomic defects, characteristic of severe and moderate OSA, as proven in previous studies.</AbstractText>Abnormalities in cardiovascular variability may be implicated in the subsequent development of cardiovascular diseases in patients with OSA. These results suggest that impaired ANS function is present in patients with OSA and can be improved by successful nCPAP therapy.</AbstractText> |
2,333,065 | Polymorphism in the cholesteryl ester transfer protein gene and the risk of early onset myocardial infarction among cigarette smokers. | Cigarette smoking and the common B1 allele of the TaqIB polymorphism have both been reported to be associated with increased cholesteryl ester transfer protein (CETP) activity and altered lipoprotein levels. Thus, it is possible that the combined presence of these two respective environmental and genetic factors may enhance cardiovascular risk. We hypothesized that susceptibility to early onset myocardial infarction (MI) among cigarette smokers may be related to the presence of TaqIB polymorphism in the CETP gene.</AbstractText>The age at onset of a first MI among current (n = 199), past (n = 345), and never (n = 270) smokers was related to the presence of the TaqIB1 and B2 alleles in a cohort of 814 first MI patients.</AbstractText>Multivariate regression analysis demonstrated that cigarette smoking was associated with a significant increase in the risk for early onset MI only among carriers of the TaqIB1 allele: current smokers with the B1B1 and B1B2 genotypes displayed a respective 9.4 (P < 0.001) and 8.4 (P < 0.001) year reduction in the age at onset of a first MI compared with never smokers, and past smokers with these genotypes exhibited a respective 3.8 (P = 0.003) and 3.7 (P = 0.01) year reduction. By contrast, current and past smoking was not associated with a significant increase in the risk for early onset MI among B2B2 homozygotes (3.0 [P = 0.28] and 0.2 [P = 0.93] year reduction, respectively). The smoking x genotype interaction was statistically significant (P = 0.04).</AbstractText>The current findings suggest that genetic factors may modify susceptibility to early onset MI among cigarette smokers.</AbstractText> |
2,333,066 | Utility of in-hospital cardiac remote telemetry in patients with unexplained syncope. | Cardiac remote telemetry (CR-TEL) is in wide use in cardiac units, but its diagnostic value in the setting of unexplained syncope is unknown.</AbstractText>One hundred and two consecutive patients (73 +/- 14 years) arriving to the emergency department due to an unexplained syncope were admitted under CR-TEL. Heart rhythm was continuously monitored from a central station by trained nurses. Events included all causes of mortality and arrhythmias unnoticed on emergency department.</AbstractText>Thirty patients (29.4%) presented events. There were no deaths during the time of monitoring (4.8 +/- 2.7 days). Events requiring transfer to the coronary care units (CCU) occurred in 15 patients (14.7%), principally due to AV-block and extreme bradycardia. Cardiac remote telemetry was diagnostic in 18 patients (17.6%) in whom the arrhythmic event occurred simultaneously with the syncopal episode. Multivariate analysis showed that age > or =86 years (P < 0.01) and heart failure on admission (P < 0.04) were the strongest predictors of events. All transfers to the CCU were documented within the first 4 days. The best cut-off point as a threshold for CR-TEL monitoring time was 72 hours (sensitivity 73%, specificity 86%).</AbstractText>Cardiac remote telemetry appears to be a useful tool in the management of patients with unexplained syncope, especially in those older and presenting heart failure on admission.</AbstractText> |
2,333,067 | The effect of hypoxia in development. | There is increasing evidence that the oxygen supply to the human embryo in the first trimester is tightly controlled, suggesting that too much oxygen may interfere with development. The use of hypoxia probes in mammalian embryos during the organogenic period indicates that the embryo is normally in a state of partial hypoxia, and this may be essential to control cardiovascular development, perhaps under the control of hypoxia-inducible factor (HIF). A consequence of this state of partial hypoxia is that disturbances in the oxygen supply can more easily lead to a damaging degree of hypoxia. Experimental mammalian embryos show a surprising degree of resilience to hypoxia, with many organogenic stage embryos able to survive 30-60 min of anoxia. However, in some embryos this degree of hypoxia causes abnormal development, particularly transverse limb reduction defects. These abnormalities are preceded by hemorrhage/edema and tissue necrosis. Other parts of the embryo are also susceptible to this hypoxia-induced damage and include the genital tubercle, the developing nose, the tail, and the central nervous system. Other frequently observed defects in animal models of prenatal hypoxia include cleft lip, maxillary hypoplasia, and heart defects. Animal studies indicate that hypoxic episodes in the first trimester of human pregnancy could occur by temporary constriction of the uterine arteries. This could be a consequence of exposure to cocaine, misoprostol, or severe shock, and there is evidence that these exposures have resulted in hypoxia-related malformations in the human. Exposure to drugs that block the potassium current (IKr) can cause severe slowing and arrhythmia of the mammalian embryonic heart and consequently hypoxia in the embryo. These drugs are highly teratogenic in experimental animals. There is evidence that drugs with IKr blockade as a side effect, for example phenytoin, may cause birth defects in the human by causing periods of embryonic hypoxia. The strongest evidence of hypoxia causing birth defects in the human comes from studies of fetuses lacking hemoglobin (Hb) F. These fetuses are thought to be hypoxic from about the middle of the first trimester and show a range of birth defects, particularly transverse limb reduction defects. |
2,333,068 | Reversal of prilocaine epidural anesthesia using epidural saline or ringer's lactate washout. | Several investigators have described the phenomena of epidural saline washout using bolus injections. This study was designed to determine whether epidural block could be reversed more effectively by infusion of crystalloid solutions via the epidural catheter.</AbstractText>One hundred male patients scheduled for outpatient surgery were enrolled in this study. After 30 min of 2% prilocaine epidural anesthesia, patients were randomly assigned to receive 45 mL of study solution as follows: (1) normal saline bolus (group NSB); (2) Ringer's lactate bolus (group RLB); (3) normal saline infusion (group NSI); (4) Ringer's lactate infusion (group RLI). Patients in the control group received no washout fluid. Motor, sensory blockade and side effects were compared among 5 groups. Ambulation time is defined as the recovery time.</AbstractText>In the control group, ambulation time (139 +/- 15 min) was significantly longer than in the washout groups (NSB 90 +/- 10, RLB 88 +/- 10, NSI 85 +/- 8, RLI 91 +/- 6 minutes) (P < .001). Two-segment sensory regression time in the control group (86 +/- 15 min) was significantly longer than in groups NSB, RLB, NSI and RLI (55 +/- 8, 51 +/- 4, 58 +/- 8, and 53 +/- 10 minutes, respectively) (P < .001).</AbstractText>We concluded that a more rapid recovery of motor and sensory blockade in patients undergoing epidural anesthesia may be achieved by the use of an epidural washout with either bolus or infusion of 45 mL normal saline or Ringer's lactate.</AbstractText> |
2,333,069 | Differential effects of superoxide radical on the action potentials in ventricular muscles, Purkinje fibers and atrial muscles in the heart of different aged rats. | The purpose of this study was to determine whether the effects of the superoxide donor menadione on myocardial electrical activity were regional and/or age-dependent. Action potentials were recorded in cardiac muscles that were isolated from 18- and 49-day old rat hearts, using a conventional microelectrode technique. Superoxide dismutase (SOD) activity was determined spectrophotometrically in regional cardiac muscles. Menadione (30 microM) significantly increased the action potential duration at 90% repolarization (APD90) in Purkinje fibers and ventricular muscles from 18-day old rats; and it decreased the APD in ventricular muscles from 49-day old rats. ATP-sensitive K+ (KATP) channel opener pinacidil blocked menadione-induced effects on the APD90 of Purkinje fibers and ventricular muscles from 18-day old rats, but did not block menadione-induced effects on the APD90 of Purkinje fibers and ventricular muscles from 49-day old rats. The cGMP-dependent protein kinase (PKG) activator or inhibitor did not inhibit the menadione-induced effects on APD90 of ventricular muscles and Purkinje fibers from 18- and 49-day old rats. The superoxide dismutase (SOD) activities in ventricular muscles from 4-, 18- and 49-day old rats, were: 1185 +/- 135, 1434 +/- 96, and 1760 +/- 144 U/mg protein, respectively; whereas, the SOD activities in atrial muscles, were: 1135.4 +/- 156.4, 1145.4 +/- 148.8, and 1243.5 +/- 175.2 U/mg protein, respectively. However, the ventricular SOD activities were significantly inhibited under hypoxic conditions. These results indicate that menadione can produce regionally differential effects on cardiac APD, which may be due to differences in the SOD activity, depending on the region and age of the cardiac tissue. |
2,333,070 | FK506-binding protein (FKBP12) regulates ryanodine receptor-evoked Ca2+ release in colonic but not aortic smooth muscle. | In smooth muscle, the ryanodine receptor (RyR) mediates Ca(2+) release from the sarcoplasmic reticulum (SR) Ca(2+) store. Release may be regulated by the RyR accessory FK506-binding protein (FKBP12) either directly, as a result of FKBP12 binding to RyR, or indirectly via modulation of the activity of the phosphatase calcineurin or kinase mTOR. Here we report that RyR-mediated Ca(2+) release is modulated by FKBP12 in colonic but not aortic myocytes. Neither calcineurin nor mTOR are required for FKBP12 modulation of Ca(2+) release in colonic myocytes to occur. In colonic myocytes, co-immunoprecipitation techniques established that FKBP12 and calcineurin each associated with the RyR2 receptor isoform (the main isoform in this tissue). Single colonic myocytes were voltage clamped in the whole cell configuration and cytoplasmic Ca(2+) concentration ([Ca(2+)](c)) increases evoked by the RyR activator caffeine. Under these conditions FK506, which displaces FKBP12 (to inhibit calcineurin) and rapamycin, which displaces FKBP12 (to inhibit mTOR), each increased the [Ca(2+)](c) rise evoked by caffeine. Notwithstanding, neither mTOR nor calcineurin are required to potentiate caffeine-evoked Ca(2+) increases evoked by each drug. Thus, the mTOR and phosphatidylinositol 3-kinase inhibitor, LY294002, which directly inhibits mTOR without removing FKBP12 from RyR, did not alter caffeine-evoked [Ca(2+)](c) transients. Nor did inhibition of calcineurin by cypermethrin, okadaic acid or calcineurin inhibitory peptide block the FK506-induced increase in RyR-mediated Ca(2+) release. In aorta, although RyR3 (the main isoform), FKBP12 and calcineurin were each present, RyR-mediated Ca(2+) release was unaffected by either FK506, rapamycin or the calcineurin inhibitors cypermethrin and okadaic acid in single voltage clamped aortic myocytes. Presumably failure of FKBP12 to associate with RyR3 resulted in the immunosuppressant drugs (FK506 and rapamycin) being unable to alter the activity of RyR. The effects of these drugs are therefore, apparently dependent on an association of FKBP12 with RyR. Together, removal of FKBP12 from RyR augmented Ca(2+) release via the channel in colonic myocytes. Neither calcineurin nor mTOR are required for the FK506- or rapamycin-induced potentiation of RyR Ca(2+) release to occur. The results indicate that FKBP12 directly inhibits RyR channel activity in colonic myocytes but not in aorta. |
2,333,071 | Changes in heart rate variability may reflect sympatholysis during spinal anaesthesia. | To investigate if changes in low-to-high frequency ratio (LF/HF), low frequency (LF) and high frequency (HF) heart rate variability reflect autonomic regulation during spinal anaesthesia (SA) in pregnant women scheduled for elective Caesarean section.</AbstractText>Prospective clinical trial. Systolic blood pressure (SBP) and heart rate variability were analysed at baseline, 5 min after SA and 15 min after SA. Patients were assigned by baseline LF/HF. Group LF/HF < 2.5 (n= 52) was compared to group LF/HF > 2.5 (n= 48). Non-parametric tests for statistical analysis.</AbstractText>Group LF/HF > 2.5 showed a significant decrease in LF/HF and LF as well as an increase in HF during SA (median, range): baseline LF/HF [4.0 (3.2/4.8)] decreased to 2.3 (1.3/3.4) at event 15 min after SA (P < 0.001). Baseline LF = 59(43/71)% decreased to 40 (27/55)% at event 15 min after SA (P < 0.05). Baseline HF = 15(13/22)% increased to 26(15/41)% at event 15 min after SA (P < 0.05). In contrast, group LF/HF < 2.5 demonstrated only moderate changes in LF/HF, LF and HF during SA. SBP decreased significantly in group LF/HF > 2.5 (median and range) lowest SBP group LF/HF > 2.5: 80 (50/127 mmHg vs. group LF/HF < 2.5: 109 (104/142) mmHg, P < 0.001. Decrease of SBP before and after SA was correlated with a decrease in LF/HF, LF, and HF, respectively: LF/HF - SBP: r= 0.30, r(2)= 0.09, P < 0.001; LF - SBP: r= 0.25, r(2)= 0.06, P < 0.05, HF, NS.</AbstractText>Changes in heart rate variability parameters in the course of SA may reflect a decrease in sympathetic activity and relative increase in parasympathetic activity as a result of the block. In the course of SA, the more pronounced the changes in heart rate variability were the more distinct the hypotension.</AbstractText> |
2,333,072 | Dexamphetamine boosts naming treatment effects in chronic aphasia. | To date, minimal research has investigated the effect of combining dexamphetamine with standard naming therapy after stroke. The present study used a double-blind, placebo-controlled, multiple baseline, crossover design with two individuals in the chronic stage of stroke recovery. Each individual attended two 4-week blocks of naming therapy (two to three treatment sessions per week). Dexamphetamine (10 mg) was administered at the start of each session during one therapy block, while a placebo was administered during the other therapy block. Therapy progress on treated and untreated items was assessed by a confrontation naming task during and after each therapy block. Both individuals showed greater progress in therapy and maintenance of therapy gains when behavioral treatment was combined with dexamphetamine rather than placebo, although this gain was only statistically significant in one individual. There was no significant improvement on a control task (nonword reading) in either individual. The results provide preliminary evidence that dexamphetamine paired with combined semantic and phonological therapy may be beneficial for the treatment of naming disorders in chronic aphasia. |
2,333,073 | Application of PatchXpress planar patch clamp technology to the screening of new drug candidates for cardiac KCNQ1/KCNE1 (I Ks) activity. | A cardiac safety concern for QT prolongation and potential for pro-arrhythmia exists due to inhibition of the cardiac slowly activating delayed rectifier potassium current, I(Ks). Selective inhibitors of I Ks have been shown to prolong the QT interval in animal models. On the other hand, I Ks has been considered as a target for anti-arrhythmic therapy due to certain biophysical and pharmacological properties and its expression pattern in the heart. Consequently, we have developed a method utilizing a human embryonic kidney (HEK)-293 cell line expressing KCNQ1/KCNE1 (genes that encode for the I Ks channel) as a model for screening of new compounds for I Ks activity. This study was designed (1) to establish and optimize the experimental conditions for measurement of I Ks using PatchXpress() 7000A (Molecular Devices Corporation, Sunnyvale, CA) and (2) to test the effects of I Ks inhibitors and compare the 50% inhibitory concentration (IC50) values determined with PatchXpress versus conventional patch clamp in order to validate the PatchXpress approach for higher-throughput I Ks screening. Biophysical properties of HEK/I Ks recorded with PatchXpress were similar to those recorded with conventional patch-clamp and reported in the literature. The IC50 values for I Ks block determined with PatchXpress correlated well with conventional patch-clamp values from HEK-293 cells as well as from native cardiac myocytes for the majority of compounds tested. Electrophysiological recording of I Ks expressed in HEK-293 cells with the PatchXpress is of acceptable quality for screening purposes. This approach can be utilized for functional prescreening of development compounds for I Ks inhibition either for optimizing lead anti-arrhythmic or other therapeutic candidates or to exclude compounds with the potential to prolong QT. |
2,333,074 | Postresuscitation N-acetylcysteine treatment reduces cerebral hydrogen peroxide in the hypoxic piglet brain. | Reactive oxygen species have been implicated in the pathogenesis of hypoxia-reoxygenation injury. However, little information is known regarding the temporal profile of cerebral hydrogen peroxide (HPO) production and its response to N-acetylcysteine (an antioxidant) administration during neonatal hypoxia-reoxygenation. Using an acute swine model of neonatal hypoxia-reoxygenation, we examined the short-term neuroprotective effects of N-acetylcysteine on cerebral HPO production and oxidative stress in the brain.</AbstractText>Controlled, block-randomized animal study.</AbstractText>University animal research laboratory.</AbstractText>Newborn piglets (1-3 days, 1.7-2.1 kg).</AbstractText>At 5 min after reoxygenation, piglets were given either saline or N-acetylcysteine (20 or 100 mg/kg/h) in a blinded, randomized fashion.</AbstractText>Newborn piglets were block-randomized into a sham-operated group (without hypoxia-reoxygenation, n = 5) and three hypoxic-reoxygenated groups (2 h of normocapnic alveolar hypoxia followed by 2h of reoxygenation, n = 7/group). Heart rate, mean arterial pressure, cortical HPO concentration, amino acid levels in cerebral microdialysate, and cerebral tissue glutathione and lipid hydroperoxide levels were examined. Hypoxic piglets were hypotensive and acidotic, and they recovered similarly in all hypoxic-reoxygenated groups. In hypoxic-reoxygenated control piglets, the cortical HPO concentration gradually increased during reoxygenation. Both doses of N-acetylcysteine abolished the increased HPO concentration and oxidized glutathione levels and tended to reduce the glutathione ratio and lipid hydroperoxide levels in the cerebral cortex (p = 0.08 and p = 0.1 vs. controls, respectively). N-acetylcysteine at 100mg/kg/h also increased the cerebral extracellular taurine levels.</AbstractText>In newborn piglets with hypoxia-reoxygenation, postresuscitation administration of N-acetylcysteine reduces cerebral HPO production and oxidative stress, probably through a taurine-related mechanism.</AbstractText> |
2,333,075 | [30 microg intrathecal clonidine prolongs labour analgesia, but increases the incidence of hypotension and abnormal foetal heart rate patterns]. | To assess the efficacy of spinal clonidine combined with bupivacaine and sufentanil and its effects on maternal and foetal outcome.</AbstractText>Prospective double-blind randomized study.</AbstractText>One hundred and five patients requesting labour analgesia had combined spinal epidural analgesia with intrathecal bupivacaine 2.5 mg and were randomly assigned to receive in addition either sufentanil 5 microg (S5), sufentanil 5 microg and clonidine 30 microg (C30), or sufentanil 10 microg (S10). Onset time, duration of analgesia, visual analogue scores, blood pressure, ephedrine requirements, heart rate, nausea, pruritus, sedation, motor block, foetal heart rate abnormalities, mode of delivery and Apgar scores were recorded.</AbstractText>Mean duration of spinal analgesia was significantly longer in patients receiving spinal clonidine compared to patients in S5 group (144+/-61 min versus 95+/-37 min). The onset time of analgesia was significantly shorter in S10 group (3+/-1 min) versus C30 group (4+/-1 min) and S5 group (4+/-1 min) (P=0.002). Hypotension was significantly more frequent in C30 group (29 versus 3% and 3% in S5 and S10 groups) (p=0,001). Foetal heart rate abnormalities and sedation were also significantly more frequent in C30 group. Mode of delivery (spontaneous, instrumental or caesarean delivery) and Apgar scores were unaffected by clonidine treatment.</AbstractText>Intrathecal clonidine 30 mug prolongs analgesia. However, it increases the incidence of hypotension, and abnormal foetal heart rate patterns. Thus, this study confirms that the use of 30 mug intrathecal clonidine for labour analgesia is not recommended.</AbstractText> |
2,333,076 | Nail-Patella syndrome: a case report and anesthetic implications. | To report a case of asystole during combined epidural and general anesthesia occurring in a patient with Nail-Patella syndrome (NPS), and to review the management and anesthetic implications of this rare genetic syndrome.</AbstractText>A 64-yr-old male with NPS, renal impairment and coronary artery disease presented for right hemicolectomy for colon cancer. Following initiation of surgery and during insertion of a nasogastric tube there was sudden loss of the patient's pulse oxymetry, and arterial pressure waveforms with an asystolic electrocardiogram signal. Atropine 0.6 mg i.v. was administered and after an asystolic period of 20-30 sec, myocardial activity commenced at 110 beatsxmin(-1) with return of normal vital signs and no further sequelae.</AbstractText>Nail-Patella syndrome can present with an array of anomalies that may be associated with perioperative complications. Glaucoma, nephropathy, vasomotor dysfunction, fragile teeth, abnormal muscle, skeletal and nerve anatomy as well as involvement of the central and/or peripheral nervous systems are common findings. In this setting it is postulated that a vasovagal reflex from esophageal stimulation by nasogastric tube placement may have caused the asystolic event. This response could have been exaggerated by the sympatholytic combination of neuraxial block, preoperative beta-blockade, and potential autonomic dysfunction secondary to NPS. Awareness of this uncommon disease and its presentation may serve to caution the anesthesiologist regarding the perioperative implications of patients with this syndrome.</AbstractText> |
2,333,077 | A comparison of dexmedetomidine and midazolam for sedation in third molar surgery. | This randomised, double-blind study compared dexmedetomidine and midazolam for intravenous sedation during third molar surgery under local anaesthesia. Sixty patients received either dexmedetomidine (up to 1 microg x kg(-1)) or midazolam (up to 5 mg), which was infused until the Ramsay Sedation Score was four or the maximum dose limit was reached. Intra-operative vital signs, postoperative pain scores and analgesic consumption, amnesia, and satisfaction scores for patients and surgeons, were recorded. Sedation was achieved by median (IQR (range)) doses of 47 microg (39-52 (25-76)) or 0.88 microg x kg(-1) (0.75-1.0 (0.6-1.0)) dexmedetomidine, and 3.6 mg (3.3-4.4 (1.9-5.0)) or 0.07 mg x kg(-1) (0.055-0.085 (0.017-0.12)) midazolam. Heart rate and blood pressure during surgery were lower in dexmedetomidine group. There was no significant difference in satisfaction or pain scores. Midazolam was associated with greater amnesia. Dexmedetomidine produces comparable sedation to midazolam. |
2,333,078 | Macrophage colony stimulating factor expression in human cardiac cells is upregulated by tumor necrosis factor-alpha via an NF-kappaB dependent mechanism. | Macrophage colony stimulating factor (M-CSF) is a key factor for monocyte and macrophage survival and proliferation. M-CSF has been implicated in cardiac healing and repair after myocardial infarction.</AbstractText>We show by immunohistochemistry and Western blotting analysis that M-CSF protein is present in human heart tissue. Cultured human adult cardiac myocytes (HACM) and human adult cardiac fibroblasts (HACF) isolated from human myocardial tissue constitutively express M-CSF. When HACM and HACF were treated with tumor necrosis factor-alpha (TNF-alpha) M-CSF protein production and M-CSF mRNA expression, determined by ELISA or by using RT-PCR, respectively, was significantly increased. To determine a possible role of nuclear factor kappaB (NF-kappaB) and activating protein 1 (AP-1) in M-CSF regulation, blockers to both pathways and an adenovirus overexpressing a dominant negative (dn) form of IkappaB kinase 2 (IKK2) were used. Only the NF-kappaB blocker dimethylfumarate and the dn IKK2, but not januskinase inhibitor-1 (JNK-I), were able to block the TNF-alpha-induced increase in M-CSF production in these cells, suggesting that the induction of M-CSF through TNF-alpha is mainly dependent on the activation of the NF-kappaB pathway. The monocyte activation marker CD11b was significantly increased after incubating U937 cells with conditioned medium from HACM or HACF as determined by FACS analysis.</AbstractText>Our in vitro data taken together with our immunohistochemistry data suggest that human cardiac cells constitutively express M-CSF. This expression of M-CSF in the human heart and its upregulation by TNF-alpha might contribute to monocyte and macrophage survival and differentiation.</AbstractText> |
2,333,079 | Conivaptan: a dual vasopressin receptor v1a/v2 antagonist [corrected]. | Several fluid retentive states such as heart failure, cirrhosis of the liver, and syndrome of inappropriate antidiuretic hormone secretion are associated with inappropriate elevation in plasma levels of arginine vasopressin (AVP), a neuropeptide that is secreted by the hypothalamus and plays a critical role in the regulation of serum osmolality and in circulatory homeostasis. The actions of AVP are mediated by three receptor subtypes V1a, V2, and V1b. The V1a receptor regulates vasodilation and cellular hypertrophy while the V2 receptor regulates free water excretion. The V1b receptor regulates adrenocorticotropin hormone release. Conivaptan is a nonpeptide dual V1a/V2 AVP receptor antagonist. It binds with high affinity, competitively, and reversibly to the V1a/V2 receptor subtypes; its antagonistic effect is concentration dependent. It inhibits CYP3A4 liver enzyme and elevates plasma levels of other drugs metabolized by this enzyme. It is approved only for short-term intravenous use. Infusion site reaction is the most common reason for discontinuation of the drug. In animals conivaptan increased urine volume and free water clearance. In heart failure models it improved hemodynamic parameters and free water excretion. Conivaptan has been shown to correct hyponatremia in euvolemic or hypervolemic patients. Its efficacy and safety for short-term use have led to the Food and Drug Administration (FDA) approval of its intravenous form for the correction of hyponatremia in euvolemic and hypervolemic states. Despite its ability to block the action of AVP on V1a receptors, no demonstrable benefit from this action was noted in patients with chronic compensated heart failure and it is not approved for this indication. Consideration should be given to further evaluation of its potential benefits in patients with acute decompensated heart failure. |
2,333,080 | The canine virtual ventricular wall: a platform for dissecting pharmacological effects on propagation and arrhythmogenesis. | We have constructed computational models of canine ventricular cells and tissues, ultimately combining detailed tissue architecture and heterogeneous transmural electrophysiology. The heterogeneity is introduced by modifying the Hund-Rudy canine cell model in order to reproduce experimentally reported electrophysiological properties of endocardial, midmyocardial (M) and epicardial cells. These models are validated against experimental data for individual ionic current and action potential characteristics, and their rate dependencies. 1D and 3D heterogeneous virtual tissues are constructed, with detailed tissue architecture (anisotropy and orthotropy, due to fibre orientation and sheet structure) of the left ventricular wall wedge extracted from a diffusion tensor imaging data set. The models are used to study the effects of tissue heterogeneity and class III drugs on transmural propagation and tissue vulnerability to re-entry. We have determined relationships between the transmural dispersion of action potential duration (APD) and the vulnerable window in the 1D virtual ventricular wall, and demonstrated how changes in the transmural heterogeneity, and hence tissue vulnerability, can lead to generation of re-entry in the 3D ventricular wedge. Two class III drugs with opposite qualitative effects on transmural APD heterogeneity are considered: d-sotalol that increases transmural APD dispersion, and amiodarone that decreases it. Simulations with the 1D virtual ventricular wall show that under d-sotalol conditions the vulnerable window is substantially wider compared to amiodarone conditions, primarily in the epicardial region where unidirectional conduction block persists until the adjacent M cells are fully repolarised. Further simulations with the 3D ventricular wedge have shown that ectopic stimulation of the epicardial region results in generation of sustained re-entry under d-sotalol conditions, but not under amiodarone conditions or in control. Again, APD increase in M cells was identified as the major contributor to tissue vulnerability--re-entry was initiated primarily due to ectopic excitation propagating around the unidirectional conduction block in the M cell region. This suggests an electrophysiological mechanism for the anti- and proarrhythmic effects of the class III drugs: the relative safety of amiodarone in comparison to d-sotalol can be explained by relatively low transmural APD dispersion, and hence, a narrow vulnerable window and low probability of re-entry in the tissue. |
2,333,081 | Renin-angiotensin-aldosterone system intervention in the cardiometabolic syndrome and cardio-renal protection. | The metabolic syndrome, also known as the cardiometabolic syndrome (CMS), is a state of metabolic and vascular dysregulation that is associated with activation of the renin-angiotensin-aldosterone system (RAAS). Clinical components of the CMS include central or visceral obesity, hypertension (HTN), dyslipidemia, insulin resistance/hyperinsulinemia, and microalbuminuria that collectively convey increases in oxidative stress, inflammation, and subsequent endothelial dysfunction. The cardio-renal inflammation and oxidative stress enhanced in the CMS increases the risk for cardiovascular disease (CVD) and renal disease end-points such as stroke, congestive heart failure, and chronic kidney disease (CKD). The development of proteinuria is known to herald progressive kidney disease (e.g. CKD) and both are now well accepted as CVD risk factors. Evidence suggests a role for visceral obesity, insulin resistance/hyperinsulinemia, HTN, and other components of the CMS lead to an increased risk for proteinuria and progressive loss of renal function. Intervention with agents that block the RAAS (e.g. ACE inhibitors and Angiotensin type 1 receptor blockers) have been shown to reduce proteinuria, CKD progression, and CVD events. Herein, we will examine the relationship between RAAS intervention and reductions in CKD and CVD events. |
2,333,082 | Influence of inversion pulse type in assessing lung-oxygen-enhancement by centrically-reordered non-slice-selective inversion-recovery half-Fourier single-shot turbo spin-echo (HASTE) sequence. | To demonstrate the influence of inversion pulse type and inversion time for assessment of oxygen-enhancement on centrically-reordered non-slice-selective inversion-recovery (IR) half-Fourier single-shot turbo spin-echo (HASTE) sequence.</AbstractText>Phantoms with and without 100% oxygen and three healthy volunteers were studied with two-dimensional (2D) centrically-reordered non-slice selective IR-HASTE sequence with either composite or block inversion-recovery pulse at increasing inversion times from 200 to 1800 msec. Signal-to-noise ratios (SNRs) of phantom, real signal differences, and relative enhancement ratios of lung parenchyma between oxygen-enhanced and non-oxygen-enhanced MR images on composite and block pulse type were statistically compared at each TI.</AbstractText>SNRs at TIs of 200 and 400 msec using the composite inversion pulse type were significantly lower than those with the block inversion pulse in the in vivo study (P < 0.05), although no significant differences were observed in the phantom study and in the in vivo study at inversion times greater than or equal to 600 msec. Real signal intensity (SI) differences at 400 and 600 msec of the composite inversion pulse type were significantly higher than those with the block inversion pulse type (P < 0.05). Relative enhancement ratio at 800 msec with the composite inversion pulse were significantly lower than that with the block inversion pulse (P < 0.05).</AbstractText>IR pulse type and inversion time have influence on assessment of oxygen-enhancement by centrically-reordered non-slice-selective IR-HASTE sequence.</AbstractText>(c) 2007 Wiley-Liss, Inc.</CopyrightInformation> |
2,333,083 | Effect of block weight on work demands and physical workload during masonry work. | The effect of block weight on work demands and physical workload was determined for masons who laid sandstone building blocks over the course of a full work day. Three groups of five sandstone block masons participated. Each group worked with a different block weight: 11 kg, 14 kg or 16 kg. Productivity and durations of tasks and activities were assessed through real time observations at the work site. Energetic workload was also assessed through monitoring the heart rate and oxygen consumption at the work site. Spinal load of the low back was estimated by calculating the cumulated elastic energy stored in the lumbar spine using durations of activities and previous data on corresponding compression forces. Block weight had no effect on productivity, duration or frequency of tasks and activities, energetic workload or cumulative spinal load. Working with any of the block weights exceeded exposure guidelines for work demands and physical workload. This implies that, regardless of block weight in the range of 11 to 16 kg, mechanical lifting equipment or devices to adjust work height should be implemented to substantially lower the risk of low back injuries. |
2,333,084 | Effects of articaine on action potential characteristics and the underlying ion currents in canine ventricular myocytes. | In spite of its widespread clinical application, there is little information on the cellular cardiac effects of articaine. In the present study, the concentration-dependent effects of articaine on action potential morphology and the underlying ion currents were studied in isolated canine ventricular cardiomyocytes.</AbstractText>Action potentials were recorded from the enzymatically dispersed myocytes using sharp microelectrodes (16 cells from 3 dogs). Conventional patch clamp and action potential voltage clamp arrangements were used to study the effects of articaine on transmembrane ion currents (37 cells from 14 dogs).</AbstractText>Articaine-induced concentration-dependent changes in action potential configuration including shortening of the action potentials, reduction of their amplitude and maximum velocity of depolarization (V(max)), suppression of early repolarization and depression of plateau. The EC50 value obtained for the V(max) block was 162 (sd 30) microM. Both the reduction of V(max) and action potential shortening were frequency dependent: the former was more prominent at shorter, while the latter at longer pacing cycle lengths. A rate dependent V(max) block, having rapid offset kinetics [tau = 91 (20) ms], was observed in addition to tonic block. Under voltage clamp conditions, a variety of ion currents were blocked by articaine: I(Ca) [EC50 = 471 (75) microM], I(to) [EC50 = 365 (62) microM], I(K1) [EC50 = 372 (46) microM], I(Kr) [EC50 = 278 (79) microM], and I(Ks) [EC50 = 326 (65) microM]. Hill coefficients were close to unity indicating a single binding site for articaine, except for I(K1).</AbstractText>Articaine can modify cardiac action potentials and ion currents at concentrations higher than the therapeutic range which can be achieved only by accidental venous injection. Since its suppressive effects on the inward and outward currents are relatively well balanced, the articaine-induced changes in action potential morphology may be moderate even in the case of overdose.</AbstractText> |
2,333,085 | Accuracy of cerebral monitoring in detecting cerebral ischemia during carotid endarterectomy: a comparison of transcranial Doppler sonography, near-infrared spectroscopy, stump pressure, and somatosensory evoked potentials. | This study compares the accuracy of cerebral monitoring systems in detecting cerebral ischemia during carotid endarterectomy.</AbstractText>The authors compared transcranial Doppler sonography (TCD), near-infrared spectroscopy (NIRS), stump pressure (SP) measurement, and somatosensory evoked potentials (SEP) in 48 patients undergoing carotid surgery during regional anesthesia. Cerebral ischemia was assumed when neurologic deterioration occurred. During clamping, the minimum mean middle cerebral artery velocity (TCD(min)), its percentage change (TCD%), the minimum regional saturation of oxygen (NIRS(min)), its percentage change (NIRS%), the mean SP, and the changes of SEP amplitude were recorded. To analyze the corresponding sensitivity and specificity of each parameter, the authors performed receiver operating characteristic analysis.</AbstractText>Neurologic deterioration occurred in 12 patients. SP and NIRS were successfully performed in all patients. TCD monitoring was not possible in 10 (21%); SEP was not possible in 2 patients (4%). All parameters provided the ability to distinguish between ischemic and nonischemic patients. TCD% and NIRS% showed significantly better discrimination than TCD(min) and NIRS(min) (P < 0.05). The highest area under the curve (AUC) was found for TCD% (AUC = 0.973), but there was no significant difference compared with NIRS% (AUC = 0.905) and SP (AUC = 0.925). The lowest AUC was found for SEP (AUC = 0.749), which was significantly lower than that for TCD%, NIRS%, and SP.</AbstractText>TCD%, NIRS%, and SP measurement provide similar accuracy for the detection of cerebral ischemia during carotid surgery. Lower accuracy was found for SEP monitoring. Because of the high rate of technical difficulties (21%), TCD monitoring was the least practical of the investigated monitoring devices.</AbstractText> |
2,333,086 | Role of p38-mitogen-activated protein kinase in ischaemic preconditioning in rat heart. | 1. Activation of p38-mitogen-activated protein kinase (MAPK) has been implicated in the signalling cascade leading to protection by ischaemic preconditioning. This, however, is controversial and there is a plethora of conflicting data in the literature. Although many experimental differences may contribute to this, two in particular may be confounding: (i) the failure to account for p38-MAPK activation during aerobic perfusion; and (ii) the use of the anti-oxidant dimethylsulphoxide (DMSO) as the vehicle for the commonly used p38-MAPK inhibitor SB203580. We have investigated the effects of aerobic perfusion, ischaemia and preconditioning on p38-MAPK activation. In addition, we have used water-soluble SB203580 hydrochloride (SB203580.HCl) and DMSO to probe the role of p38-MAPK in preconditioning and ischaemic injury. 2. Activation of p38-MAPK in rat isolated hearts was assessed using a dual phosphospecific antibody during cannulation, aerobic perfusion and index, autolytic and preconditioned ischaemia. The effect of SB203580.HCl (10 mmol/L) in ischaemic preconditioning and ischaemia/reperfusion was tested using recovery of function and tetrazolium (TTC) staining as end-points. 3. Aerobic perfusion induced rapid activation (34% of maximal ischaemia-induced increase; P < 0.05) of p38-MAPK after 2 min that returned to baseline after 30 min. Index, autolytic and preconditioned ischaemia activated p38-MAPK, with index ischaemia peaking after 15 min (520% of basal; P < 0.05) before declining. SB203580.HCl blocked p38-MAPK activity, but did not block ischaemic preconditioning when bracketing the trigger phase and was not protective when given during ischaemia. 4. In the rat isolated heart, activation of p38-MAPK is neither a unique feature of preconditioning nor a prerequisite. Previous studies using SB203580 may have been complicated by failure to account for the activation of p38-MAPK by the protocol itself and the anti-oxidant properties of the most commonly used vehicle DMSO. |
2,333,087 | Fadrozole reverses cardiac fibrosis in spontaneously hypertensive heart failure rats: discordant enantioselectivity versus reduction of plasma aldosterone. | Reversal of cardiac fibrosis is a major determinant of the salutary effects of mineralocorticoid receptor antagonists in heart failure. Recently, R-fadrozole was coined as an aldosterone biosynthesis inhibitor, offering an appealing alternative to mineralocorticoid receptor antagonists to block aldosterone action. The present study aimed to evaluate the effects of R- and S-fadrozole on plasma aldosterone and urinary aldosterone excretion rate and to compare their effectiveness vs. the mineralocorticoid receptor antagonist potassium canrenoate to reverse established cardiac fibrosis. Male lean spontaneously hypertensive heart failure (SHHF) rats (40 wk) were treated for 8 wk by sc infusions of low (0.24 mg/kg.d) or high (1.2 mg/kg.d) doses of R- or S-fadrozole or by potassium canrenoate via drinking water (7.5 mg/kg.d). At the high dose, plasma aldosterone levels were decreased similarly by R- and S-fadrozole, whereas urinary aldosterone excretion rate was reduced only by S-fadrozole. In contrast, whereas at the high dose, R-fadrozole effectively reversed preexistent left ventricular interstitial fibrosis by 50% (vs. 42% for canrenoate), S-fadrozole was devoid of an antifibrotic effect. The low doses of the fadrozole enantiomers did not change cardiac fibrosis or plasma aldosterone but similarly reduced urinary aldosterone excretion rate. In conclusion, R-fadrozole may possess considerable therapeutic merit because of its potent antifibrotic actions in the heart. However, the observed discordance between the aldosterone-lowering and antifibrotic effects of the fadrozole enantiomers raises some doubt about the mechanism by which R-fadrozole diminishes cardiac collagen and about the generality of the concept of lowering aldosterone levels to treat the diseased heart. |
2,333,088 | Quasi-trapezoidal pulses to selectively block the activation of intrinsic laryngeal muscles during vagal nerve stimulation. | The stimulation of the vagus nerve has been used as an anti-epileptic treatment for over a decade, and its use for depression and chronic heart failure is currently under investigation. Co-activation of the intrinsic laryngeal muscles may limit the clinical use of vagal stimulation, especially in the case of prolonged activation. To prevent this, the use of a selective stimulation paradigm has been tested in seven acute pig experiments. Quasi-trapezoidal pulses successfully blocked the population of the largest and fastest vagal myelinated fibers being responsible for the co-activation. The first response in the vagus compound action potential was reduced by 75 +/- 22% (mean +/- SD) and the co-activated muscle action potential by 67 +/- 25%. The vagal bradycardic effects remained unchanged during the selective block, confirming the leading role of thin nerve fibers for the vagal control of the heart. Quasi-trapezoidal pulses may be an alternative to rectangular pulses in clinical vagal stimulation when the co-activation of laryngeal muscles must be avoided. |
2,333,089 | Low-frequency fluctuations in the cardiac rate as a source of variance in the resting-state fMRI BOLD signal. | Heart rate fluctuations occur in the low-frequency range (<0.1 Hz) probed in functional magnetic resonance imaging (fMRI) studies of resting-state functional connectivity and most fMRI block paradigms and may be related to low-frequency blood-oxygenation-level-dependent (BOLD) signal fluctuations. To investigate this hypothesis, temporal correlations between cardiac rate and resting-state fMRI signal timecourses were assessed at 3 T. Resting-state BOLD fMRI and accompanying physiological data were acquired and analyzed using cross-correlation and regression. Time-shifted cardiac rate timecourses were included as regressors in addition to established physiological regressors (RETROICOR (Glover, G.H., Li, T.Q., Ress, D., 2000. Image-based method for retrospective correction of physiological motion effects in fMRI: RETROICOR. Magn Reson Med 44, 162-167) and respiration volume per unit time (Birn, R.M., Diamond, J.B., Smith, M.A., Bandettini, P.A., 2006b. Separating respiratory-variation-related fluctuations from neuronal-activity-related fluctuations in fMRI. NeuroImage 31, 1536-1548). Significant correlations between the cardiac rate and BOLD signal timecourses were revealed, particularly negative correlations in gray matter at time shifts of 6-12 s and positive correlations at time shifts of 30-42 s (TR=6 s). Regressors consisting of cardiac rate timecourses shifted by delays of between 0 and 24 s explained an additional 1% of the BOLD signal variance on average over the whole brain across 9 subjects, a similar additional variance to that explained by respiration volume per unit time and RETROICOR regressors, even when used in combination with these other physiological regressors. This suggests that including such time-shifted cardiac rate regressors will be beneficial for explaining physiological noise variance and will thereby improve the statistical power in future task-based and resting-state fMRI studies. |
2,333,090 | Prenatal diagnosis of congenital complete heart block. | Congenital complete heart block (CHB) is a conduction defect with an incidence in the general population of 1/15,000 to 1/22,000 live births. It is frequently associated with structural heart defects or maternal autoimmune disease. We describe a case of CHB associated with maternal systemic lupus erythematosus and review our previous cases and experience of CHB. |
2,333,091 | Characterization of JC virus in cerebrospinal fluid from HIV-1 infected patients with progressive multifocal leukoencephalopathy: insights into viral pathogenesis and disease prognosis. | To analyze virological and immunological features of AIDS-related progressive multifocal leukoencepalophathy (PML) and their association to disease prognosis.</AbstractText>In HIV-infected patients with virologically confirmed PML, JC virus (JCV) DNA load and levels of Macrophage Chemoattractant Protein (MCP)-1 were determined in cerebrospinal fluid. JCV genotypes, rearrangements and JCV DNA binding sites for cellular transcription factors were analyzed by sequencing the viral VP1 region and regulatory region (RR).</AbstractText>45 patients were analyzed: 60% were exposed to highly active antiretroviral therapy (HAART) after PML and 24% before the disease onset. JCV DNA load in cerebrospinal fluid was a strong predictor of patients survival. Lower levels of JCV DNA in cerebrospinal fluid were associated with the following virologic factors: viral genotype 4 (p = 0.043), more rearrangements in the RR (p = 0.046), duplication of RR block B (p = 0.028), and duplication of binding sites for cellular transcription factor NF-1 (p = 0.060). In patients with prior antiretroviral exposure there was a trend towards a higher number of binding sites for cellular transcription factors (p = 0.068). Lower JCV load was also predicted by exposure to HAART (p = 0.010), higher baseline CD4 counts (p = 0.009) and higher cerebrospinal fluid MCP-1 levels (p = 0.036). In a multiple regression model, MCP-1 levels were independently associated with JCV load.</AbstractText>HAART leads to a partial immune-mediated control of JCV replication; the virus may tend to escape through the selection of rearrangements in the RR, some associated with enhanced viral replication efficiency, other resulting in multiplication of binding sites for cellular transcription factors.</AbstractText> |
2,333,092 | Novel 2,7-dialkyl-substituted 5(S)-amino-4(S)-hydroxy-8-phenyl-octanecarboxamide transition state peptidomimetics are potent and orally active inhibitors of human renin. | The action of renin is the rate-limiting step of the renin-angiotensin system (RAS), a key regulator of blood pressure. Effective renin inhibitors directly block the RAS entirely at source and, thus, may provide a vital weapon for hypertension therapy. Our efforts toward identifying novel small-molecule peptidomimetic renin inhibitors have resulted in the design of transition-state isosteres such as 1 bearing an all-carbon 8-phenyl-octanecarboxamide framework. Optimization of the extended P3 portion of 1 and extensive P2' modifications provided analogues with improved in vitro potencies in the presence of plasma. X-ray resolution of rh-renin/38a in the course of SAR work surprisingly unveiled the exploitation of a previously unexplored pocket (S3sp) important for strong binding affinities. Several inhibitors demonstrated oral efficacy in sodium-depleted marmosets. The most potent, 38a, induced dose-dependently a pronounced reduction in mean arterial blood pressure, paralleled by complete blockade of active plasma renin, up to 8 h post-dose. Oral bioavailability of 38a was 16% in marmosets. |
2,333,093 | Inhibition of L-type Ca2+ channel current and negative inotropy induced by arachidonic acid in adult rat ventricular myocytes. | We have previously shown an increase in arachidonic acid (AA) release in response to proinflammatory cytokines in adult rat ventricular myocytes (ARVM). AA is known to alter channel activities; however, its effects on cardiac L-type Ca(2+) channel current (I(Ca,L)) and excitation-contraction coupling remain unclear. The present study examined effects of AA on I(Ca,L), using the whole cell patch-clamp technique, and on cell shortening (CS) and the Ca(2+) transient of ARVM. I(Ca,L) was monitored in myocytes held at -70 mV and internally equilibrated and externally perfused with Na(+)- and K(+)-free solutions. Exposure to AA caused a voltage-dependent block of I(Ca,L) concentration dependently (IC(50) 8.5 microM). The AA-induced inhibition of I(Ca,L) is consistent with its hyperpolarizing shift in the voltage-dependent properties and reduction in maximum slope conductance. In the presence of AA, BSA completely blocked the AA-induced suppression of I(Ca,L) and CS. Intracellular load with AA had no effect on the current density but caused a small depolarizing shift in the I(Ca,L) activation curve, suggesting a site-specific action of AA. Moreover, intracellular AA had no effect on the extracellular AA-induced decrease in I(Ca,L). Pretreatment with indomethacin, an inhibitor of cyclooxygenase, or addition of nordihydroguaiaretic acid, an inhibitor of lipoxygenase, had no effect on AA-induced changes in I(Ca,L). Furthermore, AA suppressed CS and Ca(2+) transients of intact ARVM with no significant effect on SR function and myofilament Ca(2+) sensitivity. Therefore, these results suggest that AA inhibits contractile function of ARVM, primarily due to its direct inhibition of I(Ca,L) at an extracellular site. |
2,333,094 | Discovery and combinatorial synthesis of fungal metabolites beauveriolides, novel antiatherosclerotic agents. | For discovery of a new type of antiatherosclerotic agents, a cell-based assay of lipid droplet accumulation using primary mouse peritoneal macrophages was conducted as a model of macrophage-derived foam cell accumulation, which occurs in the early stage of atherosclerogenesis. During the screening of microbial metabolites for inhibitors of lipid droplet accumulation, 13-membered cyclodepsipeptides, known beauveriolide I and new beauveriolide III, were isolated from the culture broth of fungal Beauveria sp. FO-6979, a soil isolate, by solvent extraction, ODS column chromatography, silica gel column chromatography, and preparative HPLC. The structure including the absolute stereochemistry of beauveriolide III was elucidated as cyclo-[(3 S,4 S)-3-hydroxy-4-methyloctanoyl- l-phenylalanyl- l-alanyl- d-alloisoleucyl] by spectral analyses, amino acid analyses, and synthetic methods. Furthermore, the absolute stereochemistry was confirmed by the total synthesis of beauveriolides. Study on the mechanism of action revealed that beauveriolides inhibited macrophage acyl-CoA:cholesterol acyltransferase (ACAT) activity to block the synthesis of cholesteryl ester (CE), leading to a reduction of lipid droplets in macrophages. There are two ACAT isozymes in mammals, ACAT1 and ACAT2. ACAT1 is ubiquitously expressed in most tissues and cells including macrophages, while ACAT2 is expressed predominantly in the liver (hepatocytes) and the intestine (enterocytes). Interestingly, beauveriolides inhibited both ACAT1 and ACAT2 to a similar extent in an enzyme assay that utilized microsomes but inhibited ACAT1 selectively in intact cell-based assays. Beauveriolides proved orally active in both low-density lipoprotein receptor and apolipoprotein E knockout mice, reducing the atheroma lesion of heart and aorta without any side effects such as diarrhea or cytotoxicity to adrenal tissues as observed for many synthetic ACAT inhibitors. To obtain more potent inhibitors, a focused library of beauveriolide analogues was prepared by combinatorial chemistry in which solid-phase assembly of linear depsipeptides was carried out using a 2-chlorotrityl linker, followed by solution-phase cyclization, yielding 104 beauveriolide analogues. Among them, diphenyl derivatives were found to show 10 times more potent inhibition of CE synthesis in macrophages than beauveriolide III. Furthermore, most analogues showed selective ACAT1 inhibition or inhibition of both ACAT1 and ACAT2, but interestingly certain analogues gave selective ACAT2 inhibition. These data indicated that subtle structural differences of the inhibitors could discriminate the active sites of the ACAT1 and ACAT2 isozymes. Efforts of further analogue synthesis would make it possible to obtain highly selective ACAT1/ACAT2 inhibitors. |
2,333,095 | Changes in respiratory and hemodynamic parameters during low-dose propofol sedation in combination with regional anesthesia for herniorrhaphy and genitourinary surgery in children. | Spontaneous vs mechanical ventilation during propofol sedation has been a subject of debate. We evaluated the safety of low-dose propofol sedation as an adjunct to regional anesthesia during herniorrhaphy and genitourinary surgery in infants and children.</AbstractText>The study was conducted in a prospective, nonrandomized manner using a consecutive sample of 62 American Society of Anesthesiologists physical status class I patients between 5 months to 11 years of age in the surgery unit of an urban University Hospital. Propofol sedation (4-8 mg x kg(-1) x h(-1) continuous infusion) was used with regional anesthesia (caudal, ilioinguinal/iliohypogastric nerve or penile block with 0.2-0.375% ropivacaine). All children were spontaneously breathing without an anesthesia circuit. Respiratory and hemodynamic parameters were continuously recorded on all patients. One-way analysis of variance (ANOVA) for repeated measurements was used to analyze changes in respiratory and hemodynamic parameters during the procedure.</AbstractText>Spontaneous ventilation was maintained in all patients with minimal changes in hemodynamic parameters. Heart rate, mean arterial pressure, and P(E)CO(2) remained stable throughout the study period: 23/62 (37%) patients exhibited signs of developing intrinsic endexpiratory pressure (PEEPi) or the presence of PEEPi because of progressive reduction of expiratory time.</AbstractText>Low-dose propofol sedation in combination with regional anesthesia for elective herniorrhaphy and genitourinary surgery in children maintains spontaneous ventilation and has minimal effects on hemodynamic parameters for sedation lasting <1 h. The presence of PEEPi is a relative contraindication to the use of this regimen in children with asthma or history of upper airway infections.</AbstractText> |
2,333,096 | Carbon monoxide and Ca2+-activated K+ channels in cerebral arteriolar responses to glutamate and hypoxia in newborn pigs. | Large-conductance calcium-activated potassium (K(Ca)) channels regulate the physiological functions of many tissues, including cerebrovascular smooth muscle. l-Glutamic acid (glutamate) is the principal excitatory neurotransmitter in the central nervous system, and oxygen tension is a dominant local regulator of vascular tone. In vivo, glutamate and hypoxia dilate newborn pig cerebral arterioles, and both dilations are blocked by inhibition of carbon monoxide (CO) production. CO dilates cerebral arterioles by activating K(Ca) channels. Therefore, the present study was designed to investigate the effects of glutamate and hypoxia on cerebral CO production and the role of K(Ca) channels in the cerebral arteriolar dilations to glutamate and hypoxia. In the presence of iberiotoxin or paxilline that block dilation to the K(Ca) channel opener, NS-1619, neither CO nor glutamate dilated pial arterioles. Conversely, neither paxilline nor iberiotoxin inhibited dilation to acute severe or moderate prolonged hypoxia. Both glutamate and hypoxia increased cerebrospinal fluid (CSF) CO concentration. Iberiotoxin that blocked dilation to glutamate did not attenuate the increase in CSF CO. The guanylyl cyclase inhibitor, 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (ODQ), which blocked dilation to sodium nitroprusside, did not inhibit dilation to hypoxia. These data suggest that dilation of newborn pig pial arterioles to glutamate is mediated by activation of K(Ca) channels, consistent with the intermediary signal being CO. Surprisingly, although 1) heme oxygenase (HO) inhibition attenuates dilation to hypoxia, 2) hypoxia increases CSF CO concentration, and 3) K(Ca) channel antagonists block dilation to CO, neither K(Ca) channel blockers nor ODQ altered dilation to hypoxia, suggesting the contribution of the HO/CO system to hypoxia-induced dilation is not by stimulating vascular smooth muscle K(Ca) channels or guanylyl cyclase. |
2,333,097 | Treatment potential for cholesterol management in patients with coronary heart disease in 15 European countries: findings from the EUROASPIRE II survey. | During the last decade, the evidence of beneficial effects of cholesterol lowering in patients with coronary heart disease (CHD) has been proven in several clinical trials. This has prompted international guidelines on prevention of CHD to include recommendations on dietary and pharmacological treatment of hyperlipidaemia with set goals on total- and LDL-cholesterol.</AbstractText>The first EUROASPIRE survey performed in 1995/1996 showed poor adherence to the European recommendations on lipid-lowering in patients with CHD. The second survey was carried out in 1999/2000 in 15 European countries and enrolled 8181 patients with CHD. Medical records were assessed and clinical examinations of risk factors including serum lipids were performed. The aim of this survey is to describe the treatment of hyperlipidaemia among CHD patients in Europe.</AbstractText>The proportion of patients not reaching the target of 5.0mmol/l was 58.3% with significant variations between countries. The use of lipid-lowering drugs was relatively high (60.9%). However, the most frequently used doses of lipid-lowering agents were much lower than the doses of proven effect used in clinical trials.</AbstractText>Although the treatment of hyperlipidaemia in CHD patients seems to be improving as compared to the first survey, a significant number of patients do not reach treatment goals. If the full potential of lipid-lowering therapy was utilised with all eligible patients treated and doses titrated correctly, more patients would benefit in terms of reduced morbidity and mortality of CHD.</AbstractText> |
2,333,098 | Comparative study of epidural administration of 10 ml of 0.1% bupivacaine with 2 mg butorphanol and 10 ml of 0.25% plain bupivacaine for analgesia during labor. | Analgesia during labor provided by two epidural drug regimens was compared in a double blind, randomized, prospective study. Group A (n = 12) received 10 ml bolus doses of 0.1% bupivacaine with butorphanol 2 mg while Group B (n = 8) received 10 ml of 0.25% plain bupivacaine. The objectives of this study was to compare, between the quality of an epidural labor analgesia using initial loading dose of 0.1% bupivacaine and 2 mg butorphanol with a initial loading dose of 0.25% bupivacaine. In Group A, incidence of motor block was 8.3% and that of prolong 2nd stage of labor was 16.7%, both were decreased in comparison with Group B, although they were not statistically significant. Hemodynamic variables were stable and no adverse neonatal and maternal outcome was observed in both groups. Addition of butorphanol to bupivacaine may be safe alternative to reduce motor block and decrease prolong 2nd stage for epidural labor analgesia. |
2,333,099 | Epinephrine in local anesthetic cancels increase in tongue mucosal blood flow after stellate ganglion block in rabbit. | The goal of this study was to compare oral mucosal blood flow and duration of anesthetic action after stellate ganglion block (SGB) using lidocaine, with or without epinephrine, and discuss the effect of epinephrine on SGB. Duration of anesthetic action was defined as elapsed time from finish of injection to recovery of common carotid blood flow (CCBF) to within+/-5% of respective control value. Male Japan White rabbits were anesthetized with isoflurane and mechanically ventilated. Common carotid blood flow and tongue mucosal tissue blood flow (TMBF) were measured with an ultrasound flowmeter and laser Doppler flowmeter, respectively. End-tidal partial pressure of carbon dioxide (ETCO(2)) and hemodynamic variables were continuously monitored, including heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP). For SGB, the tip of the needle was placed on the left transverse process of the cervical vertebra, 1-2 mm caudal to the cricoid cartilage. Either 0.1 ml of 1% lidocaine (Group L) or 1% lidocaine containing 10 mug/ml epinephrine (Group LE) was injected for SGB. There were no differences in values at immediately before SGB and at the time when maximal change in CCBF was observed after SGB for ETCO(2), HR, SBP, DBP or MAP in either group. CCBF showed a significant increase in Group L after SGB. In contrast, CCBF only showed a slight increase in Group LE. TMBF showed a significant increase in Group L after SGB, but not in Group LE. No differences in time required for maximal effect were observed between the two groups. In contrast, duration of anesthetic action in Group LE was significantly longer than that in Group L. Addition of epinephrine to local anesthetic solutions is not suitable for SGB, as it may not facilitate an increase in tissue blood flow, which is the primary objective of SGB. |
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