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2,333,900 |
To B or not to B cells-mediate a healthy start to life.
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Maternal immune responses during pregnancy are critical in programming the future health of a newborn. The maternal immune system is required to accommodate fetal immune tolerance as well as to provide a protective defence against infections for the immunocompromised mother and her baby during gestation and lactation. Natural immunity and antibody production by maternal B cells play a significant role in providing such immunoprotection. However, aberrations in the B cell compartment as a consequence of maternal autoimmunity can pose serious risks to both the mother and her baby. Despite their potential implication in shaping pregnancy outcomes, the role of B cells in human pregnancy has been poorly studied. This review focuses on the role of B cells and the implications of B cell depletion therapy in pregnancy. It highlights the evidence of an association between aberrant B cell compartment and obstetric conditions. It also alludes to the potential mechanisms that amplify these B cell aberrances and thereby contribute to exacerbation of some maternal autoimmune conditions and poor neonatal outcomes. Clinical and experimental evidence suggests strongly that maternal autoantibodies contribute directly to the pathologies of obstetric and neonatal conditions that have significant implications for the lifelong health of a newborn. The evidence for clinical benefit and safety of B cell depletion therapies in pregnancy is reviewed, and an argument is mounted for further clinical evaluation of B cell-targeted therapies in high-risk pregnancy, with an emphasis on improving neonatal outcomes and prevention of neonatal conditions such as congenital heart block and fetal/neonatal alloimmune thrombocytopenia.
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2,333,901 |
Epidural anesthesia and postoperatory analgesia with alpha-2 adrenergic agonists and lidocaine for ovariohysterectomy in bitches.
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The aim of this study was to determine the viability and cardiorespiratory effects of the association of epidural alpha-2 adrenergic agonists and lidocaine for ovariohysterectomy (OH) in bitches. Forty-two bitches were spayed under epidural anesthesia with 2.5 mg/kg body weight (BW) of 1% lidocaine with adrenaline (CON) or in association with 0.25 mg/kg BW of xylazine (XYL), 10 μg/kg BW of romifidine (ROM), 30 μg/kg BW of detomidine (DET), 2 μg/kg BW of dexmedetomidine (DEX), or 5 μg/kg BW of clonidine (CLO). Heart rate (HR), respiratory rate (fR) and arterial pressures were monitored immediately before and every 10 min after the epidural procedure. Blood gas and pH analysis were done before, and at 30 and 60 min after the epidural procedure. Animals were submitted to isoflurane anesthesia if they presented a slightest sign of discomfort during the procedure. Time of sensory epidural block and postoperative analgesia were evaluated. All animals in CON and DEX, 5 animals in ROM and CLO, 4 animals in XYL, and 3 in DET required supplementary isoflurane. All groups, except CLO, showed a decrease in HR. There was an increase in arterial pressures in all groups. Postoperative analgesia lasted the longest in XYL. None of the protocols were totally efficient to perform the complete procedure of OH; however, xylazine provided longer postoperative analgesia than the others.</Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Pohl</LastName><ForeName>Virgínia H</ForeName><Initials>VH</Initials><AffiliationInfo><Affiliation>Rural Science Center, Federal University of Santa Maria, Santa Maria, RS, Brazil, 97105-900.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Carregaro</LastName><ForeName>Adriano B</ForeName><Initials>AB</Initials></Author><Author ValidYN="Y"><LastName>Lopes</LastName><ForeName>Carlize</ForeName><Initials>C</Initials></Author><Author ValidYN="Y"><LastName>Gehrcke</LastName><ForeName>Martielo I</ForeName><Initials>MI</Initials></Author><Author ValidYN="Y"><LastName>Muller</LastName><ForeName>Daniel C M</ForeName><Initials>DC</Initials></Author><Author ValidYN="Y"><LastName>Garlet</LastName><ForeName>Clarissa D</ForeName><Initials>CD</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D016449">Randomized Controlled Trial</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>Canada</Country><MedlineTA>Can J Vet Res</MedlineTA><NlmUniqueID>8607793</NlmUniqueID><ISSNLinking>0830-9000</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D058647">Adrenergic alpha-2 Receptor Agonists</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000701">Analgesics, Opioid</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000894">Anti-Inflammatory Agents, Non-Steroidal</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D006993">Hypnotics and Sedatives</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D013843">Thiazines</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D013844">Thiazoles</NameOfSubstance></Chemical><Chemical><RegistryNumber>76I7G6D29C</RegistryNumber><NameOfSubstance UI="D009020">Morphine</NameOfSubstance></Chemical><Chemical><RegistryNumber>98PI200987</RegistryNumber><NameOfSubstance UI="D008012">Lidocaine</NameOfSubstance></Chemical><Chemical><RegistryNumber>VG2QF83CGL</RegistryNumber><NameOfSubstance UI="D000077239">Meloxicam</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D058647" MajorTopicYN="N">Adrenergic alpha-2 Receptor Agonists</DescriptorName><QualifierName UI="Q000008" MajorTopicYN="N">administration & dosage</QualifierName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000701" MajorTopicYN="N">Analgesics, Opioid</DescriptorName><QualifierName UI="Q000008" MajorTopicYN="N">administration & dosage</QualifierName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000767" MajorTopicYN="N">Anesthesia, Epidural</DescriptorName><QualifierName UI="Q000662" MajorTopicYN="Y">veterinary</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000894" MajorTopicYN="N">Anti-Inflammatory Agents, Non-Steroidal</DescriptorName><QualifierName UI="Q000008" MajorTopicYN="N">administration & dosage</QualifierName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D004285" MajorTopicYN="N">Dogs</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006993" MajorTopicYN="N">Hypnotics and Sedatives</DescriptorName><QualifierName UI="Q000008" MajorTopicYN="N">administration & dosage</QualifierName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D007044" MajorTopicYN="N">Hysterectomy</DescriptorName><QualifierName UI="Q000662" MajorTopicYN="Y">veterinary</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008012" MajorTopicYN="N">Lidocaine</DescriptorName><QualifierName UI="Q000008" MajorTopicYN="N">administration & dosage</QualifierName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000077239" MajorTopicYN="N">Meloxicam</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D009020" MajorTopicYN="N">Morphine</DescriptorName><QualifierName UI="Q000008" MajorTopicYN="N">administration & dosage</QualifierName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D010052" MajorTopicYN="N">Ovariectomy</DescriptorName><QualifierName UI="Q000662" MajorTopicYN="Y">veterinary</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D010149" MajorTopicYN="N">Pain, Postoperative</DescriptorName><QualifierName UI="Q000517" MajorTopicYN="N">prevention & control</QualifierName><QualifierName UI="Q000662" MajorTopicYN="Y">veterinary</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D013843" MajorTopicYN="N">Thiazines</DescriptorName><QualifierName UI="Q000008" MajorTopicYN="N">administration & dosage</QualifierName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D013844" MajorTopicYN="N">Thiazoles</DescriptorName><QualifierName UI="Q000008" MajorTopicYN="N">administration & dosage</QualifierName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading></MeshHeadingList><OtherAbstract Type="Publisher" Language="fre">L’objectif de la présente étude était de déterminer l’efficacité et les effets cardio-respiratoires d’une anesthésie épidurale par combinaison d’agonistes adrénergiques alpha-2 et de lidocaïne pour effectuer une hystéro-ovariectomie (OH) chez des chiennes. Quarante-deux chiennes ont été châtrées sous anesthésie épidurale réalisée avec de la lidocaïne 1 % à un dosage de 2,5 mg/kg de poids vif (BW) avec de l’adrénaline (CON) ou en association avec 0,25 mg/kg BW de xylazine (XYL), 10 μg/kg BW de romifidine (ROM), 30 μg/kg BW de detomidine (DET), 2 μg/kg de dexmedetomidine (DEX), ou 5 μg/kg BW de clonidine (CLO). La fréquence cardiaque (HR), le rythme respiratoire (f<sub>R</sub>) et la pression artérielle ont été mesurés immédiatement avant et à des intervalles de 10 minutes après la procédure épidurale. Des analyses des gaz sanguins et du pH ont été effectuées avant et 30 et 60 minutes après la procédure épidurale. Les animaux ont été mis sous anesthésie à l’isoflurane s’ils présentaient le moindre signe d’inconfort durant la procédure. La durée du temps de blocage sensitif et d’analgésie postopératoire a été évaluée. Tous les animaux CON et DEX, 5 animaux ROM et CLO, 4 animaux XYL et 3 animaux DET ont nécessité de l’isoflurane. Tous les groupes, sauf le groupe CLO, ont présenté une réduction de HR. Il y a eu une augmentation de la pression artérielle dans tous les groupes. L’analgésie post-opératoire a été la plus longue dans le groupe XYL. Aucun des protocoles n’était complètement efficace pour permettre la procédure complète d’OH; toutefois, la xylazine a fourni une analgésie post-opératoire plus longue que les autres médicaments. Traduit par Docteur Serge Messier
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2,333,902 |
Initial assessment of single and repeat doses of inhaled umeclidinium in patients with chronic obstructive pulmonary disease: two randomised studies.
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To characterise the safety, tolerability, pharmacodynamics (bronchodilatory effect) and pharmacokinetics of inhaled umeclidinium in patients with chronic obstructive pulmonary disease (COPD). The first investigation was a single dose, randomised, double-blind, placebo-controlled study (clinicaltrials.gov: NCT00515502) in which ipratropium bromide-sensitive patients received umeclidinium (250μg, 500μg, and 1000μg), tiotropium bromide 18μg or placebo. Patients were randomised to receive four out of five possible treatments as an incomplete block four-way cross-over. A subsequent study (clinicaltrials.gov: NCT700732472) was focused on assessment of safety, tolerability and pharmacokinetics of umeclidinium (250μg and 1000μg) administered once-daily for 7 days in a randomised, double-blind, placebo-controlled, parallel-group design. Of the 24 patients randomised for the single dose study, 20 completed; 31 out of 38 patients completed the repeat dose study. Most adverse events were mild-to-moderate and transient. Examination of heart rate, QTc interval, blood pressure and clinical laboratory assessments raised no concern over the safety of umeclidinium. Evidence of pharmacology was demonstrated in first study by statistically significant increases in specific airway conductance (sGaw) for up to 24h for all active treatments compared with placebo. Increases in forced expiratory volume in 1s were also observed. Pharmacokinetic analysis demonstrated that maximum observed plasma umeclidinium concentration (Cmax) was reached rapidly (time to Cmax: ∼5-15min) after single and repeat doses; 1.5-1.9-fold accumulation was observed after repeat-dosing. Single and repeat doses of umeclidinium were well tolerated and produced clinically relevant lung function improvements over 24h in patients with COPD.
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2,333,903 |
Effect of mepivacaine in an infraorbital nerve block on minimum alveolar concentration of isoflurane in clinically normal anesthetized dogs undergoing a modified form of dental dolorimetry.
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To evaluate the effects of a routinely used infraorbital nerve block, performed for dental procedures, on the anesthetic requirement for isoflurane in dogs.</AbstractText>Prospective controlled study.</AbstractText>8 healthy adult Beagles.</AbstractText>Dogs were anesthetized with isoflurane, and the minimum alveolar concentration (MAC) of isoflurane was established. A modification of a well-established method of stimulating the dental pulp, dental dolorimetry, was used to deliver a noxious stimulus (electrical stimulation) for isoflurane MAC determination. Once the isoflurane MAC was established, an infraorbital nerve block was performed with mepivacaine. The isoflurane MAC was then determined with the addition of the nerve block. Measurements of heart rate and mean arterial blood pressure were obtained at specified time points (baseline and prevention and elicitation of purposeful movement) during the determination of MAC and in response to the noxious stimulus.</AbstractText>The mean ± SD isoflurane MAC without an infraorbital nerve block was 1.12 ± 0.13%. Isoflurane MAC with the regional mepivacaine anesthesia was 0.86 ± 0.11%. A significant reduction in isoflurane MAC (23%) was seen after the infraorbital nerve block, compared with results before the nerve block. With the exception of baseline measurements, no significant differences were found between treatments (isoflurane alone vs isoflurane with regional mepivacaine anesthesia) in heart rate or mean arterial blood pressure before or after the noxious stimulus.</AbstractText>The significant reduction in MAC of isoflurane supported the practice of the addition of regional anesthesia for painful dental procedures to reduce the dose-dependent cardiorespiratory effects of general anesthesia.</AbstractText>
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2,333,904 |
Spectral heart rate variability in rats with cyclophosphamide-induced hemorrhagic cystitis treated with cyclooxygenase inhibitors.
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The pathogenesis of cyclophosphamide-induced hemorrhagic cystitis (CP-HC) is complex, involving the im- pact of many systemically and locally released agents on autonomic nervous system (ANS) activity, that affects bladder functioning. The purpose of our study was to provide an indirect evaluation of ANS functional status in experimental CP-HC model, involving prostaglandin synthesis block resulting from administration of cyclooxygenase inhibitors. The ANS activity was estimated through the spectral analysis of heart rate variability (HRV) in CP-HC rats divided into three study groups: 1-control, 2-treated with meloxicam (MLX) that preferentially blocks COX-2, and 3-treated with piroxicam (PRX) that inhibits COX1 and 2 activity. In animals treated either with MLX or PRX, the percent distribution of the spectrum in relation to components of very low (VLF) and low (LF) frequency was not different from the control group. PRX-treated group displayed nearly two times lower percent share of the high frequency (HF) component compared to the control. Moreover, an increase of the normalized LF (nLF) value with simultaneous reduction of the normalized HF (nHF) value were noted in PRX-treated rat with no change of these parameters for MLX-treated rats. The HRV analysis in CP-HC rats receiving PRX, indicated a functional reorganization manifested by reduced parasym- pathetic activity and increased sympathetic tonus. A partial prostaglandin synthesis block caused by COX-2 inhibitor (meloxicam) caused no significant changes of evaluated HRV parameters compared to the control. Assessing functional changes of the ANS caused by prostaglandin synthesis block it should be stated that prostaglandins synthesized by the constitutive COX-1 isoform seem to maintain the parasympathetic activity, which may be associated with the cholinergic anti-inflammatory pathway and resolution of inflammation in course of cyclophosphamide-induced cystitis.
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2,333,905 |
Transtracheal lidocaine injection reduces the anesthetic requirements in brachial plexus surgeries.
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The purpose of this study was to evaluate the efficacy of transtracheal lidocaine injection to reduce the anesthetic requirements in patients who underwent brachial plexus surgery under general anesthesia.</AbstractText>This was a prospective randomized controlled study conducted in 40 consecutive adult patients.</AbstractText>The patients were randomly allotted to two groups of 20 patients each. Group A patients received a transtracheal injection of 4 ml of 2% lidocaine before induction of anesthesia and group B patients did not receive it. The two groups were compared in terms of intraoperative propofol requirements and hemodynamic parameters.</AbstractText>Statistical analysis was done using Student's t-test for independent samples.</AbstractText>The propofol requirements were significantly less in group A in terms of the number of intraoperative events requiring propofol bolus at various time intervals in 3 h duration (4 vs. 77), the number of patients requiring propofol bolus injections (2 vs. 20), propofol infusion (0 vs. 20), and total propofol requirement (6 vs. 377 mg). After induction, patients in group B showed a statistically significant high heart rate, systolic blood pressure, and mean arterial pressure.</AbstractText>The present study showed that the group of patients who received transtracheal block with lidocaine had a reduction in the requirement of the induction agent, propofol, and were more stable hemodynamically in the intraoperative period compared to those patients who did not receive transtracheal lidocaine. We conclude that transtracheal injection of lidocaine performed just prior to induction of general anesthesia is an effective alternative to intraoperative propofol infusion when long-acting muscle relaxants are to be avoided.</AbstractText>
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2,333,906 |
Addition of intrathecal fentanyl to bupivacaine clonidine mixture effect on quality of subarachnoid block and postoperative analgesia.
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This study was undertaken in 100 patients scheduled for lower limb orthopaedic surgeries.</AbstractText>The objective of this study was to study the effect of addition of intrathecal fentanyl to bupivacaine clonidine mixture on the quality of subarachnoid block and compare it with intrathecal bupivacaine clonidine mixture without fentanyl.</AbstractText>In this prospective and double blind randomized controlled study, one hundred patients, between 20-40 years of age, of either sex, weighing between 40-65 Kg, measuring more than 150 cm in height, of ASA Grade I and II who were undergoing orthopaedic lower limb surgeries were selected in order to study the quality of subarachnoid block and post-operative analgesia produced by a combination of bupivacaine clonidine and fentanyl in comparison with bupivacaine clonidine.</AbstractText>The patients were randomly divided in two groups of 50 each: Group BC: 2.4 ml of 0.5% hyperbaric bupivacaine (12 mg) + 0.2 ml (30 μg) clonidine + 0.4 ml of 0.9% NaCl. Group BCF: 2.4 ml of 0.5% hyperbaric bupivacaine (12 mg) + 0.2 ml (30 μg) clonidine + 0.4 ml (20 μg) of fentanyl. The total volume of solution in both the groups was 3.0 ml. The quality of subarachnoid block and post-operative analgesia were studied.</AbstractText>The data thus obtained was statistically analysed using the following tests: Unpaired student's t-test. Average % change in data over baseline values to detect trends. A 'P' value of <0.05 was considered to be statistically significant.</AbstractText>There was no significant difference in duration of sensory and motor blockade in group BCF compared to BC. The duration of analgesia as assessed by, either VAS score of >5 or demand of additional analgesia was > 524.6 ± 32.21 mins in group BC and > 774.4 ± 59.59 mins in group BCF. This prolongation of duration of analgesia in group BCF compared to group BC has statistical significance. Blood pressure and heart rate changes were not significantly different among groups, whereas sedation and pruritus were significantly more frequent in Group BCF.</AbstractText>In conclusion, this study has demonstrated that addition of 20 μg fentanyl to intrathecal 30 μg clonidine and 12 mg bupivacaine enhanced the duration of post-operative analgesia with moderately increased sedation and was not associated with hemodynamic instability or other complications.</AbstractText>
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2,333,907 |
Efficacy and safety of intrathecal pentazocine as a sole anesthetic agent for lower limb surgeries.
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The administration of opioids intrathecally as a sole anesthetic has proven to be effective in providing adequate surgical anesthesia without much hemodynamic instability.</AbstractText>This study aims to determine the efficacy and safety of intrathecal pentazocine as a sole anesthetic drug in patients undergoing lower limb surgeries.</AbstractText>It was a randomized single blinded study conducted in 60 patients undergoing lower limb surgeries.</AbstractText>The patients were randomly divided into 2 groups of 30 patients in each group. Group A received 2 ml (60 mg) intrathecal pentazocine and Group B received 2 ml intrathecal 0.5% bupivacaine heavy before surgery. Duration of surgery, onset of sensory, and motor blockade and their duration, heart rate (HR), mean arterial pressure (MAP), and time for first rescue analgesia were statistically analyzed.</AbstractText>Group B showed a statistically significant earlier onset of sensory (2.54 ± 0.87 vs. 3.66 ± 1.10 min) and motor blocks (2.22 ± 0.77 vs. 3.29 ± 1.06 min). The majority of patients in the group A (30%) attained the highest level of sensory block of T11, whereas the majority in group B (33.3%) attained the highest level of sensory block of T8. Majority in the Group A (60%) showed a motor block of Bromage scale Grade III at the beginning of surgery, whereas the majority in Group B (80%) showed a motor block of Bromage scale Grade IV. Duration of sensory block was significantly prolonged in group B (124.33 ± 14.84 vs. 115.60 ± 18.39 min). However, duration of motor blockade was similar in both groups. Group B patients required first analgesia earlier than Group A (5.24 ± 1.98 h vs. 2.48 ± 0.51 h) which was significant. There was no difference between groups with regard to HR intra-operatively. On comparison of the pre-induction MAP between 2 groups, there was no difference. But later on at 1, 3, 5 min intervals, the MAP was less in group B. But at 10 and 15 min there was no significant difference between groups. The significantly reduced MAP in group B was evident again at 30, 45, and 60 min. There was no difference between groups at 90 and 120 min. Group B required first analgesia earlier than group A which was statistically significant.</AbstractText>Because of adequate surgical anesthesia, intraoperative hemodynamic stability and prolonged post-operative analgesia, we recommend the use of intrathecal pentazocine as a sole anesthetic agent for lower limb surgeries.</AbstractText>
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2,333,908 |
Thoracic epidural anesthesia for laparoscopic cholecystectomy using either bupivacaine or a mixture of bupivacaine and clonidine: A comparative clinical study.
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Traditionally laparoscopic cholecystectomy is done under general anesthesia. But recently there is a growing interest to get it conducted under central neuraxial blockade. We conducted a clinical study comprising bupivacaine alone or a combination of bupivacaine and clonidine (2 μg/kg) in thoracic epidural anesthesia for laparoscopic cholecystectomy (LC). The aim was to attenuate the undesirable hemodynamic changes due to pneumoperitoneum (PNO) and achieve a better qualitative blockade.</AbstractText>After taking approval from Institutional Ethical Committee, 50 adult patients of ASA grade I and II were divided into two groups; group A where bupivacaine was given with 2 μg/kg of clonidine (Cloneon, Neon) and in group B bupivacaine (Anawin, Neon) was given with 1 ml of saline as placebo. Thoracic epidural was given at the T9-T10 or T10-T11 interspace to obtain a block of T4-L2 dermatome. Hemodynamic parameters like heart rate (HR), noninvasive blood pressure (NIBP), respiratory rate (RR), electrocardiogram (ECG), oxygen saturation (SpO2) and arterial pressure of carbon dioxide (PaCO2) were monitored and readings were recorded before and 10 minutes (min.) after the blockade and then at 5 min, 15 min and 30 min after PNO and 15 min after exsufflation.</AbstractText>All the parameters of the patients in group A remained stable but the patients of group B showed an increase in mean arterial pressure (MAP) and HR at 5, 15 and 30 min after PNO and 15 min after exsufflation as compared to Group A. PaCO2, SpO2 and RR values in both the groups were comparable. In group A, two patients complained of shoulder pain while in group B12 patients complained of shoulder pain.</AbstractText>Thoracic epidural anesthesia for LC is a satisfactory alternative technique in selected cases. Addition of clonidine (2 μg/kg) to bupivacaine produces better qualitative anesthetic conditions. It prevents hemodynamic perturbations produced by pneumoperitoneum and also decreases the incidence of shoulder pain. Thus we strongly advocate the incorporation of clonidine as an adjuvant in thoracic epidural anesthesia for LC.</AbstractText>
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2,333,909 |
Can low dose spinal anesthesia combined with ultrasound guided bilateral ilioinguinal-iliohypogastric nerve blocks avoid use of additional epidural catheter in high risk obstetric cases? Our experience from two cases.
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Critical obstetric cases associated with cardiac pathology may pose real challenge for anaesthesiologist during Caesarean section. Meticulous perioperative care and suitable selection of anaesthesia technique are the key to successful outcome. Single shot spinal anaesthesia is not used any more because of serious haemodynamic consequence. Progressive and controlled epidural local anaesthetic injection is mostly used in such cases. But recently combined spinal epidural anaesthesia and continuous spinal anaesthesia are suggested due to better precise control of haemodynamics and quicker onset. However, institution of such complex technique may require time which may not be feasible in emergency situations. Use of bilateral ilioinguinal-iliohypogastric nerve block along with low dose spinal anaesthesia may obviate the need of additional epidural catheter in such complicated cases. We hereby present our experience from two cases.
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2,333,910 |
The anti-motility signaling mechanism of TGFβ3 that controls cell traffic during skin wound healing.
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When skin is wounded, migration of epidermal keratinocytes at the wound edge initiates within hours, whereas migration of dermal fibroblasts toward the wounded area remains undetectable until several days later. This "cell type traffic" regulation ensures proper healing of the wound, as disruptions of the regulation could either cause delay of wound healing or result in hypertrophic scars. TGFβ3 is the critical traffic controller that selectively halts migration of the dermal, but not epidermal, cells to ensure completion of wound re-epithelialization prior to wound remodeling. However, the mechanism of TGFβ3's anti-motility signaling has never been investigated. We report here that activated TβRII transmits the anti-motility signal of TGFβ3 in full to TβRI, since expression of the constitutively activated TβRI-TD mutant was sufficient to replace TGFβ3 to block PDGF-bb-induced dermal fibroblast migration. Second, the three components of R-Smad complex are all required. Individual downregulation of Smad2, Smad3 or Smad4 prevented TGFβ3 from inhibiting dermal fibroblast migration. Third, Protein Kinase Array allowed us to identify the protein kinase A (PKA) as a specific downstream effector of R-Smads in dermal fibroblasts. Activation of PKA alone blocked PDGF-bb-induced dermal fibroblast migration, just like TGFβ3. Downregulation of PKA's catalytic subunit nullified the anti-motility signaling of TGFβ3. This is the first report on anti-motility signaling mechanism by TGFβ family cytokines. Significance of this finding is not only limited to wound healing but also to other human disorders, such as heart attack and cancer, where the diseased cells have often managed to avoid the anti-motility effect of TGFβ.
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2,333,911 |
Thoracic paravertebral block for postoperative pain management in percutaneous nephrolithotomy patients: a randomized controlled clinical trial.
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To investigate the effect of thoracic paravertebral block (PVB) on pain control and morphine consumption in percutaneous nephrolithotomy operations.</AbstractText>This randomized controlled clinical study was performed on 60 American Society of Anesthesiologists (ASA) I-II patients between the ages of 18 and 60 years who underwent percutaneous nephrolithotomy with approval of the ethical committee and written consent of the patients. Patients were randomly allocated into two groups: group P had 4 ml of 0.5% levobupivacaine injected at each of the T10, T11, and T12 paravertebral spaces and a standard PVB, and group C received 4 ml of 0.9% NaCl solution. All patients were given standard general anesthesia. The follow-up of saturation, heart rate, peripheral oxygen, and blood pressure values was recorded before induction, intraoperatively, and postoperatively. At postoperative 1, 2, 6, 12, and 24 h, the visual analog scale (VAS), Ramsey sedation score, respiratory rate, and 24-hour total morphine consumption were recorded. In addition, side effects and satisfaction of patients were recorded.</AbstractText>VAS scores and total morphine consumption were lower in group P than in group C: 2.3 vs. 4.3 and 22.3 vs. 43.2 mg, respectively (p < 0.05). The level of satisfaction was higher in group P than group C. Differences between groups in other parameters were not significant.</AbstractText>Thoracic PVB with levobupivacaine provided a good postoperative analgesia and increased patient satisfaction for those who underwent percutaneous nephrolithotomy.</AbstractText>Copyright © 2012 S. Karger AG, Basel.</CopyrightInformation>
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2,333,912 |
Investigating the changes in heart rate asymmetry (HRA) with perturbation of parasympathetic nervous system.
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The heart rate asymmetry (HRA) is a disproportionate distribution of heart rate signal. The current study was designed to assess the changes in HRA in experimental conditions using Poincaré plot during parasympathetic blockade (atropine infusion) and parasympathetic enhancement (scopolamine administration). After atropine infusion, the heart rate variability in 5 out of 8 subjects was found asymmetric. In contrast, all 8 subjects were found to be asymmetric during scopolamine administration. The physiological relevance of HRA was demonstrated by showing correlation with standard frequency domain parameters during all phases of the experiment. The deviation of asymmetry index (GI ( p )) from symmetric range was further analyzed, which was maximum during scopolamine administration and minimum during atropine infusion. These findings suggest that parasympathetic block reduces the prevalence of HRA, and has significant correlation of GI ( p ) with frequency domain features of HRV analysis.
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2,333,913 |
Ambulatory anesthesia in an adult patient with corrected hypoplastic left heart syndrome.
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With recent advancements in clinical science, an increasing number of patients with congenital heart defects are surviving into adulthood and presenting for noncardiac surgeries. We describe one such example of a 26-year-old patient with corrected hypoplastic left heart syndrome presenting for knee arthroscopy and performed under general anesthesia with preoperative ultrasound guided saphenous nerve block. In this case, we review the anesthetic implications of corrected single ventricle physiology, anesthetic implications, as well as discuss the technique and role of saphenous nerve block in patients undergoing knee arthroscopy.
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2,333,914 |
Simulations of complex and microscopic models of cardiac electrophysiology powered by multi-GPU platforms.
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Key aspects of cardiac electrophysiology, such as slow conduction, conduction block, and saltatory effects have been the research topic of many studies since they are strongly related to cardiac arrhythmia, reentry, fibrillation, or defibrillation. However, to reproduce these phenomena the numerical models need to use subcellular discretization for the solution of the PDEs and nonuniform, heterogeneous tissue electric conductivity. Due to the high computational costs of simulations that reproduce the fine microstructure of cardiac tissue, previous studies have considered tissue experiments of small or moderate sizes and used simple cardiac cell models. In this paper, we develop a cardiac electrophysiology model that captures the microstructure of cardiac tissue by using a very fine spatial discretization (8 μm) and uses a very modern and complex cell model based on Markov chains for the characterization of ion channel's structure and dynamics. To cope with the computational challenges, the model was parallelized using a hybrid approach: cluster computing and GPGPUs (general-purpose computing on graphics processing units). Our parallel implementation of this model using a multi-GPU platform was able to reduce the execution times of the simulations from more than 6 days (on a single processor) to 21 minutes (on a small 8-node cluster equipped with 16 GPUs, i.e., 2 GPUs per node).
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2,333,915 |
Analgesic efficacy of low-dose intrathecal neostigmine in combination with fentanyl and bupivacaine for total knee replacement surgery.
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Intrathecal (IT) neostigmine has been used as an adjunct to spinal anesthesia. The purpose of this study was to determine whether a combination of low-dose neostigmine IT would enhance analgesia of a fixed dose of fentanyl IT, in patients undergoing unilateral total knee replacement (TKR) surgery with spinal anesthesia.</AbstractText>Forty-five patients scheduled for unilateral TKR were randomized to one of the three groups (n = 15) and prospectively studied using placebo-controlled, double-blinded design.</AbstractText>A 19-G epidural catheter was introduced through the L3-L4 interspace with patient in the sitting position, followed by spinal anesthesia administration through the L3-L4 interspace. Fifteen milligrams of hyperbaric bupivacaine (3 ml) plus the test drug (0.5 ml) was administered IT. The test drug was normal saline (0.5 ml) in group I; fentanyl 20 mcg (0.4 ml) and normal saline (0.1 ml) in group II; and fentanyl 20 mcg (0.4 ml) and neostigmine 1 mcg (0.1 ml) in group III. Characteristics of sensory and motor block, heart rate, and blood pressure were recorded intraoperatively. Postoperatively, pain scores, postoperative nausea and vomiting (PONV) scores, and sedation scores, and postoperative analgesic dose were recorded.</AbstractText>Forty-five patients were enrolled in this study and 43 patients were subjected to statistical analysis. Overall 24-h visual analog score in group III was significantly less than in those who received fentanyl alone (P = 0.00). The durations of complete analgesia and effective analgesia were longer for all patients in group III compared with group II (P < 0.05) and group I (P < 0.005) patients. The total number of epidural top ups (rescue analgesia) required was less in group II (P < 0.05) and group III (P < 0.005) patients, compared with the control group. The incidence of nausea and vomiting was not increased in group III patients.</AbstractText>The addition of 1 mcg neostigmine IT increased the duration of analgesia and decreased the analgesic consumption in 24 h in TKR. There was no increase in the incidence of adverse effects.</AbstractText>
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2,333,916 |
Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy.
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Vici syndrome is a recessively inherited multisystem disorder characterized by callosal agenesis, cataracts, cardiomyopathy, combined immunodeficiency and hypopigmentation. To investigate the molecular basis of Vici syndrome, we carried out exome and Sanger sequence analysis in a cohort of 18 affected individuals. We identified recessive mutations in EPG5 (previously KIAA1632), indicating a causative role in Vici syndrome. EPG5 is the human homolog of the metazoan-specific autophagy gene epg-5, encoding a key autophagy regulator (ectopic P-granules autophagy protein 5) implicated in the formation of autolysosomes. Further studies showed a severe block in autophagosomal clearance in muscle and fibroblasts from individuals with mutant EPG5, resulting in the accumulation of autophagic cargo in autophagosomes. These findings position Vici syndrome as a paradigm of human multisystem disorders associated with defective autophagy and suggest a fundamental role of the autophagy pathway in the immune system and the anatomical and functional formation of organs such as the brain and heart.
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2,333,917 |
Comparison of haemodynamic changes in patients undergoing unilateral and bilateral spinal anaesthesia.
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To assess the haemodynamic changes in patients receiving unilateral and bilateral spinal anaesthesia with their pre-anaesthesia recordings.</AbstractText>Quasi-experimental study.</AbstractText>Main Operation Theater, Liaquat National Hospital, Karachi, from May 2006 to February 2007.</AbstractText>Sixty patients meeting the inclusion criteria were randomly allocated in two groups of 30 patients each. One and a half ml of 0.75% hyperbaric bupivacaine was injected with free flow of cerebrospinal fluid using a 23 gauge quincke needle. Lumbar puncture was performed in the sitting position at 3 - 4 or 4 - 5 lumbar interspace. Patients were then assigned to the supine or lateral decubitus position for 10 minutes. Heart rate, systolic, mean and diastolic blood pressures of patients were recorded with their pre-anaesthesia readings in the 1st, 5th, 15th, 30th and then at every 15th minute till the end of procedure. Recovery room readings were also taken.</AbstractText>The systolic, mean and diastolic blood pressure changes were significant in both groups. But from 1st minute to recovery room, statistically significant difference (p < 0.05) was found at each time interval, the unilateral groups (group A) being more stable with respect to pre-anaesthesia readings. The decrease in heart rate was comparable in both groups.</AbstractText>Unilateral spinal anaesthesia was associated with a more stable cardiovascular profile, therefore, it is a valuable technique for high risk patients.</AbstractText>
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2,333,918 |
Intraoperative antinociception and postoperative analgesia following epidural anesthesia versus femoral and sciatic nerve blockade in dogs undergoing stifle joint surgery.
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To compare analgesic efficacy of preoperative epidural anesthesia with efficacy of femoral and sciatic nerve blockade in dogs undergoing hind limb orthopedic surgery.</AbstractText>Prospective randomized blinded clinical study.</AbstractText>22 dogs requiring stifle joint surgery.</AbstractText>Dogs were premedicated with acepromazine and morphine, and anesthesia was induced with diazepam and propofol and maintained with sevoflurane in oxygen. Prior to surgery, a combination of 1.0% lidocaine solution with 0.25% bupivacaine solution was administered either into the lumbosacral epidural space (11 dogs) or perineurally along the femoral and sciatic nerves (11). Intraoperative nociception was assumed if heart rate or systolic blood pressure increased by > 10% from baseline, in which case fentanyl (2 μg/kg [0.9 μg/lb], IV) was administered as rescue analgesia. Following recovery from anesthesia, signs of postoperative pain were assessed every 30 minutes for 360 minutes from the time of local anesthetic administration via the modified Glasgow pain scale. Patients with scores > 5 (scale, 0 to 20) received hydromorphone (0.1 mg/kg [0.05 mg/lb], IV) as rescue analgesia and were then withdrawn from further pain scoring.</AbstractText>Treatment groups did not differ significantly in the number fentanyl boluses administered for intraoperative rescue analgesia. Time to administration of first postoperative rescue analgesia was comparable between groups. Furthermore, there was no significant difference between groups in baseline pain scores, nor were there significant differences at any other point during the postoperative period.</AbstractText>Femoral and sciatic nerve blocks provided intraoperative antinociception and postoperative analgesia similar to epidural anesthesia in dogs undergoing stifle joint surgery.</AbstractText>
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2,333,919 |
Lipopolysaccharide-induced hypothermia and hypotension are associated with inflammatory signaling that is triggered outside the brain.
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Little is known about the neuroimmune mechanisms responsible for the switch from fever to hypothermia observed in severe forms of systemic inflammation. We evaluated whether bacterial lipopolysaccharide (LPS) acting directly on the brain could promote a fever-hypothermia switch as well as the hypotension that is often associated with hypothermia in models of systemic inflammation. At an ambient temperature of 22°C, freely moving rats received intracerebroventricular (i.c.v.) injections of LPS at doses ranging from 0.5 to 25μg. Despite the use of such high doses, the prevailing thermal response was fever. To investigate if a hypothermic response could be hidden within the prevailing febrile response, rats were pretreated with a cyclooxygenase-2 inhibitor (SC-236, 3.5mg/kg i.v.) known to block fever, but this strategy also failed to reveal any consistent hypothermic response following i.c.v. LPS. At the doses tested, i.c.v. LPS was similarly ineffective at inducing hypotension. Additional doses of LPS did not need to be tested because the 25-μg dose was already sufficient to induce both hypothermia and hypotension when administered peripherally (intra-arterially). An empirical 3D model of the interplay among body temperature, arterial pressure and heart rate following intra-arterial LPS reinforced the strong association of hypothermia with hypotension and, at the same time, exposed a bell-shaped relationship between heart rate and body temperature. In summary, the present study demonstrates that hypothermia and hypotension are triggered exclusively by LPS acting outside the brain and provides an integrated model of the thermal and cardiovascular responses to peripheral LPS.
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2,333,920 |
Randomized clinical trial comparing effectiveness of intracorpus spongiosum block versus topical anesthesia for performing visual internal urethrotomy for urethral stricture disease.
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To compare the efficacy and safety of intracorpus spongiosum block (ICSB) over topical anesthesia for performing visual internal urethrotomy (VIU) in a randomized clinical trial.</AbstractText>VIU for urethral stricture can be performed under various types of anesthesia, including topical anesthesia. Although recent studies have shown that ICSB and general anesthesia have comparable efficacy for performing VIU, no studies have compared ICSB with topical anesthesia. Forty consenting patients with single, short, passable anterior urethral stricture were randomized into two groups. Group 1 patients received topical 2% lignocaine jelly and group 2 patients received 1% lignocaine ICSB for undergoing VIU. Pain perception during and after the procedure was assessed by visual analog scale (VAS). The changes in vital parameters during the procedure and procedure-related complications were recorded. Statistical analysis was done using the Mann-Whitney test or t test.</AbstractText>The mean±standard deviation VAS scores intraoperatively (2.85±1.34) and at 1-hour postoperatively (1.17±0.96) were significantly lower (P<01) in group 2 patients than the corresponding scores in group 1 (4.9±1.9 and 2.35±1.34 respectively). The intraoperative rise in pulse rate and in blood pressure were significantly greater (P<.05) in group 1 patients (13±5.1/min and 11.3±6.44 mm Hg) than in group 2 (8.05±5.54/min and 6.35±5.86 mm Hg).</AbstractText>ICSB is safe and more effective than topical anesthesia for providing pain relief during VIU. This should become the local anesthesia technique of choice for performing VIU.</AbstractText>Copyright © 2013 Elsevier Inc. All rights reserved.</CopyrightInformation>
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2,333,921 |
An allosteric mechanism for drug block of the human cardiac potassium channel KCNQ1.
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The intracellular aspect of the sixth transmembrane segment within the ion-permeating pore is a common binding site for many voltage-gated ion channel blockers. However, the exact site(s) at which drugs bind remain controversial. We used extensive site-directed mutagenesis coupled with molecular modeling to examine mechanisms in drug block of the human cardiac potassium channel KCNQ1. A total of 48 amino acid residues in the S6 segment, S4-S5 linker, and the proximal C-terminus of the KCNQ1 channel were mutated individually to alanine; alanines were mutated to cysteines. Residues modulating drug block were identified when mutant channels displayed <50% block on exposure to drug concentrations that inhibited wild-type current by ≥90%. Homology modeling of the KCNQ1 channel based on the Kv1.2 structure unexpectedly predicted that the key residue modulating drug block (F351) faces away from the permeating pore. In the open-state channel model, F351 lines a pocket that also includes residues L251 and V254 in S4-S5 linker. Docking calculations indicated that this pocket is large enough to accommodate quinidine. To test this hypothesis, L251A and V254A mutants were generated that display a reduced sensitivity to blockage with quinidine. Thus, our data support a model in which open state block of this channel occurs not via binding to a site directly in the pore but rather by a novel allosteric mechanism: drug access to a side pocket generated in the open-state channel configuration and lined by S6 and S4-S5 residues.
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2,333,922 |
Inhibiting the clathrin-mediated endocytosis pathway rescues K(IR)2.1 downregulation by pentamidine.
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Drug-induced ion channel trafficking disturbance can cause cardiac arrhythmias. We showed that the antiprotozoic pentamidine decreased K(IR)2.x carried I(K1) current and that inhibiting protein degradation in the lysosome increased intracellular K(IR)2.1 levels. In this study, we aim to identify and then inhibit preceding steps in clathrin-mediated endocytosis of K(IR)2.1 to further restore normal levels of functional K(IR)2.1 channels. K(IR)2.1 trafficking in HEK293 cells was studied by live cell imaging, immunofluorescence microscopy, and Western blot following pharmacological intervention with dynasore (Dyn), chlorpromazine (CPZ), bafilomycin A1 (Baf), or chloroquine (CQ). K(IR)2.1 function was determined by patch-clamp electrophysiology. CQ induced lysosomal build-up of full length (3.8 ± 0.8-fold) and N-terminal cleaved K(IR)2.1 protein. Baf induced late endosomal build-up of full length protein only (6.1 ± 1.6-fold). CPZ and Dyn increased plasma membrane-localized channel and protein levels (2.6 ± 0.4- and 4.2 ± 1.1-fold, respectively). Dyn increased I(K1) (at -60 mV) from 31 ± 6 to 55 ± 7 pA/pF (N = 9 and 13 respectively, p < 0.05), while the CPZ effect on current density was not testable due to acute I(K1) block. Baf and CQ did not significantly enhance I(K1) densities. Pentamidine (10 μM, 48 h) reduced K(IR)2.1 levels to 0.6 ± 0.1-fold, which could be rescued by Baf (3.2 ± 0.9), CPZ (1.2 ± 0.3), or Dyn (1.2 ± 0.3). Taken together, the clathrin-mediated endocytosis pathway functions in K(IR)2.1 degradation. Pentamidine-induced downregulation of K(IR)2.1 can be rescued at the level of the plasma membrane, implying that acquired trafficking defects can be rescued.
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2,333,923 |
Selective inhibition of Cx43 hemichannels by Gap19 and its impact on myocardial ischemia/reperfusion injury.
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Connexin-43 (Cx43), a predominant cardiac connexin, forms gap junctions (GJs) that facilitate electrical cell-cell coupling and unapposed/nonjunctional hemichannels that provide a pathway for the exchange of ions and metabolites between cytoplasm and extracellular milieu. Uncontrolled opening of hemichannels in the plasma membrane may be deleterious for the myocardium and blocking hemichannels may confer cardioprotection by preventing ionic imbalance, cell swelling and loss of critical metabolites. Currently, all known hemichannel inhibitors also block GJ channels, thereby disturbing electrical cell-cell communication. Here we aimed to characterize a nonapeptide, called Gap19, derived from the cytoplasmic loop (CL) of Cx43 as a hemichannel blocker and examined its effect on hemichannel currents in cardiomyocytes and its influence in cardiac outcome after ischemia/reperfusion. We report that Gap 19 inhibits Cx43 hemichannels without blocking GJ channels or Cx40/pannexin-1 hemichannels. Hemichannel inhibition is due to the binding of Gap19 to the C-terminus (CT) thereby preventing intramolecular CT-CL interactions. The peptide inhibited Cx43 hemichannel unitary currents in both HeLa cells exogenously expressing Cx43 and acutely isolated pig ventricular cardiomyocytes. Treatment with Gap19 prevented metabolic inhibition-enhanced hemichannel openings, protected cardiomyocytes against volume overload and cell death following ischemia/reperfusion in vitro and modestly decreased the infarct size after myocardial ischemia/reperfusion in mice in vivo. We conclude that preventing Cx43 hemichannel opening with Gap19 confers limited protective effects against myocardial ischemia/reperfusion injury.
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2,333,924 |
[Pharmacodynamic study of racemic TJ0711 on renal hypertensive rats after long-term administration].
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The study is to observe the effect of racemic TJ0711 on blood pressure and heart rate as well as protection of cardiovascular system of renal hypertensive rats after long-term administration. The renal hypertensive models were established by the two-kidney, one-clip (2K1C) method in Wistar rats. Four weeks later, assigned the rats whose SBP had increased at least 4 kPa randomly into 5 groups: racemic TJ0711 10, 20 and 40 mg x kg(-1) groups, carvedilol control group, model group and sham group (n=10), ig administration once daily. The changes of BP (blood press) and HR (heart rate) before and after administration were measured by tail-cuff method weekly. Plasma samples of all animals were taken in 6-8 weeks, and plasma MDA as well as renin, angiotensin II (Ang II) and endothelin-1 (ET-1) levels were measured. Left ventricle was cut off after 9 weeks, and left ventricular weight index (LVWI) and hydroxyproline were measured. The significant decrease of the BP of TJ0711 40 mg x kg(-1) group was observed after TJ0711 ig administration for 4 weeks, and this effect remained till the end of the study. In 8th week, the systolic blood pressure values were: TJ0711 40 mg x kg(-1) group 18.93 +/- 1.82 kPa (vs 21.30 +/- 2.30 kPa, P < 0.05); 20 mg x kg(-1) group 20.68 +/- 3.29 kPa (vs 22.19 +/- 2.88 kPa). The plasma MDA level of all treated groups was significantly lower than that of model group, so were the plasma renin, Ang II and ET-1 levels (P < 0.05). LVWI and hydroxyproline content of myocardial tissue decreased to some extent, but was not significant as compared with that of model group. The study showed that TJ0711 repeated dosing could reduce BP level beginning from drug administration; besides block adrenal alpha and beta receptors to play an antihypertensive role. The sustained antihypertensive effect also related to reduce plasma vasoconstrictor substances and oxidation product MDA. These effects benefited cardiovascular protection.
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2,333,925 |
Influence of local anesthetics with or without epinephrine 1/80000 on blood pressure and heart rate: A randomized double-blind experimental clinical trial.
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Local anesthesia (LA) with epinephrine have an important role in pain and bleeding control. However, most clinicians believe LA + epinephrine may cause rapid raise in blood pressure (BP) and heart rate (HR). The aim of this research was to compare the changes in HR and BP after administration of lidocaine with and without epinephrine 1/80000 in two infiltration (INF) and inferior alveolar nerve block methods (IANB).</AbstractText>The study was a randomized double-blind experimental clinical trial. Forty subjects were divided into two equal groups and two subgroups. In one group, INF and in the other group, IANB were used and, further, in one subgroup lidocaine and in another subgroup, lidocaine plus epinephrine were used. BP and HR were recorded before and 10 min after. The paired t-test for intragroup differences and independent t-test for intergroup analysis were used at the significant level of P≤0.05.</AbstractText>The mean BP and HR values were reduced after injection of lidocaine in both INF and IANB compared with baseline. The differences were statistically significant (P < 0.05), but, on comparing these values between the two injection methods, the differences were not statically significant (P = 0.089 and 0.066, respectively). The mean BP and HR values were increased after injection of lidocaine plus epinephrine in both INF and IANB compared with baseline, and these were statistically significant (P < 0.05) but, on comparing these values between the two methods, the differences were not statically significant (P = 0.071 and 0.092, respectively).</AbstractText>The rise in BP and HR following injection of lidocaine plus epinephrine was statistically significant compared with baseline in both INF and IANB, but this was not clinically and numerically considerable.</AbstractText>
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2,333,926 |
Acute β-adrenergic activation triggers nuclear import of histone deacetylase 5 and delays G(q)-induced transcriptional activation.
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During hemodynamic stress, catecholamines and neurohumoral stimuli may induce co-activation of G(q)-coupled receptors and β-adrenergic receptors (β-AR), leading to cardiac remodeling. Dynamic regulation of histone deacetylase 5 (HDAC5), a transcriptional repressor, is crucial during stress signaling due to its role in epigenetic control of fetal gene markers. Little is known about its regulation during acute and chronic β-AR stimulation and its cross-interaction with G(q) signaling in adult cardiac myocytes. Here, we evaluate the potential cross-talk between G(q)-driven and β-AR mediated signaling at the level of nucleocytoplasmic shuttling of HDAC5. We show the translocation of GFP-tagged wild type HDAC5 or mutants (S279A and S279D) in response to β-AR or G(q) agonists. Isoproterenol (ISO) or PKA activation results in strong nuclear accumulation of HDAC5 in contrast to nuclear export driven by Ca(2+)-calmodulin protein kinase II and protein kinase D. Moreover, nuclear accumulation of HDAC5 under acute ISO/PKA signaling is dependent on phosphorylation of Ser-279 and can block subsequent G(q)-mediated nuclear HDAC5 export. Intriguingly, the attenuation of G(q)-induced export is abolished after chronic PKA activation, yet nuclear HDAC5 remains elevated. Last, the effect of chronic β-AR signaling on HDAC5 translocation was examined in adult myocytes from a rabbit model of heart failure, where ISO-induced nuclear import is ablated, but G(q)-agonist mediated export is preserved. Acute β-AR/PKA activation protects against hypertrophic signaling by delaying G(q)-mediated transcriptional activation. This serves as a key physiological control switch before allowing genetic reprogramming via HDAC5 nuclear export during more severe stress, such as heart failure.
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2,333,927 |
Dexmedetomidine as an adjuvant to ropivacaine prolongs peripheral nerve block: a volunteer study.
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Dexmedetomidine is an α-2-receptor agonist which might be used as an additive to local anaesthetics for various regional anaesthetic techniques. We therefore designed this prospective, double-blinded, controlled volunteer study to investigate the effects of dexmedetomidine as an adjuvant to ropivacaine on peripheral nerve block.</AbstractText>Ultrasound-guided ulnar nerve block (UNB) was performed in 36 volunteers with either 3 ml ropivacaine 0.75% (R), 3 ml ropivacaine 0.75% plus 20 µg dexmedetomidine (RpD), or 3 ml ropivacaine 0.75% plus systemic 20 µg dexmedetomidine (RsD). UNB-related sensory and motor scores were evaluated.</AbstractText>Sensory onset time of UNB was not different between the study groups, whereas motor onset time was significantly faster in Group RpD when compared with the other study groups [mean (sd)] [21 (15) vs 43 (25) min in Group RsD and 47 (36) min in Group R, P<0.05 Group RpD vs other groups]. The duration of sensory block was 350 (54) min in Group R, 555 (118) min in Group RpD, and 395 (40) min in Group RsD (P<0.01 Group RpD vs other groups, P<0.05 Group RsD vs Group R). Motor block duration was similar to the duration of sensory block.</AbstractText>A profound prolongation of UNB of ∼60% was detected with perineural dexmedetomidine when added to 0.75% ropivacaine. The systemic administration of 20 µg dexmedetomidine resulted in a prolongation of ∼10% during UNB with 0.75% ropivacaine. Eudra-CT No.: 2012-000030-19.</AbstractText>
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2,333,928 |
[Effects of continuous interscalene brachial plexus block plus general anesthesia versus general anesthesia alone on perioperative management of arthroscopic rotator cuff repair surgery].
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To compare continuous interscalene brachial plexus block (CISB) in the patients undergoing rotator cuff repair surgery.</AbstractText>A total of 60 patients undergoing rotator cuff repair surgery were randomly assigned to either ISB plus GA group (ISB + GA group) or GA group. Preoperatively, an interscalene catheter was placed in the ISB + GA group patients. Both groups received general anesthesia. The intraoperative mean arterial pressure (MAP) at the level of external acoustic meatus was maintained at a target of 60 - 65 mm Hg with a continuous infusion of remifentanil. Postoperatively, the patients in the ISB + GA and GA groups received CISB and patient controlled intravenous analgesia (PCIA) respectively for 48 h.</AbstractText>Surgical field conditions were similar in two groups (P = 1.000). Compared to the GA group, the consumption of remifentanil [(0.04 ± 0.03) vs (0.14 ± 0.03) µg×kg(-1)×min(-1), P < 0.01] and the inhalational concentration of sevoflurane(1.80% ± 0.5% vs 2.1% ± 0.5%, P < 0.05)were lower in the ISB + GA group. Compared to the GA group, the values of MAP and heart rate (HR) were lower at all postoperative time-points in the ISB + GA group(P < 0.05). The postoperative measurements of numerical rating pain score (NRPS) were lower (P < 0.01) and the level of patient satisfaction was greater in the ISB + GA group [8(6 - 10) vs 7 (5 - 10), P < 0.01].</AbstractText>In comparisons with GA alone for rotator cuff repair surgery, the combined uses of ISB and GA may achieve a better perioperative control of hemodynamic responses, a markedly reduced consumption of general anesthetics, a rapid recovery of consciousness from anesthesia, superior analgesia with fewer side effects and greater patient satisfaction.</AbstractText>
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2,333,929 |
Encapsidation of RNA-polyelectrolyte complexes with amphiphilic block copolymers: toward a new self-assembly route.
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Amphiphilic block copolymers are molecules composed of hydrophilic and hydrophobic segments having the capacity to spontaneously self-assemble into a variety of supramolecular structures like micelles and vesicles. Here, we propose an original way to self-assemble amphiphilic block copolymers into a supported bilayer membrane for defined coating of nanoparticles. The heart of the method rests on a change of the amphiphilicity of the copolymer that can be turned off and on by varying the polarity of the solvent. In this condition, the assembly process can take advantage of specific molecular interactions in both organic solvent and water. While the concept potentially could be applied to any type of charged substrates, we focus our interest on the design of a new type of polymer assembly mimicking the virus morphology. A capsid-like shell of glycoprotein-mimic amphiphilic block copolymer was self-assembled around a positively charged complex of siRNA and polyethyleneimine. The process requires two steps. Block copolymers first interact with the complexes dispersed in DMSO through electrostatic interactions. Next, the increase of the water content in the medium triggers the hydrophobic effect and the concomitant self-assembly of free block copolymer molecules into a bilayer membrane at the complex surface. The higher gene silencing activity of the copolymer-modified complexes over the complexes alone shows the potential of this new type of nanoconstructs for biological applications, especially for the delivery of therapeutic biomolecules.
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2,333,930 |
[Ultrasound-guided peripheral nerve block for high-risk patients with arteriosclerosis obliterans in lower limb surgery--a report of nine cases].
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Most patients with arteriosclerosis obliterans (ASO) have severe complications such as coronary artery disease, congestive heart failure and chronic kidney disease. They receive long-term antithrombotic therapy which is a contraindication to neuraxial anesthesia. In this retrospective study, we reviewed nine high-risk patients with ASO (revised cardiac risk index more than three) who underwent an urgent lower limb surgery under ultrasound-guided peripheral nerve block (PNB). In all cases, intraoperative hemodynamic changes remained minimized. In eight of the nine cases, analgesics are not required until 10 hours after the operation. No complication related to PNB occurred. Ultrasoundguided PNB for patients with ASO undergoing lower limb surgery can be a useful anesthetic technique, providing cardiovascular stability and good postoperative analgesia.
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2,333,931 |
Blood pressure lowering efficacy of potassium-sparing diuretics (that block the epithelial sodium channel) for primary hypertension.
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Potassium-sparing diuretics, which block the epithelial sodium channel (ENaC), are widely prescribed for hypertension as a second-line drug in patients taking other diuretics (e.g. thiazide diuretics) and much less commonly prescribed as monotherapy. Therefore, it is essential to determine the effects of ENaC blockers on blood pressure (BP), heart rate and withdrawals due to adverse effects (WDAEs) when given as a first-line or second-line therapy.</AbstractText>To quantify the dose-related reduction in systolic blood pressure (SBP) and diastolic blood pressure (DBP) of ENaC blocker therapy as a first-line or second-line drug in patients with primary hypertension.</AbstractText>We searched CENTRAL (The Cochrane Library 2012), MEDLINE (1950 to August 2012), EMBASE (1980 to August 2012) and reference lists of articles.</AbstractText>Double-blind, randomized, controlled trials in patients with primary hypertension that evaluate, for a duration of 3 to 12 weeks, the BP lowering efficacy of: 1) fixed-dose monotherapy with an ENaC blocker compared with placebo; or 2) an ENaC blocker in combination with another class of anti-hypertensive drugs compared with the respective monotherapy (without an ENaC blocker).</AbstractText>Two authors independently assessed the risk of bias and extracted data. Study authors were contacted for additional information. WDAE information was also collected from the trials.</AbstractText>No trials evaluating the BP lowering efficacy of ENaC blockers as monotherapy in patients with primary hypertension were identified. Only 6 trials evaluated the BP lowering efficacy of low doses of amiloride and triamterene as a second drug in 496 participants with a baseline BP of 151/102 mm Hg. The additional BP reduction caused by the ENaC blocker as a second drug was estimated by comparing the difference in BP reduction between the combination and monotherapy groups. The addition of low doses of amiloride and triamterene in these trials did not reduce BP. An estimate of the dose-related BP lowering efficacy for ENaC blockers was not possible because of a lack of trial data at higher doses.</AbstractText><AbstractText Label="AUTHORS' CONCLUSIONS" NlmCategory="CONCLUSIONS">ENaC blockers do not have a statistically or clinically significant BP lowering effect at low doses but trials at higher doses are not available. The review did not provide a good estimate of the incidence of harms associated with ENaC blockers.</AbstractText>
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2,333,932 |
The relative influences of phosphometabolites and pH on action potential morphology during myocardial reperfusion: a simulation study.
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Myocardial ischemia-reperfusion (IR) injury represents a constellation of pathological processes that occur when ischemic myocardium experiences a restoration of perfusion. Reentrant arrhythmias, which represent a particularly lethal manifestation of IR injury, can result when ischemic tissue exhibits decreased excitability and/or changes of action potential duration (APD), conditions that precipitate unidirectional conduction block. Many of the cellular components that are involved with IR injury are modulated by pH and/or phosphometabolites such as ATP and phosphocreatine (PCr), all of which can be manipulated in vivo and potentially in the clinical setting. Using a mathematical model of the cardiomyocyte that we previously developed to study ischemia and reperfusion, we performed a series of simulations with the aim of determining whether pH- or phosphometabolite-related processes play a more significant role in generating changes in excitability and action potential morphology that are associated with the development of reentry. In our simulations, persistent shortening of APD, action potential amplitude (APA), and depolarization of the resting membrane potential were more severe when ATP and PCr availability were suppressed during reperfusion than when extracellular pH recovery was inhibited. Reduced phosphometabolite availability and pH recovery affected multiple ion channels and exchangers. Some of these effects were the result of direct modulation by phosphometabolites and/or acidosis, while others resulted from elevated sodium and calcium loads during reperfusion. In addition, increasing ATP and PCr availability during reperfusion was more beneficial in terms of increasing APD and APA than was increasing the amount of pH recovery. Together, these results suggest that therapies directed at increasing ATP and/or PCr availability during reperfusion may be more beneficial than perturbing pH recovery with regard to mitigating action potential changes that increase the likelihood of reentrant arrhythmias.
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2,333,933 |
Transversus abdominis plane block in combination with general anesthesia provides better intraoperative hemodynamic control and quicker recovery than general anesthesia alone in high-risk abdominal surgery patients.
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Patients with severe cardiovascular disease are frequently hemodynamically unstable during abdominal surgery. Improving the safety of such patients by stabilizing intraoperative hemodynamics remains a major concern for anesthesiologists. Transversus abdominis plane (TAP) block in combination with general anesthesia may facilitate optimum anesthetic management of these high-risk patients.</AbstractText>Patients with cardiovascular disease classified as American Society of Anesthesiologists (ASA) physical status 3 were enrolled. The patients were undergoing elective abdominal surgery and were randomized to a group receiving general anesthesia and TAP block (Group T, N.=33) or a group receiving general anesthesia alone (Group G, N.=35). We compared the groups for intraoperative hemodynamic stability, anesthesia emergence time, amounts of anesthetics and opioids given, and frequency of emergency treatment with cardiovascular agents. A preliminary study demonstrated that systolic blood pressure and heart rate were maintained stable within 70-110% of their preanesthesia values throughout surgery in ASA 1 elderly patients without cardiovascular disease. Thus, the hemodynamically stable time was defined as the time when systolic blood pressure and heart rate were 70-110% of their preanesthesia values. The ratio of hemodynamically stable time to total operative time was used as an index of hemodynamic stability.</AbstractText>The median (minimum-maximum) percentage of hemodynamically stable time was longer in Group T (91[50-100]%) than Group G (79[40-91]%, P<0.01). The mean sevoflurane concentration, amount of fentanyl given and frequency of vasopressor use were lower in Group T than Group G (P<0.05). Anesthesia emergence time was shorter in Group T (14[4-30] min) than Group G (18[9-52] min, P<0.01). No worsening of cardiovascular complications was observed.</AbstractText>For abdominal surgery in patients with severe cardiovascular disease, combining TAP block with general anesthesia promotes intraoperative hemodynamic stability and early emergence from anesthesia.</AbstractText>
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2,333,934 |
Role of the JAK/STAT signaling pathway in the pathogenesis of acute myocardial infarction in rats and its effect on NF-κB expression.
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The Janus kinase/signal transducer and activator of transcription pathway (JAK/STAT signaling pathway) is involved in the development of numerous cardiovascular diseases, although the specific role of this pathway in the pathogenesis of acute myocardial infarction (AMI) has not been elucidated. The purpose of this study was to evaluate the role of the JAK/STAT signaling pathway in the onset of AMI in rats. We also tested the effect of this pathway on nuclear factor κB (NF-κB) expression in the myocardium and tumor necrosis factor-α (TNF-α) levels in the plasma of AMI rats. An AMI rat model was successfully established and AG490 was used to block the JAK/STAT signaling pathway. The plasma TNF-α levels of AMI rats were measured by ELISA. The protein expression of NF-κB in the myocardial cells of AMI rats was detected by immunohistochemistry. The infarction area was significantly smaller in rats treated with AG490 after coronary artery ligation (group C) compared with that in the myocardial infarction control group (group B). The left ventricular mass indices in the sham surgery group (group A) and group C were significantly lower compared with those of group B. Plasma TNF-α concentrations in group B were significantly higher compared with those of groups A and C. There were significantly fewer cardiomyocytes positively exhibiting NF-κB protein expression in groups A and C compared with group B. The JAK/STAT signaling pathway is involved in the onset of myocardial infarction and may also be involved in left ventricular remodeling after myocardial infarction. The involvement of the JAK/STAT signaling pathway in the onset of myocardial infarction may be correlated with its effects on the expression of NF-κB and TNF-α.
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2,333,935 |
Development of a flexible optical fiber based high resolution integrated PET∕MRI system.
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The simultaneous measurement of PET and magnetic resonance imaging (MRI) is an emerging field for molecular imaging research. Although optical fiber based PET∕MRI systems have advantages on less interference between PET and MRI, there is a drawback in reducing the scintillation light due to the fiber. To reduce the problem, the authors newly developed flexible optical fiber bundle based block detectors and employed them for a high resolution integrated PET∕MRI system.</AbstractText>The flexible optical fiber bundle used 0.5 mm diameter, 80 cm long double clad fibers which have dual 12 mm × 24 mm rectangular inputs and a single 24 mm × 24 mm rectangular output. In the input surface, LGSO scintillators of 0.025 mol.% (decay time: ∼31 ns: 0.9 mm × 1.3 mm × 5 mm) and 0.75 mol.% (decay time: ∼46 ns: 0.9 mm × 1.3 mm × 6 mm) were optically coupled in depth direction to form depth-of-interaction detector, arranged in 11 × 13 matrix and optically coupled to the fiber bundle. The two inputs of the bundle are bent for 90°, bound to one, and are optically coupled to a Hamamatsu 1-in. square position sensitive photomultiplier tube.</AbstractText>Light loss due to the fiber bundle could be reduced and the performance of the block detectors was improved. Eight optical fiber based block detectors (16 LGSO blocks) were arranged in a 56 mm diameter ring to form a PET system. Spatial resolution and sensitivity were 1.2 mm full-width at half-maximum and 1.2% at the central field-of-view, respectively. Sensitivity change was less than 1% for 2 °C temperature changes. This PET system was integrated with a 0.3 T permanent magnet MRI system which has 17 cm diameter hole at the yoke area for insertion of the PET detector ring. There was no observable interference between PET and MRI. Simultaneous imaging of PET and MRI was successfully performed for small animal studies.</AbstractText>The authors confirmed that the developed high resolution PET∕MRI system is promising for molecular imaging research.</AbstractText>
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2,333,936 |
Periprosthetic atypical mycobacterial infection in breast implants: a new kid on the block!
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Breast augmentation is one of the most commonly performed cosmetic surgical procedures. Infection in the breast implant surgery can range from simple wound infection to periprosthetic infection usually with skin commensals such as staphylococci. However, with routine use of broad-spectrum antibiotics atypical mycobacterial infections are being increasingly reported.</AbstractText>We studied 12 cases of atypical mycobacterial breast implant infections over a period of 8 years from 2002 to 2010. Six of them were primarily operated at our centre and six referred from elsewhere after implant infection. Age range was 30-40 years and follow-up after secondary surgery ranged from 1 to 5 years. All patients were explanted and started on combination antibiotics namely, clarithromycin, gatifloxacillin and linezolid for 3 months. After a period of 3 months, all patients underwent implant surgery again with the same antibiotic cover for 6 weeks.</AbstractText>All the secondary implant augmentations were successful. Organisms grown in primary culture were Mycobacterium fortuitum and M. chelonei. All patients were satisfied with the final breast form and size achieved.</AbstractText>The possibility of an atypical mycobacterial infection should always be at the back of the mind of an alert surgeon to prevent a periprosthetic infection from compromising the final aesthetic result of a breast implant procedure. Diagnosed early and eradicated in time, the final result is not compromised.</AbstractText>Copyright © 2012 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.</CopyrightInformation>
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2,333,937 |
Sick sinus syndrome in a dog: treatment with dual-chambered pacemaker implantation.
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A 2-year-old male castrated boxer dog was presented because of a history of syncope. Electrocardiogram tracings obtained with a cardiac event monitor showed bradycardia culminating in asystole. Sick sinus syndrome was diagnosed and treated with transvenous implantation of a dual-chambered permanent pacemaker.</Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Burrage</LastName><ForeName>Heather</ForeName><Initials>H</Initials><AffiliationInfo><Affiliation>Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, Prince Edward Island. [email protected]</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D002363">Case Reports</PublicationType><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>Canada</Country><MedlineTA>Can Vet J</MedlineTA><NlmUniqueID>0004653</NlmUniqueID><ISSNLinking>0008-5286</ISSNLinking></MedlineJournalInfo><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004283" MajorTopicYN="N">Dog Diseases</DescriptorName><QualifierName UI="Q000628" MajorTopicYN="Y">therapy</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D004285" MajorTopicYN="N">Dogs</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004562" MajorTopicYN="N">Electrocardiography</DescriptorName><QualifierName UI="Q000662" MajorTopicYN="N">veterinary</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D010138" MajorTopicYN="N">Pacemaker, Artificial</DescriptorName><QualifierName UI="Q000662" MajorTopicYN="Y">veterinary</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D012804" MajorTopicYN="N">Sick Sinus Syndrome</DescriptorName><QualifierName UI="Q000628" MajorTopicYN="N">therapy</QualifierName><QualifierName UI="Q000662" MajorTopicYN="Y">veterinary</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D016896" MajorTopicYN="N">Treatment Outcome</DescriptorName></MeshHeading></MeshHeadingList><OtherAbstract Type="Publisher" Language="fre"><b>Syndrome du dysfonctionnement sinusal chez un chien : traitement par l’implantation d’un stimulateur cardiaque à double chambre.</b> Un chien Boxer castré âgé de 2 ans a été présenté en raison d’une anamnèse de syncope. Les tracés d’électrocardiogrammes obtenus avec un moniteur de l’activité cardiaque ont montré une bradycardie culminant par une pause cardiaque. Le syndrome du dysfonctionnement sinusal a été diagnostiquée et traitée par l’implantation d’un stimulateur cardiaque à double chambre. (Traduit par Isabelle Vallières)
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2,333,938 |
Caregiver burden and nonachievement of healthy lifestyle behaviors among family caregivers of cardiovascular disease patients.
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To determine whether caregiver burdens are associated with lifestyle behaviors 1 year following the hospitalization of a family member with cardiovascular disease (CVD).</AbstractText>Prospective follow-up study of National Heart Lung and Blood Institute sponsored Family Intervention Trial for Heart Health participants.</AbstractText>Hospital-based recruitment/baseline visit with 1-year follow-up.</AbstractText>Family members of hospitalized CVD patients (N  =  423; 67% female; 36% racial/ethnic minority; mean age 49 years).</AbstractText>Systematic evaluation at 1 year to determine heart-healthy diet (defined as <10% kcal from saturated fat; Block 98 Food Frequency Questionnaire) and physical activity (defined as ≥4 d/wk; Behavioral Risk Factor Surveillance System Survey) behaviors and caregiver burdens (five domains: employment, financial, physical, social, and time; Caregiver Strain Questionnaire).</AbstractText>Logistic regression adjusted for covariates.</AbstractText>Heart-healthy diet was less frequent among caregivers citing feeling overwhelmed (odds ratio [OR]  =  .50; 95% confidence interval [CI]  =  .26-.97), sleep disturbance (OR  =  .51; 95% CI  =  .27-.96), financial strain (OR  =  .41; 95% CI  =  .20-.86), upsetting behavior (OR  =  .48; 95% CI  =  .25-.92), and/or time demands (OR  =  .47; 95% CI  =  .26-.85) as burdens. Physical activity was less frequent among caregivers reporting financial strain (OR  =  .32; 95% CI  =  .13-.81) or upsetting patient behavior (OR  =  .33; 95% CI  =  .15-.76) as burdens. The most commonly cited caregiver burdens included changes in personal plans (39%), time demands (38%), and sleep disturbance (30%).</AbstractText>Caregiver burdens were associated with nonachievement of heart-healthy diet and physical activity behaviors among family caregivers 1 year after patient discharge. When developing heart-health promotion interventions, caregiver burden should be considered as a possible barrier to prevention among family members of CVD patients.</AbstractText>
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2,333,939 |
Microscopic variations in interstitial and intracellular structure modulate the distribution of conduction delays and block in cardiac tissue with source-load mismatch.<Pagination><StartPage>v3</StartPage><EndPage>v9</EndPage><MedlinePgn>v3-v9</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1093/europace/eus267</ELocationID><Abstract><AbstractText Label="AIMS" NlmCategory="OBJECTIVE">Reentrant activity in the heart is often correlated with heterogeneity in both the intracellular structure and the interstitial structure surrounding cells; however, the combined effect of cardiac microstructure and interstitial resistivity in regions of source-load mismatch is largely unknown. The aim of this study was to investigate how microstructural variations in cell arrangement and increased interstitial resistivity influence the spatial distribution of conduction delays and block in poorly coupled regions of tissue.</AbstractText><AbstractText Label="METHODS AND RESULTS" NlmCategory="RESULTS">Two-dimensional 0.6 cm × 0.6 cm computer models with idealized and realistic cellular structure were used to represent a monolayer of ventricular myocytes. Gap junction connections were distributed around the periphery of each cell at 10 μm intervals. Regions of source-load mismatch were added to the models by increasing the gap junction and interstitial resistivity in one-half of the tissue. Heterogeneity in cell shape and cell arrangement along the boundary between well-coupled and poorly coupled tissue increased variability in longitudinal conduction delays to as much as 10 ms before the onset of conduction block, resulting in wavefront breakthroughs with pronounced curvature at distinct points along the boundary. Increasing the effective interstitial resistivity reduced source-load mismatch at the transition boundary, which caused a decrease in longitudinal conduction delay and an increase in the number of wavefront breakthroughs.</AbstractText><AbstractText Label="CONCLUSION" NlmCategory="CONCLUSIONS">Microstructural variations in cardiac tissue facilitate the formation of isolated sites of wavefront breakthrough that may enable abnormal electrical activity in small regions of diseased tissue to develop into more widespread reentrant activity.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Hubbard</LastName><ForeName>Marjorie Letitia</ForeName><Initials>ML</Initials><AffiliationInfo><Affiliation>Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA. [email protected]</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Henriquez</LastName><ForeName>Craig S</ForeName><Initials>CS</Initials></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>R01 HL093711</GrantID><Acronym>HL</Acronym><Agency>NHLBI NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>HL093711-01A2</GrantID><Acronym>HL</Acronym><Agency>NHLBI NIH HHS</Agency><Country>United States</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D052061">Research Support, N.I.H., Extramural</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>Europace</MedlineTA><NlmUniqueID>100883649</NlmUniqueID><ISSNLinking>1099-5129</ISSNLinking></MedlineJournalInfo><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000200" MajorTopicYN="N">Action Potentials</DescriptorName><QualifierName UI="Q000502" MajorTopicYN="Y">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D003198" MajorTopicYN="N">Computer Simulation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006168" MajorTopicYN="N">Guinea Pigs</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006329" MajorTopicYN="N">Heart Conduction System</DescriptorName><QualifierName UI="Q000502" MajorTopicYN="Y">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008564" MajorTopicYN="N">Membrane Potentials</DescriptorName><QualifierName UI="Q000502" MajorTopicYN="Y">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008955" MajorTopicYN="Y">Models, Cardiovascular</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D032383" MajorTopicYN="N">Myocytes, Cardiac</DescriptorName><QualifierName UI="Q000502" MajorTopicYN="Y">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D009431" MajorTopicYN="N">Neural Conduction</DescriptorName><QualifierName UI="Q000502" MajorTopicYN="Y">physiology</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="entrez"><Year>2012</Year><Month>10</Month><Day>30</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2012</Year><Month>11</Month><Day>1</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2013</Year><Month>4</Month><Day>26</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">23104912</ArticleId><ArticleId IdType="pmc">PMC3482616</ArticleId><ArticleId IdType="doi">10.1093/europace/eus267</ArticleId><ArticleId IdType="pii">eus267</ArticleId></ArticleIdList><ReferenceList><Reference><Citation>Luke RA, Saffitz JE. 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Circ Res. 1993;73:914–25. doi:10.1161/01.RES.73.5.914.</Citation><ArticleIdList><ArticleId IdType="doi">10.1161/01.RES.73.5.914</ArticleId><ArticleId IdType="pubmed">8403261</ArticleId></ArticleIdList></Reference><Reference><Citation>Badie N, Bursac N. Novel micropatterned cardiac cell cultures with realistic ventricular microstructure. Biophys J. 2009;96:3873–85. doi:10.1016/j.bpj.2009.02.019.</Citation><ArticleIdList><ArticleId IdType="doi">10.1016/j.bpj.2009.02.019</ArticleId><ArticleId IdType="pmc">PMC3297758</ArticleId><ArticleId IdType="pubmed">19413993</ArticleId></ArticleIdList></Reference></ReferenceList></PubmedData></PubmedArticle><PubmedBookArticle><BookDocument><PMID Version="1">23136681</PMID><ArticleIdList><ArticleId IdType="bookaccession">NBK109900</ArticleId></ArticleIdList><Book><Publisher><PublisherName>National Center for Biotechnology Information (US)</PublisherName><PublisherLocation>Bethesda (MD)</PublisherLocation></Publisher><BookTitle book="micad">Molecular Imaging and Contrast Agent Database (MICAD)</BookTitle><PubDate><Year>2004</Year></PubDate><BeginningDate><Year>2004</Year></BeginningDate><EndingDate><Year>2013</Year></EndingDate><Medium>Internet</Medium></Book><ArticleTitle book="micad" part="F18-5">[<sup>18</sup>F]-Fluoro-2-deoxy-d-glucose-folate
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[<sup>18</sup>F]-Fluoro-2-deoxy-d-glucose ([<sup>18</sup>F]FDG)-folate, abbreviated as [<sup>18</sup>F]-5, is a conjugate of [<sup>18</sup>F]-fluorodeoxyglucose and folate, which was synthesized by al Jammaz et al. for use with positron emission tomography (PET) of tumors by targeting glucose metabolism and folate receptor (1). 2-Deoxy-d-glucose (2DG) was originally synthesized to inhibit glucose utilization by cancer cells and was later labeled with <sup>18</sup>F for imaging purposes (2, 3). [<sup>18</sup>F]FDG, like glucose, is transported into cells by glucose transporters and converted to [<sup>18</sup>F]FDG-6-phosphate ([<sup>18</sup>F]FDG-6-P) within cells. Because [<sup>18</sup>F]FDG-6-P cannot be further metabolized, it is then trapped within cells. Tumor cells are highly proliferative and have a high rate of glucose metabolism compared to normal tissue. Consequently, tumor cells accumulate much more [<sup>18</sup>F]FDG-6-P than normal cells. PET imaging with [<sup>18</sup>F]FDG ([<sup>18</sup>F]FDG-PET) has been widely accepted as a standard modality in the detection, staging, and therapy response monitoring of various malignant tumors. However, there are several limitations for the clinical use of [<sup>18</sup>F]FDG-PET (4, 5). First, [<sup>18</sup>F]FDG can accumulate in several important organs, including the brain and heart, which not only limits its use in these organs but also causes toxicity to them. Second, [<sup>18</sup>F]FDG-PET is not suitable for imaging well-differentiated, low-malignant, and slow-growing tumors because these tumors often have low glucose utilization. Third, activated inflammatory cells have been found to take up considerable [<sup>18</sup>F]FDG; thus, false-positivity may become an issue when inflammatory cell infiltrate is prominent in tumors or other diseases. In an effort to develop new [<sup>18</sup>F]FDG-based imaging probes, al Jammaz et al. synthesized two conjugates, [<sup>18</sup>F]-5 and [<sup>18</sup>F]-8, by conjugating [<sup>18</sup>F]FDG with folate and methotrexate (MTX), respectively, using the readily available oxime-reactive [<sup>18</sup>F]FDG building block (1). Folate is vital for the rapid proliferation of tumor cells, and folate receptor is highly affinitive and overexpressed in various types of human tumors (6, 7). In contrast, healthy cells are severely restricted in possessing folate receptors. In addition, folate conjugates have well been characterized as drugs, drug carriers, and imaging agents (8, 9). MTX is a folic acid analog but possesses a relatively low affinity for folate receptor. Studies by al Jammaz et al. showed that [<sup>18</sup>F]-5 was more suitable for tumor imaging than [<sup>18</sup>F]-8 (1). This chapter summarizes the data obtained with [<sup>18</sup>F]-5 and [<sup>18</sup>F]-8.
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2,333,940 |
Kinetic quantification of protein polymer nanoparticles using non-invasive imaging.
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Protein polymers are repetitive amino acid sequences that can assemble monodisperse nanoparticles with potential applications as cancer nanomedicines. Of the currently available molecular imaging methods, positron emission tomography (PET) is the most sensitive and quantitative; therefore, this work explores microPET imaging to track protein polymer nanoparticles over several days. To achieve reliable imaging, the polypeptides were modified by site-specific conjugation using a heterobifunctional sarcophagine chelator, AmBaSar, which was subsequently complexed with (64)Cu. AmBaSar/(64)Cu was selected because it can label particles in vivo over periods of days, which is consistent with the timescales required to follow long-circulating nanotherapeutics. Using an orthotopic model of breast cancer, we observed four elastin-like polypeptides (ELPs)-based protein polymers of varying molecular weight, amino acid sequence, and nanostructure. To analyze this data, we developed a six-compartment image-driven pharmacokinetic model capable of describing their distribution within individual subjects. Surprisingly, the assembly of an ELP block copolymer (78 kD) into nanoparticles (R(h) = 37.5 nm) minimally influences pharmacokinetics or tumor accumulation compared to a free ELP of similar length (74 kD). Instead, ELP molecular weight is the most important factor controlling the fate of these polymers, whereby long ELPs (74 kD) have a heart activity half-life of 8.7 hours and short ELPs (37 kD) have a half-life of 2.1 hours. These results suggest that ELP-based protein polymers may be a viable platform for the development of multifunctional therapeutic nanoparticles that can be imaged using clinical PET scanners.
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2,333,941 |
Poloxamer 188 (p188) as a membrane resealing reagent in biomedical applications.
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Maintenance of the integrity of the plasma membrane is essential for maintenance of cellular function and prevention of cell death. Since the plasma membrane is frequently exposed to a variety of mechanical and chemical insults the cell has evolved active processes to defend against these injuries by resealing disruptions in the plasma membrane. Cell membrane repair is a conserved process observed in nearly every cell type where intracellular vesicles are recruited to sites of membrane disruption where they can fuse with themselves or the plasma membrane to create a repair patch. When disruptions are extensive or there is an underlying pathology that reduces the membrane repair capacity of a cell this defense mechanism may prove insufficient and the cell could die due to breakdown of the plasma membrane. Extensive loss of cells can compromise the integrity and function of tissues and leading to disease. Thus, methods to increase membrane resealing capacity could have broad utility in a number of disease states. Efforts to find reagents that can modulate plasma membrane reseal found that specific tri-block copolymers, such as poloxamer 188 (P188, or Pluronic F68), can increase the structural stability and resealing of the plasma membrane. Here we review several current patents and patent applications that present inventions making use of P188 and other copolymers to treat specific disease states such as muscular dystrophy, heart failure, neurodegenerative disorders and electrical injuries, or to facilitate biomedical applications such as transplantation. There appears to be promise for the application of poloxamers in the treatment of various diseases, however there are potential concerns with toxicity with long term application and bioavailability in some cases.
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2,333,942 |
Methods for robust in vivo strain estimation in the carotid artery.
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A hierarchical block-matching motion tracking algorithm for strain imaging is presented. Displacements are estimated with improved robustness and precision by utilizing a Bayesian regularization algorithm and an unbiased subsample interpolation technique. A modified least-squares strain estimator is proposed to estimate strain images from a noisy displacement input while addressing the motion discontinuity at the wall-lumen boundary. Methods to track deformation over the cardiac cycle incorporate a dynamic frame skip criterion to process data frames with sufficient deformation to produce high signal-to-noise displacement and strain images. Algorithms to accumulate displacement and/or strain on particles in a region of interest over the cardiac cycle are described. New methods to visualize and characterize the deformation measured with the full 2D strain tensor are presented. Initial results from patients imaged prior to carotid endarterectomy suggest that strain imaging detects conditions that are traditionally considered high risk including soft plaque composition, unstable morphology, abnormal hemodynamics and shear of plaque against tethering tissue can be exacerbated by neoangiogenesis. For example, a maximum absolute principal strain exceeding 0.2 is observed near calcified regions adjacent to turbulent flow, protrusion of the plaque into the arterial lumen and regions of low echogenicity associated with soft plaques. Non-invasive carotid strain imaging is therefore a potentially useful tool for detecting unstable carotid plaque.
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2,333,943 |
Salivary alpha-amylase changes promoted by sustained exposure to affective pictures.
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We studied the changes in salivary alpha-amylase (sAA) and other psychophysiological indices (heart rate, skin conductance, and corrugator supercilii activity) elicited by sustained exposure to affective pictures. Thirty-nine subjects viewed five blocks of pictures depicting mutilations, human attack, neutral scenes, sport/adventure, and erotica. Each block comprised 12 pictures of the same content. Saliva samples were collected before and after each block of pictures. The results showed that mutilation pictures promoted the greatest increase in sAA activity and output, as well as greater corrugator supercilii activity than pleasant pictures. Skin conductance response did not differ among high arousal picture contents. Changes in sAA varied with the affective valence but not with the arousal ratings of the pictures. Our results point to sAA as an index directly related to the unpleasantness elicited by sustained exposure to affective stimuli.
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2,333,944 |
Detecting drug-induced prolongation of the QRS complex: new insights for cardiac safety assessment.
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Drugs slowing the conduction of the cardiac action potential and prolonging QRS complex duration by blocking the sodium current (I(Na)) may carry pro-arrhythmic risks. Due to the frequency-dependent block of I(Na), this study assesses whether activity-related spontaneous increases in heart rate (HR) occurring during standard dog telemetry studies can be used to optimise the detection of class I antiarrhythmic-induced QRS prolongation.</AbstractText>Telemetered dogs were orally dosed with quinidine (class Ia), mexiletine (class Ib) or flecainide (class Ic). QRS duration was determined standardly (5 beats averaged at rest) but also prior to and at the plateau of each acute increase in HR (3 beats averaged at steady state), and averaged over 1h period from 1h pre-dose to 5h post-dose.</AbstractText>Compared to time-matched vehicle, at rest, only quinidine and flecainide induced increases in QRS duration (E(max) 13% and 20% respectively, P<0.01-0.001) whereas mexiletine had no effect. Importantly, the increase in QRS duration was enhanced at peak HR with an additional effect of +0.7 ± 0.5 ms (quinidine, NS), +1.8 ± 0.8 ms (mexiletine, P<0.05) and +2.8 ± 0.8 ms (flecainide, P<0.01) (calculated as QRS at basal HR-QRS at high HR).</AbstractText>Electrocardiogram recordings during elevated HR, not considered during routine analysis optimised for detecting QT prolongation, can be used to sensitise the detection of QRS prolongation. This could prove useful when borderline QRS effects are detected. Analysing during acute increases in HR could also be useful for detecting drug-induced effects on other aspects of cardiac function.</AbstractText>Copyright © 2012 Elsevier Inc. All rights reserved.</CopyrightInformation>
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2,333,945 |
Nonequilibrium arrhythmic states and transitions in a mathematical model for diffuse fibrosis in human cardiac tissue.
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We present a comprehensive numerical study of spiral- and scroll-wave dynamics in a state-of-the-art mathematical model for human ventricular tissue with fiber rotation, transmural heterogeneity, myocytes, and fibroblasts. Our mathematical model introduces fibroblasts randomly, to mimic diffuse fibrosis, in the ten Tusscher-Noble-Noble-Panfilov (TNNP) model for human ventricular tissue; the passive fibroblasts in our model do not exhibit an action potential in the absence of coupling with myocytes; and we allow for a coupling between nearby myocytes and fibroblasts. Our study of a single myocyte-fibroblast (MF) composite, with a single myocyte coupled to N(f) fibroblasts via a gap-junctional conductance G(gap), reveals five qualitatively different responses for this composite. Our investigations of two-dimensional domains with a random distribution of fibroblasts in a myocyte background reveal that, as the percentage P(f) of fibroblasts increases, the conduction velocity of a plane wave decreases until there is conduction failure. If we consider spiral-wave dynamics in such a medium we find, in two dimensions, a variety of nonequilibrium states, temporally periodic, quasiperiodic, chaotic, and quiescent, and an intricate sequence of transitions between them; we also study the analogous sequence of transitions for three-dimensional scroll waves in a three-dimensional version of our mathematical model that includes both fiber rotation and transmural heterogeneity. We thus elucidate random-fibrosis-induced nonequilibrium transitions, which lead to conduction block for spiral waves in two dimensions and scroll waves in three dimensions. We explore possible experimental implications of our mathematical and numerical studies for plane-, spiral-, and scroll-wave dynamics in cardiac tissue with fibrosis.
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2,333,946 |
Characterization of the molecular architecture of human caveolin-3 and interaction with the skeletal muscle ryanodine receptor.
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Caveolin-3 facilitates both caveolae formation and a range of cell signaling pathways, including Ca(2+) homeostasis.</AbstractText>Caveolin-3 forms a disc-shaped nonamer that binds the Ca(2+)-release channel, RyR1.</AbstractText>Multiple caveolin-3 nonamers bind to a single RyR1 homotetramer.</AbstractText>First three-dimensional structural insights into caveolin-3 assembly, interactions with RyR1 suggest a novel role in muscle contraction and/or for channel localization within the membrane. Caveolin-3 (cav-3), an integral membrane protein, is a building block of caveolae as well as a regulator of a number of physiological processes by facilitating the formation of multiprotein signaling complexes. We report that the expression of cav-3 in insect (Sf9) cells induces caveola formation, comparable in size with those observed in native tissue. We have also purified the recombinant cav-3 determining that it forms an oligomer of ∼220 kDa. We present the first three-dimensional structure for cav-3 (using transmission electron microscopy and single particle analysis methods) and show that nine cav-3 monomers assemble to form a complex that is toroidal in shape, ~16.5 nm in diameter and ~ 5.5 nm in height. Labeling experiments and reconstitution of the purified cav-3 into liposomes have allowed a proposal for the orientation of the protein with respect to the membrane. We have identified multiple caveolin-binding motifs within the ryanodine receptor (RyR1) sequence employing a bioinformatic analysis. We have then shown experimentally that there is a direct interaction between recombinant cav-3 nonamers and purified RyR1 homotetramers that would imply that at least one of the predicted cav-3-binding sites is exposed within the fully assembled RyR1 structure. The cav-3 three-dimensional model provides new insights as to how a cav-3 oligomer can bind multiple partners in close proximity to form signaling complexes. Furthermore, a direct interaction with RyR1 suggests a possible role for cav-3 as a modifier of muscle excitation-contraction coupling and/or for localization of the receptor to regions of the sarcoplasmic reticulum.</AbstractText>
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2,333,947 |
Large conductance Ca2+-activated and voltage-activated K+ channels contribute to the rise and maintenance of estrogen-induced uterine vasodilation and maintenance of blood pressure.
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Uterine blood flow (UBF) increases greater than 4-fold 90 min after systemic estradiol-17β (E2β) in nonpregnant sheep and remains elevated longer than 6-8 h; mean arterial pressure (MAP) is unchanged. Large-conductance Ca(+2)-activated (BK(Ca)) and voltage-activated (K(V)) K(+) channels contribute to the acute rise in UBF; their role in maintaining UBF and MAP longer than 90 min is unknown. We examined this in five nonpregnant, ovariectomized ewes with uterine artery (UA) flow probes and catheters in a UA for infusion of K(+) channel inhibitors and uterine vein to sample venous effluent. Animals received systemic E2β (1.0 μg/kg; control), E2β+UA tetraethylammonium (TEA; 0.4-0.8 mm, n = 4), and E2β+UA 4-aminopyridine (4-AP; 0.01-0.08 mm, n = 4) to block BK(Ca) and K(V), respectively, while monitoring MAP, heart rate, and UBF. Uterine cGMP synthesis was measured. Ninety minutes after E2β, UBF rose 4.5-fold, uterine vascular resistance (UVR) fell greater than 5-fold and MAP was unchanged [78 ± 0.8 (sem) vs. 77 ± 1.5 mm Hg] in control studies and before UA inhibition with TEA and 4-AP. Between 90 and 120min, UBF, UVR, and MAP were unchanged after E2β alone. E2β+TEA dose dependently decreased ipsilateral UBF and increased UVR (24 ± 8.9 and 38 ± 16%, respectively, at 0.8 mm; P < 0.03); MAP was unchanged. Contralateral UBF/UVR were unaffected. E2β+4-AP also dose dependently decreased ipsilateral UBF and increased UVR (27 ± 5.3 and 76 ± 18%, respectively, at 0.08 mm; P < 0.001); however, MAP rose 27 ± 6.9% (P ≤ 0.006). E2β increased uterine cGMP synthesis greater than 3.5-fold and was unaffected by local K(+) channel inhibition. BK(Ca) and K(V) contribute to the rise and maintenance of E2β-induced uterine vasodilation, which is partially cGMP dependent. Systemic vascular K(V) also contributes to maintaining MAP after systemic E2β.
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2,333,948 |
Heterogeneity of ATP-sensitive K+ channels in cardiac myocytes: enrichment at the intercalated disk.
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Ventricular ATP-sensitive potassium (K(ATP)) channels link intracellular energy metabolism to membrane excitability and contractility. Our recent proteomics experiments identified plakoglobin and plakophilin-2 (PKP2) as putative K(ATP) channel-associated proteins. We investigated whether the association of K(ATP) channel subunits with junctional proteins translates to heterogeneous subcellular distribution within a cardiac myocyte. Co-immunoprecipitation experiments confirmed physical interaction between K(ATP) channels and PKP2 and plakoglobin in rat heart. Immunolocalization experiments demonstrated that K(ATP) channel subunits (Kir6.2 and SUR2A) are expressed at a higher density at the intercalated disk in mouse and rat hearts, where they co-localized with PKP2 and plakoglobin. Super-resolution microscopy demonstrate that K(ATP) channels are clustered within nanometer distances from junctional proteins. The local K(ATP) channel density, recorded in excised inside-out patches, was larger at the cell end when compared with local currents recorded from the cell center. The K(ATP) channel unitary conductance, block by MgATP and activation by MgADP, did not differ between these two locations. Whole cell K(ATP) channel current density (activated by metabolic inhibition) was ∼40% smaller in myocytes from mice haploinsufficient for PKP2. Experiments with excised patches demonstrated that the regional heterogeneity of K(ATP) channels was absent in the PKP2 deficient mice, but the K(ATP) channel unitary conductance and nucleotide sensitivities remained unaltered. Our data demonstrate heterogeneity of K(ATP) channel distribution within a cardiac myocyte. The higher K(ATP) channel density at the intercalated disk implies a possible role at the intercellular junctions during cardiac ischemia.
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2,333,949 |
Factors affecting fetal bradycardia following combined spinal epidural for labor analgesia: a matched case-control study.
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The combined spinal epidural (CSE) technique for labor analgesia has become increasingly popular owing to its rapid onset of analgesia. However, incidences of fetal bradycardia following CSE have been reported. This study aimed to identify predictors of fetal bradycardia post CSE, such as a decrease in pain scores, the block height, Prostin (dinoprostone; Pfizer) use, and dosage of oxytocin.</AbstractText>From May 2008 to October 2008, 29 patients were identified to have had an episode of fetal bradycardia. Each case was then matched to three controls, according to age and American Society of Anesthesiology status, selected from 2345 parturients who received a CSE during this period.</AbstractText>A unit improvement in the pain score was associated with an increase in the odds of fetal bradycardia by 1.28 (95 % confidence interval [CI]: 1.02-1.60). In a second logistic regression model including sensory level higher than T9, the effect size remained consistent with an odds ratio of 1.22 (95 % CI: 0.97-1.53), supporting the theory that a higher level of sympathetic block (with a higher sensory block taken as a surrogate marker) results in an increased risk of fetal bradycardia. The dosage of oxytocin and the quantity of Prostin used were not found to be risk factors.</AbstractText>The difference between pre- and post-CSE pain scores, and a higher sensory block height, which are surrogates for a greater degree of sympatholysis, were found to be risk factors for fetal bradycardia post CSE.</AbstractText>
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2,333,950 |
Maternal autoantibody levels in congenital heart block and potential prophylaxis with antiinflammatory agents.
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The importance of maternal autoantibody levels in congenital heart block and elucidation of maternal factors that may reduce disease burden require further clarification.</AbstractText>Pregnancies complicated by maternal anti-Ro antibodies from 2007 through 2011 were retrospectively reviewed.</AbstractText>In all, 33 women were followed up throughout pregnancy. Semiquantitative maternal anti-La levels were significantly higher in pregnancies complicated by fetal heart block of any degree (median difference, 227.5; P = .04), but there was no difference in maternal anti-Ro levels. In all, 94% of fetuses maintained normal conduction when the mother was treated with hydroxychloroquine or daily prednisone therapy throughout pregnancy, compared to 59% in the untreated group (odds ratio, 0.1; P = .04).</AbstractText>Pregnancies complicated by fetal heart block did not have higher levels of maternal anti-Ro antibodies. Maternal anti-La level may be a useful predictor of fetal heart block. Maternal treatment with either hydroxychloroquine or daily low-dose prednisone throughout pregnancy may provide a protective effect.</AbstractText>Copyright © 2013 Mosby, Inc. All rights reserved.</CopyrightInformation>
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2,333,951 |
Neurodevelopment in children with and without congenital heart block born to anti-Ro/SSA-positive mothers.
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To define factors influencing neurodevelopment in children with and without complete congenital heart block (CHB) born to mothers with Ro/SSA autoantibodies.</AbstractText>Medical records of a population-based cohort of siblings with (n = 60) and without (n = 54) CHB born 1974-2009 to anti-Ro/SSA-positive mothers were retrieved from children primary healthcare centres and school health services and used to extract data on neurodevelopment.</AbstractText>Impaired neurodevelopment was reported in 16% of the children (18/114) during the follow-up time of 13.0 (8.2-17.5) years, median (quartiles). Reported problems included speech (9%), motor (8%) and learning (8%) impairment, attention deficit (5%) and behavioural impairment (4%). Impairment in motor skill development was more common in boys (p < 0.001) if the child was born preterm (p < 0.001). Learning impairment was significantly influenced by maternal SLE (p < 0.005), while attention deficits was influenced by both maternal SLE (p < 0.05) and CHB in the child (p < 0.05).</AbstractText>Our data indicate that in addition to well-established factors such as male sex and being born preterm, both maternal SLE and CHB may influence neurodevelopment. Follow-up of neurodevelopment should therefore be considered for children with CHB, especially if the mother is diagnosed with SLE.</AbstractText>©2012 The Author(s)/Acta Paediatrica ©2012 Foundation Acta Paediatrica.</CopyrightInformation>
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2,333,952 |
Capability of different non-nutritive feed additives on improving productive and physiological traits of broiler chicks fed diets with or without aflatoxin during the first 3 weeks of life.
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An experiment was conducted to determine whether some non-nutritive feed additives (NNFA) could block the adverse effects of aflatoxin (AF) on growth performance and physiological parameters of Cobb broilers throughout the period from 1 to 21 day of age. There were eight treatments consisting of two levels of AF at 0 and 200 ppb and four NNFA within each AF level. These additives included mannan oligosaccharides (MOS) at 2 g/kg diet, hydrated sodium calcium aluminosilicate (HSCAS) at 2 g/kg diet and Lactobacillus acidophilus (Lac) at 2 g/kg diet. At 21 day of age, five chickens of each treatment were slaughtered to study dressing percentage and relative weight of inner organs and glands. AF had a significant negative effect on body weight gain (BWG), and feed intake, while impairing feed conversion ratio (FCR). Aflatoxin significantly increased percentage liver, lymphocyte (%), monocyte (%), serum triglyceride level, and the aspartate aminotransferase (AST), and alanine aminotransferase (ALT), concentrations while decreasing dressing percentage, intestinal percentage, white blood cells (WBCs), red blood cells (RBCs), haemoglobin (Hgb), packed cell volume (PCV), heterophil (%), heterophil/lymphocyte ratio, total serum protein and serum albumin. Aflatoxin adversely affected the morphology of the liver, bursa and the thymus. There was a significant interaction between AF and NNFA on the relative weights of liver, heart and intestine. Lac completely blocked the negative effects of AF on the percentage liver and the heart and partially on the intestine. In conclusion, Lac was most effective in reversing the adverse effects of AF on growth and FCR and on the percentage, functions and morphology of the liver. Hydrated sodium calcium aluminosilicate also improved the economic traits of broilers but was less effective than Lac and more effective than MOS.
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2,333,953 |
Globular adiponectin protects H9c2 cells from palmitate-induced apoptosis via Akt and ERK1/2 signaling pathways.
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Cardiomyocytes apoptosis is an important contributor to myocardial dysfunction and heart failure. Adiponectin has cardioprotective effects, potential mechanisms behind it are not clear in cardiomyocytes. The purpose of the study was to investigate whether adiponectin can block palmitate-induced apoptosis and the underlying biochemical mechanism in H9c2 cells.</AbstractText>H9c2 cells were treated with palmitate presence or absence of 2.5 μg/mL globular adiponectin. The effect on the cell viability of H9c2 cells was evaluated using MTT assay, and cell apoptosis was determined by Hoechst 33342 staining. Protein expression was measured using the western blot method.</AbstractText>Our results showed that the palmitate treatment induced apoptosis in H9c2 cells, which was associated with increasing the level of cleaved caspase-3 and cleaved PARP. Meanwhile, palmitate-induced apoptosis increased the protein level of p-ERK1/2, and decreased the protein level of p-Akt significantly. However, levels of both of these proteins were restored to the normal when pretreated with adiponectin, and followed with the decrease of cleaved caspase-3 and cleaved PARP. In line with these results, the protective effect of adiponectin can be blocked by PI3K/Akt inhibitor LY294002, and palmitate-induced apoptosis can be attenuated by ERK1/2 inhibitor U0126.</AbstractText>Taken together, the present study demonstrated that adiponectin protects H9c2 cells from palmitate-induced apoptosis via PI3K/Akt and ERK1/2 signaling pathways. Our results reveal a link between adiponectin and cardiomyocytes apoptosis, suggesting that adioponectin may be a promising therapeutic for the treatment of lipotoxicity cardiomyopathy.</AbstractText>
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2,333,954 |
Natriuretic peptides block synaptic transmission by activating phosphodiesterase 2A and reducing presynaptic PKA activity.
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The heart peptide hormone atrial natriuretic peptide (ANP) regulates blood pressure by stimulating guanylyl cyclase-A to produce cyclic guanosine monophosphate (cGMP). ANP and guanylyl cyclase-A are also expressed in many brain areas, but their physiological functions and downstream signaling pathways remain enigmatic. Here we investigated the physiological functions of ANP signaling in the neural pathway from the medial habenula (MHb) to the interpeduncular nucleus (IPN). Biochemical assays indicate that ANP increases cGMP accumulation in the IPN of mouse brain slices. Using optogenetic stimulation and electrophysiological recordings, we show that both ANP and brain natriuretic peptide profoundly block glutamate release from MHb neurons. Pharmacological applications reveal that this blockade is mediated by phosphodiesterase 2A (PDE2A) but not by cGMP-stimulated protein kinase-G or cGMP-sensitive cyclic nucleotide-gated channels. In addition, focal infusion of ANP into the IPN enhances stress-induced analgesia, and the enhancement is prevented by PDE2A inhibitors. PDE2A is richly expressed in the axonal terminals of MHb neurons, and its activation by cGMP depletes cyclic adenosine monophosphates. The inhibitory effect of ANP on glutamate release is reversed by selectively activating protein kinase A. These results demonstrate strong presynaptic inhibition by natriuretic peptides in the brain and suggest important physiological and behavioral roles of PDE2A in modulating neurotransmitter release by negative crosstalk between cGMP-signaling and cyclic adenosine monophosphate-signaling pathways.
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2,333,955 |
Aldosterone synthase inhibition in humans.
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Aldosterone synthase (CYP11B2) inhibition has emerged as a new option for the treatment of hypertension, heart failure and renal disorders, in addition to mineralocorticoid receptor (MR) blockade. The aim is to decrease aldosterone concentrations in both plasma and tissues, thereby decreasing MR-dependent and MR-independent effects in the cardiac, vascular and renal target organs. LCI699 was the first orally active aldosterone-synthase inhibitor to be developed for human use. Its structure is similar to that of FAD286, the dextroenantiomer of the aromatase inhibitor, fadrozole. It dose-dependently decreases plasma and urine aldosterone concentrations by up to 70 or 80% and increases plasma renin activity in healthy male subjects on a low-sodium diet. LCI699 does not decrease basal plasma cortisol concentrations at doses of 0.5-3 mg q.d., but it blocks the cortisol response to adrenocorticotropic hormone (ACTH) at doses ≥ 3 mg q.d. In a proof-of-concept study in patients with primary aldosteronism (PA), LCI699 (0.5-1 mg b.i.d.) induced a dose-dependent and reversible 70-80% decrease in plasma and urinary aldosterone concentration accompanied by a massive dose-dependent accumulation of deoxycorticosterone (>+700%), the aldosterone precursor, in the plasma, thereby confirming the inhibition of the CYP11B2 gene product. This effect was associated with a rapid correction of hypokalaemia, a modest decrease in blood pressure (BP) and a mild increase in plasma renin concentration in patients with PA. LCI699 administration induced biological signs of partial inhibition of the glucocorticoid axis, such as dose-dependent increases in both plasma ACTH and 11-deoxycortisol (the precursor of cortisol) concentrations, consistent with the inhibition of the CYP11B1 gene product. An 8-week placebo-controlled dose-response study on patients with Stage 1 and 2 essential hypertension reported an optimal decrease in BP with a dose of 1 mg LCI699 q.d., which had an antihypertensive effect similar to that of 50 mg b.i.d. eplerenone. A blunted cortisol response to ACTH was observed in 20% of patients, but the clinical and biological safety and tolerability of LCI699 were similar to those of placebo and eplerenone. The discovery of this first orally active aldosterone synthase inhibitor, LCI699, has provided new opportunities to assess the feasibility and the haemodynamic, biological and safety consequences as well as the limitations of this new approach to block the aldosterone pathway in hypertensive patients. However, as the effects of LCI699 on the glucocorticoid axis limit the use of higher doses range because of the loss of selectivity for CYP11B2, this aldosterone synthase inhibitor cannot replace the MR blockade in patients with hypertension, other cardiovascular or renal disorders. The development of second-generation aldosterone synthase inhibitors with a higher selectivity index for CYP11B2 than LCI699 should make it possible to test this approach at much higher doses in these patients, after the necessary toxicology and Phase I studies.
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2,333,956 |
Pitstop 2 is a potent inhibitor of clathrin-independent endocytosis.
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Clathrin independent endocytosis (CIE) is a form of endocytosis present in all cells that mediates the entry of nutrients, macromolecules and membrane proteins into cells. When compared to clathrin-dependent endocytosis (CDE), however, much less is known about the machinery involved in forming CIE endosomes. One way to distinguish CIE from CDE has been to deplete cells of coat proteins involved in CDE such as clathrin or the dynamin GTPase, leading to a block of CDE but not CIE. A drawback of such genetic manipulations is that depletion of proteins important for mediating CDE over a period of days can have complex indirect effects on cellular function. The identification of chemical compounds that specifically and rapidly block CDE or CIE would facilitate the determination of whether a process involved CDE or CIE. To date, all of those compounds have targeted CDE. Dynasore and the dynoles specifically target and block dynamin activity thus inhibiting CDE but not most forms of CIE. Recently, a new compound called pitstop 2 was identified as an inhibitor of the interaction of amphiphysin with the amino terminal domain of clathrin, and shown to inhibit CDE in cells. Here we show that pitstop 2 is also a potent inhibitor of CIE. The effects of pitstop 2 are not restricted to inhibition of clathrin since knockdown of clathrin fails to rescue the inhibition of endocytosis of CIE proteins by the drug. Thus pitstop 2 has additional cellular targets besides the amino terminal domain of clathrin and thus cannot be used to distinguish CIE from CDE.
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2,333,957 |
Combinations of fentanyl and levobupivacaine for post-thoracotomy pain.
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The aim of the present study is to evaluate the analgesic activity, patient satisfaction, and side effect profile of different concentrations of levobupivacaine plus fentanyl administered through thoracic epidural patient-controlled analgesia in patients undergoing thoracotomy. The study included 60 patients who were randomly divided into three groups. At the end of the surgery, group I (n = 20) received 0.125% levobupivacaine plus 3 mg fentanyl, group II received 0.1% levobupivacaine plus 3 mg fentanyl, and group III received 0.05% levobupivacaine plus 3 mg fentanyl via an epidural catheter placed at the level of T(10-11) or T(11-12). For all groups, the patient-controlled analgesia device was programmed to deliver a loading dose of 14 mL at an infusion rate of 4 mL/h, and a bolus dose of 2 mL/h, with a locked out interval of 15 minutes and 60 mL of a 4-hour limit. The following parameters were evaluated at 5, 10, 15, 20, 30, and 40 minutes and at 1, 2, 4, 8, 16, and 24 hours after admission to the intensive care unit, at which nausea and vomiting scales, Visual Analog Scale I-II, Ramsay sedation scale, Bromage scale, pupil diameter, arterial blood pressure, heart rate, respiratory rate, and SpO(2) were measured and recorded. Any side effect was also documented. As the result of the evaluation, visual Analog Scale I-II scores, patient satisfaction scores, mean arterial blood pressure, and heart rate significantly differed in group I as compared with groups II and III. No side effects were encountered except mild nausea, which was seen in group III and did not require treatment. Motor blockage, pupil size, respiratory rate, and SpO(2) were not monitored in any of the patients in all groups. In conclusion, our study suggested that the use of 0.125% levobupivacaine, together with 3 mg/mL fentanyl, constitutes a good combination, and can be used safely without causing hemodynamic change and motor block.
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2,333,958 |
Chaotic dynamics in cardiac aggregates induced by potassium channel block.
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Chaotic rhythms in deterministic models can arise as a consequence of changes in model parameters. We carried out experimental studies in which we induced a variety of complex rhythms in aggregates of embryonic chick cardiac cells using E-4031 (1.0-2.5 μM), a drug that blocks the hERG potassium channel. Following the addition of the drug, the regular rhythm evolved to display a spectrum of complex dynamics: irregular rhythms, bursting oscillations, doublets, and accelerated rhythms. The interbeat intervals of the irregular rhythms can be described by one-dimensional return maps consistent with chaotic dynamics. A Hodgkin-Huxley-style cardiac ionic model captured the different types of complex dynamics following blockage of the hERG mediated potassium current.
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2,333,959 |
Planning comparison of intensity modulated radiation therapy delivered with 2 tangential fields versus 3-dimensional conformal radiotherapy for cardiac sparing in women with left-sided breast cancer.
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In women with unfavorable thoracic anatomy undergoing left breast radiation therapy (RT) after breast-conserving surgery, a significant volume of the heart may receive high-dose radiation, which has been shown previously to be associated with increased late cardiac morbidity and mortality. Use of intensity modulated radiation therapy (IMRT) has been proposed to reduce cardiac dose in these patients. We compared cardiac exposure from IMRT delivered from 2 opposed fields and 3-dimensional conformal radiation therapy (3DCRT) plans employing simple heart blocks.</AbstractText>Fourteen patients with left-sided breast cancer treated with breast-conserving surgery and RT were identified to have unfavorable cardiac anatomy, defined as maximum heart depth (MHD) ≥1.0 cm within the unblocked opposed tangential fields. 3DCRT plans utilized dynamic wedges, segments, and custom heart blocks designed by the treating physician. Tangent IMRT plans were optimized to reduce cardiac dose while maintaining planning target volume (PTV) coverage equal to that achieved with the 3DCRT plan. We generated tangential field plans with complete heart block (CHB) or no heart block (NHB) for comparison. Plans were normalized to deliver 46 Gy to the PTV. Dose to the heart, PTV, and lumpectomy cavity were compared.</AbstractText>Mean MHD was 1.44 cm (1.0-1.86 cm). There was no significant difference in PTV receiving >95% of the prescription dose between 3DCRT and IMRT, as intended. Mean V30 to the heart was 0% for CHB plans, 1.7% for 3DCRT plans, 1.8% for IMRT plans, and 3.3% for NHB plans, respectively. There was no significant difference in heart V30 for 3DCRT and IMRT plans (P = .8). IMRT plans delivered 256 total monitor units compared with 201 in 3DCRT plans (P < .01).</AbstractText>Inverse-planned tangent IMRT does not reduce high-dose radiation to the heart compared with 3DCRT, incorporating a simple heart block in women with left-sided cancer and unfavorable cardiac anatomy when PTV coverage was equalized for both plans. In select patients with early-stage breast cancer and unfavorable thoracic anatomy, 3DCRT with heart block may be sufficient to adequately protect the heart from high-dose radiation.</AbstractText>Copyright © 2012 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.</CopyrightInformation>
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2,333,960 |
Randomised controlled trial of group cognitive behaviour therapy versus brief intervention for depression in cardiac patients.
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To determine whether a six-session group cognitive behaviour therapy (CBT) programme results in a greater reduction in depression symptoms than a brief intervention alone in cardiac patients with clinically significant symptoms of depression.</AbstractText>Fifty-seven community dwelling cardiac patients scoring >13 on the Beck Depression Inventory-II (BDI-II) received a single-session brief intervention. They were then block randomised to either six sessions of group CBT (n = 25) or no further intervention (BI; n = 32). All were re-assessed at 2, 6 and 12 months. Differences between treatment groups in the primary (BDI-II) and secondary [rates of depression; anxiety symptoms, as measured by the Hospital Anxiety and Depression Scale-Anxiety (HADS-A)] outcomes were examined using generalised linear mixed models with a random intercept term for the individual.</AbstractText>Significant improvements were seen for the total group from baseline to 12 months on BDI-II and HADS-A scores. However, no differences were found between the CBT and BI conditions on change in BDI-II score, rates of major depressive episode or HADS-A score. Post hoc analysis on the total group found 12-month symptom non-remission was associated with higher baseline BDI-II score (p = 0.03), more visits to health professionals 12 months prior to baseline (p = 0.05) and a greater likelihood of either drinking alcohol over recommended levels or smoking at baseline (p = 0.01).</AbstractText>Group CBT of up to six sessions did not result in greater reductions in depression or anxiety symptoms compared with a single-session brief intervention. Further work should focus on the efficacy and role of brief interventions, and addressing smoking and alcohol misuse in cardiac patients with depression.</AbstractText>
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2,333,961 |
Association of left ventricular diastolic function with systolic dyssynchrony: a population study.
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Left ventricular (LV) (dys)synchrony has an important impact on LV function and structure. Our study aimed to describe the distribution and determinants of LV mechanical delay indexes in the general population and to assess an association of different Doppler indexes reflecting LV diastolic function with LV mechanical delay indexes.</AbstractText>In 200 subjects enrolled in a family-based population study (46.5% women; mean age, 57.9; 48% hypertensive), we performed echocardiography with tissue synchronization imaging (TSI) and two-dimensional speckle tracking. We measured the maximum difference in time to peak systolic velocity between any 2 of 12 LV segments (Ts-max); the standard deviation of time to peak systolic velocity of 12 segments (Ts-sd); the difference in time to peak systolic velocity and strain between septal and lateral LV walls and the strain delay index in septal and lateral walls [septal and lateral (SDI)]. In univariable and multivariable regression analyses, TSI indexes and lateral SDI independently increased with age (P ≤ 0.027) and body mass index (P ≤ 0.010). Ts-max and Ts-sd also increased with female sex (P ≤ 0.0002) and decreased with heart rate (P ≤ 0.0004). Septal SDI only increased with female sex (P < 0.0001). Among the Doppler indexes of LV diastolic function, only E/e' was significantly and positively associated with TSI indexes (P ≤ 0.037) and lateral SDI (P = 0.0026), but not with septal SDI (P = 0.69). In participants with advanced stage of LV diastolic dysfunction, TSI indexes were prolonged compare with subjects with normal LV diastolic function (P ≤ 0.002).</AbstractText>We demonstrated that in unselected subjects LV diastolic dysfunction was associated with mechanical LV dyssynchrony as assessed by echocardiography.</AbstractText>
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2,333,962 |
Trends in permanent pacemaker implantation in the United States from 1993 to 2009: increasing complexity of patients and procedures.
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This study sought to define contemporary trends in permanent pacemaker use by analyzing a large national database.</AbstractText>The Medicare National Coverage Determination for permanent pacemaker, which emphasized single-chamber pacing, has not changed significantly since 1985. We sought to define contemporary trends in permanent pacemaker use by analyzing a large national database.</AbstractText>We queried the Nationwide Inpatient Sample to identify permanent pacemaker implants between 1993 and 2009 using the International Classification of Diseases-Ninth Revision-Clinical Modification procedure codes for dual-chamber (DDD), single-ventricular (VVI), single-atrial (AAI), or biventricular (BiV) devices. Annual permanent pacemaker implantation rates and patient demographics were analyzed.</AbstractText>Between 1993 and 2009, 2.9 million patients received permanent pacemakers in the United States. Overall use increased by 55.6%. By 2009, DDD use increased from 62% to 82% (p < 0.001), whereas single-chamber ventricular pacemaker use fell from 36% to 14% (p = 0.01). Use of DDD devices was higher in urban, nonteaching hospitals (79%) compared with urban teaching hospitals (76%) and rural hospitals (72%). Patients with private insurance (83%) more commonly received DDD devices than Medicaid (79%) or Medicare (75%) recipients (p < 0.001). Patient age and Charlson comorbidity index increased over time. Hospital charges ($2011) increased 45.3%, driven by the increased cost of DDD devices.</AbstractText>There is a steady growth in the use of permanent pacemakers in the United States. Although DDD device use is increasing, whereas single-chamber ventricular pacemaker use is decreasing. Patients are becoming older and have more medical comorbidities. These trends have important health care policy implications.</AbstractText>Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.</CopyrightInformation>
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2,333,963 |
Myocardin regulates BMP10 expression and is required for heart development.
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Myocardin is a muscle lineage-restricted transcriptional coactivator that has been shown to transduce extracellular signals to the nucleus required for SMC differentiation. We now report the discovery of a myocardin/BMP10 (where BMP10 indicates bone morphogenetic protein 10) signaling pathway required for cardiac growth, chamber maturation, and embryonic survival. Myocardin-null (Myocd) embryos and embryos harboring a cardiomyocyte-restricted mutation in the Myocd gene exhibited myocardial hypoplasia, defective atrial and ventricular chamber maturation, heart failure, and embryonic lethality. Cardiac hypoplasia was caused by decreased cardiomyocyte proliferation accompanied by a dramatic increase in programmed cell death. Defective chamber maturation and the block in cardiomyocyte proliferation were caused in part by a block in BMP10 signaling. Myocardin transactivated the Bmp10 gene via binding of a serum response factor-myocardin protein complex to a nonconsensus CArG element in the Bmp10 promoter. Expression of p57kip2, a BMP10-regulated cyclin-dependent kinase inhibitor, was induced in Myocd-/- hearts, while BMP10-activated cardiogenic transcription factors, including NKX2.5 and MEF2c, were repressed. Remarkably, when embryonic Myocd-/- hearts were cultured ex vivo in BMP10-conditioned medium, the defects in cardiomyocyte proliferation and p57kip2 expression were rescued. Taken together, these data identify a heretofore undescribed myocardin/BMP10 signaling pathway that regulates cardiomyocyte proliferation and apoptosis in the embryonic heart.
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2,333,964 |
Mechanical preconditioning enables electrophysiologic coupling of skeletal myoblast cells to myocardium.
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The effect of mechanical preconditioning on skeletal myoblasts in engineered tissue constructs was investigated to resolve issues associated with conduction block between skeletal myoblast cells and cardiomyocytes.</AbstractText>Murine skeletal myoblasts were used to generate engineered tissue constructs with or without application of mechanical strain. After in vitro myotube formation, engineered tissue constructs were co-cultured for 6 days with viable embryonic heart slices. With the use of sharp electrodes, electrical coupling between engineered tissue constructs and embryonic heart slices was assessed in the presence or absence of pharmacologic agents.</AbstractText>The isolation and expansion procedure for skeletal myoblasts resulted in high yields of homogeneously desmin-positive (97.1% ± 0.1%) cells. Mechanical strain was exerted on myotubes within engineered tissue constructs during gelation of the matrix, generating preconditioned engineered tissue constructs. Electrical coupling between preconditioned engineered tissue constructs and embryonic heart slices was observed; however, no coupling was apparent when engineered tissue constructs were not subjected to mechanical strain. Coupling of cells from engineered tissue constructs to cells in embryonic heart slices showed slower conduction velocities than myocardial cells with the embryonic heart slices (preconditioned engineered tissue constructs vs embryonic heart slices: 0.04 ± 0.02 ms vs 0.10 ± 0.05 ms, P = .011), lower maximum stimulation frequencies (preconditioned engineered tissue constructs vs embryonic heart slices: 4.82 ± 1.42 Hz vs 10.58 ± 1.56 Hz; P = .0009), and higher sensitivities to the gap junction inhibitor (preconditioned engineered tissue constructs vs embryonic heart slices: 0.22 ± 0.07 mmol/L vs 0.93 ± 0.15 mmol/L; P = .0004).</AbstractText>We have generated skeletal myoblast-based transplantable grafts that electrically couple to myocardium.</AbstractText>Copyright © 2012 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.</CopyrightInformation>
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2,333,965 |
Cardiocirculatory intraoperative assessment during single-shot caudal anaesthesia in children: comparison between levobupivacaine and ropivacaine.
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Caudal block with levobupivacaine or ropivacaine is the most commonly used regional anaesthesia in children.</AbstractText>The aim of study was to compare the cardiocirculatory profile induced in two matched groups of young patients, submitted to caudal anaesthesia with levobupivacaine or ropivacaine for an elective subumbilical surgery. Sixty children were enrolled: thirty received levopubivacaine 0.25% and thirty ropivacaine 0.2%. Intraoperative heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP) were monitored at following times: Ta0 (after anaesthesia induction), Tal (after caudal anaesthesia), Ta2 (five minutes later), Ta3 (ten minutes later), Ts1 (at surgical incision), Ts2, Ts3, Ts4, Ts5 (every 10 minutes during surgery), Taw (at the awakening).</AbstractText>In both groups the cardiocirculatory trend remained within normal ranges at all times considered, demonstrating the safety of the method with both drugs. Both groups showed a similar trend at the different monitoring times: low decrease in HR, SBP and DBP after caudal block, slight increase in parameters after skin incision, slight decrease during surgery, increase at awakening. Regarding SBP and DBP, the levobupivacaine group children generally showed higher levels compared to the ropivacaine group, especially for DBP.</AbstractText>Paediatric caudal anaesthesia is an effective method with an very infrequent complication rate. Possible hypotheses for differing haemodynamic behaviour could include a stronger vasoconstriction reflex of innervated areas during caudal anaesthesia with levobupivacaine and a lower levobupivacaine induced block of the sympathetic fibers, related to different pharmacokinetic profile of low concentrations of the local anaesthetics used in paediatric epidural space.</AbstractText>
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2,333,966 |
Development of new drugs for COPD.
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Chronic obstructive pulmonary disease (COPD) is an increasing global health problem and cause of death. COPD is a chronic inflammatory disease predominantly affecting small airways and lung parenchyma that leads to progressive airway obstruction. However, current therapies fail to prevent either disease progression or mortality. The mainstay of current drug therapy is long-acting bronchodilators. Several once daily inhaled β(2)-agonists and muscarinic antagonists (and combinations) are now in development. No treatments effectively suppress chronic inflammation in COPD lungs. With better understanding of the inflammatory and destructive process in the pathophysiology of COPD, several new therapeutic targets have been identified. Several mediator antagonists or inhibitors tested in COPD have so far been disappointing, but CXCR2 antagonists that block pulmonary neutrophil and monocyte recruitment are more promising. Broad spectrum anti-inflammatory drugs may be more effective, and include inhibitors of the proinflammatory enzymes phosphodiesterase-4, p38 mitogen-activated protein kinase, Janus kinases, NF-κB kinase and PI3 kinase-γ and -δ, but side effects after oral administration are a major limitation so that in future inhaled delivery may be necessary. A new promising approach is reversal of corticosteroid resistance through increasing histone deacetylase-2 (HDAC2) activity. This might be achieved by existing treatments such as theophylline, nortriptyline and macrolides, or more selectively by PI3 kinase-δ inhibitors. Thus although there have been major advances in the development of long-acting bronchodilators for COPD, it has proved difficult to find anti-inflammatory treatments that are safe and effective.
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2,333,967 |
Intracardial embryonic delivery of developmental modifiers in utero.
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Our knowledge of organ ontogeny is largely based on loss-of-function (knockout) or gain-of-function (transgenesis) approaches. However, developmental modulators such as proteins, mRNAs, microRNAs(miRNAs), small interfering RNAs, and other small molecules may complement the above DNA-modifying technologies in a much more direct way. Unfortunately, their use is often limited by the ability of these compounds to cross the placenta and reach physiologically relevant concentrations when administered systemically to the mother. The design of safe and effective techniques to deliver these compounds into the embryo is therefore an area of great scientific potential. In this article we report a new method for introducing developmental modulators into murine embryos by means of direct injection into the heart. Unlike other reported methods that require surgical exposure of the uterus, our percutaneous ultrasound-guided approach allows for the intracardial injection of mouse embryos as early as embryonic day 10.5 (e10.5) and throughout gestation in a minimally invasive manner that largely preserves embryo viability. This system offers a critical advantage over in vitro settings because the effects of any given treatment can be observed without disturbing the native environment of the developing organ. Procedures are described for the delivery and detection of transducible proteins as well as morpholinos designed to block the expression of specific miRNAs within the living embryo.
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2,333,968 |
A novel accessory molecule Trim59 involved in cytotoxicity of BCG-activated macrophages.
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BCG-activated macrophages (BAM) could kill the tumor cells through cell-cell contact. In this process membrane proteins play an important role. However, up to date, few membrane proteins were revealed. In this study, we selected a surface molecule named Trim59, which was specifically expressed on BAM membrane (compared with the negative control). We cloned and prokaryoticly expressed the extracellular domain of Trim59, purified the recombinant protein and generated polyclonal antibodies. Immunohistochemistry showed that Trim59 abundantly expressed in spleen, stomach and ovary; intermediately expressed in brain, lung, kidney, muscle and intestine; but not in thymus, liver, heart, uterus. Using the antibodies to block Trim59 on BAM significantly reduced BAM cytotoxicity against MCA207 cells. This demonstrated that Trim59 serves as an indispensable molecule in maintaining BAM activity. Overexpression of Trim59 in Raw264.7 cell line failed to lyse target MCA207 cells, which potentiated Trim59 per se could not enhance macrophage cytotoxicity; on another hand, overexpression of Trim59 enhance the pinocytosis and Phagocytosis activity of Raw-264.7, which imply Trim59 might mediate the cell-molecule interaction. Our results indicate Trim59 might be an essential accessory molecule in mediating BAM tumoricidal functions; and Trim59 is a phagocytosis-correlated molecule.
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2,333,969 |
Computational assessment of drug-induced effects on the electrocardiogram: from ion channel to body surface potentials.
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Understanding drug effects on the heart is key to safety pharmacology assessment and anti-arrhythmic therapy development. Here our goal is to demonstrate the ability of computational models to simulate the effect of drug action on the electrical activity of the heart, at the level of the ion-channel, cell, heart and ECG body surface potential.</AbstractText>We use the state-of-the-art mathematical models governing the electrical activity of the heart. A drug model is introduced using an ion channel conductance block for the hERG and fast sodium channels, depending on the IC(50) value and the drug dose. We simulate the ECG measurements at the body surface and compare biomarkers under different drug actions.</AbstractText>Introducing a 50% hERG-channel current block results in 8% prolongation of the APD(90) and 6% QT interval prolongation, hERG block does not affect the QRS interval. Introducing 50% fast sodium current block prolongs the QRS and the QT intervals by 12% and 5% respectively, and delays activation times, whereas APD(90) is not affected.</AbstractText>Both potassium and sodium blocks prolong the QT interval, but the underlying mechanism is different: for potassium it is due to APD prolongation; while for sodium it is due to a reduction of electrical wave velocity. This study shows the applicability of in silico models for the investigation of drug effects on the heart, from the ion channel to the ECG-based biomarkers.</AbstractText>© 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.</CopyrightInformation>
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2,333,970 |
Cutaneous analgesia after subcutaneous injection of memantine and amantadine and their systemic toxicity in rats.
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The purpose of the study is to find subcutaneous equianalgesic doses of memantine, amantadine and bupivacaine and use these doses to quantify the cardiovascular and central nervous system toxicity of these agents after intravenous administration. Memantine, amantadine and bupivacaine, a local anesthetic, in a dose-related fashion were determined for cutaneous analgesia by a block of the cutaneous trunci muscle reflex in rats, and equipotent doses were calculated. Following rapid intravenous infusion of equianalgesic bupivacaine, memantine, amantadine and saline (vehicle) in rats, we observed the onset time of seizure, apnea and impending death, and monitored mean arterial blood pressure and heart rate. Memantine and amantadine elicited dose-dependent cutaneous analgesia. At the 50% effective dose (ED(50)), the rank of potencies was bupivacaine [1.8 (1.7-2.0)]>memantine [19.1 (17.6-21.8)]>amantadine [36.1 (32.0-40.3)] (P<0.05). On ED(25), ED(50) and ED(75) basis, the duration caused by bupivacaine was similar to that caused by memantine or amantadine. At equianalgesic doses, the infusion time of memantine or amantadine required to induce seizure, impending death, and apnea was longer than that of bupivacaine during rapid intravenous infusion (P<0.01). The decreasing slope in mean arterial blood pressure and heart rate was slower with memantine and amantadine when compared with bupivacaine at equivalent doses (P<0.01). Our data showed that memantine and amantadine (i) were equal to bupivacaine at producing durations of cutaneous analgesia but (ii) were less likely than bupivacaine to cause cardiovascular and central nervous system toxicity.
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2,333,971 |
Identification of novel NaV1.7 antagonists using high throughput screening platforms.
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Congenital Insensitivity to Pain (CIP) is a loss of function mutation resulting in a truncated NaV1.7 protein, suggesting a pivotal role in pain signaling and rendering it an important pharmaceutical target for multiple pain conditions. The structural homology in the NaV-channel family makes it challenging to design effective analgesic compounds without inducing for example cardiotoxicity or seizure liabilities. An additional approach to structural isoform selectivity is to identify compounds with use- or state-dependent profiles, i.e. inhibition efficacy based on the gating of the ion channel. In general nerve cells in damaged or inflamed tissue are more depolarized and electrically active compared to healthy nerve cells in for instance the heart. This observation has led to the design of two types of screening protocols emulating the voltage condition of peripheral neurons or cardiac tissue. The two voltage protocols have been developed to identify both use- and state-dependent antagonists. In this paper we describe an attempt to merge the two different protocols into one to increase screening efficacy, while retaining relevant state- and use-dependent pharmacology. The new protocol is constructed of two stimulation pulses and a slow voltage ramp for simultaneous assessment of resting and state-dependent block. By comparing all protocols we show that the new protocol indeed filter compounds for state-dependence and increase the prediction power of selecting use-dependent compounds.
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2,333,972 |
Relationships of coronary heart disease with 27-hydroxycholesterol, low-density lipoprotein cholesterol, and menopausal hormone therapy.
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Menopausal hormone therapy (MHT) increases the risk of coronary heart disease (CHD) in older women with elevated low-density lipoprotein (LDLC) levels. The endogenous estrogen receptor antagonist 27-hydroxycholesterol (27OHC) is correlated with LDLC levels and may block the beneficial effects of estrogen on the cardiovascular system.</AbstractText>We conducted a nested case-control study in the Women's Health Initiative trials of 350 CHD cases and 813 matched controls to explore potential mediation by 27OHC of the dependence of the CHD risk elevation with MHT on LDLC. Baseline levels of 27OHC were not associated with CHD risk when LDLC was included in the multivariable models. The odds ratio for CHD associated with increased LDLC was 1.15 (95% confidence interval, 1.08-1.23) and was unchanged at 1.14 (95% confidence interval, 1.07-1.22) when 27OHC was added to the model. Baseline 27OHC did not interact with MHT on CHD risk (P=0.81). In contrast, LDLC levels modified the effect of MHT on CHD risk (P for interaction=0.02), and adding 27OHC did not affect this result. With the use of log scales, the effect of MHT on CHD increased linearly with increasing level of baseline LDLC, with a transition from no risk to increased risk at ≈3.36 mmol/L (130 mg/dL).</AbstractText>This study found that 27OHC does not independently increase the risk of CHD, does not modify the increased risk of CHD resulting from MHT, and does not mediate the interaction of LDLC with MHT. Measuring blood lipids may aid in counseling individual women about initiating MHT and cardiovascular risk mitigation.</AbstractText>URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000611.</AbstractText>
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2,333,973 |
Male circumcision.
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Male circumcision consists of the surgical removal of some, or all, of the foreskin (or prepuce) from the penis. It is one of the most common procedures in the world. In the United States, the procedure is commonly performed during the newborn period. In 2007, the American Academy of Pediatrics (AAP) convened a multidisciplinary workgroup of AAP members and other stakeholders to evaluate the evidence regarding male circumcision and update the AAP's 1999 recommendations in this area. The Task Force included AAP representatives from specialty areas as well as members of the AAP Board of Directors and liaisons representing the American Academy of Family Physicians, the American College of Obstetricians and Gynecologists, and the Centers for Disease Control and Prevention. The Task Force members identified selected topics relevant to male circumcision and conducted a critical review of peer-reviewed literature by using the American Heart Association's template for evidence evaluation. Evaluation of current evidence indicates that the health benefits of newborn male circumcision outweigh the risks; furthermore, the benefits of newborn male circumcision justify access to this procedure for families who choose it. Specific benefits from male circumcision were identified for the prevention of urinary tract infections, acquisition of HIV, transmission of some sexually transmitted infections, and penile cancer. Male circumcision does not appear to adversely affect penile sexual function/sensitivity or sexual satisfaction. It is imperative that those providing circumcision are adequately trained and that both sterile techniques and effective pain management are used. Significant acute complications are rare. In general, untrained providers who perform circumcisions have more complications than well-trained providers who perform the procedure, regardless of whether the former are physicians, nurses, or traditional religious providers. Parents are entitled to factually correct, nonbiased information about circumcision and should receive this information from clinicians before conception or early in pregnancy, which is when parents typically make circumcision decisions. Parents should determine what is in the best interest of their child. Physicians who counsel families about this decision should provide assistance by explaining the potential benefits and risks and ensuring that parents understand that circumcision is an elective procedure. The Task Force strongly recommends the creation, revision, and enhancement of educational materials to assist parents of male infants with the care of circumcised and uncircumcised penises. The Task Force also strongly recommends the development of educational materials for providers to enhance practitioners' competency in discussing circumcision's benefits and risks with parents. The Task Force made the following recommendations:Evaluation of current evidence indicates that the health benefits of newborn male circumcision outweigh the risks, and the benefits of newborn male circumcision justify access to this procedure for those families who choose it. Parents are entitled to factually correct, nonbiased information about circumcision that should be provided before conception and early in pregnancy, when parents are most likely to be weighing the option of circumcision of a male child. Physicians counseling families about elective male circumcision should assist parents by explaining, in a nonbiased manner, the potential benefits and risks and by ensuring that they understand the elective nature of the procedure. Parents should weigh the health benefits and risks in light of their own religious, cultural, and personal preferences, as the medical benefits alone may not outweigh these other considerations for individual families. Parents of newborn boys should be instructed in the care of the penis, regardless of whether the newborn has been circumcised or not. Elective circumcision should be performed only if the infant's condition is stable and healthy. Male circumcision should be performed by trained and competent practitioners, by using sterile techniques and effective pain management. Analgesia is safe and effective in reducing the procedural pain associated with newborn circumcision; thus, adequate analgesia should be provided whenever newborn circumcision is performed.Nonpharmacologic techniques (eg, positioning, sucrose pacifiers) alone are insufficient to prevent procedural and postprocedural pain and are not recommended as the sole method of analgesia. They should be used only as analgesic adjuncts to improve infant comfort during circumcision. If used, topical creams may cause a higher incidence of skin irritation in low birth weight infants, compared with infants of normal weight; penile nerve block techniques should therefore be chosen for this group of newborns. Key professional organizations (AAP, the American Academy of Family Physicians, the American College of Obstetricians and Gynecologists, the American Society of Anesthesiologists, the American College of Nurse Midwives, and other midlevel clinicians such as nurse practitioners) should work collaboratively to:Develop standards of trainee proficiency in the performance of anesthetic and procedure techniques, including suturing; Teach the procedure and analgesic techniques during postgraduate training programs; Develop educational materials for clinicians to enhance their own competency in discussing the benefits and risks of circumcision with parents; Offer educational materials to assist parents of male infants with the care of both circumcised and uncircumcised penises. The preventive and public health benefits associated with newborn male circumcision warrant third-party reimbursement of the procedure. The American College of Obstetricians and Gynecologists has endorsed this technical report.
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2,333,974 |
Task-related component analysis for functional neuroimaging and application to near-infrared spectroscopy data.
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Reproducibility of experimental results lies at the heart of scientific disciplines. Here we propose a signal processing method that extracts task-related components by maximizing the reproducibility during task periods from neuroimaging data. Unlike hypothesis-driven methods such as general linear models, no specific time courses are presumed, and unlike data-driven approaches such as independent component analysis, no arbitrary interpretation of components is needed. Task-related components are constructed by a linear, weighted sum of multiple time courses, and its weights are optimized so as to maximize inter-block correlations (CorrMax) or covariances (CovMax). Our analysis method is referred to as task-related component analysis (TRCA). The covariance maximization is formulated as a Rayleigh-Ritz eigenvalue problem, and corresponding eigenvectors give candidates of task-related components. In addition, a systematic statistical test based on eigenvalues is proposed, so task-related and -unrelated components are classified objectively and automatically. The proposed test of statistical significance is found to be independent of the degree of autocorrelation in data if the task duration is sufficiently longer than the temporal scale of autocorrelation, so TRCA can be applied to data with autocorrelation without any modification. We demonstrate that simple extensions of TRCA can provide most distinctive signals for two tasks and can integrate multiple modalities of information to remove task-unrelated artifacts. TRCA was successfully applied to synthetic data as well as near-infrared spectroscopy (NIRS) data of finger tapping. There were two statistically significant task-related components; one was a hemodynamic response, and another was a piece-wise linear time course. In summary, we conclude that TRCA has a wide range of applications in multi-channel biophysical and behavioral measurements.
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2,333,975 |
Two-player partnered exergame for obesity prevention: using discrepancy in players' abilities as a strategy to motivate physical activity.
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Physical inactivity is associated with obesity and type 2 diabetes. A key obstacle to physical activity is lack of motivation. Although some interactive exercise games (i.e., exergames--video games that require physical exertion in order to play) motivate players to exercise more, few games take advantage of group dynamics to motivate players' duration of exercise. In a test of the Köhler motivation gain effect, this study varied the ability level of a virtually presented partner in an interactive exergame that focused on abdominal strength to identify effects on a subject's (S') persistence with the task.</AbstractText>Male (n = 63) and female (n = 72) undergraduate students were randomly assigned to one of four conditions (individual control or low-, moderate-, or high- partner discrepancy) in a conditions × gender factorial design and tested on a series of isometric abdominal exercises using PlayStation 2 EyeToy: Kinetic software. They performed the first series of five exercises alone (trial block 1), and after a rest period, those in the partner conditions performed remaining trials (trial block 2) with a same-sex virtually presented partner whom they could observe during their performance, while those in the individual control condition performed the remaining trials alone. In the partner conditions, the partner's performance was manipulated to be always better than the S's, the exact difference depending on the discrepancy condition. The partnered tasks were conjunctive; that is, success in the game depended on the performance of the weaker team member. Persistence, the outcome measure for this study, consisted of the total number of seconds the S held the exercise position.</AbstractText>Using planned orthogonal contrasts on difference scores between blocks 1 and 2, results showed that persistence was significantly (p < .001) greater in all experimental conditions with a virtually presented partner (M = 33.59 s) than in the individual control condition (M = -49.04 s). Subjects demonstrated more persistence in the moderate-discrepancy condition (M = 51.36 s) than in the low-discrepancy condition (M = 22.52 s) or the high-discrepancy condition (M = 26.89 s). A significant quadratic trend confirmed the expected inverted-U function relating partner discrepancy and persistence (p = .025). Although Ss persisted longer and had higher heart rate in partnered conditions, they did not perceive their exertion to be any higher than those in the individual condition.</AbstractText>Virtually presented partners who are moderately more capable than participants are the most effective at improving persistence in exergame tasks.</AbstractText>© 2012 Diabetes Technology Society.</CopyrightInformation>
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2,333,976 |
Efficacy of lignocaine with clonidine and adrenaline in minor oral surgical procedure.
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Use of vasoconstrictors in local anaesthesia is well known. The study was done on 30 patients who underwent removal of bilateral impacted third molars. The aim of the study was to compare the efficacy of lignocaine with clonidine and lignocaine with adrenaline in respect to onset, duration of anaesthesia, and postoperative analgesia along with hemodynamic stability (systolic blood pressure, diastolic blood pressure, mean arterial pressure, heart rate in intraoral nerve block. The patients were randomly selected of both sexes (male and female) between the age group of 18-40 years. Patients received 2 mL of 2% lignocaine with adrenaline (12.5 μg/mL) on one side and 2 mL of 2% lignocaine with clonidine (15 μg/mL) on the other side at two different appointments. 2 millilitres of drug was administered in both the test group and the control group. Statistically there was significant decrease in intraoperative and postoperative systolic blood pressure, diastolic blood pressure, mean arterial pressure, and heart rate in the lignocaine with clonidine group. The efficacy of clonidine based on visual analog scale was similar to adrenaline. No significant operative complications were observed.
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2,333,977 |
Lack of association between folate receptor autoantibodies and conotruncal congenital heart defects.
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Conotruncal cardiac defects are partially prevented by maternal folic acid supplementation. However, the biochemical mechanism is unknown. Maternal autoantibodies to folate receptors, previously associated with increased risk for neural tube defects, also may account for this effect. This study aimed to examine the titers of folate receptor-blocking autoantibodies in mothers of children with conotruncal congenital heart defects and to compare them with those in the general population. Serum samples were obtained from 22 women whose pregnancies were complicated by conotruncal congenital heart malformations. Groups of samples were analyzed for autoantibodies against [(3)H] folic acid-labeled folate receptors, quantitative amounts of immunoglobulin G (IgG) and IgM autoantibodies to the folate receptor, and for ability to block-bind folic acid to receptors. No elevated levels of antibodies binding to [(3)H] folic acid-labeled folate receptors were found. No difference was found in antifolate receptor alpha-IgG or IgM median levels between cases (261 vs. 240 μg/mL) and control subjects (773 vs. 924 μg/mL). There was no increased blocking of folic acid binding between cases [0.69 ng/mL; 95 % confidence interval (CI), 0.006-0.01] and control subjects (0.69 ng/mL; 95 % CI, 0.003-0.013). Although epidemiologic evidence suggests that periconceptual folic acid may prevent many conotruncal congenital heart defects, the current study suggests that this effect is unlikely to be explained by the presence of maternal autoantibodies to folate receptor. These data suggest that a strategy of screening women for such autoantibodies will not identify a high-risk group of women to target for supplemental folic acid to prevent congenital heart defects.
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2,333,978 |
Trafficking of an endogenous potassium channel in adult ventricular myocytes.
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The roles of several small GTPases in the expression of an endogenous potassium current, I(to,f), in adult rat ventricular myocytes have been investigated. The results indicate that forward trafficking of newly synthesized Kv4.2, which underlies I(to,f) in these cells, requires both Rab1 and Sar1 function. Expression of a Rab1 dominant negative (DN) reduced I(to,f) current density by roughly one-half relative to control, mCherry-transfected myocytes. Similarly, expression of a Sar1DN nearly halved I(to,f) current density. Rab11 is not essential to trafficking of Kv4.2, as expression of a Rab11DN had no effect on I(to,f) over the time frames investigated here. In a process dependent on intact endoplasmic reticulum (ER)-to-Golgi transport, however, overexpression of wild-type Rab11 resulted in a doubling of I(to,f) density; block of ER-to-Golgi traffic by Brefeldin A completely abrogated the effect. Also implicated in the trafficking of Kv4.2 are Rab5 and Rab4. Rab5DN expression increased endogenous I(to,f) by two- to threefold, nonadditively with inhibition of dynamin-dependent endocytosis. And, in a phenomenon similar to that previously reported for myoblast-expressed Kv1.5, Rab4DN expression roughly doubled endogenous peak transient currents. Colocalization experiments confirmed the involvement of Rab4 in postinternalization trafficking of Kv4.2. There was little role evident for the lysosome in the degradation of internalized Kv4.2, as overexpression of neither wild-type nor DN isoforms of Rab7 had any effect on I(to,f). Instead, degradation may depend largely on the proteasome; the proteasome inhibitor MG132 significantly increased I(to,f) density.
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2,333,979 |
The effect of celiac plexus block on heart rate variability.
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Celiac plexus block (CPB) can be used for treating intra-abdominal visceral pain syndromes. The celiac plexus is the largest plexus of the sympathetic nervous system. Several nerve blocks have a marked effect on autonomic nervous activity. Furthermore, stellate ganglion block changes cardiac autonomic nervous activity. Thus, CPB could influence the sympathetic activity of the cardiac plexus. The aim of the present study was to see whether CPB modulated heart rate variability (HRV) in patients with pancreatic cancer.</AbstractText>Twelve patients received neurolytic CPB using 14 ml absolute alcohol. Data recorded in a palm-sized electrocardiographic unit were analyzed for HRV.</AbstractText>CPB using a neurolytic solution did not induce any significant changes in the low-frequency (LF)/high-frequency (HF) ratio of HRV (LF/HF, P = 0.4642). Furthermore, the procedure did not induce any significant changes in blood pressure (systolic, P = 0.5051; diastolic, P = 0.5180).</AbstractText>CPB did not induce any significant changes in HRV or hemodynamics.</AbstractText>
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2,333,980 |
Management of pregnancy in systemic lupus erythematosus.
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Systemic lupus erythematosus (SLE) is an autoantibody-mediated systemic autoimmune disease, predominantly affecting young females. Pregnancy is increasingly common in the setting of SLE, as survival and quality of life of patients improve. Although live births can be achieved in the most cases, pregnancy in patients with SLE remains a high-risk condition. Maternal and fetal mortality and morbidity are considerably increased, compared with the general population. Aberrations in pregnancy-related maternal immune adaptations are likely contributors. Active maternal disease, renal involvement, specific autoantibody subsets and advanced organ damage are predictors of poor outcome. Therapeutic options are limited during pregnancy as maternal benefit has to be weighed against fetal risk. Prevention of preterm birth and refractory pregnancy loss, as well as management of established neonatal heart block remain unmet needs. Further research should address these important issues that affect young patients with SLE and their babies.
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2,333,981 |
Reduced metabolic insulin sensitivity following sub-acute exposures to low levels of ambient fine particulate matter air pollution.
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Epidemiological studies suggest that fine particulate matter (PM2.5) may increase the risk for developing diabetes mellitus (DM). To evaluate possible mechanisms explaining these associations, we investigated if sub-acute ambient-level exposures can impair insulin sensitivity. Twenty-five healthy adults living in rural Michigan were transported to an urban location for 5 consecutive days (exposure-block) of daily 4- to 5-hour-long ambient air pollution exposures. Health outcomes, including the homeostasis model assessment of insulin resistance (HOMA-IR) the primary outcome of insulin sensitivity, were measured at 3 time points in relation to exposure-blocks: 7days prior to start; on the last exposure-day; and 7days after completion. PM2.5 was monitored at the urban exposure site and at community monitors near subjects' residences. We calculated 3 "sub-acute" exposure periods (approximately 5-days-long) starting retrospective from the time of health outcome measurements (PM2.5 ranges: 9.7±3.9 to 11.2±3.9μg·m(-3)). A 10μg·m(-3) increase in sub-acute PM2.5 exposures was associated with increased HOMA-IR (+0.7, 95% confidence interval (CI) 0.1 to 1.3; p=0.023) and reduced heart rate variability (standard deviation of normal-to-normal intervals [-13.1ms, 95%CI -25.3 to -0.9; p=0.035]). No alterations in other outcomes (inflammatory markers, vascular function) occurred in relation to PM2.5 exposures. Our findings suggest that ambient PM2.5, even at low levels, may reduce metabolic insulin sensitivity supporting the plausibility that air pollution could potentiate the development of DM.
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2,333,982 |
Comparison of conventional parallel beamforming with plane wave and diverging wave imaging for cardiac applications: a simulation study.
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When imaging the heart, good temporal resolution is beneficial for capturing the information of short-lived cardiac phases (in particular, the isovolumetric phases). To increase the frame rate, parallel beamforming is a commonly used technique for fast cardiac imaging. Conventionally, a 4 multiple-line-acquisition (4MLA) system increases the frame rate by a factor of 4, making use of a broadened transmit beam to reduce block-like artifacts. As an alternative, it has been proposed to transmit an unfocused beam (i.e., plane wave or diverging wave) for which a large number of parallel receive beams (i.e., 16) can be formed for each transmit. However, to keep the spatial resolution acceptable in these approaches, spatial compounding of overlapping successive transmits is required. As a result, the effective gain in frame rate is similar to that of a 4MLA system. To date, it remains unclear how conventional 4MLA compares to plane-wave or diverging-wave imaging when operating at similar frame rate. The goal of this study was therefore to directly contrast the performance of these beamforming methods by computer simulation. In this study, the performance of 4 different imaging systems was investigated by quantitatively evaluating the characteristics of their beam profiles. The results showed that the conventional 4MLA and plane wave imaging were very competitive imaging strategies when operating at a similar frame rate. 4MLA performed better in the near field (i.e., 10 to 50 mm), whereas plane-wave imaging had better beam profiles in the far field (i.e., 50 to 90 mm). Although diverging-wave imaging had the poorest performance in the present study, it could potentially be improved by optimizing the settings.
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2,333,983 |
Assessment of pain and hemodynamic response in older children undergoing circumcision: comparison of eutectic lidocaine/prilocaine cream and dorsal penile nerve block.
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To evaluate whether dorsal penile nerve block (DPNB) or local topical anesthesia (LT) provided better postoperative analgesia and less hemodynamic stimulation during and after circumcision surgery with Plastibell in older children.</AbstractText>Forty-one subjects (age: 2-13 years) undergoing circumcision with Plastibell were randomly divided into LT and DPNB groups. Inhalation induction was performed with an 8% end-tidal sevoflurane concentration. In the LT group, a eutectic ointment of 5% lidocaine and 5% prilocaine was applied to the foreskin 1 h before surgery. At 10 min after anesthesia induction, the end-tidal sevoflurane concentration was decreased to 2%. In the other group, a DPNB was performed with 0.5% bupivacaine (1 mg/kg). Heart rate (HR), respiratory rate, mean arterial pressure (MAP), and involuntary movements were evaluated at anesthesia induction (T0), 1 min after DPNB (T1), 1 min after incision (T2), and 1 min after surgery (T3). Pain was evaluated at 1 and 24 h after surgery, and complications were evaluated at 24 h after surgery.</AbstractText>The groups were homogeneous with respect to age, weight, glans diameter, penile length, Kayaba classification, and surgical duration. The LT group showed increased HR (p = 0.073) and MAP (p = 0.046) at T2 as compared to T0. No hemodynamic changes were observed in the HPDB group. The LT group showed a higher pain score at 1 h after surgery than the DPNB group, whereas the DPNB group had a higher incidence of hematoma (p = 0.02) at 24 h after surgery.</AbstractText>Anesthesia with 5% lidocaine and 5% prilocaine cream during circumcision of older children with Plastibell under general anesthesia with sevoflurane does not provide satisfactory perioperative hemodynamic stability or postoperative analgesia.</AbstractText>Copyright © 2012 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.</CopyrightInformation>
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2,333,984 |
Congenital and neonatal lupus erythematosus: two case reports.
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Neonatal lupus erythematosus is an autoimmune disease produced by the passage of maternal antinuclear antibodies and extractable nuclear antigen antibodies through the placenta. At the moment of the diagnosis, the mothers are asymptomatic in 40 to 60% of cases. The most common manifestations are cutaneous lesions and congenital heart block. The cutaneous findings are variable and usually begin within the first weeks or months of life. Congenital lupus erythematosus is a congenital variant of neonatal lupus erythematosus. We present one case of congenital lupus erythematosus and one case of neonatal lupus erythematous, showing the variability of this disease.
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2,333,985 |
Triclosan impairs excitation-contraction coupling and Ca2+ dynamics in striated muscle.
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Triclosan (TCS), a high-production-volume chemical used as a bactericide in personal care products, is a priority pollutant of growing concern to human and environmental health. TCS is capable of altering the activity of type 1 ryanodine receptor (RyR1), but its potential to influence physiological excitation-contraction coupling (ECC) and muscle function has not been investigated. Here, we report that TCS impairs ECC of both cardiac and skeletal muscle in vitro and in vivo. TCS acutely depresses hemodynamics and grip strength in mice at doses ≥12.5 mg/kg i.p., and a concentration ≥0.52 μM in water compromises swimming performance in larval fathead minnow. In isolated ventricular cardiomyocytes, skeletal myotubes, and adult flexor digitorum brevis fibers TCS depresses electrically evoked ECC within ∼10-20 min. In myotubes, nanomolar to low micromolar TCS initially potentiates electrically evoked Ca(2+) transients followed by complete failure of ECC, independent of Ca(2+) store depletion or block of RyR1 channels. TCS also completely blocks excitation-coupled Ca(2+) entry. Voltage clamp experiments showed that TCS partially inhibits L-type Ca(2+) currents of cardiac and skeletal muscle, and [(3)H]PN200 binding to skeletal membranes is noncompetitively inhibited by TCS in the same concentration range that enhances [(3)H]ryanodine binding. TCS potently impairs orthograde and retrograde signaling between L-type Ca(2+) and RyR channels in skeletal muscle, and L-type Ca(2+) entry in cardiac muscle, revealing a mechanism by which TCS weakens cardiac and skeletal muscle contractility in a manner that may negatively impact muscle health, especially in susceptible populations.
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2,333,986 |
Manipulating connexin communication channels: use of peptidomimetics and the translational outputs.
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Gap junctions are key components underpinning multicellularity. They provide cell to cell channel pathways that enable direct intercellular communication and cellular coordination in tissues and organs. The channels are constructed of a family of connexin (Cx) membrane proteins. They oligomerize inside the cell, generating hemichannels (connexons) composed of six subunits arranged around a central channel. After transfer to the plasma membrane, arrays of Cx hemichannels (CxHcs) interact and couple with partners in neighboring attached cells to generate gap junctions. Cx channels have been studied using a range of technical approaches. Short peptides corresponding to sequences in the extra- and intracellular regions of Cxs were used first to generate epitope-specific antibodies that helped studies on the organization and functions of gap junctions. Subsequently, the peptides themselves, especially Gap26 and -27, mimetic peptides derived from each of the two extracellular loops of connexin43 (Cx43), a widely distributed Cx, have been extensively applied to block Cx channels and probe the biology of cell communication. The development of a further series of short peptides mimicking sequences in the intracellular loop, especially the extremity of the intracellular carboxyl tail of Cx43, followed. The primary inhibitory action of the peptidomimetics occurs at CxHcs located at unapposed regions of the cell's plasma membrane, followed by inhibition of cell coupling occurring across gap junctions. CxHcs respond to a range of environmental conditions by increasing their open probability. Peptidomimetics provide a way to block the actions of CxHcs with some selectivity. Furthermore, they are increasingly applied to address the pathological consequences of a range of environmental stresses that are thought to influence Cx channel operation. Cx peptidomimetics show promise as candidates in developing new therapeutic approaches for containing and reversing damage inflicted on CxHcs, especially in hypoxia and ischemia in the heart and in brain functions.
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2,333,987 |
Oxysterol generation and liver X receptor-dependent reverse cholesterol transport: not all roads lead to Rome.
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Cell cholesterol metabolism is a tightly regulated process, dependent in part on activation of nuclear liver X receptors (LXRs) to increase expression of genes mediating removal of excess cholesterol from cells in the reverse cholesterol transport pathway. LXRs are thought to be activated predominantly by oxysterols generated enzymatically from cholesterol in different cell organelles. Defects resulting in slowed release of cholesterol from late endosomes and lysosomes or reduction in sterol-27-hydroxylase activity lead to specific blocks in oxysterol production and impaired LXR-dependent gene activation. This block does not appear to be compensated by oxysterol production in other cell compartments. The purpose of this review is to summarize current knowledge about oxysterol-dependent activation by LXR of genes involved in reverse cholesterol transport, and what these defects of cell cholesterol homeostasis can teach us about the critical pathways of oxysterol generation for expression of LXR-dependent genes.
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2,333,988 |
A novel dual-fluorescence strategy for functionally validating microRNA targets in 3' untranslated regions: regulation of the inward rectifier potassium channel K(ir)2.1 by miR-212.
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Gene targeting by microRNAs is important in health and disease. We developed a functional assay for identifying microRNA targets and applied it to the K(+) channel K(ir)2.1 [KCNJ2 (potassium inwardly-rectifying channel, subfamily J, member 2)] which is dysregulated in cardiac and vascular disorders. The 3'UTR (untranslated region) was inserted downstream of the mCherry red fluorescent protein coding sequence in a mammalian expression plasmid. MicroRNA sequences were inserted into the pSM30 expression vector which provides enhanced green fluorescent protein as an indicator of microRNA expression. HEK (human embryonic kidney)-293 cells were co-transfected with the mCherry-3'UTR plasmid and a pSM30-based plasmid with a microRNA insert. The principle of the assay is that functional targeting of the 3'UTR by the microRNA results in a decrease in the red/green fluorescence intensity ratio as determined by automated image analysis. The method was validated with miR-1, a known down-regulator of K(ir)2.1 expression, and was used to investigate the targeting of the K(ir)2.1 3'UTR by miR-212. The red/green ratio was lower in miR-212-expressing cells compared with the non-targeting controls, an effect that was attenuated by mutating the predicted target site. miR-212 also reduced inward rectifier current and K(ir)2.1 protein in HeLa cells. This novel assay has several advantages over traditional luciferase-based assays including larger sample size, amenability to time course studies and adaptability to high-throughput screening.
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2,333,989 |
Membrane permeable local anesthetics modulate Na(V)1.5 mechanosensitivity.
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Voltage-gated sodium selective ion channel Na(V)1.5 is expressed in the heart and the gastrointestinal tract, which are mechanically active organs. Na(V)1.5 is mechanosensitive at stimuli that gate other mechanosensitive ion channels. Local anesthetic and antiarrhythmic drugs act upon Na(V)1.5 to modulate activity by multiple mechanisms. This study examined whether Na(V)1.5 mechanosensitivity is modulated by local anesthetics. Na(V)1.5 channels were expressed in HEK-293 cells, and mechanosensitivity was tested in cell-attached and excised inside-out configurations. Using a novel protocol with paired voltage ladders and short pressure pulses, negative patch pressure (-30 mmHg) in both configurations produced a hyperpolarizing shift in the half-point of the voltage-dependence of activation (V(1/2a)) and inactivation (V(1/2i)) by about -10 mV. Lidocaine (50 µM) inhibited the pressure-induced shift of V(1/2a) but not V(1/2i). Lidocaine inhibited the tonic increase in pressure-induced peak current in a use-dependence protocol, but it did not otherwise affect use-dependent block. The local anesthetic benzocaine, which does not show use-dependent block, also effectively blocked a pressure-induced shift in V(1/2a). Lidocaine inhibited mechanosensitivity in Na(V)1.5 at the local anesthetic binding site mutated (F1760A). However, a membrane impermeable lidocaine analog QX-314 did not affect mechanosensitivity of F1760A Na(V)1.5 when applied from either side of the membrane. These data suggest that the mechanism of lidocaine inhibition of the pressure-induced shift in the half-point of voltage-dependence of activation is separate from the mechanisms of use-dependent block. Modulation of Na(V)1.5 mechanosensitivity by the membrane permeable local anesthetics may require hydrophobic access and may involve membrane-protein interactions.
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2,333,990 |
Differential effects of predosing on tumor and tissue uptake of an 111In-labeled anti-TENB2 antibody-drug conjugate.
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TENB2, also known as tomoregulin or transmembrane protein with epidermal growth factor-like and 2 follistatin-like domains, is a transmembrane proteoglycan overexpressed in human prostate tumors. This protein is a promising target for antimitotic monomethyl auristatin E (MMAE)-based antibody-drug conjugate (ADC) therapy. Nonlinear pharmacokinetics in normal mice suggested that antigen expression in normal tissues may contribute to targeted mediated disposition. We evaluated a predosing strategy with unconjugated antibody to block ADC uptake in target-expressing tissues in a mouse model while striving to preserve tumor uptake and efficacy.</AbstractText>Unconjugated, unlabeled antibody was preadministered to mice bearing the TENB2-expressing human prostate explant model, LuCaP 77, followed by a single administration of (111)In-labeled anti-TENB2-MMAE for biodistribution and SPECT/CT studies. A tumor-growth-inhibition study was conducted to determine the pharmacodynamic consequences of predosing.</AbstractText>Preadministration of anti-TENB2 at 1 mg/kg significantly increased blood exposure of the radiolabeled ADC and reduced intestinal, hepatic, and splenic uptake while not affecting tumor accretion. Similar tumor-to-heart ratios were measured by SPECT/CT at 24 h with and without the predose. Consistent with this, the preadministration of 0.75 mg/kg did not interfere with efficacy in a tumor-growth study dosed at 0.75 mg or 2.5 mg of ADC per kilogram.</AbstractText>Overall, the potential to mask peripheral, nontumor antigen uptake while preserving tumor uptake and efficacy could ameliorate toxicity and may significantly affect future dosing strategies for ADCs.</AbstractText>
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2,333,991 |
LMI1195 PET imaging in evaluation of regional cardiac sympathetic denervation and its potential role in antiarrhythmic drug treatment.
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Regional cardiac sympathetic denervation (RCSD) associated with reduced noradrenaline transporter (NAT) function has been linked to cardiac arrhythmia. This study examined the association of LMI1195, an (18)F-labeled NAT substrate developed for positron emission tomography (PET) imaging, with NAT in vitro, and its imaging to detect RCSD and guide antiarrhythmic drug treatment in vivo.</AbstractText>LMI1195 association with NAT was assessed in comparison with other substrates, noradrenaline (NA) and (123)I-metaiodobenzylguanidine (MIBG), in NAT-expressing cells. LMI1195 cardiac imaging was performed for evaluation of RCSD in a rabbit model surgically developed by regional phenol application on the left ventricular (LV) wall. The normal LV areas in images were quantified as regions with radioactivity ≥50 % maximum. Potential impact of RCSD on dofetilide, an antiarrhythmic drug, induced ECG changes was assessed.</AbstractText>NAT blockade with desipramine reduced LMI1195 cell uptake by 90 ± 3 %, similar to NA and MIBG. NA, MIBG, or self inhibited LMI1195 cell uptake concentration-dependently with comparable IC(50) values (1.09, 0.21, and 0.90 μM). LMI1195 cardiac imaging differentiated innervated and denervated areas in RCSD rabbits. The surgery resulted in a large denervated LV area at 2 weeks which was partially recovered at 12 weeks. Myocardial perfusion imaging with flurpiridaz F 18 showed normal perfusion in RCSD areas. Dofetilide induced more prominent QTc prolongation in RCSD than control animals. However, changes in heart rate were comparable.</AbstractText>LMI1195 exhibits high association with NAT and can be used for imaging RCSD. The detected RCSD increases cardiac risks to the antiarrhythmic drug, dofetilide, by inducing more QTc prolongation.</AbstractText>
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2,333,992 |
Stem cell factor is responsible for the rapid response in mature mast cell density in the acutely stressed heart.
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In the abdominal aortocaval (AV) fistula model of heart failure, we have shown that the acute doubling of cardiac mature mast cell (MC) density involved the maturation, but not proliferation, of a resident population of immature cardiac MCs. An increase in stem cell factor (SCF) may be responsible for this MC maturation process. Thus, the purpose of this study was to determine if: 1) myocardial SCF levels are increased following the initiation of cardiac volume overload; 2) the incubation of left ventricular (LV) tissue slices with SCF results in an increase in mature MC density; and 3) chemical degranulation of mature cardiac MCs in LV tissue slices results in an increase in SCF and mature MC density via MC chymase. Male rats with either sham or AV fistula surgery were studied at 6h and 1 and 3 days post-surgery. LV slices from normal male rat hearts were incubated for 16h with media alone or media containing one of the following: 1) recombinant rat SCF (20 ng/ml) to determine the effects of SCF on MC maturation; 2) the MC secretagogue compound 48/80 (20 μg/ml) to determine the effects of MC degranulation on SCF levels and mature MC density; 3) media containing compound 48/80 and anti-SCF (5 μg/ml) to block the effects of SCF; 4) chymase (100 nM) to determine the effects of chymase on SCF; and 5) compound 48/80 and chymostatin (chymase inhibitor, 10 μM) to block the effects of MC chymase. In AV fistula animals, myocardial SCF was significantly elevated above that in the sham group at 6h and 1 day post fistula by 2 and 1.8 fold, respectively, and then returned to normal by 3 days; this increase slightly preceded significant increases in MC density. Incubation of LV slices with SCF resulted in a doubling of mature MC density and this was concomitant with a significant decrease in the number of immature mast cells. Incubation of LV slices with compound 48/80 increased media SCF levels and mature MC density and with anti-SCF and chymostatin prevented these compound 48/80-induced increases. Incubation with chymase increased media SCF levels and mature MC density. These findings indicate that activated mature cardiac mast cells are responsible, in a paracrine fashion, for the increase in mature MC density post AV fistula by rapidly increasing SCF levels via the release of chymase.
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2,333,993 |
Annexin A2 is a natural extrahepatic inhibitor of the PCSK9-induced LDL receptor degradation.
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Proprotein convertase subtilisin/kexin-9 (PCSK9) enhances the degradation of hepatic low-density lipoprotein receptor (LDLR). Deletion of PCSK9, and loss-of-function mutants in humans result in lower levels of circulating LDL-cholesterol and a strong protection against coronary heart disease. Accordingly, the quest for PCSK9 inhibitors has major clinical implications. We have previously identified annexin A2 (AnxA2) as an endogenous binding partner and functional inhibitor of PCSK9. Herein, we studied the relevance of AnxA2 in PCSK9 inhibition and lipid metabolism in vivo. Plasma analyses of AnxA2(-/-) mice revealed: i) a ∼1.4-fold increase in LDL-cholesterol without significant changes in VLDLs or HDLs, and ii) a ∼2-fold increase in circulating PCSK9 levels. Western blotting and immunohistochemistry of AnxA2(-/-) tissues revealed that the LDLR was decreased by ∼50% in extrahepatic tissues, such as adrenals and colon. We also show that AnxA2-derived synthetic peptides block the PCSK9≡LDLR interaction in vitro, and adenoviral overexpression of AnxA2 in mouse liver increases LDLR protein levels in vivo. These results suggest that AnxA2 acts as an endogenous regulator of LDLR degradation, mostly in extrahepatic tissues. Finally, we identified an AnxA2 coding polymorphism, V98L, that correlates with lower circulating levels of PCSK9 thereby extending our results on the physiological role of AnxA2 in humans.
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2,333,994 |
Bisphenol A binds to the local anesthetic receptor site to block the human cardiac sodium channel.
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Bisphenol A (BPA) has attracted considerable public attention as it leaches from plastic used in food containers, is detectable in human fluids and recent epidemiologic studies link BPA exposure with diseases including cardiovascular disorders. As heart-toxicity may derive from modified cardiac electrophysiology, we investigated the interaction between BPA and hNav1.5, the predominant voltage-gated sodium channel subtype expressed in the human heart. Electrophysiology studies of heterologously-expressed hNav1.5 determined that BPA blocks the channel with a K(d) of 25.4±1.3 µM. By comparing the effects of BPA and the local anesthetic mexiletine on wild type hNav1.5 and the F1760A mutant, we demonstrate that both compounds share an overlapping binding site. With a key binding determinant thus identified, an homology model of hNav1.5 was generated based on the recently-reported crystal structure of the bacterial voltage-gated sodium channel NavAb. Docking predictions position both ligands in a cavity delimited by F1760 and contiguous with the DIII-IV pore fenestration. Steered molecular dynamics simulations used to assess routes of ligand ingress indicate that the DIII-IV pore fenestration is a viable access pathway. Therefore BPA block of the human heart sodium channel involves the local anesthetic receptor and both BPA and mexiletine may enter the closed-state pore via membrane-located side fenestrations.
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2,333,995 |
Redox-sensitive sulfenic acid modification regulates surface expression of the cardiovascular voltage-gated potassium channel Kv1.5.
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Kv1.5 (KCNA5) is expressed in the heart, where it underlies the I(Kur) current that controls atrial repolarization, and in the pulmonary vasculature, where it regulates vessel contractility in response to changes in oxygen tension. Atrial fibrillation and hypoxic pulmonary hypertension are characterized by downregulation of Kv1.5 protein expression, as well as with oxidative stress. Formation of sulfenic acid on cysteine residues of proteins is an important, dynamic mechanism for protein regulation under oxidative stress. Kv1.5 is widely reported to be redox-sensitive, and the channel possesses 6 potentially redox-sensitive intracellular cysteines. We therefore hypothesized that sulfenic acid modification of the channel itself may regulate Kv1.5 in response to oxidative stress.</AbstractText>To investigate how oxidative stress, via redox-sensitive modification of the channel with sulfenic acid, regulates trafficking and expression of Kv1.5.</AbstractText>Labeling studies with the sulfenic acid-specific probe DAz and horseradish peroxidase-streptavidin Western blotting demonstrated a global increase in sulfenic acid-modified proteins in human patients with atrial fibrillation, as well as sulfenic acid modification to Kv1.5 in the heart. Further studies showed that Kv1.5 is modified with sulfenic acid on a single COOH-terminal cysteine (C581), and the level of sulfenic acid increases in response to oxidant exposure. Using live-cell immunofluorescence and whole-cell voltage-clamping, we found that modification of this cysteine is necessary and sufficient to reduce channel surface expression, promote its internalization, and block channel recycling back to the cell surface. Moreover, Western blotting demonstrated that sulfenic acid modification is a trigger for channel degradation under prolonged oxidative stress.</AbstractText>Sulfenic acid modification to proteins, which is elevated in diseased human heart, regulates Kv1.5 channel surface expression and stability under oxidative stress and diverts channel from a recycling pathway to degradation. This provides a molecular mechanism linking oxidative stress and downregulation of channel expression observed in cardiovascular diseases.</AbstractText>
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2,333,996 |
Anthocyanins block ischemia-induced apoptosis in the perfused heart and support mitochondrial respiration potentially by reducing cytosolic cytochrome c.
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Anthocynanins, found in fruits and vegetables, have a variety of protective properties, which have generally been attributed to their antioxidant capacity. However, antioxidants are generally strong reductants, and some reductants have been found to block apoptosis by reducing cytosolic cytochrome c, which prevents caspase activation. We tested the ability of various anthocyanins: to reduce cytochrome c, to support cytochrome c-induced mitochondrial respiration and to inhibit apoptosis induced by heart ischemia. Anthocyanins such as delphinidin-3-glucoside (Dp3G) and cyanidin-3-glucoside (Cy3G) were able to reduce cytochrome c directly and rapidly, whereas pelargonidin-3-glucoside (Pg3G), malvinidin-3-glucoside (Mv3G) and peonidin-3-glucoside (Pn3G) had relatively low cytochrome c reducing activities. Dp3G and Cy3G but not Pg3G supported mitochondrial state 4 respiration in the presence of exogenous cytochrome c. Pre-perfusion of hearts with 20 μM Cy3G but not Pg3G prevented ischemia-induced caspase activation. This suggests that the ability of anthocyanins to block caspase activation may be due to their ability to reduce cytosolic cytochrome c. This article is part of a Directed Issue entitled: Bioenergetic dysfunction, adaptation and therapy.
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2,333,997 |
Acute effects of cigarette smoking on insulin resistance and arterial stiffness in young adults.
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It is unclear whether changes in insulin sensitivity or arterial stiffness in cigarette smokers could explain the link between cigarette smoking and diabetes mellitus. The purpose of the study was to evaluate the acute effects of cigarette smoking on insulin resistance and arterial stiffness in a cohort of young healthy adults.</AbstractText>Metabolic risk components, hemodynamic parameters, plasma nitrite/nitrate and high-sensitivity C-reactive protein (hsCRP) levels, were compared between smokers and age- and gender-matched controls (non-smokers). In smokers, these levels were determined 8-h following cigarette abstinence and an hour after smoking.</AbstractText>One hundred nineteen smokers and age-matched non-smokers (mean age, 32 years; 83% men) were included in this study. Compared with non-smokers, smokers had a significantly higher number of abnormal metabolic risk components, HOMA-IR index and total nitrite/nitrate levels. There were no differences in brachial/central blood pressure, augmentation index and hsCRP between smokers and non-smokers. An hour after smoking, smokers had significantly higher levels of HOMA-IR, total nitrite/nitrate, hsCRP and heart rate compared with baseline levels. By contrast, brachial/central blood pressure and augmentation index were unchanged after cigarette smoking. Baseline vascular and insulin resistance status predicted the extent of rise in the HOMA-IR and augmentation indices acutely after cigarette smoking (adjusted R(2) 0.358 and 0.124, p < 0.001 respectively).</AbstractText>Individuals with more advanced vascular damage and insulin resistance are vulnerable to the acute effects of cigarette smoking.</AbstractText>Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.</CopyrightInformation>
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2,333,998 |
Prevention of hypotension and prolongation of postoperative analgesia in emergency cesarean sections: A randomized study with intrathecal clonidine.
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Different adjuvants been tried out for neuraxial anesthesia in emergency caesarean section so that the dose of the local anesthetic can be reduced and hypotension thereby prevented.</AbstractText>The present study was carried out in patients presenting for emergency lower segment caesarean section (LSCS) to establish the dose of intrathecal clonidine that would allow reduction of the dose of local anesthetic (thereby reducing the incidence and magnitude of hypotension) while at the same time providing clinically relevant prolongation of spinal anesthesia without significant side effects.</AbstractText>This randomized clinical study was carried out in our institution among 100 pregnant females who underwent emergency caesarean section. The participants were divided randomly into four groups: A, B, C, and D, each comprising 25 parturients. Subarachnoid block was performed using a 26G Quincke needle, with 12 mg of hyperbaric bupivacaine (LA) in group A, 9 mg of LA + 30 μg of clonidine in group B, LA + 37.5 μg of clonidine in group C, and LA + 45 μg of clonidine in group D. The solution was uniformly made up to 2.2 mL with normal saline in all the groups. Onset of analgesia at T(10) level, sensory and motor blockade levels, maternal heart rate and blood pressure, neonatal Apgar scores, postoperative block characteristics, and adverse events were looked for and recorded. Statistical analysis was carried out with SPSS(®) version 10.0 for Windows(®), using the ANOVA test with post hoc significance, the Chi-square test, and the Mann-Whitney U test. P<.05 was considered significant and P<.0001 as highly significant.</AbstractText>One hundred patients were enrolled for this study. The four groups were comparable with regard to demographic data and neonatal Apgar scores. Onset and establishment of sensory and motor analgesia was significantly shorter in groups C and D, while hypotension (and the use of vasopressors) was significantly higher in groups A and D. Perioperative shivering, nausea, and vomiting were significantly higher in groups A and D, while incidence of dry mouth was significantly higher in group D.</AbstractText>The addition of 45 μg, 37.5 μg, and 30 μg of clonidine to hyperbaric bupivacaine results in more prolonged complete and effective analgesia, allowing reduction of up to 18% of the total dose of hyperbaric bupivacaine. From the results of this study, 37.5 μg of clonidine seems to be the optimal dose.</AbstractText>
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2,333,999 |
Anesthesia with nontracheal intubation in thoracic surgery.
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To study one-lung respiration during VATS wedge resection of bullae and pulmonary nodules with nontracheal intubation, and to explore the changes of vital signs when patients return to two-lung ventilation.</AbstractText>Twenty-two patients with normal cardiopulmonary function and absence of contraindications to epidural anesthesia were included in this study. VATS wedge resection of bullae or pulmonary nodules was performed. 0.5% Ropivacain was administrated for epidural anesthesia (T8-9), and 2 mL of 2% lidocaine was used for local anesthetic block of the intrathoracic vagus nerves. The BIS value was maintained between 50 and 70 by target-controlled infusion of propofol and remifentanil. Electrocardiogram (ECG), heart rate (HR), blood pressure (Bp), pulse oxygen saturation (SpO(2)), respiratory rate (RR), bispectral index (BIS) and urine volume were monitored.</AbstractText>None patients were converted to endotracheal intubation during anesthesia. MAP and SpO(2) after wound disclosure were stable (P>0.05), level of CVP significantly elevated, HR and RR increased (P<0.05), PaCO(2) increased gradually while PaO(2) remained stable. Fifteen minutes after wound closure, MAP, RR and SpO(2) returned to their pre-anesthesia levels, PH value gradually recovered, PaCO(2) tended to decrease and returned to normal one hour after wound closure. Physical agitation occurred in one case due to inadequate epidural anesthesia during skin incision. Cough before intrathoracic vagal blockade was noted in two cases (9.1%) because of lobe traction.</AbstractText>Nontracheal intubation is feasible in VATS wedge resection of bullae and pulmonary nodules. The patients are with stable intraoperative vital signs and none experiences hypoxemia; intraoperative hypercapnia is tolerable and transient, which can be improved quickly when bilateral lungs resume spontaneous respiration.</AbstractText>
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