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2,334,300 |
Cell-penetrating peptide-modified block copolymer micelles promote direct brain delivery via intranasal administration.
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In order to develop non-invasive and effective nose-to-brain delivery of drugs, we synthesized Tat analog-modified methoxy poly(ethylene glycol) (MPEG)/poly(ε-caprolactone) (PCL) amphiphilic block copolymers through the ester bond.</AbstractText>We evaluated the brain distribution of coumarin, acting as a model chemical, after intravenous or intranasal administration of MPEG-PCL. In addition, cellular uptake of coumarin by rat glioma cells transfected with coumarin-loaded MPEG-PCL or MPEG-PCL-Tat was determined. Finally, we determined the brain distribution and biodistribution after intranasal administration of coumarin-loaded MPEG-PCL-Tat.</AbstractText>The amount of coumarin in the brain after intranasal administration was significantly higher than that after intravenous administration. In addition, cellular uptake of coumarin using MPEG-PCL was the lowest, while cellular uptake of coumarin using Tat-modified MPEG-PCL (MPEG-PCL-Tat) was higher than that of MPEG-PCL. Therefore, the brain distribution of coumarin administered using MPEG-PCL-Tat was significantly greater than that using MPEG-PCL. Then, the coumarin distribution after MPEG-PCL-Tat administration in non-targeted tissues (lung, liver, heart, kidney and spleen) was lower than that after coumarin administration without nanomicelles.</AbstractText>We have demonstrated that utilization of nano-sized micelles modified with Tat can facilitate direct intranasal brain delivery.</AbstractText>
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2,334,301 |
Fluoroscopic Radiation Exposure during Percutaneous Kyphoplasty.
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The author measured levels of fluoroscopic radiation exposure to the surgeon's body based on the different beam directions during kyphoplasty.</AbstractText>This is an observational study. A series of 84 patients (96 vertebral bodies) were treated with kyphoplasty over one year. The patients were divided into four groups based on the horizontal and vertical directions of the X-Ray beams. We measured radiation exposure with the seven dosimetry badges which were worn by the surgeon in each group (total of 28 badges). Twenty-four procedures were measured in each group. Cumulative dose and dose rates were compared between groups.</AbstractText>Fluoroscopic radiation is received by the operator in real-time for approximately 50% (half) of the operation time. Thyroid protectors and lead aprons can block radiation almost completely. The largest dose was received in the chest irrespective of beam directions. The lowest level of radiation were received when X-ray tube was away from the surgeon and beneath the bed (dose rate of head, neck, chest, abdomen and knee : 0.2986, 0.2828, 0.9711, 0.8977, 0.8168 mSv, respectively). The radiation differences between each group were approximately 2.7-10 folds.</AbstractText>When fluoroscopic guided-KP is performed, the X-Ray tube should be positioned on the opposite side of the operator and below the table, otherwise the received radiation to the surgeon's body would be 2.7-10 times higher than such condition.</AbstractText>
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2,334,302 |
Efficacy and side effects of intraoperative analgesia with intrathecal bupivacaine and levobupivacaine: a retrospective study in 82 dogs.
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To evaluate spinal (intrathecal) anaesthesia (SA) in addition to general anaesthesia in dogs, and report the incidence of side effects and cardiovascular response (CR) to surgery.</AbstractText>Retrospective clinical study.</AbstractText>One hundred and fifteen dogs undergoing general anaesthesia for surgery caudal to the diaphragm between 2005 and 2008.</AbstractText>Records of anaesthetized dogs that had received SA with bupivacaine or levobupivacaine 0.5%, together with morphine or fentanyl were reviewed. Success rate of SA, complication rate and incidence of CR were recorded and examined in relation to the dose of local anaesthetic administered and the type of surgery. Univariate and Cusum analysis were performed to identify independent predictors of response to surgical stimulation and characterize the learning curve for the technique, respectively.</AbstractText>Eighty-two dogs received successful SA. The Cusum plot suggested that a failure rate of 10% is achieved when the procedure is performed more than 66 times. Median local anaesthetic dose related to weight was 0.40 mg kg(-1) (0.3-0.5), and to spinal cord length 0.1 mg cm(-1) (0.07-0.12). Morphine was added to the local anaesthetic in 56 and fentanyl in 22 dogs. CR post-stimulus occurred in 29 cases: 11 of 22 ovariohysterectomies, 14 of 33 hindlimb-surgeries, 2 of 10 caudal-abdominal-surgeries and 2 of 17 Caesarean sections. Anaesthetic dose related to weight was not a predictor of CR. Bradycardia occurred in seven, hypotension in 24, urinary retention in four and hypersalivation in 6 of 82 dogs.</AbstractText>SA was practicable to apply, but in this study did not totally block CR, Side effects were minimal, with an incidence similar to that in humans.</AbstractText>SA can be used in clinical cases with few side effects although monitoring of and ensuing treatment of hypotension is required. Comparative prospective studies are required to establish efficacy and a reliable dose.</AbstractText>© 2011 The Authors. Veterinary Anaesthesia and Analgesia © 2011 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesiologists.</CopyrightInformation>
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2,334,303 |
Successful resuscitation from bupivacaine-induced cardiovascular collapse with intravenous lipid emulsion following femoral nerve block in an emergency department.
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We report a case of a 69-year-old woman with femoral neck fracture undergoing bupivacaine femoral nerve block for preoperative analgesia in an ED. Seizure and cardiovascular collapse developed immediately after instillation of local anaesthetic. Resuscitation including 20% lipid emulsion was successful in achieving normalization of haemodynamic parameters and ECG QRS duration. No adverse sequelae of lipid administration were observed. We recommend the immediate availability of lipid emulsion in emergency room settings where local anaesthetics are used.
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2,334,304 |
The 'overly-sensitive' heart: sodium channel block and QRS interval prolongation.
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Cardiac safety remains of paramount importance in the development of successful clinical drug candidates. Great progress has been made recently in understanding liabilities associated with delayed ventricular repolarization (manifest as QT prolongation) and in predicting (thus avoiding) drugs that delay repolarization based on application of strategic preclinical assays. Following the advances made in clinical electrophysiological monitoring and conduct of thorough QT studies, focus is now shifting towards monitoring of additional drug-induced effects, particularly on ventricular conduction (measured as changes in the QRS interval on the ECG) as part of evolving clinical thorough ECG studies. In this issue of the British Journal of Pharmacology, a study by Harmer et al. proposes provisional safety margins for QRS prolongation in man based on retrospective clinical data and a single in vitro approach to assess potency of block of cardiac sodium current (hNav1.5), the ionic current responsible for ventricular conduction (observed as QRS prolongation). The present commentary places their study in context with evolving preclinical cardiac electrophysiological safety assessments, along with discussions focused on ensuring the proper 'translation' of preclinical findings with potential clinical concerns. Given the extant limitations and uncertainties of presently available data, as well as our limited understanding of the pro-arrhythmic potential associated with these changes, due caution should be applied when considering the proposed in vitro-based margins for drug-induced QRS prolongation measured clinically. Additional validation with multiple preclinical models and more rigorous clinical safety studies will be necessary to substantiate these recommended margins.</AbstractText>This article is a commentary on Harmer et al., pp. 260-273 of this issue. To view this paper visit http://dx.doi.org/10.1111/j.1476-5381.2011.01415.x.</AbstractText>© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.</CopyrightInformation>
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2,334,305 |
Effect of transition from sitaxsentan to ambrisentan in pulmonary arterial hypertension.
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Currently available endothelin receptor antagonists for treating pulmonary arterial hypertension block either the endothelin (ET) receptor A or both A and B receptors. Transition from one endothelin receptor antagonist to another may theoretically alter side-effects or efficacy. We report our experience of a transition from sitaxsentan to ambrisentan, both predominant ET(A) receptor antagonists, in pulmonary arterial hypertension patients.</AbstractText>At Baylor Pulmonary Hypertension Center, 18 patients enrolled in the open-label extension phase of the original sitaxsentan studies (Sitaxsentan To Relieve ImpaireD Exercise) were transitioned to ambrisentan (from July 2007 to September 2007) at the time of study closure. Pre-transition (PreT), 1 month (1Mth) and 1 year (1Yr) post-transition assessments of 6-minute walk distance (6MWD), brain naturetic peptide (BNP) levels, WHO functional class (WHO FC), Borg dyspnea score (BDS), oxygen saturation, liver function, and peripheral edema were compared.</AbstractText>6MWD was 356 ± 126 m at PreT, 361 ± 125 m at 1Mth, and 394 ± 114 m at 1Yr (mean ± SD). There was no difference in the walk distance at 1Mth and 1Yr post transition compared with PreT (P=0.92, 0.41 respectively). Oxygen saturation was no different at 1Mth and 1Yr to PreT level (P=0.49 and P=0.06 respectively). BNP was 178 ± 44 pg/mL at PreT, 129 ± 144 pg/mL at 1Mth and 157 ± 201 at 1Yr. Peripheral edema was present in 7/18 patients at PreT, in 8/16 patients at 1Mth, and in 6/13 patients at 1Yr post transition. Proportions of patients with edema over these 3 time points did not change significantly (P=0.803). At 1Yr, 2 patients had died, 1 had undergone lung transplantation, 1 had relocated, and 1 patient was started on intravenous prostacyclin therapy. Over 3 points (baseline, 1 month, and 1 year), there was no significant change in function class (P=0.672).</AbstractText>Our limited data suggest that ET(A) receptor antagonists can be switched from one to another with sustained exercise capacity and maintained WHO FC with no increase in incidence of peripheral edema.</AbstractText>© 2011 Safdar, publisher and licensee Dove Medical Press Ltd.</CopyrightInformation>
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2,334,306 |
Rings in the neonate.
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Neonatal lupus erythematosus (NLE) is an uncommon disease of the neonate. It is believed to be caused by the transplacental passage of maternal autoantibodies to the ribonucleoproteins (Ro/SSA, La/SSB or rarely U RNP) as these are almost invariably present in NLE sera. The most common clinical manifestations include cutaneous lupus lesions and congenital complete heart block. Hepatobiliary and haematologic abnormalities are reported less frequently. We describe a patient with cutaneous NLE to illustrate and raise awareness of the characteristic annular eruption of this condition. We also emphasize the need for thorough investigation for concomitant organ involvement and for maternal education regarding risk in future pregnancies.
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2,334,307 |
Dendroaspis natriuretic peptide and the designer natriuretic peptide, CD-NP, are resistant to proteolytic inactivation.
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Designer natriuretic peptides (NPs) represent an active area of drug development. In canine and human studies, the designer natriuretic peptide CD-NP demonstrated more desirable therapeutic potential than recombinant B-type NP (BNP), which is known as nesiritide and is approved for treatment of acute decompensated heart failure. However, why CD-NP is more effective than BNP is not known. We previously reported that CD-NP is a poorer activator of human guanylyl cyclase-A (GC-A) and a better activator of human guanylyl cyclase-B than BNP. Here, guanylyl cyclase bioassays were used to compare the susceptibility of CD-NP verses ANP, BNP, CNP and DNP to inactivation by human kidney membranes. The half time (t(1/2)) for CD-NP inactivation was increased by factors of 13, 3 and 4 compared to ANP, BNP and CNP, respectively, when measured in the same assay. Surprisingly, DNP failed to undergo complete inactivation and was the most degradation resistant of the peptides tested. The neutral endopeptidase (NEP) inhibitor, phosphoramidon, blocked inactivation of CNP and CD-NP, but not BNP or DNP. In contrast, the general serine and cysteine protease inhibitor, leupeptin, completely blocked the degradation of BNP and CD-NP, but did not block CNP inactivation unless phosphoramidon was included in the assay. Thus, NPs with shorter carboxyl tails (ANP and CNP) are degraded by phosphoramidon-sensitive proteases and NPs with extended carboxyl tails (BNP, DNP and CD-NP) are resistant to NEP degradation and degraded by leupeptin-sensitive proteases. We conclude that DNP and CD-NP are highly resistant to proteolysis and that proteolytic resistance contributes to the beneficial cardiovascular properties of CD-NP. We suggest that this property may be exploited to increase the half-life of NP-based drugs.
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2,334,308 |
Protective athletic equipment slows initiation of CPR in simulated cardiac arrest.
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Standard protective athletic equipment used in collision sports such as American football poses a unique challenge to rescuers because they block access to both the airway and chest. The main objective of this investigation was to determine the effect of athletic equipment on the initiation of CPR. The feasibility of performing compressions over the chest protector as a potential time-saving step was also evaluated.</AbstractText>Thirty-four certified athletic trainers performed CPR on a manikin wearing protective equipment during a simulated episode of cardiac arrest. For one trial the protective equipment was removed or unfastened prior to initiating CPR, and for another, chest compressions were initiated over the protective equipment. The following were recorded for comparison purposes: time until first breath and first compression; percentage of compressions delivered to the recommended depth; compression rate; accuracy of hand placement; percentage of compressions without full chest recoil.</AbstractText>Although chest compressions began sooner when compressions were delivered over the chest protector, this improvement was not statistically significant. A more notable positive outcome resulting from keeping the chest protector on was an increase in the number of compressions that were delivered to the recommended depth. Unfortunately, one of the significant negative outcomes of performing chest compression over the chest pad was the increased percentage of compressions that did not obtain full chest recoil.</AbstractText>Although removal of the chest protector delays the initiation of chest compressions, keeping the chest protector on during CPR does not appear to be a feasible option.</AbstractText>Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.</CopyrightInformation>
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2,334,309 |
Carotid Artery Wall Motion Estimation from Consecutive Ultrasonic Images: Comparison between Block-Matching and Maximum-Gradient Algorithms.
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Radial movement of the arterial wall is a well-known indicator of the mechanical properties of arteries in arterial disease examinations. In the present study, two different motion estimation methods, based on the block-matching and maximum-gradient algorithms, were examined to extract the radial displacement of the carotid artery wall.</AbstractText>Each program was separately implemented to the same axial consecutive ultrasound images of the carotid artery of 10 healthy men, and the radial displacement waveform of this artery was extracted during two cardiac cycles. The results of the two methods were compared using the linear regression and Bland-Altman statistical analyses. The maximum and mean displacements traced by the block-matching algorithm were compared with the same parameters traced by the maximum-gradient algorithm. The frame numbers in which the maximum displacement of the wall occurred were compared too.</AbstractText>There were no significant differences between the maximum and the mean displacements traced by the block-matching algorithm and the same parameters traced by the maximum-gradient algorithm according to the pair t-test analysis (p value > 0.05). There was a significant correlation between the radial movement of the common carotid artery measured with the block-matching and maximum-gradient methods (with a correlation coefficient of 0.89 and p value < 0.05). The Bland-Altman analysis results confirmed a good agreement between the two methods in measuring the radial movement, with a mean difference and limits of agreement of 0.044 ± 0.038. The results showed that both methods found the maximum displacement occurring in the same frame.</AbstractText>Both block-matching and maximum-gradient algorithms can be used to extract the radial displacement of the carotid artery wall and in addition, with respect to the pixel size as error, the same results can be obtained.</AbstractText>
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2,334,310 |
Prolonged corrected QT interval in anti-Ro/SSA-positive adults with systemic lupus erythematosus.
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To examine whether anti-Ro/SSA antibodies are associated with an increased risk of corrected QT (QTc) prolongation, and to study the stability of this relationship over time.</AbstractText>Patients fulfilling the American College of Rheumatology (ACR) criteria for systemic lupus erythematosus (SLE) were invited to undergo a 12-lead resting electrocardiogram (EKG) in the pilot phase of our project, performed between February 2002 and March 2005. The same study population was used to perform a second similar analysis with a larger sample between April 2005 and May 2007. Multivariate logistic regression models were fit to estimate the cross-sectional association between anti-Ro/SSA and other demographic and clinical variables on QTc prolongation. The other potentially associated factors examined included age, sex, disease duration, lupus activity (Systemic Lupus Erythematosus Disease Activity Index 2000 update), damage (Systemic Lupus International Collaborating Clinics/ACR Damage Index), potassium and magnesium levels, and medications with the potential to prolong the QTc interval.</AbstractText>Cross-sectional analysis of the pilot data (n = 150 patients) showed an association of prolonged QTc with the presence of anti-Ro/SSA (adjusted odds ratio [OR] 12.6; 95% confidence interval [95% CI] 2.3, 70.7). In the second larger study (n = 278), the association was replicated, with a narrower 95% CI (adjusted OR 5.1; 95% CI 1.5, 17.4). In the 118 patients with 2 EKG assessments, the results were consistent over time.</AbstractText>Anti-Ro/SSA was associated with QTc prolongation in both our pilot data and a larger SLE cohort sample. Patients positive for anti-Ro/SSA may benefit from EKG testing and appropriate counseling should be considered for those identified with QTc prolongation.</AbstractText>Copyright © 2011 by the American College of Rheumatology.</CopyrightInformation>
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2,334,311 |
Calcium and osteoprotegerin regulate IGF1R expression to inhibit vascular calcification.
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Osteoprotegerin (OPG) inhibits vascular calcification in vitro, and OPG(-/-) mice develop vascular calcification. Insulin-like growth factor-1 (IGF1) signalling has been implicated in vascular smooth muscle cell (VSMC) survival; however, the role of IGF1-receptor (IGF1R) expression in calcification is unclear. We sought to determine whether the protective effects of OPG in vascular calcification were mediated by IGF1R.</AbstractText>Calcium-induced mineralization of VSMCs was blocked in cells expressing the IGF1R and by treatment with OPG. OPG induced IGF1R mRNA, protein, and transcription optimally at 1 ng/mL. Calcium also positively regulated both OPG and IGF1R, and siRNA targeting of OPG inhibited calcium-inducible IGF1R mRNA. Addition of calcium to VSMCs reduced camptothecin-stimulated apoptosis and increased expression of survival genes Bcl2 and nuclear factor-kappa B without altering levels of proliferation. Calcium's induction of IGF1R and OPG was dose and time dependent but was blunted at higher calcium doses. Calcium- and OPG-inducible IGF1R transcription occurred between -446 and -188 bp of the IGF1R promoter, and inducible-IGF1R expression was blocked by specificity protein-1 (Sp1) silencing studies. Furthermore, elevated IGF1R and OPG protein levels were present in calcified atherosclerotic tissue.</AbstractText>We have shown for the first time that IGF1R expression and activity via OPG can modulate VSMC calcification in vitro. We suggest a feedback mechanism: moderate calcium levels increase OPG, which then increases IGF1R to enhance VSMC survival and block calcification induced by calcium. In contrast, high calcium leads to inhibition of IGF1R expression and activity to stimulate VSMC calcification further.</AbstractText>
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2,334,312 |
Next-generation association studies for complex traits.
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A new study successfully applies complementary whole-genome sequencing and imputation approaches to establish robust disease associations in an isolated population. This strategy is poised to help elucidate the role of variants at the low end of the allele frequency spectrum in the genetic architecture of complex traits.
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2,334,313 |
Cardiac ion channel current modulation by the CFTR inhibitor GlyH-101.
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The role in the heart of the cardiac isoform of the cystic fibrosis transmembrane conductance regulator (CFTR), which underlies a protein kinase A-dependent Cl(-) current (I(Cl.PKA)) in cardiomyocytes, remains unclear. The identification of a CFTR-selective inhibitor would provide an important tool for the investigation of the contribution of CFTR to cardiac electrophysiology. GlyH-101 is a glycine hydrazide that has recently been shown to block CFTR channels but its effects on cardiomyocytes are unknown. Here the action of GlyH-101 on cardiac I(Cl.PKA) and on other ion currents has been established. Whole-cell patch-clamp recordings were made from rabbit isolated ventricular myocytes. GlyH-101 blocked I(Cl.PKA) in a concentration- and voltage-dependent fashion (IC(50) at +100 mV=0.3 ± 1.5 μM and at -100 mV=5.1 ± 1.3 μM). Woodhull analysis suggested that GlyH-101 blocks the open pore of cardiac CFTR channels at an electrical distance of 0.15 ± 0.03 from the external membrane surface. A concentration of GlyH-101 maximally effective against I(Cl.PKA) (30 μM) was tested on other cardiac ion currents. Inward current at -120 mV, comprised predominantly of the inward-rectifier background K(+) current, I(K1), was reduced by ∼43% (n=5). Under selective recording conditions, the Na(+) current (I(Na)) was markedly inhibited by GlyH-101 over the entire voltage range (with a fractional block at -40 mV of ∼82%; n=8). GlyH-101 also produced a voltage-dependent inhibition of L-type Ca(2+) channel current (I(Ca,L)); fractional block at +10 mV of ∼49% and of ∼28% at -10 mV; n=11, with a ∼-3 mV shift in the voltage-dependence of I(Ca,L) activation. Thus, this study demonstrates for the first time that GlyH-101 blocks cardiac I(Cl.PKA) channels in a similar fashion to that reported for recombinant CFTR. However, inhibition of other cardiac conductances may limit its use as a CFTR-selective blocker in the heart.
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2,334,314 |
Left ventricular apical ballooning syndrome after pacemaker implantation in a male.
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Left apical ballooning syndrome, also known as Takotsubo cardiomyopathy (TTC), characterized by transient left ventricular dysfunction is increasingly recognized worldwide. Predominantly affecting females, this condition mimics myocardial infarction and often occurs in the setting of emotional or physical stress. We report the case of a 77-year-old male who was admitted to the hospital for complete heart block and developed TTC after pacemaker implantation. To our knowledge, this is the first report of TTC development after pacemaker implantation in a male.
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2,334,315 |
Differing effects of rapamycin and mTOR kinase inhibitors on protein synthesis.
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mTOR (mammalian target of rapamycin) forms two distinct types of complex, mTORC (mTOR complex) 1 and 2. Rapamycin inhibits some of the functions of mTORC1, whereas newly developed mTOR kinase inhibitors interfere with the actions of both types of complex. We have explored the effects of rapamycin and mTOR kinase inhibitors on general protein synthesis and, using a new stable isotope-labelling method, the synthesis of specific proteins. In HeLa cells, rapamycin only had a modest effect on total protein synthesis, whereas mTOR kinase inhibitors decreased protein synthesis by approx. 30%. This does not seem to be due to the ability of mTOR kinase inhibitors to block the binding of eIFs (eukaryotic initiation factors) eIF4G and eIF4E. Analysis of the effects of the inhibitors on the synthesis of specific proteins showed a spectrum of behaviours. As expected, synthesis of proteins encoded by mRNAs that contain a 5'-TOP (5'-terminal oligopyrimidine tract) was impaired by rapamycin, but more strongly by mTOR kinase inhibition. Several proteins not known to be encoded by 5'-TOP mRNAs also showed similar behaviour. Synthesis of proteins encoded by 'non-TOP' mRNAs was less inhibited by mTOR kinase inhibitors and especially by rapamycin. The implications of our findings are discussed.
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2,334,316 |
Evaluation of effects of sciatic and femoral nerve blocks in sheep undergoing stifle surgery.
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The authors evaluated the effects of locally anesthetizing the sciatic and femoral nerves in sheep undergoing stifle (femorotibial) surgery (16 sheep received nerve blocks; 16 sheep underwent a nerve localization procedure but received no nerve blocks). Heart rate, mean arterial blood pressure and end-tidal isoflurane were recorded every 5 min while sheep were anesthetized. At some of the observed time points, the mean heart rate in the sheep that had received no nerve blocks was significantly higher than in the sheep that had received the nerve blocks. Postoperatively, each sheep was assigned scores for comfort and attitude, movement, flock behavior, feeding behavior and appetite and respiratory rate (based on predefined descriptions). Though the authors found no undesirable effects of this local anesthesia, beneficial effects of the nerve blocks were minimal or not readily apparent under the conditions of this study.
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2,334,317 |
Do antioxidant vitamins ameliorate the beneficial effects of exercise training on insulin sensitivity?
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Exercise training has numerous health benefits, and in patients with type 2 diabetes mellitus and metabolic syndrome, it can improve insulin sensitivity and glucose control. A recent publication suggests that antioxidant vitamins (C and E) block these effects on blood glucose. This investigation was undertaken to determine whether antioxidant vitamins ameliorate the beneficial effects of cardiac rehabilitation and exercise training (CRET) on insulin sensitivity and glucose metabolism in patients with coronary heart disease (CHD).</AbstractText>We assessed CHD risk factors, including clinical indices of glucose metabolism, and evaluated the effects of exercise training in 315 patients with CHD with diabetes mellitus and/or metabolic syndrome before and after a 3-month program of CRET. Patients were divided into 2 groups based on self-reported antioxidant vitamin (vitamins C and E) consumption.</AbstractText>Both groups, 113 patients (36%) consuming vitamins (Vits group) and 202 patients (64%) who reported no vitamin use (no-Vits group) were statistically similar at baseline. Following CRET, patients improved exercise capacity (10%, P < .0001), fasting blood glucose (-7%, P < .0001), percent body fat (-3%, P = .0001), high-sensitive Creactive protein (-31%, P = .003), and various lipids and behavioral parameters, but there was no significant improvement in glycosylated hemoglobin following formal CRET. Both Vits group and no-Vits group achieved statistically similar improvements in fasting blood glucose, body fat, and other CHD risk factors.</AbstractText>Commercially available antioxidant supplements (mean dose of 400 IU of vitamin E and 500 mg of vitamin C) do not ameliorate the health benefits of exercise training, including fasting blood glucose, in CHD patients</AbstractText>
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2,334,318 |
Effects of maternal supplementary oxygen on the newborn for elective cesarean deliveries under spinal anesthesia.
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The aim of this investigation was to determine whether supplementary oxygen provided by either nasal cannula or face mask versus room air might affect fetal oxygenation during elective cesarean section under spinal anesthesia by assessing maternal and neonatal regional cerebral oxygenation (rSO(2)) with a cerebral oximeter.</AbstractText>Ninety parturients were randomly allocated into three groups: two groups received 5 L/min oxygen by either nasal cannula (Group NC, n = 30) or face mask (Group FM, n = 30), respectively, and the third group was allowed to breathe room air (Group RA, n = 30). After maternal mean arterial pressure, heart rate and peripheral oxygen saturation had been monitored, rSO(2) was determined by cerebral oximeter. Umbilical artery (UA) and venous (UV) blood samples were collected for blood gas analysis. Neonatal rSO(2) and Apgar scores were recorded.</AbstractText>The mean maternal rSO(2) which was recorded 3 and 5 min after administration of the spinal block in Group FM was lower than that of Group NC (p = 0.033 and 0.042, respectively). Neonatal rSO(2), UA pH, UV pH and UA base excess (BE) were lower in Group FM than in the other groups (p < 0.05). The Apgar score (1 min) in Group FM was lower than that of Group RA (p = 0.046).</AbstractText>The effect of maternal supplementary oxygen on the newborn has been demonstrated by a cerebral oximeter monitor and supported by umbilical cord blood gas analysis and Apgar scores.</AbstractText>
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2,334,319 |
Novel oral anticoagulants: focus on stroke prevention and treatment of venous thrombo-embolism.
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Anticoagulation for the long-term treatment and prevention of thrombo-embolic diseases as well as for stroke prevention in atrial fibrillation (AF) has been accomplished by vitamin K antagonists for the last half century. Although effective under optimal conditions, the imminent risk of a recurrent event vs. the risk of bleeding due to the narrow therapeutic window, numerous food- and drug interactions, and the need for regular monitoring complicate the long-term use of these drugs and render treatment with these agents complicated. As a result, novel anticoagulants which selectively block key factors in the coagulation cascade are being developed. The efficacy and safety of the direct thrombin inhibitor dabigatran etexilate, as well as of the selective factor Xa inhibitors rivaroxaban and apixaban, have been demonstrated in Phase III trials for stroke prevention in AF and the treatment and secondary prophylaxis of venous thrombo-embolism. This review summarizes the results from recently published pivotal clinical trials and discusses the opportunities as well as uncertainties in the clinical applications of these novel agents.
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2,334,320 |
Effect of dietary organic microminerals on starter pig performance, tissue mineral concentrations, and liver and plasma enzyme activities.
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Weanling pigs (n = 160) were used to evaluate dietary essential microminerals (Cu, Fe, Mn, Se, and Zn) on performance, tissue minerals, and liver and plasma enzymatic activities during a 35-d postweaning period. A randomized complete block design with 5 treatments and 8 replicates was used in this study. Organic microminerals were added to complex nursery diets at 0 (basal), 50, 100, or 150% of the requirements of microminerals listed by the 1998 NRC. A fifth treatment contained inorganic microminerals at 100% NRC and served as the positive control. Pigs were bled at intervals with hemoglobin (Hb), hematocrit (Hct), glutathione peroxidase, and ceruloplasmin activities determined. Six pigs at weaning and 1 pig per pen at d 35 were killed, and the liver, heart, loin, kidney, pancreas, and the frontal lobe of the brain were collected for micromineral analysis. The liver was frozen in liquid N for determination of enzymatic activities. The analyzed innate microminerals in the basal diet met the NRC requirement for Cu and Mn but not Fe, Se, and Zn. Performance was not affected from 0 to 10 d postweaning, but when microminerals were added to diets, ADG, ADFI, and G:F improved (P < 0.01) from 10 to 35 d and for the overall 35-d period. Pigs fed the basal diet exhibited parakeratosis-like skin lesions, whereas those fed the supplemental microminerals did not. This skin condition was corrected after a diet with the added microminerals was fed. When the basal diet was fed, Hb and Hct declined, but supplemental microminerals increased Hb and Hct values. Liver catalase activity increased (P < 0.01) when microminerals were fed. The Mn superoxide dismutase activity tended to decline quadratically (P = 0.06) when supplemental microminerals were fed above that of the basal diet. Liver plasma glutathione peroxidase activities were greater (P < 0.01) when dietary organic and inorganic micromineral were fed. Liver concentrations of microminerals increased linearly (P < 0.01) as dietary microminerals increased, indicating that the liver was the primary storage organ. Micromineral tissue concentrations were least in pigs fed the basal diet and increased (quadratic, P < 0.01) to the 50% level of organic microminerals in the various tissues collected. The results indicated that innate microminerals, Cu and Mn, from a complex nursery diet may meet the micromineral needs of the weaned pig, but the need for Fe, Se, or Zn was not met by the basal diet.
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2,334,321 |
Prospective cohort study of lead exposure and electrocardiographic conduction disturbances in the Department of Veterans Affairs Normative Aging Study.
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No studies have examined the association between cumulative low-level lead exposure and the prospective development of electrocardiographic conduction abnormalities, which may mediate the association between lead and several cardiovascular end points.</AbstractText>We prospectively examined the association between lead exposure and the development of electrocardiographic conduction abnormalities.</AbstractText>We assessed blood lead, bone lead--a biomarker of cumulative lead exposure--measured with K-shell X-ray fluorescence, and electrocardiographic end points among 600 men in the Normative Aging Study who were free of electrocardiographic abnormalities at the time of the baseline ECG. Of these men, we had follow-up data from a second electrocardiogram for 496 men 8.1 (SD = 3.1) years later, on average. We used repeated measures linear regression to analyze change in electrocardiographic conduction timing and logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for developing specific conduction disturbances and adjusted for potential confounders.</AbstractText>Mean (± SD) blood (5.8 ± 3.6), patella bone (30.3 ± 17.7), and tibia bone (21.6 ± 12.0) lead concentrations were similar to those found in samples from the general U.S. population and much lower than those reported in occupationally exposed groups. Compared with those in the lowest tertile of tibia lead, those in the highest had a 7.94-ms (95% CI, 1.42-14.45) increase in heart rate-corrected QT (QTc) interval and a 5.94-ms increase in heart rate-corrected QRS (95% CI, 1.66-10.22) duration > 8 years. Those in the highest tertile of tibia lead also had increased odds of QT prolongation (QTc ≥ 440 msec; OR = 2.53; 95% CI, 1.22-5.25) and JT prolongation (heart rate-corrected JT > 360 msec; OR = 2.53; 95% CI, 0.93-6.91). Results were weaker for patella lead. No associations were identified with blood lead.</AbstractText>This study suggests that low-level cumulative exposure to lead is associated with worse future cardiac conductivity in the ventricular myocardium, as reflected in QT interval characteristics.</AbstractText>
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2,334,322 |
The diet quality of adult women participating in a behavioural weight-loss programme.
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Diet quality plays an important role in health and has been shown to impact the risk of heart disease and certain cancers. The present study aimed to examine baseline and 16-week follow-up levels of energy intake, energy density and diet quality, as measured by the Healthy Eating Index 2005 (HEI-2005), in overweight and obese women participating in a behavioural weight-loss programme.</AbstractText>Sixty-six women [mean (SD) age 48.6 (10.8) years; body mass index 31.8 (3.7) kg m(-2) ; 92% Caucasian] completed dietary measures at baseline and follow-up. All participants received a 16-week Internet Behavioural weight-loss programme based on the core of the Diabetes Prevention Program. Dietary intake was measured using the 2005 Block food frequency questionnaire. Diet quality was calculated using the HEI-2005. Paired t-tests were used to determine changes over time.</AbstractText>There was a reduction in reported energy intake [7.867 (3.232) MJ versus 5.748 (1.775) MJ, P < 0.001] over the 16 weeks. Participants had an increase in diet quality [HEI score = 53.9 (9.9) versus 57.4 (10.6), P = 0.002] as well as a reduction in energy density [0.0088 (0.0021) MJ g(-1) to 0.0080 (0.0021) MJ g(-1) (P = 0.002)]. All micronutrient intakes decreased over the 16 weeks.</AbstractText>  Participation in a 16-week behavioural weight-loss programme significantly improved diet quality and reduced dietary energy density and energy intake in adult women. However, despite the overall increase in diet quality score, there were deficiencies in key micronutrients in the diets of most women at the conclusion of the 16-week study.</AbstractText>© 2011 The Authors. Journal of Human Nutrition and Dietetics © 2011 The British Dietetic Association Ltd.</CopyrightInformation>
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2,334,323 |
Empirical mode decomposition analysis of HRV data from patients undergoing local anaesthesia (brachial plexus block).
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Spectral analysis of heart rate variability (HRV) is used for the assessment of cardiovascular autonomic control. In this study, a data-driven adaptive technique called empirical mode decomposition (EMD) and the associated Hilbert spectrum has been used to evaluate the effect of local anaesthesia on HRV parameters in a group of 14 patients undergoing axillary brachial plexus block. The normalized amplitude Hilbert spectrum was used to calculate the error index associated with the instantaneous frequency. The amplitude and the frequency values were corrected in the region where the error was higher than twice standard deviation. The intrinsic mode function (IMF) components were assigned to the LF and the HF part of the signal by making use of the centre frequency and the standard deviation spectral extension estimated from the marginal spectrum of the IMF components. The optimal range of the stopping criterion was found to be between 4 and 9 for the HRV data. The statistical analysis showed that the LF/HF ratio decreased within an hour of the application of the brachial plexus block compared to the values at the start of the procedure. These changes were observed in 13 of the 14 patients included in this study.
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2,334,324 |
Comparison of Gal and non-Gal-mediated cardiac xenograft rejection.
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This study compares the pathologic condition of delayed xenograft rejection in Gal-positive and Gal-knockout cardiac xenografts after pig-to-baboon heterotopic cardiac xenotransplantation when the induced anti-Gal antibody response is unregulated, blocked, or absent.</AbstractText>Baboon recipients of Gal-positive, CD46 pig hearts were treated with an αGal polymer (group 1; n=11) or Gal-specific immunoapheresis (group 2; n=8) to block anti-Gal antibody. Gal-knockout cardiac xenografts recipients (group 3; n=5) received no anti-Gal therapy. Perioperative and interim biopsies were examined and antibody responses were determined.</AbstractText>No hyperacute rejection was seen and histologic findings were similar across the groups. All groups showed vascular antibody deposition in perioperative and interim biopsies and in explant samples. A prominent antibody response was detected only in group 2. Complement activation was evident by C3d deposition but deposition of C5b and C5b-9 was limited. Earliest evidence of myocardial injury was myocyte vacuolization in the absence of microvascular thrombosis or coagulative necrosis that developed later. Histology of explanted hearts exhibited mainly microvascular thrombosis and coagulative necrosis with little evidence of interstitial hemorrhage or edema.</AbstractText>The histology of rejection seemed independent of the anti-Gal or non-Gal immune response. Myocyte vacuolization seems to be an early feature of delayed xenograft rejection presaging more classic pathologic features.</AbstractText>
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2,334,325 |
Comparative effectiveness and safety of medications for type 2 diabetes: an update including new drugs and 2-drug combinations.
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Given the increase in medications for type 2 diabetes mellitus, clinicians and patients need information about their effectiveness and safety to make informed choices.</AbstractText>To summarize the benefits and harms of metformin, second-generation sulfonylureas, thiazolidinediones, meglitinides, dipeptidyl peptidase-4 (DPP-4) inhibitors, and glucagon-like peptide-1 receptor agonists, as monotherapy and in combination, to treat adults with type 2 diabetes.</AbstractText>MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched from inception through April 2010 for English-language observational studies and trials. The MEDLINE search was updated to December 2010 for long-term clinical outcomes.</AbstractText>Two reviewers independently screened reports and identified 140 trials and 26 observational studies of head-to-head comparisons of monotherapy or combination therapy that reported intermediate or long-term clinical outcomes or harms.</AbstractText>Two reviewers following standardized protocols serially extracted data, assessed applicability, and independently evaluated study quality.</AbstractText>Evidence on long-term clinical outcomes (all-cause mortality, cardiovascular disease, nephropathy, and neuropathy) was of low strength or insufficient. Most medications decreased the hemoglobin A(1c) level by about 1 percentage point and most 2-drug combinations produced similar reductions. Metformin was more efficacious than the DPP-4 inhibitors, and compared with thiazolidinediones or sulfonylureas, the mean differences in body weight were about -2.5 kg. Metformin decreased low-density lipoprotein cholesterol levels compared with pioglitazone, sulfonylureas, and DPP-4 inhibitors. Sulfonylureas had a 4-fold higher risk for mild or moderate hypoglycemia than metformin alone and, in combination with metformin, had more than a 5-fold increased risk compared with metformin plus thiazolidinediones. Thiazolidinediones increased risk for congestive heart failure compared with sulfonylureas and increased risk for bone fractures compared with metformin. Diarrhea occurred more often with metformin than with thiazolidinediones.</AbstractText>Only English-language publications were reviewed. Some studies may have selectively reported outcomes. Many studies were small, were of short duration, and had limited ability to assess clinically important harms and benefits.</AbstractText>Evidence supports metformin as a first-line agent to treat type 2 diabetes. Most 2-drug combinations similarly reduce hemoglobin A(1c) levels, but some increased risk for hypoglycemia and other adverse events.</AbstractText>Agency for Healthcare Research and Quality.</AbstractText>
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2,334,326 |
Downregulation of the CXC chemokine receptor 4/stromal cell-derived factor 1 pathway enhances myocardial neovascularization, cardiomyocyte survival, and functional recovery after myocardial infarction.
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Although adequate numbers of hematopoietic progenitor cells reside in the human bone marrow, the extent of endogenous neovascularization after myocardial infarction remains insufficient. The aim of this study was to identify the role of the CXC chemokine receptor 4/stromal cell-derived factor 1 axis in the mobilization and homing of hematopoietic progenitor cells in the ischemic heart.</AbstractText>Human bone marrow-derived hematopoietic progenitor cells or saline were injected systemically into athymic nude rats 48 hours after myocardial infarction. Myocardial and bone marrow expression of stromal cell-derived factor 1 and chemotaxis of hematopoietic progenitor cells were measured in vitro in the presence or absence of stromal cell-derived factor 1. The role of the CXC chemokine receptor 4/stromal cell-derived factor 1 axis was investigated by means of antibody blockade or systemic administration of granulocyte colony-stimulating factor. Morphologic analysis included measurement of the infarct area, capillary density, and apoptosis, whereas left ventricular function was measured by means of echocardiographic analysis.</AbstractText>Expression of postinfarct stromal cell-derived factor 1 was increased by 67% in the bone marrow and decreased by 43% in myocardium. Disruption of bone marrow stromal cell-derived factor 1/CXC chemokine receptor 4 interactions by antibody blockade resulted in a redirection of human hematopoietic progenitor cells from the bone marrow to the ischemic heart and augmented neovascularization and cardiomyocyte survival. Similarly, systemic administration of granulocyte colony-stimulating factor to block CXC chemokine receptor 4/stromal cell-derived factor 1 interaction resulted in increased mobilization and homing of hematopoietic progenitor cells to the ischemic heart, which translated to augmented myocardial neovascularization, prevention of apoptosis, and improved cardiac function.</AbstractText>Bone marrow stromal cell-derived factor 1 upregulation after myocardial ischemia prevents mobilization of endogenous hematopoietic progenitor cells. We provide evidence that disruption of stromal cell-derived factor 1/CXC chemokine receptor 4 interactions allows redirection of hematopoietic progenitor cells to ischemic myocardium and enhances recovery of left ventricular function.</AbstractText>Copyright © 2011 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.</CopyrightInformation>
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[Recurrent syncope due to sick sinus syndrome in a patient with myasthenia gravis associated with thymoma].
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We report a 51-year-old man who was admitted to our hospital due to repeated episodes of syncope associated with generalized myasthenic symptoms. Due to myasthenic symptoms with the presence of anti-AchR antoantibody, he was diagnosed as myasthenia gravis (MG) associated with thymoma. However, Holter ECG showed long pause with maximum R-R interval of 3.8 seconds and paroxysmal atrial fibrillation, indicating the diagnosis of sick sinus syndrome. After pace maker implantation and combination therapy with thymomectomy and steroid administration, no arrhythmia in repeated Holter ECG was found. In addition, an anti-kv1.4 antibody was positive in our case. The involvement of cardiomyopathy in patients with MG has been reported, including the association with sudden death. The anti-kv1.4 antibody was recently identified in cases of myasthenia gravis associated with cardiomyositis. After treatments, no arrhythmia was found in our case. Although the cardiomyopathy was not diagnosed in our case because of lacking of histological confirmation, clinical course associated with positive anti-kv1.4 antibody suggested that the cause of syncope might be immune-related cardiomyopathy. To prevent fatal complication of arrhythmia, appropriate examination and therapy against cardiomyopathy associated with myasthenia gravis should be considered.
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2,334,328 |
From syncitium to regulated pump: a cardiac muscle cellular update.
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The primary purpose of this article is to present a basic overview of some key teaching concepts that should be considered for inclusion in an six- to eight-lecture introductory block on the regulation of cardiac performance for graduate students. Within the context of cardiac excitation-contraction coupling, this review incorporates information on Ca(2+) microdomains and local control theory, with particular emphasis on the role of Ca(2+) sparks as a key regulatory component of ventricular myocyte contraction dynamics. Recent information pertaining to local Ca(2+) cycling in sinoatrial nodal cells (SANCs) as a mechanism underlying cardiac automaticity is also presented as part of the recently described coupled-clock pacemaker system. The details of this regulation are emerging; however, the notion that the sequestration and release of Ca(2+) from internal stores in SANCs (similar to that observed in ventricular myocytes) regulates the rhythmic excitation of the heart (i.e., membrane ion channels) is an important advancement in this area. The regulatory role of cardiac adrenergic receptors on cardiac rate and function is also included, and fundamental concepts related to intracellular signaling are discussed. An important point of emphasis is that whole organ cardiac dynamics can be traced back to cellular events regulating intracellular Ca(2+) homeostasis and, as such, provides an important conceptual framework from which students can begin to think about whole organ physiology in health and disease. Greater synchrony of Ca(2+)-regulatory mechanisms between ventricular and pacemaker cells should enhance student comprehension of complex regulatory phenomenon in cardiac muscle.
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2,334,329 |
Cyclic AMP is both a pro-apoptotic and anti-apoptotic second messenger.
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The second messenger cyclic AMP (cAMP) can either stimulate or inhibit programmed cell death (apoptosis). Here, we review examples of cell types that show pro-apoptotic or anti-apoptotic responses to increases in cAMP. We also show that cells can have both such responses, although predominantly having one or the other. Protein kinase A (PKA)-promoted changes in phosphorylation and gene expression can mediate pro-apoptotic responses, such as in murine S49 lymphoma cells, based on evidence that mutants lacking PKA fail to undergo cAMP-promoted, mitochondria-dependent apoptosis. Mechanisms for the anti-apoptotic response to cAMP likely involve Epac (Exchange protein activated by cAMP), a cAMP-regulated effector that is a guanine nucleotide exchange factor (GEF) for the low molecular weight G-protein, Rap1. Therapeutic approaches that activate PKA-mediated pro-apoptosis or block Epac-mediated anti-apoptotisis may provide a means to enhance cell killing, such as in certain cancers. In contrast, efforts to block PKA or stimulate Epac have the potential to be useful in diseases settings (such as heart failure) associated with cAMP-promoted apoptosis.
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2,334,330 |
A randomised controlled trial of the effect of music therapy and verbal relaxation on chemotherapy-induced anxiety.
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To determine the effect of music therapy and verbal relaxation on state anxiety and anxiety-induced physiological manifestations among patients with cancer before and after chemotherapy.</AbstractText>Cancer and its treatment provoke a series of changes in the emotional sphere of the patient's anxiety. Music therapy and verbal relaxation had reported the anxiety reduction effect on patients with cancer receiving chemotherapy. Few studies have been undertaken comparing music therapy and verbal relaxation in differentiating high-normal state anxiety subsample.</AbstractText>A randomised controlled trial and permuted block design were used. Outpatient chemotherapy clinic operated by a University medical centre in southern Taiwan.</AbstractText>Ninety-eight patients were randomised into three groups: the music therapy group received one-hour single music session; the verbal relaxation group received 30 minutes of guided relaxation; the control group received usual care. Spielberger State-Trait Anxiety Instrument, Emotional Visual Analog Scale, three biobehavioural indicators: skin temperature, heart rate and consciousness level were measured during and after chemotherapy.</AbstractText>Music therapy had a greater positive effect on postchemotherapy anxiety than verbal relaxation and control groups and a significantly increase in skin temperature. Patients with high state anxiety receiving music therapy had a greater drop in postchemotherapy anxiety than did the normal state anxiety subsample.</AbstractText>Both music and verbal relaxation therapy are effective in reducing chemotherapy-induced anxiety. Thirty minutes of intervention initiates anxiety reduction. Patients with high state anxiety receiving chemotherapy obtain the most benefit from music or verbal relaxation.</AbstractText>Prior to chemotherapy, patients with high state anxiety must be sorted from all patients as they are more responsive to interventions. Oncology nurses can offer music and verbal relaxation as adjuvant interventions to reduce chemotherapy-induced anxiety and enhance the quality of care.</AbstractText>© 2011 Blackwell Publishing Ltd.</CopyrightInformation>
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2,334,331 |
Regulation of calcium channels and exocytosis in mouse adrenal chromaffin cells by prostaglandin EP3 receptors.
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Prostaglandin (PG) E(2) controls numerous physiological functions through a family of cognate G protein-coupled receptors (EP1-EP4). Targeting specific EP receptors might be therapeutically useful and reduce side effects associated with nonsteroidal anti-inflammatory drugs and selective cyclooxygenase-2 inhibitors that block prostanoid synthesis. Systemic immune challenge and inflammatory cytokines have been shown to increase expression of the synthetic enzymes for PGE(2) in the adrenal gland. Catecholamines and other hormones, released from adrenal chromaffin cells in response to Ca(2+) influx through voltage-gated Ca(2+) channels, play central roles in homeostatic function and the coordinated stress response. However, long-term elevation of circulating catecholamines contributes to the pathogenesis of hypertension and heart failure. Here, we investigated the EP receptor(s) and cellular mechanisms by which PGE(2) might modulate chromaffin cell function. PGE(2) did not alter resting intracellular [Ca(2+)] or the peak amplitude of nicotinic acetylcholine receptor currents, but it did inhibit Ca(V)2 voltage-gated Ca(2+) channel currents (I(Ca)). This inhibition was voltage-dependent and mediated by pertussis toxin-sensitive G proteins, consistent with a direct Gβγ subunit-mediated mechanism common to other G(i/o)-coupled receptors. mRNA for all four EP receptors was detected, but using selective pharmacological tools and EP receptor knockout mice, we demonstrated that EP3 receptors mediate the inhibition of I(Ca). Finally, changes in membrane capacitance showed that Ca(2+)-dependent exocytosis was reduced in parallel with I(Ca). To our knowledge, this is the first study of EP receptor signaling in mouse chromaffin cells and identifies a molecular mechanism for paracrine regulation of neuroendocrine function by PGE(2).
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2,334,332 |
A rare variant in MYH6 is associated with high risk of sick sinus syndrome.
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Through complementary application of SNP genotyping, whole-genome sequencing and imputation in 38,384 Icelanders, we have discovered a previously unidentified sick sinus syndrome susceptibility gene, MYH6, encoding the alpha heavy chain subunit of cardiac myosin. A missense variant in this gene, c.2161C>T, results in the conceptual amino acid substitution p.Arg721Trp, has an allelic frequency of 0.38% in Icelanders and associates with sick sinus syndrome with an odds ratio = 12.53 and P = 1.5 × 10⁻²⁹. We show that the lifetime risk of being diagnosed with sick sinus syndrome is around 6% for non-carriers of c.2161C>T but is approximately 50% for carriers of the c.2161C>T variant.
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2,334,333 |
A2B adenosine receptors inhibit superoxide production from mitochondrial complex I in rabbit cardiomyocytes via a mechanism sensitive to Pertussis toxin.
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A(2B) adenosine receptors protect against ischaemia/reperfusion injury by activating survival kinases including extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase (PI3K). However, the underlying mechanism(s) and signalling pathway(s) remain undefined.</AbstractText>HEK 293 cells stably transfected with human A(2B) adenosine receptors (HEK-A(2B) ) and isolated adult rabbit cardiomyocytes were used to assay phosphorylation of ERK by Western blot and cation flux through cAMP-gated channels by patch clamp methods. Generation of reactive oxygen species (ROS) by mitochondria was measured with a fluorescent dye.</AbstractText>In HEK-A(2B) cells, the selective A(2B) receptor agonist Bay 60-6583 (Bay 60) increased ERK phosphorylation and cAMP levels, detected by current through cAMP-gated ion channels. However, increased cAMP or its downstream target protein kinase A was not involved in ERK phosphorylation. Pertussis toxin (PTX) blocked ERK phosphorylation, suggesting receptor coupling to G(i) or G(o) proteins. Phosphorylation was also blocked by inhibition of PI3K (with wortmannin) or of ERK kinase (MEK1/2, with PD 98059) but not by inhibition of NO synthase (NOS). In cardiomyocytes, Bay 60 did not affect cAMP levels but did block the increased superoxide generation induced by rotenone, a mitochondrial complex I inhibitor. This effect of Bay 60 was inhibited by PD 98059, wortmannin or PTX. Inhibition of NOS blocked superoxide production because NOS is downstream of ERK.</AbstractText>Activation of A(2B) adenosine receptors reduced superoxide generation from mitochondrial complex I through G(i/o) , ERK, PI3K, and NOS, all of which have been implicated in ischaemic preconditioning.</AbstractText>© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.</CopyrightInformation>
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2,334,334 |
Neonatal lupus erythematosus: clinical character, investigation, and outcome.
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Neonatal lupus erythematosus is an uncommon maternal auto-antibody-associated disease characterized by cutaneous, cardiac, hepatic, hematological, neurological, and pulmonary involvement. A retrospective study was performed to review clinical manifestations, investigation results, outcomes of neonatal lupus erythematosus patients and their mothers at the Department of Pediatrics, Siriraj Hospital during 1993 to 2008. Seventeen neonatal lupus erythematosus patients (10 girls and seven boys) were identified. Cutaneous, cardiac, hepatobiliary, and hematological involvement was found in 70.6%, 64.7%, 52.9%, and 35.3% of infants, respectively. Skin lesions were erythematous patches (91.7%), subacute cutaneous lupus erythematosus (50%), petechiae (41.7%), persistent cutis marmorata (16.7%), and discoid lesions (8.3%). Congenital heart block was found in nine cases, and structural abnormalities were found in nine cases. All sera of patients were positive for antinuclear antibodies. Patients (87.5%) showed positive antiRo/SSA, and 50% had positive antiLa/SSB antibodies. Most neonatal lupus erythematosus mothers (64.7%) were asymptomatic. Five mothers were diagnosed with systemic lupus erythematosus, and one mother was diagnosed with mixed connective tissue disease. All maternal sera was positive for antinuclear antibodies and antiRo/SSA antibody. Seven patients required pacemaker implantation. The mortality rate was 11.8%, caused by congestive heart failure and pneumonia. Antinuclear antibody tests should be used as one of the screening tests in mothers or patients suspected of having neonatal lupus erythematosus.
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2,334,335 |
Periosteal nociceptors induced hypotension and bradycardia under spinal anesthesia -A report of two cases-.
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The sudden hemodynamic disturbance in the perioperative period can occur because of various surgical and anesthetic reasons but hemodynamic collapse due to noxious stimulus of periosteum stripping has not been described. We report two cases of severe hypotension and bradycardia during periosteum stripping in orthopedic surgery under subarachnoid block even though the block level was adequate. In our patients, hemodynamic collapse occurred specifically at a moment when surgeons manipulated periosteum and fall in blood pressure and heart rate was sudden in onset. The hemodynamic disturbance did not appear to be related to vagally mediated or due to blockade of sympathetic fibers but appeared to be related to periosteal nociceptors.
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2,334,336 |
The target concentration of remifentanil to suppress the hemodynamic response to endotracheal intubation during inhalational induction with desflurane.
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Anesthesia induction with desflurane is troublesome because of the frequent sympathetic hyperactivity during desflurane administration. We thought that a low concentration of desflurane combined with a target-controlled infusion (TCI) of remifentanil would eliminate the desflurane-related complications and provide hemodynamic stability during desflurane induction. An up-and-down study was planned to find the target effect-site concentration of remifentanil to block the hemodynamic response to endotracheal intubation, the highest level of stimulus, during anesthesia induction with administering desflurane at 1 MAC.</AbstractText>Remifentanil TCI was initiated before desflurane administration. When the preset target was achieved, spontaneous inhalation of desflurane 1 MAC was performed until the patients became unconscious. Laryngoscopic tracheal intubation was facilitated with rocuronium injection. The starting concentration of remifentanil and the test space were 5 and 1 ng/ml, respectively. The criteria for up-and-down was a 20% increase of the mean arterial pressure or heart rate after intubation. The median effective concentration (EC(50)) of remifentanil was calculated from 6 independent pairs. The complications related with remifentanil and desflurane were assessed during the study.</AbstractText>We studied 20 patients using 2-5 ng/ml of the effect-site concentrations of remifentanil. The EC(50) of remifentanil was 3.7 ng/ml. Loss of consciousness was achieved at 125 ± 22 s after desflurane inhalation and this was irrespective of the combined remifentanil concentrations. Any remifentanil-related complication was not observed. Transient cough was seen in one patient who received 2 ng/ml of remifentanil.</AbstractText>We demonstrated that uncomplicated induction with desflurane was possible by the use of target-controlled remifentanil. The EC(50) of remifentanil to block the hemodynamic response to tracheal intubation was 3.7 ng/ml during inhalational induction with 1 MAC desflurane.</AbstractText>
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2,334,337 |
p38 MAPK-dependent small HSP27 and αB-crystallin phosphorylation in regulation of myocardial function following cardioplegic arrest.
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We previously demonstrated that myocardial p38 mitogen-activated protein kinase (MAPK) and heat shock protein 27 (HSP27) are phosphorylated following cardioplegic arrest in patients undergoing cardiac surgery and correlate with reduced cardiac function. The following studies were performed to determine whether inhibition of p38 MAPK and/or overexpression of nonphosphorylatable HSP27 improves cardiac function following cardioplegic arrest. Langendorff-perfused isolated rat hearts were subjected to 2 h of intermittent cold cardioplegia followed by 30 min of reperfusion. Hearts were treated with (CP+SB) or without (CP) the p38 MAPK inhibitor SB-203580 (5 μM) supplied in the cardioplegia. Sham-treated hearts served as controls. In separate experiments, isolated rat ventricular myocytes infected with either green fluorescent protein (GFP) or a nonphosphorylatable HSP27 mutant (3A-HSP27) were subjected to 3 h of cold hypoxic cardioplegia and simulated reperfusion (CP) followed by video microscopy and length change measurements. Baseline parameters of cardiac function were similar between groups [left ventricular developed pressure (LVDP), 119 ± 4.9 mmHg; positive and negative first derivatives of LV pressure (± dP/dt), 3,139 ± 245 and 2, 314 ± 110 mmHg/s]. CP resulted in reduced cardiac function (LVDP, 72.2 ± 5.8 mmHg; ± dP/dt, 2,076 ± 231 and -1,317 ± 156 mmHg/s) compared with baseline. Treatment with 5 μM SB-203580 significantly improved CP-induced cardiac function (LVDP, 101.9 ± 0 mmHg; ± dP/dt, 2,836 ± 163 and -2,108 ± 120 mmHg/s; P = 0.03, 0.01, and 0.04, CP+SB vs. CP). Inhibition of p38 MAPK significantly lowered CP-induced p38 MAPK, HSP27, and αB-crystallin (cryAB) phosphorylation. In vitro CP decreased myocyte length changes from 10.3 ± 1.5% (GFP) to 5.7 ± 0.8% (GFP+CP). Infection with 3A-HSP27 completely rescued CP-induced decreased myocyte contraction (11.1 ± 1.0%). However, infection with 3A-HSP27 did not block the endogenous HSP27 response. We conclude that inhibition of p38 MAPK and subsequent HSP27 and cryAB phosphorylation and/or overexpression of nonphosphorylatable HSP27 significantly improves cardiac performance following cardioplegic arrest. Modulation of HSP27 phosphorylation may improve myocardial stunning following cardiac surgery.
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2,334,338 |
Neuromedin S regulates cardiovascular function through the sympathetic nervous system in mice.
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Intracerebroventricular (icv) injection of neuromedin S (NMS) in mice increased the heart rate in a dose-dependent manner. On the other hand, genetically NMS deficient mice (NMS-KO mice) exhibited a decreased heart rate and significant extension of the QRS and PR interval in the electrocardiogram complex. Although treatment with a parasympathetic nerve blocker, methylscopolamine, and a sympathetic nerve blocker, timolol, respectively increased and decreased the heart rate in both NMS-KO and wild-type mice, the extent of the decrease induced by timolol was smaller in NMS-KO than in wild-type mice. In addition, pretreatment with timolol completely inhibited the NMS-induced heart rate increase in wild-type mice. No expression of mRNA for NMS or the NMS receptor was evident in the heart by RT-PCR analysis. These results suggest that endogenous NMS may regulate cardiovascular function by activating the sympathetic nervous system.
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2,334,339 |
Osteocalcin: an endocrine link between bone and glucose metabolism.
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Impaired glucose metabolism is common and contributes to the risk of diabetes and cardiovascular disease. Deletion of the gene for the osteoblast-derived protein, osteocalcin, leads to insulin resistance in mice, while the addition of osteocalcin increases insulin secretion from β-cells and adiponectin expression in adipocytes. Osteocalcin deficiency in γ-carboxyl groups, undercarboxylated osteocalcin, was found to improve insulin secretion and sensitivity in experiments. Recent studies have examined the relevance of these findings to glucose metabolism and cardiovascular risk in humans. Low total osteocalcin levels are associated with insulin resistance, diabetes and metabolic syndrome in observational studies. New therapeutic approaches to diabetes and heart disease may be anticipated if this bone-derived protein is involved in the regulation of glucose metabolism and cardiovascular risk.</Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Yeap</LastName><ForeName>Bu B</ForeName><Initials>BB</Initials><AffiliationInfo><Affiliation>a School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia and Department of Endocrinology and Diabetes, Level 2, T Block, Fremantle Hospital, Alma Street, Fremantle, Western Australia 6160, Australia. [email protected].</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>Expert Rev Endocrinol Metab</MedlineTA><NlmUniqueID>101278293</NlmUniqueID><ISSNLinking>1744-6651</ISSNLinking></MedlineJournalInfo><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">cardiovascular disease</Keyword><Keyword MajorTopicYN="N">diabetes mellitus</Keyword><Keyword MajorTopicYN="N">insulin resistance</Keyword><Keyword MajorTopicYN="N">metabolic syndrome</Keyword><Keyword MajorTopicYN="N">osteocalcin</Keyword><Keyword MajorTopicYN="N">undercarboxylated osteocalcin</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="entrez"><Year>2018</Year><Month>10</Month><Day>7</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2011</Year><Month>3</Month><Day>1</Day><Hour>0</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2011</Year><Month>3</Month><Day>1</Day><Hour>0</Hour><Minute>1</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">30290445</ArticleId><ArticleId IdType="doi">10.1586/eem.11.7</ArticleId></ArticleIdList></PubmedData></PubmedArticle><PubmedBookArticle><BookDocument><PMID Version="1">21735563</PMID><ArticleIdList><ArticleId IdType="bookaccession">NBK55754</ArticleId></ArticleIdList><Book><Publisher><PublisherName>Agency for Healthcare Research and Quality (US)</PublisherName><PublisherLocation>Rockville (MD)</PublisherLocation></Publisher><BookTitle book="cer27">Oral Diabetes Medications for Adults With Type 2 Diabetes: An Update</BookTitle><PubDate><Year>2011</Year><Month>03</Month></PubDate><AuthorList Type="authors" CompleteYN="Y"><Author ValidYN="Y"><LastName>Bennett</LastName><ForeName>Wendy L</ForeName><Initials>WL</Initials><AffiliationInfo><Affiliation>Johns Hopkins University Evidence-based Practice Center</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Wilson</LastName><ForeName>Lisa M</ForeName><Initials>LM</Initials><AffiliationInfo><Affiliation>Johns Hopkins University Evidence-based Practice Center</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bolen</LastName><ForeName>Shari</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Johns Hopkins University Evidence-based Practice Center</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Maruthur</LastName><ForeName>Nisa</ForeName><Initials>N</Initials><AffiliationInfo><Affiliation>Johns Hopkins University Evidence-based Practice Center</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Singh</LastName><ForeName>Sonal</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Johns Hopkins University Evidence-based Practice Center</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Chatterjee</LastName><ForeName>Ranee</ForeName><Initials>R</Initials><AffiliationInfo><Affiliation>Johns Hopkins University Evidence-based Practice Center</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Marinopoulos</LastName><ForeName>Spyridon S</ForeName><Initials>SS</Initials><AffiliationInfo><Affiliation>Johns Hopkins University Evidence-based Practice Center</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Puhan</LastName><ForeName>Milo A</ForeName><Initials>MA</Initials><AffiliationInfo><Affiliation>Johns Hopkins University Evidence-based Practice Center</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ranasinghe</LastName><ForeName>Padmini</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Johns Hopkins University Evidence-based Practice Center</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Nicholson</LastName><ForeName>Wanda K</ForeName><Initials>WK</Initials><AffiliationInfo><Affiliation>Johns Hopkins University Evidence-based Practice Center</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Block</LastName><ForeName>Lauren</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>Johns Hopkins University Evidence-based Practice Center</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Odelola</LastName><ForeName>Olaide</ForeName><Initials>O</Initials><AffiliationInfo><Affiliation>Johns Hopkins University Evidence-based Practice Center</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Dalal</LastName><ForeName>Deepan S</ForeName><Initials>DS</Initials><AffiliationInfo><Affiliation>Johns Hopkins University Evidence-based Practice Center</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ogbeche</LastName><ForeName>Grace E</ForeName><Initials>GE</Initials><AffiliationInfo><Affiliation>Johns Hopkins University Evidence-based Practice Center</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Chandrasekhar</LastName><ForeName>Aditya</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Johns Hopkins University Evidence-based Practice Center</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hutfless</LastName><ForeName>Susan</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Johns Hopkins University Evidence-based Practice Center</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bass</LastName><ForeName>Eric B</ForeName><Initials>EB</Initials><AffiliationInfo><Affiliation>Johns Hopkins University Evidence-based Practice Center</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Segal</LastName><ForeName>Jodi B</ForeName><Initials>JB</Initials><AffiliationInfo><Affiliation>Johns Hopkins University Evidence-based Practice Center</Affiliation></AffiliationInfo></Author></AuthorList><CollectionTitle book="hscompeffcollect">AHRQ Comparative Effectiveness Reviews</CollectionTitle><Medium>Internet</Medium><ReportNumber>Report No.: 11-EHC038-EF</ReportNumber></Book><Language>eng</Language><PublicationType UI="D016454">Review</PublicationType><Abstract><AbstractText Label="OBJECTIVES">Given the number of medications available for type 2 diabetes mellitus, clinicians and patients need information about their effectiveness and safety to make informed choices. The objective of this review was to summarize the benefits and harms of medications (metformin, second-generation sulfonylureas, thiazolidinediones, meglitinides, dipeptidyl peptidase-4 [DPP-4] inhibitors, and glucagon-like peptide-1 [GLP-1] receptor agonists), as monotherapy and in combination, for the treatment of adults with type 2 diabetes.<AbstractText Label="DATA SOURCES">We searched the MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases from inception through April 2010 for original English-language articles and sought unpublished data from the Food and Drug Administration and others.<AbstractText Label="REVIEW METHODS">Two reviewers independently screened titles to identify studies that assessed intermediate outcomes (e.g., hemoglobin A1c [HbA1c]), long-term clinical outcomes (e.g., mortality), and harms (e.g., hypoglycemia) in head-to-head monotherapy or combination therapy comparisons. Two reviewers serially extracted data for each article using standardized protocols, assessed applicability, and independently evaluated study quality.<AbstractText Label="RESULTS" NlmCategory="RESULTS">The review included 140 randomized controlled trials and 26 observational studies. We graded evidence as low or insufficient for long-term clinical outcomes of all-cause mortality, cardiovascular disease, nephropathy, and neuropathy. Most medications lowered HbA1c on average by 1 absolute percentage point, but metformin was more efficacious than the DPP-4 inhibitors. Two-drug combinations had similar HbA1c reduction. Compared with metformin, thiazolidinediones and sulfonylureas had a more unfavorable effect on weight (mean difference of +2.6 kg). Metformin decreased low density lipoprotein cholesterol relative to pioglitazone, sulfonylureas, and DPP-4 inhibitors. Sulfonylureas had a fourfold higher risk of mild/moderate hypoglycemia compared with metformin alone, and, in combination with metformin, had more than a fivefold increased risk compared with metformin plus thiazolidinediones. Thiazolidinediones had an increased risk of congestive heart failure relative to sulfonylureas and bone fractures relative to metformin. Diarrhea occurred more often for metformin compared with thiazolidinedione users.<AbstractText Label="CONCLUSIONS" NlmCategory="CONCLUSIONS">Comprehensive information comparing benefits and harms of diabetes medications can facilitate personalized treatment choices for patients. Although the long-term benefits and harms of diabetes medications remain unclear, the evidence supports use of metformin as a first-line agent. Comparisons of two-drug combinations showed little to no difference in HbA1c reduction, but some combinations increased risk for hypoglycemia and other adverse events.
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A review of Healthways' Medicare Health Support program and final results for two cohorts.
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Chronic care management programs have been shown to offer a scalable approach for improving health and reducing health care costs in commercially insured populations. Medicare Health Support (MHS) was a government-sponsored program designed to determine whether that success could be translated to a Medicare fee-for-service population with complex chronic diseases. The purpose of this article is to provide an overview of MHS and its Phase I study design, and to review the officially reported outcomes of the arm of the study in which Healthways, Inc. provided program services. MHS employed a block randomized design; consent was requested after randomization and evaluation included all eligible individuals, irrespective of that consent. Healthways accepted 2 study cohorts. The first cohort included beneficiaries with diabetes and/or heart failure (Intervention, N=19,936; Control, N=9995) for a 3-year study period. The second cohort entered after 1 year and included beneficiaries with heart failure, with or without diabetes (Intervention, N=4238; Control, N=2106). Comparisons of total health care spending between the Intervention and Control groups found gross savings of $3.8 and $5.7 million for the first and second Intervention cohorts, respectively, and these savings exceeded program costs for the second cohort. Improvements in evaluated clinical measures were demonstrated in the first Intervention cohort, and overall program satisfaction was 94%. Clinical measures and satisfaction were not evaluated for the second cohort. These results indicate that Healthways successfully adapted its commercial chronic care management program for a Medicare fee-for-service population and achieved high satisfaction, improved clinical measures, and financial savings.
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2,334,341 |
Ionic mechanisms of electrophysiological properties and repolarization abnormalities in rabbit Purkinje fibers.
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Purkinje cells play an important role in drug-induced arrhythmogenesis and are widely used in preclinical drug safety assessments. Repolarization abnormalities such as action potential (AP) prolongation and early afterdeploarizations (EAD) are often observed in vitro upon pharmacological interventions. However, because drugs do not act on only one defined target, it is often difficult to fully explain the mechanisms of action and their potential arrhythmogenicity. Computational models, when appropriately detailed and validated, can be used to gain mechanistic insights into the mechanisms of action of certain drugs. Nevertheless, no model of Purkinje electrophysiology that is able to reproduce characteristic Purkinje responses to drug-induced changes in ionic current conductances such as AP prolongation and EAD generation currently exists. In this study, a novel biophysically detailed model of rabbit Purkinje electrophysiology was developed by integration of data from voltage-clamp and AP experimental recordings. Upon validation, we demonstrate that the model reproduces many key electrophysiological properties of rabbit Purkinje cells. These include: AP morphology and duration, both input resistance and rate dependence properties as well as response to hyperkalemia. Pharmacological interventions such as inward rectifier K(+) current and rapid delayed rectifier K(+) current block as well as late Na(+) current increase result in significant AP changes. However, enhanced L-type Ca(2+) current (i(CaL)) dominates in EAD genesis in Purkinje fibers. In addition, i(CaL) inactivation dynamics and intercellular coupling in tissue strongly modulate EAD formation. We conclude that EAD generation in Purkinje cells is mediated by an increase in i(CaL) and modulated by its inactivation kinetics.
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2,334,342 |
Cardiopulmonary arrest in spinal anesthesia.
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Spinal anesthesia is an integral part of the daily routine of countless anesthesiologists. It is considered to be a safe procedure, although some complications related to this technique, among them the most feared is cardiopulmonary arrest (cardiac arrest, CA), do exist. The real incidence of CA related to spinal anesthesia, as well as its etiology, is not known and has motivated this review article.</AbstractText>Articles published in the last twenty years in Medline indexed journals and in a textbook were reviewed. The objective of the present review was to identify the incidence of spinal block anesthesia-related CA and the etiology of those cases. We also tried to identify possible risk factors. Finally, treatment strategies described in the literature were reviewed in order to determine the best conduct when facing a case of CA during spinal anesthesia.</AbstractText>The incidence of spinal anesthesia-related CA varies, and it seems to be lower when compared to that of general anesthesia. In the past, it was believed that CA was due to hypoxemia related especially to excessive sedation. However, nowadays, it is known that the etiology of CA during spinal block anesthesia is related to cardiocirculatory factors, mainly a reduction of preload resulting from sympathetic blockade. Other factors that increase the risk of developing CA also exist. Among those factors, the following should be mentioned: changes in patient positioning and hypovolemia. It is very important to institute treatment as soon as possible. Besides a vagolytic agent, early use of a sympathomimetic drug, especially adrenaline, is also recommended to minimize damage to the patient.</AbstractText>Copyright © 2011 Elsevier Editora Ltda. All rights reserved.</CopyrightInformation>
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PDGF-induced vascular smooth muscle cell proliferation is associated with dysregulation of insulin receptor substrates.
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In vascular smooth muscle cells (VSMCs), platelet-derived growth factor (PDGF) plays a major role in inducing phenotypic switching from contractile to proliferative state. Importantly, VSMC phenotypic switching is also determined by the phosphorylation state/expression levels of insulin receptor substrate (IRS), an intermediary signaling component that is shared by insulin and IGF-I. To date, the roles of PDGF-induced key proliferative signaling components including Akt, p70S6kinase, and ERK1/2 on the serine phosphorylation/expression of IRS-1 and IRS-2 isoforms remain unclear in VSMCs. We hypothesize that PDGF-induced VSMC proliferation is associated with dysregulation of insulin receptor substrates. Using human aortic VSMCs, we demonstrate that prolonged PDGF treatment led to sustained increases in the phosphorylation of protein kinases such as Akt, p70S6kinase, and ERK1/2, which mediate VSMC proliferation. In addition, PDGF enhanced IRS-1/IRS-2 serine phosphorylation and downregulated IRS-2 expression in a time- and concentration-dependent manner. Notably, phosphoinositide 3-kinase (PI 3-kinase) inhibitor (PI-103) and mammalian target of rapamycin inhibitor (rapamycin), which abolished PDGF-induced Akt and p70S6kinase phosphorylation, respectively, blocked PDGF-induced IRS-1 serine phosphorylation and IRS-2 downregulation. In contrast, MEK1/ERK inhibitor (U0126) failed to block PDGF-induced IRS-1 serine phosphorylation and IRS-2 downregulation. PDGF-induced IRS-2 downregulation was prevented by lactacystin, an inhibitor of proteasomal degradation. Functionally, PDGF-mediated IRS-1/IRS-2 dysregulation resulted in the attenuation of insulin-induced IRS-1/IRS-2-associated PI 3-kinase activity. Pharmacological inhibition of PDGF receptor tyrosine kinase with imatinib prevented IRS-1/IRS-2 dysregulation and restored insulin receptor signaling. In conclusion, strategies to inhibit PDGF receptors would not only inhibit neointimal growth but may provide new therapeutic options to prevent dysregulated insulin receptor signaling in VSMCs in nondiabetic and diabetic states.
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2,334,344 |
Protein kinase C-independent inhibition of arterial smooth muscle K(+) channels by a diacylglycerol analogue.
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Analogues of the endogenous diacylglycerols have been used extensively as pharmacological activators of protein kinase C (PKC). Several reports show that some of these compounds have additional effects that are independent of PKC activation, including direct block of K(+) and Ca(2+) channels. We investigated whether dioctanoyl-sn-glycerol (DiC8), a commonly used diacylglycerol analogue, blocks K(+) currents of rat mesenteric arterial smooth muscle in a PKC-independent manner.</AbstractText>Conventional whole-cell and inside-out patch clamp was used to measure the inhibition of K(+) currents of rat isolated mesenteric smooth muscle cells by DiC8 in the absence and presence of PKC inhibitor peptide.</AbstractText>Mesenteric artery smooth muscle K(v) currents inactivated very slowly with a time constant of about 2 s following pulses from -65 to +40 mV. Application of 1 µM DiC8 produced an approximate 40-fold increase in the apparent rate of inactivation. Pretreatment of the cells with PKC inhibitor peptide had a minimal effect on the action of DiC8, and substantial inactivation still occurred, indicating that this effect was mainly independent of PKC. We also found that DiC8 blocked BK and K(ATP) currents, and again a significant proportion of these blocks occurred independently of PKC activation.</AbstractText>These results show that DiC8 has a direct effect on arterial smooth muscle K(+) channels, and this precludes its use as a PKC activator when investigating PKC-mediated effects on vascular K(+) channels.</AbstractText>© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.</CopyrightInformation>
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Update on modern neuraxial analgesia in labour: a review of the literature of the last 5 years.
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Several strategies and alternative therapies have been used to provide analgesia for labour pain. Over the last few years, a number of improvements have enhanced the efficacy and safety of neuraxial analgesia and ultimately have improved mothers' satisfaction with their birth experience. As labour analgesia is a field of obstetric anaesthesia that is rapidly evolving, this review is an update, from a clinical point of view, of developments over the last 5-7 years. We discuss advantages and controversies related to combined spinal-epidural analgesia, patient controlled epidural analgesia and the integration of computer systems into analgesic modalities. We also review the recent literature on future clinical and research perspectives including ultrasound guided neuraxial block placement, epidural adjuvants and pharmacogenetics. We finally look at the latest work with regards to epidural analgesia and breastfeeding.
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2,334,346 |
The influence of attention and arousal on emotion perception in adults with severe traumatic brain injury.
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Many people with traumatic brain injury (TBI) have poor emotion recognition, with negative emotions more frequently impaired. They can also display abnormal affective responses to emotionally charged material, however, the mechanisms underpinning such deficits are unclear. This study examined whether affective responsivity can be improved by focusing attention and whether responsivity is associated with perception accuracy. Eighteen adults with moderate-to-severe TBI and 18 control participants viewed facial expressions while skin conductance (SCR) and evoked cardiac deceleration (ECD) (used as indices of orientation) and skin conductance levels (SCL) (used as an index of phasic arousal) were monitored. They viewed two blocks of faces (8 angry and 8 happy per block), passively in the first block and with the instruction to identify the emotional expression in the second. No differences between conditions, emotions or groups were found using SCR. Both groups demonstrated increasing ECD for the attend condition relative to the passive condition. For the passive task the control group showed increasing SCL (sensitisation) over trials when viewing angry faces and decreasing SCL (habituation) to happy faces. No differences between emotions were shown for the TBI group who rapidly habituated to both expressions. For the attend task, there was no evidence of habituation for either expression for either the control or TBI participants. Physiological measures did not correlate to accuracy in recognising emotions. The results suggest that increasing attentional demands improves orientation and emotional engagement (arousal) to emotional faces following TBI. However, the relationship to this and emotion perception accuracy remains unclear.
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2,334,347 |
[Pitfalls of anesthesiologic management in paediatric strabismus surgery].
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Strabismus surgery is one of the most common paediatric operation procedures. As associated with congenital syndrome, congenital heart disease and neuromuscular disorder, the anesthesiologic management has to be planned carefully. Considering high incidences of oculocardiac reflex (OCR) and postoperative nausea and vomiting (PONV) anesthesia can be performed to decrease both. Induction of anesthesia with ketamine or midzolam reduces risk of oculocardiac reflex, whereas propofol or remifentanil lead to higher incidences of OCR. A combination anti-emetic therapy from different drug classes is recommend to patients at high risk for nausea and vomiting like patients undergoing strabismus surgery. A combination therapy of ondansetron and dexamethasone lead to a risk reduction of PONV to at least 10 %. Further, the incidence of OCR and PONV is significantly reduced in children receiving peribulbar block on top of general anaesthesia.
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2,334,348 |
Effect of caudal block on sevoflurane requirement for lower limb surgery in children with cerebral palsy.
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Caudal block is a widely used technique for providing perioperative pain management in children. In this randomized double-blinded study, we evaluated the effects of preoperative caudal block on sevoflurane requirements in children with cerebral palsy (CP) undergoing lower limb surgery while bispectral index (BIS) values were maintained between 45 and 55.</AbstractText>52 children undergoing Achilles-tendon lengthening were randomized to receive combined general-caudal anesthesia (caudal group, n = 27) or general anesthesia alone (control group, n = 25). Caudal block was performed with a single dose of 0.7 ml·kg(-1) of 1.0% lidocaine containing epinephrine at 5 μg·ml(-1). The control group received no preoperative caudal block. The endtidal sevoflurane concentrations (ET(sev)) were adjusted every minute to maintain the BIS values between 45 and 55.</AbstractText>The ET(sev) required to maintain the BIS values were not significantly different between the control and caudal groups after induction of anesthesia [2.1 (0.2) vs 2.2 (0.4); P = 0.773]. However, significantly higher ET(sev) was observed in the control group before surgical incision [2.0 (0.2) vs 1.8 (0.3); P = 0.013] and during the first 20 min after surgical incision [2.2 (0.3) vs 1.4 (0.3); P < 0.001]. There was no significant difference in BIS values between the control and caudal groups throughout the study period (P > 0.05). In the caudal group, the caudal block was successful in 25 of 27 (92.6%) patients.</AbstractText>Caudal block effectively reduced sevoflurane requirements by 36% compared to general anesthesia alone in children with CP undergoing lower limb surgery while BIS values were maintained between 45 and 55.</AbstractText>© 2011 Blackwell Publishing Ltd.</CopyrightInformation>
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2,334,349 |
Efficient Calculation of QM/MM Frequencies with the Mobile Block Hessian.
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The calculation of the analytical second derivative matrix (Hessian) is the bottleneck for vibrational analysis in QM/MM systems when an electrostatic embedding scheme is employed. Even with a small number of QM atoms in the system, the presence of MM atoms increases the computational cost dramatically: the long-range Coulomb interactions require that additional coupled perturbed self-consistent field (CPSCF) equations need to be solved for each MM atom displacement. This paper presents an extension to the Mobile Block Hessian (MBH) formalism for QM/MM calculations with blocks in the MM region and its implementation in a parallel version of the Q-Chem/CHARMM interface. MBH reduces both the CPU time and the memory requirements compared to the standard full Hessian QM/MM analysis, without the need to use a cutoff distance for the electrostatic interactions. Special attention is given to the treatment of link atoms which are usually present when the QM/MM border cuts through a covalent bond. Computational efficiency improvements are highlighted using a reduced chorismate mutase enzyme system, consisting of 24 QM atoms and 306 MM atoms, as a test example. In addition, the drug bortezomib, used for cancer treatment of myeloma, has been studied as a test case with multiple MBH block choices and both a QM and QM/MM description. The accuracy of the calculated Hessians is quantified by imposing Eckart constraints, which allows for the assessment of numerical errors in second derivative procedures. The results show that MBH within the QM/MM description not only is a computationally attractive method but also produces accurate results.
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2,334,350 |
A randomized comparison of different doses of intrathecal levobupivacaine combined with fentanyl for elective cesarean section: prospective, double-blinded study.
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Levobupivacaine may produce a sensory and motor block different from that produced by bupivacaine, which is the most popular local anesthetic in parturients undergoing cesarean section. The aim of this study was to investigate the block characteristics, the clinical efficacy, surgeon and patient satisfaction, and hemodynamic effects of using different doses of intrathecal plain levobupivacaine combined with fentanyl.</AbstractText>One hundred twenty women undergoing elective cesarean section with a combined spinal-epidural technique were enrolled. The parturients were randomly assigned to receive one of the following: levobupivacaine 5 mg (group 5), 7.5 mg (group 7.5) or 10 mg (group 10), all combined with fentanyl 25, 15 or 10 μg, respectively.</AbstractText>Anesthesia was effective in 60, 82.5 and 100% of the patients in the levobupivacaine 5, 7.5 and 10 mg groups, respectively. Levobupivacaine 10 mg provided longer durations of analgesia and motor block and greater patient and surgeon satisfaction, although the incidence of hypotension was lower in groups 5 and 7.5 than in group 10 (12.5, 17.5 and 42.5%, respectively). Intraoperative epidural supplementation was higher in group 5 than in group 7.5 (40 and 17.5%, respectively), whereas no patients in group 10 were given an epidural bolus dose.</AbstractText>The incidence of hypotension was higher in the levobupivacaine 10 mg group, even though this group presented more effective anesthesia and greater patient and surgeon satisfaction compared with the levobupivacaine 5 and 7.5 mg groups. As a result, we believe that levobupivacaine 7.5 mg combined with fentanyl 15 μg is suitable for combined spinal-epidural anesthesia in elective cesarean section.</AbstractText>
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2,334,351 |
Prevention of metastasis in a 4T1 murine breast cancer model by doxorubicin carried by folate conjugated pH sensitive polymeric micelles.
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This study primarily focused on the anti-metastatic activity of doxorubicin (DOX) loaded in a pH-sensitive mixed polymeric micelle formed from two block polymers: poly(L-lactide) (PLLA) (Mn 3000)-b-poly(ethylene glycol) (PEG) (Mn 2000)-folate and poly(L-histidine) (PHis) (Mn 4700)-b-PEG (Mn 2000). Tumor formation and metastasis in mice were examined using a murine mammary carcinoma cell of 4T1 which is one of the most aggressive metastatic cancer cell lines. The efficacy was evaluated by tumor size, body weight change, survival rate, dorsal skin fold window chamber model, and histological observation of the lung, heart, liver and spleen after treatment with various DOX formulations. When the tumor reached 50-100 mm³ in size, the mice were treated 4 times at a 3-day interval at a dose of 10 mg DOX/kg. The mixed micelle formulation resulted in retarded tumor growth, no weight loss, and no death for 4-5 weeks. In another set of the in vivo test for histological evaluation of the organs, the mice were similarly treated but the formulations were injected one day after 4T1 cell inoculation. The treatment by DOX loaded mixed micelle showed no apparent metastasis till 28 days. However, significant metastasis to the lung and heart was observed on Day 28 when the mice were treated with DOX carried by PBS, PLLA-b-PEG micelle and PHis-b-PEG micelle.
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2,334,352 |
Transient receptor potential genes and human inherited disease.
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Transient receptor potential (TRP) genes have been implicated in a wide array of human disorders, from cancers to bipolar disorder. The extraordinary range of diseases in whose pathogenesis they may play a role exemplifies the equally broad range of functions of the TRP proteins. TRP proteins primarily form homomeric or heteromeric channels in the cell membrane but there may also be intracellular non-channel functions for TRPs. Mutations in TRP genes have been causally associated with at least 12 hereditary human diseases. This chapter aims to summarise those associations and focuses on the following diseases: focal segmental glomerulosclerosis; polycystic kidney disease; brachyolmia; spondylometaphyseal dysplasia; metatropic dysplasia; hereditary motor and sensory neuropathy; spinal muscular atrophy; congenital stationary night blindness; progressive familial heart block; hypomagnesaemia; and mucolipidosis. There appears to be very little to connect these disorders except the involvement of a TRP gene but by understanding more about the genes involved in diseases, we understand more about disease biology and about the function of those genes causally associated. This feedback loop of information will serve to enhance our knowledge of disease and elucidate basic gene and protein function of the TRPs.
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2,334,353 |
A prospective, multicentre, observational cohort study of analgesia and outcome after pneumonectomy.
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Meta-analysis and systematic reviews of epidural compared with paravertebral blockade analgesia techniques for thoracotomy conclude that although the analgesia is comparable, paravertebral blockade has a better short-term side-effect profile. However, reduction in major complications including mortality has not been proven.</AbstractText>The UK pneumonectomy study was a prospective observational cohort study in which all UK thoracic surgical centres were invited to participate. Data presented here relate to the mode of analgesia and outcome. Data were analysed for 312 patients having pneumonectomy at 24 UK thoracic surgical centres in 2005. The primary endpoint was a major complication.</AbstractText>The most common type of analgesia used was epidural (61.1%) followed by paravertebral infusion (31%). Epidural catheter use was associated with major complications (odds ratio 2.2, 95% confidence interval 1.1-3.8; P=0.02) by stepwise logistic regression analysis.</AbstractText>An increased incidence of clinically important major post-pneumonectomy complications was associated with thoracic epidural compared with paravertebral blockade analgesia. However, this study is unable to provide robust evidence to change clinical practice for a better clinical outcome. A large multicentre randomized controlled trial is now needed to compare the efficacy, complications, and cost-effectiveness of epidural and paravertebral blockade analgesia after major lung resection with the primary outcome of clinically important major morbidity.</AbstractText>
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2,334,354 |
Ischemic preconditioning requires opening of pannexin-1/P2X(7) channels not only during preconditioning but again after index ischemia at full reperfusion.
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Protection of the ex vivo rat heart from ischemia/reperfusion injury can be provided by ischemic preconditioning (IPC). Previous studies revealed that a complex of pannexin-1 with the P2X₇ receptor forms a channel during IPC that results in the release of cardioprotectants such as adenosine and sphingosine 1-phosphate (S1P) that bind to G-protein-coupled cell surface receptors triggering cardioprotective cell signaling pathways. Antagonists of both pannexin-1 (carbenoxolone and mefloquine) and P2X₇ receptors (brilliant blue G) are known to block IPC when administered at the time of preconditioning (Vessey et al. J Cardiovasc Pharmacol Ther 15:190, 2010). We now demonstrate that these same antagonists also block the cardioprotective effects of IPC when added after the index ischemia during full reperfusion. Likewise, addition at full reperfusion of binding antagonists to the endogenous cardioprotectants S1P (VPC) or adenosine (8-SPT) reduced the effectiveness of IPC. These data suggest that IPC has a component that requires the release of cardioprotectants via pannexin-1/P2X₇ channels not only during preconditioning phase but again during the early stages of reperfusion following the index ischemia. It was found that the level of cardioprotectant release required at reperfusion to achieve cardioprotection was lower when hearts had been preconditioned. Further, pharmacologic preconditioning with S1P or adenosine was also blocked at reperfusion by antagonists of the pannexin-1/P2X₇ channels indicating that pharmacologic preconditioning also requires opening of the channel at full reperfusion. In untreated hearts, key components of the PI3 kinase/Akt signaling pathway were revealed by western analysis to be lost during ischemia. This correlates with an inability to generate phospho-Akt at reperfusion. IPC prevents this loss and thereby primes the cell for response to cardioprotectants released at full reperfusion.
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2,334,355 |
Targeting inflammation in heart failure with histone deacetylase inhibitors.
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Cardiovascular insults such as myocardial infarction and chronic hypertension can trigger the heart to undergo a remodeling process characterized by myocyte hypertrophy, myocyte death and fibrosis, often resulting in impaired cardiac function and heart failure. Pathological cardiac remodeling is associated with inflammation, and therapeutic approaches targeting inflammatory cascades have shown promise in patients with heart failure. Small molecule histone deacetylase (HDAC) inhibitors block adverse cardiac remodeling in animal models, suggesting unforeseen potential for this class of compounds for the treatment of heart failure. In addition to their beneficial effects on myocardial cells, HDAC inhibitors have potent antiinflammatory actions. This review highlights the roles of HDACs in the heart and the potential for using HDAC inhibitors as broad-based immunomodulators for the treatment of human heart failure.
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2,334,356 |
Biomarkers of myocardial stress and systemic inflammation in patients who engage in heart failure self-care management.
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Self-care is believed to improve heart failure (HF) outcomes, but the mechanisms by which such improvement occurs remain unclear.</AbstractText>We completed a secondary analysis of cross-sectional data collected on adults with symptomatic HF to test our hypothesis that effective self-care is associated with less myocardial stress and systemic inflammation. Multivariate logistic regression modeling was used to determine if better HF self-care reduced the odds of having serum levels of amino-terminal pro-B-type natriuretic peptide and soluble tumor necrosis factor α receptor type 1 at or greater than the sample median. Heart failure self-care was measured using the Self-care of Heart Failure Index.</AbstractText>The sample (n=168) was predominantly male (65.5%), and most (50.6%) had New York Heart Association III HF (mean left ventricular ejection fraction, 34.9% [SD, 14.0%]); mean age was 58.8 (SD, 11.5) years. Self-care management was an independent factor in the model (block χ=14.74; P=.005) after controlling for pertinent confounders (model χ=52.15; P<.001). Each 1-point increase in self-care management score (range, 15-100) was associated with a 12.7% reduction in the odds of having levels of both biomarkers at or greater than the sample median (adjusted odds ratio, 0.873; 95% confidence interval, 0.77-0.99; P=.03).</AbstractText>Better self-care management was associated with reduced odds of myocardial stress and systemic inflammation over and above pharmacological therapy and other common confounding factors. Teaching HF patients early symptom recognition and self-care of symptoms may decrease myocardial stress and systemic inflammation.</AbstractText>Copyright © 2011 Lippincott Williams & Wilkins.</CopyrightInformation>
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2,334,357 |
Cardiac safety in cluster headache patients using the very high dose of verapamil (≥720 mg/day).
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Use of high doses of verapamil in preventive treatment of cluster headache (CH) is limited by cardiac toxicity. We systematically assess the cardiac safety of the very high dose of verapamil (verapamil VHD) in CH patients. Our work was a study performed in two French headache centers (Marseilles-Nice) from 12/2005 to 12/2008. CH patients treated with verapamil VHD (≥720 mg) were considered with a systematic electrocardiogram (EKG) monitoring. Among 200 CH patients, 29 (14.8%) used verapamil VHD (877±227 mg/day). Incidence of EKG changes was 38% (11/29). Seven (24%) patients presented bradycardia considered as nonserious adverse event (NSAE) and four (14%) patients presented arrhythmia (heart block) considered as serious adverse event (SAE). Patients with EKG changes (1,003±295 mg/day) were taking higher doses than those without EKG changes (800±143 mg/day), but doses were similar in patients with SAE (990±316 mg/day) and those with NSAE (1,011±309 mg/day). Around three-quarters (8/11) of patients presented a delayed-onset cardiac adverse event (delay ≥2 years). Our work confirms the need for systematic EKG monitoring in CH patients treated with verapamil. Such cardiac safety assessment must be continued even for patients using VHD without any adverse event for a long time.
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2,334,358 |
Androgen stimulates endothelial cell proliferation via an androgen receptor/VEGF/cyclin A-mediated mechanism.
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Growing evidences support that androgen displays beneficial effects on cardiovascular functions although the mechanism of androgen actions remains to be elucidated. Modulation of endothelial cell growth and function is a potential mechanism of androgen actions. We demonstrated in the present study that androgens [dihydrotestosterone (DHT) and testosterone], but not 17β-estradiol, produced a time- and dose-dependent induction of cell proliferation in primary human aortic endothelial cells (HAECs) as evident by increases in viable cell number and DNA biosynthesis. Real-time qRT-PCR analysis showed that DHT induced androgen receptor (AR), cyclin A, cyclin D1, and vascular endothelial growth factor (VEGF) gene expression in a dose- and time-dependent manner. The addition of casodex, a specific AR antagonist, or transfection of a specific AR siRNA blocked DHT-induced cell proliferation and target gene expression, indicating that the DHT effects are mediated via AR. Moreover, coadministration of SU5416 to block VEGF receptors, or transfection of a specific VEGF-A siRNA to knockdown VEGF expression, produced a dose-dependent blockade of DHT induction of cell proliferation and cyclin A gene expression. Interestingly, roscovitine, a selective cyclin-dependent kinase inhibitor, also blocked the DHT stimulation of cell proliferation with a selective inhibition of DHT-induced VEGF-A expression. These results indicate that androgens acting on AR stimulate cell proliferation through upregulation of VEGF-A, cyclin A, and cyclin D1 in HAECs, which may be beneficial to cardiovascular functions since endothelial cell proliferation could assist the repair of endothelial injury/damage in cardiovascular system.
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2,334,359 |
[Application of laryngeal mask airway anaesthesia combined with sacral canal block in pediatric anaesthesia].
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To compare the advantages and disadvantages between laryngeal mask airway anaesthesia combined with sacral canal block and single tracheal tube anaesthesia in pediatric surgery.</AbstractText>Sixty 2-12-year-old children for lower limb or lower abdominal surgery were randomly assigned into two groups: a group that was given laryngeal mask airway anaesthesia combined with sacral canal block and a group was given single tracheal tube anaesthesia (n=30 each). Mean arterial pressure (MAP), SpO₂ and heart rate (HR) were recorded before induction of anaesthesia, before and after insertion of laryngeal mask airway (LMA) or tracheal tube (TT) and after removal of LMA or TT. The waking-up time, VAS pain scores and the frequency of mania were recorded after surgery.</AbstractText>There were no significant differences in MAP, SpO₂ and HR between the combined and single anaesthesia groups before anaesthesia and insertion of LMA or TT, while the MAP and HR in the combined anaesthesia group were significantly lower than those in the single anaesthesia group after insertion and removal of LMA or TT (P<0.05). The VAS pain scores were significantly lower and the waking-up time was significantly shorter in the combined anaesthesia group than those in the single anaesthesia group (P<0.05) after surgery. The frequency of mania after surgery in the combined anaesthesia group was significantly lower than that in the single anaesthesia group (P<0.05).</AbstractText>The hemodynamics is more stable in children during the induction and the waking-time of laryngeal mask anesthesia combined with sacral canal block. The anesthesia may relieve postoperative pain, shorten the waking-up time and decrease the frequency of mania.</AbstractText>
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2,334,360 |
A multiscale simulation system for the prediction of drug-induced cardiotoxicity.
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The preclinical assessment of drug-induced ventricular arrhythmia, a major concern for regulators, is typically based on experimental or computational models focused on the potassium channel hERG (human ether-a-go-go-related gene, K(v)11.1). Even if the role of this ion channel in the ventricular repolarization is of critical importance, the complexity of the events involved make the cardiac safety assessment based only on hERG has a high risk of producing either false positive or negative results. We introduce a multiscale simulation system aiming to produce a better cardiotoxicity assessment. At the molecular scale, the proposed system uses a combination of docking simulations on two potassium channels, hERG and KCNQ1, plus three-dimensional quantitative structure-activity relationship modeling for predicting how the tested compound will block the potassium currents IK(r) and IK(s). The obtained results have been introduced in electrophysiological models of the cardiomyocytes and the ventricular tissue, allowing the direct prediction of the drug effects on electrocardiogram simulations. The usefulness of the whole method is illustrated by predicting the cardiotoxic effect of several compounds, including some examples in which classic hERG-based models produce false positive or negative results, yielding correct predictions for all of them. These results can be considered a proof of concept, suggesting that multiscale prediction systems can be suitable for being used for preliminary screening in lead discovery, before the compound is physically available, or in early preclinical development when they can be fed with experimentally obtained data.
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2,334,361 |
Using an agent-based model to analyze the dynamic communication network of the immune response.
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The immune system behaves like a complex, dynamic network with interacting elements including leukocytes, cytokines, and chemokines. While the immune system is broadly distributed, leukocytes must communicate effectively to respond to a pathological challenge. The Basic Immune Simulator 2010 contains agents representing leukocytes and tissue cells, signals representing cytokines, chemokines, and pathogens, and virtual spaces representing organ tissue, lymphoid tissue, and blood. Agents interact dynamically in the compartments in response to infection of the virtual tissue. Agent behavior is imposed by logical rules derived from the scientific literature. The model captured the agent-to-agent contact history, and from this the network topology and the interactions resulting in successful versus failed viral clearance were identified. This model served to integrate existing knowledge and allowed us to examine the immune response from a novel perspective directed at exploiting complex dynamics, ultimately for the design of therapeutic interventions.</AbstractText>Analyzing the evolution of agent-agent interactions at incremental time points from identical initial conditions revealed novel features of immune communication associated with successful and failed outcomes. There were fewer contacts between agents for simulations ending in viral elimination (win) versus persistent infection (loss), due to the removal of infected agents. However, early cellular interactions preceded successful clearance of infection. Specifically, more Dendritic Agent interactions with TCell and BCell Agents, and more BCell Agent interactions with TCell Agents early in the simulation were associated with the immune win outcome. The Dendritic Agents greatly influenced the outcome, confirming them as hub agents of the immune network. In addition, unexpectedly high frequencies of Dendritic Agent-self interactions occurred in the lymphoid compartment late in the loss outcomes.</AbstractText>An agent-based model capturing several key aspects of complex system dynamics was used to study the emergent properties of the immune response to viral infection. Specific patterns of interactions between leukocyte agents occurring early in the response significantly improved outcome. More interactions at later stages correlated with persistent inflammation and infection. These simulation experiments highlight the importance of commonly overlooked aspects of the immune response and provide insight into these processes at a resolution level exceeding the capabilities of current laboratory technologies.</AbstractText>
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2,334,362 |
Histamine release associated with intravenous delivery of a fluorocarbon-based sevoflurane emulsion in canines.
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The purpose of this study was to evaluate the effectiveness of a novel fluorocarbon-based sevoflurane emulsion in dogs previously shown to produce short-term rodent anesthesia. On the basis of an unexpected allergic-type clinical reaction, we also tested the hypothesis that this type of formulation causes histamine release and complement activation. Physiological parameters, plasma histamine levels (radioimmunoassay), and complement activation (enzyme immunoassay) were quantified in response to emulsion components, including F13M5 (the emulsion's fluorocarbon-based polymer) and methoxy poly(ethylene glycol) 5000 (the polymer's hydrophilic block). Although the emulsion produced general anesthesia in dogs, they also experienced hypotension and clinical signs suggestive of an allergic-like response (i.e., vasodilation, urticaria, and pruritus upon recovery). Emulsions lacking sevoflurane failed to induce anesthesia but did elicit the allergic response. Plasma histamine levels were significantly increased following injection of micellar solutions of F13M5. Direct complement activation by the emulsion or its components was weak or absent. An allergic response leading to histamine release, likely initiated by the F13M5 component via an immunoglobulin pathway, is associated with an intravenous fluorocarbon-based emulsion of sevoflurane. Subsequently, its usefulness in medicine in its present formulation is limited.
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2,334,363 |
Vascular hyperpolarization to β-adrenoceptor agonists evokes spreading dilatation in rat isolated mesenteric arteries.
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β-Adrenoceptor stimulation causes pronounced vasodilatation associated with smooth muscle hyperpolarization. Although the hyperpolarization is known to reflect K(ATP) channel activation, it is not known to what extent it contributes to vasodilatation.</AbstractText>Smooth muscle membrane potential and tension were measured simultaneously in small mesenteric arteries in a wire myograph. The spread of vasodilatation over distance was assessed in pressurized arteries following localized intraluminal perfusion of either isoprenaline, adrenaline or noradrenaline.</AbstractText>Isoprenaline stimulated rapid smooth muscle relaxation associated at higher concentrations with robust hyperpolarization. Noradrenaline or adrenaline evoked a similar hyperpolarization to isoprenaline if the α(1)-adrenoceptor antagonist prazosin was present. With each agonist, glibenclamide blocked hyperpolarization without reducing relaxation. Focal, intraluminal application of isoprenaline, noradrenaline or adrenaline during block of α(1)-adrenoceptors evoked a dilatation that spread along the entire length of the isolated artery. This response was endothelium-dependent and inhibited by glibenclamide.</AbstractText>Hyperpolarization is not essential for β-adrenoceptor-mediated vasodilatation. However, following focal β-adrenoceptor stimulation, this hyperpolarization underlies the ability of vasodilatation to spread along the artery wall. The consequent spread of vasodilatation is dependent upon the endothelium and likely to be of physiological relevance in the coordination of tissue blood flow.</AbstractText>© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.</CopyrightInformation>
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2,334,364 |
Knocking out angiotensin II in the heart.
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Despite ongoing medical advances, cardiovascular disease continues to be a leading health concern. The renin-angiotensin system (RAS) plays an important role in regulating cardiovascular function, and is, therefore, the subject of extensive study. Several drugs currently used to treat hypertension and heart failure are designed to target angiotensin II synthesis and function, but thus far, none have been able to completely block the effects of RAS signaling. This review discusses current and emerging approaches towards inhibiting cardiac RAS function in order to further improve cardiovascular disease outcomes.
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2,334,365 |
Pharmacological activity of novel 2-hydroxyacetophenone isatin derivatives on cardiac and vascular smooth muscles in rats.
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Isatin (1H-indole-2,3 dione) is an endogenous compound with biological activities. Many of its derivatives have pharmacological effects, including inhibition of cyclic guanosine monophosphate levels in cardiac tissue; sedative-hypnotic profiles; anticonvulsant, analgesic, antithermic, and anti-inflammatory activities; and anxiolytic, antimicrobial, and proapoptotic effects. Carbamates derived from isatin have a vasorelaxant profile. This study investigated the activity of 2 novel 2-hydroxyacetophenone derivatives of isatin (named MB101 and MB130) on the contractility of rat aorta and papillary muscles. Both compounds induced a concentration-dependent relaxation (5-100 μM) in the endothelium-intact aorta that was abolished by N-nitro-L-arginine methyl ester. Atropine, a muscarinic receptor antagonist, significantly prevented vasodilatation of 100 μM MB101. In contrast, atropine caused no significant alteration in MB130-induced vasorelaxation. Naloxone, a nonselective opioid receptor antagonist, completely prevented the relaxing effect of MB101 and MB130 at all concentrations. In papillary muscles, only MB130 induced a significant depression, and this contractile response was not altered by propranolol and atropine. Both the compounds reduced systolic and diastolic pressures in a dose-dependent manner in anesthetized rats. The 2-hydroxyacetophenones produced direct effects on vascular tonus through either muscarinic or opioid pathways. MB130 produced cardiac depression by opioid receptors and bradykinin because pretreatment HOE140 or with naloxone, an antagonist of type-2, bradykinin were able to partially block the decrease in twitch amplitude in papillary muscles induced by MB130. These findings provide information for designing new strategies for the treatment of cardiovascular disorders.
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2,334,366 |
Reversal of rocuronium-induced neuromuscular block by sugammadex is independent of renal perfusion in anesthetized cats.
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Sugammadex is a selective relaxant binding agent designed to encapsulate the aminosteroidal neuromuscular blocking agent rocuronium, thereby reversing its effect. Both sugammadex and the sugammadex-rocuronium complex are eliminated by the kidneys. This study investigated the effect of sugammadex on recovery of rocuronium-induced neuromuscular block in cats with clamped renal pedicles, as a model for acute renal failure.</AbstractText>Twelve male cats were divided into two groups and anesthetized with medetomidine, ketamine, and alpha-chloralose. The cats were intubated and ventilated with a mixture of oxygen and air. Neuromuscular monitoring was performed by single twitch monitoring. Rocuronium 0.5 mg/kg i.v. was administered. After spontaneous recovery from neuromuscular block, both renal pedicles were ligated. A second dose of rocuronium 0.5 mg/kg i.v. was given. One minute after disappearance of the twitches, in Group 1 placebo (0.9% saline) and in Group 2 sugammadex 5.0 mg/kg i.v. was administered. Onset time, duration of neuromuscular block, and time to recovery to 25, 50, 75, and 90% were determined.</AbstractText>After renal pedicle ligation, sugammadex reversed rocuronium-induced neuromuscular block significantly faster than spontaneous recovery. Mean time (SEM) to 90% recovery of the twitch response was 4.7 (0.25) min (Group 2) versus 31.1 (5.0) min (Group 1) (p < 0.0001). No signs of recurrence of neuromuscular block were observed for 90 min after complete twitch restoration. Sugammadex caused no significant cardiovascular effects.</AbstractText>Sugammadex rapidly and effectively reversed rocuronium-induced neuromuscular block in anesthetized cats, even when both renal pedicles were ligated and renal elimination of the drugs was no longer possible.</AbstractText>
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2,334,367 |
Cyclic adenosine diphosphate ribose activates ryanodine receptors, whereas NAADP activates two-pore domain channels.
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The mechanism by which cyclic adenosine diphosphate ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP) mobilize intracellular Ca(2+) stores remains controversial. It is open to question whether cADPR regulates ryanodine receptors (RyRs) directly, as originally proposed, or indirectly by promoting Ca(2+) uptake into the sarco/endoplasmic reticulum by sarco/endoplasmic reticulum Ca(2+)-ATPases. Conversely, although we have proposed that NAADP mobilizes endolysosomal Ca(2+) stores by activating two-pore domain channels (TPCs), others suggest that NAADP directly activates RyRs. We therefore assessed Ca(2+) signals evoked by intracellular dialysis from a patch pipette of cADPR and NAADP into HEK293 cells that stably overexpress either TPC1, TPC2, RyR1, or RyR3. No change in intracellular Ca(2+) concentration was triggered by cADPR in either wild-type HEK293 cells (which are devoid of RyRs) or in cells that stably overexpress TPC1 and TPC2, respectively. By contrast, a marked Ca(2+) transient was triggered by cADPR in HEK293 cells that stably expressed RyR1 and RyR3. The Ca(2+) transient was abolished following depletion of endoplasmic reticulum stores by thapsigargin and block of RyRs by dantrolene but not following depletion of acidic Ca(2+) stores by bafilomycin. By contrast, NAADP failed to evoke a Ca(2+) transient in HEK293 cells that expressed RyR1 or RyR3, but it induced robust Ca(2+) transients in cells that stably overexpressed TPC1 or TPC2 and in a manner that was blocked following depletion of acidic stores by bafilomycin. We conclude that cADPR triggers Ca(2+) release by activating RyRs but not TPCs, whereas NAADP activates TPCs but not RyRs.
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2,334,368 |
Novel 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors: a patent review.
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Cardiovascular disease (CVD) is a leading cause of death worldwide and hypercholesterolemia, or elevated low-density lipoprotein cholesterol (LDL-C), is a key risk factor. The standard of care for treating hypercholesterolemia is the use of HMG-CoA reductase inhibitors, also known as statins, which block the rate-limiting step of cholesterol biosynthesis. In widespread clinical use, statins have proven safe and effective for both primary prevention of coronary heart disease and secondary prevention of coronary events.</AbstractText>This review summarizes the patent literature and advances in the discovery and development of new HMG-CoA reductase inhibitors from 2000 to 2010.</AbstractText>The discovery of statins has had significant impact on reducing the worldwide burden of cardiovascular disease; nevertheless, the fact that heart disease remains a leading cause of death indicates that additional efforts are still needed. Using current statins, most patients at low and moderate risk of CVD reach recommended LDL-C targets, but a significant portion of patients in the high risk category fail to achieve optimal LDL-C targets. The potential introduction of novel statins with increased efficacy and tolerability profiles may represent an opportunity to further reduce the incidence of cardiovascular disease. Herein, I review the patent literature and examine the properties of several next generation statin clinical candidates.</AbstractText>
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2,334,369 |
Heart rate variability assessment to stratify risk of autonomic imbalance during subarachnoid block: A prospective study.
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Hypotension after subarachnoid block is a common adverse event which can be predicted by simple, safe and indirect measure of autonomic activity.</AbstractText>Heart rate variability has been accepted as an indirect measure of autonomic activity.</AbstractText>It was to evaluate preoperatively risk of hypotension after subarachnoid block.</AbstractText>This is controlled, randomized blind prospective study.</AbstractText>One hundred adult patients of either sex in the age group of 25 to 60 years belonging to ASA physical status of I to III, scheduled for elective infra-umbilical surgery, were enrolled for this randomized prospective study. During preanesthetic check their HRV was analyzed for time domain and frequency domain parameters. They were classified into two groups of 50 patients each depending on their low to high frequency ratios (LF/HF). Group I included patients with LF/HF <2.5 and Group II included patients with LF/HF >2.5. Sensitivity of LF/HF for prediction of hypotension greater than 20% of baseline was tested.</AbstractText>The present study showed significant differences of systolic blood pressure (SBP) after subarachnoid block, depending on baseline LF/HF. Patients with low LF/HF showed lowest SBP of 106.08 ± 3.19 (15.22% fall of base line SBP) as compared to high LF/HF which showed 87.62 ± 8.71 (30.26% fall of base line SBP). Baseline LF/HF parameter correlated significantly with proportionate decrease in SBP after subarachnoid blocks.</AbstractText>Hemodynamic parameter was analyzed by using student t test on statgraphic version 5.1.</AbstractText>Analysis of low and high frequency ratio, reflect autonomic control and may be used as an indirect measure for risk stratification of hypotension after subarachnoid block with high sensitivity.</AbstractText>
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2,334,370 |
Cardiac Hormones Target the Ras-MEK 1/2-ERK 1/2 Kinase Cancer Signaling Pathways.
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The heart is a sophisticated endocrine gland synthesizing the atrial natriuretic peptide prohormone which contains four peptide hormones, i.e., atrial natriuretic peptide, vessel dilator, kaliuretic peptide and long-acting natriuretic peptide, which decrease up to 97% of human pancreatic, breast, colon, prostate, kidney and ovarian carcinomas as well as small-cell and squamous cell lung cancer cells in cell culture. In vivo, these four cardiac hormones eliminate up to 80% of human pancreatic adenocarcinomas, two-thirds of human breast cancers, and up to 86% of human small-cell lung cancers growing in athymic mice. Their signaling in cancer cells includes inhibition of up to 95% of the basal activity of Ras, 98% inhibition of the phosphorylation of the MEK 1/2 kinases and 97% inhibition of the activation of basal activity of the ERK 1/2 kinases mediated via the intracellular messenger cyclic GMP. They also completely block the activity of mitogens such as epidermal growth factor's ability to stimulate ERK and Ras. They do not inhibit the activity of ERK in healthy cells such as human fibroblasts. The final step in their anticancer mechanism of action is that they enter the nucleus as demonstrated by immunocytochemical studies to inhibit DNA synthesis within cancer cells.
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2,334,371 |
Combined posterior lumbar plexus-sciatic nerve block versus combined femoral-obturator-sciatic nerve block for ACL reconstruction.
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We compared the efficacy of combined posterior lumbar plexus-sciatic nerve block with that of combined femoral-obturator-sciatic nerve block as anesthesia for anterior cruciate ligament reconstruction surgery, because both block combinations have been recommended for lower limb arthroscopic and reconstructive surgery.</AbstractText>Forty-eight patients undergoing elective unilateral anterior cruciate ligament reconstruction under local anesthesia were randomized to undergo either combined posterior lumbar plexus-sciatic nerve block (Group 1), or combined femoral-obturator-sciatic nerve block (Group 2). Blocks were performed using nerve stimulation and bupivacaine 0.5% mixed with lignocaine 2%. Systolic and diastolic blood pressure, heart rate, and pulse oximetry were recorded. Quality of anesthesia, motor and sensory block, time to first analgesic use, sedation, and need for general anesthesia were recorded, along with verbal postoperative pain scores, and side effects.</AbstractText>No patient in Group 1 and two patients in Group 2 needed general anesthesia. Complete sensory blockade was higher in Group 1 than in Group 2. However, complete motor blockade was similar in both groups. In Group 1, verbal pain scores were lower than in Group 2. Time to first analgesic was similar between the two groups. Total analgesic consumption was lower in Group 1. No significant differences were found for heart rate, pulse oximetry, or systolic and diastolic blood pressure between the groups, and no signs of toxicity were encountered.</AbstractText>Combined posterior lumbar plexus-sciatic nerve block provided more comfortable intraoperative anesthesia and better postoperative analgesia than combined femoral-obturator-sciatic nerve block for anterior cruciate ligament reconstruction surgery.</AbstractText>
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2,334,372 |
Synthetic LXR agonist suppresses endogenous cholesterol biosynthesis and efficiently lowers plasma cholesterol.
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The liver X receptors (LXRs) are key regulators of genes involved in cholesterol homeostasis. Natural ligands and activators of LXRs are oxysterols. Numerous steroidal and non-steroidal synthetic LXR ligands are under development as potential drugs for individuals suffering from lipid disorders. N,N-dimethyl-3β-hydroxycholenamide (DMHCA) is a steroidal ligand of LXRs that exerts anti-atherogenic effects in apolipoprotein E-deficient mice without causing negative side effects such as liver steatosis or hypertriglyceridemia. In this report, we investigated the consequences of DMHCA treatment on cholesterol homeostasis in vivo and in vitro. Despite its hydrophobicity, DMHCA is readily absorbed by C57BL/6 mice and taken up by intestinal cells, the lung, heart and kidneys, but is undetectable in the brain. DMHCA significantly reduces cholesterol absorption and uptake in duodenum and jejunum of the small intestine and in turn leads to a reduction of plasma cholesterol by 24%. The most striking finding of this study is that DMHCA inhibited the enzyme 3β-hydroxysterol-Δ24-reductase resulting in an accumulation of desmosterol in the plasma and in feces. Thus, the reduction of plasma cholesterol was due to a block in the final step of cholesterol biosynthesis. Taken together, DMHCA is an interesting compound with properties distinct from other LXR ligands and might be used to study desmosterol-mediated effects in cells and tissues.
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2,334,373 |
Ca2+ entry following P2X receptor activation induces IP3 receptor-mediated Ca2+ release in myocytes from small renal arteries.
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P2X receptors mediate sympathetic control and autoregulation of the renal circulation triggering contraction of renal vascular smooth muscle cells (RVSMCs) via an elevation of intracellular Ca(2+) concentration ([Ca(2+) ](i) ). Although it is well-appreciated that the myocyte Ca(2+) signalling system is composed of microdomains, little is known about the structure of the [Ca(2+) ](i) responses induced by P2X receptor stimulation in vascular myocytes.</AbstractText>Using confocal microscopy, perforated-patch electrical recordings, immuno-/organelle-specific staining, flash photolysis and RT-PCR analysis we explored, at the subcellular level, the Ca(2+) signalling system engaged in RVSMCs on stimulation of P2X receptors with the selective agonist αβ-methylene ATP (αβ-meATP).</AbstractText>RT-PCR analysis of single RVSMCs showed the presence of genes encoding inositol 1,4,5-trisphosphate receptor type 1(IP(3) R1) and ryanodine receptor type 2 (RyR2). The amplitude of the [Ca(2+) ](i) transients depended on αβ-meATP concentration. Depolarization induced by 10 µmol·L(-1) αβ-meATP triggered an abrupt Ca(2+) release from sub-plasmalemmal ('junctional') sarcoplasmic reticulum enriched with IP(3) Rs but poor in RyRs. Depletion of calcium stores, block of voltage-gated Ca(2+) channels (VGCCs) or IP(3) Rs suppressed the sub-plasmalemmal [Ca(2+) ](i) upstroke significantly more than block of RyRs. The effect of calcium store depletion or IP(3) R inhibition on the sub-plasmalemmal [Ca(2+) ](i) upstroke was attenuated following block of VGCCs.</AbstractText>Depolarization of RVSMCs following P2X receptor activation induces IP(3) R-mediated Ca(2+) release from sub-plasmalemmal ('junctional') sarcoplasmic reticulum, which is activated mainly by Ca(2+) influx through VGCCs. This mechanism provides convergence of signalling pathways engaged in electromechanical and pharmacomechanical coupling in renal vascular myocytes.</AbstractText>© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.</CopyrightInformation>
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2,334,374 |
Tetramethylphenylenediamine protects the isolated heart against ischaemia-induced apoptosis and reperfusion-induced necrosis.
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Cytochrome c when released from mitochondria into cytosol triggers assembly of the apoptosome resulting in caspase activation. Recent evidence suggests that reduced cytochrome c is unable to activate the caspase cascade. In this study, we investigated whether a chemical reductant of cytochrome c, N,N,N',N'-tetramethylphenylene-1,4-diamine (TMPD), which we have previously shown to block cytochrome c-induced caspase activation, could prevent ischaemia-induced apoptosis in the rat perfused heart.</AbstractText>The Langendorff-perfused rat hearts were pretreated with TMPD and subjected to stop-flow ischaemia or ischaemia/reperfusion. The activation of caspases (measured as DEVD-p-nitroanilide-cleaving activity), nuclear apoptosis of cardiomyocytes (measured by dUTP nick end labelling assay), mitochondrial and cytosolic levels of cytochrome c (measured spectrophotometrically and by elisa), and reperfusion-induced necrosis (measured as the activity of creatine kinase released into perfusate) were assessed.</AbstractText>We found that perfusion of the hearts with TMPD strongly inhibited ischaemia- or ischaemia/reperfusion-induced activation of caspases and partially prevented nuclear apoptosis in cardiomyocytes. TMPD did not prevent ischaemia- or ischaemia/reperfusion-induced release of cytochrome c from mitochondria into cytosol. TMPD also inhibited ischaemia/reperfusion-induced necrosis.</AbstractText>These results suggest that TMPD or related molecules might be used to protect the heart against damage induced by ischaemia/reperfusion. The mechanism of this protective effect of TMPD probably involves electron reduction of cytochrome c (without decreasing its release) which then inhibits the activation of caspases.</AbstractText>© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.</CopyrightInformation>
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2,334,375 |
Early cholestasis in neonatal lupus erythematosus.
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Neonatal lupus erythematosus is an immune-mediated disease caused by transplacental passage of maternal autoantibodies, primarily anti-Ro (SSA) and anti-La (SSB). The major clinical manifestations are congenital heart block, cutaneous lupus lesions, and hematologic problems. Hepatic, pulmonary, and neurological involvements are rare. We report a 5-day-old male neonate, born to a clinically asymptomatic mother, presenting with conjugated hyperbilirubinemia, cutaneous lupus lesions, congenital heart block, and thrombocytopenia. Both the neonate and his mother had high titers of antinuclear antibodies (1:640), anti-Ro (SSA), and anti-La (SSB) antibodies. The thrombocytopenia improved with prednisolone (2 mg/kg/day) for 14 days. The skin lupus rashes and bilirubin resolved 2 months later, and liver enzymes were completely normal by 6 months.
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2,334,376 |
Early administration of L-arginine in experimental acute spinal cord injury impairs long-term motor function recovery.
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Recently, we reported that L-arginine, a nitric oxide precursor, reverses altered drug disposition induced by acute spinal cord injury (SCI) by increasing hepatic blood flow, without affecting mean arterial pressure and heart rate, whereas others have shown that it produces neuroprotection in several models of acute neurologic damage. Its use as a therapeutic agent for microcirculatory alterations associated with spinal shock seems promising. Therefore, here we have tested its influence on long-term morphofunctional neurologic outcome.</AbstractText>Intravenous L-arginine (300 mg/kg per dose) was administered to adult rats after SCI of moderate intensity according to the following schemes (n=6): (1) single dose at 1 hour, (2) single dose at 24 hour, and (3) repeated doses first at 24 hour and then daily for 7 days. Control injured rats received the vehicle (saline solution).</AbstractText>Contrary to our expectations, locomotor function, assessed using the Basso-Beattie-Bresnahan scale for 8 weeks, was significantly worse in the L-arginine treated groups compared with the control group. Areas of both spared white matter and myelin stain at the epicenter seemed reduced in rats that received L-arginine as a single dose at 1 hour after injury but were not significantly different from the control group.</AbstractText>L-arginine as used here interfered with the functional outcome of rats subjected to SCI, suggesting that L-arginine or its metabolic products may be neurotoxic. Because of its potential utility for acute SCI suggested in the past, strategies should be designed to block its apparent neurotoxicity.</AbstractText>
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2,334,377 |
A case of schistosoma reflexum in a cat with chromosomal aberrations.
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A 2-year-old, female Persian cat was presented with a history of distocia. In her first pregnancy, she had whelped four kittens and had eaten all of them right after parturition. She had mated again with the same tomcat. Well-developed foetuses with weak foetal heart beats were observed in the ultrasonographic examination. En block ovariohysterectomy was performed. Three live and mature foetuses were obtained from the uterus; two of them were female foetuses and had no anatomical problem but the third one exhibiting multiple malformations was a male and diagnosed as 'schistosoma reflexum' (SR). The vertebral column deviated markedly to the right (scoliosis) at thoracolumbar region, and the middle lumbar and the sacral vertebrae were directed dorsocranially (lordosis). The entire small intestine, a part of large intestine, stomach, spleen and the right kidney were displayed out of the body, and it seemed that the listed internal organs were protruded from an abdominal cleft associated with the allantoic membrane. Liver, lungs and heart were hypoplastic. The large intestine was seen to have blind end (atresia recti), but anus was normal. Cerebrum and cerebellum were noticed as normal in sizes. Chromosome preparations from lymphocyte cultures of the foetus showed chromosomal aberrations including chromatid and chromosome breaks, exchange figures, non-homologous pairing, whereas no abnormalities were detected in the chromosome preparations from mother's cultures. This is probably the first case of SR in a cat, which was examined in detail from clinical, pathological, radiological and chromosomal angles.
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2,334,378 |
Pitfalls of programming sensing polarities using the coronary sinus lead in biventricular pacemakers.
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Knowledge of the available sensing polarities in biventricular pacemakers is necessary for appropriate troubleshooting and avoiding possible pitfalls of cardiac resynchronization therapy programming, as illustrated through this case presentation.
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2,334,379 |
Diagnosing Lyme Carditis Presenting With Complete Heart Block.
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Diagnosing self-limited conduction abnormality of Lyme carditis in absence of pathognomonic skin rash or history of tick bite is challenging but necessary to avoid placement of pacemaker particularly in young patients. High degree of clinical suspicion, rapidly progressing conduction block and prompt response to antibiotics may help in diagnosis.
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2,334,380 |
Cardioneuroablation for Treating AV Functional Block Without Pacemaker Implantation: Does it Really Work?
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[Figure: see text]
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2,334,381 |
Evaluation of quality of recovery score in mothers and neonatal outcome assessment after surgery using preoperative dexamethasone for caesarean section.
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Quality of recovery (QoR) after surgery is an essential measure of early postoperative health status of the patient. The incidence of caesarean section (CS) has increased in the last few decades. Numerous studies have been conducted for reduction of pain after CS but only a few on the effect of preoperative dexamethasone on QoR after CS. This study is designed to evaluate QoR with dexamethasone and neonate outcome assessment after CS.</AbstractText>This is a prospective, randomised study in which patients undergo CS under spinal anaesthesia (SA). Patients received either 8 mg (2 ml) of dexamethasone IV (group D, n = 30) or 2 ml of 0.9% normal saline (group C; n = 30) before SA. The QoR-40 and Apgar score, neonatal respiratory distress, haemodynamic response and ill effects were recorded.</AbstractText>The baseline haemodynamic (heart rate, mean arterial pressure (MRP), Respiratory rate (RR) and pulse oximetry) parameters were comparable in both the groups. The mean global score and each score in group D was better than that of group C (p < 0.001). The mean duration of block in group D (169.83 ± 9.05 min) was more than that in group C (163.33 ± 11.91 min) (p < 0.021). The incidence of neonatal respiratory distress, neonatal intensive care unit admission and Apgar score at 1 min and at 5 min of birth was comparable between the groups.</AbstractText>Dexamethasone has a positive effect on early postoperative recovery of patients undergoing CS with a delay in regression of spinal block and without any significant adverse effects on neonatal outcomes.</AbstractText>© 2020 Director General, Armed Forces Medical Services. Published by Elsevier, a division of RELX India Pvt. Ltd.</CopyrightInformation>
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2,334,382 |
Toxicities of microplastic fibers and granules on the development of zebrafish embryos and their combined effects with cadmium.
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Toxicity of microplastics (MPs) in granular form to aquatic animals has been frequently tested, whereas the effects of fibrous MPs remain further explored. In this study, the effects of polyethylene terephthalate granular particles (p-PET, approximately 150 μm in diameter) and fibers (f-PET, approximately 3-5 mm in length and 20 μm in diameter) on the development of zebrafish embryos and their joint effects with cadmium (Cd) were compared. p-PET and f-PET accelerated the velocities of blood flow and heart rate and inhibited hatching in zebrafish embryos because of their barrier effects on the channels in the embryonic chorion and enhanced the mechanical strength of the chorion. The Cd content in the chorion increased by p-PET due to the adsorption of p-PET on the chorion. By contrast, more f-PET dissociated in culture medium and resulted in low Cd content in the chorion. Given that chorion can effectively block p-PET and f-PET, the Cd accumulation in eggs significantly decreased (p < 0.05) under p-PET/f-PET and Cd combined treatment because of the reduction in the bioavailability of Cd. Therefore, p-PET and f-PET decreased the toxicities of Cd on all the target endpoints in this study, and the detoxification effect of f-PET at 72 hpf was more significant than that of p-PET. These results suggest that the toxicity induced by MPs might be form-related.
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2,334,383 |
Effects of maternal and post-weaned rumen-protected folic acid supplementation on slaughter performance and meat quality in offspring lambs.
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The present study was undertaken to evaluate the influence of rumen-protected folic acid (RPFA) on slaughter performance, visceral organ and gastrointestinal tract coefficients, and meat quality in lambs. Sixty-six lambs from 120 Hu ewes were selected based on body weight and maternal diets and then assigned to six groups using a randomised block experimental design in a 3 × 2 factorial arrangement. The first factor was folic acid (FA) as RPFA in the maternal diet (0 mg/kg (M0F), 16 mg/kg (M16F) or 32 mg/kg (M32F) on DM basis). The second factor was FA in the lambs' diet from weaning until slaughter (0 mg/kg (OC) or 4·0 mg/kg (OF)). The results indicated that the addition of 16 mg/kg FA to the maternal diet increased pre-slaughter weight (PSW), dressing and meat percentage, the reticulum and omasum coefficients, length of the jejunum and ileum, tail fat and perirenal fat coefficient and a* value of the meat colour. The addition of RPFA to the lambs' diet increased PSW, dressing and meat percentage, eye muscle area, abomasum weight, weight and length of the small intestine, but reduced the coefficients of tail fat. An M × O interaction was observed for the weights of heart, lungs, rumen and total stomach, weight and coefficient of omental fat and the girth rib value. Collectively, RPFA in the maternal and lambs' diet improved slaughter performance and meat quality by stimulating the morphological development of the gastrointestinal tract and the distribution of fat in the body.
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2,334,384 |
Sequence-Controlled Polyurethane Block Copolymer Displays Differentiated Immunoglobulin-G Adsorption That Influences Human Monocyte Adhesion and Activity.
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The ability to specify an adsorbed protein layer through the polymer chemistry design of immunomodulatory biomaterials is important when considering a desired immune response, such as reducing pro-inflammatory activity. Limited work has been undertaken to elucidate the role of monomer sequence in this process, when copolymeric systems are involved. In this study, we demonstrate the advantage of an alternating radical copolymerization strategy as opposed to a random statistical copolymerization to order monomers in the synthesis of degradable polar-hydrophobic-ionic polyurethanes (D-PHI), biomaterials originally designed to reduce inflammatory monocyte activation. A monomer system consisting of a vinyl-terminated polyurethane cross-linker, maleic acid (MA), and ethyl vinyl ether (EVE), not only generated a diverse chemical environment of polar, hydrophobic, and ionic functional groups, but also formed a charge transfer complex (CTC) reactive to alternating polymerizations. Conversion of MA and EVE occurred in a constant proportion regardless of monomer availability, a phenomenon not observed in conventional D-PHI formulations. For feeds with unequal molar quantities of MA and EVE, the final conversion was limited and proportional to the limiting reagent, leading to an overall higher polyurethane cross-linker content. The presence of a reactive CTC was also found to limit the monomer conversion. Compared to a D-PHI with random monomer arrangement using methacrylic acid (MAA) and methyl methacrylate (MMA), a reduction in Fab region exposure from adsorbed immunoglobulin G and a reduction in average adherent monocyte activity were found in the sequence-controlled version. These results represent the first example of using an alternating copolymerization approach to generate regularly defined polymer chemistries in radical chain-growth biomaterials for achieving immunomodulation, and highlight the importance of considering sequence control as a design strategy for future immunomodulatory biomaterial development.
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2,334,385 |
Cattle and carcass performance, and life cycle assessment of production systems utilizing additive combinations of growth promotant technologies.
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The objective of this study was to determine the impact of beef production systems utilizing additive combinations of growth promotant technologies on animal and carcass performance and environmental outcomes. Crossbred steer calves (<i>n</i> =120) were stratified by birth date, birth weight, and dam age and assigned randomly to one of four treatments: 1) no technology (NT; control), 2) antibiotic treated (ANT; NT plus therapeutic antibiotics and monensin and tylosin), 3) implant treated (IMP; ANT plus a series of 3 implants, and 4) beta-agonist treated (BA; IMP plus ractopamine-HCl for the last 30 d prior to harvest). Weaned steers were fed in confinement (dry lot) and finished in an individual feeding system to collect performance data. At harvest, standard carcass measures were collected and the United States Department of Agriculture (USDA) Yield Grade and Quality Grade were determined. Information from the cow-calf, growing, and finishing phases were used to simulate production systems using the USDA Integrated Farm System Model, which included a partial life cycle assessment of cattle production for greenhouse gas (GHG) emissions, fossil energy use, water use, and reactive N loss. Body weight in suckling, growing, and finishing phases as well as hot carcass weight was greater (<i>P</i> < 0.05) for steers that received implants (IMP and BA) than non-implanted steers (NT and ANT). The average daily gain was greater (<i>P</i> < 0.05) for steers that received implants (IMP and BA) than non-implanted steers during the suckling and finishing phases, but no difference (<i>P</i> = 0.232) was detected during the growing phase. Dry matter intake and gain:feed were greater (<i>P</i> < 0.05) for steers that received implants than non-implanted steers during the finishing phase. Steers that received implants responded (<i>P</i> < 0.05) with a larger loin muscle area, less kidney pelvic and heart fat, advanced carcass maturity, reduced marbling scores, and a greater percentage of carcasses in the lower third of the USDA Choice grade. This was offset by a lower percentage of USDA Prime grading carcasses compared with steers receiving no implants. Treatments did not influence (<i>P</i> > 0.05) USDA Yield grade. The life cycle assessment revealed that IMP and BA treatments reduced GHG emissions, energy use, water use, and reactive nitrogen loss compared to NT and ANT. These data indicate that growth promoting technologies increase carcass yield while concomitantly reducing carcass quality and environmental impacts.
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2,334,386 |
Intraosseous anesthesia in symptomatic irreversible pulpitis: Impact of bone thickness on perception and duration of pain.
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Intraosseous anesthesia (IO) allows the anesthetic solution to be injected directly into the cancellous bone. The anesthetic solution immediately reaches the periapical region, and thus the axonal area of the nerve, where it can temporarily disable the sodium pump. The effect is felt almost without any time delay, and only a small amount of anesthetic solution is required.</AbstractText>This study aims to investigate the efficacy of IO using the Anesto® device after infiltration anesthesia (IA) and/or inferior alveolar nerve block anesthesia (IANB) failed to work in symptomatic irreversible pulpitis (hot tooth). The 33 patients included in the study were treated additionally with 1.7 ml articaine hydrochloride with 1:100,000 epinephrine hydrochloride (Ultracain® D-S, Sanofi-Aventis, Frankfurt, Germany) IO.</AbstractText>The electrical pulp test showed that 95.76% of the volunteers reacted positively to the combination of IANB or IA with the IO. In women, the additive IO was effective at 97.22%. In men, the IO led to pain elimination in 94.00% of cases. The duration of the IO was less than a quarter of an hour (13.03 min). The IO worked longer in women than in men (13.61 min vs. 12.33 min). Overall, more than every third tooth that needed trepanation was located in the posterior area of the mandible (36.4%). Treatment of hot teeth in this area was associated with an increased pulse rate and increased residual pain. There was a moderate correlation (Spearman-Rho [IRI] = 0.280) between the Visual Analog Scale (VAS) score and bone density, and a significant correlation (IRI = 0.612) between subjective residual pain and bone width. The IO resulted in a moderate, transient increase in the pulse rate by approximately 20 bpm. This is similar to the temporary increase in heart rate after conventional anesthesia techniques in non-preloaded patients and can be considered clinically irrelevant.</AbstractText>IO with the Anesto® device as an extension and deepening of local pain elimination is recommended for the treatment of hot teeth.</AbstractText>Copyright © 2020 Journal of Dental Anesthesia and Pain Medicine.</CopyrightInformation>
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2,334,387 |
Cope's sign: A lesson for novice physicians.
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We report a case of a 28-year-old male who presented in the emergency room with a history of two episodes of syncope in the last 3 days at home. ECG was done in the emergency room which was suggestive of complete heart block. The patient had a history of pain on and off in the right upper quadrant region (RUQ) after having a meal. Ultrasonography of the abdomen was advised which revealed acute calculous cholecystitis. A temporary pacemaker was inserted and an emergency laparoscopic cholecystectomy was planned. The patient recovered postoperatively and converted back to sinus rhythm. Considering the patient's age, normal cardiac workup, and his complete heart block disappeared after the removal of his gallbladder, it was postulated that this patient had a case of cardio-biliary reflex (Cope's sign).
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2,334,388 |
Permeation Rates of Oxygen through a Lipid Bilayer Using Replica Exchange Transition Interface Sampling.
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Several simulations strategies have emerged to predict the permeability of solutes across membranes, which is important for many biological or industrial processes such as drug design. The widespread inhomogeneous solubility-diffusion (ISD) model is based on the Smoluchowski equation and describes permeation as purely diffusive. The counting method, which counts membrane transitions in a long molecular dynamics (MD) trajectory, is free of this diffusive assumption, but it lacks sufficient statistics when the permeation involves high free energy barriers. Metadynamics and variations thereof can overcome such barriers, but they generally lack the kinetics information. The milestoning framework has been used to describe permeation as a rare event, but it still relies on the Markovian assumption between the milestones. Replica Exchange Transition Interface Sampling (RETIS) has been shown to be an effective method for sampling rare events while simultaneously describing the kinetics without assumptions. This paper is the first permeation application of RETIS on an all-atom lipid bilayer consisting of 1-palmitoyl-2-oleoyl-<i>sn</i>-glycero-3-phosphocholine (POPC) to compute the entrance, escape and complete transition of molecular oxygen. Conventional MD was performed as a benchmark, and the MD rates from counting were converted to rate constants, giving good agreement with the RETIS values. Moreover, a correction factor was derived to convert the collective order parameter in RETIS, which was aimed to improve efficiency, to a single-particle order parameter. With this work, we showed how the exact kinetics of drug molecules permeation can be assessed with RETIS even if the permeation is truly a rare event or if the permeation is non-Markovian. RETIS will therefore be a valuable tool for future permeation studies.
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2,334,389 |
Ultrasound-guided Erector Spinae Plane Block (US-ESPB)-Anesthetic block: Case report.
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The Ultrasound-guided Erector Spinae Plane Block (US-ESPB), used as an anesthesiological block, could represent a safe and effective alternative for thoracic wall surgery especially in fragile, obese patients and those with respiratory and/or hemodynamic problems.
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2,334,390 |
Intensity Control During Block-Periodized High-Intensity Training: Heart Rate and Lactate Concentration During Three Annual Seasons in World-Class Cross-Country Skiers.
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<b>Purpose:</b> To describe heart rate (HR) and blood lactate (Bla<sup>-</sup>) responses during high-intensity interval training (HIT) in a long-term block-periodized HIT regimen in world-class cross-country (XC) skiers. <b>Methods:</b> Data were collected in 14 world-class female XC skiers (aged 25 ± 5 years; body mass, 60.4 ± 6.5 kg; and maximal HR, 194 ± 8 beats · min<sup>-1</sup>) throughout three entire seasons. The HR and Bla<sup>-</sup> values were determined at the end of 572 intervals performed during 63 sessions and 17 HIT blocks utilizing different exercise modes: running, running with poles, and skiing (on-snow and roller ski) with classic and skating techniques. <b>Results:</b> The mean HR was 91 ± 3% of HR<sub>max</sub> with a corresponding Bla<sup>-</sup> of 7.3 ± 2.1 mmol · L<sup>-1</sup>. The average HR and Bla<sup>-</sup> values were relatively similar across the different exercise modes, except for a lower HR (~90 vs. 92% of HR<sub>max</sub>) for on-snow and roller ski classical skiing and lower Bla<sup>-</sup> values (5.9 vs. 7.0-7.8 mmol · L<sup>-1</sup>) for on-snow classical skiing compared to the other modes, both <i>P</i> < 0.05. An increase in HR and Bla<sup>-</sup> was observed from interval working periods 1 to 3 (90-92% of HR<sub>max</sub> and 6.5-7.7 mmol · L<sup>-1</sup>) and further from 3 to 5 (92-93% of HR<sub>max</sub> and 7.7-9.0 mmol · L<sup>-1</sup>), all <i>P</i> < 0.05. <b>Conclusions:</b> We describe long-term use of HIT-block periodization among world-class XC skiers who achieved target HR and Bla<sup>-</sup> levels in all six exercise modes employed. According to athletes and coaches, the key to successful blocks was intensity control to allow for high-quality HIT sessions throughout the entire HIT block.
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2,334,391 |
Repeated Sprint Training in Hypoxia: Case Report of Performance Benefits in a Professional Cyclist.
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Repeated sprint training in hypoxia (RSH) has gained unprecedented popularity among the various strategies using hypoxia as an additional stimulus to improve performance. This case study reports the benefits of 150 repeated sprints in normobaric hypoxia over 10 days in a professional cyclist. After 3 weeks of endurance training in November, the cyclist performed five RSH sessions at a simulated altitude of 3,300 m on his own bicycle attached to an indoor trainer in a hypoxic chamber (FiO<sub>2</sub> 14.1 ± 0.1%, PiO<sub>2</sub> 94.6 ± 1.4 mm Hg). Each session consisted of four blocks of seven all-out sprints of 6 s interspersed with 14 s active recovery (for a total of 126 s per block). After 12 min of warm-up with a single isolated 6 s reference sprint, the sessions included a first and a second sprinting block with 4 min 54 s active recovery in-between. After 9 min 54 s active recovery including an isolated 6 s reference sprint, a third and a fourth block were performed with 4 min 54 s active recovery in-between, before an active cool-down of 9 min 54 s. The total duration was thus of 50 min <i>per session</i> for a total hypoxic exposure of 250 min exercising. Power output and heart rate were monitored at 1 Hz. Lactate concentration ([La]) and pulse oxygen saturation (SpO<sub>2</sub>) were measured at the start and end of each block during the first and fifth training session. Basal SpO<sub>2</sub> was of 83% during session one and 85.5% during session five. When comparing the first and fifth training session, peak power increased for the best 1 s value (+8%) and the best 5 s average (+10%) to reach 1,041 W and 961 W, respectively. Average power for all blocks (including active recoveries) increased from 334 to 354 W with a similar average heart rate during the sessions (146'<sup>.</sup>min<sup>-1</sup>). Peak [La] was increased from 12.3 to 13.8 mmol<sup>.</sup>l<sup>-1</sup>. In conclusion, this case report illustrates a 10-days RSH intervention perceived as efficient in a professional cyclist and shown to improve total work (6-s sprints) produced for a similar physiological strain.
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2,334,392 |
Hemodynamic effects of carbetocin administered as an intravenous bolus or infusion during cesarean delivery.
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Postpartum hemorrhage is the leading cause of maternal mortality. Oxytocin being the most popular uterotonic agent, has been routinely administered after both vaginal delivery and cesarean section. Carbetocin is a newer uterotonic agent and provides the benefit of a longer duration of action without additional administration post-delivery.</AbstractText>We recruited 34 women undergoing elective cesarean section under spinal anesthesia. All patient was received spinal anesthesia using 0.5% hyperbaric Marcaine 8-10 mg in conjugation with fentanyl 20 μg in the left lateral decubitus position. Hartmann's solution 10-15 ml/kg was administered before carbetocin. The operation started as soon as sensory block at level T4-T6 was confirmed. A non-invasive hemodynamic monitoring cuff (Finometer®</sup>) was attached to the patient's finger soon after the induction of spinal anesthesia. Using the Finometer, we recorded the heart rate and mean arterial pressure at every 15 s, starting from 15 s before the administration of carbetocin to 5 min after. After the removal of the placenta, the bolus group was administered intravenous bolus injection of carbetocin 100 μg and the infusion group was administered carbetocin 100 μg diluted in 50 ml normal saline, over 5 min using an infusion pump.</AbstractText>The demographic data showed no significant difference between the two groups. Furthermore, there were no significant hemodynamic differences between the two groups.</AbstractText>The method of administration of carbetocin does not influence its hemodynamic effects.</AbstractText>Copyright © the Korean Society of Anesthesiologists, 2020.</CopyrightInformation>
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2,334,393 |
Comparison of chloroquine-like molecules for lysosomal inhibition and measurement of autophagic flux in the brain.
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Measurement of autophagic flux in vivo is critical to understand how autophagy can be used to combat disease. Neurodegenerative diseases have a special relationship with autophagy, which makes measurement of autophagy in the brain a significant research priority. Currently, measurement of autophagic flux is possible through use of transgenic constructs, or application of a lysosomal inhibitor such as chloroquine. Unfortunately, chloroquine is not useful for measuring autophagic flux in the brain and the use of transgenic animals necessitates cross-breeding of transgenic strains and maintenance of lines, which is costly. To find a drug that could block lysosomal function in the brain for the measurement of autophagic flux, we selected compounds from the literature that appeared to have similar properties to chloroquine and tested their ability to inhibit autophagic flux in cell culture and in mice. These chemicals included chloroquine, quinacrine, mefloquine, promazine and trifluoperazine. As expected, chloroquine blocked lysosomal degradation of the autophagic protein LC3B-II in cell culture. Quinacrine also inhibited autophagic flux in cell culture. Other compounds tested were not effective. When injected into mice, chloroquine caused accumulation of LC3B-II in heart tissue, and quinacrine was effective at blocking LC3B-II degradation in male, but not female skeletal muscle. None of the compounds tested were useful for measuring autophagic flux in the brain. During this study we also noted that the vehicle DMSO powerfully up-regulated LC3B-II abundance in tissues. This study shows that chloroquine and quinacrine can both be used to measure autophagic flux in cells, and in some peripheral tissues. However, measurement of flux in the brain using lysosomal inhibitors remains an unresolved research challenge.
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2,334,394 |
Straddle versus Conventional Chest Compressions in a Confined Space; a Comparative Study.
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When cardiac arrest occurs in a confined space, such as in an aircraft or ambulance, kneeling by the patient's side may be difficult. Straddle chest compression is an alternative technique that can be used in a confined space. This study was performed to compare the quality of chest compressions in straddle versus conventional CPR on a manikin model.</AbstractText>The participants were randomized into two groups using the sequential numbered, opaque, sealed envelope method chosen through block-of-four randomization: straddle and conventional chest compression technique. Each participant performed a maximum of 4 minutes of hands-only chest compressions, and quality parameters (compression rate and depth) were recorded from the defibrillator's monitor.</AbstractText>124 participants with mean age of 26.67 ± 6.90 years (27.58% male) were studied. There was no difference in the mean compression rate between the conventional and straddle chest compression techniques (126.18 ± 17.11 and 127.01 ± 21.01 compressions/min, respectively; p = 0.811) or their mean compression depth (43.8 ± 9.60 and 43.4 ± 9.10 mm, respectively; p = 0.830). The participants' comfort and fatigue were assessed through changes in their vital signs. In both methods, statistically significant differences were observed in vital signs before and after performing chest compression, but the differences were not clinically significant. In addition, there was no difference between the 2 groups in this regard.</AbstractText>The quality of CPR using the straddle chest compression was as good as conventional chest compression technique. No significant differences were found in the quality of chest compressions or the participants' comfort and fatigue levels.</AbstractText>
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2,334,395 |
Effects of dexmedetomidine as an adjuvant in thoracic paravertebral block on EC50 of propofol for successful laryngeal mask insertion: a randomized controlled trial.
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Dexmedetomidine as an adjuvant can improve the duration and the quality of thoracic paravertebral block (TPVB); however, its quantitative effect on propofol infusion is unclear. This study aimed to investigate the effect of dexmedetomidine as an adjuvant in TPVB on the medium effective concentration (EC50) of propofol for successful laryngeal mask insertion.</AbstractText>Sixty breast cancer patients who underwent elective modified radical mastectomy were enrolled and randomized at a 1:1 ratio into control group (Group C, n=30) or dexmedetomidine group (Group D, n=30). Ultrasound-guided T3 paravertebral block was performed before induction of anesthesia. In Group C, 0.5% ropivacaine 0.3 mL/kg was injected into T3 paravertebral space, while subjects in Group D received 0.5% ropivacaine 0.3 mL/kg with dexmedetomidine (1 µg/kg). Propofol target-controlled infusion (TCI) was performed, with an initial target effect-site concentration of 5 µg/mL determined for both groups. The laryngeal mask was inserted once the effect chamber achieved the target concentration. Subsequent target concentrations were adjusted by Dixon up-down sequential method, where dose modifications were performed by 0.5 mg/mL intervals, based on the success of the laryngeal mask insertion. Probit analysis was used to determine the propofol EC50. Mean arterial pressure (MAP), heart rate (HR), bispectral index (BIS) and application of atropine or ephedrine was recorded. Participants, TPVB giver, and data recorder were blinded to group assignment.</AbstractText>Propofol EC50 for successful laryngeal mask insertion were statistically significant, with 5.256 µg/mL (95% CI: 4.833, 5.738 µg/mL) in Group C and 3.172 µg/mL (95% CI: 2.701, 3.621 µg/mL) in Group D. Both groups displayed significantly lower MAP and HR, post propofol TCI (P<0.05). However, subjects in Group D exhibited lower MAP and HR levels compared to patients in Group C (P<0.05). Application of atropine (0% vs.</i> 10%) and ephedrine (20.0% vs.</i> 13.3%) were not significantly different between two groups.</AbstractText>Dexmedetomidine, administered as an adjuvant in TPVB, can reduce the TCI concentration of propofol for successful laryngeal mask placement in females. The target concentration of propofol requires adjustment and close monitoring of hemodynamic changes, post induction is warranted.</AbstractText>Chinese Clinical Trial Registry ChiCTR1800016614.</AbstractText>2020 Annals of Translational Medicine. All rights reserved.</CopyrightInformation>
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2,334,396 |
Ultrasound-guided stellate ganglion block alleviates stress responses and promotes recovery of gastrointestinal function in patients.
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This study aimed to investigate the effect of preoperative ultrasound-guided stellate ganglion block (SGB) on the perioperative stress responses and gastrointestinal functions of patients undergoing laparoscopic colorectal cancer surgery.</AbstractText>A total of 60 colorectal cancer patients were enrolled in study and were randomized to be treated with or without SGB therapy. In the SGB group, patients were injected with 7 mL 0.5% ropivacaine in stellate ganglion under ultrasound guidance before anesthesia. Mean artery pressure (MAP), heart rate (HR), recovery of bowel sound and first exhaust, as well as levels of motilin, gastrin, norepinephrine, cortisol, interleukin-6 (IL-6) and C-reactive protein (CRP) were recorded at various time points.</AbstractText>26 patients in the SGB group and 27 patients in the control group were analyzed. No significant differences in MAP or HR were observed between the two groups before, during and after the surgery. SGB promoted recovery of gastrointestinal functions, as evidenced by earlier recovery of bowel sound and first exhaust, as well as increased motilin and gastrin levels. SGB also attenuated stress responses, as shown in reduced norepinephrine, cortisol, IL-6 and CRP levels.</AbstractText>SGB promotes the recovery of gastrointestinal functions and reduces stress responses of colorectal patients undergoing laparoscopic colorectal cancer surgery.</AbstractText>Copyright © 2020 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.</CopyrightInformation>
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2,334,397 |
Long non-coding RNA HOTAIR induces GLI2 expression through Notch signalling in systemic sclerosis dermal fibroblasts.
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Systemic sclerosis (SSc) is characterised by tissue fibrosis of the major organs of the body including the skin, lungs and heart. We have previously reported that the lncRNA HOTAIR plays a central role in the activation of SSc myofibroblasts, the key cellular elements of fibrosis. HOTAIR induces fibroblast activation through H3K27me3-mediated activation of the Notch signalling pathway. Here we aimed to identify the signalling events downstream of Notch that drive SSc myofibroblast activation.</AbstractText>Patient fibroblasts were obtained from full-thickness forearm skin biopsies of 3 adult patients with SSc of recent onset. The lncRNA HOTAIR was expressed in healthy dermal fibroblasts by lentiviral transduction. Hedgehog signalling pathway was inhibited with GANT61 and GLI2 siRNA. Gamma secretase inhibitors RO4929097 and DAPT were used to block Notch signalling. GSK126 was used to inhibit Enhancer of Zeste 2 (EZH2).</AbstractText>Overexpression of HOTAIR in dermal fibroblasts induced the expression of the Hedgehog pathway transcription factor GLI2. This is mediated by activation of Notch signalling following epigenetic downregulation of miRNA-34a expression. Inhibition of H3K27 methylation and Notch signalling reduced expression of GLI2 in HOTAIR-expressing fibroblasts as well as in SSc dermal fibroblasts. Importantly, the inhibition of GLI2 function using GANT61 or siRNA mitigates the pro-fibrotic phenotype induced by HOTAIR.</AbstractText>Our data indicates that GLI2 expression is stably upregulated in SSc myofibroblasts through HOTAIR and that GLI2 mediates the expression of pro-fibrotic markers downstream of Notch.</AbstractText>
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2,334,398 |
Acute psycho-physiological responses to perceptually regulated hypoxic and normoxic interval walks in overweight-to-obese adults.
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We investigated psycho-physiological responses to perceptually regulated interval walks in hypoxia versus normoxia in obese individuals.</AbstractText>Within-participants repeated measures.</AbstractText>Ten obese adults (BMI=32±3kg/m-2</sup>) completed a 60-min interval session (15×2min walking at a rating of perceived exertion of 14 on the 6-20 Borg scale with 2min of rest) either in hypoxia (FiO2</sub>=13.0%, HYP) or normoxia (NOR). A third trial replicating the HYP speed pattern was carried out in normoxia as a control (CON). Exercise responses were analysed comparing the average of 1st to 3rd exercise bouts to those of the 4th-6th, 7th-9th, 10th-12th and 13th-15th exercise bouts (block 1 versus 2, 3, 4 and 5).</AbstractText>Treadmill speed was slower during block 4 (6.14±0.67 versus 6.24±0.73km/h-1</sup>) and block 5 (6.12±0.64 versus 6.25±0.75km/h-1</sup>) in HYP compared to NOR or CON (p=0.009). Compared to NOR and CON, heart rate was +6-10% higher (p=0.001), whilst arterial oxygen saturation (-12-13%) was lower (p<0.001) in HYP. Perceived limb discomfort was lower in HYP and CON versus NOR (-21±4% and -34±6%; p=0.004).</AbstractText>In overweight-to-obese adults, perceptually regulated interval walks in hypoxia versus normoxia leads to progressively slower speeds along with lower limb discomfort and larger physiological stress than normoxia. Walking at the speed adopted in hypoxia produces similar psycho-physiological responses at the same absolute intensity in normoxia.</AbstractText>Copyright © 2020 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.</CopyrightInformation>
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2,334,399 |
[Evaluation of dentists regulatory systems stress during the provision of dental care according to pulse oximetry data].
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To evaluate the status of individual hemodynamic parameters (HR) and respiratory indicators of dentists performing local anesthesia. Material and methods. In the period from April 2019 to December 2019 the determination of heart rate (Heart rate) and blood saturation at 120 doctors aged 25-55 years was performed. The value of blood saturation by non-invasive pulse oximeter technique: SpO2</sub> measurement range 0-99%; heart rate range 18-300 beats per minute. The limit of 95-98% was considered normal. However, we consider it correct to note the introduction of an error of 0.1% due to the constant wearing of a dentist's tight polymer mask. All subjects were preliminarily determined by Robergs-Landvere formula: maximum heart rate (MF)=205.8-(0.685·age).</AbstractText>Maximum HR limits for the groups of subjects were 185.6±3.1 beats per minute in the first group; 178.7±3.1 beats per minute in the second group; 171.5±3.4 beats per minute in the third group. In all groups the tendency to decrease blood saturation in case of pain appearance in patients during treatment against the background of block anesthesia, as well as during anesthesia on the mandible was determined. The definition of SpO2</sub> showed a slight downward trend in blood saturation when pain occurs within normal parameters. Thus, the limit of changes in the index against the background of performed local anesthesia on the mandible was 95.2-96.1% and 96.3-96.6% on the maxilla.</AbstractText>Measurement of arterial oxygen saturation in dentists showed a tendency for a slight decrease in this indicator within the normal range when the patient developed pain. Thus, the limit of changes in the indicator against the background of local anesthesia on the lower jaw was 95.2-96.1%, on the upper jaw - 96.3-96.6%.</AbstractText>
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