Miracle-dz/UniFAR-FTUs huggingface dataset:
Comparative Effects of Bupivacaine and Ropivacaine on Intracellular Calcium Transients and Tension in Ferret Ventricular Muscle

Background:Recent evidence suggests that ropivacaine exerts markedly less cardiotoxicity compared with bupivacaine; however, the mechanisms are not fully understood at the molecular level. Methods:Isolated ferret ventricular papillary muscles were microinjected with the Ca2+-binding photoprotein aequorin, and intracellular Ca2+ transients and tension were simultaneously measured during twitch in the absence and presence of bupivacaine or ropivacaine. Results:Bupivacaine and ropivacaine (10, 30, and 100 &mgr;m) reduced peak systolic [Ca2+]i and tension in a concentration-dependent manner. The effects were significantly greater for bupivacaine, particularly on tension (approximately twofold). The percentage reduction of tension was linearly correlated with that of [Ca2+]i for both anesthetics, with the slope of the relationship being ≈1.0 for ropivacaine and ≈1.3 for bupivacaine (slope difference, P < 0.05), suggesting that the cardiodepressant effect of ropivacaine results predominantly from inhibition of Ca2+ transients, whereas bupivacaine suppresses Ca2+ transients and the reaction beyond Ca2+ transients, i.e., myofibrillar activation, as well. BAY K 8644, a Ca2+ channel opener, abolished the inhibitory effects of ropivacaine on Ca2+ transients and tension, whereas BAY K 8644 only partially inhibited the effects of bupivacaine, particularly the effects on tension. Conclusion:The cardiodepressant effect of bupivacaine is approximately twofold greater than that of ropivacaine. Bupivacaine suppresses Ca2+ transients more markedly than does ropivacaine and reduces myofibrillar activation, which may at least in part underlie the greater inhibitory effect of bupivacaine on cardiac contractions. These results suggest that ropivacaine has a more favorable profile as a local anesthetic in the clinical settings.
A Testis-specific Androgen Receptor Coregulator That Belongs to a Novel Family of Nuclear Proteins*

We have characterized a novel partner for androgen receptor (AR), termed ARIP3, that interacts with the DNA-binding domain/zinc finger region of AR and is predominantly expressed in the testis. Rat ARIP3 is a nuclear protein comprising 572 amino acids. It modulates AR-dependent but not basal transcription, suggesting that ARIP3 acts as an AR transcriptional coregulator. Except for the C-terminal AR-interacting domain, ARIP3 contains distinct regions that are also present in two recently described proteins, a protein inhibitor of activated Stat3 and an RNA helicase II-interacting protein (Gu/RH-II binding protein). Conserved structural features of these proteins indicate the existence of a gene family involved in the regulation of various transcription factors. Collectively, ARIP3 belongs to a novel nuclear protein family and is perhaps the first tissue-specific coregulator of androgen receptor.
Threshold Signaling of Human Th0 Cells in Activation and Anergy: Modulation of Effector Function by Altered TCR Ligand1

Molecular interactions between TCR and its natural ligand, in the presence of costimulatory signals, elicit T cell effector functions, whereas subtle changes in the structure of antigenic peptides may induce only selected T cell effector function including anergy. In this study, we have investigated the immunological activity of an altered TCR ligand (p 2, 28–40A34,36) derived from the immunodominant T cell epitope of the group 2 allergen of house dust mite, in which residues at positions 34 and 36 were substituted by alanine. Elevated IFN-γ synthesis was induced by equimolar concentrations of the analogue compared with native peptide (p 2, 28–40) and was paralleled by increased down-regulation of cell surface CD3. IL-5 and IL-10 production exhibit the same sensitivity to both peptides, implying that the induction of T cell effector functions are not all proportional to TCR occupancy. Both native peptide and the analogue bound to MHC class II (DRB1*1101) molecules with similar affinities. Furthermore, p 2, 28–40A34,36 induced T cell anergy at lower concentrations than native peptide. During the induction of anergy, TGF-β production was comparable for both peptides, whereas IL-10 secretion was markedly increased but more so in response to p 2, 28–40A34,36. Membrane expression of costimulatory ligands CD80 and CD86 was similar for native peptide and p 2, 28–40A34,36 and increased in activation, whereas only CD86 was elevated during anergy. The modulation of T cell effector function with altered TCR ligands may have practical applications in reprogramming allergic inflammatory responses through the induction of T cell anergy and/or the promotion of Th1 cytokines.
Low frequency of RET mutations in Hirschsprung disease in Sweden

Hirschsprung disease is a congenital malformation, where absence of intramural ganglia in the hindgut results in a defect in the coordination of peristaltic movement. This leads to ileus in the newborn or, more often, constipation in children and adults. The disease affects one in 5000 live births. Siblings of affected cases are at an increased risk (4%) of developing the disease. Among cases, males are affected more often than females.
Pharmacogenetics of Calcineurin Inhibitors in Renal Transplantation

Cyclosporine A and tacrolimus (Tac) are inmunosuppresive drugs with a narrow therapeutic range. Underdosing is associated with organ rejection, whereas overdosing could result in toxicity. Therapeutic drug monitoring at different postdose times is necessary to maintain the blood concentrations within a target window. These calcineurin inhibitors are characterized by a broad interindividual pharmacokinetics variability, which makes the determination of the initial dose difficult. In a patient receiving a dose, the amount of the drug that is measured in the blood determines its bioavailability, which depends on the absorption, biotransformation, and elimination of the drug. These processes are primarily controlled by efflux pumps and enzymes of the cytochrome P (CYP) 450 family. DNA variants at the genes encoding these proteins contribute to the interindividual heterogeneity for calcineurin inhibitors metabolism. Cyclosporine A and Tac are metabolized by CYP3A4 and CYP3A5, and several single nucleotide polymorphisms in the two genes have been associated with differences in drug clearance. Carriers of the CYP3A5 wild-type allele have a higher CYP3A5 expression compared with individuals who are homozygous for a common DNA variant that affects gene splicing (CYP3A5*3). For renal transplant recipients receiving Tac, homozygotes for this nonexpression allele would exhibit significantly lower Tac clearance and may require a lower dose to remain within the blood target concentration compared with CYP3A5 expressors. To date, this CYP3A5 variant is the only reported genetic factor to predict the appropiate starting dosage of Tac, avoiding overdosing and improving the outcome of renal transplantation.
Jitter testing for multi-Gigabit backplane SerDes - techniques to decompose and combine various types of jitter

The recent trend for broadband backplanes is changing from bus-based architectures to fabric/mesh-based high-speed architectures. Freed from heavy loading effects of a bus, modern backplane serializers and deserializers (SerDes) soared to multi-Gigabit-per-second (Gb/s) rate. The increasing integration density, coupled with the increasing data rate, makes jitter testing more critical than ever However, the techniques for jitter testing of a multi-Gigabit backplane SerDes are different from its long haul transceiver counterparts. As specified in some leading communication standards, such as Gigabit Ethernet, Infiniband, and Fiber Channel, jitter is specified in terms of deterministic jitter (DJ), random jitter (RJ), sinusoidal/periodic jitter (PJ) and total jitter (TJ) - as separate specs. To properly test backplane transceivers to these industrial standards, we need to decompose different kinds of jitter in a jitter measurement, and also generate a signal composed of different kinds of jitter for jitter-tolerance testing. Despite its importance, jitter test equipment suited for backplane SerDes is in its infancy. In this article, we describe, compare, and correlate some existing techniques. The backplane jitter test requirements for the test and measurement industry are defined from an IC test engineering perspective.
Cumulative Incidence and Prevalence of Childhood Autism in Children in Japan

Background An epidemiological survey of childhood autism as defined in ICD–10 Research Criteria was conducted in the northern part of Yokohama, Japan. Method The routine health checkup for 18-month-old children served as the initial mass-screening, and all facilities which provide child care services function to detect all cases with childhood autism and refer them to the Yokohama Rehabilitation Centre. Cumulative incidence of childhood autism up to 5 years of age among the birth cohort of 1988, and prevalence on 1 January 1994, among residents born in 1988 were estimated. Results Cumulative incidence and prevalence were 16.2 per 10 000 and 21.1 per 10 000, respectively. Children with high-functioning autism who had IQs of 70 and over constituted approximately half of all the children with childhood autism. Conclusion It was confirmed through better detection of high-functioning cases that childhood autism in Japan is more common than formerly estimated.
Development of a scatter correction technique and its application to HDR I192r multicatheter breast brachytherapy.

This article introduces a scatter correction (SC) technique for high-dose-rate (HDR) I192r brachytherapy dose calculations in the absence of a full scatter environment near the skin. The technique uses dosimetry data derived by Monte Carlo (MC) simulations for the Nucletron microSelectron v2 HDR I192r source. The data include the primary and scatter components of the radial dose function and the anisotropy function in addition to a SC table. The dose to a point of interest for each dwell position is estimated by first calculating the primary and scatter doses in an infinite water phantom. The scatter dose is then scaled by a SC factor that depends on the distances between the point of interest, the dwell positions, and the body contour of the patient. SC calculations in water phantoms of three different shapes, as well as computed tomography-based geometries of 18 multicatheter breast patients, are compared with Task Group 43 (TG-43) and PTRAN_CT MC calculations. The SC calculations show improvement over TG-43 for all test cases while taking 50% longer to run. The target and skin doses for the breast patient plans are unaffected by tissue inhomogeneities, as indicated by an agreement better than 1% between the SC and MC results. On average, TG-43 overestimates the target coverage by 2% and the dose to the hottest 0.1cm3 (D0.1cc) of the skin by 5%. The low-density lung causes the lung and heart D0.1cc to differ by up to 3% for the SC method and by 2%-5% for TG-43 compared with MC calculations. The SC technique is suitable for HDR I192r dose calculations near the skin provided that the dose is nearly unperturbed by internal inhomogeneities. It has been validated for multicatheter breast brachytherapy.
Increased expression of activating factors in large osteoclasts could explain their excessive activity in osteolytic diseases

Large osteoclasts (≥10 nuclei) predominate at sites of pathological bone resorption. We hypothesized this was related to increased resorptive activity of large osteoclasts and have demonstrated previously that larger osteoclasts are 8‐fold more likely to be resorbing than small osteoclasts (2–5 nuclei). Here we ask whether these differences in resorptive activity can be explained by differences in expression of factors involved in osteoclast signaling, fusion, attachment, and matrix degradation. Authentic rabbit osteoclasts and osteoclasts derived from RAW264.7 cells showed similar increases in c‐fms expression (1.7‐ to 1.8‐fold) in large osteoclasts suggesting that RAW cells are a viable system for further analysis. We found 2‐ to 4.5‐fold increases in the expression of the integrins αv and β3, the proteases proMMP9, matMMP9 and pro‐cathepsinK, and in activating receptors RANK, IL‐1R1, and TNFR1 in large osteoclasts. In contrast, small osteoclasts had higher expression of the fusion protein SIRPα1 and the decoy receptor IL‐1R2. The higher expression of activation receptors and lower expression of IL‐1R2 in large osteoclasts suggest they are hyperresponsive to extracellular factors. This is supported by the observation that the resorptive activity in large osteoclasts was more responsive to IL‐1β, and that this increased activity was inhibited by the IL‐1 receptor antagonist, IL‐1ra. This increased responsiveness of large osteoclasts to IL‐1 may, in part, explain the pathological bone loss noted in inflammatory diseases. The heterogeneity in receptor expression and the differential response to cytokines and their antagonists could prove useful for selective inhibition of large osteoclasts actively engaged in pathological bone loss. J. Cell. Biochem. 101: 205–220, 2007. © 2007 Wiley‐Liss, Inc.
Reperfusion after primary angioplasty for ST-elevation myocardial infarction: predictors of success and relationship to clinical outcomes in the APEX-AMI angiographic study.

AIMS We studied the clinical, demographic, and angiographic factors associated with successful reperfusion and the relationship between angiographic indices and clinical outcomes in a subset of the APEX-AMI trial, which tested the efficacy of pexelizumab in ST-elevation myocardial infarction patients undergoing primary percutaneous coronary intervention (PCI). METHODS AND RESULTS Among 5745 patients enrolled in the trial, 1018 underwent independent quantitative angiographic evaluation by a core laboratory. Successful epicardial reperfusion was defined as TIMI (thrombolysis in myocardial infarction) flow grade 3 or corrected TIMI frame count (cTFC) <28 frames, and successful myocardial reperfusion as TIMI myocardial perfusion grade (TMPG) 2 or 3. TIMI 3 flow after PCI occurred in 85%, cTFC < 28 in 58% (mean cTFC was 27 +/- 20), and TMPG 2 or 3 in 91%. Overall 90 day clinical outcomes were 2.7% for mortality and 8.2% for the composite of death, congestive heart failure (CHF), or shock. After adjustment for baseline characteristics, TMPG 2/3 after PCI was associated with younger age [odds ratio (OR) for 10 year increase 0.75, 95% confidence interval (CI) 0.59-0.96, P = 0.023], pre-PCI TIMI flow 2/3 (OR 3.5, 95% CI 1.7-7.1, P = 0.001), and ischaemic time [for every hour, OR 0.81 (0.69-0.96), P = 0.015]. TMPG 2/3 after PCI was significantly associated with 90 day mortality (adjusted hazard ratio 0.26, 95% CI 0.09-0.78, P = 0.013). Neither post-PCI TMPG nor TIMI flow grade was significantly associated with 90 day death/CHF/shock. CONCLUSION Younger age, patent infarct-related artery at presentation, and ischaemic time predicted higher likelihood of successful myocardial perfusion, which was associated with improved survival.
First in humans: A new molecularly defined vaccine shows excellent safety and strong induction of long-lived Mycobacterium tuberculosis-specific Th1-cell like responses

Tuberculosis (TB) remains a major killer worldwide. The only available TB-vaccine, the nearly century-old Mycobacterium bovis BCG, has had only a limited effect on TB incidence. Therefore, developing new TB vaccines is a key priority, and the first new generation TB vaccines are now being tested in clinical trials. Here we describe the development and first testing in humans of a novel, wholly synthetic TB subunit vaccine. This vaccine has proven safe and highly immunogenic in all species in which it was tested, including mice, guinea pigs, non-human primates and humans. Most encouragingly, following vaccination in humans, strong IFN-γ responses persisted through at least 2½ years of follow-up, indicating induction of a substantial memory response by this new TB vaccine. These findings encourage further preclinical and clinical studies with TB subunit vaccines and cellular immunity-stimulating new adjuvants.
Physical detection of influenza A epitopes identifies a stealth subset on human lung epithelium evading natural CD8 immunity

Significance Influenza A viruses (IAVs) are a cause of major morbidity in the human population. Being RNA viruses, replication is error prone, and proteins such as viral envelope hemagglutinin rapidly mutate. Current vaccines stimulate antibodies targeting exposed virion proteins but require annual reformation due to constant sequence variation. In contrast, vaccines that stimulate CD8 T cells directed at conserved peptides from internal proteins would offer stable immunity if these peptides are displayed by HLA proteins on infected cells. Currently, functional readouts infer the IAV peptides displayed. Using new MS technology, epitopes on infected human HLA-A2+ lung epithelium are identified and abundances characterized. The data show interconnections between viral evasion, immunodominance, and stealth responses that will aid in developing cellular vaccines against influenza. Vaccines eliciting immunity against influenza A viruses (IAVs) are currently antibody-based with hemagglutinin-directed antibody titer the only universally accepted immune correlate of protection. To investigate the disconnection between observed CD8 T-cell responses and immunity to IAV, we used a Poisson liquid chromatography data-independent acquisition MS method to physically detect PR8/34 (H1N1), X31 (H3N2), and Victoria/75 (H3N2) epitopes bound to HLA-A*02:01 on human epithelial cells following in vitro infection. Among 32 PR8 peptides (8–10mers) with predicted IC50 < 60 nM, 9 were present, whereas 23 were absent. At 18 h postinfection, epitope copies per cell varied from a low of 0.5 for M13–11 to a high of >500 for M158–66 with PA, HA, PB1, PB2, and NA epitopes also detected. However, aside from M158–66, natural CD8 memory responses against conserved presented epitopes were either absent or only weakly observed by blood Elispot. Moreover, the functional avidities of the immunodominant M158–66/HLA-A*02:01-specific T cells were so poor as to be unable to effectively recognize infected human epithelium. Analysis of T-cell responses to primary PR8 infection in HLA-A*02:01 transgenic B6 mice underscores the poor avidity of T cells recognizing M158–66. By maintaining high levels of surface expression of this epitope on epithelial and dendritic cells, the virus exploits the combination of immunodominance and functional inadequacy to evade HLA-A*02:01-restricted T-cell immunity. A rational approach to CD8 vaccines must characterize processing and presentation of pathogen-derived epitopes as well as resultant immune responses. Correspondingly, vaccines may be directed against “stealth” epitopes, overriding viral chicanery.
Characterization and quantitation by flow cytometry of membranous microparticles formed during activation of platelet suspensions with ionophore or thrombin

The typical data presentation by flow cytometry of platelet suspensions stimulated with calcium ionophore A-23187, thrombin, C5b-9, or other agonists shows a unimodal decrease (or 'left-shift') in forward angle light scatter. Many reports in the literature interpret these findings as indicative of the appearance of small membranous microparticles generated from the platelets as part of the activation response. Investigators may attempt to quantify the microparticles by calculation of the percentage of counts falling below a gate set around the forward angle light scatter distribution of fresh, non-activated platelets. We believe that this approach can lead to erroneous results unless the total particle count in the sample is also determined. The true change in total particle count in a platelet sample is easily estimated on the flow cytometer by adding a known amount of fluorescent beads to the platelet suspension and noting a change in the ratio of bead versus non-bead event counts as a result of the stimulus added. Using this technique under settings considered routine for platelet analysis on a FACScan flow cytometer (Becton-Dickinson), we have found that particle counts increased very little (less than a doubling) in platelet suspensions stimulated with 1-10 w M A-23187 or 0.01-0.5 U/ml thrombin or with sera from patients with diagnosed heparin-induced thrombocytopenia (HIT). Only by employing high sensitivity settings for signal thresholding on orthogonal light scatter, combined with fluorescence gating on high prevalence surface antigens, were we able to detect significant increases (5- or 6-fold) in total particle count in the same experiments. The new events we observed were separated by a decade or more (log scale) from intact platelets on the light scatter plots and fluorescence histograms in a bimodal distribution. We postulate that the unimodal-shifted population of events seen under routine settings after stimulation with ionophore is really degranulated platelets, and only the much smaller new modal subpopulation represents microparticles released as new entities into the platelet suspension. We conclude that without high sensitivity settings for data acquisition, it is most likely incorrect to claim that the left-shifted events on flow cytometry light scatter plots appearing contiguous with the distribution of activated platelets are released microparticles.
Manifestation, Attribution, and Coping With Depression Among Asian Indians From the Perspectives of Health Care Practitioners

The study explores cultural influences on depression and care outcomes among Asian Indians with depression. Data were collected from interviews of 23 multidisciplinary mental health professionals and retrospective review of 20 medical records of patients. Findings revealed a major influence of social and cultural context in expression of symptoms, illness attribution, help-seeking behaviors, and communication patterns. Religious beliefs and social stigma attached to mental illness contributed to prolonged denial of condition, difficulty in sharing emotional problems with professional caregivers, and delayed professional intervention. The traditional family hierarchy rooted in age and gender inequality interfered with help-seeking behaviors and adherence to prescribed regimen as well as heightened some family conflicts and hindered family adaptation after migration to the United States.