1,032 research outputs found
Inhibition of the unique repolarisation K+ channel current IKur by verapamil in human atrial myocytes
Abstract no. CVS-03published_or_final_versio
Differential Effects of Tyrosine Kinase Inhibitors on Volume-sensitive Chloride Current in Human Atrial Myocytes: Evidence for Dual Regulation by Src and EGFR Kinases
To determine whether protein tyrosine kinase (PTK) modulates volume-sensitive chloride current (I Cl.vol) in human atrial myocytes and to identify the PTKs involved, we studied the effects of broad-spectrum and selective PTK inhibitors and the protein tyrosine phosphatase (PTP) inhibitor orthovanadate (VO 4 -3). I Cl.vol evoked by hyposmotic bath solution (0.6-times isosmotic, 0.6T) was enhanced by genistein, a broad-spectrum PTK inhibitor, in a concentration-dependent manner (EC 50 = 22.4 μM); 100 μM genistein stimulated I Cl.vol by 122.4 ± 10.6%. The genistein-stimulated current was inhibited by DIDS (4,4′-diisothiocyanostilbene-2,2′-disulfonic acid, 150 μM) and tamoxifen (20 μM), blockers of I Cl.vol. Moreover, the current augmented by genistein was volume dependent; it was abolished by hyperosmotic shrinkage in 1.4T, and genistein did not activate Cl - current in 1T. In contrast to the stimulatory effects of genistein, 100 μM tyrphostin A23 (AG 18) and A25 (AG 82) inhibited I Cl.vol by 38.2 ± 4.9% and 40.9 ± 3.4%, respectively. The inactive analogs, daidzein and tyrphostin A63 (AG 43), did not alter I Cl.vol. In addition, the PTP inhibitor VO 4 -3 (1 mM) reduced I Cl.vol by 53.5 ± 4.5% (IC 50 = 249.6 μM). Pretreatment with VO 4 -3 antagonized genistein-induced augmentation and A23- or A25-induced suppression of I Cl.vol. Furthermore, the selective Src-family PTK inhibitor PP2 (5 μM) stimulated I Cl.vol, mimicking genistein, whereas the selective EGFR (ErbB-1) kinase inhibitor tyrphostin B56 (AG 556, 25 μM) reduced I Cl.vol, mimicking A23 and A25. The effects of both PP2 and B56 also were substantially antagonized by pretreatment with VO 4 -3. The results suggest that I Cl.vol is regulated in part by the balance between PTK and PTP activity. Regulation is complex, however. Src and EGFR kinases, distinct soluble and receptor-mediated PTK families, have opposing effects on I Cl.vol, and multiple target proteins are likely to be involved.published_or_final_versio
The Effect of Solvent Vapor Annealing on Drug-Loaded Electrospun Polymer Fibers
Electrospinning has emerged as a powerful strategy to develop controlled release drug delivery systems but the effects of post-fabrication solvent vapor annealing on drug-loaded electrospun fibers have not been explored to date. In this work, electrospun poly(ԑ-caprolactone) (PCL) fibers loaded with the hydrophobic small-molecule spironolactone (SPL) were explored. Immediately after fabrication, the fibers are smooth and cylindrical. However, during storage the PCL crystallinity in the fibers is observed to increase, demonstrating a lack of stability. When freshly-prepared fibers are annealed with acetone vapor, the amorphous PCL chains recrystallize, resulting in the fiber surfaces becoming wrinkled and yielding shish-kebab like structures. This effect does not arise after the fibers have been aged. SPL is found to be amorphously dispersed in the PCL matrix both immediately after electrospinning and after annealing. In vitro dissolution studies revealed that while the fresh fibers show a rapid burst of SPL release, after annealing more extended release profiles are observed. Both the rate and extent of release can be varied through changing the annealing time. Further, the annealed formulations are shown to be stable upon storage
Assessing the Health of Richibucto Estuary with the Latent Health Factor Index
The ability to quantitatively assess the health of an ecosystem is often of
great interest to those tasked with monitoring and conserving ecosystems. For
decades, research in this area has relied upon multimetric indices of various
forms. Although indices may be numbers, many are constructed based on
procedures that are highly qualitative in nature, thus limiting the
quantitative rigour of the practical interpretations made from these indices.
The statistical modelling approach to construct the latent health factor index
(LHFI) was recently developed to express ecological data, collected to
construct conventional multimetric health indices, in a rigorous quantitative
model that integrates qualitative features of ecosystem health and preconceived
ecological relationships among such features. This hierarchical modelling
approach allows (a) statistical inference of health for observed sites and (b)
prediction of health for unobserved sites, all accompanied by formal
uncertainty statements. Thus far, the LHFI approach has been demonstrated and
validated on freshwater ecosystems. The goal of this paper is to adapt this
approach to modelling estuarine ecosystem health, particularly that of the
previously unassessed system in Richibucto in New Brunswick, Canada. Field data
correspond to biotic health metrics that constitute the AZTI marine biotic
index (AMBI) and abiotic predictors preconceived to influence biota. We also
briefly discuss related LHFI research involving additional metrics that form
the infaunal trophic index (ITI). Our paper is the first to construct a
scientifically sensible model to rigorously identify the collective explanatory
capacity of salinity, distance downstream, channel depth, and silt-clay content
--- all regarded a priori as qualitatively important abiotic drivers ---
towards site health in the Richibucto ecosystem.Comment: On 2013-05-01, a revised version of this article was accepted for
publication in PLoS One. See Journal reference and DOI belo
Circuit dissection of the role of somatostatin in itch and pain
Stimuli that elicit itch are detected by sensory neurons that innervate the skin. This information is processed by the spinal cord; however, the way in which this occurs is still poorly understood. Here we investigated the neuronal pathways for itch neurotransmission, particularly the contribution of the neuropeptide somatostatin. We find that in the periphery, somatostatin is exclusively expressed in Nppb+ neurons, and we demonstrate that Nppb+somatostatin+ cells function as pruriceptors. Employing chemogenetics, pharmacology and cell-specific ablation methods, we demonstrate that somatostatin potentiates itch by inhibiting inhibitory dynorphin neurons, which results in disinhibition of GRPR+ neurons. Furthermore, elimination of somatostatin from primary afferents and/or from spinal interneurons demonstrates differential involvement of the peptide released from these sources in itch and pain. Our results define the neural circuit underlying somatostatin-induced itch and characterize a contrasting antinociceptive role for the peptide
Absence of association between angiotensin converting enzyme polymorphism and development of adult respiratory distress syndrome in patients with severe acute respiratory syndrome: a case control study
BACKGROUND: It has been postulated that genetic predisposition may influence the susceptibility to SARS-coronavirus infection and disease outcomes. A recent study has suggested that the deletion allele (D allele) of the angiotensin converting enzyme (ACE) gene is associated with hypoxemia in SARS patients. Moreover, the ACE D allele has been shown to be more prevalent in patients suffering from adult respiratory distress syndrome (ARDS) in a previous study. Thus, we have investigated the association between ACE insertion/deletion (I/D) polymorphism and the progression to ARDS or requirement of intensive care in SARS patients. METHOD: One hundred and forty genetically unrelated Chinese SARS patients and 326 healthy volunteers were recruited. The ACE I/D genotypes were determined by polymerase chain reaction and agarose gel electrophoresis. RESULTS: There is no significant difference in the genotypic distributions and the allelic frequencies of the ACE I/D polymorphism between the SARS patients and the healthy control subjects. Moreover, there is also no evidence that ACE I/D polymorphism is associated with the progression to ARDS or the requirement of intensive care in the SARS patients. In multivariate logistic analysis, age is the only factor associated with the development of ARDS while age and male sex are independent factors associated with the requirement of intensive care. CONCLUSION: The ACE I/D polymorphism is not directly related to increased susceptibility to SARS-coronavirus infection and is not associated with poor outcomes after SARS-coronavirus infection
Closing in on Asymmetric Dark Matter I: Model independent limits for interactions with quarks
It is argued that experimental constraints on theories of asymmetric dark
matter (ADM) almost certainly require that the DM be part of a richer hidden
sector of interacting states of comparable mass or lighter. A general requisite
of models of ADM is that the vast majority of the symmetric component of the DM
number density must be removed in order to explain the observed relationship
via the DM asymmetry. Demanding the efficient
annihilation of the symmetric component leads to a tension with experimental
limits if the annihilation is directly to Standard Model (SM) degrees of
freedom. A comprehensive effective operator analysis of the model independent
constraints on ADM from direct detection experiments and LHC monojet searches
is presented. Notably, the limits obtained essentially exclude models of ADM
with mass 1GeV 100GeV annihilating to SM quarks via
heavy mediator states. This motivates the study of portal interactions between
the dark and SM sectors mediated by light states. Resonances and threshold
effects involving the new light states are shown to be important for
determining the exclusion limits.Comment: 18+6 pages, 18 figures. v2: version accepted for publicatio
Less Anterior Knee Pain with a Mobile-bearing Prosthesis Compared with a Fixed-bearing Prosthesis
Anterior knee pain is one of the major short-term complaints after TKA. Since the introduction of the mobile-bearing TKA, numerous studies have attempted to confirm the theoretical advantages of a mobile-bearing TKA over a fixed-bearing TKA but most show little or no actual benefits. The concept of self-alignment for the mobile bearing suggests the posterior-stabilized mobile-bearing TKA would provide a lower incidence of anterior knee pain compared with a fixed-bearing TKA. We therefore asked whether the posterior-stabilized mobile-bearing knee would in fact reduce anterior knee pain. We randomized 103 patients scheduled for cemented three-component TKA for osteoarthrosis in a prospective, double-blind clinical trial. With a 1-year followup, more patients experienced persistent anterior knee pain in the posterior-stabilized fixed-bearing group (10 of 53, 18.9%) than in the posterior-stabilized mobile-bearing group (two of 47, 4.3%). No differences were observed for range of motion, visual analog scale for pain, Oxford 12-item questionnaire, SF-36, or the American Knee Society score. The posterior-stabilized mobile-bearing knee therefore seems to provide a short-term advantage compared with the posterior-stabilized fixed-bearing knee
Avaliação biomecânica do cimento ortopédico combinado com antibiótico e azul de metileno
Salmonella paratyphi C: Genetic Divergence from Salmonella choleraesuis and Pathogenic Convergence with Salmonella typhi
BACKGROUND: Although over 1400 Salmonella serovars cause usually self-limited gastroenteritis in humans, a few, e.g., Salmonella typhi and S. paratyphi C, cause typhoid, a potentially fatal systemic infection. It is not known whether the typhoid agents have evolved from a common ancestor (by divergent processes) or acquired similar pathogenic traits independently (by convergent processes). Comparison of different typhoid agents with non-typhoidal Salmonella lineages will provide excellent models for studies on how similar pathogens might have evolved. METHODOLOGIES/PRINCIPAL FINDINGS: We sequenced a strain of S. paratyphi C, RKS4594, and compared it with previously sequenced Salmonella strains. RKS4594 contains a chromosome of 4,833,080 bp and a plasmid of 55,414 bp. We predicted 4,640 intact coding sequences (4,578 in the chromosome and 62 in the plasmid) and 152 pseudogenes (149 in the chromosome and 3 in the plasmid). RKS4594 shares as many as 4346 of the 4,640 genes with a strain of S. choleraesuis, which is primarily a swine pathogen, but only 4008 genes with another human-adapted typhoid agent, S. typhi. Comparison of 3691 genes shared by all six sequenced Salmonella strains placed S. paratyphi C and S. choleraesuis together at one end, and S. typhi at the opposite end, of the phylogenetic tree, demonstrating separate ancestries of the human-adapted typhoid agents. S. paratyphi C seemed to have suffered enormous selection pressures during its adaptation to man as suggested by the differential nucleotide substitutions and different sets of pseudogenes, between S. paratyphi C and S. choleraesuis. CONCLUSIONS: S. paratyphi C does not share a common ancestor with other human-adapted typhoid agents, supporting the convergent evolution model of the typhoid agents. S. paratyphi C has diverged from a common ancestor with S. choleraesuis by accumulating genomic novelty during adaptation to man
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