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At least 1,585 records · Page 88Linked to original sources
PubMed2004

The burden of atrial fibrillation: should we abandon antiarrhythmic drug therapy?

Atrial fibrillation (AF) is the most common sustained arrhythmia, exacting a substantial toll in cardiovascular morbidity and mortality. Until recently, the prevailing philosophy has been that restoration and maintenance of normal sinus rhythm, as opposed to control of ventricular response rate, was the optimal approach to treatment of AF. A series of landmark trials (AFFIRM, RACE, STAF, and PIAF) have called this strategy into question, suggesting outcomes are equivalent with both approaches. These data do not mean that rhythm control is not beneficial, but highlight the limitations of current therapies to achieve and maintain sinus rhythm. Limitations of the rhythm-control strategy may be related to our difficulty in accurately documenting symptomatic benefit from this approach, the lack of efficacy and excessive adverse-effect burden associated with currently available antiarrhythmic agents, and selection biases in the enrollment of patients in clinical trials of rhythm control versus rate control, making the trials incompletely representative of the population eligible for therapy. New pharmacologic agents under development feature increased atrial selectivity or multi-channel-blocking properties (or both). As a result, these compounds may be more effective in prolonging atrial refractoriness and may also have reduced proarrhythmic potential. It is premature to abandon the concept of rhythm control in AF until we have trials designed to include younger and highly symptomatic patients, more sensitive tools to measure symptomatic improvement, and safer, more effective antiarrhythmic agents.

Anti-Arrhythmia Agents↗
PubMed1995

Diminished teratogenicity of retinoid X receptor-selective synthetic retinoids.

One feature that contraindicates the wide therapeutic use of retinoids is their teratogenicity. Synthetic retinoids are distinguishable from each other on the basis of their partial or exclusive preference in binding and activation of all-trans retinoic acid receptors (RARs) or retinoid X receptors (RXRs). Using mouse embryo limb bud cells in micromass cultures as a bioassay, we examined the inhibitory activities of a number of standard and novel retinoids on chondrogenic cell differentiation. Transient cotransfection of HeLa cells was used to measure the ability of each retinoid to induce transcription of a reporter gene by activating RAR alpha, RAR beta, RAR gamma, or RXR alpha chimeric constructs. All retinoids in this study that activated RARs to any degree in the cotransfection assay also inhibited chondrogenesis in vitro, whereas retinoids that were either specific for RXR or inactive in the cotransfection assay did not. The activity of RAR-selective agonists and the inactivity of RXR-specific agonists in the cotransfection assay correlated well with the relative teratogenicity of six of the representative retinoids studied when orally administered at day 11 to pregnant ICR mice.

Animals↗
PubMed2006

Ca2+-dependent regulation of a non-selective cation channel from Aplysia bag cell neurones.

Ca2+-activated, non-selective cation channels feature prominently in the regulation of neuronal excitability, yet the mechanism of their Ca2+ activation is poorly defined. In the bag cell neurones of Aplysia californica, opening of a voltage-gated, non-selective cation channel initiates a long-lasting afterdischarge that induces egg-laying behaviour. The present study used single-channel recording to investigate Ca2+ activation in this cation channel. Perfusion of Ca2+ onto the cytoplasmic face of channels in excised, inside-out patches yielded a Ca2+ activation EC50 of 10 microm with a Hill coefficient of 0.66. Increasing Ca2+ from 100 nm to 10 microm caused an apparent hyperpolarizing shift in the open probability (Po) versus voltage curve. Beyond 10 microm Ca2+, additional changes in voltage dependence were not evident. Perfusion of Ba2+ onto the cytoplasmic face did not alter Po; moreover, in outside-out recordings, Po was decreased by replacing external Ca2+ with Ba2+ as a charge carrier, suggesting Ca2+ influx through the channel may provide positive feedback. The lack of Ba2+ sensitivity implicated calmodulin in Ca2+ activation. Consistent with this, the application to the cytoplasmic face of calmodulin antagonists, calmidazolium and calmodulin-binding domain, reduced Po, whereas exogenous calmodulin increased Po. Overall, the data indicated that the cation channel is activated by Ca2+ through closely associated calmodulin. Bag cell neurone intracellular Ca2+ rises markedly at the onset of the afterdischarge, which would enhance channel opening and promote bursting to elicit reproduction. Cation channels are essential to nervous system function in many organisms, and closely associated calmodulin may represent a widespread mechanism for their Ca2+ sensitivity.

Animals↗
PubMed2005

Monitoring sequence space as a test for the target of selection in viruses.

An essential feature of viral quasispecies, predicted from quasispecies theory, is that the target of selection is the mutant distribution as a whole. To test molecularly the mutant composition selected from a viral quasispecies we reconstructed a mutant distribution using 19 antigenic variants of foot-and-mouth disease virus (FMDV). Each variant was marked by a specific amino acid replacement at a major antigenic site of the virus that conferred resistance to a monoclonal antibody (mAb). The variants were introduced in the mutant spectrum of a biological FMDV clone, at a frequency commonly found in FMDV quasispecies. The reconstructed quasispecies (and a number of control populations) were allowed to replicate in the presence or absence of the mAb. The mutant distribution that became dominant as a result of antibody selection included at least ten of the 19 mutants initially used to reconstruct the quasispecies. No such biased mutant repertoire was found in control populations. The results show that a mutant distribution was selected, and are incompatible with selection of an individual genome, which then generated multiple mutants upon further replication. An ample representation of variants immediately following a selection event should contribute to subsequent adaptability of the virus.

Amino Acid Sequence↗
PubMed2004

Extraction of shift invariant wavelet features for classification of images with different sizes.

An effective shift invariant wavelet feature extraction method for classification of images with different sizes is proposed. The feature extraction process involves a normalization followed by an adaptive shift invariant wavelet packet transform. An energy signature is computed for each subband of these invariant wavelet coefficients. A reduced subset of energy signatures is selected as the feature vector for classification of images with different sizes. Experimental results show that the proposed method can achieve high classification accuracy of 98.5 percent and outperforms the other two image classification methods.

Algorithms↗
PubMed1997

Acidic cytosolic proteins are preferentially imported into rat liver lysosomes.

Previous studies have reported that lysosomes isolated from human diploid fibroblasts and from rat liver can selectively import and degrade specific proteins. We have now reinvestigated this selectivity using an in vitro assay with rat liver lysosomes and an extract of cytosolic proteins prepared from cultured cells labeled to equilibriums with [35S-]methionine. Analysis by two-dimensional gel electrophoresis and autoradiography of the cytosolic proteins bound to the lysosomal membrane and imported into the lysosomes shows that when all cytosolic proteins are simultaneously present in the in vitro assay the lysosomal uptake also occurs in a specific manner. These findings suggest that isolated lysosomes are able to discriminate among different proteins, selecting those with certain features for lysosomal degradation. Additional characterization of the cytosolic proteins which are selectively imported by lysosomes shows that a common structural feature of most, but not all, of these proteins is an acidic isoelectric point (pI <6.0) and a small or intermediate size. This observation is in agreement with earlier studies which established a relationship between the in vivo half-lives of cytosolic proteins in rat liver and their net charge, with acidic proteins, in general, being degraded more rapidly than neutral or basic proteins. The reasons for this preference are still uncertain, although a possible explanation is presented.

Acids↗
PubMedDate not supplied

Presynaptic selection of afferent inflow in the spinal cord.

The synaptic effectiveness of sensory fibers ending in the spinal cord of vertebrates can be centrally controlled by means of specific sets of GABAergic interneurons that make axo-axonic synapses with the terminal arborizations of the afferent fibers. In the steady state, the intracellular concentration of chloride ions in these terminals is higher than that predicted from a passive distribution, because of an active transport mechanism. Following the release of GABA by spinal interneurons and activation of GABA(A) receptors in the afferent terminals, there is an outwardly directed efflux of chloride ions that produces primary afferent depolarization (PAD) and reduces transmitter release (presynaptic inhibition). Studies made by intrafiber recording of PAD, or by measuring changes in the intraspinal threshold of single afferent terminals (which is reduced during PAD), have further indicated that muscle and cutaneous afferents have distinctive, but modifiable PAD patterns in response to segmental and descending stimuli. This has suggested that PAD and presynaptic inhibition in the various types of afferents is mediated by separate sets of last-order GABAergic interneurons. Direct activation, by means of intraspinal microstimulation, of single or small groups of last-order PAD-mediating interneurons shows that the monosynaptic PAD elicited in Ia and Ib afferents can remain confined to some sets of the intraspinal collaterals and not spread to nearby collaterals. The local character of PAD allows cutaneous and descending inputs to selectively inhibit the PAD of segmental and ascending intraspinal collaterals of individual muscle spindle afferents. It thus seems that the intraspinal branches of the sensory fibers are not hard wired routes that diverge excitation to spinal neurons, but are instead dynamic pathways that can be centrally controlled to address information to selected neuronal targets. This feature appears to play an important role in the selection of information flow in muscle spindles that occurs at the onset of voluntary contractions in humans.

Animals↗
PubMed2003

Extensive structure-activity studies of lactam derivatives of MT-II and SHU-9119: their activity and selectivity at human melanocortin receptors 3, 4, and 5.

The melanocortin system is involved in the regulation of several diverse physiologic pathways. Recently we have demonstrated that replacing His6 by Pro6 in the well-known antagonist SHU-9119 resulted in a potent agonist at the hMC5R (EC50 = 0.072 nm) with full antagonist activity at the hMC3R and the hMC4R. We have designed, synthesized, and pharmacologically characterized a series of peptide analogs of MT-II and SHU-9119 at the human melanocortin receptors MC3R, MC4R and MC5R. All these peptides were modified at position 6 with a Pro instead of a His residue. In this study, we have identified new scaffolds which are antagonists at the hMC4R and hMC3R. Additionally, we have discovered a new selective agonist at the hMC4R, Ac-Nle-c[Asp-Pro-D-Phe-Arg-Trp-Lys]-Pro-Val-NH2 (6, PG-931) which will be useful in further biologic investigations of the hMC4R. PG-931 was about 100-fold more selective for the hMC4R vs. the hMC3R (IC50 = 0.58 and 55 nm, respectively). Some of these new analogs have exceptional biologic potencies at the hMC5R and will be useful in further efforts to differentiate the substructural features responsible for selectivity at the hMC3R, hMC4R, and hMC5R.

Animals↗
PubMed2006

What is being masked in object substitution masking?

Object substitution masking (OSM) is said to occur when a perceptual object is hypothesized that is mismatched by subsequent sensory evidence, leading to a new hypothesized object being substituted for the first. For example, when a brief target is accompanied by a longer lasting display of nonoverlapping mask elements, reporting of target features may be impaired. J. T. Enns and V. Di Lollo (2000) considered it an outstanding question whether OSM masks some or all aspects of a target. The authors report three experiments demonstrating that OSM can selectively affect target features. Participants may be able to detect a target while being unable to report other aspects of it or to report the color but not the orientation of a target (or vice versa). We discuss these findings in relation to two other visual phenomena.

Analysis of Variance↗
PubMed2001

Texture analysis and morphological processing of magnetic resonance imaging assist detection of focal cortical dysplasia in extra-temporal partial epilepsy.

In many patients, focal cortical dysplasia (FCD) is characterized by minor structural changes that may go unrecognized by standard radiological analysis. To increase the sensitivity of magnetic resonance imaging (MRI) for the detection of subtle lesions of FCD, we developed voxel-based image postprocessing methods, including first-order texture analysis and morphological processing modeled on known MRI features of FCD. We selected 16 patients with histologically proven FCD. Image processing features were calculated over a neighborhood for each voxel in the three-dimensional T1-weighted MRI. Three feature maps were generated: (1) gray matter thickness map to model cortical thickening, (2) gradient map to model blurring of the gray matter-white matter junction, and (3) relative intensity map to model the hyperintense signal within the lesion. Two observers detected lesions on conventional MRI in 8/16 and on ratio maps in 14/16 patients. Sensitivity was 87.5% (14/16) for the ratio maps compared to 50% (8/16) for MRI (p < 0.003). Specificity was 95% (19/20) for ratio maps and 100% (20/20) for MRIs. Cohen's kappa was 0.53 for MRIs, indicating moderate agreement, and 0.83 for ratio maps, indicating strong agreement beyond chance between the 2 observers. The image-processing methods developed in this study improve visual detection of FCD, even in cases where no lesion is obvious on MRI. These techniques could increase the number of patients with partial epilepsy who could benefit from surgery.

Cell Movement↗
PubMed1986

A further search for selective antagonists at M2-muscarinic receptors.

In an attempt to obtain more selective antagonists acting at muscarinic M2-receptors, analogues of 4-diphenylacetoxy-N-methylpiperidine methobromide (4-DAMP methobromide) have been synthesized. These were tested, along with silabenzhexol, procyclidine, sila-procyclidine and AFDX-116, in dose-ratio experiments with guinea-pig isolated atria at 30 degrees C and ileum at 30 degrees C and 37 degrees C. The agonist was carbachol and the selectivity was assessed from the difference between log K for receptors in ileum and log K for receptors in atria. The selectivity was not related to the affinity and some weakly active compounds retained appreciable selectivity but no compound had greater selectivity than 4-DAMP methobromide or pentamethylene bis-(4-diphenylacetoxy-N-methylpiperidinium) bromide. Structure-activity relations are discussed. There seem to be steric limits to affinity but there are no obvious indications of the structural features associated with selectivity. It is suggested that more selective drugs may be obtained by introducing groups which may reduce affinity.

Animals↗
PubMed2006

Advanced gastrointestinal stromal tumor patients with complete response after treatment with imatinib mesylate.

AIM: Most gastrointestinal stromal tumors (GISTs) express constitutively activated mutant isoforms of kit kinase or platelet-derived growth factor receptor alpha (PDGFRA), which are potential therapeutic targets for imatinib mesylate (Glivec). Partial response occurred in almost two thirds of GIST patients treated with Glivec. However, complete response (CR) after Glivec therapy was sporadically reported. Here we illustrated advanced GIST patients with CR after Glivec treatment. METHODS: Between January 2001 and June 2005, 42 advanced GIST patients were treated with Glivec. Patients were administered 400 mg of Glivec in 100-mg capsules, taken orally daily with food. The response of the tumor to Glivec was evaluated after one month, three months, and every three months thereafter or whenever medical need was indicated. Each tumor of patients was investigated for mutations of kit or PDGFRA. RESULTS: The median follow-up time of the 42 advanced GIST patients treated with Glivec was 16.9 months (range, 1.0-47.0 months). Overall, 3 patients had complete response CR (7.1%), 26 partial response (67.8%), 5 stationary disease (11.9%), and 3 progressive disease (11.9%). The median duration of Glivec administration for the three patients was 36 months (range, 23-36 months). The median time to CR after Glivec treatment was 20 months (range, 9-26 months). Deletion and insertion mutations of c-kit exon 11 and insertion mutation of c-kit exon 9 were found in two cases and one case, respectively. CONCLUSION: Complete response (CR) can be achi-eved in selected advanced GIST patients treated with Glivec. The median time to CR after Glivec treatment was 20 months. Deletion and insertion mutations of kit exon 11 and insertion mutation of kit exon 9 contribute to the genetic features in these selected cases.

Antineoplastic Agents↗
PubMed2003

Hot spot detection based on feature space representation of visual search.

This paper presents a new framework for capturing intrinsic visual search behavior of different observers in image understanding by analysing saccadic eye movements in feature space. The method is based on the information theory for identifying salient image features based on which visual search is performed. We demonstrate how to obtain feature space fixation density functions that are normalized to the image content along the scan paths. This allows a reliable identification of salient image features that can be mapped back to spatial space for highlighting regions of interest and attention selection. A two-color conjunction search experiment has been implemented to illustrate the theoretical framework of the proposed method including feature selection, hot spot detection, and back-projection. The practical value of the method is demonstrated with computed tomography image of centrilobular emphysema, and we discuss how the proposed framework can be used as a basis for decision support in medical image understanding.

Adult↗
PubMed1999

[An approach to the cytologic diagnostic criteria of hepatocellular carcinoma by fine needle aspiration biopsy].

OBJECTIVE: To identify useful cytologic features for diagnosis of hepatocellular carcinoma (HCC). METHODS: Fine needle aspiration(FNA) smears from 61 patients with proven HCC, 19 patients with metastatic tumors in the liver and 16 patients with non-neoplastic lesion of the liver were reviewed in order to detect the relevant cytologic changes associated with HCC. Step-wise logistic regression analysis was done to select useful cytologic features in discriminating HCC from metastatic tumors and non-neoplastic lesions of liver. RESULTS: Nine cytologic features observed were significantly associated with HCC: abundant tissue fragments(91.8%); trabecular pattern(91.8%); sinusoidal endothelial cells (47.5%); polygonal cells with centrally placed nuclei(82.0%); increased nuclear to cytoplasmic ratio(95.1%); large nucleoli(55.7%); bile granules(31.1%); cytoplasmic vacuoles(27.9%) and atypical naked hepatocyte nuclei(88.5%). In distinquishing HCC from metastatic tumors, polygonal cells with centrally placed nuclei, bile granules and trabecular pattern were useful cytologic features. Of the 61 patients with HCC, the logistic model correctly predicted 60(98.4%) as having HCC, while of the 19 patients with metastatic tumors, 18(94.7%) were correctly predicted. In distinquishing HCC from non-neoplastic liver disease, abundant tissue fragments, trebecular pattern, increased nuclear to cytoplasmic ratio and atypical naked hepatocyte nuclei were selected. When the four criteria were used, the sensitivity of diagnosing HCC was 100% and the specificity was 93.8%. CONCLUSION: Abundant tissue fragments, polygonal cells with centrally placed nuclei, increased nuclear to cytoplasmic ratio, trebecular pattern, atypical naked hepatocyte nuclei and bile granules are useful features for identifying HCC by FNA biopsy.

Biopsy, Needle↗
PubMed1985

[Tumor-targeted chemotherapy with lipid contrast medium and macro molecular anticancer agents theoretical considerations and clinical outcome].

Theoretical considerations for tumor-selective chemotherapy are described which based on the unique character of the tumor neovasculature. Namely, most solid tumors possess four different unique features: hypervasculature, enhanced permeability even to macromolecules, architectural differences, and lack of the lymphatic recovery system. Lipid or lipid contrast medium and macromolecular anticancer agents using prototype drug smancs can be utilized for cancer-selective targeting based on the above four features. Selective targeting with lipid contrast medium with smancs has offered two clinical benefits; definite and pronounced antitumor effect and diagnostic value. These effects can be primarily attributed to the tumor-selective accumulation of the agent, i.e., more than 1,000 times greater in the tumor than in the plasma. As a consequence very few side effects are observed clinically. Primary or secondary hepatoma and lung cancer showed size reduction in more than 90 % of treated patients. Very few side effects such as hematosuppression or inhibited liver function were observed in these cases. Prolongation of life-span was marked in the patients. The above results indicate a new future direction for the development of the tumor-selective chemotherapy.

Animals↗
PubMed1998

The discovery and structure-activity relationships of nonpeptide, low molecular weight antagonists selective for the endothelin ET(B) receptor.

The systematic modification of the ETA selective N-(5-isoxazolyl)benzene-sulfonamide endothelin antagonists to give ETB selective antagonists is reported. The reversal in selectivity was brought about by substitution of the 4-position with aryl and substituted aryl groups. Of all the aromatic substituents studied, the para-tolyl group gave rise to the most active and selective ETB antagonist. Larger substituents caused a decrease in both ETB activity and selectivity. A similar trend was observed by substitution at the 5-position of the N-(5-isoxazolyl)-2-thiophenesulfonamide ETA receptor antagonists. The para-tolyl group was again found to be optimal for the ETB activity and selectivity. The structural features that were found to be favorable for binding to the ETB receptor, that is, the presence of a linear, conjugated pi-system of definite shape and size, have been successfully incorporated into the design of ETB selective polycyclic aromatic sulfonamides antagonists.

Animals↗
PubMed2006

Commitment issues: linking positive selection signals and lineage diversification in the thymus.

The thymus is responsible for the production of CD4+ helper and CD8+ cytotoxic T cells, which constitute the cellular arm of the immune system. These cell types derive from common precursors that interact with thymic stroma in a T-cell receptor (TCR)-specific fashion, generating intracellular signals that are translated into function-specific changes in gene expression. This overall process is termed positive selection, but it encompasses a number of temporally distinct and possibly mechanistically distinct cellular changes, including rescue from apoptosis, initiation of cell differentiation, and commitment to the CD4+ or CD8+ T-cell lineage. One of the puzzling features of positive selection is how specificity of the TCR controls lineage commitment, as both helper and cytolytic T cells utilize the same antigen-receptor components, with the exception of the CD4 or CD8 coreceptors themselves. In this review, we focus on the signals required for positive selection, particularly as they relate to lineage commitment. Identification of genes encoding transcriptional regulators that play a role in T-cell development has led to significant recent advances in the field. We also provide an overview of nuclear factors in this context and, where known, how their regulation is linked to the same TCR signals that have been implicated in initiating and regulating positive selection.

Animals↗