Cyclooxygenase (COX-2) selective inhibitors. Any better than NSAIDs?
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Anti-Inflammatory Agents, Non-Steroidal↗
Biomedical subjects
A Nguyen
Publications and source records attributed to A Nguyen.
In vivo gene expression profile analysis of metallothionein in renal cell carcinoma.
The antiapoptotic and mitogenic responses of metallothionein (MT) have been well documented in vitro. While MT protein overexpression, frequently encountered in a number of human primary tumors, has been shown to be correlated with disease progression, little information is available on the in vivo isoform expression of MT. In this study we have demonstrated the occurrence of MT proteins and further defined their differential expression profile in human primary renal cell carcinoma (RCC). Pooled normal human kidney RNA and paired biopsy specimens (tumor and control) obtained from 11 patients diagnosed with RCC with tumor grade ranging from 1-3 and a pathological staging of T2-T3 (N0M0) were used for the study. Samples were analyzed for the presence of MT protein using immunohistochemical (IHC) analysis and for MT isoform-specific mRNA expression by reverse transcriptase polymerase chain reaction. Metallothionein protein assumed both cytoplasmic and nuclear staining in cancer cells and was detected in eight of 11 samples (72%) with polyclonal antibodies. The immunoreactivity of MT protein, but not its cellular localization, in RCC specimens suggests a relationship between and advanced disease. While alterations in the basal level of expression of MT-1E, MT-1F and MT-1X genes remained unchanged, significant up-regulation of MT-2A and down-regulation of MT-1A and MT-1G transcripts was observed in RCC tissue specimens when compared with controls. Intriguingly, the paired RCC biopsy specimens had lower MT-1H transcripts than pooled normal human controls. We here provide the first report of the differential expression of MT isoforms in human RCC and that this data further support the role of MT-2A in tumorigenesis.
Adult↗
Clinical presentation as a guide to the identification of GERD in children.
OBJECTIVE: to determine if there is a correlation between common otolaryngologic symptoms and presence of gastroesophageal reflux disease (GERD) in children. METHODS: charts of 295 children presenting with suspicion of GERD were reviewed for presenting symptoms including: (1) airway symptoms: stertor, stridor, frequent cough, recurrent croup, wheezing, nasal congestion, obstructive apnea, blue spells, hoarseness, throat clearing; (2) feeding symptoms: wet burps, globus sensation, frequent emesis, dysphagia, choking/gagging, sore throat, halitosis, food refusal, stomach aches, arching, drooling, chest pain, irritability, and failure to thrive. At least one positive test of barium esophagram, gastric scintiscan, pH probe or esophageal biopsy resulted in inclusion in the GERD positive group. RESULTS: 214 children had GERD diagnosed while 81 had no positive tests for GERD. Between the GERD positive and GERD negative groups, the significantly different symptoms were stertor (P=0.040), cyanotic spells (P=0.043), frequent emesis (P=0.007), failure to thrive (P=0.006), and choking/gagging (P=0.044). Three pooled variables were created: airway flow (stertor, stridor, cyanotic spells), airway irritation (frequent cough, recurrent croup, throat clearing), and feeding (dysphagia, failure to thrive, frequent emesis). GERD patients who were 2 years or less were compared to those older than 2 years and all three of these pooled variables were significantly different between these groups (P<0. 001). CONCLUSION: children who present with a certain constellation of airway or feeding symptoms are more likely to have a positive GERD test. Children 2 years old or less are more likely to present with airway symptoms or feeding difficulties while children older than 2 years are more likely to present with airway irritation.
Airway Obstruction↗
Human alpha 1,3/4 fucosyltransferases. Characterization of highly conserved cysteine residues and N-linked glycosylation sites.
Human alpha1,3 fucosyltransferases (FucTs) contain four highly conserved cysteine (Cys) residues, in addition to a free Cys residue that lies near the binding site for GDP-fucose (Holmes, E. H., Xu, Z. , Sherwood, A. L., and Macher, B. A. (1995) J. Biol. Chem. 270, 8145-8151). The participation of the highly conserved Cys residues in disulfide bonds and their functional significance were characterized by mass spectrometry (MS) analyses and site-directed mutagenesis, respectively. Among the human FucTs is a subset of enzymes (FucT III, V, and VI) having highly homologous sequences, especially in the catalytic domain, and Cys residues in FucT III and V were characterized. The amino acid sequence of FucT III was characterized. Peptides containing the four conserved Cys residues were detected after reduction and alkylation, and found to be involved in disulfide bonds. The disulfide bond pattern was characterized by multiple stage MS analysis and the use of Glu-C protease and MS/MS analysis. Disulfide bonds in FucT III occur between Cys residues (Cys(81) to Cys(338) and Cys(91) to Cys(341)) at the N and C termini of the catalytic domain, bringing these ends close together in space. Mutagenesis of highly conserved Cys residues to Ser in FucT V resulted in proteins lacking enzymatic activity. Three of the four mutants have molecular weights similar to wild type enzyme and maintained an ability to bind GDP, whereas the other (Cys(104)) produced a series of lower molecular weight bands when characterized by Western blot analysis, and did not bind GDP. FucTs have highly conserved, potential N-linked sites, and our mass spectrometry analyses demonstrated that both N-linked sites are modified with oligosaccharides.
Amino Acid Sequence↗
Sensory changes associated with selective neck dissection.
OBJECTIVE: To evaluate sensory changes in the head and neck region associated with selective neck dissection with or without preservation of cervical root branches. DESIGN: Retrospective cohort study. SETTING: University tertiary referral hospital and a Veterans Affairs hospital. PATIENTS: Fifty-seven patients who had undergone 84 neck dissections with or without preservation of the sensory cervical root branches 3 or more months before evaluation. INTERVENTIONS: Questionnaire combined with head and neck sensory examination. MAIN OUTCOME MEASURES: Neck and facial sensory function. RESULTS: Neck dissections with preservation of the cervical rootlets were most likely to be associated with a small area of anesthesia in the upper neck below the body of the mandible and anterior to the mid-body of the mandible (P=.03). Neck dissections without rootlet-preserving technique increased the area of anesthesia to include all other areas of the neck (P= .02). CONCLUSIONS: Preservation of the cervical root branches resulted in a small, limited, and uniform area of the neck rendered permanently anesthetic. Conversely, sacrifice of the nerve branches led to a pattern of anesthesia involving the entire neck.
Aged↗
Chromosomes are target sites for photodynamic therapy as demonstrated by subcellular laser microirradiation.
The present investigation has been undertaken to examine the possibility that the cell nucleus, and specifically the genetic material, is a target site for photodynamic therapy. PTK2 and Hep-2 cells are pretreated with a medium containing 15 microg/ml (0.09 mM) 5-aminolevulinic acid (ALA). Individual fluorescence images are recorded for each selected cell using a cooled charge-coupled device (CCD). A laser microbeam system generating 630 nm is used for subcellular-region irradiation of specific targets: chromosomes, the mitotic spindle, the perispindle region and the peripheral cytoplasm. Nuclei of interphase cells are also irradiated. Data comparing the sensitivities of the different subcellular microirradiation sites in ALA-treated mitotic cells demonstrate that under the irradiation conditions used, the chromosome is the most sensitive subcellular target followed by the perispindle region, the peripheral cytoplasm and spindle, and, lastly, the interphase nucleus.
Aminolevulinic Acid↗
Correlation of findings on direct laryngoscopy and bronchoscopy with presence of extraesophageal reflux disease.
OBJECTIVE: To determine the correlation between findings at direct laryngoscopy and bronchoscopy and presence of extraesophageal reflux disease (EERD). STUDY DESIGN: Retrospective chart review METHODS: Operative notes of 155 children undergoing direct laryngoscopy and bronchoscopy between 1996 and 1999 for airway symptoms for whom there was a suspicion of EERD were examined. Gastroesophageal reflux disease (GERD) was considered present if at least one test was positive (including upper GI series, pH probe, gastric scintiscan, or esophageal biopsy). RESULTS: A total of 130 (84%) patients had GERD diagnosed. Ninety percent had at least one laryngotracheal abnormality: 83% had an abnormal larynx and 66% had an abnormal trachea. Laryngeal abnormalities in GERD included postglottic edema, 69%; arytenoid edema, 30%; large lingual tonsil, 16%; vocal fold edema, 12%; vocal fold nodule, 12%; ventricular obliteration, 5%; and hypopharyngeal cobblestoning, 3%. Tracheobronchial abnormalities in GERD included tracheal cobblestoning, 33%; blunting of carina, 12.5%; subglottic stenosis, 11%; increased secretions, 11%; and generalized edema or erythema, 5%. The best sensitivity or specificity was obtained by combining postglottic edema, arytenoid edema, and vocal fold edema, resulting in a sensitivity of 75% and a specificity of 67%. Positive predictive value was 100% for the combination of postglottic edema and any vocal fold or ventricular abnormality. CONCLUSION: Laryngoscopy and bronchoscopy can reveal findings with a high positive predictive value for the presence of GERD. Endoscopy of the upper airway in children with clinical signs and symptoms of EERD is a promising tool for diagnosis.
Bronchi↗
Review and management of patients with the prothrombin G20210A polymorphism.
A single mutation in the 3'-untranslated region of the prothrombin gene, resulting in a G to A substitution, was recently reported. This finding added to the growing list of genetic disorders thought to be responsible for familial thrombophilia. Although most studies are in general agreement about the elevated risk of venous thrombosis in individuals carrying this mutation, its role in the first event of venous thromboembolism and recurrent events is unclear. Even less clear is the role that this mutation plays in the formation of arterial thrombosis (including coronary artery disease and cerebral ischemia), as studies show contradicting results. Because of this, it is not recommended as part of the routine screening of patients with venous thromboembolism. However, there are certain subgroups of patients who should undergo testing. The discovery of this prothrombin mutation has important clinical implications because it is the second most common cause of genetic thrombophilia, second only to the factor V Leiden. Moreover, its discovery likely will augment the clinician's ability to systematically risk-stratify an individual's likelihood of developing spontaneous thrombosis.
3' Untranslated Regions↗
Prothrombin G20210A polymorphism and thrombophilia.
Recently, a single mutation in the 3'-untranslated region of the prothrombin gene was reported, resulting in a G-to-A substitution. This finding added to the growing list of genetic disorders thought to be responsible for familial thrombophilia. Although most studies generally agree about the increased risk of venous thrombosis in individuals carrying this mutation, its role in the first event of venous thromboembolism and in recurrent events is unclear. Even less clear is the role this mutation has in the formation of arterial thrombosis (including coronary artery disease and cerebral ischemia) due to contradicting results of studies. This mutation has important clinical implications since it is a common cause of genetic thrombophilia, second only to the factor V Leiden mutation. However, the mutation by itself may not be enough to trigger disease because thromboembolic disease is now generally accepted as a multifactorial disorder. Careful evaluation of this mutation will augment the clinician's ability to stratify systematically an individual's risk of developing spontaneous thrombosis.
Adenosine↗
Pyogenic granuloma (pregnancy tumor) of the nasal cavity. A case report.
BACKGROUND: Pyogenic granuloma is a benign lesion of unknown etiology that occurs in the skin and mucous membranes. It has been reported as a common lesion of the oral cavity and, less commonly, the nasal cavity. Although its etiology is unclear, pyogenic granuloma has long been associated with pregnancy, oral contraceptives and trauma. The term pregnancy tumor has been used to reflect the association with pregnancy; nevertheless, pyogenic granuloma is often misdiagnosed in obstetric patients. CASE: We present the case of a 37-year-old, pregnant woman with an enlarging nasal mass ultimately diagnosed as pyogenic granuloma. The patient was treated successfully with endoscopic excision of the lesion. CONCLUSION: Pyogenic granuloma is a rapidly growing lesion that should be considered in the differential diagnosis of any gravid patient with a mass in the oral or nasal cavity. The lesion may result in complications of the pregnancy, and management should be individualized for each patient.
Adult↗
In vitro response of neuromuscular blockers after chronic carbamazepine treatment in rats.
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Animals↗
Ability of a nondepleting anti-CD4 antibody to inhibit Th2 responses and allergic lung inflammation is independent of coreceptor function.
Nondepleting anti-CD4 Abs have been used in vivo to induce Ag-specific immunological tolerance in Th1 responses, including tissue allograft rejection and autoimmune diabetes. To examine whether this Ab (YTS177.9) acts by provoking a Th2 shift, we tested the effect in a mouse model of allergic lung inflammation. Interestingly, nondepleting anti-CD4 treatment induces tolerance to allergens as well, especially when given during initial priming. In vitro studies indicate that the effect of the Ab is independent of CD4 coreceptor function, as Ab treatment also inhibits proliferation and induces a persistent anergy in naive CD4 T cells stimulated by anti-CD3/CD28. Moreover, the Ab stimulated a distinct pattern of tyrosine phosphorylation in T cells even in the absence of TCR triggering, suggesting that signaling through CD4 alone induces significant physiological changes in T cell function. These results show that tolerance induced by anti-CD4 triggering is not a simple shift in Th1/Th2 effector function or depletion of Ag-specific cells, but may instead induce a persistent clonal anergy capable of blocking subsequent immunity.
Administration, Intranasal↗
Congenital nephrotic syndrome in mice lacking CD2-associated protein.
CD2-associated protein (CD2AP) is an 80-kilodalton protein that is critical for stabilizing contacts between T cells and antigen-presenting cells. In CD2AP-deficient mice, immune function was compromised, but the mice died at 6 to 7 weeks of age from renal failure. In the kidney, CD2AP was expressed primarily in glomerular epithelial cells. Knockout mice exhibited defects in epithelial cell foot processes, accompanied by mesangial cell hyperplasia and extracellular matrix deposition. Supporting a role for CD2AP in the specialized cell junction known as the slit diaphragm, CD2AP associated with nephrin, the primary component of the slit diaphragm.
Adaptor Proteins, Signal Transducing↗
Effects of ethanol on platelet responses associated with adhesion to collagen.
Adhesion of platelets to collagen in damaged blood vessels or ruptured atherosclerotic plaques is important in hemostasis and arterial thrombosis. Adhesion to collagen results in secretion of granule contents and formation of thromboxane A2; thromboxane A2 and released ADP synergistically promote aggregation around platelets adherent to collagen. Ethanol inhibits collagen-induced platelet aggregation, secretion, arachidonate mobilization, and thromboxane A2 formation but does not inhibit platelet adhesion to de-endothelialized rabbit aortae. We investigated whether ethanol affects the initial signalling events and responses of platelets adherent to collagen, independent of the actions of secondary agonists. Suspensions of washed human platelets, labelled by incorporation of [3H]oleate into phospholipids, were used to measure platelet adhesion to collagen by a filtration method; studies were done in the presence of an ADP-removing system and blockers of receptors for thromboxane A2, platelet-activating factor, serotonin, and fibrinogen. Ethanol (87 mM) did not affect the rate or extent of platelet adhesion to collagen or secretion of [14C]serotonin from prelabelled platelets adherent to collagen, but ethanol did inhibit thromboxane A2 formation. Previous studies showed that ethanol does not affect platelet stimulation by arachidonate, leading to the suggestion that reduced mobilization of arachidonate, rather than inhibition of its conversion to thromboxane A2, is responsible for inhibition by ethanol of thromboxane A2 formation. Here, we show by a gel mobility shift assay and immunoblotting, that ethanol delays the collagen-induced increase in the phosphorylation of cytosolic phospholipase A2, the enzyme responsible for arachidonate mobilization. However, ethanol has no effect on collagen-induced tyrosine phosphorylation of phospholipase Cgamma2, determined by immunoprecipitation and immunoblotting. Thus, ethanol's effect on signal transduction in collagen-adherent platelets occurs distal to phosphorylation of phospholipase Cgamma2 but proximal to phosphorylation of cytosolic phospholipase A2.
Adenosine Diphosphate↗
JE-2147: a dipeptide protease inhibitor (PI) that potently inhibits multi-PI-resistant HIV-1.
We designed, synthesized, and identified JE-2147, an allophenylnorstatine-containing dipeptide HIV protease inhibitor (PI), which is potent against a wide spectrum of HIV-1, HIV-2, simian immunodeficiency virus, and various clinical HIV-1 strains in vitro. Drug-resistant clinical HIV-1 strains, isolated from seven patients who had failed 9-11 different anti-HIV therapeutics after 32-83 months, had a variety of drug-resistance-related amino acid substitutions and were highly and invariably resistant to all of the currently available anti-HIV agents. JE-2147 was, however, extremely potent against all such drug-resistant strains, with IC(50) values ranging from 13-41 nM (<2-fold changes in IC(50) compared with that of wild-type HIV-1). The emergence of JE-2147-resistant HIV-1 variants in vitro was substantially delayed compared with that of HIV-1 resistant to another allophenylnorstatine-containing compound, KNI-272, and other related PIs. Structural analysis revealed that the presence of a flexible P2' moiety is important for the potency of JE-2147 toward wild-type and mutant viruses. These data suggest that the use of flexible components may open a new avenue for designing PIs that resist the emergence of PI-resistant HIV-1. Further development of JE-2147 for treating patients harboring multi-PI-resistant HIV-1 is warranted.
Adult↗
Evectins: vesicular proteins that carry a pleckstrin homology domain and localize to post-Golgi membranes.
We have identified two vesicular proteins, designated evectin (evt)-1 and -2. These proteins are approximately 25 kDa in molecular mass, lack a cleaved N-terminal signal sequence, and appear to be inserted into membranes through a C-terminal hydrophobic anchor. They also carry a pleckstrin homology domain at their N termini, which potentially couples them to signal transduction pathways that result in the production of lipid second messengers. evt-1 is specific to the nervous system, where it is expressed in photoreceptors and myelinating glia, polarized cell types in which plasma membrane biosynthesis is prodigious and regulated; in contrast, evt-2 is widely expressed in both neural and nonneural tissues. In photoreceptors, evt-1 localizes to rhodopsin-bearing membranes of the post-Golgi, an important transport compartment for which specific molecular markers have heretofore been lacking. The structure and subcellular distribution of evt-1 strongly implicate this protein as a mediator of post-Golgi trafficking in cells that produce large membrane-rich organelles. Its restricted cellular distribution and genetic locus make it a candidate gene for the inherited human retinopathy autosomal dominant familial exudative vitreoretinopathy and suggest that it also may be a susceptibility gene for multiple sclerosis.
Amino Acid Sequence↗
Effects of Th2 cytokines on chemokine expression in the lung: IL-13 potently induces eotaxin expression by airway epithelial cells.
Airway inflammation associated with asthma is characterized by massive infiltration of eosinophils, mediated in part by specific chemoattractant factors produced in the lung. Allergen-specific Th2 cells appear to play a central role in asthma; for example, adoptively transferred Th2 cells induced lung eosinophilia associated with induction of specific chemokines. Interestingly, Th2 supernatant alone administered intranasally to naive mice induced eotaxin, RANTES, monocyte-chemotactic protein-1, and KC expression along with lung eosinophilia. We tested the major cytokines individually and found that IL-4 and IL-5 induced higher levels of macrophage-inflammatory protein-1alpha and KC; IL-4 also increased the production of monocyte-chemotactic protein-1; IL-13 and IL-4 induced eotaxin. IL-13 was by far the most potent inducer of eotaxin; indeed, a neutralizing anti-IL-13 Ab removed most of the eotaxin-inducing activity from Th2 supernatants, although it did not entirely block the recruitment of eosinophils. While TNF-alpha did not stimulate eotaxin production by itself, it markedly augmented eotaxin induction by IL-13. IL-13 was able to induce eotaxin in the lung of JAK3-deficient mice, suggesting that JAK3 is not required for IL-13 signaling in airway epithelial cells; however, eosinophilia was not induced in this situation, suggesting that JAK3 transduces other IL-13-mediated mechanisms critical for eosinophil recruitment. Our study suggests that IL-13 is an important mediator in the pathogenesis of asthma and therefore a potential target for asthma therapy.
Animals↗
UK-78,282, a novel piperidine compound that potently blocks the Kv1.3 voltage-gated potassium channel and inhibits human T cell activation.
1. UK-78,282, a novel piperidine blocker of the T lymphocyte voltage-gated K+ channel, Kv1.3, was discovered by screening a large compound file using a high-throughput 86Rb efflux assay. This compound blocks Kv1.3 with a IC50 of approximately 200 nM and 1:1 stoichiometry. A closely related compound, CP-190,325, containing a benzyl moiety in place of the benzhydryl in UK-78,282, is significantly less potent. 2 Three lines of evidence indicate that UK-78,282 inhibits Kv1.3 in a use-dependent manner by preferentially blocking and binding to the C-type inactivated state of the channel. Increasing the fraction of inactivated channels by holding the membrane potential at - 50 mV enhances the channel's sensitivity to UK-78,282. Decreasing the number of inactivated channels by exposure to approximately 160 mM external K+ decreases the sensitivity to UK-78,282. Mutations that alter the rate of C-type inactivation also change the channel's sensitivity to UK-78,282 and there is a direct correlation between tau(h) and IC50 values. 3. Competition experiments suggest that UK-78,282 binds to residues at the inner surface of the channel overlapping the site of action of verapamil. Internal tetraethylammonium and external charybdotoxin do not compete UK-78,282's action on the channel. 4. UK-78,282 displays marked selectivity for Kv1.3 over several other closely related K+ channels, the only exception being the rapidly inactivating voltage-gated K+ channel, Kv1.4. 5. UK-78,282 effectively suppresses human T-lymphocyte activation.
Animals↗