Biomedical subjects
J M Wright
Publications and source records attributed to J M Wright.
Zn2+ potentiates steady-state ATP activated currents in rat nodose ganglion neurons by increasing the burst duration of a 35 pS channel.
Zn2+ and ATP are normally present in serum at low levels and are released from some neurons during synaptic activity. In whole-cell recordings, 10 microM Zn2+ potentiated steady-state currents in rat nodose ganglion nerve cells by 18% in 0.5 microM ATP and 120% in 2 microM ATP. Fluctuation analysis of whole-cell suggested the mechanism was increased burst duration. In single-channel recordings, 10 microM Zn2+ did not increase the ATP-activated channel conductance but did increase the mean burst duration of the 35 pS primary open conductance state. These observations indicate that Zn2+ potentiates the steady-state response to extracellular ATP by increasing the burst duration of the channels.
Omeprazole therapy in resistant reflux disease.
Explore the source record for details and available documents.
Increased proteolytic activity of the granule neurons may contribute to neuronal death in the weaver mouse cerebellum.
The weaver mouse mutation is a genetic defect of unknown origin that leads to impairment of cerebellar granule neuronal migration and to neuronal cell death. We investigated laminin expression and proteolytic enzyme activity in this migration-deficient mouse mutant in vivo and in vitro to search for a molecular basis for the weaver defect. The weaver cerebellum showed a general increase in immunoreactivity for laminin, for a neurite outgrowth domain of the B2 chain of laminin, and for tissue plasminogen activator compared to the normal animals. Zymographic assays and immunocytochemistry confirmed that tissue plasminogen activator was the proteolytic enzyme synthesized in excess in the weaver mouse cerebellum in vivo. When placed in culture, the weaver granule neurons survived poorly on a laminin substratum, and failed to extend long neurites, unlike the normal cerebellar granule neurons. The cultured weaver granule neurons were proteolytically overactive and secreted excessive amounts of tissue plasminogen activator, which was likely to interfere with their neurite outgrowth potential on a laminin substratum. Indeed, the weaver granule neurons but not the normal neurons degraded laminin from their culture substratum and deposited a neurite outgrowth domain of the B2 chain of laminin onto their surfaces. Electrophysiology showed that the weaver granule neurons had poor resting membrane potentials (-38 V), whereas the normal neurons had normal resting membrane potentials of (-61 V). The resting membrane potentials of the weaver granule neurons were restored to near normal (-59 V) by a protease inhibitor, aprotinin. Aprotinin also rescued the weaver granule neurons from death on a laminin substratum and promoted their neurite outgrowth to the level of the normal animals. These results indicate that increased proteolytic activity accompanied with increased synthesis of laminin, and its B2 chain, distinguish the weaver mutation from the normal animals. These molecular changes may contribute to the impairment of granule neuronal migration and to the neuronal death, characteristic of the weaver mutation.
Multiconformational analysis of solution NOE data for the Ac-(L)proline-(D)alanine-NHMe dipeptide in a nonprotic solvent.
Solution NOE data for the dipeptide, Ac-(L)proline-(D)alanine-NHMe (1), have been obtained in the viscous solvent, 75:25 polychlorotrifluoroethylene:chloroform-d1. In this solvent at a 500 MHz 1H NMR spectrometer frequency, 1 exhibits large, negative NOE enhancements. The quantified 2D-NOESY time courses for 1 are analyzed with the multiconformational analysis technique, conformer population analysis (CPA). Thus, experimental NOE data for a molecule that is known to adopt at least three conformational motifs are used to explore the factors influencing the structural characterization of conformationally supple molecules by NOE. Both the quantitative and qualitative interpretations of solution NOE data for the simple molecule, 1, are demonstrated to critically depend on the extent to which one relies on empirical force-field energetics to determine which structures are energetically viable and on the methods by which trial structures are generated. Other influences include the relative weighting of contributions to the fitting-error function by large vs small NOE cross peaks and inclusion vs exclusion of null data, i.e., whether the absence of NOE cross peaks is included in the fitting procedure. Factors that do not appear to exert significant influence on the interpretation of these NOE data include (1) whether conformational interconversion is assumed to be slow or fast with respect to T1, (2) the inclusion of diagonal cross-peak data in the fitting procedure, and (3) what structures are assumed in the calibration of rotational correlation times from the observed data.
Comparison of the efficacy and safety of once-daily versus twice-daily formulations of diltiazem in the treatment of systemic hypertension. The Canadian Multicenter Diltiazem-CD Hypertension Trial Group.
The efficacy and safety of optimally titrated once-daily (CD) and twice-daily (SR) diltiazem were compared in 111 patients with mild to moderate systemic hypertension [seated diastolic blood pressure (DBP) > or = 95 mmHg and < or = 114 mmHg] in a multicenter, randomized, double-blind, placebo run-in, parallel-group trial. Following a 4 week washout and placebo-controlled run-in period, patients were randomized to receive diltiazem CD 180 mg and matching placebo (n = 54), or diltiazem SR 90 mg bid (n = 57). Total daily doses were titrated from 180 mg to 360 mg to achieve a goal of seated DBP < 90 mmHg during a 6 week titration period. The patients continued to receive their optimal dose for a 6 week follow-up period. Ninety-six (96) patients (diltiazem CD: 47, diltiazem SR: 49) completed the study protocol, with 60% of the diltiazem CD and 55% of the diltiazem SR patients achieving the goal of seated DBP of < 90 mmHg (p = 0.685). Although significant decreases occurred in seated and standing measurements of diastolic and systolic BP and heart rate with treatment in both groups, there were no significant differences between treatment groups. Both medications were well tolerated, with a similar frequency of adverse effects [diltiazem CD: 24/54 (37%) patients; diltiazem SR: 24/57 (42.1%) patients] with the most frequently reported adverse effects being headache and edema.
24 hour blood pressure control with once-daily versus twice-daily formulations of diltiazem.
The antihypertensive effects of once-daily diltiazem CD over a 24 hour period were compared with twice-daily diltiazem SR in 95 patients with mild to moderate hypertension using ambulatory blood pressure monitoring. This trial was designed as a multicenter, double-blind, parallel-group study. Following a 2 to 4 week placebo run-in period, diltiazem was administered as once-daily CD or twice-daily SR, starting with 180 mg daily and increasing to a maximum of 360 mg daily, to achieve a seated diastolic blood pressure goal of < or = 90 mmHg as measured by cuff between 08:00 and 10:00 in the morning. Following drug titration, patients received a maintenance dose of diltiazem for an additional 6 week follow-up phase. Twenty-four hour ambulatory blood pressure monitoring recordings were obtained at the end of the placebo, titration, and maintenance phases. Both diltiazem CD and diltiazem SR significantly reduced both systolic and diastolic blood pressure over the 24 hour day and maintained a normal circadian pattern. As well, treatment with once-a-day diltiazem CD significantly decreased the slope of the early morning rise of diastolic and mean blood pressure. Thus, diltiazem CD is as effective as diltiazem SR in lowering diastolic blood pressure over a 24 hour period and has the advantage of a once-daily formulation.
A model of isoniazid-induced hepatotoxicity in rabbits.
Isoniazid (INH) continues to be an effective drug used for chemoprophylaxis and treatment of tuberculosis. Unfortunately, INH is associated with significant hepatotoxicity in up to 2% of individuals exposed, and if this adverse event is not recognized early it can be fatal. Research on INH-induced hepatotoxicity has been hampered by the lack of a suitable animal model that closely resembles the toxicity in humans. The mechanism of INH-induced hepatotoxicity is still unknown. The present study describes the development of a reliable model of INH-induced hepatotoxicity in rabbits. The protocol involves repeated injections of INH over a 2-day period, resulting in significant hepatic necrosis as indicated by elevations of plasma argininosuccinic acid lyase activity. Pretreatment with phenobarbital increased the occurrence of INH-induced hepatic necrosis from approximately 60% (9 out of 15 rabbits) with INH alone to more than 90% (13 out of 14 rabbits). Morphological indices were used to demonstrate the presence of INH-induced hepatotoxicity, and biochemical indices were used to demonstrate both the presence and severity of INH-induced hepatotoxicity in this model. This model may prove useful for further investigations into the mechanism of INH-induced hepatotoxicity.
Pharmacologic management of congestive heart failure.
This article is a review of the pharmacologic management of congestive heart failure (CHF) and a summary of the medical literature that guides current treatment strategies. Despite advances in the treatment of CHF, it remains a common diagnosis with a poor prognosis. Because CHF is a progressive syndrome with heterogeneous features of cardiac dysfunction, effective management requires combination therapies and evolving treatment strategies. The mechanism of action, goals of therapy, and demonstrated efficacy of each of the various agents used in the treatment of CHF are discussed.
Nucleotide sequence and genomic organization of cichlid fish minisatellites.
We have cloned, sequenced, and determined the genomic organization of minisatellites from the African cichlid fish, Oroechromis niloticus. We estimate that minisatellites related in sequence to the Jeffreys' core probes 33.6 and 33.15 occur approximately every 1000 kilobase pairs in the cichlid fish genome. Sequencing of three minisatellites revealed that the size of the monomer units of the tandem arrays ranged from 7 to 24 base pairs (bp). One minisatellite appeared to contain a higher ordered periodicity of 90-120 bp superimposed on the apparent 15 bp monomer repeat, indicating a particularly large unit of homogenization for a minisatellite array. Sequence heterogeneity of repeat units within tandem arrays varied considerably from one minisatellite to another. Hybridization of cloned minisatellites to genomic DNA of cichlid fishes generated, in most instances, multilocus fingerprint patterns, indicating that families of minisatellites related by sequence exist in the cichlid genome. Two minisatellite clones, however, generated polymorphic single locus fingerprints, suggesting that these loci are conserved in closely related African cichlids. The cross hybridization of these cichlid minisatellites within and between related taxa, as well as to unrelated fish species such as Atlantic salmon (Salmo salar), complement the human minisatellite sequences for the study of genetic relationships among individuals from a wide range of fish species.
Intrabony lymphoma simulating periradicular inflammatory disease.
Intrabony lymphoma can mimic periradicular inflammatory disease of pulpal origin. Mismanagement of such cases can result if the clinician presumes the condition is inflammatory and fails to submit a tissue specimen for evaluation. This article reviews the features of jaw lymphoma and documents the importance of early diagnosis and histopathologic examination.
Primary structure of the speC gene encoding biosynthetic ornithine decarboxylase in Escherichia coli.
A 2.91-kb fragment of the Escherichia coli chromosome containing the speC gene, encoding biosynthetic ornithine decarboxylase (ODC) was sequenced. The speC gene is encoded by a 2133-bp ORF; the deduced amino-acid sequence contains 711 residues whose predicted molecular mass is 79,505 Da.
Can SINEs: a family of tRNA-derived retroposons specific to the superfamily Canoidea.
A repetitive element of approximately 200 bp was cloned from harbour seal (Phoca vitulina concolour) genomic DNA. The sequence of the element revealed putative RNA polymerase III control boxes, a poly A tail and direct terminal repeats characteristic of SINEs. Sequence and secondary structural similarities suggest that the SINE is derived from a tRNA, possibly tRNA-alanine. Southern blot analysis indicated that the element is predominately dispersed in unique regions of the seal genome, but may also be present in other repetitive sequences, such as tandemly arrayed satellite DNA. Based on slot-blot hybridization analysis, we estimate that 1.3 x 10(6) copies of the SINE are present in the harbour seal genome; SINE copy number based on the number of clones isolated from a size-selected library, however, is an order of magnitude lower (1-3 x 10(5) copies), an estimate consistent with the abundance of SINEs in other mammalian genomes. Database searches found similar sequences have been isolated from dog (Canis familiaris) and mink (Mustela vison). These, and the seal SINE sequences are characterized by an internal CT dinucleotide microsatellite in the tRNA-unrelated region. Hybridization of genomic DNA from representative species of a wide range of mammalian orders to an oligonucleotide (30mer) probe complementary to a conserved region of the SINE confirmed that the element is unique to carnivores of the superfamily Canoidea.
The utility of SATA satellite DNA sequences for inferring phylogenetic relationships among the three major genera of tilapiine cichlid fishes.
The SATA satellite DNA family of sequences, composed of three size variants of approximately 237, 230, and 209 bp, is conserved in the genomes of tilapiine and haplochromine cichlid fishes. In the present study we examined the utility of the SATA sequences for inferring phylogenetic relationships among the three major genera of tilapiine fishes, Oreochromis, Sarotherodon, and Tilapia. Hybridization of the monomer SATA repeat to genomic DNA of representative cichlid species established conservation of the sequence in the African tilapine and haplochromine lineages and its absence from other cichlid lineages. Bootstrapped DNA parsimony and neighbor-joining analyses of derived consensus sequences revealed two distinct clades, one containing the mouthbrooding genera Oreochromis and Sarotherodon, and the other containing the substrate spawning genus Tilapia. These results are consistent with recent independent studies using mitochondrial DNA and establish the utility of the SATA satellite DNA family for phylogenetic reconstruction. Concerted evolution of the SATA sequences was also demonstrated within the tilapiine tribe.
NSAID use and efficacy in the emergency department: single doses of oral ibuprofen versus intramuscular ketorolac.
OBJECTIVE: To compare the clinical efficacy of single doses of intramuscular ketorolac and oral ibuprofen in the emergency department (ED) treatment of acute pain. DESIGN: A retrospective analysis of data collected during a prospective survey of pain management efficacy. The design was noninterventional, and therapy was selected by the treating physician independent of the trial. SETTING: Urban teaching hospital adult patient emergency department. PARTICIPANTS: A convenience sample of ED patients in acute pain. INTERVENTIONS: Patients received ibuprofen 800 mg po (n = 95), or ketorolac 60 mg im (n = 30) as a single dose. Therapy was selected by the treating physician and was not influenced by the study. RESULTS: Data collected were a 100-mm visual analog pain scale at patient arrival and discharge, verbal description of pain relief, patient demographics, pain management data, and discharge diagnosis. Baseline pain intensity was higher in patients receiving ketorolac (77 mm median) than in those receiving ibuprofen (65 mm, p = 0.02). Pain relief was similar (p = 0.29) with either treatment when assessed by visual analog scale or patient definition of pain relief. CONCLUSIONS: A single dose of either nonsteroidal antiinflammatory drug produced similar pain relief in the general ED population during clinical treatment of pain. Ketorolac should not necessarily be considered a more effective analgesic than ibuprofen in these commonly used doses.
Oral precancerous lesions and conditions.
Although oral cancer accounts for less than 5% of the total incidence of all malignancies, approximately half of the oral cancer patients die of their disease. Most oral cancer arises from surface epithelium. The epithelium initially undergoes dysplastic or premalignant changes which can last for years before invasion. Dysplastic epithelium usually produces morphological tissue changes that are detectable clinically. This review discusses the clinical and pathological aspects of oral precancerous lesions and conditions and briefly addresses therapeutic modalities.
Inhibition and induction of cytochrome P4502E1-catalyzed oxidation by isoniazid in humans.
We studied the effect of isoniazid administration on the cytochrome P4502E1-catalyzed elimination of chlorzoxazone and acetaminophen. Isoniazid, 300 mg daily, was administered for 7 days to a group of 10 volunteer slow acetylators. Acetaminophen, 500 mg, and chlorzoxazone, 750 mg, were administered on separate occasions before isoniazid, during the period of isoniazid administration, and after the discontinuation of isoniazid. Isoniazid inhibited the clearance of chlorzoxazone by 58%, as assessed from plasma data, and inhibited the formation of acetaminophen thioether metabolites (a measure of the formation of the hepatotoxin N-acetyl-p-benzoquinone imine and catechol oxidative metabolites of acetaminophen, as determined from their recovery in urine, by 63% and 49%, respectively. Two days after the discontinuation of isoniazid, the clearance of chlorzoxazone was increased over the value before isoniazid by 56%. Acetaminophen thioether but not catechol metabolites were increased by 56% 1 day after the discontinuation of isoniazid and had returned to the pre-isoniazid value 3 days after the discontinuation of isoniazid. We conclude that the time course of the interaction with regard to chlorzoxazone elimination and formation is compatible with an inhibition-induction effect of isoniazid on cytochrome P4502E1. The mechanism of this biphasic effect is probably induction by protein stabilization, which results in inhibition of catalytic activity while isoniazid is present.
Nucleotide sequence of the D-loop region of the sperm whale (Physeter macrocephalus) mitochondrial genome.
We have amplified, by the polymerase chain reaction, and have sequenced the D-loop region of the mitochondrial DNA from the sperm whale (Physeter macrocephalus). The sperm whale D-loop was aligned with D-loop sequences from four other cetaceans (Commerson's dolphin, orca, fin whale, and minke whale) and an out-group (cow). This alignment showed the sperm whale sequence to be larger than that of other cetaceans. In addition, some sequence blocks were highly conserved among all six species, suggesting roles in the functioning of mitochondrial DNA. Other blocks that were previously reported to be well conserved among cetaceans showed little sequence conservation with the sperm whale D-loop, which argues against the functional importance of these sequence blocks in cetaceans.