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Biomedical subjects

M O'Connor

Publications and source records attributed to M O'Connor.

At least 37 records · Page 2Linked to original sources
PubMed2001

CD147 is a signaling receptor for cyclophilin B.

Cyclophilins A and B (CyPA and CyPB) are cyclosporin A binding proteins that can be secreted in response to inflammatory stimuli. We recently identified CD147 as a cell-surface receptor for CyPA and demonstrated that CD147 is an essential component in the CyPA-initiated signaling cascade that culminates in ERK activation and chemotaxis. Here we demonstrate that CD147 also serves as a receptor for CyPB. CyPB induced Ca(2+) flux and chemotaxis of CD147-transfected, but not control, CHO cells, and the chemotactic response of primary human neutrophils to CyPB was blocked by antibodies to CD147. These results suggest that CD147 serves as a receptor for extracellular cyclophilins.

Animals↗
PubMed2001

Covert recognition in acquired and developmental prosopagnosia.

BACKGROUND: Some patients with prosopagnosia have covert recognition, meaning that they retain some familiarity or knowledge of facial identity of which they are not aware. OBJECTIVE: To test the hypothesis that prosopagnosic patients with right occipitotemporal lesions and impaired face perception lack covert processing, whereas patients with associative prosopagnosia and bilateral anterior temporal lesions possess it. METHODS: Eight patients with prosopagnosia were tested with a battery of four face recognition tests to determine their ability to discriminate between famous and unknown faces. RESULTS: Measures of overt familiarity revealed better residual discrimination in patients with acquired prosopagnosia than in those with the developmental form. With forced-choice methods using famous faces paired with unknown faces, no patient demonstrated covert familiarity. However, when the semantic cue of the name of the famous face was provided, covert processing was present in all five patients with acquired prosopagnosia, including the three with extensive right-sided lesions and impaired perceptual discrimination of facial configuration. Sorting unrecognized faces by occupation was also performed above chance in three of these five patients. In contrast, none of the three patients with developmental prosopagnosia had covert processing, even though two demonstrated flawless performance on similar tests of name (rather than face) recognition. Overt familiarity correlated highly with the degree of covert recognition. CONCLUSIONS: Extensive right occipitotemporal lesions with significant deficits in face perception are not incompatible with covert face processing. Covert processing is absent in developmental prosopagnosia, because this condition likely precludes the establishment of a store of accurate facial memories. The presence of covert processing correlates with the degree of residual overt familiarity, indicating that these are related phenomena.

Adult↗
PubMed2001

Prospects for public participation on nuclear risks and policy options: innovations in governance practices for sustainable development in the European Union.

We outline the potential participative governance and risk management in application to technological choices in the nuclear sector within the European Union (EU). Well-conducted public participation, stakeholder consultation and deliberation procedures can enhance the policy process and improve the robustness of strategies dealing with high-stakes investment and risk management challenges. Key nuclear issues now confronting EU member states are: public concern with large-scale environmental and health issues; the Chernobyl accident (and others less catastrophic) whose effect has been to erode public confidence and trust in the nuclear sector; the maturity of the nuclear plant, hence the emerging prominence of waste transportation, reprocessing and disposal issues as part of historical liability within the EU; the nuclear energy heritage of central and eastern European candidate countries to EU accession. The obligatory management of inherited technological risks and uncertainties on large temporal and geographical scales, is a novel feature of technology assessment and governance. Progress in the nuclear sector will aid the development of methodologies for technological foresight and risk governance in fields other than the nuclear alone.

Decision Making↗
PubMed2001

Analysis of mutations at residues A2451 and G2447 of 23S rRNA in the peptidyltransferase active site of the 50S ribosomal subunit.

On the basis of the recent atomic-resolution x-ray structure of the 50S ribosomal subunit, residues A2451 and G2447 of 23S rRNA were proposed to participate directly in ribosome-catalyzed peptide bond formation. We have examined the peptidyltransferase and protein synthesis activities of ribosomes carrying mutations at these nucleotides. In Escherichia coli, pure mutant ribosome populations carrying either the G2447A or G2447C mutations maintained cell viability. In vitro, the G2447A ribosomes supported protein synthesis at a rate comparable to that of wild-type ribosomes. In single-turnover peptidyltransferase assays, G2447A ribosomes were shown to have essentially unimpaired peptidyltransferase activity at saturating substrate concentrations. All three base changes at the universally conserved A2451 conferred a dominant lethal phenotype when expressed in E. coli. Nonetheless, significant amounts of 2451 mutant ribosomes accumulated in polysomes, and all three 2451 mutations stimulated frameshifting and readthrough of stop codons in vivo. Furthermore, ribosomes carrying the A2451U transversion synthesized full-length beta-lactamase chains in vitro. Pure mutant ribosome populations with changes at A2451 were generated by reconstituting Bacillus stearothermophilus 50S subunits from in vitro transcribed 23S rRNA. In single-turnover peptidyltransferase assays, the rate of peptide bond formation was diminished 3- to 14-fold by these mutations. Peptidyltransferase activity and in vitro beta-lactamase synthesis by ribosomes with mutations at A2451 or G2447 were highly resistant to chloramphenicol. The significant levels of peptidyltransferase activity of ribosomes with mutations at A2451 and G2447 need to be reconciled with the roles proposed for these residues in catalysis.

Binding Sites↗
PubMed2001

Enhancement of translation by the epsilon element is independent of the sequence of the 460 region of 16S rRNA.

The epsilon enhancer element is a pyrimidine-rich sequence that increases expression of T7 gene 10 and a number of Escherichia coli mRNAs during initiation of translation and inhibits expression of the recF mRNA during elongation. Based on its complementarity to the 460 region of 16S rRNA, it has been proposed that epsilon exerts its enhancer activity by base pairing to this complementary rRNA sequence. We have tested this model of enhancer action by constructing mutations in the 460 region of 16S rRNA and examining expression of epsilon-containing CAT reporter genes and recF-lacZ fusions in strains expressing the mutant rRNAs. Replacement of the 460 E.coli stem-loop with that of Salmonella enterica serovar Typhimurium or a stem-loop containing a reversal of all 8 bp in the helical region produced fully functional rRNAs with no apparent effect on cell growth or expression of any epsilon-containing mRNA. Our experiments confirm the reported effects of the epsilon elements on gene expression but show that these effects are independent of the sequence of the 460 region of 16S rRNA, indicating that epsilon-rRNA base pairing does not occur.

Bacterial Proteins↗
PubMed2001

Mutagenesis of the peptidyltransferase center of 23S rRNA: the invariant U2449 is dispensable.

U2449 is one of many invariant residues in the central loop of domain V of 23S rRNA, a region that constitutes part of the peptidyltransferase center of the ribosome. In Escherichia coli, this U is post-transcriptionally modified to dihydrouridine (D) and is the only D modification found in E.coli rRNAs. To analyze the role of this base and its modification in ribosomal function, all three base substitutions were constructed on a plasmid copy of the rrnB operon and assayed for their ability to support cell growth in a strain of E.coli lacking chromosomal rrn operons. Both purine substitution mutations were not viable. However, growth and antibiotic sensitivity of cells expressing only the mutant D2449C rRNA was indistinguishable from wild type. We conclude that while a pyrimidine is required at position 2449 for proper ribosomal function, the D modification is dispensable.

Base Sequence↗
PubMed2001

Altered discrimination of start codons and initiator tRNAs by mutant initiation factor 3.

IF3 is essential for ensuring the fidelity of the initiation step of translation in bacterial cells. Mutations at residues R99 and R131 in the C-terminal domain of the factor have previously been shown to increase initiation from the non-canonical GUA codon. Here we show that these mutant forms of IF3 fail to discriminate against initiation from many different non-AUG codons. They also enhance the activity of mutant tRNAs carrying changes in the three consecutive G-C pairs that are conserved in the anticodon stem of initiator tRNAs. In addition, the IF3 mutants stimulate initiations from leaderless mRNAs and from internal initiation codons, in the absence of any SD-anti-SD interaction. These results indicate that IF3 ensures the accuracy of initiation by inspecting both the codon-anticodon pairing and unique features of the initiator tRNA as well as suppressing initiation from other potential start sites within the mRNA.

Base Sequence↗
PubMed2001

Patient-controlled analgesia and intra-operative suggestion.

In a double-blind randomised study, we investigated the influence of positive intra-operative suggestions, presented to anaesthetised patients undergoing total abdominal hysterectomy, on postoperative pain, nausea and vomiting. One hundred and forty patients were randomly allocated to listen to one of four tapes containing either white noise or positive suggestions. The positive suggestions related to pain, postoperative nausea and vomiting, or both. We found that the positive intra-operative suggestions had no beneficial effects in reducing postoperative pain or nausea scores, nor was the consumption of morphine or anti-emetics reduced.

Adult↗
PubMed2001

Interactions between HIV-1 gp120, chemokines, and cultured adult microglial cells.

HIV dementia (HIVD), a disease that is apparently mediated by neurotoxins and viral proteins secreted by HIV infected microglia, is characterized neuropathologically by an increased number of activated microglia in the brains of affected individuals. Consequently, the rational design of potential therapeutic strategies should take into account the mechanisms that lead to microglial activation and to their increased prominence in the adult brain. In this regard, one leading hypothesis proposes that microglia are recruited to specific sites in the central nervous system (CNS) as a result of interactions between microglial chemokine receptors and chemokines, or even the viral glycoprotein gp120, which binds chemokine receptors in the process of cellular entry. Adult microglia express the functional chemokine receptors CCR5 and CXCR4 molecules that mediate chemotaxis in these and other cell types. We determined that purified adult microglial cultures contain a heterogeneous population with respect to their ability to respond to the alpha- and beta-chemokines, SDF1alpha, and MIP-1beta. A mean of 14.6% of the microglia assayed responded to both alpha- and beta-chemokines (CCR5(+)CXCR4(+) phenotype); 45.4% of microglia were phenotyped as CCR5(+)CXCR4(-); 12.9% of the microglia were CXCR4(+)CCR5(-); and 27.0% of microglia did not respond to either chemokine. No increase in intracellular calcium levels was seen in the vast majority of microglia exposed to the soluble HIV envelope protein, gp120, or to HIV envelope (gp120/gp41) expressed on MLV virus pseudotypes. However, exposure of microglia to soluble fractalkine or to other chemokines resulted in an intracellular calcium flux. Our results raise the possibility of microglial heterogeneity with respect to their response to chemokines, and indicate that any effects due to gp120 are likely to be considerably less robust than the response of microglia to the natural ligands of their chemokine receptors, for example SDF1alpha and MIP-1beta.

AIDS Dementia Complex↗
PubMed2001

Selected contribution: HSP20 phosphorylation in nitroglycerin- and forskolin-induced sustained reductions in swine carotid media tone.

Cyclic nucleotide-induced relaxation of maximally activated arterial smooth muscle has two phases. 1) The initial relaxation transient is typically characterized by a rapid reduction in force associated with brief reductions in myoplasmic Ca(2+) concentration ([Ca(2+)](i)) and myosin regulatory light chain (MRLC) phosphorylation on serine (Ser)-19 (Ser(19)). 2) The sustained inhibitory response is typically associated with Ser(16) phosphorylation of heat shock protein 20 (HSP20) without sustained reductions in [Ca(2+)](i) or MRLC phosphorylation. We investigated whether the extent of Ser(16)-HSP20 phosphorylation quantitatively correlated with the sustained inhibitory response. With addition of nitroglycerin to histamine-stimulated swine carotid media, the initial relaxation transient was associated with a decrease in MRLC phosphorylation without an increase in Ser(16)-HSP20 phosphorylation. During the sustained phase of nitroglycerin-induced relaxation and during force redevelopment induced by washout of nitroglycerin in the continued presence of histamine, the level of Ser(16)-HSP20 phosphorylation, but not MRLC phosphorylation, correlated with inhibition of force. Forskolin, which increases cAMP concentration, also induced a sustained inhibitory response that was associated with increases in Ser(16)-HSP20 phosphorylation without reductions in MRLC phosphorylation levels. Forskolin increased Ser(16)-HSP20 phosphorylation to a greater extent and inhibited force more completely than that observed with nitroglycerin. Increases in Ser(16)-HSP20 phosphorylation correlated with the degree of force inhibition regardless of whether the relaxation was induced by nitroglycerin or forskolin. These data are consistent with the hypothesis that Ser(16)-HSP20 phosphorylation may be a cyclic nucleotide-dependent, yet MRLC phosphorylation-independent, inhibitor of smooth muscle contractile force.

Animals↗
PubMed2001

Inpatient hospice triage of 'after-hours' calls to a community palliative care service.

This article reports on a retrospective study of the provision of 'after-hours' telephone support by a community palliative care service during 1996 and 1997. Calls received outside of normal office hours were triaged through an inpatient hospice unit located in the same building as the community team. During the study period, 629 patient or carer calls were received, predominantly between 5pm and 11 pm. The main reasons cited for using the after-hours service were medication queries, pain, seeking advice from the nurse and anxiety. The triage nurse successfully handled 30% of the calls. The remaining 70% of calls were transferred to the on-call community palliative care nurse, resulting in 251 home visits. Visits were not predicted by call reason, patient living arrangements, diagnosis or clinical problems; the patient being close to death or having died was a predominant reason for visiting. It was found, however, that call outcomes could be partly predicted by the identity of the triage nurse. It is argued that the findings of this study raise important issues related to the provision of after-hours palliative care and the training of staff providing triage of calls from patients and families at home.

Female↗
PubMed2001

Patient safety in guideline-based decision support for hypertension management: ATHENA DSS.

The Institute of Medicine recently issued a landmark report on medical error.1 In the penumbra of this report, every aspect of health care is subject to new scrutiny regarding patient safety. Informatics technology can support patient safety by correcting problems inherent in older technology; however, new information technology can also contribute to new sources of error. We report here a categorization of possible errors that may arise in deploying a system designed to give guideline-based advice on prescribing drugs, an approach to anticipating these errors in an automated guideline system, and design features to minimize errors and thereby maximize patient safety. Our guideline implementation system, based on the EON architecture, provides a framework for a knowledge base that is sufficiently comprehensive to incorporate safety information, and that is easily reviewed and updated by clinician-experts.

Artificial Intelligence↗
PubMed2000

A randomized, double-blind trial comparing azithromycin and clarithromycin in the treatment of disseminated Mycobacterium avium infection in patients with human immunodeficiency virus.

Two hundred and forty-six patients infected with human immunodeficiency virus (HIV) who also had disseminated Mycobacterium avium complex received either azithromycin 250 mg every day, azithromycin 600 mg every day, or clarithromycin 500 mg twice a day, each combined with ethambutol, for 24 weeks. Samples drawn from patients were cultured and clinically assessed every 3 weeks up to week 12, then monthly thereafter through week 24 of double-blind therapy and every 3 months while on open-label therapy through the conclusion of the trial. The azithromycin 250 mg arm of the study was dropped after an interim analysis showed a lower rate of clearance of bacteremia. At 24 weeks of therapy, the likelihood of patients' developing 2 consecutive negative cultures (46% vs. 56%, P=.24) or 1 negative culture (59% vs. 61%, P=.80) was similar for azithromycin 600 mg (n=68) and clarithromycin (n=57), respectively. The likelihood of relapse was 39% versus 27% (P=.21) on azithromycin compared with clarithromycin, respectively. Of the 6 patients who experienced relapse, none of those randomized to receive azithromycin developed isolates resistant to macrolides, compared with 2 of 3 patients randomized to receive clarithromycin [corrected]. Mortality was similar in patients comprising each arm of the study (69% vs. 63%; hazard, 95.1% confidence interval, 1.1 [0.7, 1.7]). Azithromycin 600 mg, when given in combination with ethambutol, is an effective agent for the treatment of disseminated M. avium disease in patients infected with HIV.

AIDS-Related Opportunistic Infections↗