PubMed Health⌕ Search

Biomedical subjects

M Murphy

Publications and source records attributed to M Murphy.

At least 55 records · Page 3Linked to original sources
PubMed1997

Telomeres of the linear chromosomes of Lyme disease spirochaetes: nucleotide sequence and possible exchange with linear plasmid telomeres.

Bacteria of the spirochaete genus Borrelia have linear chromosomes about 950 kbp in size. We report here that these linear chromosomes have covalently closed hairpin structures at their termini that are similar but not identical to those reported for linear plasmids carried by these organisms. Nucleotide sequence analysis of the chromosomal telomeric regions indicates that unique, apparently functional genes lie within a few hundred bp of each of the telomeres, and that there is an imperfect 26 bp inverted repeat at the two telomeres. In addition, we characterize a major chromosomal length polymorphism within the right telomeric regions of various Borrelia isolates, and show that sequences similar to those near the right telomere are often found on linear plasmids in B. burgdorferi (sensu stricto) isolates from nature. Sequences similar to a number of other regions of the chromosome, including those near the left telomere, were not found on B. burgdorferi plasmids. These observations suggest that there has been historical exchange of genetic information between the linear plasmids and the right end of the linear chromosome.

Amino Acid Sequence↗
PubMed1997

Obstetric complications in autism: consequences or causes of the condition?

OBJECTIVE: To determine whether and why obstetric complications are associated with autism. METHOD: Obstetric histories, obtained at maternal interview and coded as an optimality score (OS), were compared in two groups: 78 families containing an autistic proband (ICD-10 criteria) and 27 families containing a down syndrome (DS) proband. The OS was examined in relation to offspring diagnosis, proband characteristics, and familial loading for autism and its phenotypic variants. RESULTS: Autistic and DS probands had a significantly elevated OS compared with unaffected siblings, regardless of birth order position. The elevation was mainly due to an increase in mild as opposed to severe obstetric adversities. In autistic probands, the OS was best predicted by familial loading for autism and its phenotypic variants, but in the absence of this measure by the number of autistic symptoms. Among siblings of autistic probands affected with autism or its variants, the OS was best predicted by the probands' OS, and in its absence, by the measure of familial loading. In DS probands and siblings the OS was associated with increased maternal age, although this did not account for the OS elevation in DS probands. CONCLUSIONS: Rather than playing any principal etiological role, the obstetric adversities associated with autism either represent an epiphenomenon of the condition or derive from some shared risk factor(s).

Adolescent↗
PubMed1997

Activity of voriconazole (UK-109,496) against clinical isolates of Aspergillus species and its effectiveness in an experimental model of invasive pulmonary aspergillosis.

Voriconazole, a new azole antifungal agent, showed potent activity against clinical isolates of Aspergillus spp. in vitro. For A. fumigatus, the MIC range was < 0.03 to 0.5 microgram/ml and the MIC at which 90% of isolates are inhibited was 0.25 microgram/ml. In an experimental model of invasive pulmonary aspergillosis which mimics infection in humans, oral voriconazole at dosages of 30 mg/kg of body weight per day significantly delayed or prevented mortality.

Amphotericin B↗
PubMed1997

The catalytic subunit of the DNA polymerase of herpes simplex virus type 1 interacts specifically with the C terminus of the UL8 component of the viral helicase-primase complex.

The herpes simplex virus type 1 (HSV-1) UL8 DNA replication protein is a component of a trimeric helicase-primase complex. Sixteen UL8-specific monoclonal antibodies (MAbs) were isolated and characterized. In initial immunoprecipitation experiments, one of these, MAb 804, was shown to coprecipitate POL, the catalytic subunit of the HSV-1 DNA polymerase, from extracts of insect cells infected with recombinant baculoviruses expressing the POL and UL8 proteins. Coprecipitation of POL was dependent on the presence of UL8 protein. Rapid enzyme-linked immunosorbent assays (ELISAs), in which one protein was bound to microtiter wells and binding of the other protein was detected with a UL8- or POL-specific MAb, were developed to investigate further the interaction between the two proteins. When tested in the ELISAs, five of the UL8-specific MAbs consistently inhibited the interaction, raising the possibility that these antibodies act by binding to epitopes at or near a site(s) on UL8 involved in its interaction with POL. The epitopes recognized by four of the inhibitory MAbs were approximately located by using a series of truncated UL8 proteins expressed in mammalian cells. Three of these MAbs recognized an epitope near the C terminus of UL8, which was subjected to fine mapping with a series of overlapping peptides. The C-terminal peptides were then tested in the ELISA for their ability to inhibit the POL-UL8 interaction: the most potent exhibited a 50% inhibitory concentration of approximately 5 microM. Our findings suggest that the UL8 protein may be involved in recruiting HSV-1 DNA polymerase into the viral DNA replication complex and also identify a potential new target for antiviral therapy.

Amino Acid Sequence↗
PubMed1997

Non-invasive investigations successfully select patients for temporal lobe surgery.

OBJECTIVES: There is controversy regarding the need for invasive monitoring in the preoperative assessment of patients with temporal lobe epilepsy. The use of a series of non-invasive investigations in identifying the seizure focus is reported in 75 consecutive adults referred for epilepsy surgery. METHODS: All had video-EEG monitoring using scalp electrodes, high resolution MRI, and neuropsychology assessment. Other investigations included volumetric MRI, PET, and ictal and interictal SPECT. The seizure focus was localised and surgery offered if MRI disclosed unilateral hippocampal atrophy or a foreign tissue lesion and other investigations were either concordant or not discordant. RESULTS: In 68 patients the seizure focus was localised and three patients were inoperable. Sixty five patients have been offered surgery and 50 have undergone temporal lobe surgery and have a follow up of at least 12 months (mean 24 months). All had pathology: hippocampal sclerosis 34, dysembryoblastic neuroepithelial tumour six, cavernoma four, dysplasia two, low grade glioma two, ganglioglioma two. Thirty nine patients (78%) are seizure free postoperatively, 29/34 with hippocampal sclerosis and 10/16 with a foreign tissue lesion. Of the 11 patients with postoperative recurrent seizures, eight have a >90% reduction in seizure frequency and three have <90% reduction in seizure frequency but a worthwhile improvement. CONCLUSIONS: Non-invasive investigations successfully select most patients for temporal lobe surgery.

Adolescent↗
PubMed1997

Safety and tolerance of methylnaltrexone in healthy humans: a randomized, placebo-controlled, intravenous, ascending-dose, pharmacokinetic study.

N-methylnaltrexone bromide (methylnaltrexone) is a quaternary opioid antagonist with a limited ability to cross the blood-brain barrier. In animal models it reverses at peripheral receptors such side effects of opioids as decreased gastrointestinal motility, emesis, and cough suppression without affecting the desired analgesic effect mediated by central nervous system receptors. Methylnaltrexone thus may be a clinically useful compound for the prevention and treatment of opioid-induced side effects. This study was designed to examine the safety and tolerance of methylnaltrexone in healthy human participants over a range of doses and to identify any adverse effects or toxicity associated with methylnaltrexone and the doses at which these adverse effects occur. Healthy male volunteers received intravenous methylnaltrexone in six ascending doses with a placebo randomly inserted into the sequence. Each participant was observed for subjective and hemodynamic changes. Electrocardiogram and laboratory studies were also performed. The dose-limiting adverse effect of methylnaltrexone was orthostatic hypotension at 0.64 mg/kg (n = 3) or 1.25 mg/kg (n = 5), which was transient and self-limiting. Plasma levels of methylnaltrexone in excess of 1,400 ng/mL were observed to be associated with orthostatic hypotension. There were no significant subjective changes, no release of histamine, and no changes in physical examination or laboratory studies during the course of the study. Pharmacokinetic analysis revealed an elimination half-life of 117.5 minutes (+/-53.2), and a clearance of 38.8 L/hr (+/-17.4) with a methylnaltrexone dose of 0.64 mg/kg. Our results indicate that methylnaltrexone is well tolerated at doses of 0.32 mg/kg in healthy humans.

Adult↗
PubMed1997

Managing an increasingly complex system.

A study of more than 170,000 health care workers (including 47,692 registered nurses [RNs]) in 138 acute care health care organizations revealed that the role of the RN is characterized by excessive numbers of activities, a loss of focus on the professional components of nursing and significant activity overlap with other job classes. Additionally, the study found that these characteristics were related to reduced morale, decreased patient and physician satisfaction with care and increased health care costs. The results of this study suggest a need for nursing leaders to develop new methods for controlling the complexity of health care systems, particularly the complexity of the RN role. Controlling complexity requires better tools for identifying system inefficiencies, more advanced skills in cross-functional work process diagnostics and more effective strategies for reducing complexity across health care systems.

Delivery of Health Care↗
PubMed1996

Wild-type p53 negatively regulates the expression of a microtubule-associated protein.

The product of the p53 tumor suppressor gene has a well-documented activity as a transcriptional activator, and several studies indicate that this function is at least in part essential for the ability of p53 to suppress cellular proliferation. However, there is growing evidence that some activities of wild-type p53 may be independent of its trans-activation function; in fact, recent investigations have indicated that the transcriptional repression function of p53, rather than its trans-activation function, may be influential in p53-mediated apoptosis. The focus of this study has been on the identification of genes that exhibit decreased expression during p53-dependent apoptosis, and therefore represent potential p53-repressed genes influential in programmed cell death. This report identifies the gene encoding the microtubule-associated protein MAP4 as one whose mRNA and protein expression decrease in cells following induction of wild-type p53. Importantly, decreased MAP4 expression following p53 induction can be inhibited by molecules that prevent p53-mediated transcriptional repression and apoptosis, such as the adenovirus E1B-19K protein and the Wilms tumor gene product WT1. Additionally, overexpression of MAP4 in cells induced to undergo p53-dependent apoptosis significantly delays this process, indicating that the negative regulation of this gene by p53 may be influential in the rapid progression of apoptosis.

Adenovirus E1B Proteins↗
PubMed1996

Glial cell line-derived neurotrophic factor promotes the development of adrenergic neurons in mouse neural crest cultures.

Growth of mouse neural crest cultures in the presence of glial cell line-derived neurotrophic factor (GDNF) resulted in a dramatic dose-dependent increase in the number of tyrosine hydroxylase (TH)-positive cells that developed when 5% chicken embryo extract was present in the medium. In contrast, growth in the presence of bone morphogenetic protein (BMP)-2, BMP-4, BMP-6, transforming growth factor (TGF) beta 1, TGF-beta 2, and TGF-beta 3 elicited no increase in the number of TH-positive cells. The TH-positive cells that developed in the presence of GDNF had neuronal morphology and contained the middle and low molecular weight neurofilament proteins. Numerous TH-negative cells with the morphology of neurons also were observed in GDNF-treated cultures. Analysis revealed that the period from 6 to 12 days in vitro was the critical time for exposure to GDNF to generate the increase in TH-positive cell number. The growth factors neurotrophin-3 and fibroblast growth factor-2 elicited increases in the number of TH-positive cells similar to that seen in response to GDNF. In contrast, nerve growth factor was unable to substitute for GDNF. These findings extend the previously reported biological activities of GDNF by showing that it can act on mouse neural crest cultures to promote the development of neurons.

Animals↗
PubMed1996

Cyclin D1 and p21/waf1 are both involved in p53 growth suppression.

Overexpression of the wild type p53 gene in normal and transformed cells induces G1 arrest of cellular proliferation. In cell lines carrying the valine 135 temperature-sensitive p53 mutant gene, restoration of wild type p53 protein conformation at the permissive temperature causes an increase in the levels of cyclin D1, as well as the cyclin/cdk inhibitor p21/waf1. Accumulation of cyclin D1 is the result both of (post)transcriptional and post-translational regulatory mechanisms. Ablation of cyclin D1 induction by antisense cDNA microinjection significantly delays the onset of growth arrest, indicating that increased cyclin D1 levels likely contribute to wild type p53 G1 arrest. Whereas antisense ablation of either cyclin D1 or p21/waf1 can delay the onset of p53-induced growth arrest, ablation of neither is able to overcome a pre-existing p53-induced G1 block. In summary, the accumulated evidence indicate that induction of both cyclin D1 and p21/waf1 are involved in establishing the p53-mediated growth arrest in murine cell lines expressing temperature sensitive p53 protein.

Amino Acid Sequence↗
PubMed1996

p53 mutation, allele loss on chromosome 17p, and DNA content in ovarian carcinoma.

The aim of this investigation was to explore the relationships between p53 mutation, DNA aneuploidy, 17p deletions, and clinical stage in ovarian cancer. Nuclear suspensions were obtained by tissue disaggregation, stained with propidium iodide, and analysed on a Coulter EPICS Elite flow cytometer. DNA cell cycle analysis was performed using Multicycle software (Phoenix Flow Systems). DNA extracted from paraffin-embedded archival carcinomas/non-tumour tissue was used as template for PCR amplification of the microsatellite dinucleotide repeat polymorphism D17S513, a locus telomeric to p53 on 17p13.1. Allele loss at D17S513 was detected in 64.5 per cent of carcinomas (20 of 31 informative cases). DNA aneuploidy was detected in 20 of 54 (37 per cent) carcinomas. Eight of ten cases previously shown to harbour p53 mutations showed aneuploid DNA content. Although ten other DNA aneuploid cases had shown no p53 mutations, the results show a statistically significant association between p53 mutation and DNA aneuploidy (P < 0.01). Furthermore, the mean DNA index of the DNA aneuploid cases was significantly higher in p53 mutant cases compared with those showing no p53 mutation (P = 0.02). There was also a significant association between p53 mutations and stage, between ploidy and stage, and between allelic deletions at D17S513 or p53 and stage, but not between these allelic deletions and ploidy. p53 mutations appear to be associated with DNA aneuploidy in ovarian cancer independently of 17p deletions. p53 mutations, DNA aneuploidy, and 17p deletions are associated with late stage.

Alleles↗
PubMed1996

Leukemia inhibitory factor and interleukin-6 are produced by diseased and regenerating skeletal muscle.

The process of skeletal muscle regeneration following injury or disease involves locally produced growth factors which control cellular proliferation and differentiation. Leukemia inhibitory factor (LIF) and interleukin-6 (IL-6) have previously been shown to promote the proliferation of myoblasts in vitro, and thus may be involved in muscle regeneration. In the present investigation, the in vivo expression of these two myogenic growth factors was examined in regenerating muscle after a crush injury of wild type mice, and in diseased skeletal muscle and diaphragm of the mdxmouse. Using Reverse transcription polymerase chain reaction we have demonstrated that while normal muscle rarely expresses mRNA for these two molecules, there is significant up-regulation following injury, coinciding with the active period of muscle regeneration. This suggests these molecules act as locally produced trauma factors. This observation is reinforced in mdxmouse muscle, which is undergoing a cycle of degeneration and regeneration, and expresses both LIF and IL-6. Using in situ hybridization we have localized mRNA for LIF expression in the mdx diaphragm, suggesting that local production of these molecules by regenerating muscle itself, as well as by other cells in muscle, plays an important role in muscle regeneration.

Animals↗
PubMed1996

Peroxynitrite augments fMLP-stimulated chemiluminescence by neutrophils in human whole blood.

The neutrophil respiratory burst was examined by the technique of luminol-dependent chemiluminescence (LDCL) triggered by submaximal concentrations of N-formyl-methionyl-leucyl-phenylalanine (fMLP) in diluted whole blood. We sought to identify the chemical species responsible for LDCL in whole blood, to examine the role of leukotriene B4 (LTB4) and other arachidonic acid metabolites as mediators of the fMLP signaling pathway, and to investigate the effect of peroxynitrite on this response. Both sodium azide and taurine significantly inhibited LDCL (93% inhibition with 100 microM azide, 52% inhibition with 10 mM taurine). More modest inhibition was seen with superoxide dismutase (SOD), catalase, the nitric oxide synthase inhibitor monomethyl-L-arginine (L-NMMA), and with inhibitors of the cyclooxygenase (indomethacin), lipoxygenase (AA-861; no effect), and cytochrome P-450 (SKF 525-A) pathways of arachidonic acid metabolism. The nitric oxide donor SIN-1 (1-100 microM) and peroxynitrite (10-300 microM) also augmented fMLP-induced LDCL. The augmentation seen with peroxynitrite and SIN-1 was attenuated by SOD. Despite the increase in LDCL, peroxynitrite caused a dose-related inhibition of fMLP-stimulated LTB4 release. In summary, our results indicate that (1) LDCL elicited by fMLP in diluted whole blood appears primarily mediated by hypochlorous acid derived from myeloperoxidase; (2) pretreatment with the nitric oxide donor SIN-1 or with peroxynitrite augments LDCL; and (3) LTB4 release does not contribute to fMLP-stimulated LDCL or in the modulation of LDCL by SIN-1 or peroxynitrite.

Antioxidants↗