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Biomedical subjects

D Murray

Publications and source records attributed to D Murray.

At least 55 records · Page 3Linked to original sources
PubMed2001

The HELLP syndrome: maternal and perinatal outcome.

The HELLP syndrome is a rare condition with a variable presentation, and in general, the outlook for mother and baby is felt to be poor. The aims of this study were to determine the maternal and perinatal outcome in cases of the HELLP syndrome at the Rotunda hospital over a five-year period. A retrospective review of all cases of confirmed HELLP syndrome from 1/1/95 to 1/9/99 was undertaken. Antenatal, intrapartum and neonatal data and in particular, maternal and neonatal complications were recorded. There were 20 cases of HELLP syndrome over the 5-year period. Mean maternal age was 29.8 (19-43) years. 70% were nulliparous. 80% delivered within 24 hours of diagnosis. 85% were delivered by caesarean section. Mean gestation at delivery was 33.5 (24-41) weeks, 65% of which were preterm. 70% of the babies were admitted to the neonatal intensive care unit (NICU). Mean birth weight was 1923g (440-4640g). Mean length of stay was 23.8 (1-68) days. 40% developed respiratory distress syndrome (RDS) with a mean duration of ventilation for these infants of 2.4 (0.5-7) days. There were 2 perinatal deaths both of whom weighed <500g. 95% of women were admitted to the High Dependency Unit. There were no maternal deaths. The mean interval to resolution of laboratory indices to within normal reference ranges was 11 (2-30) days. Maternal morbidity was high, but short-term, with full resolution in all cases. Once the diagnosis was made, delivery was immediate. The neonatal morbidity was also high and was most closely related to the gestation at delivery.

Female↗
PubMed2001

Porcine enteric spirochete infections in the UK: surveillance data and preliminary investigation of atypical isolates.

Investigations into the possible causes of colitis and typhlocolitis were carried out on 98 pig units in the United Kingdom between 1997 and 1999. Brachyspira pilosicoli was identified most commonly, occurring as the suggested primary agent in 18% of the outbreaks but forming part of mixed infections in another 24% of outbreaks. The equivalent figures for other bacterial pathogens were: B. hyodysenteriae, 13% and 16%; Lawsonia intracellularis, 10% and 15%: Salmonella species, 6% and 12%; and Yersinia species, 4% and 10%. Unclassified Brachyspira species of unknown pathogenicity were identified in 12% of outbreaks. The 24 unclassified isolates divided into three groups on the basis of their phenotypic characteristics. In addition, there were 50 atypical Brachyspira species isolates that showed differences between their phenotypic characteristics and genetic identity based on sequence analysis of a section of the 23S rDNA gene. Four representative atypical isolates were found to be pathogenic as a result of an experimental oral challenge study in pigs.

Animals↗
PubMed2000

E2F1 and p53 are dispensable, whereas p21(Waf1/Cip1) cooperates with Rb to restrict endoreduplication and apoptosis during skeletal myogenesis.

We describe temporal and genetic analyses of partially rescued Rb mutant fetuses, mgRb:Rb-/-, that survive to birth and reveal specific defects in skeletal muscle differentiation. We show that in the absence of Rb, these fetuses exhibit increased apoptosis, bona fide endoreduplication, and incomplete differentiation throughout terminal myogenesis. These defects were further augmented in composite mutant fetuses, mgRb:Rb-/-:p21-/-, lacking both Rb and the cyclin-dependent kinase inhibitor p21(Waf1/Cip1). Although E2F1 and p53 mediate ectopic DNA synthesis and cell death in several tissues in Rb mutant embryos, both endoreduplication and apoptosis persisted in mgRb:Rb-/-:E2F1-/- and mgRb:Rb-/-:p53-/- compound mutant muscles. Thus, combined inactivation of Rb and p21(Waf1/Cip1) augments endoreduplication and apoptosis, whereas E2F1 and p53 are dispensable during aberrant myogenesis in Rb-deficient fetuses.

Animals↗
PubMed2000

ERCC1 expression as a molecular marker of cisplatin resistance in human cervical tumor cells.

Cisplatin is a valuable adjuvant to radiotherapy for the treatment of cervical cancer. Because the advantage of combining cisplatin with radiotherapy is likely to be attributable to additive cell killing by these 2 agents, such protocols should primarily benefit patients who have inherently cisplatin-sensitive tumors. Development of a molecular assay to rapidly evaluate the cisplatin responsiveness of cervical tumors would thus be extremely valuable. We investigated whether high pre-treatment mRNA levels of the ERCC1 nucleotide excision repair gene are predictive of cisplatin resistance in early-passage human cervical cancer cells, as they are in several other tumor types. Expression of the ERCC1 gene at the mRNA and protein levels was established by Northern and Western blotting, respectively, in a panel of single-cell-derived cervical carcinoma cell lines that exhibited a wide range of inherent sensitivity to cisplatin. There was a significant (p </= 0.011) correlation between ERCC1 mRNA levels and cisplatin resistance in these cell lines. However, there was no obvious relationship between ERCC1 protein levels and cisplatin resistance. Thus, the association between high ERCC1 mRNA levels and cisplatin resistance might be an epiphenomenon. Nonetheless, pre-treatment ERCC1 mRNA levels may be a useful molecular marker for identifying cervical tumors likely to be refractory to cisplatin, and further investigation in clinical biopsy material is warranted.

Antineoplastic Agents↗
PubMed2000

Membrane binding of peptides containing both basic and aromatic residues. Experimental studies with peptides corresponding to the scaffolding region of caveolin and the effector region of MARCKS.

We have studied the binding of peptides containing both basic and aromatic residues to phospholipid vesicles. The peptides caveolin(92-101) and MARCKS(151-175) both contain five aromatic residues, but have 3 and 13 positive charges, respectively. Our results show the aromatic residues insert into the bilayer and anchor the peptides weakly to vesicles formed from the zwitterionic lipid phosphatidylcholine (PC). Incorporation of a monovalent acidic lipid (e.g., phosphatidylserine, PS) into the vesicles enhances the binding of both peptides via nonspecific electrostatic interactions. As predicted from application of the Poisson-Boltzmann equation to atomic models of the peptide and membranes, the enhancement is larger (e.g., 10(4)- vs 10-fold for 17% PS) for the more basic MARCKS(151-175). Replacing the five Phe with five Ala residues in MARCKS(151-175) decreases the binding to 10:1 PC/PS vesicles only slightly (6-fold). This result is also consistent with the predictions of our theoretical model: the loss of the attractive hydrophobic energy is partially compensated by a decrease in the repulsive Born/desolvation energy as the peptide moves away from the membrane surface. Incorporating multivalent phosphatidylinositol 4, 5-bisphosphate (PIP(2)) into PC vesicles produces dramatically different effects on the membrane binding of the two peptides: 1% PIP(2) enhances caveolin(92-101) binding only 3-fold, but increases MARCKS(151-175) binding 10(4)-fold. The strong interaction between the effector region of MARCKS and PIP(2) has interesting implications for the cellular function of MARCKS.

Amino Acids, Cyclic↗
PubMed2000

Repulsive axon guidance: Abelson and Enabled play opposing roles downstream of the roundabout receptor.

Drosophila Roundabout (Robo) is the founding member of a conserved family of repulsive axon guidance receptors that respond to secreted Slit proteins. Little is known about the signaling mechanisms which function downstream of Robo to mediate repulsion. Here, we present genetic and biochemical evidence that the Abelson (Abl) tyrosine kinase and its substrate Enabled (Ena) play direct and opposing roles in Robo signal transduction. Genetic interactions support a model in which Abl functions to antagonize Robo signaling, while Ena is required in part for Robo's repulsive output. Both Abl and Ena can directly bind to Robo's cytoplasmic domain. A mutant form of Robo that interferes with Ena binding is partially impaired in Robo function, while a mutation in a conserved cytoplasmic tyrosine that can be phosphorylated by Abl generates a hyperactive Robo receptor.

Animals↗
PubMed2000

Binding of equine infectious anemia virus matrix protein to membrane bilayers involves multiple interactions.

Human immunodeficiency virus (HIV) and equine infectious anemia virus (EIAV) are closely related lentiviruses that infect immune cells, but their pathogenesis differ. Localization to the cytosolic leaflet of the plasma membrane is critical for replication of both viruses. This localization is accomplished through the matrix (MA) domain of the Gag precursor protein. In HIV-1, association of MA to anionic membranes appears to be primarily driven by a linear cluster of basic residues in the MA domain and an N-myristoylation signal. Interestingly, the MA protein of EIAV does not contain either of these signals. To understand which factors could promote EIAV assembly we characterized the membrane binding properties of its MA protein using fluorescence and biochemical methods. We find that EIAV MA exists as a multimer in solution whose protein-protein interactions are destabilized by membrane binding. EIAV MA binds strongly to electrically neutral membranes as well as to negatively charged membranes. Fluorescence quenching and chemical modification techniques, as well as trypsin proteolysis, indicate a different exposure of the EIAV MA Trp residues when bound to the two types of membranes, and EIAV MA proteolysis by trypsin differs when bound to the two types of membranes. Based on these data and the known structures of closely related matrix proteins, we constructed a structural model. This model predicts that EIAV MA binds to negatively charged membranes, but EIAV MA has an additional membrane binding region rich in residues that partition favorably into the membrane headgroup region. This secondary site may play a role in early events of viral infection.

Amino Acid Sequence↗
PubMed2000

The transcription factor deltaEF1 is inversely expressed with type II collagen mRNA and can repress Col2a1 promoter activity in transfected chondrocytes.

The regulation of Col2a1, which encodes type II collagen, likely results from a balance of both positive and negative proteins. Here we present evidence that the transcription factor deltaEF1 participates in the negative regulation of Col2a1 transcription. A deletion analysis suggested that a region between -100 and -307 of the rat Col2a1 gene was required for activity in differentiating chick limb bud mesenchymal cells; however, mutation of a conserved E2 box site in this region actually increased promoter activity. Supershift analysis demonstrated that deltaEF1, a known transcriptional repressor, bound to the E2 box in a sequence-dependent manner. Chick limb bud mesenchymal cells, which do not express type II collagen, expressed abundant deltaEF1 mRNA, but, following differentiation in micromass culture, deltaEF1 mRNA expression was lost. Primary embryonic chick sternal chondrocytes, which express abundant type II collagen, displayed minimal levels of deltaEF1 mRNA. The inhibition of Col2a1 transcription following treatment of chick sternal chondrocytes with growth factors was accompanied by increased deltaEF1 expression. Overexpression of deltaEF1 in differentiated chondrocytes resulted in decreased expression of a reporter construct containing a collagen II promoter/enhancer insert; however, this negative regulation was not dependent on the proximal E2 box. This is the first report of a specific transcription factor involved in the negative regulation of Col2a1.

Animals↗
PubMed2000

Factors affecting distant disease-free survival for primary invasive breast cancer: use of a log-normal survival model.

BACKGROUND: Invasive breast cancer is a frequently diagnosed disease that now comes with an ever expanding array of therapeutic management options. We assessed the effects of 20 prognostic factors in a multivariate context. METHODS: We accrued clinical data for 156 consecutive patients with stage 1-3 primary invasive breast cancer who were diagnosed in 1989-1990 at the Henrietta Banting Breast Center, and followed to 1995. There is complete follow-up for 91% of patients (median follow-up of 4.9 years). The event of interest was distant recurrence (for distant disease-free survival, DFS). We used Cox and log-normal step-wise regression to assess the multivariate effects of the following factors on DFS: age, tumor size, nodal status, histology, tumor and nuclear grade, lymphovascular and perineural invasion (LVPI), ductal carcinoma-in-situ (DCIS) type, DCIS extent, DCIS at edge of tumor, ER and PgR, ERICA, adjuvant systemic therapy, ki67, S-phase, DNA index, neu oncogene, and pRb. RESULTS: There was strong evidence against the Cox assumption of proportional hazards for nodal status, and nodal status was not in the Cox step-wise model. With step-wise log-normal regression, a large tumor size (P < .001), positive nodes (P = .002), high nuclear grade (P = .01), presence of LVPI (P = .03), and infiltrating duct carcinoma not otherwise specified (P = .05) were associated with a reduction in DFS. CONCLUSIONS: For nodal status, there was strong evidence against the Cox assumption of proportional hazards, and it was not included in the Cox model although it was in the log-normal model. Only traditional factors were included in the step-wise models. Thus, this statistical management of prognostic markers in breast cancer appears to be very important.

Adult↗
PubMed2000

Issues relating to long-term follow-up in hip arthroplasty surgery: a review of 598 cases at 7 years comparing 2 prostheses using revision rates, survival analysis, and patient-based measures.

We reviewed 598 cemented Charnley and Hi-nek total hip arthroplasties at 7 years. Data were obtained from general practitioners, hospital medical notes, microfilm, and patient questionnaires. Outcome measures were revision rates, survival analysis, 12-item Oxford Hip Score, and satisfaction ratings. There were 471 Charnley (79%) and 127 Hi-nek (21%) total hip arthroplasties; 139 deaths (23%) occurred, and 5 (<1%) were lost to follow-up. Characteristics of the Charnley and Hi-nek patient groups were similar, with more information missing for Charnley cases. Revision rates were Charnley, 37 (8%), and Hi-nek, 6 (5%) (not significant). Survival analysis revealed no difference between the 2 groups (P = .23). The patients' median Oxford Hip Score was low/good (19), slightly worse for the Hi-nek group (not significant). Taking all evidence together, neither implant was outperforming the other at 7 years.

Arthroplasty, Replacement, Hip↗
PubMed2000

Ameloblastic carcinoma ex ameloblastoma of the mandible with malignancy-associated hypercalcemia.

Ameloblastoma is a rare, locally destructive, benign neoplasm of the jawbones, which arises from epithelium derived from the epithelial components of the developing tooth. Ameloblastic carcinoma is the term used to designate any ameloblastoma in which there is histologic evidence of malignancy in the primary tumor, regardless of whether it has metastasized. Most ameloblastic carcinomas are presumed to have arisen de novo, with few cases of malignant transformation of ameloblastoma being apparent. Hypercalcemia is the most common metabolic complication of malignancy. Although malignancy-associated hypercalcemia is often reported in association with other malignancies, it is exceedingly unusual in association with ameloblastoma, malignant ameloblastoma, or ameloblastic carcinoma. We describe a patient with multiple recurrences of ameloblastoma, with subsequent malignant transformation presenting with malignancy-associated hypercalcemia.

Adult↗
PubMed2000

Timing transantarctic disjunctions in the Atherospermataceae (Laurales): evidence from coding and noncoding chloroplast sequences.

Previous studies of the small Southern Hemisphere family Atherospermataceae have drawn contradictory conclusions regarding the number of transantarctic disjunctions and role of transoceanic dispersal in its evolution. Clarification of intergeneric relationships is critical to resolving (1) whether the two Chilean species, Laurelia sempervirens and Laureliopsis philippiana, are related to different Austral-Pacific species, implying two transantarctic disjunctions as suggested by morphology; (2) where the group is likely to have originated; and (3) whether observed disjunctions reflect the breakup of Gondwana. We analyzed chloroplast DNA sequences from six regions (the rbcL gene, the rpl16 intron, and the trnL-trnF, trnT-trnL, psbA-trnH, and atpB-rbcL spacer regions; for all six regions, 4,372 bp) for all genera and most species of Atherospermataceae, using parsimony and maximum likelihood (ML). The family's sister group, the Chilean endemic Gomortega nitida (Gomortegaceae), was used to root the tree. Parsimony and ML yielded identical single best trees that contain three well-supported clades (> or = 75% bootstrap): Daphnandra and Doryphora from south-eastern Australia; Atherosperma and Nemuaron from Australia-Tasmania and New Caledonia, respectively; and Laurelia novac-zelandiac and Laureliopsis philippiana from New Zealand and Chile, respectively. The second Chilean species, Laurelia sempervirens, is sister to this last clade. Likelihood ratio testing did not reject the molecular clock assumption for the rbcL data, which can therefore be used for divergence time estimates. The atherosperm fossil record, which goes back to the Upper Cretaceous, includes pollen, wood, and leaf fossils from Europe, Africa, South America, Antarctica, New Zealand, and Tasmania. Calibration of rbcL substitution rates with the fossils suggests an initial diversification of the family at 100-140 million years ago (MYA), probably in West Gondwana, early entry into Antarctica, and long-distance dispersal to New Zealand and New Caledonia at 50-30 MYA by the ancestors of L. novae-zelandiae and Nemuaron.

Antarctic Regions↗
PubMed2000

The intrinsic electrostatic potential and the intermediate ring of charge in the acetylcholine receptor channel.

A ring of aligned glutamate residues named the intermediate ring of charge surrounds the intracellular end of the acetylcholine receptor channel and dominates cation conduction (Imoto et al. 1988). Four of the five subunits in mouse-muscle acetylcholine receptor contribute a glutamate to the ring. These glutamates were mutated to glutamine or lysine, and combinations of mutant and native subunits, yielding net ring charges of -1 to -4, were expressed in Xenopus laevis oocytes. In all complexes, the alpha subunit contained a Cys substituted for alphaThr244, three residues away from the ring glutamate alphaGlu241. The rate constants for the reactions of alphaThr244Cys with the neutral 2-hydroxyethyl-methanethiosulfonate, the positively charged 2-ammonioethyl-methanethiosulfonate, and the doubly positively charged 2-ammonioethyl-2'-ammonioethanethiosulfonate were determined from the rates of irreversible inhibition of the responses to acetylcholine. The reagents were added in the presence and absence of acetylcholine and at various transmembrane potentials, and the rate constants were extrapolated to zero transmembrane potential. The intrinsic electrostatic potential in the channel in the vicinity of the ring of charge was estimated from the ratios of the rate constants of differently charged reagents. In the acetylcholine-induced open state, this potential was -230 mV with four glutamates in the ring and increased linearly towards 0 mV by +57 mV for each negative charge removed from the ring. Thus, the intrinsic electrostatic potential in the narrow, intracellular end of the open channel is almost entirely due to the intermediate ring of charge and is strongly correlated with alkali-metal-ion conductance through the channel. The intrinsic electrostatic potential in the closed state of the channel was more positive than in the open state at all values of the ring charge. These electrostatic properties were simulated by theoretical calculations based on a simplified model of the channel.

Animals↗
PubMed2000

Lack of correlation between DNA strand breakage and p53 protein levels in human fibroblast strains exposed to ultraviolet lights.

The contribution of DNA strand breaks accumulating in the course of nucleotide excision repair to upregulation of the p53 tumor suppressor protein was investigated in human dermal fibroblast strains after treatment with 254 nm ultraviolet (UV) light. For this purpose, fibroblast cultures were exposed to UV and incubated for 3 h in the presence or absence of l-beta-D-arabinofuranosylcytosine (araC) and/or hydroxyurea (HU), and then assayed for DNA strand breakage and p53 protein levels. As expected from previous studies, incubation of normal and ataxia telangiectasia (AT) fibroblasts with araC and HU after UV irradiation resulted in an accumulation of DNA strand breaks. Such araC/HU-accumulated strand breaks (reflecting nonligated repair-incision events) following UV irradiation were not detected in xeroderma pigmentosum (XP) fibroblast strains belonging to complementation groups A and G. Western blot analysis revealed that normal fibroblasts exhibited little upregulation of p53 (approximately 1.2-fold) when incubated without araC after 5 J/m2 irradiation, but showed significant (three-fold) upregulation of p53 when incubated with araC after irradiation. AraC is known to inhibit nucleotide excision repair at both the damage removal and repair resynthesis steps. Therefore, the potentiation of UV-induced upregulation of p53 evoked by araC in normal cells may be a consequence of either persistent bulky DNA lesions or persistent incision-associated DNA strand breaks. To distinguish between these two possibilities, we determined p53 induction in AT fibroblasts (which do not upregulate p53 in response to DNA strand breakage) and in XP fibroblasts (which do not exhibit incision-associated breaks after UV irradiation). The p53 response after treatment with 5 J/m2 UV and incubation with araC was similar in AT, XPA, XPG and normal fibroblasts. In addition, exposure of XPA and XPG fibroblasts to UV (5, 10 or 20 J/m2) followed by incubation without araC resulted in a strong upregulation of p53. We further demonstrated that HU, an inhibitor of replicative DNA synthesis (but not of nucleotide excision repair), had no significant impact on p53 protein levels in UV irradiated and unirradiated human fibroblasts. We conclude that upregulation of p53 at early times after exposure of diploid human fibroblasts to UV light is triggered by persistent bulky DNA lesions, and that incision-associated DNA strand breaks accumulating in the course of nucleotide excision repair and breaks arising as a result of inhibition of DNA replication contribute little (if anything) to upregulation of p53.

Ataxia Telangiectasia↗
PubMed2000

The influence of hypoxia on the relative sensitivity of human tumor cells to 62.5 MeV (p-->Be) fast neutrons and 4 MeV photons.

Fast neutrons have been used in the clinical radiation therapy of tumors largely because of experimental evidence that their cytotoxic effects are much less dependent on oxygen levels than those of low-LET photons. The potential therapeutic advantage of fast neutrons based on hypoxia alone can be calculated as the "hypoxic gain factor", which is the ratio of the OERs for the fast-neutron compared to the photon beams. The hypoxic gain factor that is generally anticipated based on studies with established mammalian cell lines is about 1.6. However, surprisingly few studies have examined the influence of hypoxia on the fast-neutron radiosensitivity of human tumor cells of different histological types. For this reason, we have determined the OERs of five human tumor cell lines exposed to 62.5 MeV (p-->Be) cyclotron-generated fast neutrons or 4 MeV photons from a clinical linear accelerator. The OERs for four chemotherapy-naive cell lines, HT29/5, Hep2, HeLa and RT112, were invariably greater for photons than for neutrons, but all of these values were lower than expected on the basis of the previous literature. Despite their low OERs, these cell lines showed hypoxic gain factors that were within the range of 1.31-1.63, indicating that such effects cannot entirely explain the disappointing clinical results obtained with fast neutrons. In contrast, comparison of the surviving fractions at clinically relevant doses (1.6 Gy of neutrons and 2.0 Gy of photons) for these four tumor cell lines suggested that little benefit should result from neutron treatment. Only the cisplatin-resistant OAW42-CP line showed a significant hypoxic gain factor by this method of analysis. We conclude that, at the dose fractions used in clinical radiation therapy, there may not be a radiobiological precedent for higher local control rates after fast-neutron irradiation of hypoxic tumor cells.

Animals↗