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Biomedical subjects

M Murphy

Publications and source records attributed to M Murphy.

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

The safety and effectiveness of the Le Fort I approach to removing central skull base lesions.

The difficulty of gaining access to the central skull base has led to the development of many surgical approaches to this area during the past decade. Yet we believe that the Le Fort I technique, which has been used for almost 140 years in orthognathic surgery, is still an excellent approach to treating anterior skull base lesions. This procedure, which entails the horizontal sectioning of the dentoalveolar maxillary segment, seemed to fall out of favor with otolaryngologists after a few reports of complications surfaced during the past 10 to 15 years. In this article, we report a series of seven patients whom we treated with a Le Fort I approach during a 3-year period for a variety of benign and malignant anterior skull base lesions. We have encountered no significant complications of surgery or recurrence of disease at a maximum postoperative followup of 3 years.

Adult↗
PubMed2001

The utility of a 3-dimensional, large-field-of-view, sodium iodide crystal--based PET scanner in the presurgical evaluation of partial epilepsy.

UNLABELLED: (18)F-FDG PET is an accurate and reliable technique for localizing medically refractory temporal lobe epilepsy, but widespread use has been hindered by limited reimbursement in many countries because of the high cost of traditional PET equipment and radioisotopes. Additionally, the place of FDG PET as a cost-effective tool for presurgical evaluation of epilepsy has been questioned because of limited data showing that FDG PET provides localization information incremental to that provided by more established techniques, particularly MRI and ictal electroencephalography (EEG). Three-dimensional (3D), large-field-of-view, sodium iodide crystal-based scanners have lower equipment and running costs and better multiplanar resolution than traditional 2-dimensional bismuth germinate (BGO) systems but have not yet been validated for evaluation of epilepsy. Our purpose was to investigate the localization rate, accuracy, and prognostic value of FDG PET images acquired on a 3D, large-field-of-view, sodium iodide crystal-based PET scanner in the presurgical evaluation of intractable partial epilepsy. We also wanted to establish the incremental value of FDG PET over established MRI and ictal EEG techniques. METHODS: Fifty-five patients who were surgical candidates because of medically refractory partial epilepsy were examined. For most of these patients, the lesions had not been clearly localized on conventional assessment. The FDG PET scans were reviewed independently by 2 reviewers who were unaware of the patients' clinical details, ictal EEG findings, and volumetric MRI results, and the FDG PET results were correlated with those of MRI and EEG and with postsurgical outcome. RESULTS: Forty-two patients (76%) had localizing FDG PET images (37 temporal, 5 extratemporal). The ictal EEG recordings were localizing in 66%, and the MRI findings were localizing in 27% (which increased to 35% after the MRI findings were reviewed again after PET). Concordance between the site of the PET localizations and the site of the MRI or EEG localizations was 100%. The PET images were localizing in 63% and 69% of patients with nonlocalizing ictal EEG and MRI findings, respectively. Twenty-one of 24 patients who subsequently underwent epilepsy surgery had localizing FDG PET images; of these 21 patients, 18 (86%) had a class I outcome. Multiple regression analysis showed the FDG PET results to be predictive of postsurgical outcome independently of the MRI findings. CONCLUSION: For intractable partial epilepsy, FDG PET using a 3D, large-field-of-view, sodium iodide crystal-based scanner provided clinically useful localizing information that was at least as accurate as the results reported for traditional BGO-based scanners. The PET images provided prognostically significant localization information incremental to that provided by volumetric MRI and ictal EEG, particularly if 1 of these studies was nonlocalizing.

Adolescent↗
PubMed2000

Reproductive factors, subfertility, and risk of neural tube defects: a case-control study based on the Oxford Record Linkage Study Register.

Periconceptual exposure to subfertility treatments is increasingly common, raising concerns about the possibility of malformations in the offspring. The authors conducted a case-control study to determine whether subfertility or its treatment was associated with increased risk of neural tube defects (NTDs). Cases were 694 women diagnosed with an NTD-affected pregnancy in Oxfordshire or West Berkshire, England, between 1970 and 1987. Cases were individually matched on maternal year of birth and year of index pregnancy to controls randomly selected from a computerized database. Data on demographic, reproductive, and obstetric factors were abstracted from patient hospital records. Overall, the period prevalences of subfertility and of subfertility treatment were 7% and 3%, respectively, No evidence was found that the risk of NTD-affected pregnancies was increased by either subfertility (odds ratio (OR) = 1.2, 95% confidence interval (CI): 0.7, 2.1) or its treatment (OR = 0.9, 95% CI: 0.4, 2.0). After adjustment, NTD-affected pregnancies were associated with female offspring (OR = 2.3, 95% CI: 1.8, 3.1), multiple birth (OR = 4.8, 95% CI: 1.2, 18.8), and higher numbers of pregnancies (p for trend = 0.005). The findings from this large, population-based study were wholly consistent with those from smaller studies that found no increased risk of NTD associated with exposure to fertility treatments but reported associations with various pregnancy outcomes.

Adult↗
PubMed2000

Molecular cloning of an Atlantic salmon nucleoside diphosphate kinase cDNA and its pattern of expression during embryogenesis.

To gain insight into the process of development in Atlantic salmon (Salmo salar), we sought to identify genes that were differentially expressed at gastrulation. A polymerase chain reaction-based differential screening strategy allowed for the isolation of an Atlantic salmon nucleoside diphosphate kinase cDNA (nm23). Structural characterisation showed a high degree of homology with a large number of previously isolated nucleoside diphosphate kinases (NM23s), both prokaryote and eukaryote, though it represents the first teleost nucleoside diphosphate kinase identified. Highest similarities were found with the type 1 and type 2 NM23 isoforms of mammals. Phylogenetic analysis indicates that the duplication event that gave rise to these isoforms occurred after the splitting of tetrapods and fish, suggesting that the salmon NM23 represents a more ancestral isoform. The position of the salmon sequence on the phylogenetic tree indicates that the salmon genome is expected to have at least three copies of genes from the nm23 gene family. Northern blot analysis showed a single transcript of approximately 0.7 kb in both embryonic and adult tissues. Examination of the temporal pattern of expression of salmon nucleoside diphosphate kinase during embryonic development revealed that this gene is first expressed at the time of gastrulation. Nucleoside diphosphate kinases are thought to have a vital role in regulatory processes such as signal transduction, proliferation and differentiation. Taken together, these results suggest that nucleoside diphosphate kinases have an important role to play in early embryogenic development in vertebrates.

Amino Acid Sequence↗
PubMed2000

Galactorrhoea and hyperprolactinaemia associated with protease-inhibitors.

We describe four patients with galactorrhoea as an isolated endocrine abnormality after use of protease inhibitors (PIs) as part of both highly active antiretroviral therapy (HAART) and postexposure prophylaxis (PEP). This reaction may be a direct effect of PIs or may be indirectly mediated by the effect of PIs on the cytochrome P450 system, thus potentiating the dopamine antagonist effects of other drugs.

Anti-HIV Agents↗
PubMed2000

Large-scale purification of antisense oligonucleotides by high-performance membrane adsorber chromatography.

Very high flux ion-exchange membranes were utilized for a novel purification of antisense oligonucleotides (20-mer). Strong anion-exchange membranes were produced by attaching polymeric ligands onto a microporous cellulosic matrix. The oligonucleotides purified were therapeutic single-stranded phosphorothioates deoxyribonucleotides. Although small-scale membrane devices (15 cm2) had similar resolution to traditional chromatographic columns; their throughputs were superior. Greater than a 1300-fold scale-up produced very similar purity and yields of the phosphorothionate product. Scale-up experiments were conducted with a 2 m2 surface area membrane module. These modules were easily capable of very high throughputs of 0.5 to 2 l/min. High purity and yields were achieved by both step and linear gradient elution.

Chromatography, Ion Exchange↗
PubMed2000

Computer support for interpreting family histories of breast and ovarian cancer in primary care: comparative study with simulated cases.

OBJECTIVES: To evaluate the potential effect of computer support on general practitioners' management of familial breast and ovarian cancer, and to compare the effectiveness of two different types of computer program. DESIGN: Crossover experiment with balanced block design. PARTICIPANTS: Of a random sample of 100 general practitioners from Buckinghamshire who were invited, 41 agreed to participate. From these, 36 were selected for a fully balanced study. INTERVENTIONS: Doctors managed 18 simulated cases: 6 with computerised decision support system Risk Assessment in Genetics (RAGs), 6 with Cyrillic (an established pedigree drawing program designed for clinical geneticists), and 6 with pen and paper. MAIN OUTCOME MEASURES: Number of appropriate management decisions made (maximum 6), mean time taken to reach a decision, number of pedigrees accurately drawn (maximum 6). Secondary measures were method of support preferred for particular aspects of managing family histories of cancer; importance of specific information on cancer genetics that might be provided by an "ideal computer program." RESULTS: RAGs resulted in significantly more appropriate management decisions (median 6) than either Cyrillic (median 3) or pen and paper (median 3); median difference between RAGs and Cyrillic 2.5 (95% confidence interval 2.0 to 3.0; P<0.0001). RAGs also resulted in significantly more accurate pedigrees (median 5) than both Cyrillic (median 3.5) and pen and paper (median 2); median difference between RAGs and Cyrillic 1.5 (1.0 to 2.0; P<0.0001). The time taken to use RAGs (median 178 seconds) was 51 seconds longer per case (95% confidence interval 36 to 65; P<0.0001) than pen and paper (median 124 seconds) but was less than Cyrillic (median 203 seconds; difference 23. (5 to 43; P=0.02)). 33 doctors (92% (78% to 98%)) preferred using RAGs overall. The most important elements of an "ideal computer program" for genetic advice in primary care were referral advice, the capacity to create pedigrees, and provision of evidence and explanations to support advice. CONCLUSIONS: RAGs could enable general practitioners to be more effective gatekeepers to genetics services, empowering them to reassure the majority of patients with a family history of breast and ovarian cancer who are not at increased genetic risk.

Breast Neoplasms↗
PubMed2000

Systematic review of the epidemiological evidence on Helicobacter pylori infection and nonulcer or uninvestigated dyspepsia.

BACKGROUND: Previous studies have yielded conflicting results and substantial uncertainty about any independent association of Helicobacter pylori infection with dyspepsia, and about any benefits of antibiotic treatments for nonulcer or uninvestigated dyspepsia. OBJECTIVES: To perform a systematic review of the literature to determine whether chronic infection with H pylori is relevant to nonulcer or uninvestigated dyspepsia. METHODS: Observational studies of associations between H pylori and dyspepsia published before April 1999 and randomized trials of the effects of H pylori eradication on dyspepsia published before January 2000 were identified by computer-assisted literature searches of relevant journals, reference lists, and discussions with authors. Relevant data were abstracted from the published reports by 2 investigators according to a fixed protocol. RESULTS: Thirty relevant observational studies were identified involving approximately 3392 patients with nonulcer dyspepsia, and 11 separate observational studies were identified, involving 6426 patients with uninvestigated dyspepsia. Reports of strong associations in small observational studies without appropriate adjustment for potential confounding factors were not generally confirmed by larger and better-designed studies. No studies have been reported, however, that can reliably confirm or exclude the existence of any weak associations. Twenty-two randomized trials of treatments against H pylori were found involving a total of 2340 patients with nonulcer dyspepsia, almost all with positive H pylori test results. Only a few of these trials involved effective antibacterial regimens with prolonged follow-up, and even these studies were too small to assess the possibility of moderate benefits. CONCLUSION: The available evidence indicates that there is no strong association between H pylori and dyspepsia, but there is insufficient evidence to confirm or refute the existence of a modest association.

Chronic Disease↗
PubMed2000

Analysis of p53-regulated gene expression patterns using oligonucleotide arrays.

Oligonucleotide microarrays were employed to quantitate mRNA levels from a large number of genes regulated by the p53 transcription factor. Responses to DNA damage and to zinc-inducible p53 were compared for their transcription patterns in cell culture. A cluster analysis of these data demonstrates that genes induced by gamma radiation, UV radiation, and the zinc-induced p53 form distinct sets and subsets with a few genes in common to all these treatments. Cell type- or cell line-specific p53 responses were detected. When p53 proteins were induced with zinc, the kinetics of induction or repression of mRNAs from p53-responsive genes fell into eight distinct classes, five different kinetics of induction, and three different kinetics of repression. In addition, low levels of p53 in a cell induced or repressed only a subset of genes observed at higher p53 levels. The results of this study demonstrate that the nature of the p53 response in diverse mRNA species depends on the levels of p53 protein in a cell, the type of inducing agent or event, and the cell type employed. Of 6000 genes examined for p53 regulatory responses, 107 induced and 54 repressed genes fell into categories of apoptosis and growth arrest, cytoskeletal functions, growth factors and their inhibitors, extracellular matrix, and adhesion genes.

Chlorides↗
PubMed2000

IHG-2, a mesangial cell gene induced by high glucose, is human gremlin. Regulation by extracellular glucose concentration, cyclic mechanical strain, and transforming growth factor-beta1.

We used cloning in silico coupled with polymerase chain reaction to demonstrate that IHG-2 is part of the 3'-untranslated region of gremlin, a member of the DAN family of secreted proteins that antagonize the bioactivities of members of the transforming growth factor (TGF)-beta superfamily. Mesangial cell gremlin mRNA levels were induced by high glucose, cyclic mechanical strain, and TGF-beta1 in vitro, and gremlin mRNA levels were elevated in the renal cortex of rats with streptozotocin-induced diabetic nephropathy in vivo. gremlin expression was observed in parallel with induction of bone morphogenetic protein-2 (BMP-2), a target for gremlin in models of cell differentiation. Together these data indicate that (a) IHG-2 is gremlin, (b) gremlin is expressed in diabetic nephropathy in vivo, (c) both glycemic and mechanical strain stimulate mesangial cell gremlin expression in vitro, (d) high glucose induces gremlin, in part, through TGFbeta-mediated pathways, and (e) Gremlin is a potential endogenous antagonist of BMPs within a diabetic glomerular milieu.

3' Untranslated Regions↗
PubMed2000

Endogenous IGF-1 regulates the neuronal differentiation of adult stem cells.

Stem cells from the adult forebrain of mice were stimulated to form clones in vitro using fibroblast growth factor-2 (FGF-2). At concentrations above 10 ng/ml of FGF-2, very few clones gave rise to neurons; however, if FGF-2 was removed after 5 days, 20-30% of clones subsequently gave rise to neurons. The number of neuron-containing clones and the number of neurons per clone was significantly enhanced, if insulin-like growth factor (IGF)-1 or heparin were added subsequent to FGF-2 removal. The spontaneous production of neurons after FGF-2 removal was shown to be due to endogenous IGF-1, since antibodies to IGF-1 and an IGF-1 binding protein totally inhibited neuronal production. Similarly, these reagents also abrogated the neuron-promoting effects of heparin. Thus, it appears that endogenous IGF-1 may be a major regulator of stem cell differentiation into neurons. Furthermore, it was found that high levels of IGF-1 or insulin promoted the maturation and affected the neurotransmitter phenotype of the neurons generated.

Animals↗
PubMed2000

Cytokine-mobilized peripheral blood progenitor cells for allogeneic reconstitution of miniature swine.

BACKGROUND: Because of the relative ease of acquisition, increased yield, and improved engraftment characteristics, mobilized peripheral blood progenitor (stem) cells (PBSCs) have recently become the preferred source for hematopoietic stem cell transplantation. In our laboratory, procurement of a megadose of PBSCs is necessary for on-going studies evaluating non-myelosuppressive transplant regimens for the induction of mixed chimerism and allograft tolerance. To exploit hematopoietic growth factor synergy, we have sought to combine growth factors with proven utility to improve PBSC mobilization and maximize our PBSC procurement through an automated collection procedure. METHODS: Mobilization characteristics of PBSCs were determined in 2-5-month-old miniature swine. Animals received either swine recombinant stem cell factor (pSCF, 100 microg/kg) and swine recombinant interleukin 3 (pIL-3, 100 microg/kg), administered intramuscularly for 8 days, or pSCF, pIL-3, and human recombinant granulocyte-colony stimulating factor (hG-CSF), at 10 microg/kg. Leukapheresis was performed beginning on day 5 of cytokine treatment and continued daily for 3 days. RESULTS: Collection of PBSCs from cytokine-mobilized animals via an automated leukapheresis procedure demonstrated a 10-fold increase in the number of total nucleated cells (TNC) (20-30 x 10(10) TNC) compared to bone marrow harvesting (2-3 x 10(10) total TNC). A more rapid rise in white blood cells (WBCs) was seen after administration of all three cytokines compared to pSCF and pIL-3 alone. An increase in colony-forming unit granulocyte-macrophage frequency measured daily from peripheral blood during cytokine treatment, was seen with the addition of hG-CSF to pSCF/pIL-3 correlating well with the rise in WBCs. Similarly, the addition of hG-CSF demonstrated a notable increase in the median progenitor cell yield from the 3-day leukapheresis procedure. Cytokine-mobilized PBSCs were capable of hematopoietic reconstitution. PBSCs mobilized with pSCF/pIL-3 were infused into an SLA-matched recipient conditioned with cyclophosphamide (50 mg/kg) and total body irradiation 1150 cGy. Neutrophil and platelet engraftment occurred on days 5 and 7, respectively, with minimal evidence of graft-versus-host disease. Complete donor chimerism has been demonstrated 331 days after transplant. CONCLUSIONS: Our preliminary results show that in this well-defined miniature swine model, recombinant swine cytokine combinations (pSCF, pIL-3 with or without hG-CSF) successfully mobilize a high yield of progenitor cells for allogeneic transplantation. Furthermore, these cytokine-mobilized PBSCs demonstrate the potential to reconstitute hematopoiesis and provide long-term engraftment in miniature swine.

Animals↗
PubMed2000

Evaluation of thresholds for benomyl- and carbendazim-induced aneuploidy in cultured human lymphocytes using fluorescence in situ hybridization.

Threshold mechanisms of activity for mutagenic agents have been debated for some time, especially for those substances which induce aneuploidy by inhibiting mitotic spindle function. No observed effect levels (NOELs) or "practical thresholds" have been demonstrated for several aneugens both in vitro and in vivo generally by either counting chromosomes in metaphase preparations or by observing micronuclei. Recently, fluorescence in situ hybridization (FISH) has proven to be a sensitive and useful technique for the assessment of aneuploidy at low concentrations. Using binucleate human lymphocytes coupled with FISH, we have been able to characterize a threshold mechanism of action for two spindle inhibitors, benomyl and its active metabolite, carbendazim. Test chemicals were added 24 h following culture initiation. After a further 20 h, cytochalasin B was added, and cells were harvested 28 h later (72 h post initiation). The distribution of chromosomes between the nuclei of binucleate cells was evaluated by fluorescence microscopy for the simultaneous detection of centromeres labeled with FITC (green) or Cy-3 (red). Six human chromosomes were investigated in pairs (1 and 8, 11 and 18, and X and 17). Abnormalities were classified as chromosome loss (including centromeric positive micronuclei), chromosome gain, non-disjunction, or polyploidy. Dose-response data were generated over a range of closely spaced concentrations at 100 ng/ml intervals. The threshold, defined as the lowest "effect" concentration using statistical methods, was determined for each chromosome. Non-disjunction proved to be the most sensitive endpoint for the detection of aneuploidy occurring at higher frequencies and lower concentrations. Results for the six chromosomes demonstrated similar dose-response data which included a series of concentrations with no statistically significant increase above background, followed by a second range of higher concentrations with a statistically significant, concentration-dependent increase. Nearly equimolar threshold concentrations were determined for benomyl- and carbendazim-induced non-disjunction.

Adult↗
PubMed2000

Psychosocial morbidity: the economic burden in a pediatric health maintenance organization sample.

OBJECTIVES: To evaluate psychosocial morbidity in pediatric primary care and to determine displaced health care utilization. DESIGN AND SETTING: A cross-sectional sample of parent-child dyads was screened using the Pediatric Symptom Checklist (PSC) at 6 pediatric sites of a health maintenance organization (HMO). Cost and utilization data were retrieved from regional databases for this sample. PARTICIPANTS: Parent-child dyads from an HMO in northern California (N = 1840). The children ranged in age from 2 to 18 years. RESULTS: In all, 13.0% of children exhibited psychosocial dysfunction. The rate of children's chronic illness was 18.4%. Multiple regression analyses measured utilization and cost of health and psychiatric care for the selected population for the previous year; the average log cost of health care per child was $393. The average health care cost for children with anxious, depressed symptoms was $805. Chronically ill children were the highest utilizers of health care, with an average log cost of $1138. When psychosocial dysfunction was present, regression models showed that health care spending was highest for young children. CONCLUSIONS: Health care utilization was higher for children with psychosocial morbidity, was higher among younger children, and decreased with age as psychiatric costs progressively increased.

Adolescent↗
PubMed2000

Effects of a monetary incentive on primary care prescribing in Ireland: changes in prescribing patterns in one health board 1990-1995.

BACKGROUND: In an attempt to curb the rapidly rising costs of primary care prescribing in Ireland, the government introduced a financial incentive scheme in 1993, to encourage general practitioners to restrain their prescribing. PURPOSE: To investigate the effects of a financial incentive scheme on GP prescribing in Ireland on prescribing costs and volume, and on some specific therapeutic areas. METHODS: Prescribing for 3 years before (1990-1992) and 3 years (1993-1995) after the introduction of incentives, based on a defined cohort of 233 general practitioners in the area of one health board. GPs were divided into tertiles based on their performance against their prescribing budgets into 'savers' (generally underspent and received incentive payments), modest overspenders and large overspenders. RESULTS: Savers were always lower cost prescribers than the other groups. They contained their rate and costs of prescribing in contrast to the other groups, e.g. percentage rise in prescribing costs in the year after the introduction of the scheme -7.9%, +1.2% and +7.3% respectively, (P < 0.05) for savers, modest overspenders and large overspenders respectively. This effect was short lived however and was gone by the third year of the study. CONCLUSIONS: The financial incentives had a marked effect on prescribing volume and cost on some practices who could achieve targets and hence incentive payments. The incentives had little effect on high spending practices. Such incentive schemes need careful evaluation if they are not to become perverse to the good health of patients.

Drug Utilization↗