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Biomedical subjects

M Murphy

Publications and source records attributed to M Murphy.

At least 217 records · Page 12Linked to original sources
PubMed1997

Minimizing racial disparity regarding receipt of a cadaver kidney transplant.

This report describes the impact of race on waiting list entry and receipt of a cadaver kidney transplant, after accounting for self-reported income, health and functional status, and patients' attitudes about dialysis and transplantation as treatment alternatives. Previous studies did not account for these race-related factors and therefore produced biased estimates of the impact of race on waiting list entry and receipt of a transplant. Data for this investigation came from a telephone survey of a national sample of 456 end-stage renal disease patients and from files maintained by the United Network for Organ Sharing and the Health Care Financing Administration. Proportional hazard models were estimated with these data. The results indicated that approximately 60% of the differences between black and white waiting list entry rates and 52% of the black-white differences in transplantation rates were due to race-related differences in socioeconomic status, health and functional status, severity of illness, biological factors, the existence of contraindications to transplantation, transplant center characteristics, and patients' attitudes about dialysis and transplantation. Potential ways to narrow racial differences further include better education about treatment alternatives for black patients, more vigorous efforts to obtain donor organs from minorities, continued research and thoughtful policy on the access-related impacts of United Network for Organ Sharing point system variances, and consolidation of some smaller waiting lists into larger regional lists.

Adolescent↗
PubMed1997

Cytokines which signal through the LIF receptor and their actions in the nervous system.

A number of different cytokines, each initially characterized on the basis of very different biological activities, all have very similar signalling pathways and share a similar tertiary structure. These cytokines include leukaemia inhibitory factor, ciliary neuronotrophic factor, oncostatin M, growth-promoting activity and cardiotrophin 1. They all have been found to regulate a number of properties of cells of the developing and mature nervous system in vitro and thus are neuroregulatory cytokines. The actions of these cytokines include regulation of neurotransmitter phenotype, differentiation of neuronal precursor cells both in the peripheral nervous system and in the spinal cord, survival of differentiated neurons, and regulation of development of both astrocytes and oligodendrocytes. In addition, studies in animal models show that these factors can rescue sensory and motor neurons from axotomy-induced cell death, which suggests that they can act as trauma factors for injured neurons. Analysis of the expression patterns of the different neuroregulatory cytokines and their receptors reveals that the receptors are expressed throughout nervous system development and following trauma, whereas the cytokines show temporal and spatial specific expression patterns. This is consistent with the idea that specific cytokines have specific roles in neural development and repair, but that their signalling pathways are shared. The phenotypes of the receptor knockouts show clear deficits in nervous system development, indicating a crucial role for LIF receptor signalling. Knockouts of individual cytokines are less dramatic, but LIF and CNTF knockouts do reveal deficits in maintenance of motor neurons or following trauma. Thus, whereas LIF and CNTF have clear roles in maintenance and following trauma, it is unclear which of the cytokines is involved in nervous system development. In clinical terms, these findings add further support to the use of these cytokines in nervous system trauma and disease.

Animals↗
PubMed1997

TP53 mutation in ovarian carcinoma.

This short report describes the detection of mutations of the TP53 tumour suppressor gene in sporadic ovarian carcinomas using archival paraffin-embedded tissues and automated fluorescent DNA sequencing. TP53 mutations were detected in eight tumours. Missense mutations predominated and all were transitions. Mutations were commonest in late-stage serous tumours. In three cases, where tissue was available, the mutations were homogeneous throughout several sections of the bilateral ovarian tumours and in omental metastases. These data confirm the findings of previous investigations describing TP53 mutation in ovarian carcinoma and demonstrate that archival paraffin-embedded tissues can be used for such analyses.

DNA Mutational Analysis↗
PubMed1997

Infertility treatment and multiple birth rates in Britain, 1938-94.

Trends in multiple birth rates are thought to have been substantially affected by subfertility treatments in the last 25 years, but there are few quantitative assessments of this. This paper examines trends in twin and higher multiple birth rates separately in Scotland, England and Wales and compares their course with corresponding multiple birth rates in the Oxford Record Linkage Study area, where the proportions following subfertility treatment are documented. National data on prescriptions for subfertility treatments reinforce the view that they have had a major effect on the trends, and currently perhaps 60% of triplet and higher order births and 15% of twins follow their use in Britain.

Birth Rate↗
PubMed1997

Neural stem cells.

This article is concerned with the idea that neural precursor cells in vertebrates can self-renew and give rise to all cell types within the nervous system. Supportive evidence for this notion of neural stem cells comes from clonal analyses undertaken both in vivo and in vitro. Neural stem cells also give rise to other cells in the body, including skin melanocytes and a range of mesenchymal cells in the head and neck. What determines the fate of these stem cells is their initial location within the developing neural tube and their final location post migration from the proliferative zone of the neural tube. A population of cells in the adult brain also have the characteristics of classical stem cells, a finding that opens the way for potential replacement therapy in nervous system-degenerative diseases. Much of the work in our laboratory has been concerned with the regulation of expansion and differentiation of these cells into their myriad progeny and the role of a series of various growth factors in this process. Different factors, such as members of the fibroblast growth factor family, act at different times to regulate stem cell proliferation and differentiation. Some factors, including members of the TGF beta superfamily, appear to be directly involved in the specification of cell fate. Finally, we are beginning to be able to determine the steps in the development of some lineages from multipotential stem cell to fully functional differentiated cell.

Animals↗
PubMed1997

Delayed early embryonic lethality following disruption of the murine cyclin A2 gene.

In higher eukaryotes, cell cycle progression is controlled by cyclin dependent kinases (Cdks) complexed with cyclins. A-type cyclins are involved at both G1/S and G2/M transitions of the cell cycle. Cyclin A2 activates cdc2 (Cdk1) on passage into mitosis and Cdk2 at the G1/S transition. Antisense constructs, or antibodies directed against cyclin A2 block cultured mammalian cells at both of these transitions. In contrast, overexpression of cyclin A2 appears to advance S phase entry and confer anchorage-independent growth, and can lead to apoptosis. A second A-type cyclin, cyclin A1 has been described recently which, in the mouse, is expressed in germ cells but not somatic tissues. To address the possible redundancy between different cyclins in vivo and also the control of early embryonic cell cycles, we undertook the targeted deletion of the murine cyclin A2 gene. The homozygous null mutant is embryonically lethal, demonstrating that the cyclin A2 gene is essential. Surprisingly, homozygous null mutant embryos develop normally until post-implantation, around day 5.5 p.c. This observation may be explained by the persistence of a maternal pool of cyclin A2 protein until at least the blastocyst stage, or an unexpected role for cyclin A1 during early embryo development.

Animals↗
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

General health of end stage renal disease program beneficiaries.

A telephone survey of a national sample of 515 Medicare End Stage Renal Disease Program beneficiaries was conducted to obtain information on their health status and its determinants. The Medical Outcomes Study Short Form-36 (SF-36) was applied during the interview process to obtain the health-status information. The reliability of each SF-36 health-status dimension was at least 0.85, and the validity of seven of the eight dimensions was high. Weighted least-squares regression results showed that health-status levels were often lower among older patients and Hispanic persons, and sometimes lower for those with low incomes. The implications of using the SF-36 for health-status measurement are also described.

Activities of Daily Living↗
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↗