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Biomedical subjects

D Stone

Publications and source records attributed to D Stone.

At least 73 records · Page 4Linked to original sources
PubMed1995

Expression of the pim-1 protooncogene: differential inducibility between alpha/beta- and gamma/delta-T cells and B cells.

The pim-1 gene encodes a serine/threonine protein kinase with expression restricted primarily to cells of hematopoietic lineage and is thought to play a role in the signal transduction events associated with lymphocyte activation. A rapid increase in pim-1 mRNA levels was found after stimulation of normal unseparated PBMCs with phorbol ester (PMA) and a calcium ionophore (ionomycin) with the peak level occurring 4 hr poststimulation. Treatment of PBMCs with ionomycin alone caused only a minimal increase in pim-1 mRNA, whereas treatment with PMA alone induced a large increase in pim-1 mRNA, suggesting that the activation of a signaling pathway involving protein kinase C is responsible for the accumulation of this transcript. In enriched subpopulations of resting alpha/beta-T cells, gamma/delta-T cells, and B cells, pim-1 expression was found to be constitutively expressed, albeit at lower levels in T cells. This basal level of pim-1 expression could be increased by stimulation of alpha/beta-T cells (approx fivefold) and gamma/delta-T cells (approximately sevenfold) with PMA plus ionomycin. In contrast, pim-1 expression was not inducible in B cells. In PBMCs, half-life determination studies showed that turnover of pim-1 mRNA was markedly prolonged as a result of message stabilization induced by PMA plus ionomycin treatment. In addition, stable pim-1 transcripts were also observed in all transformed lymphoid cell lines examined. Taken together, these results suggest that the stability of pim-1 transcripts may be linked to the regulation of cell growth and represent the first direct demonstration that pim-1 expression is indeed regulated in a cell-type-specific manner.

Animals↗
PubMed1995

Alpha-tocopherol mediated peroxidation in the copper (II) and met myoglobin induced oxidation of human low density lipoprotein: the influence of lipid hydroperoxides.

The principal antioxidant in human LDL, alpha-tocopherol, is converted to the alpha-tocopheroxyl radical after reaction with peroxyl radicals or Cu2+, and, if it does not terminate with peroxyl radicals, could initiate lipid peroxidation; a phenomenon called 'tocopherol mediated peroxidation'. Only in the presence of Cu2+ and low levels of lipid hydroperoxides was an alpha-tocopherol dependent decrease in the resistance of LDL to oxidation detected. This suggests that tocopherol mediated peroxidation will probably not contribute significantly as a pro-oxidant process in those individuals most at risk of developing atherosclerosis through an oxidative mechanism.

Azoles↗
PubMed1995

Epidemiology of Down's syndrome in a Scottish city.

The aim of the study was to investigate aspects of the epidemiology of Down's syndrome (DS) in a population subjected to continuous surveillance. Data were obtained from the Glasgow Register of Congenital Anomalies. Over the period 1980-90, 173 cases of DS were identified (1.2 per 1000 births), of which 135 (78.1%) were livebirths, five (2.9%) were stillbirths and 33 (19.1%) were terminations following prenatal diagnosis. The increasing risk of DS with advancing maternal age was confirmed, although most DS pregnancies occurred in women aged under 35. While the birth prevalence of DS did not vary significantly over time, there was a significant increase in DS pregnancy prevalence. The proportion of all DS pregnancies terminated showed a statistically significant rise from 14% in 1980-87 to 31% in 1988-90 following the introduction of a new screening marker for DS risk. Almost half of DS pregnancies in women aged 35 and over ended in termination following prenatal diagnosis compared with only 7% in women under 35. There was a statistically significant excess risk of DS pregnancy in the more prosperous areas of the city; this excess persisted, but was not statistically significant, after standardising the rates for maternal age. These findings suggest that there is no scope for reducing service provision for DS children on the basis of the epidemiological trends, that the antenatal screening programme, while benefiting from the recent introduction of serum markers of risk, continues to have a greater impact on older women, and that further aetiological research using population based registries is required.

Abortion, Therapeutic↗
PubMed1995

Long-term care reimbursement issues.

There have been dramatic changes in long-term care funding recently. Considered only an insignificant part of the continuum of care system just a few years ago, this level of care is now looked to as a wellspring for desperately needed health care cost reductions. Government, insurance companies, intermediaries, large providers, and consumer and physician groups are actively focused on the development and expansion of alternative care provision sites; sub-acute care; hospice; home health care; social, medical, and rehabilitative day care; assisted living and adult congregate care facilities; risk or capitation contracting; expanded health maintenance organizations; alternative care providers; and alternative care approaches. In addition, the improvement in reimbursement is reviewed and is one aspect in ensuring that the economics are right for those needed services to continue to be provided.

Abstracting and Indexing↗
PubMed1994

Human (THP-1) macrophages oxidize LDL by a thiol-dependent mechanism.

The oxidative modification of low-density lipoprotein by macrophages may be an important mechanism in the pathogenesis of atherosclerosis. The human monocytic leukaemia cell line THP-1, when stimulated with phorbol ester, shares many properties with human monocyte-derived macrophages. Oxidation of LDL by these cells was characterised by depletion of alpha-tocopherol, increases in thiobarbituric acid reactive substances and increases in electrophoretic mobility. The LDL particles were also converted to a form which increased accumulation of cholesteryl esters within macrophages. The oxidative mechanism appeared to be dependent upon the presence of thiols in the cellular medium. Oxidation of LDL by THP-1 macrophages, and production of thiols by these cells, were dependent upon the presence of L-cystine in the medium. Furthermore, cellular oxidation of LDL could be partially mimicked by the addition of cysteine to Hams F10 medium. Macrophage-independent oxidation of LDL, mediated by the addition of copper ions, was inhibited by cystine and cysteine in phosphate buffered saline, but not in Hams F10 medium. The glutathione content of THP-1 macrophages was also dependent upon the presence of cysteine or cystine in the medium, but inhibition of glutathione synthesis by buthionine sulfoximine did not prevent the production of thiols or the oxidation of LDL by THP-1 macrophages.

Buthionine Sulfoximine↗
PubMed1993

Changes in mitochondrial matrix free calcium in perfused rat hearts subjected to hypoxia-reoxygenation.

Reperfusion or reoxygenation of ischaemic or hypoxic cardiac tissue results in increases in total cell calcium and cell lysis both of which are dependent on mitochondrial function. Although changes which occur during this period of exposure of the tissue to hypoxia predispose the heart to take up calcium on reoxygenation, the mechanisms involved are not well understood. In the present study we have investigated the effects of hypoxia and reoxygenation on the concentration of intramitochondrial (matrix) free Ca2+ ([Ca2+]m) using mitochondria loaded in the intact heart with fura-2. During periods of up to 80 min hypoxia, total tissue calcium content was unchanged. Over this period [Ca2+]m rose from an initial value of 156 +/- 26 nM to 360 +/- 33 nM and 574 +/- 62 nM at 50 and 80 min of hypoxia, respectively; values that are within the expected physiological range for [Ca2+]m. Reoxygenation after 50 min hypoxia resulted in no further change in [Ca2+]m whereas reoxygenation after 80 min hypoxia resulted in a 10-fold increase in this parameter. These results provide clear evidence that [Ca2+]m increases during hypoxia and suggest that the ability of the cell to maintain Ca2+ homeostasis is lost on reoxygenation after prolonged hypoxia with the result that [Ca2+]m exceeds the normal physiological range.

Adenosine Triphosphate↗
PubMed1993

Detection of HIV-1 by polymerase chain reaction and culture in seronegative intravenous drug users in an inner-city emergency department.

STUDY BACKGROUND: After a health care worker's unprotected exposure to a patient's blood, the current recommendation is to obtain consent from the source for serologic testing for HIV. If the test is negative, no further follow-up of the exposed provider is usually indicated. OBJECTIVE: To determine if patients testing negative for HIV-1 antibody on routine serology harbor occult HIV-1 infection. DESIGN: Cross-sectional, identity-unlinked, patient-related data and blood sample procurement for HIV-1 infection. SETTING: Inner-city university hospital emergency department with high HIV-1 seroprevalence among patients. TYPE OF PARTICIPANTS: IV drug users not known to have HIV-1 infection. MEASUREMENTS: Serum samples were analyzed for HIV-1 antibodies by enzyme immunoassay and Western blot. Peripheral mononuclear cells were analyzed for HIV-1 provirus by polymerase chain reaction and viral culture. MAIN RESULTS: Of 131 patients, 36 (27.5%) were Western blot-confirmed seropositive for HIV-1. Of the 95 seronegative patients, six (6.3%) were polymerase chain reaction positive, and one of these was confirmed with culture. The negative predictive value of standard serology was 93.5% with polymerase chain reaction alone and 98.9% with concordant polymerase chain reaction and culture results. CONCLUSION: There may be a significant number of ED patients in HIV-1 prevalent populations who have occult HIV-1 infection not detectable by serology at the time of a health care provider exposure. Although these data suggest that further prospective study is warranted to better quantify the frequency of this phenomenon, these preliminary data suggest that current Centers for Disease Control recommendations regarding provider exposures may need to be reappraised for certain situations.

Adult↗
PubMed1993

Factors limiting the effectiveness of prenatal screening for anencephaly and spina bifida in a high-risk area.

The effectiveness of a prenatal screening programme in reducing the birth prevalence of anencephaly and spina bifida (ASB) is influenced by three principal factors: the proportion of affected pregnancies screened (uptake), the proportion of affected pregnancies detected on screening (sensitivity) and the proportion of affected pregnancies terminated when detected (compliance). The purpose of the study was two-fold: to develop an epidemiologically-based method for the retrospective monitoring of these three factors and to attempt to quantify their relative importance in relation to the outcome of screening. Data on births and terminations associated with ASB for the period 1976-1986 were obtained from the Glasgow Register of Congenital Anomalies and from the Department of Medical Genetics, Yorkhill Hospitals. Increasing proportions of affected pregnancies screened, detected and terminated were observed, to a greater degree for anencephaly than for spina bifida. The relationships between uptake, sensitivity, compliance and terminations are described in the form of a simple arithmetic expression. In policy terms, further efforts are required to increase all three in order to improve the effectiveness of screening for spina bifida.

Abortion, Therapeutic↗
PubMed1993

Accommodation and chromatic aberration: effect of spatial frequency.

When subjects view an edge in white light, a colour fringe, produced by longitudinal chromatic aberration (LCA) of the eye, is formed at the edge. The colour fringe changes with changes in focus, and serves as a complex colour-coded cue for reflex accommodation. Fincham found that 60% of his subjects failed to accommodate appropriately when the colour fringe was removed with an achromatizing lens or by the use of monochromatic light. Our experiment sought to determine the spatial frequencies at which LCA is most effective. We monitored accommodation in 10 subjects while they viewed sinusoidally moving sine-wave gratings (1-3 D at 0.2 Hz; 1-10.5 c/deg) in a Badal optometer. The targets were 'white' gratings with LCA normal, doubled, neutralized or reversed. Doubling the aberration has minimal effect, removing the aberration reduces gain and increases phase-lag, and reversing the aberration severely disrupts accommodation. Sensitivity to these chromatic cues exists at all spatial frequencies tested, but is most prominent between 3 and 5 c/deg. These results support the view that the system monitors focus by comparing contrast in red-green and perhaps blue-yellow colour-opponent mechanisms.

Accommodation, Ocular↗
PubMed1993

Approaches to the construction of new candidate poliovirus type 3 vaccine strains.

The World Health Organization has called for improvements to oral polio vaccines (OPV), particularly the type 3 component. Our improved understanding of the genetic basis of attenuation and antigenicity of this strain gives rise to possibilities for constructing new derivatives via mutagenesis of infectious cDNA. This article reviews progress made with various approaches to constructing a new type 3 candidate vaccine strain. These include the construction of antigen chimaeras of poliovirus based on the Sabin type 1 strain, the introduction of new genetically stable attenuation mutations into the 5' non-coding region (NCR) of the type 3 poliovirus genome, and the introduction of mutations which may increase the thermostability of the type 3 vaccine.

Antibodies, Viral↗
PubMed1992

Pro-oxidant effects of lipoxygenase-derived peroxides on the copper-initiated oxidation of low-density lipoprotein.

It has been proposed that lipoxygenases, specifically 15-lipoxygenase, may play an important role in promoting the oxidation of low-density lipoprotein (LDL) in the artery wall. It is well known that peroxides are unstable in the presence of transition metals, decomposing to form the alkoxy and peroxy radicals, and so initiating lipid peroxidation. To test whether lipoxygenase-derived peroxides may promote the oxidation of LDL in the presence of copper, the lipoprotein was enriched with lipid peroxides derived from the enzymic action of 5- and 15-lipoxygenases on either linoleic or arachidonic acid. All of these products were found to promote oxidation, whereas the related hydroxy fatty acids had no effect. This suggests that lipoxygenase-derived peroxides associated with the LDL particle may promote peroxidation in the presence of a suitable transition metal catalyst. This result has implications both for the mechanism of the potential pro-oxidant action of lipoxygenases in vivo and for the ex vivo assessment of the oxidizability of LDL samples isolated from different donors.

Arachidonic Acid↗
PubMed1992

The loading of fura-2 into mitochondria in the intact perfused rat heart and its use to estimate matrix Ca2+ under various conditions.

When rat hearts were perfused with a medium containing 10 microM fura-2/AM for 1 hr at 37 degrees C a significant amount of the derived fura-2 could be detected in subsequently isolated mitochondria. This procedure allowed the measurement of matrix free Ca2+ concentration ([Ca2+]m) of mitochondria rapidly isolated from whole hearts by a method which avoids artefactual redistribution of Ca2+. [Ca2+]m in mitochondria prepared from control hearts and incubated with respiratory substrates and EGTA was found to be 172 +/- 23 nM (mean +/- S.E.M.). When hearts were subjected to either increased mechanical work or treatment with 1 microM L-epinephrine (for 2 mins) [Ca2+]m increased to 916 +/- 138 nM and 727 +/- 65 nM respectively. The presence of ruthenium red (2.5 microM) in the perfusion medium prior to and during inotropic intervention diminished these increases in [Ca2+]m(to 316 +/- 28 nM and 218 +/- 18 nM respectively) but did not affect control values. Addition of Na+ ions to incubated mitochondria to enhance mitochondrial Ca2+ egress diminished these increases in [Ca2+]m due to pre-treatment with positive inotropes (compared to controls). These changes in [Ca2+]m were broadly parallelled by changes in the active non-phosphorylated form of pyruvate dehydrogenase (PDH) under all circumstances. These results provide further evidence that the activation of PDH by positive inotropes is accomplished by, and at least in part due to, raised mitochondrial matrix free [Ca2+] and that such increases can be maintained in isolated and suitably incubated mitochondria.

Animals↗