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Biomedical subjects

D R Jones

Publications and source records attributed to D R Jones.

At least 109 records · Page 6Linked to original sources
PubMed1998

Identification and characterization of a new oncogene derived from the regulatory subunit of phosphoinositide 3-kinase.

p85/p110 phosphoinositide 3-kinase (PI3K) is a heterodimer composed of a p85-regulatory and a p110-catalytic subunit, which is involved in a variety of cellular responses including cytoskeletal organization, cell survival and proliferation. We describe here the cloning and characterization of p65-PI3K, a mutant of the regulatory subunit of PI3K, which includes the initial 571 residues of the wild type p85alpha-protein linked to a region conserved in the eph tyrosine kinase receptor family. We demonstrate that this mutation, obtained from a transformed cell, unlike previously engineered mutations of the regulatory subunit, induces the constitutive activation of PI3K and contributes to cellular transformation. This report links the PI3K enzyme to mammalian tumor development for the first time.

3T3 Cells↗
PubMed1998

The missing voice: impacts of health system change on low-income communities.

Unique problems in obtaining adequate health care face poor urban communities. These include the rising number of uninsured, abuses in the managed-care system, the unwillingness of private providers to deliver health care for either Medicaid recipients or the uninsured, and an insufficient supply of primary care physicians in minority neighborhoods. If the managed-care system is to bring decent health care to poor urban communities, it must avoid the mistakes of the past. The health care system must be community based, oriented toward primary care, sufficiently funded, and universally accessible. There needs to be better coordination between medical schools and community health requirements and better support for public health facilities. Without adequate health care for the poor, urban living will eventually become more onerous for all.

Forecasting↗
PubMed1998

Automated, ambulatory, or conventional blood pressure measurement in pregnancy: which is the better predictor of severe hypertension?

OBJECTIVES: Our purpose was to investigate the benefit, if any, of automated blood pressure monitoring over obstetric day unit conventional blood pressure measurement in the assessment of hypertensive pregnancies. STUDY DESIGN: A prospective, observational study was carried out in two large teaching hospitals. Three hundred and forty-eight women with a confirmed clinic blood pressure of at least 140/90 mm Hg were recruited. Conventional blood pressure measurements (< or =5) were obtained on the day unit and simultaneously an ambulatory blood pressure monitor was applied for 24 hours. The predictive ability of day unit assessment (blood pressure > 140/90 mm Hg) and automated blood pressure monitoring (blood pressure > 130/85 mm Hg) was compared. Principal outcome measures included the occurrence of severe hypertension (> 160/110 mm Hg) and proteinuria (> 500 mg or 2+) within (a) 2 weeks and (b) the remainder of the pregnancy. Thompson's method was used to compare sensitivity and specificity of the day unit blood pressure and automated blood pressure monitoring. RESULTS: Three hundred and forty-eight women were recruited to the study. The comparison between automated blood pressure monitoring and conventional blood pressure measurement for both sensitivity and specificity for systolic and diastolic blood pressure revealed increased sensitivity and decreased specificity with automated blood pressure monitoring for all principal outcomes except development of proteinuria for systolic blood pressure. Sensitivity for the outcomes was increased with automated blood pressure monitoring by between 14% and 27% for systolic blood pressure and between 7% and 39% for diastolic blood pressure, with the greatest improvement seen for the development of severe hypertension within 2 weeks of assessment. CONCLUSIONS: In the assessment of hypertensive pregnancies, automated blood pressure measurement was a significantly better predictor (compared with conventional day unit assessment) for the development of severe hypertension within 2 weeks of assessment for both systolic and diastolic blood pressure.

Adult↗
PubMed1998

The interaction of diltiazem with lovastatin and pravastatin.

BACKGROUND: Lovastatin is oxidized by cytochrome P4503A to active metabolites but pravastatin is active alone and is not metabolized by cytochrome P450. Diltiazem, a substrate and a potent inhibitor of cytochrome P4503A enzymes, is commonly coadministered with cholesterol-lowering agents. METHODS: This was a balanced, randomized, open-label, 4-way crossover study in 10 healthy volunteers, with a 2-week washout period between the phases. Study arms were (1) administration of a single dose of 20 mg lovastatin, (2) administration of a single dose of 20 mg pravastatin, (3) administration of a single dose of lovastatin after administration of 120 mg diltiazem twice a day for 2 weeks, and (4) administration of a single dose of pravastatin after administration of 120 mg diltiazem twice a day for 2 weeks. RESULTS: Diltiazem significantly (P < .05) increased the oral area under the serum concentration-time curve (AUC) of lovastatin from 3607 +/- 1525 ng/ml/min (mean +/- SD) to 12886 +/- 6558 ng/ml/min and maximum serum concentration (Cmax) from 6 +/- 2 to 26 +/- 9 ng/ml but did not influence the elimination half-life. Diltiazem did not affect the oral AUC, Cmax, or half-life of pravastatin. The average steady-state serum concentrations of diltiazem were not significantly different between the lovastatin (130 +/- 58 ng/ml) and pravastatin (110 +/- 30 ng/ml) study arms. CONCLUSION: Diltiazem greatly increased the plasma concentration of lovastatin, but the magnitude of this effect was much greater than that predicted by the systemic serum concentration, suggesting that this interaction is a first-pass rather than a systemic event. The magnitude of this effect and the frequency of coadministration suggest that caution is necessary when administering diltiazem and lovastatin together. Further studies should explore whether this interaction abrogates the efficacy of lovastatin or enhances toxicity and whether it occurs with other cytochrome P4503A4-metabolized 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, such as simvastatin, fluvastatin, and atorvastatin.

Administration, Oral↗
PubMed1998

The contribution of intestinal and hepatic CYP3A to the interaction between midazolam and clarithromycin.

OBJECTIVE: To assess the relative contribution of intestinal and hepatic CYP3A inhibition to the interaction between the prototypic CYP3A substrates midazolam and clarithromycin. METHODS: On day 1, 16 volunteers (eight men and eight women; age range, 20 to 40 years; weight range, 45 to 100 kg) received simultaneous doses of midazolam intravenously (0.05 mg/kg over 30 minutes) and orally (4 mg of a stable isotope, 15N3-midazolam). Starting on day 2, 500 mg clarithromycin was administered orally twice daily for 7 days. On day 8, intravenous and oral doses of midazolam were administered 2 hours after the final clarithromycin dose. Blood and urine samples were assayed for midazolam, 15N3-midazolam, and metabolites by gas chromatography-mass spectrometry. RESULTS: There was no significant (p > 0.05) difference in the urinary excretion of 1'-hydroxymidazolam after intravenous and oral dosing on day 1 or day 8, indicating that the oral dose was completely absorbed into the gut wall. The oral clearance of midazolam was found to be significantly greater in female subjects (1.9 +/- 1.0 versus 1.0 +/- 0.3 L/hr/kg; p < 0.05) than in male subjects but not systemic clearance (0.35 +/- 0.1 versus 0.44 +/- 0.1 L/hr/kg). For women not receiving oral contraceptives (n = 6) a significant gender-related difference was observed for systemic and oral clearance and for area under the curve and elimination half-life after oral administration. A significant (p < 0.05) reduction in the systemic clearance of midazolam from 28 +/- 9 L/hr to 10 +/- 3 L/hr occurred after clarithromycin administration. Oral midazolam availability was significantly increased from 0.31 +/- 0.1 to 0.75 +/- 0.2 after clarithromycin dosing. Likewise, intestinal and oral availability were significantly increased from 0.42 +/- 0.2 to 0.83 +/- 0.2 and from 0.74 +/- 0.1 to 0.90 +/- 0.04, respectively. A significant correlation was observed between intestinal and oral availability (n = 32, r = 0.98, p < 0.05). After clarithromycin administration, a significant correlation was observed between the initial hepatic or intestinal availability and the relative increase in hepatic or intestinal availability, respectively. Female subjects exhibited a greater extent of interaction after oral and intravenous dosing than male subjects (p < 0.05). CONCLUSION: These data indicate that in addition to the liver, the intestine is a major site of the interaction between oral midazolam and clarithromycin. Interindividual variability in first-pass extraction of high-affinity CYP3A substrates such as midazolam is primarily a function of intestinal enzyme activity.

Adult↗
PubMed1998

Foliar leaching of 137Cs from Eriophorum vaginatum L., Scirpus caespitosus L. and Erica tetralix L.

Evidence of extensive leaching losses of nutrients, particularly of K, suggest that loss of 137Cs by foliar leaching could be considerable and could stimulate further root uptake and redistribution of 137Cs in plants. This study investigated the foliar leaching of 137Cs from two deciduous graminoid species, Eriophorum vaginatum and Scirpus caespitosus and one evergreen shrub, Erica tetralix. Plants were labelled with 137Cs via the roots and subjected to a leaching treatment in August and November and changes in both leachate and plant 137Cs activity were determined. Leaching losses were significantly reduced in November compared with August in the deciduous species, but not in the evergreen E. tetralix. A reduction in the total activity of 137Cs of leached plants was observed not only in leaves but also in stems and roots in some instances, suggesting that 137Cs from these organs had been redistributed to replenish that lost by leaching from the leaves. The data suggest that leaching losses were greater from older and senescent leaves than from younger leaves of E. vaginatum. The extent to which this is an accurate representation of foliar leaching of field-grown plants by rainfall, and the likely fate of 137Cs lost by foliar leaching are discussed.

Journal Article↗
PubMed1998

The role of glycosyl-phosphatidylinositol in signal transduction.

Glycosyl-phosphatidylinositol (GPI) lipids have a structural role as protein anchors to the cell surface. In addition, they are implicated in hormone, growth factor and cytokine signal transduction. Their phosphodiesteric hydrolysis mediated by an activated phospholipase results in the generation of water soluble oligosaccharide species termed the inositol phosphoglycan (IPG). This product has been demonstrated to possess biological properties when added exogenously to cells mimicking the biological effects of a variety of extracellular ligands. This may be accomplished since IPG is generic for a family of closely related species which are released in a tissue-specific manner and additionally have cell-specific targets. Micro-organic synthesis has recently been able to shed new light on this topic by the introduction of defined oligosaccharide analogues of IPG for the assessment of their biological activity. These have complemented the findings observed with purified IPG from biological sources thus strengthening the belief that the GPI/IPG signalling system represents a truly novel aspect of transmembrane signalling.

Animals↗
PubMed1998

Fetal therapy: prospects for transplantation early in pregnancy. In utero stem cell transplantation and gene therapy: second international meeting, Nottingham, UK, 1-2 September 1997.

The meeting was punctuated by discussion sessions enabling delegates and speakers to debate issues raised. A number of questions were aired and areas that need to be addressed with some urgency were highlighted. Tolerance induction in utero is now considered feasible and can be added to the potential outcomes of IUT. Agreement must be reached on the source of stem cells for IUT, and stem cell banking will need to meet internationally accepted standards. Finally, the transplantation protocol itself must be agreed, a challenge that must be met if IUT is to join the mainstream of therapeutic protocols.

Animals↗
PubMed1998

Stem cell transplantation into the fetal recipient: challenges and prospects.

The interest in therapeutic intervention for those inherited disorders that can be diagnosed early in pregnancy has recently intensified. In-utero transplantation of haematopoietic stem cells (IUT-HSC), a therapy which could be proffered before pathological manifestations of a disorder become apparent, offers considerable potential benefit. However, as reports of IUT-HSC procedures become more prolific, it is necessary to consider the optimum modus operandi for each group of disorders targeted for therapy in order to develop effective procedures that make a real difference to the outcome. This review outlines the current status and prospects of IUT-HSC. It also offers a view of some of the challenges for IUT-HSC to overcome to find wider clinical applications.

Female↗
PubMed1998

Pancoast tumors of the lung.

Pancoast or superior pulmonary sulcus tumors are uncommon primary bronchogenic carcinomas that produce a characteristic clinical syndrome of upper extremity pain and Horner's syndrome. Treatment of patients with this malignancy has traditionally involved irradiation alone or preoperative irradiation followed by resection. Recent advances in the management of Pancoast tumors include the importance of mediastinoscopy in staging the tumor before treatment begins. A complete resection should be accomplished including a lobectomy whenever possible. The current treatment protocol involves induction chemoradiotherapy followed by surgery.

Carcinoma, Bronchogenic↗
PubMed1998

Carbon dioxide transport in alligator blood and its erythrocyte permeability to anions and water.

Deoxygenation of alligator red blood cells (RBCs) caused binding of two HCO3- equivalents per hemoglobin (Hb) tetramer at physiological pH. At lowered pH, some HCO3- binding also occurred to oxygenated Hb. The erythrocytic total CO2 content was large, and Hb-bound HCO3-, free HCO3-, and carbamate contributed about equally in deoxygenated cells. The nonbicarbonate buffer values of RBCs and Hb were high, and the Hb showed a significant fixed acid Haldane effect. Binding of HCO3- on deoxygenation occurred without a change in RBC intracellular pH, revealing equivalence between oxylabile HCO3- and H+ binding. Erythrocyte volume, plasma pH, and plasma HCO3- concentration also varied little with the degree of oxygenation. Diffusional water permeability was higher in oxygenated than deoxygenated RBCs. The RBCs have rapid band 3-mediated Cl- and HCO3- transport, which was not affected by degree of oxygenation, but net fluxes of Cl- and HCO3- via the anion exchanger are small during blood circulation at rest. Most of the CO2 taken up into the blood as it flows through tissue capillaries is carried within the erythrocytes as Hb-bound HCO3- until CO2 is excreted when blood flows through pulmonary capillaries.

Acid-Base Equilibrium↗
PubMed1998

The prospects for in utero stem cell transplantation.

In utero transplantation of haematopoietic stem cells into the foetus, early in gestation, offers a new approach to genetic disorders. Immunological naivete and the sterile uterine environment are perfect conditions for transplantation, so that even mismatched cells will engraft. There have been notable successes world-wide, although numbers are small, which gives encouragement to further work directed at means to enhance and sustain engraftment in a foetal recipient. For example, stem cells for transplant can be obtained from various sources but these have different properties that can be exploited for therapy in specific disorders. However, some disorders may not be amenable to in utero transplantation and there is need to achieve consensus in order to ensure that the procedure is used appropriately, for the benefit of all.

Journal Article↗
PubMed1998

A military application of a medical self-care program.

The cost of health care is a growing concern to the military. Many military clinic appointments and emergency department visits are unnecessary; they are for minor, self-limiting illnesses and injuries that could be treated at home. Military health care can no longer afford the luxury of treating minor illnesses and injuries in the hospital setting. This paper examines one method for military beneficiaries to obtain health care services appropriately. A selected group of military family members received a medical self-care book and an education session, which resulted in more appropriate decision-making about when to use the health care system. This was a 6-month, experimental study using control and experimental groups, with surveys before and after the study period. The self-care book was used 628 times to help make more informed decisions about when to seek medical care. The mean number of clinic and emergency room visits (p = 0.02) decreased for those using the medical self-care book.

Adult↗
PubMed1997

Glycosyl-phosphatidylinositol-phospholipase type D: a possible candidate for the generation of second messengers.

Membrane associated glycosyl-phosphatidylinositols have been shown to be the precursors of inositol phosphoglycan second messengers. Extraction of human liver membranes and purification by serial thin layer chromatography revealed three glycolipids which co-migrated with glycosyl-phosphatidylinositol from rat liver. These lipidic fractions were partially sensitive to treatment with nitrous acid and to hydrolysis by glycosyl-phosphatidylinositol-specific phospholipase D from bovine serum. In parallel, glycosyl-phosphatidylinositol isolated from rat liver was found to be a substrate for the enzyme generating a biologically active inositol phosphoglycan species (determined by measuring inhibition of protein kinase A activity and stimulation of cell proliferation within the chicken embryo cochleovestibular ganglion). This molecule was recognised by an anti-inositol phosphoglycan antibody. Hence, we propose that glycosyl-phosphatidylinositol-specific phospholipase D could be implicated in cellular signalling.

Animals↗
PubMed1997

Isolation and partial characterisation of insulin-mimetic inositol phosphoglycans from human liver.

Extracts of human liver were found to contain activities which copurified and coeluted with the two major subtypes of mediators (type A and type P) isolated from insulin-stimulated rat liver. The putative type A mediator from human liver inhibited cAMP-dependent protein kinase from bovine heart, decreased phosphoenolypyruvate carboxykinase mRNA levels in rat hepatoma cells, and stimulated lipogenesis in rat adipocytes. The putative type P mediator stimulated bovine heart pyruvate dehydrogenase phosphatase. Both fractions were able to stimulate proliferation of EGFR T17 fibroblasts and the type A was able to support growth in organotypic cultures of chicken embryo cochleovestibular ganglia. Both activities were resistant to Pronase treatment and the presence of carbohydrates, phosphate, and free-amino groups were confirmed in the two fractions. These properties are consistent with the structure/ function characteristics of the type A and P inositolphosphoglycans (IPG) previously characterized from rat liver. Further, the ability of the human-derived mediators to interact with rat adipocytes and bovine-derived metabolic enzymes suggests similarity in structure between the mediators purified from different species. Galactose oxidase-susceptible membrane-associated glycosylphosphatidylinositols (GPI) have been proposed to be the precursors of IPG. GPI was purified from human liver membranes followed by treatment with galactose oxidase and reduction with NaB3H4. Serial t.l.c. revealed three radiolabeled bands which comigrated with the putative GPI precursors found in rat liver. These galactose-oxidase-reactive lipidic compounds, however, were only partially susceptible to hydrolysis with phosphatidylinositol-specific phospholipase C from Bacillus thuringiensis and were resistant to glycosylphosphatidylinositol-specific phospholipase C from Trypanosoma brucei. These data indicate that IPG molecules with insulin-like biological activities are present in human liver.

Adult↗