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Biomedical subjects

A Hughes

Publications and source records attributed to A Hughes.

At least 109 records · Page 6Linked to original sources
PubMed1995

Cardiac function during orthotopic liver transplantation with venovenous bypass.

We have studied the effect of varying the flow of a venovenous bypass system during orthotopic liver transplantation. During these manipulations, central venous (n = 9) or pulmonary artery occlusion (n = 9) pressures were kept constant. There was no change in right ventricular systolic or diastolic function in either group, suggesting that any conformational change of the ventricle during bypass is not of functional significance. The extrapolated volume loading required to compensate for the absence of bypass is of the order of 3000 ml.

Adult↗
PubMed1995

Effects of tyrosine kinase inhibitors on the contractility of rat mesenteric resistance arteries.

1. A pharmacological characterization of tyrosine kinase inhibitors (TKI) belonging to two distinct groups (competitors at the ATP-binding site and the substrate-binding site, respectively) was performed, based on their effects on the contractility of rat mesenteric arteries. 2. Both the ATP-site competitors (genistein and its inactive analogue, daidzein) and the substrate-site competitors (tyrphostins A-23, A-47 and the inactive analogue, A-1) reversibly inhibited noradrenaline (NA, (10 microM)) and KCl (125 mM) induced contractions, concentration-dependently. Genistein was slightly but significantly more potent than daidzein; the tyrphostins were all less potent than genistein, and there were no significant differences between the individual potencies. The tyrosine kinase substrate-site inhibitor bis-tyrphostin had no inhibitory effect. 3. Genistein, daidzein, A-23 and A-47 each suppressed the contraction induced by Ca2+ (1 microM) in alpha-toxin permeabilized arteries. A-1 and bis-tyrphostin had little or no effect on contraction of the permeabilized arteries. 4. Genistein was significantly more potent than daidzein with respect to inhibition of the contraction induced by 200 nM Ca2+ in the presence of NA (100 microM) and GTP (3 microM). The effect of A-23, A-47, A-1 and bis-tyrphostin was similar in permeabilized arteries activated with Ca2+ (200 nM) + NA (100 microM) + GTP (3 microM) and permeabilized arteries activated with 1 microM Ca2+. 5. Genistein (30 microM) reduced the fura-2 measured intracellular calcium activity ([Ca2+]j) in arteries stimulated with NA but had no effect on [Ca2+]i in arteries stimulated with KCl (125 mM).6. The potent effect of the TKIs in this study is consistent with a role for tyrosine kinases in the mechanisms which regulate both cytoplasmic Ca2+ levels and the effect of Ca2+ on the contractile apparatus in smooth muscle cells in resistance arteries. However, the results must be interpreted cautiously because the enzyme inhibitors may have a poor specificity in intact tissues and because the presumed inactive analogues had potent effects.

Animals↗
PubMed1995

In vivo gene therapy for hyperlipidemia: phenotypic correction in Watanabe rabbits by hepatic delivery of the rabbit LDL receptor gene.

Elevations of plasma total or LDL cholesterol are major risk factors for cardiovascular disease. Efforts directed at preventing and treating cardiovascular disease have often focused on reducing the levels of these substances in the blood. The Watanabe Heritable Hyperlipidemic Rabbit, which has exceedingly high plasma cholesterol levels resulting from an LDL receptor deficiency, provides an excellent animal model for testing new treatments. A recombinant adenoviral vector containing the rabbit LDL receptor cDNA was administered to Watanabe rabbits. Plasma total cholesterol levels in the treated animals were reduced from 825.5 +/- 69.8 (mean +/- SD) to 247.3 +/- 61.5 mg/dl 6 d after infusion. These animals also demonstrated a 300-400% increase in plasma levels of HDL cholesterol and apo AI 10 d after treatment. As a result, the LDL:HDL ratio exhibited a dramatic decrease. Because only the rabbit LDL receptor gene was used for treatment, the results strongly suggest that the elevations of plasma HDL cholesterol and apo AI were secondary to a reduction in plasma total cholesterol in the treated animals. These results suggest an inverse relationship between plasma LDL and HDL cholesterol levels and imply that reduction of LDL cholesterol levels may have a beneficial effect on plasma HDL cholesterol.

Animals↗
PubMed1995

Carboplatin in combination with paclitaxel in advanced ovarian cancer: dose determination and pharmacokinetic and pharmacodynamic interactions.

Data from various phase I/II studies of carboplatin in combination with paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) have suggested that the degree of thrombocytopenia seen is less than that expected when carboplatin is given alone. However, some studies also have suggested that the area under the plasma concentration-time curve (AUC) of carboplatin is lower than that expected, raising the possibility of a pharmacokinetic interaction. Patients with advanced epithelial ovarian cancer were treated with first-line carboplatin (AUC = 7, using the 51Cr EDTA [edetic acid] clearance method) and escalating doses of paclitaxel. Thrombocytopenia was mild and was significantly less when the paclitaxel dose was 175 mg/m2 versus 150 mg/m2. Paclitaxel kinetics were nonlinear, as previously reported. The achieved carboplatin AUC was 7 +/- 1 mg/mL.min, indicating that the pharmacokinetics of carboplatin are not affected by paclitaxel. Glomerular filtration rates measured in 184 patients using the 51Cr EDTA clearance method were compared with rates estimated from the plasma creatinine level using the Cockcroft-Gault or Jeliffe formulas and showed a significant bias of these two formulas. Clearances above 50 mL/min were underestimated by an amount that became greater as the clearance increased and was approximately 25% to 35% for patients with clearances in the normal range. Since creatinine-based methods have been used in many previous studies, care is needed in interpreting the predicted AUC values from these studies. Carboplatin and paclitaxel may be given safely in combination at full doses, and the thrombocytopenia seen is significantly less than that observed with single-agent carboplatin. No evidence exists of a pharmacokinetic interaction, and the observation in some studies that the carboplatin AUC was lower than expected was probably due to the methodology used to estimate the glomerular filtration rate.

Adult↗
PubMed1994

Inhibition of human vascular smooth muscle cell proliferation by lovastatin: the role of isoprenoid intermediates of cholesterol synthesis.

Restenosis remains the largest single obstacle to the long-term success of invasive vascular interventions. Lovastatin, an HMG-CoA reductase inhibitor, has been shown to reduce myointimal hyperplasia in animal models of restenosis and in one clinical coronary restenosis trial. We have assessed the effect of lovastatin on the growth of cultured human vascular smooth muscle cells derived from saphenous vein and vascular graft stenoses. Lovastatin (2 microM) inhibited proliferation over 14 days in saphenous vein (and graft stenoses) derived vascular smooth muscle cells by 42% and 32% respectively: this was not significantly different. Lovastatin (10 microM) reduced [methyl 3H]-thymidine uptake by 51% in saphenous vein-derived cells. These concentrations were significantly higher than those achieved in plasma during therapeutic dosage. Lovastatin-induced inhibition of vascular smooth muscle cell proliferation and [methyl 3H]-thymidine uptake was completely reversed by adding mevalonate (100 microM) but cholesterol (10-40 micrograms ml-1) had no effect. Isopentenyl adenine (25-50 microM) did not affect the inhibition of [methyl 3H]-thymidine uptake by lovastatin (10 microM), but farnesol (20 microM), another isoprenoid precursor of cholesterol synthesis, reversed the antiproliferative effect.

Adenine↗
PubMed1994

Type 3 burning mouth syndrome: psychological and allergic aspects.

A subgroup of patients with burning mouth syndrome was investigated. The clinical history of these patients differed from the norm in that symptoms were intermittent and affected unusual sites. In addition, routine investigations were supplemented with a more detailed psychological evaluation than reported previously and also a possible allergic component was studied by patch testing. The study has shown that this subgroup differs from burning mouth syndrome patients overall in that emotional instability and allergic reactions, particularly to food additives, are of etiological significance and require to be taken into consideration in terms of patient management.

Aged↗
PubMed1993

Dopa resistance in multiple-system atrophy: loss of postsynaptic D2 receptors.

Postmortem autoradiography was used to explore the mechanisms underlying L-dopa resistance in 2 patients with multiple-system atrophy. Indices of striatal presynaptic dopamine terminal loss and dopamine (D1 and D2) receptors were provided by 3H-mazindol, 3H-SCH 23390, and 125I-sulpiride binding. Neuronal loss, gliosis, and loss of postsynaptic D2 receptors preferentially involved the middle and posterior of the putamen, that region of the striatum most intimately involved in motor function. Loss of D1 receptors in the same area occurred in only 1 patient. These findings suggest that in multiple-system atrophy, resistance to L-dopa is due to a loss of putamental D2 receptors. The differential effects on D1 and D2 receptors in 1 patient implies that different subpopulations of striatal neurons were selectively involved.

Aged↗
PubMed1993

Sexual practices, sexually transmitted diseases and other risk factors for HIV among injecting drug users.

Data were collected from 814 clients attending anonymously for counselling before tests for human immunodeficiency virus (HIV) infection at the Burnett Clinic in Auckland. Just over 10 per cent of clients (n = 83) reported ever having injected drugs. This group was matched according to age, gender, ethnicity and sexual orientation with an equal sized control group drawn from clients who had not injected drugs. The groups were compared in terms of their sexual practices, sexual partnerships, other drug use, current and past health status and their perception of HIV risk. The injecting drug users reported more sex partners than the nonusers, they were less likely to be in a relationship and they were less likely to be monogamous. Vaginal and oral sex were the most common practices in both groups but anal sex was more common among users than the nonusers. Regular condom use was reported by less than a quarter of each group. The health status of drug users was generally poorer than that of the nonusers. They reported greater use of alcohol and other drugs, more mental health problems, and more symptoms of ill health. They also had experienced more sexually-transmitted diseases. Only 1 per cent of users and 2 per cent of nonusers tested positively for HIV, although users saw themselves and their partners as at greater risk of HIV infection than the nonusers.

AIDS Serodiagnosis↗
PubMed1993

Force, membrane potential, and [Ca2+]i during activation of rat mesenteric small arteries with norepinephrine, potassium, aluminum fluoride, and phorbol ester. Effects of changes in pHi.

In activated rat mesenteric small arteries, the effect of pHi on force, membrane potential, and free cytosolic calcium ([Ca2+]i) was assessed. Arteries were mounted in a myograph for isometric force development, and [Ca2+]i, pHi, or membrane potential was measured simultaneously with force. During activation with norepinephrine, potassium, aluminum fluoride (AlF-4), and phorbol 12-myristate 13-acetate (PMA, a phorbol ester), the vessels depolarized and [Ca2+]i increased, although the ratio of force to [Ca2+]i was less during potassium activation than with the other types of activation. Changes in pHi, with a constant pHo, were induced with NH4Cl or by changing PCO2. In resting vessels, the effects of the changes in pHi on tension, membrane potential, and [Ca2+]i were negligible. In vessels activated with norepinephrine or AlF-4, alkalinization caused an acute decrease of tone, which could be explained by a decrease in [Ca2+]i consequent to repolarization of the membrane. In vessels activated with potassium or PMA, the effects of alkalinization were smaller. This is consistent with acute alkalinization, affecting steps proximal in the excitation-contraction coupling distal to activation of G proteins. Acidification caused a transient increase in tone and [Ca2+]i, irrespective of the mode of stimulation, without affecting the membrane potential. Ryanodine did not abolish the transient increase in tone and [Ca2+]i. Thus, acute intracellular acidification may induce tone by release of an intracellular ryanodine-insensitive calcium pool or by affecting transmembranal calcium flux although in a membrane potential-independent way.

Aluminum↗
PubMed1993

Perceptions and reactions of the public to diarrhoea.

A questionnaire about diarrhoea and how people react to it was answered by 400 people aged 16-70 years, most of whom were in employment (77% of respondents). There was wide variation in perceptions and reactions. Older persons and people in skilled trades were more likely to consider any increased bowel looseness or frequency of their usual bowel habit as diarrhoea, compared to younger persons and people in professional and managerial positions. Over half the respondents rated a single soft stool as diarrhoea, and almost a third accepted likewise an increased frequency of defaecation. The most unpleasant aspect of diarrhoea was considered to be incontinence with soiling of underclothes. At the onset of diarrhoea, 16% of respondents would not wait even a day or two but would go straight to a pharmacist, and 8% would go direct to a doctor. Persons in professional and managerial positions were less likely to attend their doctor straight away than people in other occupational groups. The findings show that for improved clinical management and public health surveillance, health professionals should not accept the term when it is used by patients, but seek details of their defaecation patterns and the form of their stools. Improved public education is needed as to self-help, appropriate treatment and when to seek pharmaceutical and medical advice.

Adolescent↗
PubMed1993

Comparison of the distribution of radioiodinated-E-17 alpha-iodovinyl-11 beta-methoxyestradiol and 2-iodo-1,1-bis(4-hydroxyphenyl)-phenylethylene estrogens in the immature female rat.

Current therapies for estrogen receptor-positive (ER+) cancers rely heavily on growth prevention by cytostatic agents rather than destruction of the cancer cells. In these studies, we compared the tissue distribution of two radioiodinated estrogens, one a triphenylethylene estrogen, IBHPE, the other steroidal, IVME2. The radioiodoestrogens were prepared using the halodestannylation reaction from the respective tributyltin precursors. The specificity of binding of these radioiodinated estrogens to the estrogen receptor (ER) was established by sucrose-density gradient analyses and their specific activities by comparison with the ER binding of 3H-estradiol of known specific activity. The time-dependent tissue distribution of the two radioiodoestrogens in immature female rats was studied to compare the relative uptake and specific retention of the two estrogens in ER target organs and assess their possible use for imaging ER positive tissues or for Auger electron-mediated ER-directed therapy. While the uterus showed only slightly poorer retention of the nonsteroidal estrogen (IBHPE) than the steroidal estrogen (IVME2), those target tissues that required blood-supplied ligand (e.g., vagina, pituitary) showed substantially higher uptake of the steroidal estrogen. IBHPE showed significantly higher blood levels at all time points. While the tissue-to-muscle ratios for IBHPE in the uterus and ovary were higher initially, the IVME2 showed higher tissue-to-muscle ratios, suggesting that the steroidal estrogen may be the more promising ligand for imaging purposes. However, IBHPE showed excellent uptake by peritoneal target tissues, with much lower concentrations in more distant target tissues (e.g., pituitary) so it might have distinct potential for therapy of intraperitoneal ER-containing cancers.

Animals↗
PubMed1992

The superficial plexiform layer: a third retinal association area.

Electron microscopy enables the identification of a new association area in the mammalian retina. It is a region whose processes and synaptic junctions form a diffuse and intermittent layer bridging the boundary between the optic nerve fibre layer and ganglion cell layer. It involves displaced amacrine cells, retinal ganglion cells and probably interplexiform cell processes. Because it is close to the vitreal surface of the retina and has several properties of a plexiform layer, it has been named the superficial plexiform layer. It is much more sparse than the outer or inner plexiform layers in the rabbit, but contains a significant and substantial density of 6,100 synapses/mm2 near the visual streak. Morphological criteria distinguish two classes of synapses in the new association area. One has features of Colonnier's symmetric type and is formed by amacrine-like processes or their terminals, onto other amacrine-like processes or the cell bodies, dendrites and axon hillocks of some large ganglion cells. It makes up 79% of the population at a density of 4,800 synapses/mm2 in the examined sample. The second class arises from large processes of the fibre layer, which resemble axons rather than amacrine cell branches, has Colonnier's asymmetric form, and synapses onto a variety of other neuronal processes and cells. At a local density of 1,300/mm2 this type forms 21% of the population. A series of experiments including Wallerian degeneration, retrograde degeneration, electron microscopy and horseradish peroxidase (HRP) transport was employed to determine the nature of the large synapse-forming processes of the fibre layer that were the most amenable to investigation. It is concluded that the processes project into the optic nerve because they can be filled with HRP by retrograde transport from the end of the transected optic nerve. Although this result is based on limited evidence, it is complemented by the observation that the majority of the fibres undergo retrograde degeneration within 25 days of optic nerve section. It is concluded that the processes are either centrifugal fibres or the axons of retinal ganglion cells. The persistence of a relatively normal density of synapse-forming large fibres for seven days after optic nerve section, without Wallerian degeneration, argues that they are not the terminals of centrifugal axons. This conclusion is complemented by a separate class of profiles that did degenerate in this short period and are concluded to represent the centrifugal fibres. The large synapsing processes of the fibre layer are concluded to be the axons of some large ganglion cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Estrogen receptor-directed radiotoxicity with Auger electrons: specificity and mean lethal dose.

To assess the feasibility of using estrogen receptor-directed therapy with Auger electron-emitting ligands for therapy of estrogen receptor (ER)-containing cancers, we synthesized and evaluated the radiotoxicity of several 123I-labeled estrogens to specifically kill ER+ cells in culture. Auger electrons have been previously shown to be of short range, generally less than the dimensions of a cell, so that to use them therapeutically a mechanism is needed to deliver the Auger electron-emitting nuclide to the vicinity of the DNA. Since it is now well established that the estrogen receptor, when bound to estrogen, forms a high affinity association with distinct estrogen response elements in the DNA, we wished to test the hypothesis that a short exposure of cells to a 123I-labeled estrogen would be specifically radiotoxic to ER+ cells, and that the decays per cell needed for cell killing would be compatible with reasonable levels of receptor occupancy. Using the halodestannylation reaction with tributyl tin precursors of several estrogens and commercially available iodine-123, we prepared the iodoestrogens, E-17 alpha(-)[123I]-iodo-11 beta-methoxyestradiol and 2(-)[123I]iodo-1,1-bis(4-hydroxyphenyl)--2-phenylethylene, at high specific activities, in several cases at essentially the specific activity of 123I itself, 240,000 Ci/mmol. When various concentrations of either of the 123I-labeled estrogens were incubated for 1 h with a subline of ER+ Chinese hamster ovary cells and the washed cells plated for survival assays, a dose-dependent, unlabeled estradiol-inhibitable reduction in survival was observed. In contrast, Chinese hamster ovary cells not expressing estrogen receptor showed little sensitivity to the radiotoxicity of the 123I-labeled estrogens. Calculations based on the assayed residence time of the iodoestrogens in the cells indicate that several hundred decays per cell are sufficient to kill cells.

Animals↗
PubMed1992

Celiprolol.

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Antihypertensive Agents↗