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Biomedical subjects

J Gilbert

Publications and source records attributed to J Gilbert.

At least 91 records · Page 5Linked to original sources
PubMed1996

Hydrogen uptake hydrogenase in Helicobacter pylori.

The peptic ulcer-causing bacterium Helicobacter pylori was found to contain an H2-uptake hydrogenase activity coupled to whole cell (aerobic) respiration. The activity was localized to membranes which functioned in the H2-oxidizing direction with a variety of artificial and physiological electron acceptors of positive redox potential. Immunoblotting of H. pylori membrane components with anti (B. japonicum) hydrogenase large and small subunit-specific antisera identified H. pylori hydrogenase peptides of approximately 65 and 26 kDa respectively, and H. pylori genomic DNA fragments hybridizing to the (B. japonicum) hydrogenase structural genes were identified. The membrane-bound activity was subject to anaerobic activation, like many NiFe hydrogenases. Difference absorption spectral studies revealed absorption peaks characteristic of b and c-type cytochromes, as well as of a bd-type terminal oxidase in the H. pylori H2-oxidizing membrane-associated respiratory chain.

Aerobiosis↗
PubMed1996

Involvement of MDR1 P-glycoprotein in multifactorial resistance to methotrexate.

Cellular resistance to methotrexate (MTX) is believed to be unaffected by expression of MDR1 P-glycoprotein (Pgp), a pleiotropic efflux pump acting on different hydrophobic compounds that enter cells by passive diffusion. A series of human leukemic CCRF-CEM sublines, isolated by multi-step selection for very high resistance to MTX, exhibit multiple mechanisms of MTX resistance, including decreased carrier-mediated uptake of MTX and DHFR gene amplification. These sublines show cross-resistance to drugs of the multi-drug resistance (MDR) family, which is correlated with relative resistance to MTX. The MTX-selected sublines show increased expression and function of the MDR1 gene, based on the measurement of MDR1 mRNA, Pgp and rhodamine 123 accumulation. Sequence analysis of the MDR1 cDNA from MTX-selected CCRF-CEM cells revealed no mutations in the protein coding region. MTX resistance in these cell lines is partially reversible by a Pgp-specific monoclonal antibody (MAb) UIC2 and a monovalent FaB fragment of UIC2. Our results indicate that Pgp can contribute to multifactorial resistance to MTX.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Morphological, biochemical, and genetic support for an apolipoprotein E effect on microtubular metabolism.

There are two distinct viewpoints on the association of the inheritance of apolipoprotein E (APOE) alleles and the age of onset distribution of Alzheimer's disease (AD): genetic and phenotypic expression. There have been multiple corroborations of the APOE-epsilon 4 association with Alzheimer's disease in populations around the world in clinic based studies as well as emerging epidemiological studies. The genetic data do not imply mechanism of pathogenesis. The phenotypic expression of AD has been based in theories based on amyloid plaques or neurofibrillary tangles. ApoE protein interacts with both beta-amyloid and tau in an isoform-specific manner. The interaction with tau had been thought to be an in vitro artifact, since apoE had not been previously localized to the neuronal cytoplasm. Immuno-EM studies have localized apoE in neuronal cytoplasm. ApoE3 interacts with both tau and MAP2c at the microtubule binding repeat domain under conditions in which apoE4 is less tightly bound. These data further support a hypothesis that apoE3 (and apoE2) protect the microtubule binding domain of tau from binding to itself to form paired helical filaments and neurofibrillary tangles, while protecting the site for microtubule stabilizing interactions with beta-tubulin. These data are supported by recent data from APOE knock-out mice demonstrating dendritic alterations leading to synaptic simplification similar to that observed in AD.

Age of Onset↗
PubMed1996

Pharmacokinetic and fetal cardiovascular effects of enalaprilat administration to maternal rhesus macaques.

OBJECTIVE: The purpose of this study was to determine the extent of placental transfer of the angiotensin-converting enzyme inhibitor enalaprilat and the effects on maternal and fetal cardiovascular parameters. STUDY DESIGN: Between gestational days 122 and 126 (term 167 days) five rhesus macaques underwent surgery for implantation of maternal and fetal vascular catheters. At least 4 days after surgery maternal and fetal blood pressures and heart rates were recorded for 1 hour. This was followed by a 5-minute maternal venous infusion of saline solution vehicle and recording for an additional hour. Enalaprilat was then infused over 5 minutes through the maternal femoral artery at doses of 0.05, 0.1, or 0.2 mg/kg. Maternal and fetal arterial blood samples were collected for determination of blood gas status and plasma enalaprilat concentrations. RESULTS: Enalaprilat rapidly crossed the placenta, and fetal values for areas under the concentration time curve were 50% to 65% of maternal values across dose groups. Drug was retained in the fetal plasma approximately threefold to fourfold longer than in maternal plasma. Maternal heart rate, blood pressure, arterial Po2 and pH were unchanged after enalaprilat infusion, as were fetal heart rate and blood gases. In contrast, fetal arterial pressure decreased significantly (19% to 23%, p < 0.01) after maternal treatment with 0.1 and 0.2 mg/kg and remained depressed throughout the 6-hour study interval. At 0.05 mg/kg fetal arterial pressure was decreased by 13% from baseline; differences were not significantly different (p > 0.05). CONCLUSIONS: Results from this study indicate that enalaprilat rapidly crosses the primate placenta with a single intravenous administration to the mother, resulting in significant and prolonged reduction of fetal arterial pressure. Because maternal cardiovascular parameters were unaffected, enalaprilat appears to have a direct effect on fetal arterial pressure.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1996

Prolonged intraperitoneal infusion of 5-fluorouracil using a novel carrier solution.

A novel peritoneal carrier solution, Icodextrin 20 (7.5%), has allowed exploration of prolonged, intraperitoneal (i.p.) infusion of the cytotoxic drug 5-fluorouracil (5-FU). A phase I and pharmacokinetic study was performed to determine the toxicities and maximum tolerated dose of prolonged and continuous intraperitoneal 5-FU in patients with peritoneal carcinomatosis. Seventeen patients were entered into this study. Each patient had a Tenckhoff catheter placed into the peritoneal cavity under general anaesthetic. After initial flushing and gradual increase in exchange volumes with Icodextrin 20, 5-FU was administered daily from Monday to Friday, 50% as a bolus in the exchange bag and 50% in an elastomeric infusor device delivering continuous 5-FU to the peritoneal cavity at 2 ml h-1. Treatment was continued for 12 weeks or until intolerable toxicity developed. Abdominal pain and infective peritonitis proved to be the main dose-limiting toxicities. Initial problems with infective peritonitis were overcome by redesign of the delivery system, and it proved possible to deliver 300 mg m-2 5-FU daily (5 days per week) for 12 weeks. Pharmacokinetic studies showed i.p. steady-state 5-FU concentrations (mean 47 500 ng ml-1) that were > 1000-fold higher than systemic venous levels (mean 30 ng ml-1).

Adult↗
PubMed1996

Palliative medicine: a new specialty changes an old debate.

The specialty of palliative care, of which palliative medicine is part, has developed from hospice care for the dying and aims to meet the various needs of those suffering from advanced incurable progressive disease. Specialist palliative care is not expensive and can be made available to all those who need it, at home, in hospital or in a hospice. Arguments in favour of permitting euthanasia for those dying as a result of a chronic disease are usually based on compassion respect for autonomy or perceived hypocrisy in existing medical practice. Each of these arguments is examined and found wanting.

Euthanasia↗
PubMed1996

Characteristics of referrals to an inpatient hospice and a survey of general practitioner perceptions of palliative care.

In order to determine symptoms, drug prescribing and physical problems of patients referred to an inpatient hospice, case notes from 130 consecutive first admissions (95 general practitioner (GP) referrals, 35 consultant referrals) were analysed. GP referrals were more likely to be constipated, require care and be discharged to home. Consultant referrals were more gravely ill, dependent and more likely to die in the hospice. On admission 76 (58%) patients were receiving opiates with co-prescription of opiate and laxative occurring in 41% (31/76) of the cases. The prescription of laxatives with the symptoms of constipation occurred in 62% (26/42) of the cases on admission. A telephone survey of 79 referring GPs revealed that 37% had attended neither a course nor a lecture relevant to palliative care in the past 3 years. GPs experienced difficulties frequently or always in: (a) managing pain (8/79); (b) managing other symptoms (25/79); (c) helping patients and relatives cope with their emotional distress (18/79); and (d) coping with their own emotional responses to death and dying (5/79). In conclusion, the differences demonstrated between the GP and consultant referrals have implications for purchasers. The high incidence of possible opiate-induced side-effects and the difficulties with symptom control expressed by some GPs indicate a continuing need for effective educational input.

Analgesics↗
PubMed1995

Analysis of a novel cDNA encoding a C219-reactive peptide isolated from methotrexate-selected multidrug-resistant human leukemic cells.

We have isolated and sequenced a novel cDNA clone (D320), from methotrexate-selected multidrug-resistant (MDR) human leukemic CCRF-CEM cells, which encodes a peptide reactive with monoclonal antibody (mAb) C219. Despite having been cloned using this ostensibly P-glycoprotein-specific mAb, clone D320 has no significant homology with either the MDR-encoding gene or, at the amino acid (aa) level, with its product, P-glycoprotein. A putative C219-binding site has been identified in D320, which differs at two positions from the 6-aa C219 epitope previously described in P-glycoprotein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Analysis of mycotoxins in food and feed: certification of DON in wheat and maize.

Worldwide there are either statutory limits or in some instances advisory guidelines for the maximum levels of mycotoxins in foods and feeds. These limits which have been agreed for the protection of human health and as standards for trade are often set at surprisingly low levels in view of both the problems of sampling and the abundant evidence of the difficulties of mycotoxin analysis, particularly so when approaching the limits of detection. Improved methodology for mycotoxins and improvements in performance even of expert laboratories have, however, been achieved through intercomparison exercises organised by the EC Measurement and Testing programme (formerly BCR). On a wider scale, participation in proficiency testing through schemes such as the UK Food Analysis Performance Assessment Scheme (FAPAS) have indicated that between 10 and 40% of laboratories experience difficulties in obtaining satisfactory results in monitoring mycotoxins. Reference materials provide an important means of checking method performance. BCR has made a unique contribution in the production and certification of maize and wheat reference materials naturally contaminated with the Fusarium mycotoxin 4-deoxynivalenol (DON), which has now been available for purchase for some 2 years.

Calibration↗
PubMed1995

The effect of matrix phase morphology on the structure of Ag-Cu-Pd dispersed phase dental amalgam.

The effect of an Ag-Cu-Pd dispersant alloy on the structure of amalgams fabricated with two different particle types of low-copper amalgam matrices was investigated. In amalgams L and L (0), a low-copper lathe-cut amalgam Aristalloy was used as the matrix. In amalgams S and S(0), the matrix used was Spheralloy, a low-copper spherical amalgam. X-ray diffraction was used to analyse the relative content of the phases in the amalgams. The presence of Pd in the dispersant of amalgams L and S resulted in a decrease in the amount of eta' (Cu6Sn5) and an increase in the amount of unreacted particles when compared to the controls L(0) and S(0). Amalgams fabricated with a spherical alloy matrix (S and S(0)) showed a greater effect than amalgams fabricated with a lathe-cut matrix alloy (L and L(0)).

Chemical Phenomena↗
PubMed1995

Modulation of skeletal muscle sodium channels by human myotonin protein kinase.

In myotonic muscular dystrophy, abnormal muscle Na currents underlie myotonic discharges. Since the myotonic muscular dystrophy gene encodes a product, human myotonin protein kinase, with structural similarity to protein kinases, we tested the idea that human myotonin protein kinase modulates skeletal muscle Na channels. Coexpression of human myotonin protein kinase with rat skeletal muscle Na channels in Xenopus oocytes reduced the amplitude of Na currents and accelerated current decay. The effect required the presence of a potential phosphorylation site in the inactivation mechanism of the channel. The mutation responsible for human disease, trinucleotide repeats in the 3' untranslated region, did not prevent the effect. The consequence of an abnormal amount of the kinase would be altered muscle cell excitability, consistent with the clinical finding of myotonia in myotonic dystrophy.

Animals↗
PubMed1995

Rehydration in palliative and terminal care: if not--why not?

Patients who are in the last few days of life are often too frail to take oral fluids and nutrition. This may be due entirely to the natural history of their disease, although the use of sedative drugs for symptom relief may contribute to a reduced level of consciousness and thus a reduced oral intake. Rehydration with intravenous (i.v.) fluids is the usual response in acute care settings, whereas the hospice movement has often argued against this approach. The issues are complex and involve not only physical, psychological and social concerns, but also ethical dilemmas. A review of the literature gives conflicting reports of the physical discomfort that may be attributed to dehydration in dying patients. There are many confounding variables, including the concomitant use of antisecretory drugs, mouth breathing and oral infection. It remains unproven whether i.v. fluids offer symptomatic relief in this situation. Hospice doctors are concerned that the use of i.v. fluids gives confusing messages to relatives about the role of medical intervention at this stage in a patient's illness. A drip may cause a physical barrier between a patient and their loved one at this important time. The use of other methods of fluid replacement are discussed. In the absence of definitive research in this area, the balance of the burdens and benefits of such treatment remains subjective. The prime goal of any treatment in terminal care should be the comfort of the patient. Decisions should be made on an individual basis, involving both patients and their carers wherever possible. Prolonging life in such circumstances is of secondary concern and i.v. fluids given in this context may be futile. The ethical dilemmas of withholding and withdrawing medical treatment in addition to those of conducting research in this area are discussed.

Dehydration↗