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Biomedical subjects

A Clark

Publications and source records attributed to A Clark.

At least 253 records · Page 14Linked to original sources
PubMed1987

Phosphonoformate (foscarnet): a pilot study in AIDS and AIDS related complex.

Phosphonoformate (PFA; a pyrophosphate analogue) is an effective inhibitor of the reverse transcriptase enzyme in many animal retroviruses. In vitro studies have shown that PFA is also an effective inhibitor of HIV (HTLV III/LAV) at doses readily attainable in vitro. A pilot study was therefore performed with a 3-week intravenous infusion of PFA in 11 patients with AIDS and AIDS-related complex (ARC). Viral isolations were performed before and at regular intervals up to 3 months post-infusion on treated patients, as well as on four untreated control patients. Virus isolation was negative after therapy in eight patients, six of whom were negative throughout the follow-up period. Virus was isolated on 70% of attempts from the four control subjects and on 20% of attempts from treated subjects. Three patients showed an improvement in delayed hypersensitivity responses. No obvious improvement was seen in patients' OKT4 positive lymphocyte counts. Treatment was not limited by side-effects with the exception of one patient who developed an axillary vein thrombosis within 4 days of treatment via a subclavian line. Treatment was therefore discontinued following administration of only one dose and the patient was excluded from further study. A further patient had reversible renal dysfunction. Other side-effects were minor, consisting of headache or thrombophlebitis at the site of infusion. These results suggest that a further trial with PFA administered over a longer period and with a longer follow-up period in AIDS and ARC patients may be warranted, particularly if an oral preparation becomes available.(ABSTRACT TRUNCATED AT 250 WORDS)

AIDS-Related Complex↗
PubMed1987

Neutrophil phagocytic and bactericidal function in primary biliary cirrhosis and other chronic liver diseases.

We have examined neutrophil phagocytosis and intracellular killing of Staphylococcus aureus in patients with primary biliary cirrhosis, alcoholic liver disease and chronic active hepatitis in comparison with age and sex matched controls. Significant decrease in neutrophil phagocytosis was found in both early and advanced primary biliary cirrhosis while impaired phagocytosis was seen in alcoholic cirrhosis but not in alcoholic fatty liver. In both disorders the effect appeared to be mediated by the patient's serum as there was no difference between patient and control neutrophil function when the test was performed in AB serum. Although total bacterial killing was reduced in chronic active hepatitis, phagocytosis was not impaired. Intracellular killing was not affected in any of the liver disease groups. These results support the view that serum factors exist in patients with liver disease which inhibit neutrophil phagocytosis. While these studies confirm earlier finding in alcoholic liver disease, this is the first demonstration of such a defect in primary biliary cirrhosis.

Adult↗
PubMed1986

Spectrum of spontaneous frameshift mutations. Sequences of bacteriophage T4 rII gene frameshifts.

The DNA sequences of 185 independent spontaneous frameshift mutations in the rIIB gene of bacteriophage T4 are described. Approximately half of the frameshifts, including those at hot spot sites, are fully consistent with classical proposals that frameshift mutations are produced by a mechanism involving the misaligned pairing of repeated DNA sequences. However, the remaining frameshifts are inconsistent with this model. Correlations between the positions of two base-pair frameshifts and the bases of DNA hairpins suggest that local DNA topology might influence frameshift mutation. Warm spots for larger deletions share the property of having endpoints adjacent to DNA sequences whose complementarity to sequences a few base-pairs away suggest that non-classical DNA misalignments may participate in deletion mutation. A model for duplication mutation as a consequence of strand displacement synthesis is discussed. In all, 15 frameshifts were complex combinations of frameshifts and base substitutions. Three of these were identical, and have extended homology to a sequence 256 base-pairs away that is likely to participate in the mutational event; the remainder are unique combinations of frameshifts and transversions. The frequency and diversity of complex mutants suggest a challenge to the assumption that the molecular evolution of DNA must depend primarily upon the accumulation of single nucleotide changes.

Base Sequence↗
PubMed1986

ATPase activity and Ca2+ transport by reconstituted tryptic fragments of the Ca2+ pump of the erythrocyte plasma membrane.

The purified Ca2+ ATPase of the erythrocyte plasma membrane has been submitted to controlled trypsin proteolysis under conditions that favor either its (putative) E1 or E2 configurations. The former configuration has been forced by treating the enzyme with Ca2+-saturated calmodulin, the latter with vanadate and Mg2+. The E1 conformation leads to the accumulation of a polypeptide of Mr 85 KDa which still binds calmodulin, the E2 conformation to the accumulation of one of Mr 81 KDa which does not. Both fragments arise from the hydrolysis of a transient 90 KDa product which has Ca2+-calmodulin dependent ATPase activity, and which retains the ability to pump Ca2+ in reconstituted liposomes. Highly enriched preparations of the 85 and 81 KDa fragments have been obtained and reconstituted into liposomes. The former has limited ATPase and Ca2+ transport ability and is not stimulated by calmodulin. The latter has much higher ATPase and Ca2+ transport activity. It is proposed that the Ca2+ pumping ATPase of erythrocytes plasma membrane contains a 9 KDa domain which is essential for the interaction of the enzyme with calmodulin and for the full expression of the hydrolytic and transport activity. This putative 9 KDa sequence contains a 4 KDa "inhibitory" domain which limits the activity of the ATPase. In the presence of this 4 KDa sequence, i.e., when the enzyme is degraded to the 85 KDa product, calmodulin can still be bound, but no longer stimulates ATPase and Ca2+ transport.

Adenosine Triphosphate↗
PubMed1986

Frameshift mutations produced by proflavin in bacteriophage T4: specificity within a hotspot.

Frameshift mutations were induced by proflavin in the rIIB gene of bacteriophage T4. rIIB DNA from each of 48 independent frameshifts was inserted into M13mp8 and sequenced. Two-thirds of the frameshifts (33/48) lie contiguous to one another in 10 base pairs of the rIIB sequence. This hotspot differs markedly from previously characterized mutagen-induced frameshift hotspots. Distinctive features of the hotspot include the absence of locally repetitive sequences, particularly G X C runs, and the fact that many different sequence changes are induced within the hotspot sequence at appreciable frequencies. Among the 33 mutants at the hotspot, 8 distinguishable DNA sequence changes were seen. All of the mutations were deletions of a single base or duplications of one or more bases. Duplications were more frequent than deletions. The patterns of the base sequence changes suggest that two specific phosphodiester bonds within the hotspot sequence are sites at which proflavin-induced mutation is initiated.

Acridines↗
PubMed1986

The effect of transfer factor on lymph node morphology in murine toxoplasmosis.

Mice were infected intraperitoneally with a low virulence strain of Toxoplasma gondii (TO) and transfer factor (TF) was prepared from the spleens of infected (TFT) and uninfected control mice (TFC). Three experimental groups of 12 mice were given either saline, TFC or TFT, by intraperitoneal injection. After 24 h half of each group of these animals were infected by intraperitoneal injection of TO cysts. In three separate experiments animals were killed at 11, 28 and 35 days and the flank and axillary nodes removed for histological examination. There was generalized lymph node enlargement with cortical and paracortical expansion. In most animals there was diffuse infiltration of the nodes by clusters of histiocytes. Administration of TFC alone led to a mild increase in node size at 11 and 28 days. Administration of TFT alone had a moderate stimulatory effect on the mouse lymph nodes with a significant increase in size at 11 days due predominantly to expansion of the paracortex. Administration of TFT and TFC followed by inoculation of TO led to an increased and more consistent histiocyte response and an increased number of paracortical T blasts compared with animals given TO alone. TFT and TFC had no demonstrable protective effect in experimental murine toxoplasmosis as assessed by quantitation of toxoplasma brain cysts. The effect of transfer factor was not antigen specific in this system.

Animals↗
PubMed1986

Dependence of pulmonary absorption kinetics on aerosol particle size.

To determine the effect of aerosol particle size upon absorption from the respiratory tract (RT), solid, polydisperse disodium fluorescein aerosols (MMDae 1.1, 3.5 and 4.4 micron) were delivered under the same respiratory regime direct to the RT of 2 Beagle dogs by positive pressure ventilation using a purpose designed administration system. Subsequent to aerosol administration the amount of fluorescein absorbed as a function of time was estimated from plasma concentration versus time and intravenous control data using a modified Loo Riegelman method. Maximum fractional deposition within the RT occurred with 3.5 micron aerosol. Fluorescein was absorbed rapidly from the RT according to an apparent first-order process the rate constant for which was independent of particle size and possibly regional deposition. Average values for absorption half lives in the 2 dogs were 17.3 and 11.4 minutes.

Aerosols↗
PubMed1985

Impairment of glutamate uptake and absence of alterations in the energy-transducing ability of old rat brain mitochondria.

The proton electrochemical gradient has been measured in old brain mitochondria isolated from 2- or 24-month-old rats with the use of different respiratory substrates. With succinate as substrate, neither the respiratory rate, membrane potential or delta pH varied with age, indicating that the dielectric strength of the mitochondrial membrane was unaltered in old animals. The ohmic behavior of the membrane was tested in experiments in which the respiratory rate was partially inhibited by malonate, and was found to be unchanged with age. When glutamate plus malate were used as substrates, the respiratory rate was substantially reduced, and a drastic decrease in glutamate uptake was observed in old rat brain mitochondria.

Aging↗
PubMed1985

Effector functions of a monoclonal aglycosylated mouse IgG2a: binding and activation of complement component C1 and interaction with human monocyte Fc receptor.

Aglycosylated monoclonal anti-DNP mouse IgG2a produced in the presence of tunicamycin was compared with the native monoclonal IgG2a with respect to its ability to interact with the first component of complement, C1, and to compete with human IgG for binding to human monocyte Fc receptors. The aglycosylated IgG2a was found to bind subcomponent C1q with an equivalent capacity to the native IgG2a, but the dissociation constant was found to be increased three-fold. When activation of C1 by the glycosylated and aglycosylated IgG2a was compared, the rate of C1 activation by the aglycosylated IgG2a was reduced approximately three-fold. In contrast aglycosylation was accompanied by a large decrease (greater than or equal to 50-fold) in the apparent binding constant of monomeric IgG2a to human monocytes. The data suggest that the aglycosylated IgG2a has a structure which differs in the CH2 domain from the native IgG2a, and that the heterogeneous N-linked oligosaccharides of this monoclonal IgG2a which occur at a conserved position in the CH2 domain play a role in maintaining the integrity of its monocyte-binding site. This lack of monocyte binding may result either from a localized conformational change occurring in a single CH2 domain or from an alteration in the CH2-CH2 cross-domain architecture which is normally structured by a pair of opposing and interacting oligosaccharides. The minimal changes in C1q binding and C1 activation suggest that the oligosaccharides are, at most, indirectly involved in these events.

Animals↗
PubMed1985

Local oxygen gradients near isolated mitochondria.

The oxygen concentration in tissue can vary on several length scales. The basic scale of variation is determined by capillary spacing. It is this scale that is manifest in the simplest Krogh cylinder model. A second, smaller scale of variation is associated with the consumption of oxygen by mitochondria. This paper gives a theoretical analysis of these smaller-scale oxygen variations near an isolated mitochondrion. To illustrate the effects of shape, we have carried out the calculations for prolate spheroids as well as for spheres. The principal result is that the local drop in oxygen pressure around a consuming mitochondrion is of the order of (gamma/3K) (3V/4 pi)2/3, where gamma is the oxygen consumption rate per unit mitochondrial volume, K is the Krogh oxygen diffusivity of the surrounding tissue, and V is the mitochondrial volume. The theory is applied to skeletal muscle in vivo and to hepatocytes in cell suspension experiments. In both cases, we find that local oxygen variations produced by oxygen consumption are much smaller than the cell-wide variations produced by the collective effect of all the mitochondria. For example, in maximally consuming skeletal muscle, the drop in oxygen pressure around a consuming mitochondrion is only of the order of 0.03 Torr.

Animals↗
PubMed1985

Oxygen delivery from red cells.

This paper deals with the theoretical analysis of the unloading of oxygen from a red cell. A scale analysis of the governing transport equations shows that the solutions have a boundary layer structure near the red-cell membrane. The boundary layer is a region of chemical nonequilibrium, and it owes its existence to the fact that the kinetic time scales are shorter than the diffusion time scales in the red cell. The presence of the boundary layer allows an analytical solution to be obtained by the method of matched asymptotic expansions. A very useful result from the analysis is a simple, lumped-parameter description of the oxygen delivery from a red cell. The accuracy of the lumped-parameter description has been verified by comparing its predictions with results obtained by numerical integration of the full equations for a one-dimensional slab. As an application, we calculate minimum oxygen unloading times for red cells.

Biological Transport, Active↗
PubMed1985

Antibody response and persistence in volunteers following immunization with varying dosages of a trivalent surface antigen influenza virus vaccine.

The serum antibody responses and 50% protective levels (PL50) of antibody were determined, using the SRH test, at one and twelve months post-vaccination in a group of student volunteers immunized with one of three dosages of a trivalent surface-antigen influenza virus vaccine, or with placebo. It was found that, for the H3, H1 and B haemagglutinin components present in the vaccine, a dose of 6 micrograms HA elicited high serum antibody responses at one month post-immunization. High mean antibody levels and a high incidence of volunteers with PL50 values of antibody against each of the HA components of the vaccine remained in the volunteer group twelve months later. The results are discussed in relation to the vaccine dosage used and the nature of the population immunized.

Antibodies, Viral↗
PubMed1985

Cytidine deaminase--a marker for pre-eclampsia?

Cytidine deaminase (cytidine aminohydrolase, EC 3.5.4.5) was measured in blood collected for routine antenatal monitoring from 590 unselected pregnant women. The enzyme measurements were made without prior knowledge of the clinical condition of the patients. Increased activity of cytidine deaminase was found in 42.9% of patients with severe pre-eclampsia, 9.1% of patients with mild pre-eclampsia and in 8.6% of normal pregnancies. These results show a poor correlation of elevated cytidine deaminase activity with pre-eclampsia and a significant false positive elevation of the enzyme activity in normal pregnancies.

Cytidine Deaminase↗