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Biomedical subjects

K J Williams

Publications and source records attributed to K J Williams.

At least 91 records · Page 5Linked to original sources
PubMed1990

Synthesis of DNA by human immunodeficiency virus reverse transcriptase is preferentially blocked at template oligo(deoxyadenosine) tracts.

The genome of human immunodeficiency virus (HIV) and especially the envelope gene are mutated with unusually high frequency during in vivo replication. Recent studies indicate that HIV reverse transcriptase (RT) is unusually error prone and that the number of generated mutations is disproportionately high within repetitive base sequences. To study the ability of recombinant and wild-type HIV RT to traverse specific homo-oligomeric stretches, we used bacteriophage M13 DNA templates that contain different oligo(purine) and oligo(pyrimidine) inserted tracts. The progress of HIV RT along these templates was potently inhibited from further progression only at a (dA)16 insert. Comparison with other polymerases indicates that the almost complete blockage of polymerization beyond an oligo(dA) insert is unique to HIV RT and Moloney murine leukemia virus RT, which has high sequence homology with HIV RT. The extent of termination of HIV RT at the oligo(dA) run is not affected by alterations in the concentration of KCl, Mg2+, dNTP, or by a decrease in pH. Obstruction of HIV RT opposite the oligo(dA) insert is not alleviated by moving the primer position further upstream from the oligo(dA) insert. Lastly, HIV RT purified directly from virions is also specifically arrested at an oligo(dA) tract. Competition experiments indicate that the concentration of active HIV RT in the presence of M13(dA)16 DNA is similar to that observed in the presence of M13(dG)16 DNA. In addition, preincubation of M13(dA)16 DNA with HIV RT does not subsequently inhibit avian myeloblastosis virus RT from successfully traversing the (dA)16 insert. Therefore, it appears that the blockage of chain elongation of HIV RT at the (dA)16 insert is not the result of trapping the enzyme at this site.

Avian Myeloblastosis Virus↗
PubMed1990

The unstirred water layer as a site of control of apolipoprotein B secretion.

Apolipoprotein B-100 (apoB) is a constituent of low density lipoproteins that has been implicated in the development of coronary artery disease (Editorial (1988) Lancet 1, 1141-1142). It is produced primarily in the liver, but mechanisms of secretory control are unclear. We examined the possibility that rapid reuptake of newly secreted lipoproteins regulates the net output of apoB by cultured liver cells. Polyclonal blocking antibodies to the low density lipoprotein receptor markedly increased apoB output, and varying the width of the unstirred water layer around the cells also changed apoB output, consistent with local reuptake. Labeled apoB added to the bulk fluid phase of the incubation media was not detectably taken up, implying that re-uptake is predominantly local. We conclude that a major site of apoB secretory control resides in the unstirred water layer, external to the cell. Because many cells secrete products for which they possess receptors, local re-uptake from the unstirred water layer may be a general mechanism for secretory control.

Antibodies↗
PubMed1989

Ecosystem-level patterns of primary productivity and herbivory in terrestrial habitats.

Ecosystems are structurally organized as food webs within which energy is transmitted between trophic levels and dissipated into the environment. Energy flow between two trophic levels is given by the amount of production at the lower level and by the proportion of production that is consumed, assimilated and respired at the higher level. Considerable evidence indicates that food-web structure varies predictably in different habitats, but much less is known about quantitative relationships among food web fluxes. Many of the energetic properties of herbivores in African game parks are associated with rainfall and, by inference, with net primary productivity. Respiratory costs per unit production at the consumer trophic level are higher for homeotherms than for heterotherms. Plant secondary chemicals affect herbivore dietary choices and the allocation of plant resources to those chemicals varies with resource availability. How these phenomena are translated into ecosystem fluxes is unknown. We present evidence that herbivore biomass, consumption and productivity are closely correlated with plant productivity, suggesting that the latter is a principal integrator and indicator of functional processes in food webs.

Animals↗
PubMed1989

Correlation between the induction of heat shock protein 70 and enhanced viral reactivation in mammalian cells treated with ultraviolet light and heat shock.

Enhanced viral reactivation (EVR) is considered to be one manifestation of an inducible response to DNA damage in mammalian cells analogous to the SOS response in Escherichia coli. EVR is characterized by the increased survival of ultraviolet (UV)-irradiated virus in cells which have been pretreated with DNA-damaging agents or by another type of cellular stress, heat shock (HS). In this study, we have analyzed the induction of nuclear proteins from Vero cells treated with either UV or HS, with the goal of identifying the protein(s) which mediate the EVR response. Results of 2-dimensional protein gel electrophoresis and fluorographic analysis of [35S]methionine-labeled nuclear proteins showed that UV-irradiation caused the increased synthesis of five proteins at 4-9 h after treatment. At 19-24 h, one of these proteins was still being synthesized at a higher level in UV-irradiated cells, and there were nine additional proteins whose syntheses were enhanced over control levels. In contrast, HS induced only one Mr 72,000 nuclear protein whose synthesis was maximal during the 4-9-h labeling period and corresponded to one of the proteins induced by UV at 19-24 h. Subsequent Western and Northern blot analyses have confirmed that this protein is a member of the heat shock protein (hsp) 70 family. Elevated nuclear levels of this protein correlated temporally with the maximum EVR response induced by each treatment (4 h after HS and 24 h after UV). Since the kinetics of EVR is different following UV and HS and parallels the difference in the induction of nuclear levels of hsp70 following each treatment, the results suggest that hsp70 may be involved in mediating the EVR response. In addition, this protein may also play a role in the recovery of DNA synthesis in UV-irradiated cells.

Blotting, Northern↗
PubMed1989

Effects of apolipoproteins A-IV and A-I on the uptake of phospholipid liposomes by hepatocytes.

We examined the effects of apolipoproteins A-IV and A-I on the catabolism of whole particles by hepatoma G2 cells and cultured primary hepatocytes. For this type of experiment, high density lipoprotein is unsuitable, because all of its lipid and protein components independently dissociate and exchange and hence poorly trace whole particle catabolism. We therefore used phosphatidylcholine liposomes with radioactive tracers entrapped within their aqueous cores. Apolipoproteins A-IV, A-I, or E added to liposomes became liposome-associated and produced no detectable release of encapsulated label. As a positive control, apolipoprotein E doubled the uptake of labeled liposomes by hepatoma cells, compared to apolipoprotein-free controls, and this increase could be blocked by the addition of excess unlabeled low density lipoprotein. Degradation of labeled liposomes by hepatoma cells was increased 6-fold by the addition of apolipoprotein E. In contrast, neither apolipoprotein A-IV nor A-I increased cellular uptake or degradation of the particles. Similar results were obtained with primary hepatocytes. In studies using apolipoprotein combinations, apolipoproteins A-IV and A-I were each able to displace apolipoprotein E from liposomes and thereby reduce cellular uptake. Our data indicate that apolipoproteins A-IV and A-I do not facilitate uptake or degradation of whole particles by liver-derived cells in vitro. However, these apolipoproteins may modulate receptor-mediated uptake of particles by reducing the amount of particle-bound apolipoprotein E.

Animals↗
PubMed1988

Macrophage cholesterol removal by triglyceride-phospholipid emulsions.

Phospholipid liposomes were previously shown to mobilize cholesterol from cultured macrophage foam cells. Because Intralipid, a clinically available triglyceride-phospholipid emulsion, contains both phospholipid liposomes and triglyceride-emulsion particles, we sought to study its effect on macrophage cholesterol mobilization. Following an 18h incubation of J774 macrophages in serum-free medium supplemented with Intralipid, cholesteryl ester content decreased by up to 50% in previously cholesterol-loaded cells, and by 25% in non-loaded cells. Both components of Intralipid, liposomes and emulsion particles, independently caused reductions in cellular cholesteryl ester. We conclude that clinically available triglyceride-phospholipid emulsions can mobilize macrophage cholesterol in vitro.

Animals↗
PubMed1988

Ceftazidime sodium carbonate versus ceftazidime arginine as empirical monotherapy in febrile neutropenic patients.

A prospective randomized trial was conducted to determine the efficacy and safety of ceftazidime sodium carbonate versus a new arginine formulation of ceftazidime as empirical monotherapy in 100 febrile neutropenic patients. The clinical cure rate for ceftazidime sodium carbonate was 91% and for ceftazidime arginine 83%. Forty-two infections could be confirmed bacteriologically. Bacteriological cure rates were 87% and 81% respectively. Only one fatal infection-related outcome occurred during the first three days of therapy (ceftazidime arginine, Corynebacterium parvum). No failures were recorded in bacteriologically proven gram-negative infections. Ceftazidime was confirmed to be safe and effective as empirical monotherapy in febrile neutropenic patients. The arginine formulation is as effective and safe as the sodium carbonate formulation, but easier to handle.

Adolescent↗
PubMed1988

Low density lipoprotein receptor-independent hepatic uptake of a synthetic, cholesterol-scavenging lipoprotein: implications for the treatment of receptor-deficient atherosclerosis.

The metabolism of infused 111In-labeled phospholipid liposomes was examined in Watanabe heritable hyperlipidemic (WHHL) rabbits, which lack low density lipoprotein (LDL) receptors, and in normal control rabbits. The half-times (t1/2) for clearance of 111In and excess phospholipid from plasma were 20.8 +/- 0.9 hr and 20.3 +/- 4.6 hr in WHHL and 20.0 +/- 0.8 hr and 19.6 +/- 2.2 hr in the normal rabbits (means +/- SEM; n = 4). By 6 hr postinfusion, the plasma concentration of unesterified cholesterol increased by 2.2 +/- 0.23 mmol/liter in WHHL and 2.1 +/- 0.04 mmol/liter in normal rabbits, presumably reflecting mobilization of tissue stores. Disappearance of excess plasma cholesterol was greater than 90% complete in both groups of rabbits by 70 hr postinfusion. By quantitative gamma camera imaging, hepatic trapping of 111In-labeled liposomes over time was indistinguishable between the two groups. At autopsy, the liver was the major organ of clearance, acquiring 22.0% +/- 1.7% (WHHL) and 16.8% +/- 1.0% (normal of total 111In. Aortic uptake of 111In was less than 0.02%. Thus, mobilization of cholesterol and hepatic uptake of phospholipid liposomes do not require LDL receptors. Because phospholipid infusions produce rapid substantial regression of atherosclerosis in genetically normal animals, our results suggest that phospholipid liposomes or triglyceride phospholipid emulsions (e.g., Intralipid) might reduce atherosclerosis in WHHL rabbits and in humans with familial hypercholesterolemia.

Animals↗
PubMed1988

Single-dose prophylaxis with cefotetan in elective abdominal surgery. A controlled trial.

Single dose cefotetan was compared with either a combination of metronidazole and cefazolin given for 24 hours or 3 doses of cefuroxime as prophylaxis in elective abdominal surgery. Wound infections and infections at remote sites (UTI and RTI) were similar in all groups. In a third group prophylaxis of abdominal surgery using a single 2g dose of cefotetan was compared to 2 doses of the same drug, given 12 hours apart. There was no demonstrable advantage to giving 2 doses. The low incidence of post-operative infections seen in all groups indicates the efficacy of cefotetan in the surgical prophylaxis of elective abdominal surgery.

Abdomen↗
PubMed1987

Phospholipid liposomes acquire apolipoprotein E in atherogenic plasma and block cholesterol loading of cultured macrophages.

A single infusion of phospholipid liposomes promptly and persistently abolished the ability of hypercholesterolemic rabbit plasma to cause cholesteryl ester loading in cultured macrophages. This phospholipid enrichment of plasma caused moderate stimulation of cellular cholesterol efflux and, unexpectedly, almost complete inhibition of cellular uptake of beta-very low density lipoprotein (beta-VLDL), the major cholesteryl ester-rich particle in hypercholesterolemic rabbit plasma. Cell viability and LDL receptor activity were unaffected. Incubation of liposomes with beta-VLDL resulted in transfer of apolipoprotein-E (apoE) to the liposomes; reisolated apoE-phospholipid liposomes then competed efficiently for cellular apoprotein receptors. Thus, a major mechanism by which phospholipid infusions result in diminished accumulation of cholesteryl ester in cultured macrophages is by blocking cellular uptake of beta-VLDL. The liposomes deplete beta-VLDL of apoE, then compete for receptor-mediated uptake. These results suggest a novel mechanism contributing to the known antiatherogenic effect of phospholipid infusions: infused liposomes acquire apoE, then block uptake of atherogenic lipoproteins by arterial wall macrophages.

Animals↗
PubMed1987

Cefuroxime axetil in the treatment of uncomplicated UTI: a comparison with cefaclor and augmentin.

Cefuroxime axetil (CAE) is an acetoxyethyl ester prodrug of cefuroxime. The efficacy and safety of cefuroxime axetil was studied in a randomized general practice trial in urological infections where cefuroxime axetil 250 mg b.d. was compared with amoxycillin/clavulanate (Augmentin, AUG) 375 mg t.d.s. A randomized trial was then performed in hospital outpatients, who received cefuroxime axetil 250 mg b.d. or cefaclor (CCL) 250 mg t.d.s. Of 140 clinically assessable patients, 108 were cured and 28 improved on cefuroxime axetil (97% success) compared with 75 cured and 13 improved out of 89 on Augmentin (99% success) and 31 cured and 7 improved out of 38 patients treated with cefaclor (97% success). Bacteriology was assessable in 101 patients given cefuroxime axetil (72% cleared), 61 of those given Augmentin (70% cleared) and 27 out of 28 (96%) given cefaclor. As expected, the predominant pathogen was E. coli, accounting for 61% of isolates overall. Drug-related adverse events occurred in 10% of patients given cefuroxime axetil, including diarrhoea in 4%. Eleven percent of patients given Augmentin suffered adverse events (5% diarrhoea) and 5% of those given cefaclor. Superinfections occurred in 4 cefaclor patients (2 Pseudomonas aeruginosa, 1 Candida, 1 E. coli) compared with 2 on cefuroxime axetil (1 Candida, 1 E. coli). Uncomplicated UTI accounted for 92% of cases in the G.P. trial and 82% of cases in the hospital trial. Cefuroxime axetil may be used safely and effectively to treat uncomplicated UTI at a dose of 250 mg b.d.

Adolescent↗
PubMed1987

Effect of lecithin:cholesterol acyltransferase on distribution of apolipoprotein A-IV among lipoproteins of human plasma.

The effect of cholesterol esterification on the distribution of apoA-IV in human plasma was investigated. Human plasma was incubated in the presence or absence of the lecithin:cholesterol acyltransferase (LCAT) inhibitor 5,5-dithiobis(2-nitrobenzoic acid) (DTNB) and immediately fractionated by 6% agarose column chromatography. Fractions were monitored for apoA-IV, apoE, and apoA-I by radioimmunoassay (RIA). Incubation resulted in an elevated plasma concentration of cholesteryl ester and in an altered distribution of apoA-IV. After incubation apoA-IV eluted in the ordinarily apoA-IV-poor fractions of plasma that contain small VLDL particles, LDL, and HDL2. Inclusion of DTNB during the incubation resulted in some enlargement of HDL; however, both cholesterol esterification and lipoprotein binding of apoA-IV were inhibited. Addition of DTNB to plasma after incubation and prior to gel filtration had no effect on the apoA-IV distribution when the lipoproteins were immediately fractionated. Fasting plasma apoE was distributed in two or three peaks; in some plasmas there was a small peak that eluted with the column void volume, and, in all plasmas, there were larger peaks that eluted with the VLDL-LDL region and HDL2. Incubation resulted in displacement of HDL apoE to larger lipoproteins and this effect was observed in the presence or absence of DTNB. ApoA-I was distributed in a single broad peak that eluted in the region of HDL and the gel-filtered distribution was unaffected by incubation either in the presence or absence of DTNB. Incubation of plasma that was previously heated to 56 degrees C to inactivate LCAT resulted in no additional movement of apoA-IV onto lipoproteins, unless purified LCAT was present during incubation. The addition of heat-inactivated LCAT to the incubation, had no effect on movement of apoA-IV. These data suggest that human apoA-IV redistribution from the lipoprotein-free fraction to lipoprotein particles appears to be dependent on LCAT action. The mechanism responsible for the increased binding of apoA-IV to the surface of lipoproteins when LCAT acts may involve the generation of "gaps" in the lipoprotein surface due to the consumption of substrate from the surface and additional enlargement of the core. ApoA-IV may bind to these "gaps," where the packing density of the phospholipid head groups is reduced.

Apolipoproteins A↗
PubMed1986

Uptake of endogenous cholesterol by a synthetic lipoprotein.

The addition of cholesterol-poor phospholipid liposomes to canine plasma in vivo and in vitro substantially alters the distribution of phospholipids, apoproteins, and, especially, cholesterol. In vivo, intravenously injected phospholipid liposomes remain discrete particles, which are readily distinguished from the normally occurring lipoproteins by their buoyant density and electrophoretic mobility. They acquire unesterified cholesterol from endogenous sources, thereby producing an acute rise in the concentration of this sterol in plasma. The liposomes also accumulate endogenous proteins, one of which is identified as apolipoprotein A-I. In vitro, phospholipid liposomes incubated with plasma acquire unesterified cholesterol and apolipoprotein A-I at the expense of high-density lipoproteins (HDL), the major carrier of cholesterol in normal canine plasma. In exchange, the HDL particles are enriched in phospholipids and become larger. At sufficiently high concentrations, the liposomes nearly completely deplete HDL of its unesterified cholesterol. Thus, there are generated two types of particles, both rich in apolipoprotein A-I and phospholipid, but one (modified HDL) containing mainly esterified cholesterol in its core and the other (modified liposomes) containing mainly unesterified cholesterol at its surface. It is concluded that phospholipid liposomes produce important changes in the distribution of lipids and protein in canine plasma, particularly at the expense of HDL. These changes appear to favor the mobilization of tissue cholesterol into the plasma, and may have application to atherosclerosis.

Animals↗
PubMed1986

Ceftazidime does not enhance cyclosporin-A nephrotoxicity in febrile bone marrow transplantation patients.

Ceftazidime was used as monotherapy for 30 febrile episodes in 28 patients, who underwent allogeneic bone marrow transplantation and who were treated concomitantly with the immunosuppressive agent cyclosporin-A. Ceftazidime did not enhance the well established nephrotoxicity of cyclosporin-A as measured by serum creatinine levels or creatinine clearance. Although an increasing number of Gram-positive infections in these patients warrants vigilance, ceftazidime as initial empirical monotherapy proved to be successful in 95% of all febrile post-transplantation patients. All Gram-negative and 69% of the Gram-positive infections were cured with ceftazidime alone. The overall clinical cure rate was 72%, with microbiological clearance in 63%. This compares favourably with aminoglycoside containing schedules and avoids the aminoglycoside associated nephrotoxicity.

Adult↗
PubMed1986

Ceftazidime alone for treating Pseudomonas aeruginosa septicaemia in neutropenic patients.

Twenty-nine patients with primary or secondary hypoplastic bone-marrow were treated successfully with ceftazidime alone for established septicaemia caused by Pseudomonas aeruginosa of which 38% strains were gentamicin-resistant . All the patients were neutropenic at the start of therapy; most were cured with microbiological confirmation before the bone marrow had regenerated. One patient died of cerebral haemorrhage due to profound thrombocytopenia without evidence of infection at autopsy. Significant toxicity was not observed. Ceftazidime alone is, therefore, a safe and effective treatment for infections caused by this organism even in the neutropenic patient.

Agranulocytosis↗