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Biomedical subjects

J Williams

Publications and source records attributed to J Williams.

At least 739 records · Page 41Linked to original sources
PubMed1990

Mutations that alter the ability of the Escherichia coli cyclic AMP receptor protein to activate transcription.

The effects of a number of mutations in the E. coli cyclic AMP receptor protein (CRP) have been determined by monitoring the in vivo expression and in vitro open complex formation at two semi-synthetic promoters that are totally CRP-dependent. At one promoter the CRP-binding site is centered around 41.5 base pairs upstream from the transcription start whilst at the other promoter it is 61.5 base pairs upstream. The CRP mutation E171K reduces expression from both promoters whilst H159L renders CRP totally inactive: neither mutation stops CRP binding at either promoter. The mutations K52N and K52Q reverse the effect of H159L and 'reeducate' CRP to activate transcription. CRP carrying both H159L and K52N activates transcription from the promoter with the CRP site at -41.5 better than wild type CRP. In sharp contrast, this doubly changed CRP is totally inactive with respect to the activation of transcription from the promoter carrying the CRP site at -61.5. Our results suggest that CRP can use different contacts and/or conformations during transcription activation at promoters with different architectures.

Amino Acid Sequence↗
PubMed1990

Bronchodilator, cardiovascular, and hypokalaemic effects of fenoterol, salbutamol, and terbutaline in asthma.

The airway response and cardiovascular and hypokalaemic effects of fenoterol, salbutamol, and terbutaline given in multiples of standard doses from metered-dose inhalers were studied in ten patients with mild asthma. In a double-blind, crossover, placebo-controlled study the subjects received 2, 6, and 18 puffs of each drug with intervals of 90 min, and forced expiratory volume in 1 s, heart rate, QTc interval, plasma potassium concentration, tremor, and bronchial reactivity to histamine were measured. All three drugs produced similar bronchodilatation. However, the rises in heart rate, QTc interval, and tremor and the fall in plasma potassium were greater after fenoterol than after salbutamol or terbutaline. The maximum mean (SD) increases in heart rate for fenoterol, salbutamol, and terbutaline were 29 (24) bpm, 8 (9) bpm, and 8 (14) bpm, respectively; falls in plasma potassium were 0.76 (0.62) mmol/l, 0.46 (0.32) mmol/l, and 0.52 (0.39) mmol/l, respectively. Fenoterol afforded no additional protection against histamine compared with salbutamol. These findings suggest that at doses based on those used in clinical practice fenoterol causes more adverse effects than salbutamol or terbutaline. The most likely explanation for these effects is that fenoterol has been marketed at a higher dose than the other beta 2-agonists; fenoterol may in addition be less selective for beta 2 receptors.

Adolescent↗
PubMed1990

De novo purine nucleotide biosynthesis: cloning of human and avian cDNAs encoding the trifunctional glycinamide ribonucleotide synthetase-aminoimidazole ribonucleotide synthetase-glycinamide ribonucleotide transformylase by functional complementation in E. coli.

The trifunctional enzyme encoding glycinamide ribonucleotide synthetase (GARS)-aminoimidazole ribonucleotide synthetase (AIRS)-glycinamide ribonucleotide transformylase (GART) was cloned by functional complementation of an E. coli mutant using an avian liver cDNA expression library. In E. coli, genes encoding these separate activities (purD, purM, and purN, respectively) produce three proteins. The avian cDNA, in contrast, encodes a single polypeptide with all three enzyme activities. Using the avian DNA as a probe, a cDNA encoding the complete coding sequence of the trifunctional human enzyme was also isolated and sequenced. The deduced amino acid sequence of the human and avian polyproteins show extensive sequence homologies to the bacterial purD, purM, and purN encoded proteins. Avian and human liver RNAs appear to encode both a trifunctional enzyme (G-ARS-AIRS-GART) as well as an RNA which encodes only GARS. The trifunctional protein has been implicated in the pathology of Downs Syndrome and molecular tools are now available to explore this hypothesis. Initial efforts to compare the expression of GARS-AIRS-GART between a normal fibroblast cell line and a Downs Syndrome cell line indicate that the levels of RNA are similar.

Acyltransferases↗
PubMed1990

Frameshifting at the internal stop codon within the mRNA for bacterial release factor-2 on eukaryotic ribosomes.

A translational frameshift is necessary in the synthesis of Escherichia coli release factor 2 (RF-2) to bypass an in-frame termination codon within the coding sequence. High-efficiency frameshifting around this codon can occur on eukaryotic ribosomes as well as prokaryotic ribosomes. This was determined from the relative efficiency of translation of RF-2 RNA compared with that for the other release factor RF-1, which lacks the in-frame premature stop codon. Since the termination product is unstable an absolute measure of the efficiency of frameshifting has not been possible. A gene fusion between trpE and RF-2 was carried out to give a stable termination product as well as the frameshift product, thereby allowing a direct determination of frameshifting efficiency. The extension of RF-2 RNA near its start codon with a fragment of the trpE gene, while still allowing high efficiency frameshifting on prokaryotic ribosomes, surprisingly gives a different estimate of frameshifting on the eukaryotic ribosomes than that obtained with RF-2 RNA alone. This paradox may be explained by long distance context effects on translation rates in the frameshift region created by the trpE sequences in the gene fusion, and may reflect that pausing and translation rate are fundamental factors in determining the efficiency of frameshifting.

Base Sequence↗
PubMed1990

The influence of net surface charge on the interaction of uropathogenic Escherichia coli with human neutrophils.

Escherichia coli strains, grown to suppress fimbrial expression, synthesised enhanced quantities of polysaccharide capsule, which significantly lessened their binding to heparin sepharose columns. In the presence of poly-L-lysine, these strains were strongly retained on the columns confirming their highly anionic nature. Uropathogenic strains of E. coli expressing type 1 fimbrial adhesins activated the respiratory burst, the degranulation response and the release of leukotrienes from human neutrophils (PMN) to a significantly greater extent than the same strains grown in a medium to suppress this fimbrial expression. The addition of the poly-cation poly-L-lysine, however, selectively increased neutrophil activation in response to these non-fimbriate strains. This dose-dependent effect was reversed by the addition of heparin suggesting a mechanism dependent on surface charge. The results of this study suggest that non-specific mechanisms involving the neutralisation of surface charge, in addition to specific receptor and adhesin mediated events could affect neutrophil activation at sites of infection.

Cell Membrane↗
PubMed1990

Cloning of a cDNA encoding adenylosuccinate lyase by functional complementation in Escherichia coli.

Adenylosuccinate lyase was cloned by functional complementation of an Escherichia coli purB mutant using an avian liver cDNA expression library. The derived amino acid sequence is homologous to the bacterial purB-encoded adenylosuccinate lyase which catalyzes the same two steps in purine biosynthesis as the enzyme from animals. Avian adenylosuccinate lyase also shows regions of extensive sequence similarity to the urea cycle enzyme, argininosuccinate lyase. This homology suggests a similar mechanism for catalysis. Homology of adenylosuccinate and argininosuccinate lyases is intriguing because chickens do not utilize the urea cycle in nitrogen excretion. This is the first report of the cloning of a eukaryotic cDNA encoding adenylosuccinate lyase, and it affords a route to isolate the corresponding human gene which has been suggested to be defective in autistic children.

Adenylosuccinate Lyase↗
PubMed1990

Elegantin and albolabrin purified peptides from viper venoms: homologies with the RGDS domain of fibrinogen and von Willebrand factor.

The RGD-containing peptides isolated from the venoms of the Viperidae constitute a new class of small cysteine-rich peptides of variable amino acid composition and biological activity (Huang, T.-F., et al. (1987) J. Biol. Chem. 262, 16157-16163; Gan, Z.R., et al. (1988) J. Biol. Chem 263, 19827-19832; Huang, T.-F., et al. (1989) Biochemistry 28, 661-668), which it is proposed by Gould et al. (unpublished data) that we call 'disintegrins'. These peptides bind to the glycoprotein IIb-IIIa receptor on the platelet surface and inhibit aggregation induced by ADP, thrombin, platelet-activating factor and collagen. These peptides are also potent inhibitors of cell adhesion to fibrinogen (Knudsen, K.M., et al. (1988) Exp. Cell Res. 179, 42-49). We report the isolation of two further RGD-peptides from the venoms of Trimeserusus elegans and Trimeserusus albolabris, purified to homogeneity with high yield by a novel, rapid reverse-phase HPLC method. The primary structures of these two peptides were determined to be single polypeptide chains of 73 amino acids. Albolabrin differed from trigramin by eight residues whilst elegantin differed by 22 residues. The molecular mass of albolabrin calculated on the basis of amino acid sequence was 7574 Da and the pI similarly calculated was 4.27. The molecular mass of elegantin was calculated to be 7806 Da and the theoretical pI to be 4.69. RGD is maintained in the same position (51-53 AA) and all 12 cysteines are identical. Our data suggest that the presence of RGD, the conserved secondary and tertiary structure, are essential for the expression of biological activity by these peptides. Both peptides inhibited ADP-induced platelet aggregation. Extended homologies around the RGDS sequences in human von Willebrand Factor and bovine fibrinogen were found with both peptides.

Amino Acid Sequence↗
PubMed1990

Leukotriene B4 generation by human monocytes and neutrophils stimulated by uropathogenic strains of Escherichia coli.

The generation of the 5-lipoxygenase product, leukotriene B4 (LTB4) by human mononuclear phagocytes (monocytes) following incubation with 25 different uropathogenic strains of Escherichia coli correlated with the haemolytic activity of the strains (r = 0.572, P less than 0.01). LTB4 generation by human neutrophils (PMN), however, was unrelated to this haemolytic potential (r = 0.164). In contrast, both prelabelled monocytes and PMN were stimulated by haemolytic strains of E. coli and by haemolytic culture supernatants to release significant amounts of [3H]arachidonic acid. There was a significant correlation between haemolytic activity and [3H]arachidonic acid release generated by individual strains from monocytes (r = 0.804, P less than 0.001) and PMN (r = 0.888, P less than 0.001). In addition, nonhaemolytic strains but not their culture supernatants were capable of causing slow release of both [3H]arachidonic acid and LTB4 from PMN and mononuclear cells. These results suggest that both the possession of haemolytic activity, and the direct interaction of bacteria with the leukocyte surface are mechanisms by which uropathogenic strains of E. coli may cause the release and metabolism of arachidonic acid. In addition, there was synergistic augmentation by nonhaemolytic bacteria of the PMN LTB4 response to haemolytic culture supernatants or to low doses of the calcium ionophore A23187. These results support an ionophore-like mechanism for the activation of the cell by haemolysin. LTB4 generation by PMN incubated with haemolytic supernatants was also augmented by particulate zymosan in a manner dependent on the dose of zymosan, suggesting that the direct interaction of E. coli with PMN may involve an activation mechanism similar to that for zymosan. These results demonstrate differing responses of peripheral mononuclear cells and PMN from the same donors to identical strains of E. coli and suggest that the generation of the potent chemotactic agent LTB4 in response to E. coli infection in vivo need not depend solely on the elaboration of cytotoxic haemolysins by individual strains.

Adenosine Triphosphate↗
PubMed1990

Application of a capture enzyme immunoassay in an outbreak of waterborne giardiasis in the United Kingdom.

A capture enzyme immunoassay (EIA) for the detection of Giardia lamblia antigen was used to examine 136 fecal samples collected during an outbreak of waterborne giardiasis in a city in the UK. Six cases of Giardia lamblia infection were detected that had previously not been diagnosed by microscopy. The capture EIA provides an efficient means of processing large numbers of samples for prompt and accurate assessment of an epidemic. It may also facilitate rapid tracing of epidemic sources.

Antigens, Protozoan↗
PubMed1990

Semen analysis and fertility assessment in rabbits: statistical power and design considerations for toxicology studies.

Semen analysis is commonly used in evaluating human response to reproductive toxicants. Serial semen samples can be collected from rabbits and fertility assessed by artificial insemination, hence this species is potentially well suited for male reproductive toxicity studies that might be extrapolated to humans. However, the size and cost of rabbits often restricts the number of animals used, reducing the sensitivity of such studies. Therefore, it was of interest to optimize study design for semen analysis and fertility assessment in rabbits. Semen samples were collected weekly from sexually mature New Zealand white rabbits and a range of parameters was analyzed (Semen--pH, volume, osmolality; Sperm--number and concentration, morphology, viability, percentage motility, motion characteristics; Seminal plasma--fructose, citric acid, carnitine and protein concentrations, acid phosphatase activity). Male fertility was assessed by inseminating female rabbits with the minimum number of motile sperm required for normal fertility, determined to be one million. The within- and between-buck variabilities were determined for all parameters and used to calculate the statistical power of different study designs. The variability of sperm number and concentration was decreased when measured in four ejaculates collected within a short period of time rather than in a single ejaculate; this was not true of other endpoints measured. In addition, use of preexposure observations further increased the statistical power for all of the parameters. These data can be used to determine the optimum design for studies of male reproductive toxicity using rabbits, with particular regard to cost and the number of animals used.

Acid Phosphatase↗
PubMed1990

Reproductive effects of diethylene glycol and diethylene glycol monoethyl ether in Swiss CD-1 mice assessed by a continuous breeding protocol.

Diethylene glycol (DEG) and diethylene glycol monoethyl ether (DEGEE) were evaluated for reproductive toxicity in CD-1 mice using a continuous breeding protocol. Compounds were administered in the drinking water at 0, 0.35, 1.75, and 3.5% w/v (DEG) or 0, 0.25 1.25, and 2.5% w/v (DEGEE). Exposure of the breeding pairs to 3.5% DEG for 14 weeks produced statistically significant decreases in the number of litters per pair, live pups per litter, proportion of pups born alive, and live pup weight. There was also a significant increase in the cumulative days to litter and a significant decrease in the number of pairs producing the third, fourth, and fifth litters for the 3.5% DEG-exposed mice. A crossover mating trial of the F0 mice to determine the affected sex was inconclusive, but suggested that offspring development was compromised in females exposed to 3.5% DEG. Slight maternal (F0) toxicity was noted for the 3.5 DEG group (7% decrease in body weight). The F1 generation, at 3.5% DEG, had decreased body weights at birth and exhibited poor postnatal survival. At the intermediate dose of DEG, body weights of both sexes were depressed at weaning, at onset of mating, and at necropsy. However, no adverse effects on reproduction were observed. DEGEE had no effect on reproduction in the F0 or F1 generation mice despite a 34% decrease in cauda epididymal sperm motility in the F1 males at 2.5% DEGEE. Other signs of toxicity observed in these F1 mice included increased relative liver weights. These data indicate that DEG is a reproductive toxicant in Swiss mice affecting fertility and reproductive performance, albeit at high doses (equivalent to 6.1 g/kg/day). However, its monoethyl derivative, DEGEE, is without adverse effects on fertility and reproductive performance.

Animals↗
PubMed1990

Distress associated with cancer as measured by the illness distress scale.

Over 400 cancer patients were given the Illness Distress Scale (IDS), a brief measure of the physical and emotional distress related to serious illness. Physical manifestations of the disease proved to be the source of greatest discomfort among these patients. Greater distress was reported by younger patients and by those who were unmarried. Also, patients with more advanced disease scored higher on the scale. The IDS appeared to measure four dimensions of distress related to the experience of illness, including loss of meaning, physical disease, medical treatment and social isolation. Scores on the instrument correlated highly with a measure of depression, the Beck Depression Inventory. The IDS appears to be a reliable and valid measure of distress associated with serious illness.

Adaptation, Psychological↗
PubMed1990

Selective deficits in Alzheimer and parkinsonian dementia: visuospatial function.

Deficits in visuospatial cognition are frequently cited as an important component of the cognitive changes accompanying Parkinson's disease. To characterize possible differences between Parkinson's (PD) and Alzheimer's (AD) dementia, patients from both groups, matched for overall dementia severity, age and education, were contrasted neuropsychologically. Visuospatial tasks dissociated from memory, were significantly compromised in both patient groups. Differential impairment was evident on visuospatial abstraction and reasoning (Object Assembly), which was most deficient in PD. Visuospatial cognition associated with memory, classified both patient groups as impaired compared to controls, but AD patients demonstrated substantially lower performance levels than those with PD. Parkinsonian dementia thus appears to have some distinct features compared to Alzheimer's disease, which may indicate differences in underlying pathogenic mechanisms.

Adult↗
PubMed1990

Incubation and maternal behaviour in domestic hens: influence of the presence of chicks on circulating luteinising hormone, prolactin and oestradiol and on behaviour.

1. The consequences of the adoption of chicks and their subsequent removal on behaviour and plasma hormone concentrations of incubating hens were investigated. Birds were divided into two group: in group A, incubating hens were given chicks for 11 d; in group B chicks were left with the hens for 3 d only. 2. Incubating hens given chicks immediately showed maternal responses. The introduction of chicks induced a gradual nest desertion. Their removal stopped nest desertion temporarily on day 4 in group B hens. 3. Plasma prolactin concentrations fell one day after introduction of chicks and continued to decline for about one week in group A hens, although there was no further significant decrease in group B hens. Circulating prolactin tended to decrease with time in both groups. 4. Plasma luteinising hormone (LH) concentrations increased concurrently with the decrease of prolactin. The increase was more abrupt in group B hens. 5. Plasma oestradiol concentrations decreased slightly on the day chicks were introduced. The decline was arrested by removal of chicks in group B; in group A the tendency was reversed about 10 days after chick introduction. 6. Irrespective of group, before chick removal hens which deserted their nest rapidly had less contact with chicks and lower prolactin concentrations.

Analysis of Variance↗
PubMed1990

Impairment of central auditory function in Alzheimer's disease.

Accuracy and laterality of ear preference on dichotic listening (DL) takes were compared in patients with Alzheimer's disease (AD) and a group of normal subjects, matched for age and education, using parameters (list length, stimulus matching, and order of recall), previously shown to significantly alter DL performance in normals. Alzheimer patients tended to show qualitatively similar, but significantly worse performance compared to controls as a function of increasing dichotic list length as well as stimulus set content (semantically, v. phonemically and unmatched dichotic items). Furthermore, these patients were unable to attend selectively to either the right- or left-ear and thus could not increase right- or left-ear advantages over the free recall procedure, an order of recall task easily mastered by the normal subjects. These results suggest that Alzheimer's disease is associated with a breakdown of cortical mechanisms involved in the selective allocation of attention.

Aged↗