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Biomedical subjects

A Wright

Publications and source records attributed to A Wright.

At least 199 records · Page 11Linked to original sources
PubMed1994

Effect of altered CH2-associated carbohydrate structure on the functional properties and in vivo fate of chimeric mouse-human immunoglobulin G1.

Immunoglobulin G (IgG) molecules are glycosylated in CH2 at Asn297; the N-linked carbohydrates attached there have been shown to contribute to antibody (Ab) stability and various effector functions. The carbohydrate attached to the IgG constant region is a complex biantennary structure. Alterations in the structure of oligosaccharide have been associated with human diseases such as rheumatoid arthritis and osteoarthritis. To study the effects of altered carbohydrate structure on Ab effector function, we have used gene transfection techniques to produce mouse-human chimeric IgG1 Abs in the Chinese hamster ovary (CHO) cell line Lec 1, which is incapable of processing the high-mannose intermediate through the terminal glycosylation steps. We also produced IgG1 Abs in Pro-5, the wild-type CHO cell line that is the parent of Lec 1. The Pro-5-produced Ab (IgG1-Pro-5) was similar to IgG1-My 1, a myeloma-produced IgG1 Ab of the same specificity, in its biologic properties such as serum half-life, ability to effect complement-mediated cytolysis, and affinity for Fc gamma RI. Although the Lec 1-produced Ab, IgG1-Lec 1, was properly assembled and retained antigen specificity, it was incapable of complement-mediated hemolysis and was substantially deficient in complement consumption, C1q binding, and C1 activation. IgG1-Lec 1 also showed reduced but significant affinity for Fc gamma R1 receptors. The in vivo half-life of IgG1-Lec 1 was shorter than that of either the myeloma- or Pro-5-produced counterpart, with more being cleared during the alpha-phase and with more rapid clearance during the beta-phase. Clearance of IgG1-Lec 1 could be inhibited by the administration of yeast-derived mannan. Thus the uptake of IgG1-Lec 1 appears to be accelerated by the presence of terminally mannosylated oligosaccharide. Therefore, certain Ab functions as well as the in vivo fate of the protein are dramatically affected by altered carbohydrate structure. Expression of Igs in cell lines with defined glycosylation mutations is shown to be a useful technique for investigating the contribution of carbohydrate structure to Ab function.

Animals↗
PubMed1994

Sciatic nerve morphology and morphometry in mature rats with streptozocin-induced diabetes.

Controversy exists as to the morphological and morphometric changes seen in experimental diabetic neuropathy (EDN). Most previous studies have utilized immature animals, with controversy as to whether the observed changes are due to maturational delays induced by hyperglycemia, or to diabetes per se. This study utilizes mature 9-month-old Sprague-Dawley rats. Six control and six hyperglycemic rats were examined 24 weeks after streptozocin injection. No morphological abnormalities were seen in the sciatic nerve at the light microscopy level. Total fascicular area and myelinated fiber density showed no significant differences (ANOVA, P > 0.05). No significant differences [ANOVA, P > 0.05 and Kolmogorov-Smirnoff (K-S), P > 0.05] between control and diabetic groups were shown for fiber, axon, and myelin areas, fiber and axon diameters, and myelin thickness. Fiber index of circularity, axon index of circularity, and g ratio were not significantly different with ANOVA (P > 0.05), but the diabetic group showed significantly lower values (P < 0.001) with K-S testing. Regression analyses of axonal area and log(n) axonal area plotted against myelin thickness showed no significant differences between the control and diabetic animals. This study in mature rats confirms the relative lack of morphological and morphometric changes in EDN which have previously been reported in studies involving immature rats. It highlights the difficulties in trying to extrapolate from EDN to human diabetic neuropathy where severe morphological and morphometric abnormalities may be present.

Animals↗
PubMed1994

The burden of screening for acoustic neuroma: asymmetric otological symptoms in the ENT clinic.

The rising numbers of legal cases relating to delay in the diagnosis of acoustic neuroma, combined with the increasing availability of magnetic resonance, is increasing pressure on otologists to make an early definitive diagnosis of cerebellopontine angle tumours. Unilateral or asymmetrical otologic symptoms not explained by external or middle ear disease are elicited in 16.6% of 500 consecutive attenders to an otolaryngology clinic. An agreed policy of risk stratification of patients with unexplained asymmetric otological symptoms is required if expense is to be limited and litigation minimized.

Adolescent↗
PubMed1994

Predictive testing for Huntington disease: social characteristics and knowledge of applicants, attitudes to the test procedure and decisions made after testing.

An investigation has been made of the social characteristics and knowledge and experience of Huntington disease (HD) for the first 80 individuals considering presymptomatic testing (applicants) at the medical genetics centres in Edinburgh and Glasgow and of attitudes to the test procedure and decisions made after testing for those who received a result. Sixty-one percent of applicants were female and 31% were over 40 years old. Almost all had a symptomatic parent but 38% did not know HD was in their family until they were over 25 years old and 48% had never received genetic counselling. Thirty-eight percent of applicants first heard of the test at the genetic clinic, 20% from a relative and 20% from the media, but none had received information from their GP. Thirty-one applicants did not have the test because they voluntarily withdrew (17 individuals), their family structure was unsuitable or no informative result was possible (11 individuals), or they were diagnosed clinically as being affected (3 individuals). Those who voluntarily withdrew did not differ significantly from the 49 who received a result in social characteristics or knowledge and experience of HD. Twenty-two individuals were found to be at increased risk (IR) (> 50% of becoming affected) and 27 to be at decreased risk (DR) (< 50% of becoming affected). There was a median period of 9 months between entering the test procedure and receiving a result and the main criticism of the procedure was that it took too long to complete and several individuals experienced considerable anxiety while awaiting their result.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Self-mobilization and organization of the genes encoding the toluene metabolic pathway of Pseudomonas mendocina KR1.

The toluene metabolic pathway of Pseudomonas mendocina KR1 is chromosomally encoded, but the pathway could be transferred by conjugation from strain KR1 to the chromosome of P. aeruginosa or P. putida. Such transconjugants utilized toluene, p-cresol, and p-hydroxybenzaldehyde. However, transconjugants were unable to further transfer toluene genes to other recipients unless Pseudomonas sex factor R68.45 was present in trans. Although the genes encoding the upper pathway for toluene metabolism in P. mendocina KR1 are sufficiently linked to permit their coordinate mobilization, they were found to be encoded in three independently regulated units: one encoding toluene-4-monooxygenase, a second encoding p-cresol methylhydroxylase and p-hydroxybenzaldehyde dehydrogenase, and a third encoding p-hydroxybenzoate hydroxylase. The last two regulatory units were cloned from the chromosome of a P. aeruginosa transconjugant onto a plasmid designated pRO1999. Analysis of pRO1999 showed that genes encoding p-cresol methylhydroxylase and p-hydroxybenzaldehyde dehydrogenase are organized as an operon; the gene encoding p-hydroxybenzaldehyde dehydrogenase is transcribed first, and this is followed by transcription of the gene encoding p-cresol methylhydroxylase. This operon is regulated by a positively acting regulator. The P. mendocina KR1 gene encoding p-hydroxybenzoate hydroxylase was linked to, but independently regulated from, the genes encoding toluene-4-monooxygenase, p-cresol methylhydroxylase, and p-hydroxybenzaldehyde dehydrogenase.

4-Hydroxybenzoate-3-Monooxygenase↗
PubMed1994

1-Methyl-4-phenylpyridinium-like neurotoxicity of a pyridinium metabolite derived from haloperidol: cell culture and neurotransmitter uptake studies.

It is now generally accepted that the nigrostriatal degenerative properties of the parkinsonian-inducing agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine are mediated by the brain monoamine oxidase B generated 1-methyl-4-phenylpyridinium metabolite (MPP+). In this article, the results are described of ongoing efforts to evaluate the MPP(+)-type neurotoxic potential of the haloperidol (HP)-derived pyridinium metabolite HPP+, a 1,4-disubstituted structural analog of MPP+, which is formed in humans and rats treated with HP. Previous studies in the rat have shown that intrastriatal perfusion of HPP+ leads to the irreversible depletion of striatal dopamine and serotonin. Furthermore, HPP+ was a potent inhibitor of NADH-supported mitochondrial respiration. This article reports that HPP+ also is toxic to dopaminergic and serotonergic neurons in cultures of embryonic mesencephalic cells, as measured by loss of the ability of exposed cells to accumulate tritium-labeled dopamine and serotonin and by immunochemical staining techniques. HPP+ also inhibited the uptake of these labeled neurotransmitters by synaptosomes prepared from mouse neostriata (dopamine) and cortical tissues (serotonin). Because HP is unlikely to be a substrate for brain monoamine oxidase B, the production and accumulation of HPP+ in the brain is probably not comparable to that of MPP+. On the other hand, chronic exposure to HP could result in brain levels of this lipophilic quaternary pyridinium species that might coincide with the late-appearing tardive dyskinesias that are observed in some HP-treated patients months and, more often, years after the initiation of HP therapy.

1-Methyl-4-phenylpyridinium↗
PubMed1993

Endotoxin induces rat lung ribonuclease activity.

Lipopolysaccharide (endotoxin), a component of Gram-negative bacteria, causes marked alterations in eukaryotic gene expression and cellular physiology. We show that within one hour of injection of endotoxin into adult rats there is an induction of ribonuclease activity in the lung. The degradation of RNA was prevented by treatment of the lung extract from endotoxin-injected rats with ribonuclease inhibitor (RNasin). We suggest that induction by endotoxin of ribonuclease activity is a novel mechanism by which cells could alter gene expression to meet an environmental challenge and caution that the presence of ribonuclease can hinder molecular biological analyses of tissue extracts from endotoxin-treated rats.

Animals↗
PubMed1993

The invasive and metastatic properties of hormone-independent but hormone-responsive variants of MCF-7 human breast cancer cells.

We have previously isolated a series of MCF-7 human breast cancer cell variants which no longer require estrogen-supplementation for tumor growth in nude mice (Clarke et al. Proc Natl Acad Sci USA 86: 3649-3653, 1989). We now report that these hormone-independent and hormone-responsive variants (MIII, MCF7/LCC1) can invade locally from solid mammary fat pad tumors, and produce primary extensions on the surface of intraperitoneal structures including liver, pancreas, and diaphragm. Both lymphatic and hematogenous dissemination are observed, resulting in the establishing of pulmonary, bone, and renal metastases. The pattern of metastasis by MIII and MCF7/LCC1 cells closely resembles that frequently observed in breast cancer patients, and provides the first evidence of metastasis from MCF-7 cells growing in vivo without supplementary estrogen. The interexperimental incidence of metastases, and the time from cell inoculation to the appearance of metastatic disease are variable. The increased metastatic potential is not associated with an increase in either the level of laminin attachment, laminin receptor mRNA expression, or secreted type IV collagenolytic activity. We also did not detect a significant decrease in the steady-state mRNA levels of the metastasis inhibitor nm23 gene. However, when growing without estrogen in vitro, MCF7/LCC1 cells produce elevated levels of the estrogen-inducible cathepsin D enzyme.

Animals↗
PubMed1993

DMBA-induced mammary tumor growth in rats exhibiting increased or decreased ability to cope with stress due to early postnatal handling or antidepressant treatment.

Depression and an ability to cope with stress are suggested to play a role in the vulnerability to breast cancer. In rats, neonatal clomipramine administration induces subsequent behavioral abnormalities that closely resemble those seen in human endogenous depression. Early postnatal handling, on the other hand, improves subsequent ability to cope with stress in rodents. The present study examined whether early clomipramine treatment or handling influences the growth of 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary tumors in female Sprague-Dawley rats. Between postnatal days 5 and 20, rat pups were injected daily with 25 mg/kg clomipramine, handled either by holding them in a hand (H-handling) or by giving them a saline injection (I-handling), or left nonhandled. During these manipulations, but not later, body weight gain was lower in the I-handled and clomipramine-treated pups than in the H-handled rats. As adults, the time spent immobile in the swim test, a model of depressive behavior and an ability to cope with stress, was significantly lengthened in the clomipramine-treated female rats, and shortened in the handled females. Measurement of plasma 17-beta-estradiol (E2) did not reveal any significant differences between the groups. The percentage of animals developing mammary tumors was significantly higher, and the length of survival shorter among the clomipramine-treated rats than among the I-handled rats. However, both groups exhibited less tumors and longer survival than the nonhandled controls. There were no differences in mammary tumor incidence or survival between the nonhandled and H-handled rats.(ABSTRACT TRUNCATED AT 250 WORDS)

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1993

Post-infectious human serum antibodies inhibit IgA1 proteinases by interaction with the cleavage site specificity determinant.

Bacterial pathogens of the genera Neisseria and Haemophilus secrete IgA1 proteinases which cleave human IgA1 in the heavy chain hinge region. The exact peptide bond cleaved is strain-dependent, but remains invariant despite repeated subculture. Haemophilus influenzae and Neisseria meningitidis produce proteinases of two cleavage site specificities (type 1 and type 2). We examined serial acute and convalescent sera from patients recovering from meningitis due to N. meningitidis or H. influenzae, and found a significant rise in serum titer of inhibitory antibodies against these enzymes. In each case the proteinase from the infecting organism was more susceptible to inhibition than were proteinases from that genus that had different cleavage specificity. Inhibition of sixteen type 1-type 2 hybrid H. influenzae IgA1 proteinases revealed complete concordance between inhibitory titer and cleavage site specificity. Inhibition of hybrid proteinases differing in a 123 amino acid segment known to determine cleavage site specificity (termed the CSD) further localized the site of antibody action to this site. These results from a limited number of patients with natural infections suggest that inhibiting antibody recognizes epitopes within the CSD. Alternatively, antibody may bind to epitopes outside the CSD and inhibit via steric hindrance.

Acute Disease↗
PubMed1993

Intra-articular ultrasonic stimulation and intracutaneous electrical stimulation: evoked potential and visual analogue scale data.

The reproducibility of focussed ultrasound-induced intra-articular pain was compared with that of electrically induced cutaneous pain over a period of time by measuring both the evoked potential (EP) amplitude and visual analogue scale (VAS) score. The responses to ultrasound were more variable than those to electrical stimulation. A greater degree of accommodation occurred during electrical stimulation compared with ultrasound stimulation. A statistically significant correlation between the EP amplitude and the VAS score was found for each form of stimulation. Changes in EP amplitude correlated with changes in the perception of pain as measured by the VAS score, rather than stimulus intensity, which remained constant for each subject throughout the duration of the experiment. A single oral dose of pethidine produced a statistically significant decrease in the EP amplitude and the VAS score in each case.

Cartilage, Articular↗
PubMed1993

Management of partial thickness burns with Granuflex 'E' dressings.

In a prospective, open, randomized and parallel group trial, 98 patients with partial thickness burns suitable for outpatient management were treated with either Granuflex 'E' (n = 49) or Bactigras (n = 49). The objective was to compare the safety, efficacy and performance characteristics of Granuflex 'E' with Bactigras. The overall rating of the dressing by the investigators and the patients showed a significant preference for Granuflex 'E'. In addition, the quality of healing was rated as 'excellent' in 56 per cent of patients treated with Granuflex 'E', compared with only 11 per cent in the group treated with the conventional dressing. Granuflex 'E' is safe, effective and flexible and we recommend that it should be used as the first-choice dressing in the management of partial skin thickness burns.

Biological Dressings↗
PubMed1993

Neurotoxicity of peptide analogues of the transactivating protein tat from Maedi-Visna virus and human immunodeficiency virus.

Infection by lentiviruses such as human immunodeficiency virus, Maedi-Visna virus and Caprine Arthritis Encephalitis Virus, is associated with a variety of neurological syndromes, but the mechanism by which the damage occurs to the nervous system is not known. The viruses do not infect neurons and so the neurotoxic actions must be mediated indirectly. Here we applied synthetic peptide analogues derived from basic regions of Maedi-Visna virus and human immunodeficiency virus transactivating protein, tat, to rat brain in vivo and found them to be potent neurotoxins. The toxicity of the Maedi-Visna virus peptide was demonstrated to be reduced by blockade of nitric oxide synthase and of N-methyl-D-aspartate channel opening. These experiments suggest that peptides derived from lentiviral tat may share a common neurotoxic action.

Amino Acid Oxidoreductases↗